Proposal Form STRATEGIC INDO-SWEDISH COOPERATIVE PROGRAMME ON “HEALTH AND DISEASE PREVENTION” A. PROJECT 1. Title of Project New strategies to heal infected wounds. 2. Specific research field Field Sub-field Medical Device Treatment to improve health of patients affected by wounds ※ please be sure to be specific. 3. Project Duration 01/05/2017 ～ 30/04/2021 (dd/mm/yyyy)(Years & Months) ※ Project duration should be 3 to 4 years all together.
Transcript
Proposal Form
STRATEGIC INDO-SWEDISH COOPERATIVE
PROGRAMME ON “HEALTH AND DISEASE PREVENTION”
A. PROJECT
1. Title of Project
New strategies to heal infected wounds.
2. Specific research field
Field Sub-field
Medical Device Treatment to improve health of patients affected by wounds
※ Project duration should be 3 to 4 years all together.
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4. Summary of Project
Keywords
Biomaterials Medical Device Wound care
Wound healing Wound chamber Treatment plan
Antimicrobial peptides Clinical trial Infections
Objectives
Infected wounds have devastating consequences for the individual, as well as immense financial effects on the health care system as a whole 1. Due to the shortcomings in treatment, these wounds not only undergo a prolonged, intense inflammatory reaction, but also show a progression of the depth of injury and infection until the wound is closed. Infection is an important cause of mortality in patients with wounds. For instance, it has been estimated that 75% of all deaths following thermal injuries are related to infections. In India, the healing of wounds is complicated by a high risk of infections and, in many cases, poor local hygiene. The overall objective of this study is to develop a treatment plan for infected wounds globally and in India in particular. The study will evaluate several novel treatment modalities with great potential for treating infected non-healing wounds. Briefly, the study focus on two main treatment platforms, ultrahigh concentrations of antibiotics delivered using a “wound chamber” and the wound dressing Epiprotect® with incorporated anti-microbial peptides (AMPs). The treatments will be evaluated in a clinical trial conducted in India and Sweden.
An online platform will be developed in order to facilitate the communication between the staff from Sweden and India and speed up the project. At the end of this project the most efficient strategy to treat infected wounds will be a part of a complete treatment plan. We expect a long lasting collaboration between Sweden and India in terms of knowledge-based cooperation in the form of clinical trials and technology transfer as well as general experiences in wound healing.
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Approach
Briefly, the objectives of this study will be reached by a collaboration between Sweden; 1. The Burn Unit at Linköping University Hospital, 2. Linköping University, 3. S2Medical AB and 4. The Center for Teaching and Research in Disaster Medicine and Traumatology, Linköping and India (Prof. Rajeev Ahuja, LN Hospital & MAMC in New Delhi). S2Medical AB has already been successful in introducing Epiprotect®, a wound dressing consisting of the biosynthetic cellulose based material eiratex®, in Egypt, currently available in several countries and continents. The benefits of Epiprotect® in wound treatment will be evaluated through clinical trials on Indian and Swedish patients from selected medical centers. A modification of Epiprotect® with incorporated Anti-Microbial Peptides (AMPs) developed in a collaboration with Linköping University will be tested under the same circumstances. A “Wound Chamber” capable of delivering ultrahigh concentrations of antibiotics have been developed at Brigham and Women’s Hospital and Harvard Medical School, Boston, US. The device is the first treatment system to encapsulate a wound and provide an incubator-like environment to encourage tissue regeneration as well as offer protection from bacterial contamination. The effects of treatment with the wound chamber will be a reduction of the burden of disability and deformity. The system provides a known concentration of antibiotic with systemic absorption curve, achieving more than 1000-fold Minimum Inhibitory Concentration (MIC) for a particular pathogen at the wound/injury site while maintaining systemic peak and trough levels lower than is possible with conventional intravenous delivery. Wound Chamber treatment of infected wounds will also be evaluated during the clinical trials proposed. Medical doctors from Sweden will travel to India together with representatives from S2Medical AB to educate the Indian team about the use of Epiprotect® and the Wound Chamber. Meanwhile, S2Medical AB will develop the online platform for education about the use of the product in order to facilitate the interaction between the two countries. By the end of the study all the partners will be involved to define a complete global treatment plan for infected wounds, based on the acquired experience from this collaboration.
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Expected Outcome
Healthcare benefits: We intend to perform a study to identify a complete treatment plan for infected wounds. The treatment plan will be optimized according to Indian needs and, in the future, will represent a possible solution to heal infected wounds all around the world. Since moist wound healing is a relatively new concept in India, the definition of a complete treatment plan for infected wounds will be a big benefit for Indian patients. Epiprotect®, unlike most of the products available on the market, heal the wounds and thereby solve the actual problem.
By local administration of antimicrobial agents, systemic uptake can be minimized while maintaining high active concentrations in the target area, thus limiting toxicity and side-effects. Both Epiprotect® with AMPs and the Wound Chamber with ultrahigh concentrations of antibiotics will be evaluated in this regard.
The wound treatment plan this project aims at developing is likely to have beneficial aspects in preventing or reducing nosocomial infections. Approximately 1 in 10 hospitalized patients will acquire an infection after admission, which results in substantial economic cost and burden on the health care system 16. The wound chamber technology described here provides a simple way of enclosing infected wounds and applying a high concentration of antibiotics, significantly reducing the risk of cross-contamination.
Economic benefits:
The cost associated with non-healing wounds is estimated at 2 – 4 % of the annual health care budget 2. Since both Epiprotect® and the Wound Chamber have the potential to close and/or protect wounds, the costs related to wound care in India will decrease. In addition, the definition of a treatment plan for infected wounds based on the use of the developed products, fabricated and commercialized in Sweden will be a big benefit for the country both in terms of job opportunities, entrepreneurship and in treatment of chronic and infected wounds.
Technological advancement benefits:
Due to the high number of patients with infected wounds globally, the clinical trial we intend to perform represents a big step forward for the development of new treatments of infected non-healing wounds. Moreover, since the Wound Chamber creates a sealed controlled wound microenvironment, it enables very precise studies of the wound healing process.
※ Attention - font: Times New Roman, size: 11 points / Do not exceed space provided.
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5. Personal Data of Principal Investigators
INDIA
Name of PI Rajeev Ahuja
Title/ Designation Dr
Department Department of Burns & Plastic Surgery
Organization LN Hospital & MAMC in New Delhi (India)
Name Organization, Division Title Degree Specialty
Rajeev B Ahuja
Department of Burns, Plastic, Maxillofacial & Microvascular
Surgery, Lok Nayak Hospital and
associated Maulana Azad Medical College, New Delhi-110 002,
INDIA
Prof. MD PlasticSurgery,woundcare
Prabhat Shrivastava
Department of Burns, Plastic, Maxillofacial & Microvascular Surgery, Lok Nayak Hospital & associated Maulana Azad Medical College, New Delhi-110002, India
Dr. MD PlasticSurgery,woundcare
Dr. Varsha Gupta
Department of Burns, Plastic, Maxillofacial & Microvascular Surgery, Lok Nayak Hospital & associated Maulana Azad Medical College, New Delhi-110002, India
Dr. MD PlasticSurgery,woundcare
Partners in Swedish Team
Name Organization, Division Title Degree Specialty
Folke Sjöberg
Dept. of Anesthesiology and Intensive Care and the Burns Intensive Care Unit, Dept. of Hand and Plastic Surgery, University Hospital, S-581 85 LINKÖPING, SWEDEN.
Prof. MD, PhD
PlasticSurgery,woundcare
Luca Conti S2Medical AB Dr. PhD Project management, R&D
Mårten Skog S2Medical AB Sir Msc Project management, data analysis
Daniel Aili Division of Molecular Physics Dept. of Physics, Chemistry and Biology, Linköping University, Sweden.
Assoc. Prof. PhD
Research on the novel material with antimicrobial peptides
Johan Junker
Center for Teaching and Research in Disaster Medicine and Traumatology, Linköping University Hospital.
Senior researcher PhD
Experience with the Wound Chamber
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B. TECHNICAL INFORMATION 1. Objectives of Project (up to 200 words)
In India, an incidence of 4.5/1000 and 10.5/1000 population has been reported for chronic and acute wounds respectively. In many of these patients, poor local hygiene and infection following surgery complicates the healing of the wounds1. A study performed by Dasgupta S and coworkers2 reported that various nosocomial pathogens were isolated in burn units and surgical wards of India. Infection is an important cause of mortality in patients with wounds. When a wound is infected an invasion and replication of microorganisms occur in the interested area, leading to cell injury and damage. It has been estimated that 75% of all deaths following thermal injuries are related to infections. Our objective is to develop a complete treatment plan for infected wounds globally and in India in particular. The study will evaluate the use of a Wound Chamber delivering ultrahigh concentrations of antibiotics directly to the wound. Also, an innovative wound dressing based on the use of AMPs will be developed and tested in Indian and Swedish medical centers.
2. Justification for collaboration, including background to the proposed project, each partner’s expertise and specific contribution to the project, and the added value of the proposed collaboration (up to 400 words)
The development of this work will be possible by the cooperation of top class teams from Sweden and India. Prof. Folke Sjöberg is the head of the burn unit of Linköping (BRIVA, Sweden). The burn unit had the highest survival rates in the world 2015. Prof. Sjöberg is author of about 200 scientific publications and has the expertise needed to follow the study from a medical prospective, to translate the results to scientific papers, to help with the design of the clinical trial and to interpret the results.
Dr. Johan Junker is a Senior Researcher at the Center for Teaching and Research in Disaster Medicine and Traumatology, Linköping University hospital. He was previously the director of Plastic Surgery and Tissue Engineering Research at Brigham and Women’s Hospital in Boston (USA) and instructor of Surgery at Harvard Medical School. Dr. Junker will be in charge of training the Indian medical doctors regarding the use of the Wound Chamber and the interpretation of the results related to Wound Chamber treatment of infected wounds.
Prof. Rajeev Ahuja is the head of the Department of Burns & Plastic Surgery, LN Hospital & MAMC in New Delhi (India). He will contribute with the design of the clinical trial and will contribute to the project with his great experience in burn care and infected wounds. Prof. Ahuja will follow the trial and transfer his know-how about infected wounds to the Swedish team.
Assoc. Prof. Daniel Aili works at Linköping University and will be responsible for the development of the new wound dressing with antimicrobial properties. He will provide expertise in nanocellulose surface functionalization and characterization of nanocellulose composite materials. Prof. Aili is a Wallenberg research fellow, author of >40 scientific publications and has 4 filed patent applications in his portfolio.
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Mårten Skog is the COO of S2Medical Ab (Sweden) and will be in charge of coordinating the project. He will contribute with the development of the online platform as well as the follow up on the use of the wound dressing.
Dr. Luca Conti is a project manager at S2Medical AB. He has a PhD in Medicine and has been working in research laboratories in Italy, Sweden and USA. Dr. Conti will be responsible for writing scientific papers describing the outcomes of the study and to develop the online platform.
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3. Descriptions of the Cooperative research project – maximum 6 pages (font size 12 pt) • Background
Relevanceandscope
An open wound is an injury leading to an external or internal break in body tissue, usually involving the skin. A wound that does not heal in a predictable amount of time is considered chronic. Patients affected by chronic wounds frequently suffer from other diseases such as diabetes and obesity. Thus, wounds often complicate an already dramatic scenario. In India, an incidence of 4.5/1000 and 10.5/1000 population has been reported for chronic and acute wounds respectively1. In many of these patients, especially the ones from rural zones, poor local hygiene and infection following surgery complicates the healing of the wounds. In fact, a study reported that various nosocomial pathogens were isolated in burn units and surgical wards of India2. Infection is an important cause of mortality in patients with wounds. When a wound is infected an invasion and replication of microorganisms occur in the area in question, leading to cell injury and tissue damage. About 75% of all deaths following thermal injuries are related to infections3.
Administration of systemic antibiotics is the standard of care in treating infected wounds, even though it is associated with increased development of antibiotic drug resistance and adverse side effects4,5. In addition, most systemic antibiotics have poor tissue penetration6, especially in burn wounds where blood vessels are destroyed. Topical antimicrobials, however, can be applied directly to the wound site, bypassing the need for an intact circulatory system7. Topical treatment has the advantage of avoiding many difficulties associated with systemic antibiotic application, such as nephropathy, allergic reactions, and disturbances of the intestinal flora, while still providing an increased concentration at the target site7.
The Wound Chamber technology will be evaluated within this project in regards to treating contaminated and infected wounds. The chamber is used to deliver local antibiotics, thereby rapidly eradicating wound infection and stopping injury progression. The chamber can be manufactured to fit a wide range of wounds with various location of the body (see fig 1).
Treatment using a wound chamber also results in complete control of the wound microenvironment, thus enabling a wide range of treatment interventions8-10. The effect of a wet environment on wound healing and subsequent scar formation has been studied by us and others for the past decades11-13. At this point, we have gained a thorough understanding of the benefit a wet environment entails. The next step, which this application is a part of, is to learn
Fig 1. A. Schematic of the wound chamber prototype. B. Manufactured wound chamber used for in vivo testing. C. Prototype for arm application. D. Prototype for face application.
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how to successfully modify this environment to facilitate wound healing. One point of attack is to reduce or eliminate the burden of infection by applying ultrahigh concentrations of antibiotics. This strategy has been shown to be highly successful in preliminary experiments 14-16. The half-life of the antibiotics in the chamber when diluted in saline and wound fluid is on the order of 24 hours. Antibiotics with concentration-dependent bactericidal activity such as Gentamicin have been found to be extremely effective in this system. Jacobsen et al.17 published a study of the application of topical antibiotics (Moxifloxacin and Gentamicin) in a porcine wound model infected with Pseudomonas aeruginosa and multi-resistant Staphylococcus aureus. Their results demonstrated that the use of antibiotics is beneficial for the topical treatment of infected wounds, because of a significant reduction in Gram-positive and -negative bacteria and an acceleration of the wound repair process.
Testing of the treatment of infected wounds (Fig 2) and burns (Fig 3) using a wound chamber with gentamicin has been performed in a porcine model14-16. The testing revealed a rapid reduction or complete elimination of infection within hours or days.
S2Medical AB, a medtech company from Linköping, has developed and commercialized a new wound dressing, Epiprotect®, based on an innovative material called eiratex®. The potential of the material was later confirmed in a collaboration project between Linköping University and the national burn center in Linköping (BRIVA), Sweden. Epiprotect® can both stimulate wound healing and prevent bacteria from penetrating into the wounds. Epiprotect® showed a
Fig 2. Treatment of wounds infected with Staphylococcus aureus using a wound chamber and gentamicin. Controls included infected wounds treated with saline, as well as non-infected wounds treated with saline and dry wounds. Gentamicin-treated wounds showed an approximately 10,000-fold reduction of bacteria in tissue, and a complete elimination of bacteria in wound fluid.
Fig 3. Treatment of burns infected with Staphylococcus aureus using a wound chamber and gentamicin and minocycline. Controls included infected wounds treated with saline, as well as non-infected wounds treated with saline and dry wounds. Wounds treated with Gentamicin or Minocycline showed an approximately 1,000,000-fold reduction of bacteria in tissue, and a complete elimination of bacteria in wound fluid.
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unique potential to replace the use of the controversial but previous undefeated wound dressings based on human or animal skin in advanced wound care. An unpublished study on this material, involving a large number of patients with severe burns and chronic wounds, has shown that it can dramatically reduce the wound healing time as compared to conventional methods (Fig. 4 and 5). S2Medical provides manufacturing, sales and development of medical devices for world leading wound healing. The new wound dressing is currently used in the national burn center in Linköping (BRIVA), Uppsala hospital, several hospitals in Egypt and is registered for sales in India, Europe and the Middle East. The introduction of Epiprotect® in India would be a big advantage for Indian patients and for the Indian healthcare system. However, in infected wounds pathogens may be trapped between the wound and the cellulose membrane and continue to grow in this moist environment. Thus, a treatment plan for the use of Epiprotect® in India has to be developed according to Indian needs. In fact, due to the high rate of infections complicated by the fact that the spectrum of bacteria isolated varies with time and geographical area18 and because of the infection problems in Indian patients, there is an urgent need to identify a treatment plan for infected wounds in India and globally.
To find the right treatment plan we aim to test the combined use of Epiprotect® and an antimicrobial based on the addition of antimicrobial peptides (AMPs).
Day 1 Day 4 Day 11
Fig. 4. Healing of a partial thickness burn assisted by Epiprotect®. Minimal pain and fast healing. Photo:
BRIVA Ismailia, Egypt
Fig. 5. Covering of an excised full thickness burn injury, a life-saving step prior to autologous transplantation of
skin. The method has previously been dependent on dressings derived from animal or human tissue. Photo: BRIVA Linköping, Sweden
The aim of this project is to define a treatment plan to treat wounds in patients, create and implement an online education platform to train the personnel involved in the study about how to use the product and improve it after a concept evaluation. The specific objectives of this project, to be developed in 4 years, are:
1) To develop an online platform to be used by medical staff from Sweden and India for the follow up of patients.
2) To make a concept plan for the treatment of patients with wounds. This will include the following activities: establishing a protocol, defining inclusion and exclusion criteria, what type of wounds to treat and type of antibiotics to be used.
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3) To perform a pilot study in India to understand how the treatment with the Wound Chamber and Epiprotect® can be performed according to Indian needs and how the experience from Indian surgeons can improve the treatment of infected wounds.
4) To test in vivo and do the safety testing of a new material with anti-microbial properties based on the use of anti-microbial peptides (AMPs) developed in collaboration between S2Medical AB and the team of Assoc. Prof. Daniel Aili at Linköping University (LiU).
5) To design and perform a randomized controlled prospective clinical trial in India and Sweden to test the Wound Chamber in combination with different antibiotics and Epiprotect® combined with AMPs to treat infected wounds (4).
6) To define a concept treatment plan according to the results obtained in the previous points. The know-how of S2Medical AB and Assoc. Prof. Daniel Aili on biomaterials, from BRIVA and Dr Junker regardning burn and wound treatment, together with the expertise from the Indian team about infected wounds will converge in a strategy to treat infected wounds according to Indian needs.
Epiprotect® has already been launched by S2Medical AB in Egypt with a similar approach. However, due to the problems related to wound infections in India, new strategies have to be developed. A big challenge of this project will be to define a complete treatment plan for infected wounds according to Indian needs. This project will be beneficial for Indian patients affected by wounds and will improve their quality of life. Also, the development of this project will result in a reduction of costs for the treatment of wound-affected patients in Indian and Swedish hospitals since the treatment will in most cases completely close the wounds. By development of an online education platform we expect to establish a strong, long-lasting collaboration between Sweden and India.
Impact Potential impact on healthcare Moist wound care is a relatively new concept in India. Only a few doctors are aware about it and many of them update themselves with the latest information. Advanced wound care products have a perception of high cost-low benefit, and hence the use of traditional products like cotton and gauze is rampant. However, the market scenario is changing fast, with increasing realization of the value of advanced wound care. The Wound-Care segment is a significant part of medical consumables: about 4 billion USD are spent every year for wound care in the country. However, advanced wound care is still a very small segment of the Indian wound care market as traditional treatment has a dominant share (RedSeer Consulting Analysis; Secondary Research; IBEF Healthcare report, Oct 2007). This project can affect the current scenario in many ways: The Wound Chamber can provide a cost-effective and easy to use treatment method for contaminated and infected wounds. Protection of the open wound may also reduce the burden of nosocomial infections. A new wound dressing with antimicrobial properties based on eiratex® will also heal infected wounds, with a big impact on the costs related to wound care in India. Also, the online platform will allow the doctors to be constantly in touch with colleagues from Sweden and to be continuously trained in the use of the novel wound care platform as well as future developments.
Potential impact on the market: moving things forward
Most of the big companies already selling in India (3M, Johnson & Johnson, Smith & Nephew and others) are making profit on wound care mainly by selling products that cover the wounds without healing them and thereby securing a long term high volume sale of their products. With
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the introduction of the new wound treatments based on Epiprotect® and/or the Wound Chamber technology, S2Medical AB will change these rules, assuring a better life for patients. The new treatment platform will improve life of patients affected by different types of wounds
and pathologies, as reported in Fig. 6. The wound care market is expected to reach $ 18.3 billion by 2019
(rnrmarketresearch survey, 2010). India along with China, Australia and Brazil is expected to serve as a new revenue pocket for the wound care market in the coming years. The Indian wound care market is currently
growing at a compound annual growth rate (CAGR) of 7.4% in comparison with 7% in the rest of the world and is expected to reach 5.5billion USD in 2020 (Morulaa health tech survey, 2013).
For these reasons, the introduction of a new wound treatment plan with its related products in India will be beneficial for Swedish economy. In such a fast growing market, India will benefit from a collaboration with BRIVA, a top class burn unit. Also, the tight connection that will be established with S2Medical AB will allow Indian centers to be constantly upgraded with top-class products. Importance of the collaboration
The national burn center in Linköping (BRIVA), Sweden, was the burn clinic with the highest survival rates in the world 2015. Thanks to this project, the know-how of doctors from BRIVA will be shared with doctors from India. Additionally, doctors from India, coordinated by Prof. Rajeev Ahuja, will share their expertise in infected wounds. S2Medical AB and the team of Assoc. Prof. Daniel Aili and Dr Johan Junker will share expertise regarding bio-materials, wound healing and treatment of infected wounds, in order to create a product that fits the Indian needs. The use of the online platform will be fundamental for a continuous collaboration between the two countries. Implementation
The pilot study will be performed under the guide of Prof. Rajeev Ahuja and his team. During the pilot study a collaboration between the two countries will be of particular importance, since both BRIVA and S2Medical AB need to better understand the needs of the Indian partners. In parallel with the clinical study, S2Medical AB will work in collaboration with Assoc. Prof. Daniel Aili from Linköping University to implement Epiprotect® by adding antimicrobial properties, as well as with Dr Johan Junker from the Center for Teaching and Research in
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Disaster Medicine and Traumatology, Linköping University Hospital further develop the Wound Chamber technology. The team of Assoc. Prof. Daniel Aili at Linköping University is working since a few years to develop methods to render BC antimicrobial using antimicrobial peptides (AMPs) in order to minimize occurrence of wound related infections and improve wound healing. In particular, two bacterial membrane disrupting AMPs (NC8 alpha and beta) with high efficacy against wound related pathogens have recently been characterized in his group and successfully incorporated into BC19. In contrast to conventional antibiotics, bacteria do not tend to become resistant to AMPs. Based on these findings a new product based on eiratex®, with antimicrobial properties, will be developed and distributed by S2Medical AB. In this project we aim to test the two AMPs already characterized by the team of Assoc. prof. Daniel Aili. In the future, we plan to test more AMPs incorporated into eiratex®. Dr Johan Junker has conducted several studies investigating treatment of infected wounds and burns using the Wound Chamber to deliver ultrahigh doses of antibiotics directly to the wound. These studies include toxicology testing, large animal wound models and a limited number of human experiments. The Wound Chamber technology is currently at the stage were a clinical study is the next logical step in bringing the new treatment to market. Actor constellations S2Medical AB will be responsible for the production of the Wound Chamber, the new material based on eiratex®, the online platform and the regulatory aspects. Assoc. Prof. Daniel Aili, from Linköping University, will be responsible for the R&D concerning the AMPs to be incorporated in the dressings, while BRIVA will be responsible for the training of the Indian doctors and the medical aspects. Dr Johan Junker will be responsible for evaluation of aspects of the project related to the Wound Chamber technology. The actor constellation is reported below.
Risks and contingency plan This project will be possible by a cooperation between Linköping University, Linköping University Hospital and a selected Indian hospital. The implementation of Epiprotect® with AMPs to get an innovative material with antimicrobial properties will avoid any problem related to antimicrobial resistance. The feasibility of the incorporation of different types of AMPs into eiratex® have already been shown that Linköping University by the team of Assoc. Prof. Daniel Aili. However, one risk is that the Epiprotect® with AMP does not pass bio-compatibility tests. In this case, the contingency plan is to either modify the peptides to increase the biocompatibility or to exclude it from the clinical trial.
1 Shukla VK, Ansari MA, Gupta SK. Wound healing research: A perspective from India. Int J Low Extrem Wounds 2005;4:7-8.
2 Dasgupta S, Das S, Chawan NS, Hazra A. Nosocomial infections in the intensive care unit: Incidence, risk factors, outcome and associated pathogens in a public tertiary teaching hospital of Eastern India. Indian J Crit Care Med. 2015 Jan;19(1):14-20.
3 Vindenes H, Bjerknes R. Microbial colonization of large wounds. Burns 1995;21:575-9.
4 Lentino, J. R., Narita, M. & Yu, V. L. New antimicrobial agents as therapy for resistant gram-positive cocci. Eur. J. Clin. Microbiol. Infect. Dis. 27, 3–15 (2008). 5 McConeghy, K. W., Mikolich, D. J. & LaPlante, K. L. Agents for the decolonization of methicillin-resistant Staphylococcus aureus. Pharmacotherapy 29, 263–80 (2009). 6 Garau, J., Bouza, E., Chastre, J., Gudiol, F. & Harbarth, S. Management of methicillin-resistant Staphylococcus aureus infections. Clin. Microbiol. Infect. 15, 125–36 (2009). 7 Neely, A. N. et al. Are Topical Antimicrobials Effective Against Bacteria That are Highly Resistant to Systemic Antibiotics? J. Burn Care Res. 30, 19–29 (2009). 8 Junker, J. P. E., Kamel, R. A., Caterson, E. J. & Eriksson, E. Clinical Impact Upon Wound Healing and Inflammation in Moist, Wet, and Dry Environments. Adv. wound care 2, 348–356 (2013). 9 Junker, J. P. E., Caterson, E. J. & Eriksson, E. The microenvironment of wound healing. J. Craniofac. Surg. 24, 12–6 (2013). 10 Kruse, C. R. et al. The external microenvironment of healing skin wounds. Wound Repair Regen. 23, 456–464 (2015). 11 Reish, R. G. et al. Modulation of scarring in a liquid environment in the Yorkshire pig: Orginal article-basic science. Wound Repair Regen. 17, 806–816 (2009). 12 Reish, R. G. & Eriksson, E. Scar Treatments: Preclinical and Clinical Studies. J. Am. Coll. Surg. 206, 719–730 (2008). 13 Reish, R. G. & Eriksson, E. Scars: a review of emerging and currently available therapies. Plast. Reconstr. Surg. 122, 1068–78 (2008). 14 Daly, L. T. et al. Topical Minocycline Effectively Decontaminates and Reduces Inflammation in Infected Porcine Wounds. Plast. Reconstr. Surg. 138, 856e–868e (2016). 15 Tsai, D. M. et al. Full-Thickness Porcine Burns Infected with Staphylococcus aureus or Pseudomonas Aeruginosa Can Be Effectively Treated with Topical Antibiotics. Wound Repair Regen. (2016). doi:10.1111/wrr.12409 16 Junker, J. P. E. et al. Topical delivery of ultrahigh concentrations of gentamicin is highly effective in reducing bacterial levels in infected porcine full-thickness wounds. Plast. Reconstr. Surg. 135, 151–9 (2015). 17 Jacobsen F, Fisahn C, Sorkin M, Thiele I, Hirsch T, Stricker I, Klaassen T, Roemer A, Fugmann B, Steinstraesser L. Efficacy of topically delivered moxifloxacin against wound infection by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2011 May;55(5):2325-34. doi: 10.1128/AAC.01071-10. 18 Ananthakrishanan AN, Kanungo R, Kumar K, Badrinath S. Detection of extended spectrum beta Lactamase producers among surgical wound infections and burn patients in JIPMER. Indian J Med Microbiol 2002;18:160-5.
19 Seng Koon Lim, Camilla Sandén, Robert Selegård, Bo Liedberg, Daniel Aili. Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity. Sci Rep. 2016; 6: 21123.
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Form-5 4. Plan for the execution of the Cooperative Project - with clear description of research
activities on both sides as well as of the elements of cooperation and exchange, 3 pages maximum
Work plan (schedule, milestones and deliverables) Workpackage 1 (Sweden): Online platform.
An online platform will be developed in order to accelerate the project and allow for rapid communication between the Sweden and India teams.
Milestones: The development of the platform.
Deliverables: A secure password protected website used to share information regarding the clinical trial and the ongoing studies.
Workpackage 2 (Sweden and India): To make a concept plan for the treatment of Indian patients with wounds.
The concept plan will consider the high number of patients with infected wounds in India.
Milestones: The definition of a concept plan, including inclusion/exclusion criteria as well as the types of antibiotics to be used in combination with the Wound Chamber.
Deliverables: A concept plan to test the Wound Chamber in India together with different antibiotics.
Workpackage 3 (Sweden and India): Design and development of a pilot study.
Under the supervision of Prof. Prof. Rajeev Ahuja the pilot study will be designed.
Milestones: The design and development of a pilot study, including criteria for the involvement of patients with wounds treated in the center, the type of wounds, the accessibility of the locations by the Swedish staff.
Deliverables: Case studies about the effects of the Wound Chamber combined with different antibiotics and Epiprotect® on patients with burns, and in particular infected wounds.
Workpackage 4 (Sweden): Implementation of a new wound dressing according to the specific needs of the Indian scenario.
Assoc. Prof. Daniel Aili from Linköping University will work to develop a new material based on eiratex® with antimicrobial properties.
Milestones: The incorporation of antimicrobial peptides on eiratex®.
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Deliverables: A product specific for the Indian market in terms of antimicrobial properties.
Workpackage 5 (Sweden): To test in vivo and do the safety testing of the new material with antimicrobial properties.
Before the start of the clinical study, the product developed in the workpackage 4 will be tested in vivo at LiU in an animal model of wound healing and the safety testing will be done though an external consultant company.
Milestones: Evaluation in vivo of the new material.
Deliverables: Results about the safety and properties of the new material.
Workpackage 6 (India): Ethics, regulatory approval and set-up of the clinical trial.
A submission for regulatory and ethical approval will be done. Clinical monitoring will be arranged and discussed between Swedish and Indian doctors. Representatives from the Swedish staff from BRIVA will travel to India to discuss how to proceed.
Milestones: The set-up of a clinical trial.
Deliverables: Appropriate ethic and regulatory approval to start the clinical trial.
Workpackage 7 (India): Clinical trial.
The new dressing will be tested in India. Patients will be recruited according to guidelines of the Declaration of Helsinki. Our plan is to have at least 10 months of clinical data collected in order to have a good indicator for a long-term performance. To start with, the product will be tested on small burns and ulcers. The patients will be divided in two groups: i) patients with infected wounds treated with the new product with antimicrobial properties ii) patients with infected wounds treated with Epiprotect® and different types of antibiotics. Interaction between Swedish and Indian medical doctors will be fundamental to assess the efficacy of the new dressing and compare it with Epiprotect®. Staff from BRIVA will travel to India to assist in the first steps.
Milestones: A clinical trial to test in India the new product based on eiratex® with antimicrobial properties.
Deliverables: Data about the different strategies to treat wounds in India.
Workpackage 8 (Sweden and India): Evaluation of the results.
Data from the clinical trial will be analyzed to identify the best strategy to treat wounds in India. The online platform will be used to share data and speed up the process.
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Milestones: The interpretation of the results from the clinical trial by Swedish and Indian staff.
Deliverables: Clinical data about the different types of strategies adopted to heal wounds.
Workpackage 9 (Sweden and India): Development of a concept treatment plan.
Based on the results obtained we will define a complete treatment plan for patients with wounds in India.
Milestones: The definition of the best treatment plan according to Indian needs.
Deliverables: Identification of a complete treatment plan for wounds from Indian patients.
The work plan is summarized in the Gantt scheme below:
Red: Swedish activity; green: Indian activity.
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5. Facilities related to project activity available at the institutions where the project will be carried out:
At the Collaborating Indian Institutions At the Collaborating Swedish Institutions
Clinical trials facility, clinicians and staffing to conduct and monitor the clinical study.
Research laboratories for cell biology.
Fully equipped biomaterials research laboratory at Linköping University.
Production facility for wound dressings at S2Medical AB headquarter.
Research laboratories for cell biology.
Animal facility.
6. Information of visiting persons for technical mission (per annum).
Estimation of the expected plan of visits; any further modification, according to the needs of joint project has to be communicated and approved by the participants institutions.
A. India to Sweden Name Organization Duration Purpose
1st Year Prof. Rajeev Ahuja LN Hospital &
MAMC in New Delhi
4 weeks Introduction to Swedish collegues about infected wounds in India Dr Varsha Gupta
Dr Prabhat Shrivastava
2nd Year Dr Varsha Gupta LN Hospital & MAMC in New
Delhi
2-3weekseach(total5
weeks)
Meeting about the design of pilot study and clinical trial
Dr Prabhat Shrivastava
3rd Year
Dr Varsha Gupta LN Hospital & MAMC in New
Delhi
3-4 weeks each (total 7
weeks)
Upgrade and case reports from the clinical trial
Dr Prabhat Shrivastava
4th Year Prof. Rajeev Ahuja LN Hospital &
MAMC in New Delhi
3weeksDissemination of the results
Dr Varsha Gupta inSweden(Symposium)Dr Prabhat Shrivastava
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B. Sweden to India
※ Attention: Please add lines if necessary.
7. Expected results of Cooperation (e.g. joint publications, patents etc.)
Are any of the expected results likely to have commercial value? (up to 100 words)
The approach of combining the unique features of eiratex® with antimicrobial peptides is of great interest from a commercial side since it will solve problems related to antibiotic resistance. In case of successful results from the clinical trial we will start the procedures to commercialize the product.
8. Personal and Professional Data (CV) of Indian and Swedish PIs must be attached.
(CV must describe the expertise of the PIs in the proposed field of work by citing relevant scientific publications or patent applications during the last 5 years. Do not exceed two pages A4 size for each PI (Font: Times New Roman, size: 11 points).
Name Organization Duration Purpose
Prof. Folke Sjöberg
Dr. Johan Junker
Dr. Luca Conti
S2Medical*ABTraining about the use of
Epiprotect® and the online platform
Dr. Johan Junker
Linköping University Hospital
Training*about*the*use*of*the*wound*chamber
Assoc. Prof. Daniel Aili
Linköping University
Prof. Folke SjöbergLinköping University Hospital
Assoc. Prof. Daniel Aili
Linköping University
Interpretation of the results
Prof. Folke SjöbergLinköping University Hospital Identification*of*the*best*strategy
Dr. Johan Junker
Linköping University Hospital
to*heal*infected*wounds
Dr. Luca Conti Dissemination*of*the*results*in*India*Dr. Mårten Skog (Symposium)
3 weeks each (total 6 weeks)
Follow the clinical trial
4th Year
2nd Year
1st Year
3rd Year
4*weeks
S2Medical*AB
Linköping University Hospital
2 week Design of a concept plan (WP2)
2*weeks*each*(total*4*weeks)*
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Folke Sjöberg - CV
NAME Bror Folke Sjöberg, MD. Ph.D., Professor Born 1956 Dept. of Anesthesiology and Intensive Care and the Burns Intensive Care Unit, Dept. of Hand and Plastic Surgery, University Hospital, S-581 85 LINKÖPING, SWEDEN. M.D., Linköping University Medical School, 1983. Specialist in Anesthesiology and Intensive care, University hospital, Linköping, Sweden, 1990. Ph.D., 1990 Title: Skeletal muscle pH and pO2, an experimental study including the application and construction of a multi-channel microelectrode for the combined measurement of tissue pH and pO2. Associate professor, 1993. Director of the Burns intensive care unit, 1996 ongoing (National burns unit). Director he Medical and Surgical Intensive Care unit (1998-9), Chairman at the Department of Anesthesiology and Intensive Care (1998-2002). All positions at the Univ. Hospital, Linkoping, Sweden: Medical Director of the Proof of Concept Clinic at the Berzelius Clinical Research Center 2002 – 2009. Appointed Professor in Critical Care and Burn Surgery, Dec. 2000. Co-Chair (pro-Prefekt) RND, Department of Clinical and experimental Medicine, Linköping University 2012-2014. Guest Professor Suez Canal University, Ismalia, Egypt. 2013 - ongoing. University Pro Vice-Chancellor, Linköping University 2014 – ongoing. Director RND the Swedish Intensive Care Registry 2011 – 2014. Medical Director, Proof of Concept Clinic CTC AB, Academic Hospital, Uppsala 2012- ongoing. Presently responsible for the teachings of 16 Ph.D. students (8 as main tutor). 23 students have previously graduated (Ph.D.). Publications: Abstracts at National and International meetings: > 350 Original publications (including editor for books and chapters, case reports, letters and full per-reviewed papers): 229 Selected publications during the past 5 years: Jonas Tyden, Heiko Herwald, Folke Sjöberg and Joakim Johansson Increased Plasma Levels of Heparin-Binding Protein on Admission to Intensive Care Are Associated with Respiratory and Circulatory Failure PLoS ONE, 2016, 11(3), e0152035. Elin Ericsson, Erik Tesselaar and Folke Sjöberg Effect of Electrode Belt and Body Positions on Regional Pulmonary Ventilation- and Perfusion-Related Impedance Changes Measured by Electric Impedance Tomography PLoS ONE, 2016, 11(6), e0155913. Lotti Orwelius, Magnus Husberg, Lars Bernfort, Per Carlsson, Mats Fredrikson, Sten Walther and Folke Sjöberg The Effect on Overall Cost and Health-Related Quality of Life by Inpatient Trajectories 3 Years Before and After Critical Illness Journal of Anesthesia & Intensive Care Medicine, 2016, 1(1), 001-009. Robin Mirdell, Fredrik Iredahl, Folke Sjöberg, Simon Farnebo and Erik Tesselaar Microvascular blood flow in scalds in children and its relation to duration of wound healing: A study using laser speckle contrast imaging Burns, 2016, 42(3), 648-654.
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Ingrid Steinvall, Moustafa Elmasry, Mats Fredrikson and Folke Sjöberg Standardised mortality ratio based on the sum of age and percentage total body surface area burned is an adequate quality indicator in burn care: An exploratory review Burns, 2016, 42(1), 28-40. Islam Abdelrahman, Amr Moghazy, Ashraf Abbas, Moustafa Elmasry, Osama Adly, Mohamed Elbadawy, Ingrid Steinvall and Folke Sjöberg A prospective randomized cost billing comparison of local fasciocutaneous perforator versus free Gracilis flap reconstruction for lower limb in a developing economy Journal of Plastic, Reconstructive & Aesthetic Surgery, 2016, 69(8), 1121-1127. Laura Pompermaier, Ingrid Steinvall, Mats Fredrikson, Johan Thorfinn and Folke Sjöberg Long-term survival after burns in a Swedish population Burns, 2016. Jian Fransen, Fredrik R. M. Huss, Lennart E Nilsson, Ulf Rydell, Folke Sjöberg and Håkan Hanberger Surveillance of antibiotic susceptibility in a Swedish Burn Center 1994-2012 Burns, 2016, 42(6), 1295-1303. Fredrik Iredahl, Alexandra Högstedt, Joakim Henricson, Folke Sjöberg, Erik Tesselaar and Simon Farnebo Skin glucose metabolism and microvascular blood flow during local insulin delivery and after an oral glucose load Microcirculation, 2016, 23(7), 597-605. Moustafa Elmasry, Ingrid Steinvall, Johan Thorfinn, Ashraf H. Abbas, Islam Abdelrahman, Osama A. Adly and Folke Sjöberg Treatment of Children With Scalds by Xenografts: Report From a Swedish Burn Centre Journal of Burn Care & Research, 2016, 37(6), E586-E591. Carolina Samuelsson, Folke Sjöberg, Goran Karlstrom, Thomas Nolin and Sten Walther Gender differences in outcome and use of resources do exist in Swedish intensive care, but to no advantage for women of premenopausal age Critical Care, 2015, 19(129). Joakim Johansson and Folke Sjöberg Response to the article by Jämsä Leukocyte receptor expression as a biomarker for severe sepsis Acta Anaesthesiologica Scandinavica, 2015, 60(3), 407-408. Joakim Johansson, Ingrid Steinvall, Heiko Herwald, Lennart Lindbom and Folke Sjöberg Alteration of Leukocyte Count Correlates With Increased Pulmonary Vascular Permeability and Decreased PaO2:FiO(2) Ratio Early After Major Burns Journal of Burn Care & Research, 2015, 36(4), 484-492. Max Bergkvist, Joakim Henricson, Fredrik Iredahl, Erik Tesselaar, Folke Sjöberg and Simon Farnebo Assessment of microcirculation of the skin using Tissue Viability Imaging: A promising technique for detecting venous stasis in the skin Microvascular Research, 2015, 101, 20-25. Principal Investigator for > 160 clinical trials ranging from phase I-IV (see above Medical director, BCRC). Regular lecturer for courses in GCP (good clinical practice) methodology.
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Dr. Rajeev B. Ahuja MBBS, MS, MCh, DNB, FICS, FACS, FAMS Honorary Consultant to Indian Armed Forces Consultant and Head, Department of Burns, Plastic, Maxillofacial & Microvascular Surgery, Lok Nayak Hospital and associated Maulana Azad Medical College, New Delhi-110 002, INDIA Qualifications M.B.B.S. 1977 Maulana Azad Medical College, N. Delhi M.S. (Gen. Surgery) 1981 P.G.I.M.E.R., Chandigarh M.Ch. (Plastic Surgery) 1983 P.G.I.M.E.R., Chandigarh Diplomat of National 1984 National Board of Examinations, Ansari Nagar, New Delhi Board (Plastic Surgery) Experience Position Period Institution From To Total Consultant 15.05.08 Till date 7 yrs & 8 months Lok Nayak Hospital
New Delhi - 110 002
Senior Plastic 3.12.92 14.05.08 15 years & Lok Nayak Hospital,
Surgeon 5 months New Delhi - 110
002
Plastic Surgeon 3.12.84 2.12.92 8 years Lok Nayak Hospital,
(Consultant) New Delhi - 110 002
Sr. Resident 1.01.82 24.11.84 2 years & P.G.I.M.E.R., Chandigarh
(Plastic Surg.) 11 months Jr. Resident 1.01.80 31.12.81 2 years P.G.I.M.E.R., Chandigarh (Gen. Surgery) House Officer 1.01.79 31.12.79 1 year Lok Nayak Hospital, (Gen. Surg. & Medicine) New Delhi - 110 002 Intern 1.01.78 31.12.78 1 year Lok Nayak Hospital, (Rotating) New Delhi - 110 002 Total Standing in Profession : 37 years Publications in the past 5 years:
1) Ahuja,RB, Mulay AM, Ahuja A. Assessment of quality of life (QOL) of burn Patients in India
BSHS-RBA scale.
Burns. 2016 May;42(3):639-47.
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2) Ahuja RB, Mulay AM, Ahuja A. Assessment of quality of life (QoL) of burn patients in
India using BSHS-RBA scale. Burns. Jan 2016. doi: 10.1016/j.burns.2015.11.011. [Epub
ahead of print]
3) Mulay AM, Ahuja A, Ahuja RB. Modification, cultural adaptation and validation of burn specific health scale-brief (BSHS-B) for Hindi speaking population. Burns. 2015 Nov;41(7):1543-9.
4) Ahuja RB, Chatterjee P, Deraje V. A critical appraisal of nonsurgical modalities for managing hypertrophic scars and keloids. Formosan J. of Surgery, 20
5) Ahuja RB, Chatterjee P, Gupta R, Shrivastava P, Gupta GK. A new paradigm in facial reanimation for long-standing palsies? Indian J Plast Surg. 2015 Jan-Apr;48(1):30-7.
6) Ahuja RB, Gupta R, Chatterjee P, Shrivastava P. Securing aesthetic outcomes for composite grafts to alar margin and columellar defects: A long term experience. Indian J Plast Surg. 2014 Sep-Dec;47(3):333-9.
7) Ahuja RB, Chatterjee P, Shrivastava P. A novel route for placing free flap pedicle from a palatal defect. Indian J Plast Surg. 2014 May;47(2):249-51.
8) Kaur R, Bala K, Ahuja RB, Srivastav P, Bansal U. Primary cutaneous mucormycosis in a patient with burn wounds due to Lichtheimia ramosa. Mycopathologia. 2014 Oct;178(3-4):291-5.
9) Ahuja RB, Chatterjee P, Gupta GK, Shrivastava P. Total upper eyelid reconstruction by single staged malar-cheek flap. Indian J Plast Surg. 2014 Jan;47(1):116-9.
10) Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride andtriamcinolone acetonide in hypertrophic scars and keloids. Burns. 2013 Oct 30. pii: S0305-4179(13)00330-6. doi: 10.1016/j.burns.2013.09.029. [Epub ahead of print]
11) Ahuja RB. Ethical practice of evidence-based medicine: A review for plastic surgeons. Indian J Plast Surg. 2013 Jan;46(1):11-7.
12) Ahuja RB, Goswami P. Cost of providing inpatient burn care in a tertiary, teaching, hospital of North India. Burns. 2013 Jun;39(4):558-64.
13) Ahuja RB, Gupta GK. A four arm, double blind, randomized and placebo controlled study of pregabalin in the management of post-burn pruritus. Burns. 2013 Feb;39(1):24-9.
14) Ahuja RB, Dash JK, Shrivastava P. A comparative analysis of liquefied petroleum gas (LPG) and kerosene related burn injuries. Burns. 2011 Dec;37(8):1403-10.
15) Ahuja RB, Gupta R, Gupta G, Shrivastava P. A comparative analysis of cetirizine, gabapentin and their combination in the relief of post-burn pruritus. Burns. 2011 March;37(2):203-207.
16) Ahuja RB. Soluble CD 163: A novel biomarker. Indian J Plast Surg. 2011 Jan;44(1):124-6.
9. Complementary resources. Cite other national or international funding resources for related scientific projects including funding agencies, funding period and grant amount.
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C. FINANCIAL INFORMATION Budget or resources for the project; one for the Swedish side and one for the Indian side
Swedish side
Note: the 20% of amount co-financed by S2Medical AB will be given as depreciation costs of the instruments used in S2Medical AB facility for the production of eiratex® and the novel dressing with antimicrobial properties. The total amount requested (India+Sweden) is 5000000 SEK.
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Indian side
Note: all the prices are in SEK.
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D. Signatures of the Principal Investi gators & Institutions
▶ Swedish PI
Name Dr. Folke Sjöberg Signature Date 2017-01-15
▶ Indian PI
Name Dr. Rajeev B. Ahuja Signature Date 2017-01-15
B. Declaration from the Heads of the Collaborating Institutions
It is certified that
i) the Institutions agree to participate in this Joint Research Project
ii) the Institutions shall provide necessary facilities for implementing the Joint Research Project
iii) the Institutions assume financial & other management responsibilities for the duration of the project to be carried out at their institution and
iv) the back-up funding for manpower, consumable etc. is available for this Joint Research Project.
Signature of the Heads of the Institutions (through scanned exchanges)
▶ Head of the Swedish Institution
Name Dr. Folke Sjöberg Signature Date 2017-01-15
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▶ Head of the Indian Institution
Name Dr. Rajeev B. Ahuja Signature Date 2017-01-15
