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ADVANCES IN WOUND HEALING TECHNIQUES

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ADVANCES IN WOUND HEALING TECHNIQUES

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Advances in Wound Healing Techniques Frost & Sullivan takes no responsibility for any incorrect information supplied to us by contributors or sources of information. Information provided here is based primarily on interviews and therefore is subject to fluctuation. Frost & Sullivan reports are limited publications containing valuable market and technical information provided to a select group of customers in response to orders. Our customers acknowledge when ordering that Frost & Sullivan reports are for our customers’ internal use and not for general publication or disclosure to third parties. No part of this report may be given, lent, resold, or disclosed to non-customers without written permission. Furthermore, no part may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the permission of the publisher. For information regarding permission, write: Technical Insights Frost & Sullivan 7550 West Interstate 10, Suite 400 San Antonio, TX 78229, USA Tel: 210-348-1000 Fax: 210-348-1003 www.frost.com or www.technical-insights.frost.com

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Table of Contents

Executive Summary Scope and Methodology .........................................................................................1

Scope and Grouping of the Research Service.............................................................. 1 Research Approach ..................................................................................................... 2

Synopsis of Wound Healing ...................................................................................4 Introduction to the Process of Wound Healing............................................................ 4 Wound Types and their Major Effects ........................................................................ 8

Essence of the Technology ...................................................................................11 Wound Healing Industry--Outline............................................................................. 11 Striking Emergent Technologies ............................................................................... 12

Assessment of Technologies Involved in Medical Devices for Wound Healing

Technology Primer ...............................................................................................15 An Overview of Surgical Wounds ............................................................................ 15 Background on Trends Observed .............................................................................. 16

Technology Advancements in Companies & Universities ....................................18 Combination Medical Device with Hydrogel nature for Wound Healing Applications.............................................................................................................. 18 Innovative Wound Dressings with Dual Active Ingredients ...................................... 21 Innovative Electrical Stimulation Medical Device for Treating Chronic Wounds..... 22 Cavitational Ultrasound-Based Device for Wound Healing ...................................... 23 Wound Drainage System Facilitating Rapid Healing ................................................ 24 Potential Surgical Biofilm Well Suited to Replace Sutures....................................... 25

Significantly Progressive Innovations in Bio-interactives Used for Wound Healing

Primer to Biological Therapies Used in Wound Care ...........................................27 Snapshot of Biotherapeutics...................................................................................... 27 Specific Applications ................................................................................................ 28

Notable Technologies in Companies ....................................................................30 Bioactive Wound Healing Gel Targeting Foot Ulcers ............................................... 30 Regenerative Wound-Healing Peptide Gel for Healing Deep Wounds ...................... 31 Mesoblast Stem Cells Employed for Accelerating Fracture Healing ......................... 32

Advances in Wound Healing Techniques

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Living Cell-Based Therapy Helping Wounds to Heal Faster..................................... 33 Dermal Wound Healing Platform Showing Huge Potential in Improving Wound Healing ..................................................................................................................... 34 Therapeutic Proteoglycan Delivery Platform for Improving Healing of Bones ......... 36 Innovative Maggot Therapy Promoting Wound Healing Process .............................. 37 Protein Kinase Family Involving Therapeutic Drug Improves Wound Healing ........ 38 Acceleration of Intrinsic Clotting Cascade to Control Surgical Bleeding.................. 39

Developments in the Academia ............................................................................41 Autologous Platelet Gel Effective in Promoting Skin Wound Healing...................... 41 Harnessing the Potential of Bionanotechnology for Treatment of Spinal Cord Injury ........................................................................................................................ 42 Research Findings Elucidating Scar-Free Lesion Curing Mechanism ....................... 43

Advancements in Alternative Wound Healing Technologies Glimpse of Other Wound Healing Products..........................................................45

Need for Alternative Wound Healing Technologies.................................................. 45 Brief Description of Add-on Wound Healing Treatments ......................................... 46

Key Technological Advancements in the Industries; Companies; Universities and Research Institutes................................................................................................50

Silicon Nanocrystals Employing Antimicrobial Wound Dressings ........................... 50 Bioelectric Stimulation Therapy for Faster Wound Healing...................................... 51 Electrical Stimulation Therapy for the Treatment of Nonhealing Wounds ................ 52 Computerized Wound Imaging Analysis and Documentation System....................... 53 Nanobandages Repair Slow-Healing Wounds Faster ................................................ 55

Technology Adoption Factor Analysis Insights into Technology-Imperative Factors .......................................................57

Technology Steering Forces...................................................................................... 57 Technology Inhibitors ............................................................................................... 59 Technology Challenging Factors............................................................................... 61

Opportunity Assessment Factors ..........................................................................64 Strategic Evaluation of Emerging Innovations Applicable to the Wound Healing Industry--SWOT Analysis ........................................................................................ 64 Risk Analysis and Risk Management of Emerging Alternative Wound Healing Technologies............................................................................................................. 67

Analyst Insights and Strategic Recommendations ................................................70 Present and Future Industry Trends Analysis ............................................................ 70 Notable Mergers and Acquisitions ............................................................................ 74 Strategic Recommendations ...................................................................................... 76

Table of Contents

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Patent Assessment; Database of Key Industry Participants; and Glossary

Review of Patents .................................................................................................79 Patents Review.......................................................................................................... 79 Key Patents in NA and Canada ................................................................................. 81 Key Patents in Rest of the World .............................................................................. 88

Key Contacts and Glossary...................................................................................92 Key Contacts............................................................................................................. 92 Glossary of Terms..................................................................................................... 94

Decision Support Database Database Tables....................................................................................................99

Diabetes Incidence--World (2002 to 2012) ............................................................... 99 Diabetic Foot Ulcer Prevalence--World (2002 to 2012) .......................................... 102 Total Healthcare Expenditure--World (2002 to 2012)............................................. 104 Per Capita Healthcare Expenditure--World (2002 to 2012)..................................... 106 Number of Dermatologists--World (2002 to 2012) ................................................. 108 Number of Physicians--World (2002 to 2012) ........................................................ 110

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Executive Summary

Scope and Methodo logy

Scope and Grouping of the Research Service

This research service--"Advances in Wound Healing Technologies"--analyses the key developments in wound healing technologies by taking into account the data on organizations, and universities engaged in research and development (R&D) together with their contact details. This research service also focuses on summarizing the main patents, which gives an extensive understanding of chief players, technology trends, and key developments involved in emergence of technologies.

This research service explores a few promising technologies in wound healing industry, which are classified here under three separate categories--medical devices, bio-interactives, and alternative techniques--all of which are used to treat both acute and chronic type of wounds. This study reviews the key developers and their major developments and a noteworthy point here is that it is likely that few of the technologies mentioned in this research service are expected to be commercialized soon or are anticipated to be marketable in the near future.

This research is not restricted to examination of budding technologies but moves far beyond emphasizing on vital industry trends, synopsis and strategic assessment of key drivers, restraints, and challenges within the wound management sector. The study presents end-user information encompassing relevant contact details of key players (both academia as well as industry), patents snapshot, and finally decision support database tables.

This study distinguishes itself by providing a dual focus on technical applications of innovative technologies as well as thorough studies of best practices and other qualitative aspects of industry. It makes an attempt to perform technology assessment of various wound healing methods including devices for closure, advanced dressings, growth factors, medical techniques for removal of microorganisms from tissues using biomolecules, wound debridement, and other advancements/ alternatives. Further, being focused globally (North American, European, and APAC), this research service aims at covering notable mergers and acquisitions influencing advancements in wound healing procedures significantly.


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In brief, this research service presents the following information in a comprehensive approach:

• An outline of key evolving technologies holding a promising solution to wound healing procedures identified in both universities as well as organizations.

• A primer to the definitions and commercial applications of each innovative technology’s category.

• Review of chief patents which will offer better understanding of notable payers and their novel findings.

• Unique segment covering the evaluation of technology imperative factors and wound healing trends foreseen to be dominating the industry

• Extensive list of key contacts in the field, including names, titles, addresses, phone numbers, Email ids, and URLs.

Research Approach

First and foremost, in order to present a systematic analysis of each topic, Technical Insights analysts carry out a review of patents to familiarize themselves with the major developers and commercial players along with their processes. Being backed up by well-built patent search data, the analysts review abstracts to distinguish key scientific and technical players, which provide insights into important industrial participants and the technical activities on which they work.

The analysts then formulate a detailed questionnaire covering the research objectives of the study, thereby functioning as a guide during the interview process. While the analysts use the structured questionnaire to ascertain inclusion of all the desired issues, they also organize interviews in a conversational manner. This approach enables a more thorough exchange of views with the respondents, and offers better insights into the applicable issues than more structured interviews may provide.

The analysts conduct primary research with the key industry participants and technology developers to obtain the required content. Interviews are completed with sources located throughout the world, in universities, national laboratories, governmental and regulatory bodies, trade associations, and end-user companies, among other key organizations.

Our analysts contact the major commercial players to find out about the advantages and disadvantages of processes and the drivers and challenges behind technologies and applications. Our analysts talk to the

Executive Summary


principal developers, researchers, engineers, business developers, analysts, strategic planners, and marketing experts, among other professionals.

The project management and research team reviews and analyzes the research data that are gathered and adds its recommendations to the draft of the final study. Having conducted both published studies and custom proprietary research covering many types of new and emerging technology activities as well as worldwide industry analysis, the management and research team adds its perspective and experience to provide an accurate, timely analysis.

The analysts then prepare written final reports for each project and sometimes present key findings in analyst briefings to clients.



Synops i s o f Wound Hea l ing

Introduction to the Process of Wound Healing

Wound Healing

Wound healing term encompasses a series of complex events commencing at the injury stage and lasting for prolonged periods (months or even years). Regeneration of damaged tissues by connective tissues formation as well as regrowth of epithelium marks the completion of wound healing process.

Collagen is a key component of each wound healing process, which is primarily produced by fibroblast cells aiding in formation of tissue structures. The versatility of collagen contributes to its usage in regeneration of tissues. By giving strength and structure to the fibers, which form tissues in the body, collagen works as a foundation to hard tissues, soft tissues, and cardiovascular tissues in the body.

In wound healing, collagen forms an integral component by forming an environment conducive to healing of wounds, thus accelerating the quality of healed tissues. Collagen plays an active role in stopping blood flow by being responsible for aggregation, adherence, and activation of platelets in the clotting mechanism. Collagen’s unique absorptive power and swelling to fill spaces in the wounds followed by trapping fluid in a sponge-like fibrous network all contribute to the active responsibilities undertaken in healing process.

Wound restoration requires the body’s natural process of revitalizing dermal and epidermal tissues during the course of which the inflammatory, proliferative, and the maturation besides remodeling stages occur. The process of wound healing generates resurfacing, reconstitution, and rejuvenation of the tensile strength of injured skin, which requires extensive understanding by the surgeons in order to promote the absence of scar formation.

Typically, scars form once the inflammatory response stimulates the discharge of chemokines that engage fibroblast cells to form a new matrix of epithelial cells for wound closure. These collagen layers aid in faster wound healing except for the fact that distinctively noticeable tissue scars are established.

Executive Summary


Stages of Healing Process

Wound healing is a highly sophisticated process that encompasses four phases, namely the reaction phase, inflammatory phase, proliferative phase, and maturation phase, all of which overlap to form a wound healing cascade.

Reaction Phase

Reaction phase(also known as coagulation phase) occurs with vessel rupture and platelet aggregation accompanied by release of cytokines and growth factors. For this phase, platelets are utilized and fibrin clot formation is the main process taking place.

Inflammatory Phase

The next step called inflammation commences immediately after an injury, which is characterized by activation of infiltrating cells. Here, neutrophils and macrophages play a significant role in releasing prostaglandins and histamines, which cause the injured area to become more permeable and also to vasodilate.

Proliferative Phase

Proliferation/migratory phase, otherwise termed as angiogenesis, includes the new blood vessels supported by their connective tissues in causing infiltration of the wounds. Moreover, the epithelium cells migrate and facilitate the growing of skin until wound closure occurs, thus moving over to the remodeling stage.

Maturation Phase

The maturation process of wound healing is achieved by continuous replacement of the collagen and re-epithelialisation by degradative enzymes. Here, changes in physical properties of extra cellular matrix, wound contraction, and connective tissue reorganization take place.

Overall completion of wound healing process is accomplished after skin surface reformation and regaining of tensile strength by the skin region. During the course of wound healing, the following dominant activities occurs in phases:



• Immediately after the injury, blood clot formation/hemostasis takes place. Here collagen helps in the formation of a plug for broken blood vessels, which stop bleeding.

• Reaction phase starts wherein vascular and cellular responses to injury site spark inflammation to take place. Vasodilation commences leading to heating and redness and causing swelling of the wound.

• Attacking of bacteria occurs wherein macrophages regulate all stages of healing producing growth factors. Multiplication of fibroblasts too happens.

• Regeneration of vascular/granular tissues followed by restoration of the epidermis and closure of the wounds. Collagen aids in providing suitable environment for active vascularization.

• Tissue reconstruction activated by increased collagen content along with reduction in scarring. Collagen imparts strength to the new tissues over time.

In special instances of surgical site infections, there is a great risk associated with any surgical procedure, which contributes to extensive patient morbidity and mortality, as well as expenditure to healthcare practitioners across the globe. Classification for operative wounds based on the degree of microbial contamination can be described as healing by primary intention and healing by secondary intention. In healing by primary intention, wound edges are brought together and held intact by mechanical means, thus allowing the wound time to heal and develop enough strength to withstand stress without support. In healing by secondary intention, when the wound is left open owing to the presence of infection, excessive trauma, and skin loss, the wound edges join together by means of granulation and contraction.

Role Played by Specific Components during Wound Healing

Cellular activity is maximized during the wound healing process through the actions of fibroblasts, epithelial and endothelial cells, and largely due to growth factors. Inflammatory cytokines, tumor necrosis factors, and proteases particularly have a stimulatory effect on cell proliferation. Macrophages synthesize fibroblast-stimulating factors, which on association with growth factors released by dead platelets induce fibroblasts to migrate into the wound bed immediately after cell damage has occurred. The presence of angioblasts is necessary for wound healing to promote new blood vessels formation growing into the wound and subsequently increasing the strength of the wound bed. In brief, the action of macrophages and polymorphs continues in all damaged tissues for all wound repair mechanisms.

Executive Summary


Responsive Factors in Wound Healing

Effectiveness of healing process depends on few factors, which promote wound healing namely:

• Adequate blood supply

• Healthy diet providing all the essential nutrients.

On the other hand, there are a few systemic and local factors affecting wound healing stages. They are:

• Metabolic rate changes during life and ageing affects wound healing

• Impaired nutritional status

• Lack/deficiency of proteins, vitamins, trace elements and minerals

• Disease processes delay wound healing

• Smoking adversely affects wound healing

• Poor surgical techniques

• Drug Treatments can affect wound healing

• Wrong dressings can affect wound healing

• Most important factor is infections which can delay or prevent wound healing.

At present, Wound care market is growing at an alarming rate worldwide which is relevant from the soaring economic, social, and personal costs allocated for treatment modalities of the chronic wound population. Generation of novel devices as well as biologicals that can minimize the treatment time in a less expensive manner is the unrealized need of the hour.



Wound Types and their Major Effects

General Outline

The natural process of wound healing largely requires specialized treatment and needs to overcome some of the common delaying factors such as infections, physical disabilities, nutritional deficiencies, suppressed immune system, and disease conditions inherent in human body. Wound care costs are increasing rapidly all over the world and novel treatment methods replacing the conventional wound healing techniques are being discovered rapidly. Hence, an accurate understanding of various types of wound conditions is of utmost importance to contribute to increased clinical efficacy and decrease in healthcare costs.

• Essentially, wounds can be categorized into two main types--acute wounds and chronic wounds.

Figure 1-1 lists the types of wounds.

Source: Frost & Sullivan

Executive Summary


• Acute wounds have the ability to heal within a defined timeframe whereas chronic wounds are associated with prolonged healing times. In chronic wounds, underlying conditions prevail and can be recurrent. A challenging aspect of chronic wounds is that their long-lasting presence induces infection in the human body. Factors contributing immensely to nonhealing, chronic wounds are infections, necrotic tissues, impaired tissue perfusion, and steroids. It is important to examine these factors thoroughly for necessitating a nonsurgical approach to wound healing. Meticulous local wound management measures contribute to faster healing of chronic wounds. On the other hand, acute wounds occurring from traumatic abrasions, lacerations, superficial skin and soft tissue injuries have the tendency to heal spontaneously devoid of any complications. Acute wounds require limited care and often bleeding from acute wounds leads to release of growth factors, which help in rapid healing.

• Another major wound classification based on the appearance of the wounds involves a necrotic/full-thickness wound, which is simply the local death of tissues having leathery texture; infected wounds that includes deposition and multiplication of organisms in tissues accompanied by host reaction; draining/exudates of wounds; and finally granular wounds where tissue formation and contraction occurs.

Acute Wounds

Acute wounds follow a normal healing process, which is characterized by four distinct but overlapping phases--hemostasis, inflammation, proliferation, and remodeling. Here unique biological markers represent healing of acute wounds. Classification of acute wounds includes surgical incisions and traumatic injuries comprising of lacerations, abrasions, penetrations, and burn injuries. Acute wounds, which are exposed cause morphology changes in the body and require moist dressing treatment in a precise manner. Typically, usage of wound drainage devices for exudate management and prevention of complications persisting in acute wounds is observed. The significance of debridement in acute wounds is to remove highly-contaminated tissues while safeguarding the nerves, blood vessels, tendons, and bones. The need for discovery of adjunctive therapies such as hyperbaric oxygen therapy, electrical modalities, genetic therapy, human growth factors, and vacuum-assisted wound closure (VAC) for complex acute wounds has been realized lately.

Chronic Wounds

The most common and suitable examples of chronic wounds are venous leg ulcers, diabetic foot ulcers, and pressure ulcers. Here, diabetic or neuropathic foot ulcers caused by loss of sensation in feet and legs result in causing injury and nonhealing wounds. Pressure ulcers, otherwise termed as bedsores accumulate as a result of squeezing of the skin between a bone and an external surface. These are commonly found to occur in wheelchair-bound or bedridden people. Venous stasis ulcers caused by poor circulation as a result of damaged valves in the veins is yet another example of chronic wounds. Reduced blood supply also causes vascular ulcers, another form of painful and difficult-to-heal wounds. Pathologic responses leading to fibrosis and all of



the above mentioned chronic nonhealing wounds are symbolized by biological markers. Novel treatment strategies targeting these highly recurrent levels of chronic wounds must ensure lessening of damage not only to the skin, but also underlying tissues. It is an observed fact that these chronic wounds occur frequently among elderly individuals.

Snapshot of Complications Accompanying Delayed Wound Healing

Problems

Tremendous research needs to be performed for reviewing some of the crucial factors, which underlie one of the prominent challenges and expensive conditions experienced by wound care healthcare professionals. Economic burden linked to chronic wounds is roughly estimated to be well over $15 billion annually in the United States alone, according to Harvard Medical School estimates. Delayed wound healing can cause prolonged suffering for the patients leading to the need for costly treatments.

Reasons Causing Complications, Which in Turn Lead to Delayed Wound Healing or Extent of Challenge

The main reason for high costs attributed to chronic wounds treatment deals with the difficulty in chronic wounds to proceed through the normal stages of repair. Moreover; difficult-to-heal wounds are related with the underlying pathology of debilitating illnesses such as diabetes and venous insufficiency, which necessitates a proactive approach/challenge to the clinicians. Some of the notable complications include sepsis, infection, pain, osteomyelitis, dermatitis, malignancy in some cases, and amputation.

Solution

In-depth understanding of pathophysiology of chronic wounds, which includes even the complex cellular and biochemical factors involved in chronic wounds is necessary to fulfill clinical requirements. This type of improved knowledge gained about wound pathophysiology can strengthen treatment strategies and enhance clinical outcomes. Moreover; acquiring know-how of the basic mechanisms of healing process will facilitate individualized treatment provision to patients affected with wound complications.

Executive Summary


Essence o f the Technology

Wound Healing Industry--Outline

Essentially, wound healing encompasses closely related stages, all of which focus on generation of resurfacing, reconstitution, and rejuvenation of the tensile strength of damaged skin. This requires a great deal of understanding by the wound care surgeons in order to facilitate the absence of scar formation. Wound restoration primarily entails the body's natural process of rejuvenating the dermal and epidermal tissues during the course of which all inflammatory, proliferative, maturation, and remodeling events occur in a timely fashion.

At present, wound healing industry is experiencing a paradigm shift from typical sutures, staples, laser activation, glues and adhesives to modern biocompatible polymers, silver dressings, tissue-engineered skin constructs, innovative treatments exploiting nanotechnology, medical devices utilizing electrical stimulation and hyperbaric oxygen therapy, and so on. Recent investigations show that wound care market is growing at an alarming rate worldwide and the social, economic, and personal expenditure associated with the treatment of the chronic wound population is emerging to be precisely calculated.

Wound healing market largely requires novelty in wound healing treatments, which are capable of overcoming few delaying factors such as infections, physical disabilities, nutritional deficiencies, suppressed immune system, and debilitating disease conditions such as diabetes inherent in the human body. Cutting-edge wound healing treatment methods being discovered are replacing conventional ones rapidly, however; the high-wound care costs associated with them is a point of concern. Companies targeting the niche market of slow healing wounds and designing advanced materials, methods, and active substances are taking advantage of the dynamic opportunities availed through improved clinical efficacy data shown by them in patients.

In the current situation, wound healing industry comprised of specialized wound care firms is aiming at developing technologies, which can significantly provide patient-compliant, cost-effective, and safe solutions to cure chronic wounds. Further, it is highly favorable that any drug/technique, which can accelerate the wound healing process is accepted to lessen the costs of patient treatment having hard-to-heal wounds or complications connected with the healing process.



Striking Emergent Technologies

Conventional Standpoint

In every surgical procedure, effective closure of wounds and stoppage of bleeding is vital to ensure successful biotherapies. Lack of complete wound closure can lead to tissue damage, infection, and scarring conditions and all of these mentioned complications have been controlled by sutures, staples, microporous tapes, skin grafts, pedicle flaps, topical hemostatic products, fibrin glues, and sealants since olden times. Wound dressings play a vital role in early healing process by leaving the wounds undisturbed and keeping the wounds intact at body temperature. Moist wound dressings are applicable for quick healing process in pressure ulcers. Some of the frequently used types of moist wound dressings include foam dressings; absorbent pad dressings/ soft silicone foam pad dressings; hydrocolloid dressings; hydrogels; hydrofibers; alginates; and gauze dressings largely used in removing bacteria and drainage of moisture.

These conventional methods of surgical closure aid in prevention of leakage predominantly for applications involving cardiovascular procedures, abdominal/pelvic, and neurosurgical procedures too. Lack of strength, tissue toxicity, associated damage from cross linking systems, and tissue-thermal damage caused by lasers are some of the notable problems recognized in traditional wound healing methods. Additionally, inability to produce better sealing for air leaks than fibrin and induction of scarring or inflammation can be observed as potential disabilities in the above mentioned older wound healing methods.

Preview of Current Technological Breakthroughs

Increased preference for regeneration of tissues rather then just closure of wounds for healing has sparked the interest in a number of novel alterations to the existing wound healing technologies. A few noteworthy technological breakthroughs have been mentioned here:

• Regenerative medicine has been found to have a direct impact on novel wound healing technologies being discovered. The long-term benefits of stem cell-based therapies for closure of partial- and full- thickness burns is being focused in all research initiatives undertaken by major companies and universities worldwide. Significant advancements in bioengineered materials have begun to play a crucial role in all medical treatments ranging from hard-to-heal wounds such as second-degree burns, chronic pressure ulcers, diabetic skin ulcers, and deep skin lacerations.

• Efficacy of maggot debridement therapy in chronic wound management has been increasingly realized in hastening the process of wound healing as well as lessening the overall costs of management. The beneficial aspects of using larvae have gained interest nowadays and maggot therapy proves to be the most viable option for wounds that fail to respond to conventional therapy.

Executive Summary


• The potential advantages of growth factors and tissue constructs can be harnessed to revolutionize wound healing. Additionally, the benefits of honey can be tapped for achieving rapid wound healing with less side effects.They are emerging to be having all the possibilities of replacing the traditional standards of allograft and autografts. Honey-based dressings can be visualized to capture a profitable market mainly due to their antimicrobial, wound cleansing, and healing properties. Honey with sufficient antibacterial potency aids in providing efficient wound care.

• Promising medical devices exploiting recently applicable adjuvant techniques in wound healing like gene therapy, nanodelivery of targeted therapies, shock wave therapy, negative pressure therapy, vacuum-assisted treatments,electrical stimulation, to name a few for ensuring safe closure of the wounds are preferred compared to the conventional invasive medical devices.

• Additionally; various antimicrobial wound dressings are evolving to achieve pain-free debridement by employing silicone and silver materials owing to their improved properties such as minimal toxicity toward mammalian cells and possessing broad spectrum of antimicrobial activity.

Figure 1-2 pinpoints the chief technologies applicable to wound healing sector.




Until recently, local wound infection has been a major challenge unconquered with limited management options for clinicians, patients, as well as healthcare providers. Numerous cutting-edge wound healing technologies are made use of during patient specific requirements these days and their increasing functionality is driving the wound healing industry to competitive strides in the global markets.


Assessment of Technologies Involved in Medical

Devices for Wound Healing

Technology Pr imer

An Overview of Surgical Wounds

Various types of surgical procedures such as incisions or excisions, open or minimal access surgery, emergency or traumatic wounds are instances of occurrence of surgical wounds. Most of these surgical wounds can be included under the acute wounds category, which follows the normal wound healing pathway and is expected to heal within the required time frame.

However; infections can impede the healing process when surgery exposes the subcutaneous tissues leading to complications. In such cases, wound management is mandatory with some form of wound dressings. Typically, surgical wound infections are significantly higher in hospitals owing to the reduced immunity state of the patient and rapid exposure to microorganisms for which body’s immune response is less. Surgical incision infections are observed in the elderly, immunocompromised, nutritionally deprived, and those with underlying debilitating diseases categories of patients. Treatment of surgical wound infections can be facilitated by antibiotics, but occasionally surgery is required for complete healing of wounds.

Fundamentally, surgical wounds can be categorized into two types, one being closed or intact surgical wounds and the other being open surgical wounds.Closed or intact surgical wounds are a form of clean, surgically induced wound that can be closed by approximating the edges of the wound with sutures, staplers, and wound closure strips. The second type of surgical wounds--open surgical wounds--can be associated with a clinical condition called dehiscence. Dehiscence is the partition of a surgical wound, which can be both partially or superficially covered as well as totally disrupted having full thickness coverage.In some special cases, surgery should be postponed until the healing of wound infection occurs. The best example in this case could be of orthopedic surgery where the patient develops deep wound or bone infection. Further, in instances of delay of surgery, there is surmounting problem of pressure ulcers occurrence that can prevail till healing of postoperative wounds takes place.



Biology of Surgical Wound Healing

There are primarily three methods of healing postoperative surgical wounds targeting prevention of bacterial invasion namely healing by primary intention, secondary intention healing, and lastly tertiary intention healing.

In healing by primary intention, edges of the wounds are brought together and enclosed with sutures and skin closure strips. It is noteworthy that surgical incision sites healing by primary intention should be very clean and skin edges are re-apposed facilitating a clot to be formed on the incision site. When a wound is left open and contraction as well as replacement of missing tissue occur along with granulation for healing, then it is termed as secondary healing intention. A few wounds such as pilonidal sinus excision and abscesses are allowed to drain so that they can heal by secondary intention and undergo delayed primary closure on clearance of infection. This mode of healing requires dressings that are best suited to the depth, size, position, and level of exudates. Tertiary intention healing encompasses delayed closure of the wounds, which are left open so that drainage of exudates, control of contamination, and further surgical procedures are complete.

Conclusion

Research evidence suggests that there is a lack of preoperative preparation as well as postoperative care of surgical wounds in patients. Patient know-how on the complete healing process as well as preventive methods for tackling some of the early signs of complications in hospital settings is one of the best available solution to embark upon for overcoming the above mentioned challenge.

Background on Trends Observed

Surgical Physiology of Wound Healing

Surgical techniques hamper the normal wound healing process

• By inducing rough handling of tissues by the surgeons.

• By causing devitalization of tissues owing to damage to the skin edges caused by invasive devices.

This can result in the increase of inflammatory stage of wound healing and cause rise in scarring of tissues. Wounds closed with inappropriate suture material can induce infection. On the other hand, skin sutures tied too tightly can also lead to tissue ischemia, thus predisposing it to infections.

Identification of bacterial colonization is primordial for reducing the morbidity resulting from surgical site infections both to control local infections as well as to lessen the risk of infections in other surgical sites.



Diagnostic signs of infections including pain, erythema, heat, edema, and purulent exudates in conjunction with serous drainage along with concurrent inflammation, discolored granulation tissues, and wound breakdown can be evident as core symptoms of infections appearing in both surgical and chronic wounds.

Categorization Trends

Ideally, a few excellent solutions having potential impact on postoperative wound infections are shaving and preoperative bathing or showering steps. Wound dressings are also largely observed to promote wound healing process by providing a moist environment that can guard the wounds from injury. Numerous types of dressings are applicable to surgical wounds catering to the costs and patient-specific treatment requirements.

Currently there is a need in the dressings market for achieving the following two goals: wound protection and containment of factors such as usage of oxygen and certain enzymes that would accelerate the process of healing.

Surgical dressings function in debridement (mechanical/chemical/autolytic) applications and secondary dressing’s usage as well. These dressings necessitate change of material frequently in the early stages of wound treatment. Currently, wound fillers are materials applied on open wounds to remove dead space, absorb exudates, and maintain a moist wound surface, which may in turn help to prevent bacterial invasion and wound infections. Some specific examples of surgical dressing’s materials include alginate dressings, composite dressings, contact layer, foam dressings, hydrocolloid dressings, and hydrogel dressings to name a few. Bases in which these agents are compounded can accelerate as well as diminish the rates of epithelialization in wound repairs.

Presently, devices designed for wound healing are expected to replace sutures, staples, and glues used for skin closure of surgical incisions and traumatic lacerations. These new generation devices discovered are found to be rapid, simple, and high-precision wound closure devices imparting greater safety in avoiding invasive injuries. These noninvasive devices offer cost-effective provision of high levels of comfort to patients, besides avoidance of infections and other potential complications.

Decrease in the overall time taken for surgical wound healing and helping in fostering the moist wound healing process are the two chief goals focused these days by wound management companies worldwide.



Technology Advancements in Companies & Univers i t i e s

Combination Medical Device with Hydrogel nature for Wound Healing Applications

Conventional hydrogel wound dressings are focused on providing a moist wound environment primarily to help cleanse and debride necrotic tissues. This essential component of any wound care regimen is observed to be not very absorptive often needing secondary dressings as an aid. There is an increasing need generated for sprayable in situ polymerizing dressing, which can be painlessly applied and possess higher conformance to the wounds and surrounding tissues. Blends of various polymers tailoring properties such as elasticity, peelability, and adhesiveness are being constantly evaluated by wound care clinicians for replacement of conventional hydrogel wound dressings.

BioCure Inc. is a medical device company that spun-off from Ciba Vision, which is the eye care unit of Novartis AG and is based in Norcross, Georgia. BioCure specializes in the development of proprietary hydrogel technologies for human use. BioCure utilizes proprietary fast cross-linking polyvinyl alcohol (PVA) hydrogel polymer technology.

The firm has recently received premarket notification clearance for its GelSpray Liquid Bandage, a sprayable wound dressing, from the Food and Drug Administration (FDA). Indications for use of the GelSpray Liquid Bandage include minor cuts and scrapes along with minor irritations of the skin. This regulatory filing by the firm represents a promising step toward the future development of cutting-edge products, which may include active ingredients to treat infection, pain, and provide control for bleeding.

The GelSpray product is an in situ polymerizing hydrogel, which makes use of a simple redox reaction to initiate the fast crosslinking. The funding for this product was sponsored through the Center for Biomaterials Research (CeMBR). This product is provided to the end-user packaged sterile in an ergonomic two-part syringe with a static mixing tip. The device facilitates controlled delivery of the GelSpray product to its intended site.



The GelSpray formulation provides the following characteristics ideal for wound healing:

• Sprayable nature of the polymer ensuring uniform and complete coverage. Alternatively, the GelSpray product can be streamed onto the wound bed if the wound is more deep and complex. This makes it ideal for debridement.

• Upon application, the polymer has high-water content, which offers good moisture content to burns.

• Simultaneous absorption and evaporation of excess moisture by the polymer aids in promoting an ideal wound healing environment.

• Adhering of the polymer only to intact skin/the periwound site and not directly to the wound bed, prevents further re-injury of the wound site. This also protects the wounds from infection.

• Highly conformal and elastic nature of the dressing enables patient mobility.

• Wearable life of up to 48 hours of the dressing and additional features of being able to be covered by compression bandages fulfills the protection of dressing from incidental contacts.

• Easily loadable nature of the polymer with active ingredients further benefits the patient and wound healing process.

• Drying out nature of the polymer over time and denser dressing facilitates second skin, which will act as a barrier to foreign particles and bacteria.

BioCure hopes to leverage its experience with the GelSpray product to develop future iterations and expand the product line. Specific developments are currently underway, which will target the management and care of more complex wounds such as burns and ulcers. The GelSpray Liquid Bandage represent a novel addition to the wound care market armored with unique advantages such as rapid in situ polymerization; biocompatible nature and versatility; elasticity and conformable; an ideal solution for managing wound exudate and delivery of active ingredients; and finally prolonged usable life requiring minimal maintenance.



Figure 2-1 highlights the sequence of application and removal involved in GelSpray Liquid Bandage's

usage.

Source: BioCure Inc.

With suitable testing being conducted in the forthcoming years, this device could offer barrier and infection control properties for wounds and closure devices such as sutures, films, and so on. The therapeutic benefits of this product are unlimited because medications are easily incorporated into the formulation and delivered to the wound site. Furthermore, the in situ forming nature of the product allows addressing of inherent challenges in certain wounds such as burns and ulcers.

Future indications for use may include the treatment of bed sore ulcers, arterial/venous ulcers, infection control, and barrier properties and externally communicating devices such as orthopedic fixation devices. The formulation and delivery system of GelSpray Liquid Bandage provides excellent clinical advantages when the dressing is sprayed onto the injury sites.

Currently, BioCure is actively keen in licensing the GelSpray product with commercial partners. Through these licensing agreements, BioCure hopes to collaborate and expand the indications for use and quickly bring the next generation products to the end user.

This spray-on in situ polymerizing hydrogel-based GelSpray Liquid Bandage product is an ongoing research initiative of BioCure, which if commercialized can become a well accepted clinical application device for wounds that have low to medium exudates.



Innovative Wound Dressings with Dual Active Ingredients

Increase in diabetes occurrence in the United States alone has necessitated the discovery of effective treatments for diabetic skin ulcers. Designing of efficient products for chronic wounds, especially diabetic-related treatment is an unmet critical need for patients and healthcare providers due to complications such as amputation incidence on lack of treatment.

Greystone Pharmaceuticals Inc., a firm specializing in patented platforms of wound care technologies has been developing novel products and applications for treating chronic wounds and nonresponding wounds. The privately held company’s product line comprises of Epi-Max in the United States and DerMax as well as MelMax in the European Union and the Middle East. The company headquartered in Fort Myers, Florida, owns numerous subsidiary firms, which include Dermagenics in the United States; Greystone Research Group, an R&D group; and Dermedics Inc. for cosmeceuticals.

Of particular importance is the wound care product termed Epi-Max, which is a simplified and sterilized wound dressing, designed for the treatment of diabetic skin ulcers. This Epi-Max product is impregnated with Greystone’s proprietary Poly Hydrated Ionogens (PHI) composition and it is meant to be the US version of Greystone Medical Group’s Der-Max product, which has been a medical device approved in the Europe. The FDA has cleared Epi-Max as a combination product that contains both a drug and a device targeting primarily treatment of diabetic skin ulcers and other wound-related conditions. This hybrid medical device encompassing a drug component has proven to be highly successful in accelerating the wound healing process specifically in the management of diabetic ulcers, decubitis ulcers, leg ulcers, and finally acute severe wounds.

The Epi-Max is noted for enabling rapid epithelialization of tissues and is well accepted as the first wound care product allowed claiming the potential of down regulating matrix metalloproteinase production (MMP). Various research studies have highlighted that this down regulation enhances chronic and acute severe wound healing. Epi-Max product is made up of sterile cellulose acetate wound dressing coated with ointment containing polyethylene glycols along with a few metal ions. This product is prescribed to manage diabetic skin ulcers, pressure ulcers, stasis ulcers, skin irritations, abrasions, and cuts and functions by promoting a moist wound environment. The three modes of action, which this acetylated regenerated cellulose (ARC) sterile wound dressing equipped with dual active ingredients utilizes are offering physical protection of the wound region; supportive moist wound environment; and dual active ingredients combination.

Epi-Max was cleared by the FDA for sale in the United States in 2005 under the medical device regulation 510(k) for usage as a combination product. This innovative Epi-Max product targeting hard-to-heal wounds holds a promising approach in the wound care industry, which has been designed from cumulative years of studies and observations of chronic wound environments and inorganic mineral effects on mineral tissues.



Innovative Electrical Stimulation Medical Device for Treating Chronic Wounds

Chronic wounds take a significantly longer time to heal as opposed to acute wounds and contribute to extensive costs resulting in severe health conditions such as infections, gangrene, and amputations. These chronic wounds posing a grave worldwide problem are in need of discovery of good technology platform that can cause rapid healing of bed sores and certain types of ulcers.

LifeWave Ltd., a leading medical device company headquartered in Tel Aviv, Israel, is currently addressing the crucial medical needs of chronic wounds management by designing the Bed Sore Treatment (BST) product. The company is at present involved in introduction of the BST device to global markets. This medical device functions by electrically stimulating the wound surface. The basic principle behind this device is the fact that enhanced healing of wounds with electrical stimulation is possible through cellular proliferation.

Figure 2-2 shows the outlook of LifeWave BST device.

Source: Life Wave Hi-Tech Medical Devices Ltd.

Bed sores on body surfaces are noticeable features of patients suffering from chronic wounds and recently, electrical stimulation has emerged as a popular treatment option. Electrical stimulation can accelerate wound healing by attraction of cell types and proliferation of cell population. Various research studies have shown that the bioelectric system of the body influences wound healing by attracting repaired cells; modifying cell membrane permeability; enhancing cellular secretion through cell membranes; and finally orientation of cell structures. The functioning of bioelectric system requires moist wound environment and the basic rationale for applying electrical stimulation is the fact that it mimics the natural electric power, which can speed up the wound healing process.

LifeWave BST device is found to deliver an alternating current of up to 20 milli amps with zero net direct current and it comprises of a pair of electrodes, which are placed on the skin surrounding the wound region. Applicability of the device extends from treatment of bed sores to severe wounds such as pressure ulcers,



venous ulcers, and diabetic ulcers. A random double-blind clinical trial has been conducted by the firm and this study was able to assess the effectiveness of BST and a placebo method for treating stage iii pressure ulcers. The uniqueness of the BST technology is that after years of research LifeWave was able to define and understand the complex association between wound healing process and the electrical activity around wounds. The company has applied the unique frequency, which exists around injuries and acute wounds for designing of LifeWave BST and this platform is able to remove the blockage, which prevents wounds from healing and turn them into acute wounds.

The BST device holds patent rights in the United States and Israel; however patents are pending in Europe. The company has been actively engaged in marketing the BST device in all approved countries. Currently, LifeWave BST is under the premarket review by the United States FDA. In the near future, more clinical supportive data highlighting the usability of BST device can prove to be beneficial to chronic wounds affected patients.

Cavitational Ultrasound-Based Device for Wound Healing

Effective wound care management and treatment is one of the key issues demanding careful and focused efforts by clinicians and healthcare providers these days. Wound healing process is highly complex encompassing four major phases, which are found to overlap forming a wound healing cascade. Coagulation, inflammation, migratory/proliferative, and remodeling phases are chief components of the wound healing process. Skin surface reformation and regaining of tensile strength by the skin region mark the completion of overall wound healing process.

One of the most challenging tasks faced by wound care researchers is the designing of innovative devices and therapies offering short, effective treatment time, and minimal costs to the chronic wound affected patients. Emergence of ultrasound technique as a complete wound healing procedure holds a positive impact on timely addressing the above mentioned challenge. Arobella Medical llc, a leading medical device technology firm based in Minnesota, which has evolved as a part of the Bacoustics family of companies, is technologically advancing wound care products for improving the lives of chronic wound population. The firm has designed an ultrasound-assisted wound therapy system called the Qoustic Wound Therapy System that utilizes ultrasonic technology for the highly-specific dissection and fragmentation of tissues. The ultrasound-assisted wound therapy system can be applicable in curing acute and chronic wounds, burns, necrotic tissues in conjunction with cleansing of saline irrigation of the wound site for debridement and exudation of fragments.

Cavitational ultrasound is directly applied to the wound bed by means of Qoustic Qurette, which is uniquely designed in the form of dome and this can be regarded as remarkable way of applying ultrasound to the wound site. Gentle cavitation as well as removal of necrotic tissues is facilitated by the patent-pending Qurette. Study findings show that a fluid medium fed simultaneously through the Qurette couples the ultrasound while the micromechanical forces applied by this ultrasound leave healthy tissues intact, thus accelerating their growth.



This cavitational ultrasound application employing the Qoustic Qurette helps in minimizing pain, in turn allowing for more efficient and faster debridement that can result in enhanced patient compatibility. The Qoustic Wound Therapy device has been cleared by the FDA for sale in the United States.

By conjoining bactericidal effects and cavitational effects into single entity, the Qoustic Wound Therapy System brings about cost effectiveness and easy applicability features that can be exploited in cleansing of fibrin deposits. This technology retards bacterial growth and preserves the granulation tissues by offering significant reduction in pain. The Qoustic Wound Therapy device holds significant promise in treatment of specific types of wounds such as venous ulcers and pressure ulcers, diabetic ulcers, arterial ulcers, and burns, which are better tolerated by patients.

Wound Drainage System Facilitating Rapid Healing

Wound drainage is believed to be an important factor in minimizing the lateral stress on wounds and it is observed that full-depth drainage system aids in achieving a low-infection rate in hospitals. Numerous negative pressure therapy devices have been developed to permit exudates to be removed while at the same time isolating the wound to safeguard it so that its healing time is reduced.

Working on a similar platform, The Wound Care Company UK Ltd. has developed the Exsudex platform for draining the wounds. This wound drainage system designed in Holland can offer proven benefits of closed suction wound therapy in easy to use settings. Harnessing the traditional method of wound treatment using closed wound drainage, the Exsudex Wound Drainage Pump delivers negative pressure at user described levels. When a drain is placed onto the wound with the dressing material and sealed using a film, automatic operation at already set levels of uninterrupted negative pressure takes place.



Figure 2-3 shows the Exsudex wound drainage pump.

Source: The WoundCare Company UK Ltd.

The working principle behind this platform is the fact that fluid movement leads to tissue formation and drainage of wounds has effects on the tissue in the wound bed. The Exsudex platform has some unique benefits like low-pressure activation, which leads to less blood loss and minimum tissue aspiration, elimination of nursing time, and presumed faster healing. The Exsudex system is developed to provide maximum usability through addition of pressure tolerance settings, thereby preventing unnecessary alarms. The Exsudex system is also relatively lightweight and portable.

The firm believes strongly that wound drainage could provide an exciting platform for testing wound interface parameters such as dressings and pressures. The Exsudex system can be hoped to be evolved into a low-cost system, which will enable wound care professionals to effectively manage time consuming wounds as well as reduce the hospital stay time to a great extent.

Potential Surgical Biofilm Well Suited to Replace Sutures

While surgical sutures are in common use for wound closure they inevitably cause damage to tissue and organs with partial loss of function. Moreover; the rate of bacterial attachment onto surgical sutures can be very high, necessitating strategies to avoid their usage. Currently used surgical adhesives/ glues can be toxic or have low-bonding strengths, which can cause leakages.



Recently, researchers at the University of New South Wales have devised a surgical adhesive film, which has the potential to replace sutures used in delicate surgical procedures. The research team led by Professor John Foster has developed this thin film device from biomaterial extracted from crab shells, which on placing above the surgical wound and exposure to an infrared laser heats the film just sufficient to meld it and the tissue, thus acting as a perfect sealant for the wounds. The device named as Surgilux is composed of materials approved by the FDA in the United States.

Figure 2-4 shows the Surgilux device being employed in situ.

Source: University of New South Wales

Clinical data suggest the strong potential of Surgilux to be utilized in brain and nerve injuries, in order to overcome many disadvantages inherent in invasive stitches/sutures. Surgilux is imbibed with antimicrobial properties that can deter postoperative infections. Surgilux can be well applied to repair damaged nerves, which have been proven by animal test data indicating a degree of permanent nerve recovery in a span of six weeks of operation time.

The team of researchers is exploring the creation of Surgilux model, which can incorporate growth factors and even stem cells to regenerate nerves, thus expanding its usability. Hence, this laser-activated adhesive thin film enables sutureless anastomsis procedures devoid of the costly disadvantages invasive stitches bring and most importantly prevents fluid leakage.


Significantly Progressive Innovations in

Bio-interactives Used for Wound Healing

Pr imer to Bio log ica l Therap ies Used in Wound Care

Snapshot of Biotherapeutics

Treatments utilizing natural body substances or drugs manufactured from bodily substances can be categorized into biotherapeutics grouping targeting protection of wounds. Fundamentally, all the biological approaches designed for wound healing aim at achieving tissue regeneration besides keeping the wound moist.

Collagen, a key connective tissue is the only biomaterial inherent in the body's tissues, which can create an optimal environment for wound healing. The wound bed comprises of multiple cell types and a specific growth factor, which can enhance the functioning of one cell type while retarding the activity of a different cell type. Research findings indicate the fact that local concentration of growth factors alters during the process of wound healing. Similar to conventional wound dressings, growth factors also act on the wound at a cellular level. Epidermal growth factor (EGF), transforming growth factor-alpha (TGF-alpha), fibroblast growth factor (FGF), and platelet-derived growth factor (PGF) are some of the notable growth factors influencing the process of wound healing.

Certain biological coverings such as allografts taken from the recipient, xenografts taken from animal sources, and tissue culture derivatives grown in a culture medium are found to be causing reduction in bacterial invasions and significant prevention of further contamination. However, long-term assessment on wounds covered with these biological coverings showed wounds lacking anchoring fibrils that can cause fragile grafts.

Biological dressings to cover burn wounds appear to be a promising option since they reduce wound sepsis to a great extent. A wide range of developments ranging from heterograft isolated from various animal sources such as lizard and porcine skins to allograft and recent usage of epidermal grafts to serve as skin substitutes have emerged as temporary wound dressings. Yet another notable development is that of using a variety of occlusive and semiocclusive artificial skin substitutes, which have undergone extensive research studies testing their feasibility. The underlying factor promoting the wide usage of these biological and artificial skin substitutes is their increased ability to heal wounds owing to the creation of moist environment. These biological dressings



are ideal for the control of minor bleedings, and for the treatment of ulcers and skin lesions such as pressure sores, venous ulcers, diabetic foot, traumatic, and surgical lesions.

In the present day world, cost-effective varieties of collagen membrane for use in extensive wound management is adopted and drug loaded collagen membranes utilizing heparin and growth factors are currently in the manufacturing stages. Microencapsulation is yet another latest approach embarked upon by wound care professionals to incorporate silver-containing local antiseptics as well as low-molecular weight heparin in severe burns for hastening wound healing process and imparting bactericidal effects.

Significant advancements in wound healing technology comprises of biologically active dressings such as bioengineered skin substitutes, matrix modifying dressings, and isolated growth factors designed through recombinant DNA techniques, to name a few. Lack of cost-effectiveness along with meticulous preparation of the wound bed prior to their usage for enhancing efficacy is two notable patient-centered challenges to be addressed with due efforts in these recent advancements. Here, proper preparation of the wound bed is required to receive these grafts to maximize their biological effectiveness. Correct moisture balance through suitable dressing selection in association with maintenance of bacterial balance are mandatory for appropriate functioning of biological dressings in enhancing wound healing.

Specific Applications

Natural wound healing therapies are increasingly being utilized for combating pain and avoiding the necessity of an amputation associated with diabetic patients. These bioactive therapies are found to be hastening the healing process through stimulation of new blood vessels in conjunction with prevention of infection. Specific applications harnessing the potential of bioactive therapies in treatment of clinical conditions are listed below:

• Partial-thickness burns of the feet can be treated using a temporary bioactive skin substitute made of bioactive adherent layer coated with proteins, which are secreted by activated human skin fibroblasts. This standard of care automatically decreases pain and is a cost-effective measure of wound healing.

• Bioactive bandages containing growth factors accelerate wound healing by employing cutting edge advances in genetic engineering and cellular preservation. These bioactive bandages can be preserved, easily transported, and handled/stored. They can release different growth factors in different wound healing stages and control release rate in light of various burn degrees.

• Leveraging of novel cell culture techniques and synthesis of bioresorbable polymers using tissue engineering strategies has evolved recently as a potential therapeutic approach in wound healing involving tissue engineering. Some of the clinical applications include bioengineering of skin, cartilage, and bones for implantation and artificial constructs of biodegradable scaffolds.



• Promotion of wound healing through cell stimulation while removing bacteria can be achieved through bioactive therapies. One such example is the usage of nanobiotechnology, which can augment the rate of wound reepithelialization by cohesion of self-assembling peptide nanofiber scaffold and EGF.

• Study findings indicate that biomaterials composed of biofunctionalized peptidic scaffold can be well-suited for the treatment of cutaneous wounds comprising of wound coverage, localized growth factor release, and wound repair activation.

• Numerous recombinant proteins beneficial for wound healing activity have been identified and these can prove to be promising wound healing extracts when commercialized appropriately.

Nowadays, due attention is given to investigating the activities of bioactive polymers, purified growth factors, biosorbable materials, and other key cytokines/interleukins for faster wound healing with reduced complications.



Notab le Technolog ies in Companies

Bioactive Wound Healing Gel Targeting Foot Ulcers

Chronic wounds as well as acute wounds represent a major complication to life if left untreated and hence there is an increasing need for products demonstrating rapid wound healing at affordable costs. Amongst the slow-healing wounds, diabetic foot ulcers demand significant attention owing to their chronic nature and their impact on patient's quality of life; such ulcers may even lead to amputation. Presently, the widely used standard-of-care therapies for treating diabetic foot ulcers comprise bandages, antibiotics, debridement, and arterial vascularization. However, these treatments are often ineffective, require handling by specially trained medical professionals, and are often very expensive.

The goal of improved therapy for chronic skin ulcers is an easy-to-use topical therapy, which is used as adjunct treatment to standard care is safe and efficacious, and that enhances the speed and frequency of wound healing.

Kuros Biosurgery AG, a biomedical firm, based at the Technopark in Zurich, Switzerland, develops unique combinations of biomaterials and bioactives for localized therapy. The company has built a robust pipeline of product candidates for a wide range of trauma, wound, and spinal indications where it strongly believes that such combination products could have a promising impact. The technology platforms owned by Kuros can be utilized to develop biologic-biomaterial product candidates that target damaged or diseased tissues. These novel products offer the benefits of achieving higher local concentrations of active drug with minimal systemic side effects. Another feature of these products is their applicability in the form of liquid, paste, gel or foam directly to the site of injury either at the time of surgery or via minimally invasive procedures.

The combination products designed by Kuros mimic the natural wound healing process, which involves the formation of a blood clot at the site of tissue damage for provision of fibrin/matrix structure for the repair of the damaged tissue as well as prevention of additional blood loss. This blood clot includes natural bioactive factors needed to stimulate the cell growth required for local tissue repair.

The wound care products designed by Kuros emulate and enhance this natural process by providing a structural repair scaffold (based on fibrin) combined with biologics (variants of growth factors) for accelerating the healing process and restoring tissue function.



Products for Wound Healing

• Kuros is developing KUR-211 for treating chronic skin ulcers. This product is based on a fibrin matrix, which includes a variant of naturally occurring growth factor as the bioactive. On application to the ulcer the fibrin matrix polymerizes to form a fibrin clot. Variant growth factor is covalently bound to the matrix, which seals the wound and offers a structure for cell in-growth. A phase i/ii a clinical study in venous ulcer patients and a pilot study in diabetic ulcers have been completed for KUR-211.

• Another product KUR-212 aims to enhance graft uptake and the rate of wound closure following meshed skin grafting. This product is based on fibrin matrix and encompasses variant Platelet-derived Growth Factor(PDGF) as a bioactive. For KUR-212, a phase I punch biopsy study has been completed and a phase ii a study in burn patients has completed patient recruitment with results expected to be reported in mid-2008.

• KUR-213 is a development-stage product targeting an undisclosed acute wound indication.

The company has signed a collaboration and licensing agreement with Baxter Healthcare involving several of Kuros fibrin-based programs in soft and hard tissue repair.

The wound healing programs developed by the company aims to provide efficacious, safe, convenient, and cost-effective therapies in the acute and chronic wound areas.

Regenerative Wound-Healing Peptide Gel for Healing Deep Wounds

Natural interactions in the body between polysaccharides and protein building blocks called peptides can be harnessed for controlling clotting/hemostasis, which could be applicable to controlled release of drugs and growth factors that are required in wound healing, bone regeneration, and other medical applications. Peptide gels can be commercially employed to be loaded with time-released therapeutic drugs such as growth factors required for accelerating wound healing.

FirstString, a biotechnology organization spun off from the Medical University of South Carolina specializing in therapeutics for scar prevention and tissue regeneration is based in Charleston, South Carolina. This firm is strongly focused on designing a class of innovative peptide-based therapeutic drugs, which can reduce inflammation and scarring and is applicable to acute and deep chronic wounds treatment. The company’s leading candidate is wound-healing peptide gel, which can rapidly heal deep wounds.



The wound-healing gel consisting of bioengineered peptide is based on a naturally occurring protein in the body that can regulate cell interactions. Tissue regeneration induced by the peptides offers a promising option to researchers for utilizing bioengineered peptides in promoting faster healing, reducing scarring, and finally restoring normal skin. The early-stage biotechnology company has begun human clinical trial process for its wound-healing peptide gel. There’s a lack of FDA-approved products for eliminating scarring and promoting wound regeneration. Realizing this unmet need, FirstString Research Inc. has designed the peptide having enormous potential to regulate intercellular communication at the site of the wound. Initial clinical studies have shown decreased scarring observed among laboratory animals on application of the peptide gel.

This commercialized topical gel product designed for the prevention of scarring has already received regulatory approval in Europe to enter clinical phase testing. In the near future, this product is expected to be approved for distribution in the United States by the FDA. Initial preclinical studies suggesting the peptide gel’s efficacy and safety in regenerating new tissues must be investigated further to ensure a better product for healing deep wounds.

Mesoblast Stem Cells Employed for Accelerating Fracture Healing

Mesoblast Limited, an adult stem cell company located in Australia, is technologically advancing treatments for orthopedic conditions along with commercialization of adult stem cell technology targeting regeneration and repair of bones and cartilages.

The company owns world-wide license to commercialize orthopedic applications of proprietary adult stem cell technology created by scientists at South Australia’s Hanson Institute and Institute of Medical and Veterinary Science (IMVS). By exploiting the mesenchymal precursor cells (MPCs)' ability to transform into bone, cartilage, fat, and other tissues, Mesoblast is developing novel cellular therapies. The basis/working principle behind this MPC technology is the fact that it is capable of both limiting the extent of the injury as well as enhancing the repair of the injured areas. The company’s approach is well demonstrated by the researchers at the Hanson Institute who have achieved successful results in vivo when MPC implantation into bone defects caused regeneration of the segmental defect area.

Adult stem cells usage in healing of bones can help eradicate the complications associated with bone grafts taken from separate incision. Moreover; adult stem cells applicability can significantly lessen the long-term hospitalization as well as expenses associated with the long-term treatment of long bone fractures.

The company possesses ownership for a series of patents and technologies, which can be linked to the identification, extraction, and culture of adult MPCs technology platform. Very recently the successful results announced from clinical trials conducted at the Royal Melbourne Hospital in 10 patients affected by nonhealing, long bone fracture of the legs unveiled an extensive opportunity in mesoblast stem cells. These clinical findings highlight the fact that mesoblast stem cells therapy can eliminate the need for a second



operation to harvest bone from the pelvis, which is the followed as the current standard clinical practice. Progress over product manufacturing and scale-up processes to Good Manufacturing Standards needed for FDA approval to begin clinical trials is also being conducted by Mesoblast Limited. The company has also recently announced that it will seek US FDA clearance for a phase 2 trial for knee osteoarthritis and will shortly commence a phase 3 trial for spinal fusion by mid 2009.

In the near future, the firm expects to develop an off-the-shelf stem cell product for improved bone healing, similar in action to a pharmaceutical drug in its dosage predictability.

Living Cell-Based Therapy Helping Wounds to Heal Faster

Hard-to-heal wounds require the quickening of natural healing process by adoption of active approaches rather than basic methods consisting of infection control, cleansing, and control of pressure measures. Biotechnology measures for wound care are increasingly being accepted as healing methods for the most resistant sores and this implementation of advanced therapies in wound healing proves to be a major concern. Prevention of diabetic foot sores and venous leg sores, two of the most frequently occurring chronic wounds poses a serious challenge to the wound care professionals nowadays. Regenerative medicine emerges to be an effective solution aimed to heal or reconstruct diseased tissues as well as support the regeneration of injured organs.

In order to address this difficult task of treating leg sores, Organogenesis based in Switzerland, has designed a bioengineered cell therapy approved by the FDA for speeding up the wound healing process and eventually attain healing in wounds previously unresponsive to treatment. This living cell-based therapy is named as Apligraf and it proves to be the only commercially available bilayered bioengineered cellular product. Apligraf consisting of two layers similar to the one present in human skin and measuring approximately 44 square centimeters circular cell construct when placed on the wound integrates into the wound, thus enhancing the healing process. Apligraf working mechanism can be a combination of various actions which include: an occlusive biologic dressing, which promotes healing by secondary intention; smart material stimulating the healing process partially due to the neonatal dermal and epidermal cells providing the matrix materials, cytokines, and other regulatory molecules in sequential manner to facilitate healing; factory synthesizing growth factors that promote cell regulation, growth, and differentiation; and finally template inducing revascularization.

This unique biological skin repair therapy is basically wrapped on with nonadhesive dressing for maintaining moisture. The active and biological role played by Apligraf in stimulating wound healing is evident from the fact that it delivers ingredients such as growth factors, cells, nutrients, and proteins to the wound site directly. Apligraf requires a medical professional’s prescription for application on the sore directly. Some of the notable advantages of Apligraf as compared to conventional wound healing products can be mentioned as:



1. Claims of approval from FDA. These are supported by evaluations in multiple controlled clinical studies proving it to possess safety, effectiveness, and acceleration of healing properties.

2. Apligraf plays an active role in wound management by delivering growth factors and proteins to the wound site intact.

3. Apligraf is in possession of structure mimicking natural human skin.

4. Simplified usage devoid of daily maintenance imparts superior healing properties to Apligraf when compared to conventional wound care techniques.

At present, Apligraf is being evaluated in the form of premarket clinical studies for treating burns and epidermolysis bullosa, which is a rare form of genetic disease having fragile skin and recurrent blister formation as main characteristics. Yet another late stage developmental product is also evolving in the firm’s product pipeline, which is a bilayered bioengineered skin with the dermal matrix generated de novo from the human dermal fibroblasts.

Organogenesis firm is actively involved in scientific collaborations related to wound healing research in the United States, which include University of Masachussetts, Harvard Medical School, Tufts University, and Rockfeller University in Lyon. Additionally; the company has acquired technologies from Biogentis as well as Nanomatrix, which enable Organogenesis in enhancing its intellectual portfolio related to wound healing.

The company strongly believes that by characterization and selection of subpopulations of cells, it can deal with extracellular matrix such as collagen in association with electrospinning technology, thereby opening novel avenues for matrix, growth factors, and cell deliveries. This Apligraf bilayered cell therapy technology platform provides exciting solution to the wide impact imposed by burns repair and wound healing associated with scarring globally.

Dermal Wound Healing Platform Showing Huge Potential in Improving Wound Healing

Presently, the emergence of wound healing pharmaceutical products is at a huge rise and their potential as a drug accelerating wound healing should be embraced. They are likely to reduce the cost of treating patients having chronic wounds or associated severe complications.

Regenerx Biopharmaceuticals Inc., a biopharmaceutical company headquartered in Maryland is focusing on the discovery of novel molecules hastening tissue and organ repair process to a great extent. The company has designed a multifaceted biomolecule, Thymosin beta 4 (T beta 4), for improved wound healing. The T beta 4 was in-licensed originally from the National Institutes of Health and has been initiated for further development.This T beta 4 is found to be one of the first genes to be turned on during occurrence of wounds



and plays an active role in regeneration, remodeling, and healing of injured tissues. The firm’s technology platform can be engaged in a wide range of biological activities, which include promotion of corneal epithelial repair; prevention of apoptosis; serving as a substrate for transglutaminase, which is the main enzyme playing a key role in blood clotting, thus enhancing wound healing; and also has potent anti-inflammatory properties. The company strongly hopes to extend this technology platform beyond topical medical applications and into internal tissue and organ repair only accessible through systemic administration.

The company is examining RGN-137 as a promising dermal wound healing drug candidate along with a phase ii clinical trial operation for RGN-259 intended to treat ophthalmic wound healing. This RGN-259 product of the company is predicted to have a strong potential in improving tensile strength as well as reducing the inflammation associated with the healing process.

Figure 3-1 illustrates a patient's eye, which would not heal after 23 days postsurgery. However

application of RGN-259 product based on Tbeta4 platform to the patient's eye heals it after 11 days.

Source: RegeneRx Biopharmaceuticals Inc.



The company is currently involved in a strategic partnership with Defiante Farmaceutica, which is a wholly-owned subsidiary of Sigma-Tau group based in Rome (Italy). Through this alliance, the company gains rights to develop and market Tbeta4 in Europe and other countries. The firm owns over 60 patents and patent applications globally.

This T beta 4 technology platform having the potential to revolutionize the treatment for tissue and organ repair must be explored further for favorable industrial applications.

Therapeutic Proteoglycan Delivery Platform for Improving Healing of Bones

Bone healing process occurring in fractured long bones is influenced by a variety of systemic and local factors and aids in restoring the tissue to its original shape, strength, as well as mechanical structure. Bone fracture healing takes place during the first two weeks period , which is the most critical period during which inflammation and revascularization occur. Studies involving fracture healing have been conducted in several animals and with different types of fractures in different bones. The challenges mainly identified with fracture healing studies have been pertaining with the stability of fixation and reproducibility. There is a raised concern created toward the need for an efficient alternative to painful patient autografts, and the shortage of donor bone grafts. Increasingly, biological therapies are beginning to be realized as suitable substitutes to bone implants and realizing this ongoing trend is of utmost importance to the musculoskeletal business.

In order to address this challenge, Agenta Biotechnologies is extending the scope of biotherapeutics for bone regeneration. Realizing the fact that wound care market is moving toward bioactivity, Agenta Biotechnologies, a privately-held biopharmaceutical company based in Alabama, United States, focuses on discovery of new drugs for healing and for tissue regeneration. Agenta’s technology platform utilizes proprietary drug-like proteoglycans for tissue healing and regeneration. These proteoglycans are a class of molecules, which can promote healing through a variety of mechanisms such as enhancing tissue hydration; blood supply increase; structure provision; and as required carriers cum activators for vital growth factors in healing. Proteoglycan therapeutics are applicable to bone, cartilage, discs in the spine, and to skin, along with serving as coatings for vascular stents and implants.

Agenta is primarily targeting bone repair for designing combination products based on growth factor-enhanced, or bio-activated, or bone grafts, and devices. The company has identified proteoglycan or perlecan to bind and present the vital growth factor, FGF, for healing when required. The firm uses rational biologic drug design for construction of new candidate therapeutics-proteoglycan core sequences intended for various wound healing indications. Supporting the uniqueness of platform technology is the fact that it meets the requirements for a modified heparan sulfate polymer in the healing wound, one with the correct polymer sequence, which is highly sulfated with the exact sulfation pattern. This explains the site-specific, customized nature of the patented platform technology.



The firm is progressively designing a therapeutic perlecan DNA product, which can be delivered in orthopedic or periodontal bone surgery for generating a FGF-binding proteoglycan during the course of healing of bones. Research studies conducted by the company have shown that heparan sulfate carbohydrate polymers synthesized by this prototype DNA product named as Perl.D1 has the ability to specifically bind the FGF molecule.

The firm has conducted preclinical trials for demonstration of delivery of Perl.D1 through a common bone graft material, which can lead to significant improvement in bone healing.

Currently, the company is collaborating with Biological Innovations LLC for development of biologically activated chitosan wound healing materials using proteoglycan technology platform. Additionally; the firm has partnership activities with Brookwood Pharmaceuticals Inc. for advancement of biologically activated chitosan wound healing materials. The firm is also seeking out-licensing opportunities and one among them being negotiating an out-license with Bonesta for the platform technology limited to bone healing indications.

Further clinical studies demonstrating effectiveness of Perl.D1 product in bone repair can generate potential to create more personalized approaches for faster healing of broken bones, bone grafts, fusions, or implants.

Innovative Maggot Therapy Promoting Wound Healing Process

There is an upsurge in the awareness of vital role played by natural therapies in combating infection as well as chronic diseases. Understanding the key role of larval therapy in treatment of wounds has begun to be widely recognized now for applications dealing with reduction in the growth of microorganisms in wounds and exercising a positive stimulation on the rate of wound healing. Rapid debridement of infected and necrotic wound elimination has been achieved by exploiting this emerging larval wound treatment. Various research studies asserting the fact that larval therapy could lead to the production of healthy granulation tissues and in turn have a stimulatory effect on wound healing has led many wound care firms to explore the exciting prospects of sterile larvae in wound healing.

ZooBiotic, a privately-held wound care organization based in Bridgend, Wales, specializes in marketing larvae products for the treatment of chronic infected and necrotic wounds. By using its expertise in biosurgical products, it has designed a novel maggot production process leading to active larvae, which will possess improved viability at the point of use as well as improved ability to digest dead tissues. The firm utilizes a specialist brand of sterile larvae named as LarvE that can be exploited in treatment of necrotic, infected, and sloughy chronic wounds. The company owns two core products, Free range LarvE and LarvE BioFOAM dressings, which when applied directly to the wound functions as a microbial barrier and encourages wound treatment. In fact, the firm has proposed that in the absence of effective conventional treatments for infected diabetic foot ulcers the usage of BioFOAM dressings should be considered as a first line therapy for all these wounds.



The LarvE BioFOAM dressings have been designed by the company to aptly combine the clinical benefits of free-range maggots with easy usability of conventional dressings. The BioFOAM dressings encompass a pouch containing maggots along with large numbers of tiny foam chips that offer an ideally suitable environment for maggot’s development. Additionally; the foam chips within the dressing facilitate a significant fluid-handling capability for dealing with wound exudates.

The core products of the firm are increasingly preferable owing to some of their unique benefits such as provision of a favorable environment, ease of use, better permeability to air and microbial barrier existence, and finally the delivery of more precise nature of treatment.

The application and clinical value of larval therapy for chronic necrotic or infected wound treatments appears to be one of the finest cost-effective alternatives when compared to existing antibiotic treatments.

Protein Kinase Family Involving Therapeutic Drug Improves Wound Healing

Chronic ulcerated wounds are currently the chief targets for novel efficacious products being discovered worldwide. Chronic wounds comprising of mainly diabetic foot ulcers, venous leg ulcers, and pressure ulcers contribute to the increased morbidity and mortality associated with surgical procedures. Increase in hospitalization instances and heavy clinical costs have urged all the wound care firms to design innovative products for the treatment of chronic and acute wounds.

By gaining unique insights into biochemical and molecular mechanisms involved in the pathological-physiology of skin cells, HealOr Ltd., an Israel-based biopharmaceutical firm has created a three-fold discovery and development platform. This proprietary platform of HealOr Ltd. enables its exploitation to technologically advance a novel class of dermatological drugs, which are both more effective as well as less toxic. The HealOr’s platform encompasses a high-throughput in vitro screening protocol for the selection of drug candidates and generation of promising therapeutic agents. This platform also comprises of a unique assessment strategy, which permits quantitative and precise analysis of in vivo results. Through this platform, HealOr can develop valid animal models, which reliably reflect various skin pathologies.

The scientists employed in the firm are equipped with in-depth knowledge of signals, which trigger cells in the wound to migrate, proliferate, differentiate, and lay down matrix fibers. This has enabled the recognition and tracking of molecular and biochemical signaling pathways imperative for normal skin physiology, thus leading the path to advancement of mechanism-based intervention in skin pathologies. The company’s technology platform showcases protein kinase C (PKC) family of serine-threonine kinases to play a vital role in skin physiology and pathology. The company’s scientists have pinpointed that regulation of PKC activity within the wound milieu facilitates the modification of skin cell properties to expedite wound closure and skin regeneration.



The firm’s leading drug candidate is named as HO/03/03 consisting of PKC-modulating agents and targeting the treatment of acute and chronic wounds in the form of topical peptide combination. This combinational drug is involved in the following roles:

• Safeguarding the wound area from external, potentially infectious pathogens.

• Halting the inflammation response around the wound gap.

• Expedition of dermal closure, tissue remodeling, contraction to ensure optimal wound healing and return of skin aesthetics.

The company has taken initiatives in corroborating both in numerous animal models and human preclinical studies in three medical centers in Israel, where safety testing and efficacy testing in chronic wound healing was conducted. The clinical results of phase 1 trials have revealed that treatment with HO/03/03 is safe and exhibits marked wound healing efficacy in chronic diabetic foot ulcers.

The company is currently seeking strategic partnerships for commercialization of HO/03/03 applicable in the acute, chronic, and veterinary wound care markets respectively.

It is anticipated earnestly that HO/03/03 will lessen the number of complications and wound infections in addition to reducing the number of amputations caused as a result of diabetic foot ulcers. The efficacy and ease-of-use of HealOr’s drug makes us believe that it can dramatically shift the standard of care in the chronic wounds market. In a nutshell, HO/03/03 drug shifts the paradigm of wound healing from merely treating symptoms to stimulating and augmenting the stages in all wound healing mechanisms.

Acceleration of Intrinsic Clotting Cascade to Control Surgical Bleeding

Rapid dehydration of blood and enhancement of clotting forms a vital procedure to be performed in wound healing owing to the positive impact these have on operative and hospital stay times. Investigations of surgical procedures reveal the fact that quick and effective control of bleeding during and post surgery can lessen blood loss and aid in the reduction of postoperative complications to a great extent. Surgical hemostatic agents derived from human plasma as well as from other sources are found to reproduce the final steps in coagulation pathways and form a stable fibrin clot. Realizing the fact that hemostasis is a prerequisite for wound healing, the European subsidiary of CryoLife Inc., is engaged in designing innovative protein biomaterials, protein hydrogel, and tissue technologies for evaluating cost reduction wound repair initiatives.

CryoLife Inc., a biological medical device firm based in Georgia, is focusing its efforts to develop implantable biological devices, surgical adhesives, as well as biomaterials for applications in cardiac, vascular, and spinal reconstruction. The company has designed an adjunctive hemostatic device in the control of capillary, venous,



and arteriolar bleeding, which is indicated in surgical procedures and named as Hemostase Micro porous Polysaccharide Hemosphere (MPH). This technology platform of the firm includes hydrophilic, flowable, microporous particles created by cross-linking purified plant polysaccharide by means of proprietary decellularization method.

Hemostase MPH on applying directly to an actively bleeding wound functions as a molecular sieve to instantly extract fluids from blood. Expansion and concentration of the serum proteins, platelets, and other formed elements on its surface occurs due to the osmotic action. A scaffold is created by the particles and their coating of compacted cells, which leads to the formation of inflexible fibrin clot immediately. Within a time span of 48 hours, the hemostase MPH particles are completely absorbed and enzymatically removed from the wound region.

The hemostase MPH is identified to be the fastest package-to-patient rapid-delivery hemostat available currently. This natural hemostatic product has demonstrated effectiveness in numerous surgical procedures and possesses unique benefits such as safety, simplified fulfillment of surgical need for hemostasis, and exhibiting rapid absorption of fluids from the blood, thereby accelerating the natural, physiologic clotting process for both diffuse as well as profuse bleeding.

The firm hopes to begin distribution of its Hemostase MPH product in the United States by second quarter of 2008. Besides this product, the company is also aiming to conduct R&D activities on protein hydrogel technologies along with ProPatch Soft Tissue Repair Matrix.

It can be anticipated that the efforts undertaken by the company in processing and distributing implantable living human tissues for usage in cardiac and vascular surgeries can prove to be of great benefit to the improvement of health amongst wound affected patients.



Deve lopments in the Academia

Autologous Platelet Gel Effective in Promoting Skin Wound Healing

Optimal wound healing process after surgery remains to be the long-standing goal expected to be achieved in surgery since ages. In conducting many such experiments, it has been comprehended that autologous platelet gel can intensify wound healing by stimulating an inflammatory response leading to rapid increase in the production of extracellular matrices and granulation tissues. Autologous platelet gel is discovered to be accelerating vascular in growth and collagen production, besides speeding up the fibroblastic proliferation.

Autologous platelet gel/APG can be obtained by processing autologous blood to concentrate platelet-rich plasma through the usage of novel devices. APG is being increasingly exploited for reconstructive, cosmetic, orthopedic, cardiovascular, and dermatologic surgery applications for enhancing tissue healing to a great extent. Working on a similar platform of investigating the abilities of APG in hastening acute skin healing process, researchers from the University of Cincinnati have conducted a prospective APG testing study in healthy volunteers.

The research team led by Professor David Hom utilized full-thickness dermal punch wounds for the acute skin healing model as it is minimally invasive, technically causing less discomfort, and easy to be examined over time. The research team engaged 80 full-thickness skin punch wounds, which were created on the lateral thighs of eight healthy volunteers for APG application and studies examination. Study designs of the groups were as following: one group involving APG application topically as a 1-time dose to a 4-mm-diameter skin punch biopsy site and other group in which APG applied topically as a 2-time dose to a 4-mm-diameter skin punch biopsy site. Investigations comprising of change in the levels of growth factors in the preparation of platelet-rich plasma for APG was done through enzyme-linked immunosorbent assay kits. The clinical measurements of wound closure over time studied by the researchers revealed the fact that APG-treated site had statistically increased wound closure compared with the control sites assessment.

The fundamental aim behind conducting this research study was to differentiate the healing efficiency of topical APG on full-thickness skin punch wounds from conventional therapy in a group of healthy volunteers. Clinical findings show that APG-treated sites exhibited improved healing during a 42-day period when compared with traditional therapies. Possible mechanisms of enhanced healing by APG could be attributed to both granulation tissue formation as well as epithelialization improvement. Moreover; wound contraction was observed to be improved by APG, thus facilitating rapid wound closure.

In the near future, thorough understanding of APG mechanism on acute full-thickness skin wounds can provide an exciting platform for soft tissue healing in surgical patients. Thus, APG treatment during surgical



procedures can be visualized to have a promising impact on the augmentation of postoperative dermal wound healing in hospitals.

Harnessing the Potential of Bionanotechnology for Treatment of Spinal Cord Injury

Spinal cord injury is basically damage caused to the spinal cord, which leads to loss of functioning involving mobility and feeling. Permanent paralysis as well as loss of sensation below the site of the injury in spinal cord damage is common owing to primarily inhibition in regeneration of damaged nerve fibers. In spinal cord injury, nerve fibers are blocked by scar tissue formation, which develops around the injury, thus resulting in lack of regeneration and growth. Various kinds of systems and procedures are being researched nowadays for recovering the body’s normal functioning and in turn encouraging the effectual treatment of spinal cord injury.

In one of the approaches targeting spinal cord injury management, researchers from the Northwestern University have displayed that a nanoengineered gel can hinder the formation of scar tissue at the injury site and empower the severed spinal cord fibers to regenerate and grow. The research team found that when the gel is injected as a liquid into the spinal cord, it can self-assemble into a scaffold, which supports the growth of new nerve fibers tremendously. The team of researchers has designed self assembling nanostructures as the building blocks of the gel for promoting neuron growth. Working of nanoengineered gel facilitates the reduction in scar tissue formation as well as instructing the stem cells to produce a helpful new cell, which creates myelin. Meanwhile, the scaffolding of the gel can improvise the growth of the axons in two critical directions, which are one upwards from the spinal cord to the brain and one downwards to the legs.

The research team led by John Kessler and co-authored by Samuel Stupp injected the gel into mice with spinal cord injury and found after six weeks that these animals had the enhanced ability to use their hind legs and walk. These animal studies represent a major stepping stone to future development of novel technologies having a great potential for treating human beings.

These research findings have been published in the April issue of The Journal of Neuroscience.

The research team expects to develop the nano-engineered gel as an acceptable pharmaceutical by the FDA.

Spinal cord injury treatment takes one step closer with technological advancement of nanoengineered gel, which when combined with stem cells, drugs, or other interventional treatments can offer an exciting cure.



Research Findings Elucidating Scar-Free Lesion Curing Mechanism

During wound restoration process, scar formation takes place once the inflammatory response stimulates the fibroblast cells to create a matrix of epithelial cells for wound closure. In typical cases of organ tissue damage, scar-associated wound healing can cause loss of organs itself owing to the hardening of collagen. This particular category of tissue scars result in major complications noticeable in the cases of alcohol-induced liver damage where fibrosis arises. Identifying a potential solution to this scar reduction menace, researchers from the University of Bristol have identified suppression of the osteopontin (OPN) gene to be responsible for wound restoration as well as scar curing mechanisms.

The team of researchers lead by Professor Paul Martin, University of Bristol, has showed that treatment of skin wounds on mice with a gel containing OPN can release antisense oligos against the protein. Subsequently, decrease in OPN levels can raise the blood vessels regeneration around the wound surface, thus accelerating the tissue reconstruction procedure. Furthermore; skin wound treatment with antisense oligos resulted in scar size reduction on a whole and the researchers have also noticed that wounds now had barely thin collagen surface, which can allow unhindered growth of blood vessels.

The findings of research studies have been published online in the Journal of Experimental Medicine, in a paper titled, "Molecular Mechanisms Linking Wound Inflammation and Fibrosis: Knockdown of Osteopontin leads to Rapid Repair and Reduced Scarring." This novel technique identified by researchers at the University of Bristol has been patented and licensed by a biotech organization for further expansion into clinical trials. The research team has received funding from the Wellcome Trust, Japanese Foundation for Research, together with Europe’s Marie Curie Grant.

These investigations at the University of Bristol have aided in discerning that white blood cells and platelet-derived growth factor supplied to the wound cells along with OPN protein can be employed as an excellent skin wound healing therapeutic targets in cases of weakening of fibrotic tissue recovery. More clinical studies must be undertaken by surgeons in order to prove the feasibility of this scar-free healing mechanism across all healthcare disciplines.


Advancements in Alternative Wound Healing

Technologies

Gl impse o f Other Wound Hea l ing Produc t s

Need for Alternative Wound Healing Technologies

Normal wound healing cascade experiences delay in healing due to different factors such as poor nutrition, systemic disease, infection, limited blood flow, unrelieved pressure, and so on. Wound care professionals have realized that various alternative/adjunctive therapies used in wound management can speed up the healing of chronic wounds by challenging the cellular processes in wound cascade. Secondary/adjunctive wound healing treatments are rapidly evolving and it is becoming very difficult to remain abreast of the advanced technologies used in cleaning or debriding a wound having substantial necrotic tissue. Assessment and preparation of the wound bed aids in proper selection of the specific topical and adjunctive therapies usage in wound treatment.

Some of the noteworthy adjunctive therapies used in wound healing can be hyperbaric oxygen therapy, vacuum-assisted wound closure method, ultrasound, electrical stimulation, human growth factors, and a few others. Utmost care should be taken in training the wound care practitioners about the usage of these secondary modalities as well as the rationale and expected outcome for both the wound and the patient. Good quality studies defining the efficacy of these novel alternative therapies must be conducted and only then should they be made to replace conventional wound healing practices. Currently, there is a paucity of scientific research involved in evaluating the alternative therapies considering the key factors such as rate of wound healing, antibacterial effect, pain relief, and treatment costs.

One of the most current concepts in wound healing revolves around the applications of alternative/adjunctive therapies in faster healing of wounds requires gaining of extensive knowledge base in this field along with suitably correlating this information with the rationale for selecting appropriate treatments for pathophysiology of wounds.



Brief Description of Add-on Wound Healing Treatments

This section concisely reviews the features of notable alternative wound healing therapies along with mention of their applications and benefits/demerits.

Hyperbaric Oxygen Therapy

Hyperbaric oxygen therapy (HBOT) refers to a medical treatment, which employs pure oxygen to speed up and improve the body's natural ability to heal. Most often, HBOT is applicable as a cost-effective adjunct or alternative therapy targeting medical indications, which include stroke, coma, peripheral neuropathy, multiple sclerosis, decubitous ulcers, delayed wound healing, and healing after cosmetic surgery. Here, intermittent usage of 100% oxygen under increased pressure is involved that is achieved by employing either a monoplace chamber or a multiplace chamber compressed with air for two to twelve patients.

Advantages

This mono-place chamber encompasses surface oxygenation of nonhealed incisions and ulcers besides the pushing of oxygen into the fluids of the body with HBOT. It has been found that the saturation of body fluids with oxygen during HBOT aids in delivering the majority of oxygen to ischemic regions. Notable benefits related to HBOT usage alone or in combination with other medical and surgical procedures could be hyperoxygenation and neovascularization.

Demerits

Increased pressure used in HBOT can produce seizures and there are incidences of toxicity associated with prolonged course of HBOT treatment.

Companies Utilizing HBOT Treatment

• Hyper Ox Inc., based in Pennsylvania, is engaged in manufacturing, staffing, and treating using multiperson hyperbaric oxygen chambers chiefly targeting diabetic wounds of the lower extremities.

• Hyperbaric Oxygen Technologies Inc., based in Dallas, provides professional patient focused hyperbaric medicine and wound care.

• OxyHeal Health Group, based in California, also focuses on designing and engineering as well as integrating all support systems for providing hyperbaric oxygen therapy to all patients.

Advancements in Alternative Wound Healing Technologies


Vacuum-Assisted Wound Closure

Negative wound pressure therapy, otherwise termed as vacuum-assisted wound closure forms an integral part of surgical procedures where it aids in promoting the formation of granulation tissues in the wound bed. Here, a specialized foam dressing attached to an evacuation tube is inserted in to the wound and covered with an adhesive drape for creation of an airtight seal. On application of negative pressure, the wound effluent gets accumulated in a canister. VAC therapy can be used for the treatment of a variety of chronic and acute wound types such as pressure ulcers, diabetic wounds, partial-thickness burns, trauma wounds, and grafts.

Advantages

Include less frequent dressing changes; good outpatient management; and a high degree of patient tolerance.

Disadvantages

Potential problems associated with using this treatment include regression in the quality of the granulation tissue owing to premature stoppage of the treatment. Further, patient compliance is another factor to be considered in topical negative pressure therapy applicable in wound care.

Companies Utilizing VAC Therapy

• Kinetic Concepts Inc., a global medical technology company focusing in advanced wound care has developed a Negative Pressure Wound Therapy(NPWT) and VAC therapy for delivering subatmospheric pressure to the wound site.

• Talley Group, based in Hampshire, UK, has designed Venturi NPWT device comprising of power unit, canister unit, and a dressing technique utilizing silicon drains and a gauze interface.

• Twin Star Medical, located in Minneapolis, Minnesota, has developed hollow fiber catheters for use with closed wounds in conjunction with NPWT and has shown a reduction of tissue swelling as well as improved tissue viability in preclinical studies.

• Blue Sky Medical, based in California, has designed the Versatile 1 Wound Vacuum System as well as recently the VISTA Versatile 1 Portable for long-term wound care management.



• Bacoustics LLC, based in Minnetonka (US), has filed a patent for invention directed toward a wound treatment device combining ultrasound therapy as well as pressure therapy. This device is capable of increasing blood circulation within the wound regions while simultaneously applying ultrasound induced topical pressure therapy to the wounds.

• Argentum Medical LLC, in collaboration with St. John's Regional Trauma and Burn Center, has developed a silver nylon fabric called Silverlon NPWT wound dressing that functions to allow unimpeded fluid flow when used with NPWT. Silverlon Negative Pressure Dressings primarily prevent infection to a great extent.

Ultrasound

Therapeutic and diagnostic uses of ultrasound have shed light on the increasing acceptance of this treatment modality as the standard of care in wound healing. Low-frequency ultrasonic wave treatment emerges to be the most viable alternative for wound debridement. Both high-frequency and low-frequency therapeutic ultrasound administered at optimum dosage are found to induce in vitro cell proliferation, protein synthesis, along with the production of cytokines by fibroblasts, osteoblasts, and monocytes. The latest application of ultrasound has been in ultrasonic exfoliation.

Advantages

Ultrasound-assisted wound therapy is particularly useful in deep, tunneling, and undermining wounds. Minimally associated pain is one of the unique features of this treatment. Further, the highly effective bactericidal effects demonstrated in the in vitro wound models treated using ultrasound are notable benefits.

Demerits

This method suffers from the disability to deliver additional interventions for example, the delivery of angiogenic materials to the required area of interest in the case of angiogenesis.

Companies Specializing in Ultrasound-Assisted Wound Treatment

• Celleration Inc., a company based in Minnesota, has designed a novel ultrasound device that uses ultrasonic sound waves to heal wounds. The device named as Mist Therapy System utilizes cellular stimulation for promoting the healing process.

• Arobella Medical LLC, based in Minnetonka, has recently devised the Qoustic Wound Therapy System, which uses ultrasonic energy for the selective dissection and fragmentation of tissues, wound debridement, and cleansing.



Electrical Stimulation

This technique involves the placement of electrodes either in direct contact, or in close proximity to a chronic wound in turn creating an electric current, which passes through the wounds. Several research studies have pinpointed the fact that electric currents can promote cellular activities such as DNA synthesis, proliferation, extracellular matrix synthesis, growth factors expression, and so on. Electric current plays an active role in the management of difficult chronic wounds such as arterial diabetic ulcers and venous stasis ulcers.

Advantages

This electrical stimulation promotes growth factor synthesis, which can activate several intracellular proteins involved in cellular proliferation. This cellular proliferation activity enhances wound healing to a great extent.

Disadvantages

Primarily, placement of one or two electrodes directly on the soft tissue wound can increase bacterial contamination, thereby complicating the wound healing process and in turn extending the treatment periods for the wound affected patients.

Companies Engaged in Providing Electrical Stimulation for Rapid Wound Healing

• Biofisica LLC, an Atlanta (Georgia)-based wound care firm has designed a novel wound care product--POSiFECT--by applying electrical stimulation as its working principle and this product. This bioelectric stimulation therapy is indicated for the management of chronic wounds.

• LifeWave Ltd., based in TelAviv, is an advanced electrical stimulation medical device firm which effectively addresses chronic wounds treatment. The LifeWave Bed Sore Treatment (BST) device can offer a noninvasive and painless treatment to treat patients inflicted with pressure ulcers.

Thus, a brief preview of the currently available wound treatment alternatives have been highlighted above.

Note: Extracorporeal shockwave therapy is yet another noninvasive treatment applicable in hospitals and surgery centers. The main benefits of this therapy are its cost-saving options as well as portability.



Key Technolog ica l Advancements in the Indus t r i e s ; Companies ; Univers i t i e s and Research Ins t i tu tes

Silicon Nanocrystals Employing Antimicrobial Wound Dressings

Hospital acquired infections, which continue to pose escalating problems to physicians, are being addressed in recent times trough antimicrobial dressings. The emergence of resistant bacteria has totally suppressed the effects of hand washing and sterilization. Antimicrobial dressings are being adopted nowadays by and large for prevention of bacterial penetration through the dressings and bacterial growth within the dressing, thereby aiding in the creation of a clean wound environment.

Smith & Nephew plc, an advanced wound management firm having offices worldwide, has adopted antimicrobial dressings as a suitable measure for prevention and reduction of infections in a variety of wounds. It has designed an absorbent antimicrobial dressing with SILCRYST Nanocrystals.This moisture control product is named as ACTICOAT encompassing a broad range of products and sizes for different wounds. These ACTICOAT dressings contribute to effective wound bed preparation comprising mainly of an absorbent 3-layer dressing. The dressing includes nanocrystalline silver-coated polyurethane layer; a white polyurethane foam layer; and finally a blue waterproof polyurethane film layer.

The functioning of ACTICOAT moisture control facilitates the provision of an effective barrier to bacterial penetration. This may be left in place over a wound region for up to 7 days and in the presence of exudates, the dressing aids in maintenance of moist wound environment. The ACTICOAT antimicrobial dressing is equipped with patented nanocrystalline technology, which sets it apart with proven bactericidal activity. It has been observed that the ACTICOAT dressing allows faster destruction of microorganisms when compared to traditional approaches such as silver sulfadiazine and this dressing can be cut into desired shape and size. Moreover, the sustained release of silver also allows fewer dressing changes, thus leading to less exposure of the wound bed to the environment.

The ACTICOAT moisture control dressing is designed for applications in light to moderately exuding wounds, which include decubitus ulcers, diabetic ulcers, first and second degree burns, and donor sites. It is strongly recommended that ACTICOAT moisture control dressings may not be used for providing treatment for infected wounds owing to some patients experiencing sensitivity to silver or alginates.

The company has also released an advanced version of ACTICOAT and named it as ACTICOAT 7, which is basically a dressing utilizing advanced silver technology to help create an optimal wound environment. In this product, a rayon/polyester core aids in management of moisture level and controlling silver release. This ACTICOAT 7 possesses silver-coated high-density polyethylene mesh allowing the passage of silver through



the dressing, and the nanocrystalline coating of pure silver provides antimicrobial barrier activity within 30 minutes that is faster than any other form of silver.

This ACTICOAT product range of Smith & Nephew plc offering faster microbial killing rates and longer wear times is set to mark a remarkable development in the field of moisture control dressings employed as an adjunct to the standard treatment regimen in order to provide a barrier to bacterial penetration.

Bioelectric Stimulation Therapy for Faster Wound Healing

Chronic wounds represent a major clinical challenge and the discovery of cost-effective treatment modalities targeting chronic wounds are currently the driving forces for many wound care companies worldwide. Further, the impact of some of the novel treatments discovered on the wound care market will be significant in terms of providing patient-friendly, cost-effective, and safer solutions to heal chronic wounds.

Kingfisher Medical, based in Leuven, Belgium, has recently received approval for introducing its KFH Novo product in Europe, which represents a remarkable innovation in noninvasive wound healing products. This revolutionary medical device can be utilized without interfering with standard conventional therapy and uniquely uses bioelectric stimulation therapy for its working. The KFH Novo product can deliver extremely low levels of currents to chronic wounds and facilitates complete tissue healing. In this device, when electrodes are placed a distance away from the wounds, enhancement of physiological processes of wound healing takes place.



Figure 4-1 shows the KFH Novo device outlined.

Source: Kingfisher Healthcare

The KFH Novo product aids in attraction of suitable cells to the wound region along with stimulation of fibroblast cells to selectively activate wound healing. This novel product also increases the production of ATP, thereby providing energy to restart tissue healing. Documented efforts of the research team at Kingfisher Healthcare suggest that the KFH Novo device raises the blood supply as well as oxygen supply to wound beds.

Some of the unique benefits that this KFH Novo device offers could be the noninvasive aspect since the electrodes are placed outside the wound and even in the wound treatment region; noninterference with ongoing standard therapies, that is, requiring no extra physician; facilitating the patient to continue to treat himself at home even after hospital discharge; ease of use with increased safety options along with cost-effective treatment options when compared to some of the locally existing therapies.

The KFH Novo technology has already received US FDA clearance for its marketing in the US and the patented, hi-tech medical device designed to alleviate fatigue and pain has recently received the CE mark in Europe too.

Currently, the company is engaged in setting up its own clinical research and provision of sound clinical data involving these specialized wound care units. The company is also conducting the Ultra-Best study (venous ulcers) in five university centers along with running of a case study program for examining other types of wounds such as diabetic foot ulcers, pressure sores, and other types of chronic wounds.



This next generation wound healing product designed by Kingfisher Healthcare is poised to address the delayed wound healing challenge experienced in treatment of venous leg ulcers, pressure sores, chronic wounds, and diabetic ulcers.

Electrical Stimulation Therapy for the Treatment of Nonhealing Wounds

Nowadays, biologically active treatments are being developed for targets in chronic wounds and these include antibacterial dressings, growth factors, tissue engineered dermal replacements, bioactive wound dressings, and specific agents such as protease inhibitors. While some of these treatments are found to be increasingly utilized for stimulating healing of recalcitrant wounds, there exists an obvious advantage to usage of alternative therapies, which is currently available for treatment of chronic wounds. Clinical research pinpoints the fact that electrical stimulation induces healing of chronic wounds to a great extent.

By harnessing the potential of bioelectric wound care dressing, Biofisica Inc., a revolutionary wound solution offering company based in Georgia has designed the POSiFECT medical device. This highly portable therapeutic intervention is capable of delivering biocurrents to the wound bed and facilitates cost-effective healing outcomes. This device is a one-piece construction made up of standard dressing materials where the biocurrent therapy is integrated into the dressing matrix. This biocurrent therapy is powered by the small electric module assembly, which when attached to the dressing is made to have a low-voltage battery supply as well as a tightly controlled microcurrent delivery system. Wound coverage is done through fitting of an adhesive-backed flap, which also aids in maintaining a moist wound environment.

Figure 4-2 shows the key components of POSiFECT bioelectric stimulation wound dressing.

Source: Biofisica Inc.



The POSiFECT therapy is based on the vital role played by bioelectric currents in wound healing. Bioelectric currents are found to promote the laying down of collagen and formation of stronger scar tissue along with allowing the increased migration of white blood cells. Biocurrents can have a significant impact on bacterial colonization in the wound where the measurement of electric currents/influence can stimulate the normal healing process. The POSiFECT bioelectric stimulation therapy wound dressing aims to provide a single use dressing, which can be applied directly to the wound or may be used in conjunction with compression bandaging treating venous leg ulcers.

Currently, numerous clinical studies demonstrate POSiFECT’s proven efficacy in treating recalcitrant ulcers, however, still more evaluations need to be done for proving the potential of POSiFECT in accelerating the healing rate of chronic wounds.

Computerized Wound Imaging Analysis and Documentation System

Wound care costs are soaring high and wound care professionals are striving to achieve more efficient and accurate modes of improving wound assessment. Upgradation of wound measurement and assessment is important for monitoring patient progress to ensure that wound healing is progressing with the specified treatment regime. There is a need arising for designing an innovative system that can precisely measure area as well as depth of wounds devoid of patient contact. Further, the creation of a unique system, which can create electronic patient records for printing, electronic distribution, and archiving is the pressing need of the hour.

Aranz Medical Limited, a subsidiary of Applied Research Associates NZ Limited (ARANZ), located in Christchurch, New Zealand, has recently designed a Silhouette product suite, which is a computerized wound imaging, analysis, and documentation system created for wound care requirements. The firm’s suite of products continuously combines resources, which enable efficient electronic data collection at the time of patient examination, thereby leading to advancements in wound assessment data collection as well as consistent maintenance of patient records. The Silhouette product suite encompasses Silhouette Mobile, a portable hand-held computer system equipped with an integrated high-resolution digital camera, which has embedded laser lighting for automated image calibration. The Silhouette product suite also includes Silhouette Central, which is a software-only data management system that can store wound information for longer time periods in addition to containing a Silhouette Desktop for the postprocessing of images acquired by Silhouette Mobile devices.



Figure 4-3 shows the Aranz Medical Silhouette Suite in the background.

Source: Aranz Medical

Some of the unique features that this Silhouette product suite possesses are: highly portable mobile system; user-friendly product usage; automatic generation of patient report, which includes serial graphs, is possible; vital measurements such as area, depth, volume, and length computation is possible; noncontact data collection, which minimizes risk of infection; and integration with other medical information systems is also possible.

Aranz Medical Silhouette has received FDA clearance and the Aranz Medical Silhouette Mobile has received the CE mark recently. The company has obtained financial support from New Zealand Trade and Enterprise and the New Zealand Foundation for Research Science and Technology in order to expand the Silhouette product suite initiative to great strides.

This Silhouette product suite, which is setting a new standard for advanced wound assessment should be exploited in the near future by wound care clinics, home health or district nursing agencies, long-term care facilities, hospitals and primary care physicians, and also by university researchers and clinical trial organizations.



Nanobandages Repair Slow-Healing Wounds Faster

Nanotechnology is increasingly being utilized for the regeneration of synthetic tissue for use in the human body, particularly for accelerating the healing process. Nanofibers generally have a larger surface area when compared to their size and can permit the cells to adhere to them better, in turn speeding up the healing process. Nanofibers developed using the electrospinning process also possesses the unique advantage of the possibility for selectively doping or introducing certain biological molecules into them, which can promote cell viability and proliferation. At present, nanoscience and nanotechnology initiatives undertaken globally are aimed at development of functional and clinically relevant tissue substitutes for use in the wound care industry. One such initiative is highlighted below where University of Akron researchers have designed nanofiber bandages for treating patients with slow-healing wounds.

The research team uses its patented technology platform targeting diabetic patients because the nanofibers release nitric oxide gas in a controlled manner (nitric oxide is a natural chemical diabetic patients don’t produce enough of, but it is crucial for body repair) to kill the parasites as well as reduce inflammation. In this manner, the research team has demonstrated that nanofiber technology facilitates the natural healing process to take place by re-establishing the vascular flow of oxygen to the wound region.

The researchers employ electricity to spin ultrafine polymer fibers while infusing them with chemicals in order to facilitate opening of a wound to oxygen. They have demonstrated that treated fibers have the ability to reduce inflammation, kill bacteria, along with repairing of slow-healing wounds at a faster rate than traditional approaches. These electrospun fibers are cost-effective, lightweight and elastic, and conform to any wound type without sticking.

Researchers have conducted phase 2 clinical trials of these bandages in infections caused by the tropical disease leishmaniasis, and found that these nanofiber bandages dramatically improve the healing duration for leishmaniasis. Impressive results showed by these nanofiber bandages in healing wounds within weeks devoid of any secondary effects indicate that this technology could be applicable in treating a variety of skin ailments.

Currently, the antiinflammatory and bactericidal properties of these nanofibers are being evaluated on the leishmania-ridden people of Columbia. The research team intends to conduct a massive phase 3 trial in mid-2008 to obtain FDA approval for the use of this nanofiber bandages in the United States wound care centers.

The research team at University of Akron has licensed this technology platform to a Minnesota-based firm for commercial manufacturing of the nanofiber bandages and hopes to introduce these nanobandages for speeding up the healing process in the wound care industry by early 2008.


Technology Adoption Factor Analysis

Ins igh t s in to Technology- Impera t ive Fac to rs

Technology Steering Forces

Rapid Uptake of Innovative Technologies

Wound care industry is exploring some of its best opportunities in cell biology and biotechnology for achieving proven outcomes. There is an upsurge in the disease management programs, which emphasize on prevention and early intervention for better wound treatments. Nowadays, the explosion of scientific information about the molecular basis of healing is driving the emergence of growth factors, gene therapy, biological dressings, and cell therapy as advanced wound care products. Wound care professionals are seeking the usage of xenogenic tissue scaffolds, bilayered human dermal substitutes, and recombinant growth factors in treatment of various wound types, thus leaving behind the conventional synthetic dressing materials usage.

Increasing Incidence of Delayed Wound Healing

Ageing society and increase in hospital stay due to prolonged illness are the two main factors identified to be causing rise in incidence of delayed wound healing. These two factors are explained in detail below:

• Rise in the life expectancy numbers has led to population explosion within the elderly category and this has been a great stimulating factor for developing advanced wound care products. Achieving faster healing rates in procedures designed for reducing infections during prolonged hospital stays has been the pressing need of the hour, in turn driving product development simplifying complications related to delayed wound healing.

• Increasing incidence of diabetes and obesity indications worldwide is an alarming issue facing the wound care sector currently. Some of the reasons causing delayed healing of wounds can be mentioned as immunocompromised patients, complications such as diabetes mellitus, cancer rejection, and other compromised conditions arising out of organ transplants, alcoholism, and vascular insufficiencies.



Existence of Competitive Scenario among the Key Industry Players

At present, the tremendous increase in the number of wound healing technologies being manufactured for commercial usage can be attributed to the user-friendly and simplfied design of such novel technologies. There is an upsurge in the number of smaller firms that are technologically advancing highly sophisticated wound healing technologies, thus initiating a tough competition situation for key industry players and their products.

Clinical Evidence Supporting the Need for Upgradation of Wound Healing Technologies

Physicians are predominantly supporting the usage of cutting-edge industry developed products for treatment depending on patient's specific requirements. The emerging product gains trustworthy acceptance in both the physician’s and patient's mind through proper clinical evidence. Moreover; evidence-based development of any product drives intensive research into designing more products of similar make in the market by companies.

Rapid Spread of Infections Accelerates the Usage of Wound Dressings

It is observed that increase in the number of hospital-prone infectious agents has spurred the development of microbial resistant technologies for mainly guarding exposed wounds. Emergence of antimicrobial wound dressings that are chiefly made of silicone and silver materials is well known among wound care professionals nowadays. Wide spread applicability of these wound dressings is due to their possession of remarkable properties such as broad spectrum of antimicrobial activity; minimal toxicity towards mammalian cells; and finally having fewer tendencies than antibiotics to induce resistance owing to its multiple target sites activity.

Implementation of Ongoing Patient Management Studies

The guidelines and revisions for wound care issued lately emphasize the prevention of wound development in long term care settings. Sharing of detailed documentation and protocols followed amongst the clinicians can help enhance preventing wounds, healing wounds, and treating infected wounds. Consistently following wound care guidelines with focus on implementation can aid in early detection and prevention of wounds. For achieving the goals of offering advanced care for patients along with minimizing the pain associated with dressings,gaining adequate knowledge about ongoing patient management studies and their unique applications represents a good business practice.



Figure 5-1 represents the key drivers of the industry.


Technology Inhibitors

Lack of Standardized Wound Healing Procedures

Wound closure and wound sealing concepts are being misunderstood these days by the end users, predominantly surgeons who fail to apply a uniform type of device for certain areas of specific interest to the surgeons. Many products are commercialized but they don't serve the unique purpose of their design, thus suffering from inability to serve the functional purpose of applications.

Tight Funding

Researchers are facing the problem of limited funding, which acts as a retarding force in the development of novel technologies by the academia. The commercialization/licensing of technologies discovered by researchers to the firms stifles majority of the innovative efforts undertaken by individual university scholars and retards academic progress in technology innovations. It would be better if partnership activities between universities and companies are encouraged rather than licensing opportunities being promoted.



Cost-Cutting Initiatives Taken by Healthcare Community

Although the prices of the available innovative technologies are high, they possess huge potential in repairing of wounds and exhibit minimal side effects. Consequently, the lowering of prices of these novel technologies by clinicians and other medical practitioners results in the lack of reliability and safety of these products when obtained in bulk for patients' therapeutic usage. Briefly, the lowering of prices can pose a threat to the increased product acceptance in wound care sector.

Regulatory Framework

The significance of proper regulatory framework in the respective regions globally is unrealized and this affects the growth of the companies specializing in designing novel wound healing products. In particular, the lack of standardized regulatory framework and guidelines in the European Union poses the difficulty for other region companies to also get involved in market penetration and pitching of their own products at reasonable rates.

Figure 5-2 shows some of the technology inhibitors.




Technology Challenging Factors

Smart Management of Complications Associated with Wound Healing

Wound healing represents a major concern for clinicians, patients, and healthcare providers. Critical colonization as well as infection of wounds pose a dual problem for clinicians. First and foremost, there is the possibility of delayed wound healing, specifically in the presence of a compromised immune system or where the wound is grossly contaminated and badly perfused. Secondly, colonized and infected wounds are a potential source for cross infection, which is a noteworthy concern owing to the continuation of multiple-drug resistant species.

Infected wounds can have additional concerns for patients including pain and discomfort, a delay in return to normal activities, and the possibility of a life-threatening illness. There is an alarming rise in treatment costs and nursing time to consider in the case of healthcare providers. Until recently, local wound infection has been envisioned as a major challenge with limited management options available. Wound assessment is a separate topic of study to be examined by the general public before handling the treatment methods best suitable for particular type of wounds catering to patient-specific requirements.

Immediate Requirement of Spread of Efficacy Awareness

In taking decisions related to best choice of wound dressings, there exists an urgent need for conducting well-controlled multipatient comparative studies, which can showcase the efficacy and drawbacks of the advanced products. Additionally; the growing healthcare expenditures evolving due to novel treatments such as tissue engineering and nanotechnology can be curbed by proper validation of clinical studies involving these upcoming wound healing trends. There is a point of concern among the wound care professionals over establishing the value of emergent techniques in healing of wounds and some of their beneficial characteristics, in turn to build brand recognition.

Growth Sustenance in a Mature Industry

One of the most challenging factors for wound care companies is to sustain growth with their existing products as well as progressive products targeting faster wound healing rates. Competition faced by the companies making similar products or technologies leads to disruptive positioning of products in a well established industry like wound management. Maintenance of good effectiveness and timely acceptance of the product in the wound healing industry are the two major factors to be looked upon with great diligence for carving a niche in the current highly competitive scenario.



Reimbursement Concerns

Many wound care devices are only a part of the hospital budget and do not account for reimbursement as an individual entity. High costs of the products involved in wound healing demands suitable reimbursements for the patients utilizing them. Stricter reimbursement can result in a declining phase in the annual budget ratio for healthcare in many countries, thus posing a great difficulty for many companies to sell their products. It is worth mentioning that lack of sufficient reimbursement can lead to patients opting for conventional procedures in wound healing that are affordable as well as inexpensive.

Controversy Existing Over the Usage of Silver Dressings

Burn affected patients, owing to their high susceptibility to infections, largely utilize topical creams or solutions containing silver as a mainstay of wound management. Likewise, huge number of silver antimicrobial wound dressings have been used for wound healing. However; disadvantages to their applicability includes staining the skin and toxicity. Moreover; the need for frequent removal and reapplication of silver sulfadiazine due to the development of pseudoeschar is both time consuming for physicians as well as painful for patients.

Currently, a range of antimicrobial wound dressings containing silver incorporated within or applied to the dressings are available for surgical use. This novel class of dressings is designed to provide the antimicrobial activity of topical silver in a more convenient application. However; the dressings themselves differ considerably in the nature of silver content and in their physical and chemical properties. Briefly; the silver release from each dressings and antibactericidal effects possessed should be assessed for healthcare applications.

Lack of Patient Compliance Data in Emerging Technologies

It is clearly evident from wound management industry trends analysis that newer therapies and products based on these innovative techniques such as dissolved oxygen therapy, electrical stimulation, negative-pressure wound therapy, ultrasound-based treatments, and few others have completely replaced the conventional utilization of moist wound dressings such as hydrogels. A great deal of investigations are being performed by the researchers to effectually analyze the flexibility of materials along with the strengthening power needed for wound repair with minimized side effects, which are all made possible at reduced costs. But all these exploration activities done by the research community fails to examine patient compliance to the novel wound healing alternatives that have been discovered.



Figure 5-3 highlights some of the key challenges observed in the wound healing industry.




Oppor tun i ty Assessment Fac to rs

Strategic Evaluation of Emerging Innovations Applicable to the Wound Healing Industry--SWOT Analysis

The key strengths, weaknesses, opportunities, and threats in the development of novel wound healing techniques sector have been briefly listed in this section.

Strengths

• Simplified operation of tissue engineering technologies can enhance wound healing procedure.

• Development of products exhibiting minimal antigenicity favors patient compliance to wound healing products.

• Ability of the wound healing products to mimic skin cell types and their functioning speeds up healing of wounds.

• Capability of clinical application of a wound healing technique in an outpatient procedure further encourages widespread usage of the wound healing product.

• Compact size of the wound closure device ensures reduced pain to the patient and increased accessibility for the physician.

• There is rise in adoption of minimally invasive options providing wound healing techniques equipped with disposable features.

• Wound healing techniques showing improved performance due to automated wound analysis and detection features eliminate the need for surgical procedures and highly-trained wound care professionals.

• Potential to bring about a rise in commercialization of innovative wound healing techniques.



Weaknesses

• Assurance of complete safety profile of the novel wound healing products designed.

• Time required in conducting more extensive controlled clinical studies for evaluation of product effectiveness.

• High research-driven expenditure generates expensive products.

• Fragility of the product usage and need generated for custom preparation.

• Technical expertise or skilled wound care professionals needed for handling advanced wound care products.

• Lack of universal adoption of certain nascent technologies such as NPWT, dissolved oxygen therapy, and electrical stimulation.

Opportunities

• Universities enabling knowledge transfer and data access for companies to commercialize the techniques/products.

• Multifunctionalty in wound healing products made possible through novel discoveries, which involves product application providing soothing pain relief to the patients

• Expansion of basic research and human evaluation studies for further enhancing the product’s wound healing effect results obtained from animal studies.

• Product satisfying optimal coverage of the wound.

• Potential to drive good quality wound assessment and wound management protocols.

• Prospective opportunities generated for wound healing firms, contract research organizations, life sciences industrial groups through collaborations and acquisition activities.

• Progressive advancements in therapies bringing personalized medicine to a reality.

• Existence of promising funding scenario in the form of institutional grants and venture capitalist funding.



Threats

• Tough competition among the key developers of wound healing technologies.

• Products possessing shorter shelf life at room temperature undergoing FDA testing and approval.

• Mismanagement/awkward handling of wound healing products can pose a threat to burn patients.

• Health insurance and reimbursement policies can pose a significant threat to hospitals as well as patients.

• Certain uncertainty issues in the regulatory environment can also hinder progress of wound healing technologies.

• Conservative mind set of people and their inability to adopt novel technologies, thus replacing the conventional ones.

Figure 5-4 shows the SWOT Analysis table.




Risk Analysis and Risk Management of Emerging Alternative Wound Healing Technologies

This section covers the main risks involved in using wound healing technologies and the effective management of these risks for achieving better wound healing outcomes.

Vacuum-Assisted Wound Therapy

Risk Factors

• The premature stoppage of the treatment given to the patient can lead to regression in the quality of the granulation tissues.

• The suction force when applied initially cause pain and discomfort to the patient.

• There is risk associated with allergies caused to the adhesive drapes.

• There are also chances of risk for causing excoriation or chafing of the skin in cases of foam not correctly cut to size.

• Possible risks associated with fulminant or incipient skin necrosis are also present.

• NPWT treatment failures largely arise due to lack of patient compliance.

Risk Management

The pain associated with application of negative pressure therapy to the wounds can be resolved by either starting at a lower pressure and then increasing to the required target pressure or alternatively by continued therapy. This VAC technique if modified to include the use of a silicone sheet, then it can be placed between the epicardium and foam for prevention of treatment failure due to lack of patient compliance. It becomes mandatory now to teach the patients effective and independent management of the VAC system to ensure safety. It can be recommended that patients receive regular clinical evaluations to monitor progress and a nutritional examination to ensure proper nutritional status.



Hyperbaric Oxygen Therapy

Risk Factors

• A patient administered with dissolved oxygen therapy may be claustrophobic.

• There are chances of occurrence of fire hazards, which are preventable by strict safety procedures.

• Transient reversible myopia can be a risk indication in the patient.

• Slight pain in the ears can occur due to a blocked Eustachian tube.

• Relative patient isolation.

Risk Management

Physicians have to understand that the role of hyperbaric oxygen therapy is evidence-based in certain well defined conditions and the hyperbaric chamber has become an integral part of hospital services. Familiarization with the most recent evidence involving this therapy is crucial for all physicians so that patients are not denied benefit of this treatment. Hyperbaric oxygen exposure must be maintained in safe time-dose limits and provision for treatment in both in patient or out patient settings must be established. Disease-specific hyperoxic dosing should follow the current treatment protocols. In cases of emergency, the precise number of treatments should be decided depending upon the clinical response of each patient.

Electrical Stimulation Treatment

Risk Factors

• Electrical induction when applied to cardiac arrest can cause thermal injury.

• Technically complicated working procedure of electrical stimulation poses a risky affair to the clinicians using them.

• Limited experience with electrical stimulation device lessens the routine usage of this treatment.

• In cases of electrical stimulation of nerve cells, the selection of suitable coating material having a safe potential range is a risk inducing point.



• Accurate surface placement of the electrodes during functional electrical stimulation procedure is yet another point of concern.

• Some patients develop an allergic skin reaction/response to the electrodes and this can prove to be fatal.

Risk Management

Electrical stimulation must be continued to be employed for three purposes mainly for aiding diagnosis, then as a therapeutic tool, and finally to restore lost functions in the body. Special care should be taken to avoid the usage of electrical nerve stimulation procedure in instances of patients with cardiac pace-makers and pregnant women in their first trimester. It should be considered here that electrical frequencies can be regulated and adjustable depending on the individual's condition. Professionals operating this electrical stimulation equipment should recognize the potential danger associated with high-voltage electrical stimulators that produce lethal quantities of electricity.



Ana lys t Ins igh t s and S t ra teg ic Recommenda t ions

Present and Future Industry Trends Analysis

Trends Observed in Wound Healing Medical Devices

Chronic dermal wounds are difficult to manage and slow to heal, inflicting pain, resulting in loss of quality of life, and are potentially life-threatening. Numerous surgical wounds become delayed healing wounds particularly in the elderly or in diabetic patients. Advanced wound healing products/devices designed to improve the healing of chronic wounds aid in faster healing and recovery of patients in conjunction with the potential to reduce economic costs associated with lengthy hospitalization.

Currently, a number of medical devices, which provide assistance in various stages of healing are being designed for helping in achieving safe closure of wounds. Hyperbaric oxygen therapy utilizing/ electrical stimulation using techniques are more preferred than conventional invasive medical devices nowadays. Clinical investigations support the fact that usage of dissolved oxygen enabling enhanced delivery along with functional electrical stimulation technique in addition to ultrasound-based devices have been increasingly exploited for faster healing of chronic wounds. These technology breakthroughs minimize wound healing time to a great extent.

There is a growing trend observed toward usability of advanced wound care dressings, in particular for antimicrobial wound dressings, owing to their potential activity against multiple drug resistant microbes and their proven clinical validity as compared to other unfriendly skin wound care dressings. In the near future, elaborate clinical studies examining the applicability of such advanced wound dressings need to be performed for better wound healing outcomes.

Some of the prominent industry players and their innovations have been highlighted below:

• Coloplast Group with global locations has recently released a breakthrough dressing, Biatin Ibu, which does the dual role of reducing pain in chronic wounds as well as managing the fluids that exude from the wounds. This innovation is expected to reduce the barriers for achieving faster wound healing. This unique dressing also provides moist wound healing along with continuous release of ibuprofen.

• Unomedical based in Denmark has launched Sorbsan Silver Antimicrobial Dressings which aids in controlling infections and promotes wound healing immensely.



• MolnLycke Healthcare based in Sweden owns Mepilex AG antimicrobial dressing that combines silver with Safetac silicone technology platform.

• Alltracell Healthcare Innovation Group, based in Dublin, Ireland, has the PolyAnhydroGlucuronic Acid(PAGA) technology platform utilizing oxidized cellulose for delivering wound dressings to the wound care sector.

• Ethicon Endo-Surgery Inc., a subsidiary of Johnson & Johnson, has several novel surgical products for carrying out minimally invasive surgical procedures.

• ConvaTec, a Bristol-Myers Squibb firm specializes in advanced wound care products and holds ownership of an unique gelling foam dressing, which combines the benefits of foam and hydrofiber to redefine patient care. This product is named as VERSIVA XC.

• Paul Hartmann AG, headquartered in West England, manufactures and provides a wide range of phased wound healing solutions ranging from traditional gauze dressings to hydroactive foams, sheet hydrogels, and silver dressings.

• Advanced Medical Solutions Group plc, based out of UK, develops products under the brandname ACTIVHEAL, for providing advanced moist wound healing environments.Through its MedLogic division, AMS leads in the sector of tissue adhesives for closing of wounds too.

• AcryMed, based at Oregon a wholly-owned subsidiary of I-FLOW Corporation, California has developed the SilvaGard Surface Engineered Antimicrobial treatment to improvise the efficacy of indwelling and implantable medical devices, besides lessening the risk of deadly medical device related-infections.

• Tepha Inc., based in Massachusetts, pioneering a novel generation of absorbable medical devices has recently designed a wide range of wound management devices using its proprietary polymers. The company's TephaFLEX sutures can be employed in every known surgical application with ease of handling and flexibility advantages.

Trends in Biointeractive Innovations Employed for Wound Healing

Recently, much of the advancements noticed in wound healing applicable technologies are mainly concerned with providing protection to the wound from getting infected through controlled release of enzymes and antimicrobial agents in the wound. There are numerous developments happening to ensure proper pain-free debridement by utilizing collagen and other polysaccharides, which are not associated with the risk of causing infection. Wound care industry is currently harnessing the potential behind natural substances such as growth factors and tissue systems, which are present under normal conditions within the living systems. Tissue



engineering and artificial constructs are also significantly advantageous as they can replace the current gold standards of autografts and allografts.

There is an increased tapping of nanotechnology, tissue engineering, and genetic-based therapies for assisting in controlled drug release, provision of desired characteristics and properties to the natural polymers, in brief providing prospective solutions to wound care.

A brief listing of commercially available biointeractives for chronic wound therapy has been discussed below:

• Advanced BioHealing Inc., based in California, has designed a unique human fibroblast-derived dermal substitute, DERMAGRAFT, which can be used in the treatment of full-thickness diabetic foot ulcers.

• Forticell Bioscience Inc., based in New York, enables faster wound healing through its bilayered cellular matrix product--OrCel. This serves as an absorbable biocompatible matrix, which provides a favorable environment for host cell migration and has been shown to comprise of cell-expressed cytokines and growth factors.

• LifeCell Corporation, based in New Jersey, owns AlloDerm, an acellular dermal matrix derived from donated human skin tissue, belonging to the banked human tissue classification by the FDA. This patented human tissue matrix can be used in the treatment of burns or full-thickness wounds.

• Genzyme Biosurgery, based in Massachusetts, has devised a unique bioengineered skin substitute called Epicel, which targets treatment of deep partial-thickness and full-thickness burns.

• Integra Lifesciences Corporation, based at New Jersey has the Integra skin substitute targeting deep partial-thickness and full-thickness burns.

Characterization of Trends Seen in Alternative Wound Healing Techniques

A keen observation of emerging trends in wound repair techniques studies suggest that negative pressure therapy, employing products are being increasingly utilized in managing infected sternal wounds that often occur post cardiac surgery. Negative pressure wound therapy as well as topical negative pressure are found to improve healing of the diabetic foot amputation site along with enhancement of skin graft integration, which have been proved by two independent recent studies conducted by clinical research team.

In cases of novel therapies and products based on ultrasound principle and electric currents, there has been complete replacement of moist wound dressings such as hydrogels. However; there is a point of concern over establishing the value of these adjunctive wound healing techniques and their beneficial features in comparison to older ones.



A snapshot of key trends observed in the development of these alternative technologies has been covered previously under the section titled, "Brief Description of Add-on Wound Healing Treatments" in Chapter 4.

Future Trends Overseen in Wound Healing Techniques Developed

Currently, a lot of research studies are being carried out for examining the efficacy of honey in wound dressings. In the near future, honey-based dressings have a huge potential to capture a lucrative market mainly due to their antimicrobial, wound cleansing, and healing properties. Future investigations are expected to yield vital information concerning the basic phenomenon of cell differentiation and tissue morphogenesis in conjunction with their crucial role played in wound healing. Moreover, experimental studies conducted in human subjects as well as animals should reveal greater insights into the role of therapeutic agents and anti-inflammatory drugs on the success of wound repair. Increasing clinical evidence must be populated regarding heparin's role in improving outcome of burn patients in terms of mortality, wound healing, pain, and cosmesis (surgical dermal tissue reconstruction method) . Much less is known about the impact of mechanical forces/physical devices on wound healing and this necessitates the exploration of principal mechanism behind many of these vacuum-assisted devices, electrical forces utilizing devices, and ultrasound-assisted devices. In the forthcoming years, wound healing strategies should have the capabilities to prevent cells from undergoing apoptosis but stimulate rapid cell division and proliferation .

Figure 5-5 shows the key industry trends observed in wound healing technologies employed over the past

few years.




Notable Mergers and Acquisitions

This section provides an overview about the key acquisitions and strategic partnerships involving wound healing innovations worldwide.

• Smith and Nephew, a global medical technology business through its Advanced Wound Management Division has entered into a preferred provider agreement with Apria Healthcare Inc., which is a leading home healthcare firm in the United States. This agreement will enable Smith and Nephew to distribute Negative Pressure Wound Therapy products in the United States home care markets. The distribution agreement also entails rental of Smith and Nephew’s EZCARE and VISTA product systems along with sale of associated disposables.

• Advanced Biohealing Inc., an industry leader in the science of regenerative medicine, based in California, has entered into an agreement with Regenesis Biomedical, which is a privately-held medical technology firm focusing on developing noninvasive regenerative medicine products. This agreement mainly focuses on the promotion of DermaGraft product within the United States government healthcare system. The terms of this exclusive deal allows Regenesis to provide its specialized sales force for marketing of Advanced Biohealing’s product DermaGraft within the Veteran’s Administration, Department of Defense, and TriCare Healthcare payer systems. This copromotion activity is believed to be one of the most effective ways to maximize reach and penetration of DermaGraft product in the present day wound care market.

• Biochemics Inc., a firm pioneering transdermal drug delivery located in Danvers (Massachusetts), has entered into research collaboration with Beth Israel Deaconess Medical Center (BIDMS) for evaluation of wound healing effects of some of the company’s novel proprietary formulations in preclinical models. This collaboration with BIDMS will offer Biochemics Inc. an exciting opportunity to further explore the use of novel transdermal drug delivery formulations to treat wound healing.

• Kinetic Concepts Inc. (KCI), a global medical technology organization holding leadership positions in advanced wound care and therapeutic support systems has acquired LifeCell, which is headquartered in New Jersey, and is the leading provider of novel biological products for soft tissue repair. This definitive agreement signed between the two companies will enable LifeCell to function as a new global biosurgery division within KCI. This combination will allow KCI to increasingly focus on the operating room and the acute care settings both with its current product offerings as well as with the development of novel products from its negative pressure technology platform.

• KCI has also entered into an exclusive worldwide license with NovaBay Pharmaceuticals Inc., a clinical stage biopharmaceutical company, based in California. Through this deal, KCI plans to develop and commercialize NeutroPhase topical solution technology applicable in the field of wound



healing and also combine KCI’s proprietary VAC instillation therapies with NeutroPhase for the cleansing of wounds.

• FLOW Corporation, a leading provider of cost-effective drug delivery devices located in California, has acquired AcryMed Inc.,Oregon which is now a wholly owned subsidiary of I-FLOW and specializes in designing of advanced wound care and infection control technologies. Through this agreement, AcryMed will manufacture for I-FLOW a novel line of silver transparent wound-site dressings, which I-FLOW intends to introduce in the near future.

• Innocoll Technologies Ltd., a wholly-owned subsidiary of Innocoll Inc., based in Virginia, has partnered with TGR Biosciences Pty. Ltd., for development of a novel wound healing product. Through this strategic collaboration, the evaluation of combinatorial product comprising of Innocoll’s collagen-based drug delivery technology and TGR Bioscience’s proprietary wound healing compound namely TGR-265 is made possible. Under the terms of this collaboration, Innocoll can incorporate TGR-265 into the CollaRx sponge and membrane formats for further examination. Funding for the development of formulated products will be done by TGR Biosciences.

• ULURU Inc., a Texas-based emerging specialty pharmaceutical firm focusing on the development of a portfolio of wound management, has entered a codevelopment agreement with ImmuneRegen Biosciences, which is a development stage biotechnology firm designing innovative therapeutics based in Arizona. This deal enables evaluation of the wound healing potential of a combination of ULURU’s hydrogel nanoparticle wound dressings and Immuneregen’s Homspera therapeutic. The terms of this agreement enables ULURU to conduct a range of in vitro and in vivo studies, which on successful completion of preclinical studies will get the rights to negotiate an exclusive license for the wound healing applications of Homspera. The codevelopment agreement could play a vital role in numerous phases of overall wound care strategy development.

• Ogenix Corporation, an Ohio-based developer of breakthrough therapy, which restores regenerative wound healing capacity, has granted an option to license its Transdermal Sustained Oxygen Therapy technology for wound healing and the treatment of skin disorders to Minerva Healthcare, a privately-held developmental stage specialty pharmaceutical company. This deal also covers the worldwide distribution of EpiFLO family of products belonging to Ogenix Corporation.

• Smith and Nephew, a global medical technology business has purchased Blue Sky Medical Group, which is a privately-held firm headquartered in Carlsbad, California. This acquisition will enable Smith and Nephew to enter the negative pressure wound therapy market and manufacture a range of negative pressure pumps as well as wound dressing kits. In this way, Smith and Nephew intends to expand rapidly in one of the fastest growing segment of the wound care markets, that is, the market for NPWT.



• Quick Med Technologies, Florida a pioneer in wound care antimicrobial innovations has entered into a multiyear patent and technology license agreement with Derma Sciences Inc., Washington which is a supplier of wound care products in both Toronto as well as China. Through this agreement, QMT’s NIMBUS Antimicrobial technology platform can be licensed to Derma Sciences on an exclusive basis for usage in specific wound care products, which include gauze sponges, gauze bandage rolls, oil emulsion acetate, and gauze packing strips.

• DelSiTech Ltd., a drug delivery firm, based in Finland, has entered into a licensing agreement with Bayer Innovation GmbH, which is a wholly owned subsidiary of Bayer, headquartered in Dusseldorf. This agreement allows Bayer to use the unique and proprietary DelSiTech Drug Delivery Technology for fiber applications in the fields of wound care and certain other applications. The terms of the agreement also includes an option for further collaboration.

Strategic Recommendations

This section highlights a few strategic recommendations based on the extensive study performed by the analyst during the course of completion of this research service.

Increased Value-Added Awareness Cultivated in the Minds of Patients, Clinicians, and Physicians

The spread of knowledge on the unique benefits and demerits can help boost the adoption of these novel techniques, thus replacing the conventional ones. Increased acceptance of the newly discovered products amongst the general public is brought about only through clinicians’ support and physicians’ recommendations. Hence, awareness in patients can lead to rise in the population willing to apply these techniques for better wound healing.

Updated Training Facilities Offered to the Wound Care Professionals

With advancements in wound healing technologies happening within a very short span of time, it becomes critical for the clinicians to upgrade their knowledge on wound healing technologies usage often. Conducting regular training courses helps instill confidence in the minds of wound care physicians to confidently operate a sophisticated technology platform/device.

Reducing the Cost of Availability of these Novel Products

Significant reduction in costs by vendors manufacturing wound healing devices could lead to better affordability options for both healthcare providers as well as patients. Considerable efforts need to be taken to ensure production of cost-effective wound healing techniques so that they can be easily purchased by poor people.



Streamlining of the Companies’ Approach toward R&D Activities

Wound care industry is booming with breakthrough technologies being developed at a rapid pace. Now, it becomes mandatory for all the major players involved in this sector to keep themselves abreast of the latest trends and to ensure higher compatibility with the existing technology platforms having a broad range of applicability. Therefore, all key industry participants have to focus on streamlining their R&D efforts in order to capitalize profits and achieve long-term growth.

Increased Funding Options for Research can Drive Clinical Discoveries

Funding for research studies to be conducted should be maximized and this benefits creation of novel wound healing techniques by leading research teams. It must be stressed that only through excellent research opportunities facilitated via funding can technology licensing or commercialization of academia specific discoveries be achieved.

Focused Efforts towards Development of Superior Antiseptic Formulations

Since the usage of antiseptics such as silver on wounds is currently being viewed with skeptism, there arises the need for improved findings or randomized controlled studies to be conducted for evaluation of antiseptics on different types of wounds and their outcomes. Continuous efforts should be focused toward advancement of promising antiseptics such as iodine, which can accelerate healing even in noninfected wounds. Thus, newer antiseptics formulations, which appear to be relatively safe and efficient in preventing infection in human wounds, should be positioned in wound care management and the cytotoxicity findings of silver activity must be reconsidered.

Good Quality of Wound Assessment and Patient Management

Identification and overcoming of barriers to healing are major concerns to the development of any wound treatment regime. Holistic review of the health conditions of the patient along with local assessment of the wound characteristics and previous history form integral parts of any good wound assessment procedure. This wound assessment assists in establishing an accurate treatment pathway for achieving improved wound healing outcomes. Preparation of wound bed by selecting appropriate treatment depending upon the wound characteristics helps to foster a conducible environment to advance healing.



Figure 5-6. Strategic Recommendations for improved wound management.


Figure 5-6 presents a few strategies that can be envisioned in bringing about improvements in acceptance of novel wound healing products discovered as well as encourage the targeted creation of less invasive breakthrough technologies with multifunctionality options.


Patent Assessment; Database of Key Industry

Participants; and Glossary

Review of Pa ten t s

Patents Review

The study of patents in wound healing techniques realm for the duration of past seven years leads us to conclude that 74% of the patents are held by companies whereas only 26% of patents are distributed within the universities. Till 2005, a large number of patents have been issued to academia and from 2006 onwards, it has been observed that the number of patents derived from companies including both emergent as well as top players in the wound care industry is on a marginal rise. Patents issued between 2000 to 2008 on evaluation reveal that from 2006 there has been rise in innovations presented for clinical approval in the wound care related technologies.

It has been observed from patent studies that there has been a tremendous increase in patents for alternative/ regenerative wound-healing applicable technologies over the past seven years. Cumulative patent data indicates that both industry participants and universities active in the wound healing research area are taking huge efforts in practical development of innovative solutions for the same. The pace in which numerous discovery platforms are transforming into clinical phases and product launches is noteworthy.



Figure 6-1 depicts here the patent distribution analysis spread among companies as well as academia.


Figure 6-2 highlights the spread of patents within a specific timeline.


Investigating the patents spread across wound-healing environment treatment methods leads us to believe that many of the core applications of the wound healing methods are multifarious and have promising potential for the near future. Many of the methods discovered for enhancing wound healing are primarily breakthroughs confined to pharmaceutically active agents, natural tissues, stem cell therapies, and increased bioactive agents



usage. These technological advances are beginning to emulate the class dynamics of conventional wound therapies with suitable demonstration of effectiveness in rapid wound healing. Numerous wound care companies are turning towards licensing value-added wound healing products accompanied by extension of partnerships with start-ups as well as universities for establishing a strong niche in this competitive wound management sector.

Through this patent analysis it is clearly evident that a strong patent and licensing portfolio enables companies to create excellent wound-healing products in addition to benefiting the company in terms of achieving enhanced clinical outcomes too. Tapping into patent information helped in identification of some of the major players having maximum innovations in wound healing treatment and they are namely Abbott Vascular Devices, Coloplast A/S, Ethicon, a subsidiary of Johnson & Johnson, Kinetic Concepts Inc., Smith & Nephew PLC, St. Jude Medical, and others. The patent information also supports the fact that there has been a gradual increase in small-size wound care companies emerging as key players owing to critical threshold advantages possessed by advanced technologies designed by them, which includes: Ready availability and ease of usage of advanced technologies in a hospital setting; Ease of application and monitoring of the wound bed; Cost-effective methods when compared to conventional treatments; and lastly excellent healing potential supported by ability to overcome pathological resistance. Focused efforts are undertaken by companies as well as universities in developing healing technologies which could lessen the hospital stay time, in turn lowering the overall healthcare expenditures.

Key Patents in NA and Canada

United States Patent 7,371,377

May 13, 2008

Antibodies to polypeptides homologous to VEGF and BMP1

Abstract

The present invention involves the identification and preparation of vascular endothelial growth factor-E (VEGF-E). VEGF-E is a novel polypeptide related to vascular endothelial growth factor (VEGF) and bone morphogenetic protein 1. VEGF-E has homology to VEGF including conservation of the amino acids required for activity of VEGF. VEGF-E can be useful in wound repair, as well as in the generation and regeneration of tissue.

Assignee: Genentech Inc. (South San Francisco, CA)

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May 13, 2008

Wound dressing and method for controlling severe, life-threatening bleeding

Abstract

This invention is directed to advanced hemorrhage control wound dressings, and methods of using and producing same. The subject wound dressing is constructed from a non-mammalian material for control of severe bleeding. The wound dressing for controlling severe bleeding is formed of a biomaterial comprising chitosan, a hydrophilic polymer, a polyacrylic polymer or a combination thereof. The kind of severe, life-threatening bleeding contemplated by this invention is typically of the type not capable of being stanched when a conventional gauze wound dressing is applied with conventional pressure to the subject wound. The wound dressing being capable of substantially stanching the flow of the severe life-threatening bleeding from the wound by adhering to the wound site, to seal the wound, to accelerate blood clot formation at the wound site, to reinforce clot formation at the wound site and prevent bleed out from the wound site, and to substantially prohibit the flow of blood out of the wound site.

Assignee: Providence Health System-Oregon (Portland, OR)

Gregory; Kenton W. (Portland, OR)

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May 6, 2008

Controlled release dressing for enzymatic debridement of necrotic and non-viable tissue in a wound

Abstract

A dressing for debridement of necrotic and non-viable tissue in a wound, wherein the dressing comprises an effective amount of one or more proteolytic enzymes incorporated in a degradable polymeric material. The dressing of the invention provides effective debridement of necrotic wounds over a prolonged period of time, as the enzymes may be released over time. As the enzymes are incorporated in the polymeric material, a high stability is achieved.

Assignee: Coloplast A/S (Humlebaek, DK)

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April 29, 2008

Wit 3.0, a novel gene to control soft tissue wound healing

Abstract

The present invention provides a method of treatment to improve wound healing and to minimize/prevent abnormal scarring caused by tissue contraction and fibrosis formation by providing a specific gene, Wit 3.0 alpha and beta sequences that is differentially expressed in wounded oral mucosa cells, relative to their decreased expression in non-wounded oral mucosa cells. One aspect of the invention is a method to treat soft tissue wound using anti-sense nucleic acid technologies. Another aspect of the present invention is a method to treat soft tissue wound using sense nucleic acid technologies. These methods can employ a complimentary nucleic acid sequence that is greater than 85% identity to Wit 3.0 alpha and/or beta sequences or greater than 90% identity to the deduced amino acids thereof.

Assignee: The Regents of the University of California (Oakland, CA)

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April 22, 2008

Pain-sensitive therapeutic wound dressings

Abstract

The invention provides a wound dressing comprising a therapeutic agent and a matrix comprising polymers joined by cross-linkages which cross-linkages comprise oligopeptidic sequences which are cleavable by a kallikrein associated with wound fluid such that the rate of release of the therapeutic agent increases in the presence of elevated kallikrein levels.

Assignee: Ethicon Inc. (Somerville, NJ)

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April 1, 2008

Polyester/cyanoacrylate tissue adhesive compositions

Abstract

This invention addresses absorbable cyanoacrylate-based tissue adhesive compositions based primarily on an alkoxy cyanoacrylate combined with one or more alkyl cyanoacrylate(s), a stabilizer against premature anionic polymerization, and/or an absorbable polymeric modifier with improved, and preferably, functional properties for use, primarily, for internal wound repair applications.

Assignee: Poly-Med Inc. (Anderson, SC)

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February 19, 2008

Methods of treating wounds using IL-23

Abstract

Provided are methods of treatment for skin disorders. In particular, treatment, the skin disorders are generally inflammatory skin disorders, including improper wound healing. Provided are methods of using of a cytokine molecule.

Assignee: Schering Corporation (Kenilworth, NJ)

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January 29, 2008

Method and apparatus for vascular and visceral clipping

Abstract

Devices and methods for achieving hemostasis and leakage control in hollow body vessels such as the small and large intestines, arteries and veins as well as ducts leading to the gall bladder and other organs. The devices and methods disclosed herein are especially useful in the emergency, trauma surgery or military setting, and most especially during damage control procedures. In such cases, the patient may have received trauma to the abdomen, extremities, neck or thoracic region. The devices utilize removable or permanently implanted, broad, soft, parallel jaw clips with minimal projections to maintain vessel contents without damage to the tissue comprising the vessel. These clips are applied using either standard instruments or custom devices that are subsequently removed leaving the clips implanted, on a temporary or permanent basis, to provide for hemostasis or leakage prevention, or both. These clips overcome the limitations of clips and sutures that are currently used for the same purposes. The clips come in a variety of shapes and sizes. The clips may be placed and removed by open surgery or laparoscopic access.

Assignee: Damage Control Surgical Technologies Inc. (Laguna Beach, CA)

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January 22, 2008

Methods and compositions for the enhancement of wound healing

Abstract

The present invention relates to methods and compositions for wound healing, and in particular, methods and compositions to promote and enhance wound healing. In particular, the present invention provides MMP derived peptides for use in enhancing wound healing.

Assignee: The Regents of the University of Michigan (Ann Arbor, MI)

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December 25, 2007

Protein compositions for promoting wound healing and skin regeneration

Abstract

Methods for stimulating proliferation and inhibiting death of cells in the epidermis and dermis of wounded and non-wounded as well as transplanted mammalian skin and transplanted skin cell suspensions are described. The methods include the steps of administering to an area of wounded or non-wounded skin therapeutically effective amounts of .alpha..sub.1-antitrypsin, alkaline phosphatase (such as placental alkaline phosphatase), transferrin, and .alpha..sub.1-acid glycoprotein in compositions that contain at least two of these proteins, or their active derivatives, as the major active components. The compositions can be administered topically and/or by injection, or both. The invention also provides regimens for restoring or maintaining the strength and thickness of wounded, non-wounded and transplanted skin as well as developing new skin from skin cell suspensions comprising periodically administering one or more compositions topically and/or by injection.

Assignee: Essential Skincare, LLC (Austin, MN)

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December 4, 2007

Elastomeric functional biodegradable copolyester amides and copolyester urethanes

Abstract

The present invention provides elastomeric copolyester amides, elastomeric copolyester urethanes, and methods for making the same. The polymers that are based on .alpha.-amino acids and possess suitable physical, chemical and biodegradation properties. The polymers are useful as carriers of drugs or other bioactive substances. The polymers can be linked, intermixed, or a combination thereof, to one or more drugs.

Assignee: Cornell Research Foundation Inc. (Ithaca, NY)

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United States Patent 7, 297,344

November 20, 2007

Preparations for the promotion of wound healing in the upper respiratory tract and/or ear

Abstract

Use of anti-inflammatory agents such as povidone iodine for the preparation of a pharmaceutical composition for the treatment of diseases of the upper respiratory tract and/or the ear which are susceptible to the administration of such agents.

Assignee: Euro-Celtique, S.A. (Luxembourg, LU)

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November 6, 2007

Beta.-Secretase variant

Abstract

The invention provides polynucleotides and polypeptides encoding an isolated amyloid inhibitor protein (APIP) and compositions thereof. The polypeptides of the subject invention can be used to inhibit the catabolism or sequential cleavage of amyloid beta precursor protein (APP) by sequential cleavage of APP by beta secretase and gamma secretase.

Assignee: Serono Genetics Institute S.A. (Evry, FR)

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Key Patents in Rest of the World

Canada: CIPO -

Abstract:

This invention pertains to therapeutic wound healing compositions for protecting

and resuscitating mammalian cells (Embodiment One(I)). This invention also pertains to therapeutic antiviral-wound healing co mpositions for reducing viral titers and increasing the proliferation and resuscitation rate of mammalian cells (Embodiment Two (II)). I n a first aspect of Embodiment One (I.A), the therapeutic wound healing composition comprises (a) pyruvate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids. In a second aspect of Embodiment One (I.B), the therapeutic wound healing composition comprises (a) pyruvate, (b) lactate, and (c) a mixture of saturated and unsaturated fatty acids. In a third aspect of Embodiment One (I.C ), the therapeutic wound healing composition comprises (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids. In a

fourth aspect of Embodiment One (I.D), the therapeutic wound healing composition comprises (a) lactate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids. In Embodiment Two (II), the therapeutic wound healing compositions of Embodiment One (I.A-D) a re combined with a therapeutically effective amount of an antiviral agent (V) to form antiviral-wound healing compositions (II.A-D + V) . This invention also pertains to methods for preparing and using the antiviral-wound healing compositions and the topical and ingestible ph armaceutical products in which the therapeutic compositions may be used.

CLAIMS Show all claims

*** Note: Data on abstracts and claims is shown in the official language in which it was submitted.

--------------------------------------------------------------------------------

(72) Inventors: (Country) MARTIN, ALAIN (United States)

(73) Owners: (Country) WARNER-LAMBERT COMPANY (United States)

(74) Agent: MACRAE & CO.

(45) Issued:



(86) PCT Filing Date: 1995-04-05

(87) PCT Publication Date: 1995-10-19

(51) International Class (IPC): A61K 38/21 (2006.01)

Patent Cooperation Treaty (PCT): Yes

(86) PCT Filing Number: PCT/US1995/004201

(87) International publication number: WO2006/027501

(85) National Entry: 1996-08-30

-------------------------------------------------------------------------------------------------------------------------------

Europe-

Publication Number: EP1874376

Publication Date: 2008-01-09

Wound Treatment Apparatus and Methods

Applicant: SMITH & NEPHEW [GB]

Brief Description: The present invention relates to apparatus and a medical wound dressing for aspirating, irrigating and/or cleansing wounds, and a method for treating wounds using such apparatus for aspirating, irrigating, and/or cleansing wounds.

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External Agent for treating wound

Applicant: MIE UNIVERSITY [JP]; MARUISHI PHARMA [JP]



Brief Description: The objective is to provide a new low-toxic drug for external use for intractable diseases, such as erosion, decubitus, and skin ulcer that prevents iodine accumulation on wound surfaces with sufficient promotion of healing.

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Biomaterial for suture

Applicant: CELLERIX S L [ES]; UNIV MADRID AUTONOMA [ES]

Brief Description: This invention refers to a biomaterial for suturing and its applications. More specifically, the present invention relates to a biomaterial for suturing coated with cells that allows accelerating the repair process, contributing in a biologically active manner to tissue healing.

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Use of Plasmonigen for Wound Healing

Applicant: OMNIO AB [SE]

Brief Description: The present invention relates to the use of plasminogen and plasmin as agents for enhancing healing of tympanic membrane perforations or other wounds, and for reducing scars or necrotic tissue forming during wound healing.

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A wound care device comprising a nitric oxide eluting polymer

Applicant: NOLABS AB [SE]

Brief Description: A device, and a manufacturing process of said device, is provided that allows for treatment of wounds. The device comprises a nitric oxide eluting polymer arranged to contact the wound area to be treated, such that a therapeutic dose of nitric oxide is eluted from said nitric oxide eluting polymer to said wound area, thus promoting healing of a wound at said wound area.

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Material promoting wound healing

Applicant: ASAHI KASEI MEDICAL CO LTD [JP]

Brief Description: The objective of the present invention is to provide a means for utilizing cells that have effects on wound healing as wound healing promoting materials by efficiently concentrating such cells within a short period of time.

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Key Contac t s and Glossa ry

Key Contacts

Companies

Sameer Shums, Project Director, BioCure Inc., 2975 Gateway Dr. Suite 100 Norcross Georgia 30071-1111. Phone: 001-678-966-3422. Fax: 001-770-416-4331. E-mail: [email protected]. URL: www.biocure.com.

Kevin Douglas, Chief Financial Officer, Greystone Pharmaceuticals Inc., 16261 Bass Road, Suite 202 Fort Myers, Florida 33908, USA. Phone: 001-239-432-2780. Fax: 001-239-432-2782. E-mail: [email protected]. URL: www.greystonepharmaceuticals.com.

Ronen Avidar, Vice President--Sales and Marketing, Life-Wave Hi-Tech Medical Devices Ltd., 1 Azrieli Center Round Tower, 41th Floor, Tel Aviv 67021. Phone: 00972-3-609-5630. Fax: 00972-3-609-5640. E-mail: [email protected]. URL: www.life-wave.com.

Glenn Carlson, Product Manager, Arobella Medical LLC, 5929 Baker Road, Suite 470, Minnetonka, Minnesota 55345. Phone: 952-345-6840. Fax: 952-345-6841. E-mail: [email protected]. URL: www.arobella.com.

Harm Jaap Smit, The Medical Company BV, Postbus 2116 3800 CC Amersfoort, Phone: 0031-33-465-0113. Fax: 0031-33-465-2191. E-mail: [email protected]. URL: www.thewoundcarecompany.co.uk.

Dr. Alistair Irvine, Director of Business Development, Kuros Biosurgery AG, Technoparkstrasse1, CH-8005 Zurich, Switzerland, Phone: 0041-44-2005600, Fax: 0041-44-2005700. E-mail: [email protected]. URL: www.kuros.ch.

Spencer.F.Robert CEO, FirstString Research Inc., SCRA Trident Research Center 5300 International Blvd. Building, C.Suite 201, N.Charleston SC 29418, Phone: 001-843-860-8372. E-mail: [email protected]. URL: www.firststringresearch.com.

Julie Meldrum, Corporate Communications Director, Mesoblast Limited, Level 39, 55 Collins Street, Melbourne, Victoria, 3000 Australia. Phone: 0061-039639-6036. Fax: 0061-0419-228-128. E-mail: [email protected]. URL: www. mesoblast.com.

Stefan Kaelin, Managing Director, Organogenesis Switzerland GmbH Baarerstrasse2, CH-6304 Zug Switzerland, Phone: 0041-41-727-6789. E-mail: [email protected]. URL: www.organogenesis.com.



J.J.Finkelstein, President and CEO, RegeneRx Biopharmaceuticals Inc., 3 Bethedsa Metro Center, Suite 630, Bethedsa, MD 20814. Phone: 001-301-280-1992. E-mail: [email protected]. URL: www.regenerx.com.

Dr. Arthur De Carlo, President and Science Director, Agenta Biotechnologies Inc., Innovation Depot, 1500 1st Ave., N. Suite L105, Birmingham, AL 35211. Phone: 001-205-307-6500. Fax: 001-205-307-6501. E-mail: [email protected]. URL: www.agentabio.com.

Dr. Tim Coombs, CEO, Zoobiotic Ltd., Units 2-4 Dunraven Business Park CoyChurch Road. Bridgend CF31 3AP, UK. Phone: 0044-845-2301810. Fax: 0044-1656-668047. E-mail: [email protected]. URL: www.zoobiotic.co.uk.

David H. Zakai, VP-Business Development, HealOr Ltd., Ness Ziona Science Park 14 Einstein St., POB 4115, Ness Ziona, Israel 74140, Phone: 001-845-362-0043. Fax: 001-845-503-2190. E-mail: [email protected]. URL: www.healor.com.

Jennifer, European Product Manager, CryoLife Europa Ltd., Bramley House, The Guildway, Old Portsmouth Road, Guildford, Surrey, UK. Phone: 0044-1483-441030. Fax : 0044-1483-452860. E-mail: [email protected]. URL: www.cryolife.com.

Nick Atkinson, Strategic Marketing Manager--Acticoat Division, Smith & Nephew, 6685, Millcreek Drive, Unit 5 Mississauga, Ontario, Canada. Phone: 001-800-387-5263. E-mail: [email protected]. URL: www.smith-nephew.com.

Mark Dauwe, Director Medical Affairs, Kingfisher Healthcare, Interleuvenlaan 62, 3001 Leuven, Belgium. Phone: 0032-1639-7834. Fax: 0032-1639-7841. E-mail: [email protected]. URL: www.kfhealth.com.

Kate Crow, Operations Director, Biofisica (UK) Ltd., Old Bank House, 59 High Street Odiham Hampshire, RG29 1LF, UK. Phone: 0044-1256-704555. Fax: 0044-1256-701930. E-mail: [email protected]. URL: www.biofisica.com.

Mark Nixon, Chief Medical Officer, ARANZ Medical Limited, 47, Hereford Street, Christchurch 8013, New Zealand. Phone : 0064-3-374-6120. Fax : 0064-3-374-6130. E-mail: [email protected]. URL: www.aranzmedical.com.



Universities

John Foster, Professor, BioPolymers Research Group, School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW2052, Australia. Phone: 0061-2-9385-2054. Fax: 0061-2-9385-1483. E-mail: [email protected]. URL: www.unsw.edu.au.

Dr. David Hom, Director, Division of Facial Plastic and Reconstructive Surgery, University of Cincinnati, 231 Albert Sabin Way, Cincinnati Ohio 45267, USA. Phone: 001-513-475-8400. Fax: 001-513-475-8228. E-mail: [email protected]. URL: www.ent.uc.edu.

Samuel I .Stupp, Board of Trustees, Professor of Materials Science and Engineering, Chemistry and Medicine, Director of the Institute for BioNanoTechnology in Medicine, Northwestern University, 633 Clark Street Evanston, IL 60208. Phone: 001-847-491-3002. E-mail: [email protected]. URL: www.northwestern.edu.

Paul Martin, Professor, Department of Biochemistry, School of Medical Sciences, University of Bristol, University Walk Bristol BS8 1TD, UK. Phone: 0044-117-331-2298. Fax: 0044-117-331-2168. E-mail: [email protected]. URL:http://www.bristol.ac.uk/biochemistry/research/pm.html.

Daniel. J.Smith, Professor, Department of Chemistry, University of Akron, 302 Buchtel Common, Akron OH 44325 USA. Phone: 001-330-972-7414. E-mail:[email protected]. URL: www.uakron.edu.

Glossary of Terms

This section highlights the essential terminology applicable to the wound healing sector for better understanding of patients as well as healthcare professionals.

Alginate--Dressing made from seaweeds comprising mainly of galuronic and mannuronic acids which can be used in determining the gel-forming properties of the final fiber. Best suited for moderate-to highly-exuding wounds.

Angiogenesis--Process of formation of capillaries by endothelial budding which occurs during the proliferative phase of healing during infiltration of blood vessels to the wound.

Autolysis--Natural, spontaneous process of separation of devitalized tissue from viable tissues. Proteolytic enzymes and macrophage activity are responsible for autolysis.

Bedsore--Term refers to ulceration of tissue lacking adequate blood supply by prolonged pressure.



Blisters--Term refers to the collective mass of fluid under the epithelial layer which can be clear, pink/red in color.

Cellulitis--Term refers to the infection of soft tissues leading to edema, redness, pain, and heat/inflammation signs.

Clean wound--A wound which is in the process of healing encompassing a bed of healthy granulation tissue devoid of surrounding cellulitis.

Collagen--Represents key components of connective tissues and constitutes the major collagen type found in mature scar tissue.

Debridement--Refers to the procedure of removing dead/unhealthy tissue from a wound.

Decubitus ulcer--Swollen sore or ulcer of the skin seen over a bony part of the body which results from a prolonged pressure on that part.

Delayed Primary Closure--Process of treating the wound with dressing changes primarily and after a time span of 48 hours suturing the wound closed when swelling has reduced and in the absence of infections.

Dirty Wound--Term represents a wound covered with proteinaceous debris in the absence of surrounding cellulitis.

Epithelialization--When epidermal cells migrate across the wound surface from the wound margins and the remaining hair follicles, it symbolizes the final stage of wound healing which is referred to as epithelialization. The color of the cells are pink/white at the wound edges.

Erythema--Redness of the skin caused by capillaries congestion in lower layer of the skin, often caused by injury, infection or inflammation.

Exudate--Open wound surface possesses tan/grayish proteinaceous material which is often referred to as exudate. The presence of exudate on a wound surface does not imply infection of the wound.

Fibrin--Forms an essential component for blood clotting whose monomers are derived from an inactive precursor called the fibrinogen.

Flap--Tissue material with blood supply which can be moved to cover the wound is termed as flap. Free, distant, and local are the three types of flaps.



Foam--Name given to a dressing designed from polyurethane which is nonadherent and can absorb large amounts of exudates in addition to being utilized as secondary dressings. This foam dressing is available impregnated with charcoal along with a waterproof backing.

Granulation tissue--Name given to the red, shiny tissue which forms at the base of an open wound during the wound healing process. Granulation tissue includes inflammatory cells necessary for wound healing along with bacteria. Vascular nature and easily bleeding nature of the granulation tissue causes a healing wound to bleed with dressing changes or minor trauma.

Hydrocolloid--Refers to a waterproof, occlusive dressing which consists of a mixture of pectins, gelatins, sodium carboxymethylcellulose, and finally elastomers. This dressing ensures an environment which promotes autolysis to debride wounds which are sloughy or necrotic.

Hydrofiber--Wound dressing which is highly absorbent made up of complete hydrocolloid. Here, the hydrocolloid is spun into fibers and needled to create a soft, nonwoven, fleece-like dressing in the form of sheet or ribbon. Hydrofiber appears to be an alternative to alginate dressing.

Hydrogel--Dressings in the form of sheet or gel which are used for shallow or low-exuding wounds. This hydrogel is ideal for cavities and are effective for desloughing and debriding wounds.

Larval Therapy--One of the effective approaches to wound debridement and removal of bacteria. Here, sterile maggots which liquefy dead tissue using enzymes are utilized in wound treatment.

Maceration--Process of softening of tissues due to retention of excessive moisture which presents as moist, red/wrinkled in appearance.

Macrophages--These are recruited to the wound area in the form of monocytes as a result of chemotactic stimuli and tissue differentiation. Macrophages also play an important role in bacterial phagocytosis and stimulation of other wound healing processes.

Necrosis--Death of tissues appearing as black/brown in color and having a leathery texture. Dead tissue is called as necrotic tissue.

Overgranulation--Granulation tissue which grows above the level of the surrounding skin, thus preventing epithelial cells from growing around the wound.

Primary Closure--Closure of wounds by suturing the edges of wound together.

Secondary Closure--Wound healing following dressing changes alone.



Slough--Term applied to the viscous yellow layer covering the wounds which is strongly adherent to it. The presence of slough can be linked to end of the inflammatory stage of healing on accumulation of dead cells in the exudate.

Tangential excision--Technique exploited for excising burned tissues which leaves the uninjured deeper tissues intact. This technique is performed in an operating room under general anesthesia.

Venous Stasis Ulcer--Indication where local loss of epidermis and variable levels of dermis along with subcutaneous tissue occurs. This disorder is characterized by slow/halted normal flow of blood through a vein.


Decision Support Database

Database Tab les

Diabetes Incidence--World (2002 to 2012)

Frost & Sullivan's decision support database services provide the historic and forecast data for demographic figures in a tabular form.

Table 7-1 gives diabetic prevalence and mortality figures, by region, for the period 2002 to 2012.

Table Diabetes Incidence ('000)

Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CAGR %

(2005 - 2012)

North America

Canada 66.6 68.0 69.4 70.9 74.0 77.3 80.9 84.6 88.5 92.7 97.2 4.62 United States 1,304.0 1,349.0 1,356.0 1,431.3 1,511.1 1,595.9 1,686.1 1,782.2 1,884.8 1,994.3 2,111.4 5.71 TOTAL 1,371 1,417 1,425 1,502 1,585 1,673 1,767 1,867 1,973 2,087 2,209 5.66 Latin America

Argentina 36.3 37.1 38.0 38.9 39.9 41.0 42.0 43.1 44.2 45.4 46.6 2.62 Brazil 242.5 251.9 261.7 272.0 282.7 293.8 305.5 317.7 330.5 343.9 357.9 4.01 Chile 25.9 27.1 28.5 29.8 31.3 32.8 34.4 36.1 37.9 39.8 41.8 4.94 Mexico 222.1 232.3 243.1 254.4 266.3 278.7 291.9 305.7 320.3 335.7 351.9 4.76 Peru 37.9 39.9 42.0 44.3 46.6 49.1 51.8 54.6 57.5 60.7 64.0 5.43 Venezuela 38.1 40.1 42.1 44.3 46.5 48.9 51.4 54.1 56.9 59.9 63.0 5.20 TOTAL 603 628 655 684 713 744 777 811 847 885 925 4.43 Asia - Pacific Australia 68.9 74.0 79.5 85.4 91.7 98.5 105.9 113.9 122.5 131.8 141.8 7.54 China 1,135.8 1,194.9 1,257.2 1,323.2 1,393.2 1,467.3 1,546.0 1,629.5 1,718.2 1,812.5 1,913.0 5.43 Hong Kong 14.9 15.5 16.1 16.7 17.4 18.1 18.8 19.6 20.4 21.3 22.1 4.11 India 1,301.0 1,354.8 1,411.2 1,470.3 1,532.4 1,597.5 1,666.1 1,738.2 1,814.4 1,894.9 1,980.2 4.37 Indonesia 97.0 101.1 105.4 109.9 114.6 119.5 124.7 130.1 135.8 141.7 148.0 4.36 Japan 154.6 159.0 163.6 168.3 173.2 178.3 183.6 189.0 194.7 200.6 206.7 2.99 Malaysia 69.0 73.3 77.8 82.7 88.0 93.5 99.5 105.9 112.7 120.1 127.9 6.44 New Zealand 4.9 5.1 5.3 5.5 5.8 6.0 6.3 6.5 6.8 7.1 7.4 4.36



Philippines 62.5 66.5 70.7 75.2 79.9 85.1 90.6 96.4 102.7 109.5 116.8 6.52 Singapore 10.8 11.2 11.6 12.1 12.5 13.0 13.5 14.0 14.6 15.1 15.7 3.89 South Korea 140.2 145.5 151.0 156.7 162.7 169.0 175.6 182.5 189.7 197.4 205.4 3.96 Taiwan 34.4 35.7 37.0 38.4 39.8 41.3 42.9 44.5 46.2 47.9 49.8 3.80 Thailand 51.7 54.8 58.1 61.5 65.2 69.1 73.2 77.6 82.3 87.3 92.7 6.04 TOTAL 3,146 3,291 3,444 3,606 3,776 3,956 4,146 4,348 4,561 4,787 5,028 4.89 Western Europe

Austria 17.3 17.9 18.5 19.1 19.7 20.4 21.1 21.8 22.6 23.4 24.2 3.45 Belgium 12.9 13.5 14.1 14.7 15.3 16.0 16.7 17.5 18.2 19.1 19.9 4.49 Denmark 5.3 5.4 5.6 5.7 5.8 5.9 6.0 6.2 6.3 6.4 6.6 2.13 Finland 13.1 13.2 13.5 13.9 14.3 14.8 15.2 15.7 16.1 16.6 17.2 3.04 France 146.0 151.7 157.5 163.5 169.7 176.1 182.7 189.5 196.5 203.7 211.0 3.69 Germany 202.1 203.4 207.5 211.7 216.1 220.6 225.3 230.1 235.1 240.3 245.7 2.17 Greece 6.7 6.8 6.9 7.0 7.1 7.3 7.4 7.5 7.6 7.8 7.9 1.72 Iceland 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1 4.47 Ireland 4.3 4.6 4.8 5.1 5.3 5.6 5.9 6.3 6.6 7.0 7.4 5.54 Italy 50.1 50.8 51.5 52.3 53.1 53.9 54.7 55.5 56.4 57.3 58.2 1.56 Luxembourg 0.4 0.4 0.4 0.4 0.4 0.4 0.5 0.5 0.5 0.5 0.5 3.22 Netherlands 16.5 17.1 17.7 18.4 19.0 19.7 20.5 21.3 22.1 22.9 23.8 3.78 Norway 5.6 5.8 6.0 6.1 6.3 6.5 6.7 6.9 7.1 7.3 7.5 2.97 Portugal 7.9 8.0 8.1 8.2 8.4 8.5 8.6 8.7 8.9 9.0 9.1 1.48 Spain 16.2 16.3 16.5 16.6 16.8 17.0 17.1 17.3 17.5 17.7 17.9 1.06 Sweden 13.3 13.7 14.1 14.6 15.0 15.5 16.0 16.5 17.0 17.6 18.1 3.19 Switzerland 13.9 14.3 14.7 15.2 15.6 16.1 16.6 17.1 17.7 18.3 18.8 3.17 United Kingdom 73.7 77.2 81.0 84.9 89.1 93.5 98.1 103.0 108.1 113.5 119.3 4.98

TOTAL 605 620 638 657 677 698 719 741 764 788 813 3.10 Eastern Europe

Czech Republic 16.7 17.3 17.9 18.6 19.3 20.0 20.7 21.5 22.3 23.1 24.0 3.72

Hungary 14.1 14.4 14.8 15.1 15.5 15.9 16.3 16.7 17.1 17.5 17.9 2.47 Poland 58.9 60.8 62.7 64.7 66.8 69.0 71.3 73.8 76.4 79.1 82.0 3.49 Russia 208.9 214.4 221.1 228.1 235.3 242.8 250.6 258.7 267.2 276.1 285.4 3.27 Turkey - - - - - - - - - - - - TOTAL 299 307 316 326 337 348 359 371 383 396 409 3.30 Middle East & Africa

Egypt 110.5 114.5 118.7 123.1 127.6 132.3 137.3 142.4 147.8 153.4 159.3 3.77 Israel 8.7 9.0 9.2 9.5 9.8 10.1 10.4 10.7 11.0 11.4 11.7 3.06 Saudi Arabia - - - - - - - - - - - - South Africa 40.2 41.6 43.0 44.5 46.1 47.8 49.5 51.3 53.1 55.1 57.1 3.62 TOTAL 159 165 171 177 184 190 197 204 212 220 228 3.69 WORLD TOTAL 6,182 6,429 6,651 6,953 7,272 7,609 7,966 8,342 8,741 9,163 9,612 4.76

Note: All figures are rounded; the base year is 2005. Source: Frost & Sullivan



Definition

The above figure represents total number of new cases of Diabetes.

Note 1. The table is derived using diabetes prevalence and mortality figures



Diabetic Foot Ulcer Prevalence--World (2002 to 2012)


Table 7-2 indicates lower leg and foot ulcer prevalence, by region, for the period 2002 to 2012.

Table Diabetes Foot Ulcer Prevalence ('000)

Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CAGR % (2005 - 2012)

North America

Canada 106.2 107.6 109.1 110.7 112.3 113.9 115.7 117.5 119.4 121.3 123.4 1.57 United States 1,600.8 1,624.5 1,649.2 1,675.0 1,701.9 1,730.8 1,761.0 1,792.6 1,825.6 1,860.2 1,896.6 1.79 TOTAL 1,707.0 1,732.1 1,758.3 1,785.7 1,814.2 1,844.7 1,876.6 1,910.0 1,945.0 1,981.6 2,019.9 1.78

Latin America

Argentina - - - - - - - - - - - - Brazil - - - - - - - - - - - - Chile - - - - - - - - - - - - Mexico - - - - - - - - - - - - Peru - - - - - - - - - - - - Venezuela - - - - - - - - - - - - TOTAL 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 -

Asia - Pacific

Australia 52.1 53.0 53.9 54.8 55.7 56.7 57.7 58.8 59.9 61.0 62.2 1.84 China 18,961.3 19,566.2 20,192.7 20,842.9 21,518.2 22,220.3 22,950.0 23,707.9 24,497.3 25,320.9 26,180.1 3.32 Hong Kong 21.2 21.8 22.4 23.1 23.8 24.5 25.2 26.0 26.8 27.6 28.5 3.05 India 5,138.3 5,291.9 5,451.8 5,617.6 5,789.6 5,968.5 6,155.0 6,349.3 6,551.6 6,762.2 6,982.2 3.17 Indonesia 142.2 146.6 151.2 155.9 160.8 165.9 171.2 176.6 182.4 188.3 194.6 3.23 Japan 503.9 506.0 508.3 510.7 513.4 516.1 519.1 522.2 525.5 529.0 532.8 0.62 Malaysia 64.3 66.9 69.6 72.4 75.4 78.5 81.8 85.3 89.0 92.9 96.9 4.28 New Zealand 5.8 5.9 6.1 6.3 6.5 6.7 6.9 7.1 7.3 7.6 7.8 3.18 Philippines 46.5 48.7 51.1 53.6 56.2 59.0 61.9 65.0 68.3 71.7 75.4 5.01 Singapore 32.0 33.0 34.0 35.1 36.3 37.5 38.7 40.0 41.3 42.7 44.2 3.36 South Korea 241.1 247.7 254.5 261.7 269.1 276.8 284.8 293.2 301.8 310.8 320.2 2.94 Taiwan 34.4 35.4 36.4 37.5 38.6 39.8 41.0 42.2 43.6 44.9 46.4 3.10 Thailand 39.4 41.2 43.0 44.9 46.9 49.0 51.2 53.5 56.0 58.6 61.3 4.56 TOTAL 25,282.4 26,064.2 26,874.9 27,716.4 28,590.3 29,499.2 30,444.5 31,427.0 32,450.6 33,518.3 34,632.5 3.25

Western Europe

Austria 21.8 21.9 22.1 22.3 22.5 22.7 22.9 23.1 23.4 23.6 23.9 1.01 Belgium 27.0 27.2 27.5 27.7 27.9 28.2 28.5 28.8 29.1 29.4 29.8 1.06 Denmark 10.2 10.3 10.4 10.5 10.6 10.7 10.8 10.9 11.0 11.1 11.3 1.08



Finland 22.2 22.5 22.8 23.1 23.4 23.8 24.2 24.5 24.9 25.3 25.7 1.58 France - - - - - - - - - - - - Germany 225.5 226.3 227.2 228.2 229.3 230.4 231.6 232.9 234.3 235.7 237.3 0.57 Greece 49.1 49.4 49.6 49.9 50.2 50.5 50.8 51.1 51.5 51.8 52.2 0.68 Iceland - - - - - - - - - - - - Ireland 6.8 6.9 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.8 7.9 1.65 Italy 229.3 230.0 230.7 231.5 232.3 233.3 234.3 235.4 236.7 238.0 239.4 0.50 Luxembourg 1.2 1.2 1.2 1.2 1.2 1.3 1.3 1.3 1.3 1.3 1.4 1.56 Netherlands 41.4 42.0 42.7 43.3 44.0 44.7 45.4 46.1 46.9 47.7 48.6 1.68 Norway - - - - - - - - - - - - Portugal 48.5 48.8 49.1 49.4 49.7 50.0 50.4 50.7 51.1 51.5 52.0 0.74 Spain - - - - - - - - - - - - Sweden 21.5 21.6 21.8 22.0 22.1 22.3 22.5 22.7 22.9 23.1 23.3 0.89 Switzerland - - - - - - - - - - - - United Kingdom 44.3 44.7 45.1 45.5 45.9 46.4 46.8 47.3 47.9 48.4 49.0 1.08 TOTAL 748.7 752.7 757.0 761.5 766.3 771.3 776.7 782.4 788.5 794.9 801.7 0.76

Eastern Europe

Czech Republic 40.7 40.9 41.1 41.4 41.6 41.9 42.1 42.4 42.7 43.1 43.4 0.70 Hungary 26.3 26.4 26.5 26.6 26.7 26.9 27.0 27.1 27.3 27.5 27.7 0.57 Poland 80.0 80.7 81.4 82.1 82.8 83.6 84.4 85.2 86.1 87.0 88.0 1.02 Russia - - - - - - - - - - - - Turkey - - - - - - - - - - - - TOTAL 147.1 148.0 149.0 150.1 151.2 152.3 153.5 154.8 156.1 157.6 159.1 0.85

Middle East & Africa

Egypt - - - - - - - - - - - - Israel - - - - - - - - - - - - Saudi Arabia - - - - - - - - - - - - South Africa - - - - - - - - - - - - TOTAL - - - - - - - - - - - -

WORLD TOTAL 27,885.1 28,697.0 29,539.1 30,413.6 31,321.9 32,267.5 33,251.4 34,274.3 35,340.2 36,452.3 37,613.1 3.10

Note: All figures are rounded; the base year is 2005. Source: Frost & Sullivan Definition

A diabetes foot ulcer is an open sore or wound on the foot of a person suffering from diabetes. The above figure represents total number of people suffering from diabetic foot ulcer

Note

1. Hyphen indicates non availability of data 2. Figures for 2005 are Frost & Sullivan estimates 3. Figures for China indicates Lower leg and foot ulcer prevalence



Total Healthcare Expenditure--World (2002 to 2012)


Table 7-3 gives total healthcare expenditures, by region, for the period 2002 to 2012.

Table Total Healthcare Expenditure (Bn USD)

Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CAGR %

(2005 - 2012)

North America

Canada 73.0 87.8 101.2 116.9 129.5 138.3 147.0 155.2 163.0 169.8 175.9 6.00 United States 1,559.0 1,678.9 1,804.7 1,936.6 2,077.5 2,232.9 2,399.2 2,573.3 2,753.9 2,944.2 3,146.3 7.18 TOTAL 1,632.0 1,766.6 1,905.9 2,053.5 2,207.0 2,371.2 2,546.3 2,728.6 2,916.8 3,114.0 3,322.1 7.11

Latin America

Argentina 11.5 14.7 17.3 20.9 23.3 25.7 27.8 29.9 31.8 33.7 35.5 7.85 Brazil 40.7 45.8 55.6 74.0 78.8 83.8 90.0 97.0 104.9 113.7 123.6 7.60 Chile 3.8 4.4 5.8 7.0 8.0 9.0 9.9 10.8 11.8 12.8 13.8 10.17 Mexico 59.6 58.5 62.2 72.3 78.8 84.7 91.0 97.5 104.0 110.4 116.7 7.08 Peru 2.4 2.7 3.1 3.6 3.9 4.2 4.5 4.9 5.2 5.6 5.9 7.46 Venezuela 4.7 4.7 6.2 7.2 8.2 9.3 10.5 11.8 13.4 15.3 17.7 13.82 TOTAL 122.7 130.8 150.2 185.0 200.9 216.7 233.8 251.8 271.1 291.5 313.2 7.81

Asia - Pacific

Australia 39.4 51.0 62.4 69.9 74.7 79.9 85.1 90.4 95.9 101.4 107.1 6.29 China 71.9 84.3 98.7 116.0 134.3 152.9 172.5 193.7 217.0 242.5 270.7 12.87 Hong Kong 9.4 9.5 10.0 10.9 11.9 13.0 14.1 15.5 16.9 18.5 20.3 9.25 India 27.5 36.1 41.9 48.5 54.0 59.8 66.1 72.8 80.0 87.5 95.5 10.16 Indonesia 6.4 8.0 8.8 9.3 10.6 12.0 13.5 15.3 17.3 19.6 22.2 13.15 Japan 315.4 339.5 374.9 379.7 394.0 406.6 414.7 424.9 437.0 451.7 467.5 3.02 Malaysia 3.6 4.0 4.6 5.2 5.9 6.7 7.6 8.6 9.6 10.8 11.9 12.66 New Zealand 5.1 6.7 8.5 9.4 10.4 11.4 12.3 13.1 13.8 14.4 14.9 6.77 Philippines 2.3 2.3 2.5 2.8 3.2 3.6 4.0 4.4 4.9 5.5 6.0 11.45 Singapore 3.7 4.0 4.3 4.6 5.0 5.3 5.7 6.2 6.6 7.1 7.6 7.46 South Korea 25.3 30.1 33.9 39.3 43.3 47.7 52.2 56.7 61.2 66.0 70.9 8.81 Taiwan 16.9 17.8 19.2 21.0 22.8 24.7 26.5 28.2 30.0 31.8 33.6 6.92 Thailand 7.8 8.5 9.6 10.7 11.9 13.3 14.8 16.6 18.7 21.1 23.8 12.18 TOTAL 534.6 601.6 679.2 727.3 781.9 836.8 889.1 946.3 1,008.8 1,077.7 1,152.0 6.79

Western Europe

Austria 15.3 19.2 22.1 23.1 24.0 24.8 25.7 26.5 27.2 27.9 28.5 3.04



Belgium 22.6 29.3 34.0 35.8 37.4 38.9 40.3 41.6 42.9 44.1 45.3 3.40 Denmark 15.2 19.2 22.2 23.4 24.4 25.4 26.4 27.4 28.3 29.3 30.3 3.78 Finland 9.5 11.8 13.6 14.4 15.1 16.0 16.9 17.7 18.5 19.3 20.1 4.90 France 139.0 176.8 205.6 217.9 228.6 239.0 249.3 259.1 268.4 277.8 286.6 3.99 Germany 211.1 258.9 294.6 305.9 314.9 323.7 332.6 341.2 349.3 358.1 366.6 2.62 Greece 13.0 17.2 19.6 22.3 23.9 25.4 27.0 28.6 30.2 31.8 33.4 5.99 Iceland 0.8 1.1 1.3 1.6 1.8 2.0 2.1 2.3 2.4 2.6 2.7 7.80 Ireland 9.7 12.8 15.4 16.3 17.9 19.3 20.8 22.3 23.8 25.3 26.8 7.43 Italy 99.6 122.3 139.7 143.4 149.1 154.0 159.0 163.8 168.1 172.0 175.4 2.92 Luxembourg 1.5 1.9 2.3 2.5 2.7 2.8 2.9 3.0 3.2 3.3 3.4 4.14 Netherlands 39.0 50.4 58.1 60.6 63.8 66.2 68.7 71.1 73.3 75.5 77.6 3.59 Norway 18.3 22.7 26.1 30.4 32.5 34.7 36.9 39.3 41.4 43.4 45.5 5.94 Portugal 11.3 14.3 16.5 17.3 18.2 19.1 20.0 20.9 21.9 22.8 23.8 4.60 Spain 49.7 65.0 77.1 88.4 94.4 100.2 106.1 112.1 117.6 123.2 128.1 5.45 Sweden 22.2 28.4 33.5 34.1 35.6 37.1 39.2 41.4 43.9 46.6 49.7 5.53 Switzerland 29.7 37.0 41.5 43.1 45.7 48.4 51.1 53.8 56.5 59.3 62.2 5.39 United Kingdom 121.0 141.5 170.0 180.7 191.9 203.3 214.8 227.0 238.7 250.4 262.6 5.49

TOTAL 828.6 1,029.6 1,193.2 1,261.1 1,321.7 1,380.3 1,439.8 1,499.0 1,555.5 1,612.8 1,668.5 4.08

Eastern Europe

Czech Republic 5.0 6.8 7.5 9.0 9.9 10.8 11.7 12.7 13.6 14.5 15.5 8.03

Hungary 4.9 6.9 8.6 9.6 10.8 11.8 12.9 13.9 14.9 15.9 16.8 8.23 Poland 12.5 13.6 15.2 17.9 19.7 21.2 22.9 24.7 26.5 28.2 29.8 7.59 Russia 21.3 26.2 32.6 38.2 43.7 48.8 53.9 58.7 63.4 67.9 72.2 9.51 Turkey 11.6 15.8 19.7 26.0 28.6 31.5 34.0 36.4 39.0 41.2 43.3 7.55 TOTAL 55.4 69.3 83.6 100.8 112.6 124.1 135.3 146.4 157.3 167.7 177.6 8.43


Egypt 4.0 3.5 3.7 4.4 5.5 6.5 7.5 8.5 9.7 11.0 12.4 16.03 Israel 9.0 9.7 10.4 11.0 11.8 12.5 13.2 14.2 15.3 16.5 17.8 7.05 Saudi Arabia 7.9 8.8 9.6 10.4 11.2 11.8 12.4 13.0 13.6 14.2 14.8 5.13 South Africa 9.1 13.6 20.0 19.6 20.5 21.6 22.7 23.9 25.2 26.7 28.4 5.50 TOTAL 30.0 35.5 43.6 45.4 49.0 52.4 55.8 59.6 63.7 68.3 73.4 7.11

WORLD TOTAL 3,203.3 3,633.5 4,055.6 4,373.0 4,673.2 4,981.4 5,300.0 5,631.6 5,973.3 6,331.9 6,706.8 6.30


The above figures indicate health care expenditure

Note

1. Figures for 2005 are Frost & Sullivan estimates



Per Capita Healthcare Expenditure--World (2002 to 2012)


Table 7-4 represents per capita healthcare expenditure in US dollars, which is derived using total healthcare expenditure and total population, by region, for the period 2002 to 2012.

Table Per Capita Healthcare Expenditure (USD) Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

North America Canada 2,289 2,725 3,114 3,564 3,912 4,142 4,365 4,570 4,758 4,915 5,050 United States 5,419 5,782 6,159 6,548 6,961 7,415 7,897 8,396 8,908 9,442 10,004 TOTAL 5,107 5,477 5,855 6,250 6,657 7,088 7,544 8,014 8,494 8,990 9,510 Latin America Argentina 299 379 443 528 584 636 684 727 768 807 842 Brazil 226 252 302 398 419 441 469 501 536 576 621 Chile 246 282 365 438 495 555 602 653 706 758 811 Mexico 581 564 593 681 733 779 828 876 924 971 1,015 Peru 90 99 111 129 137 147 156 165 175 185 195 Venezuela 194 189 247 283 319 355 396 440 495 557 638 TOTAL 317 334 379 461 495 528 564 601 641 682 726 Asia - Pacific Australia 2,013 2,584 3,135 3,477 3,689 3,909 4,129 4,355 4,580 4,808 5,040 China 56 65 76 89 102 116 130 145 161 179 198 Hong Kong 1,393 1,398 1,461 1,583 1,713 1,857 2,014 2,188 2,382 2,598 2,838 India 27 34 39 45 49 54 59 64 69 75 81 Indonesia 28 34 37 39 43 48 54 60 67 75 84 Japan 2,605 2,844 2,557 2,476 2,663 2,918 2,904 2,998 3,101 3,183 3,285 Malaysia 159 173 195 216 242 270 300 333 368 405 441 New Zealand 1,294 1,706 2,118 2,337 2,549 2,777 2,961 3,126 3,255 3,380 3,472 Philippines 27 27 29 32 36 40 43 47 51 56 61 Singapore 890 937 995 1,041 1,109 1,174 1,245 1,324 1,411 1,502 1,596 South Korea 527 623 699 807 887 972 1,061 1,147 1,234 1,327 1,423 Taiwan 752 785 844 918 991 1,068 1,136 1,203 1,273 1,343 1,411 Thailand 123 134 151 166 184 204 225 251 282 316 355 TOTAL 186 209 209 218 237 259 270 286 303 320 339 Western Europe Austria 1,879 2,353 2,701 2,828 2,929 3,028 3,127 3,222 3,309 3,392 3,471 Belgium 2,187 2,837 3,282 3,458 3,601 3,740 3,875 4,000 4,116 4,231 4,336 Denmark 2,838 3,560 4,098 4,302 4,473 4,642 4,818 4,980 5,134 5,304 5,466 Finland 1,827 2,277 2,610 2,749 2,895 3,052 3,216 3,368 3,511 3,665 3,814



France 2,320 2,938 3,403 3,593 3,755 3,913 4,068 4,216 4,355 4,496 4,627 Germany 2,563 3,142 3,575 3,711 3,821 3,929 4,038 4,144 4,246 4,354 4,461 Greece 1,229 1,614 1,840 2,085 2,232 2,373 2,519 2,661 2,805 2,954 3,104 Iceland 2,897 3,759 4,448 5,400 6,000 6,600 7,100 7,355 7,871 8,387 8,839 Ireland 2,508 3,265 3,882 4,042 4,397 4,703 4,998 5,305 5,593 5,886 6,184 Italy 1,720 2,108 2,406 2,468 2,565 2,648 2,734 2,819 2,893 2,964 3,025 Luxembourg 3,378 4,065 4,913 5,383 5,702 5,833 5,959 6,204 6,300 6,520 6,588 Netherlands 2,417 3,105 3,563 3,695 3,866 3,998 4,127 4,251 4,368 4,482 4,588 Norway 4,029 4,982 5,705 6,614 7,043 7,486 7,961 8,427 8,846 9,260 9,654 Portugal 1,087 1,361 1,565 1,640 1,716 1,792 1,874 1,954 2,036 2,122 2,204 Spain 1,238 1,615 1,915 2,191 2,336 2,478 2,621 2,765 2,901 3,036 3,158 Sweden 2,475 3,163 3,731 3,786 3,941 4,106 4,328 4,573 4,838 5,124 5,457 Switzerland 4,039 4,995 5,576 5,752 6,077 6,404 6,737 7,076 7,415 7,766 8,120 United Kingdom 2,019 2,354 2,820 2,989 3,166 3,345 3,525 3,714 3,895 4,075 4,262 TOTAL 2,114 2,620 3,030 3,195 3,342 3,484 3,628 3,772 3,909 4,048 4,183 Eastern Europe Czech Republic 486 663 731 879 971 1,059 1,145 1,239 1,333 1,427 1,518 Hungary 487 686 855 963 1,078 1,186 1,295 1,403 1,507 1,609 1,706 Poland 324 353 393 463 510 550 594 642 688 732 776 Russia 147 181 227 267 305 343 380 416 451 485 517 Turkey 173 233 286 374 406 442 473 502 531 557 580 TOTAL 204 255 308 371 414 456 497 537 577 615 651 Middle East & Africa

Egypt 45 47 50 59 66 73 81 88 95 103 112 Israel 1,498 1,585 1,676 1,755 1,852 1,941 2,037 2,166 2,301 2,452 2,614 Saudi Arabia 323 348 371 394 415 428 440 452 464 477 490 South Africa 204 306 449 441 465 490 517 548 581 619 663 TOTAL 202 237 286 295 311 327 343 361 380 401 424 WORLD TOTAL 720 811 881 939 998 1,059 1,116 1,177 1,238 1,302 1,367

Definition

The above figures represent per capita Healthcare Expenditure in US Dollars. Per Capita Healthcare expenditure is derived using Total Healthcare Expenditure and Total Population.

Note 1. Regional and World total are calculated using weighted average of countries in the region and are not the simple average 2. Figures for 2005 are Frost & Sullivan estimates



Number of Dermatologists--World (2002 to 2012)


Table 7-5 represents the registered members of dermatological/ skin associations of respective countries, by region, for the period 2002 to 2012.

Table Number of Dermatologists

Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CAGR % (2005 - 2012)

North America Canada 505 511 517 523 529 535 540 546 552 557 563 1.06 United States 8,300 8,410 8,529 8,659 8,801 8,956 9,125 9,308 9,496 9,712 9,944 2.00 TOTAL 8,805 8,921 9,046 9,182 9,330 9,491 9,665 9,854 10,048 10,269 10,507 1.94 Latin America Argentina 1,032 1,051 1,074 1,100 1,129 1,161 1,197 1,236 1,277 1,320 1,365 3.21 Brazil 4,414 4,474 4,535 4,600 4,669 4,742 4,820 4,903 4,991 5,084 5,183 1.76 Chile 192 195 198 202 206 210 214 218 223 228 233 2.07 Mexico 2,849 2,910 2,973 3,038 3,105 3,174 3,245 3,318 3,393 3,471 3,552 2.27 Peru 220 224 228 233 238 243 248 254 260 266 272 2.25 Venezuela 1,156 1,174 1,192 1,211 1,232 1,255 1,280 1,306 1,333 1,361 1,390 2.03 TOTAL 9,863 10,028 10,200 10,384 10,579 10,785 11,004 11,235 11,477 11,730 11,995 2.12 Asia - Pacific Australia 256 258 260 262 264 266 269 272 275 278 281 1.05 China 164 168 173 178 183 188 194 200 206 212 218 2.96 Hong Kong - - - - - - - - - - - - India 3,392 3,593 3,800 4,013 4,232 4,458 4,691 4,931 5,178 5,432 5,694 5.07 Indonesia 239 244 249 254 260 266 272 278 284 291 298 2.30 Japan 9,543 9,690 9,840 9,994 10,152 10,315 10,483 10,656 10,834 11,017 11,206 1.66 Malaysia 64 66 68 70 72 74 76 78 80 82 84 2.60 New Zealand 42 43 43 44 45 46 47 48 49 51 53 2.76 Philippines 323 329 336 343 351 359 367 375 383 392 401 2.24 Singapore 49 51 53 55 57 59 62 65 68 71 74 4.45 South Korea - - - - - - - - - - - - Taiwan - - - - - - - - - - - - Thailand - - - - - - - - - - - - TOTAL 14,072 14,442 14,822 15,213 15,616 16,031 16,461 16,903 17,357 17,826 18,309 2.69 Western Europe

Austria 716 723 729 735 741 747 752 757 762 767 772 0.69 Belgium 479 493 507 521 536 551 566 581 598 615 632 2.78



Denmark 207 211 215 219 224 229 234 239 244 249 254 2.12 Finland 294 302 311 320 329 339 349 359 370 381 392 2.96 France 3,394 3,446 3,500 3,556 3,613 3,672 3,733 3,797 3,863 3,932 4,004 1.73 Germany 5,000 5,010 5,021 5,034 5,049 5,067 5,088 5,112 5,140 5,172 5,208 0.52 Greece 744 820 900 982 1,066 1,152 1,241 1,333 1,429 1,529 1,633 7.37 Iceland 22 23 25 27 29 31 33 36 39 42 45 7.60 Ireland 81 86 91 96 101 106 112 118 124 130 136 5.08 Italy 2,931 2,965 3,000 3,037 3,079 3,123 3,169 3,218 3,270 3,325 3,384 1.59 Luxembourg 21 22 23 24 26 28 30 33 36 39 42 8.32 Netherlands 526 530 534 538 543 548 553 558 564 570 576 0.99 Norway 194 192 198 201 205 209 213 216 219 222 224 1.49 Portugal 218 222 226 231 236 241 246 251 256 262 268 2.14 Spain 1,915 1,957 2,000 2,044 2,088 2,132 2,177 2,222 2,267 2,312 2,357 2.04 Sweden 360 366 373 380 387 394 402 412 422 432 444 2.32 Switzerland 385 385 410 425 440 455 470 486 502 518 535 3.31 United Kingdom 624 645 668 694 724 758 796 838 884 933 985 5.26 TOTAL 18,111 18,398 18,731 19,064 19,416 19,782 20,164 20,566 20,989 21,430 21,891 2.02 Eastern Europe Czech Republic 788 795 802 809 816 824 832 840 848 856 864 0.96 Hungary 637 645 652 659 666 672 679 685 692 698 704 0.93 Poland 311 312 313 314 315 317 319 321 323 325 328 0.68 Russia 350 351 352 353 354 355 356 358 360 362 364 0.47 Turkey 1,250 1,274 1,298 1,322 1,346 1,371 1,396 1,421 1,447 1,474 1,503 1.86 TOTAL 3,336 3,377 3,417 3,457 3,497 3,539 3,582 3,625 3,670 3,715 3,763 1.23 Middle East & Africa

Egypt 320 325 331 337 343 350 357 364 372 380 388 2.08 Israel 245 247 250 253 256 259 262 265 268 271 274 1.14 Saudi Arabia 165 171 177 184 191 199 207 215 224 233 242 4.02 South Africa 141 143 145 147 150 153 157 162 168 174 181 3.18 TOTAL 871 886 903 921 940 961 983 1,006 1,032 1,058 1,085 2.42 WORLD TOTAL 55,058 56,052 57,119 58,221 59,378 60,589 61,859 63,189 64,573 66,028 67,550 2.17


Dermatologist is a Doctor who specializes in all aspects of skin care and Medical, Surgical and Laser management of disorders of the skin and hair including skin cancer. The above figures represent the registered members of dermatological/Skin associations of respective countries

Note 1. Hyphen indicates non availability of data 2. Figures for 2005 are Frost & Sullivan estimates



Number of Physicians--World (2002 to 2012)


Table 7-6 gives total number of active physicians, by region, for the period 2002 to 2012.

Table Number of Physicians ('000)

Region / Country 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

CAGR %

(2005 - 2012)

North America

Canada 59.4 60.9 61.8 61.6 62.5 63.4 64.4 65.4 66.4 67.5 68.6 1.56 United States 853.2 871.5 886.7 902.3 918.4 934.9 952.1 969.8 988.1 1,006.5 1,024.9 1.84 TOTAL 912.6 932.4 948.5 963.9 980.9 998.3 1,016.4 1,035.1 1,054.5 1,074.0 1,093.5 1.82

Latin America

Argentina 119.9 122.8 125.7 128.6 131.5 134.5 137.5 140.5 143.5 146.5 149.5 2.16 Brazil 371.5 376.9 382.6 388.3 394.3 400.4 406.7 413.2 419.9 426.8 433.9 1.61 Chile 16.7 17.1 17.3 17.4 17.6 17.8 18.0 18.2 18.5 18.7 18.9 1.21 Mexico 138.4 141.4 144.5 147.6 150.9 154.1 157.5 161.0 164.5 168.2 171.9 2.20 Peru 32.6 33.2 33.8 34.4 35.0 35.7 36.4 37.1 37.9 38.7 39.6 2.05 Venezuela 47.1 47.8 48.5 49.3 50.1 50.9 51.8 52.7 53.6 54.6 55.6 1.74 TOTAL 726.2 739.2 752.3 765.7 779.4 793.5 807.9 822.6 837.8 853.4 869.4 1.84

Asia - Pacific

Australia 55.2 55.4 55.6 55.8 55.9 56.1 56.3 56.6 56.8 57.0 57.3 0.40 China 2,097.8 2,110.3 2,123.2 2,136.1 2,149.8 2,163.8 2,178.0 2,192.4 2,207.1 2,222.1 2,237.4 0.67 Hong Kong 9.7 9.9 10.2 10.4 10.7 11.0 11.3 11.6 11.9 12.2 12.5 2.68 India 599.9 612.2 625.1 638.5 652.5 667.0 682.1 697.8 714.1 731.2 748.9 2.32 Indonesia 37.0 37.6 38.2 38.8 39.4 40.1 40.8 41.6 42.4 43.2 44.0 1.85 Japan 262.7 266.5 270.4 274.4 278.5 282.7 287.1 291.5 296.0 300.7 305.5 1.55 Malaysia 16.7 17.2 17.7 18.2 18.8 19.3 19.9 20.4 21.0 21.6 22.2 2.85 New Zealand 5.6 5.9 6.0 6.1 6.2 6.3 6.4 6.6 6.7 6.8 6.9 1.90 Philippines 99.5 101.7 103.9 106.1 108.3 110.5 112.7 114.9 117.1 119.3 121.6 1.96 Singapore 6.0 6.3 6.5 6.7 6.9 7.0 7.2 7.4 7.6 7.8 8.0 2.56 South Korea 76.9 79.2 81.5 83.8 86.3 88.7 91.2 93.7 96.3 98.9 101.6 2.77 Taiwan 31.5 32.5 33.5 34.5 35.5 36.5 37.6 38.7 39.8 40.9 42.0 2.86 Thailand 26.6 27.6 28.7 29.7 30.7 31.8 32.9 34.0 35.1 36.2 37.4 3.33 TOTAL 3,325.1 3,362.2 3,400.3 3,439.0 3,479.4 3,520.8 3,563.3 3,607.0 3,651.8 3,697.9 3,745.3 1.24

Western Europe

Austria 26.7 27.4 28.1 28.9 29.7 30.5 31.3 32.2 33.1 34.1 35.1 2.82 Belgium 46.3 47.3 48.4 49.5 50.7 51.9 53.2 54.5 55.8 57.2 58.7 2.47 Denmark 15.7 15.9 16.1 16.3 16.5 16.7 17.0 17.2 17.4 17.6 17.7 1.20



Finland 16.5 16.6 16.8 17.0 17.2 17.4 17.6 17.9 18.1 18.3 18.6 1.25 France 198.7 201.4 204.1 206.9 209.7 212.6 215.5 218.5 221.5 224.5 227.6 1.37 Germany 275.2 277.9 280.6 283.4 286.3 289.2 292.1 295.1 298.1 301.1 304.2 1.02 Greece 48.6 49.3 50.1 50.8 51.5 52.3 53.0 53.8 54.6 55.4 56.2 1.47 Iceland 1.0 1.1 1.1 1.1 1.1 1.1 1.2 1.2 1.2 1.2 1.2 2.02 Ireland 9.4 10.3 10.6 10.9 11.3 11.6 12.0 12.4 12.8 13.2 13.6 3.22 Italy 353.5 358.3 363.2 368.1 373.1 378.1 383.2 388.3 393.5 398.7 404.0 1.34 Luxembourg 1.2 1.2 1.2 1.3 1.3 1.4 1.4 1.5 1.5 1.6 1.6 3.26 Netherlands 50.9 52.2 53.5 54.9 56.3 57.7 59.1 60.6 62.1 63.5 65.0 2.44 Norway 13.7 14.2 14.5 14.7 15.0 15.2 15.5 15.7 16.0 16.3 16.5 1.67 Portugal 33.8 34.3 34.8 35.4 35.9 36.5 37.1 37.7 38.3 38.9 39.6 1.61 Spain 120.2 122.7 125.3 127.9 130.5 133.2 136.0 138.8 141.6 144.6 147.6 2.07 Sweden 29.1 29.8 30.4 31.1 31.7 32.4 33.1 33.8 34.4 35.1 35.8 2.03 Switzerland 25.9 26.5 27.0 27.6 28.1 28.7 29.3 29.9 30.5 31.1 31.8 2.03 United Kingdom 126.1 129.8 133.5 137.3 141.2 145.2 149.2 153.3 157.4 161.6 165.9 2.72

TOTAL 1,392.4 1,416.1 1,439.4 1,463.1 1,487.2 1,511.7 1,536.7 1,562.0 1,587.8 1,613.9 1,640.6 1.65

Eastern Europe

Czech Republic 35.8 36.0 36.2 36.5 36.8 37.1 37.4 37.7 38.0 38.4 38.8 0.90 Hungary 32.5 32.9 33.2 33.4 33.7 34.1 34.4 34.7 35.1 35.4 35.8 1.00 Poland 88.1 88.6 89.0 89.5 89.9 90.4 90.8 91.2 91.6 92.0 92.4 0.45 Russia 608.6 609.0 610.4 611.9 613.5 615.2 617.1 619.2 621.5 624.0 626.8 0.36 Turkey 95.2 96.2 97.3 98.4 99.5 100.7 101.9 103.1 104.4 105.7 107.1 1.23 TOTAL 860.1 862.7 866.1 869.7 873.4 877.4 881.5 885.9 890.6 895.6 900.9 0.52


Egypt 54.6 56.4 58.2 60.1 62.0 64.0 66.0 68.1 70.3 72.6 74.9 3.21 Israel 24.4 25.1 25.7 26.5 27.2 28.0 28.8 29.6 30.5 31.5 32.4 2.97 Saudi Arabia 32.5 33.1 33.6 34.2 34.8 35.4 36.0 36.7 37.4 38.1 38.9 1.87 South Africa 29.4 29.4 29.5 30.1 30.8 31.4 32.1 32.9 33.6 34.4 35.2 2.27 TOTAL 140.9 143.9 147.0 150.8 154.7 158.8 163.0 167.3 171.9 176.5 181.4 2.69

WORLD TOTAL 7,357.2 7,456.4 7,553.5 7,652.1 7,754.9 7,860.4 7,968.8 8,080.0 8,194.4 8,311.4 8,431.1 1.40


The above figures represent total number of active Physicians.

Note

1. Figures for 2005 are Frost & Sullivan estimates 2. Figures for Australia indicates General Physicians headcount, Full time equivalent physicians and Full time workload equivalent physicians 3. Figures for New Zealand indicates number of active general practitioners and active specialists 4. Figures for Thailand indicates number of registered doctors to Ministry of health

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