Combating medical device foulingJacqueline L. Harding1 and Melissa M. Reynolds1,2
1 Department of Chemistry, Colorado State University, 1872 Campus Delivery, Fort Collins, CO 80523, USA2 School of Biomedical Engineering, Colorado State University, 1872 Campus Delivery, Fort Collins, CO 80523, USA
Review
Glossary
Biocompatible: denotes a material that does not illicit an adverse response
when interfaced with a host environment.
Biofilm: a complex assembly of microorganisms and proteins that are attached
to the surfaces of medical devices, which interfaces with the biological
When interfaced with the biological environment, bio-medical devices are prone to surface biofouling due toadhesion of microbial or thrombotic agents as a result ofthe foreign body response. Surface biofouling of medicaldevices occurs as a result of nonspecific adhesion ofnoxious substrates to the surface. Approaches for bio-fouling-resistant surfaces can be categorized as eitherthe manipulation of surface chemical functionalities orthrough the incorporation of regulatory biomolecules.This review summarizes current strategies for creatingbiofouling-resistant surfaces based on surface hydrophi-licity and charge, biomolecule functionalization, anddrug elution. Reducing the foreign body response andrestoring the function of cells around the device mini-mizes the risk of device rejection and potentially inte-grates devices with surrounding tissues and fluids. Inaddition, we discuss the use of peptides and NO asbiomolecules that not only inhibit surface fouling, butalso promote the integration of medical devices with thebiological environment.
Device rejection: common reasons leading to failureMedical devices (see Glossary) play a key role in thetreatment of ailments and are meant to substitute, andin some cases restore, biological function. However, theinclusion of synthetic materials used for orthopedics,catheters, infusion lines, vascular stents and grafts, andsutures into a biological environment triggers a foreignbody response. The foreign body response to artificialmaterials often results in biofouling, thereby limitingthe clinical lifetime of the device. Furthermore, theincreasing use of invasive medical procedures for theimplantation of devices leads to an increased risk for thedevelopment of device-associated infections. Current esti-mates place the occurrence of bacterial-related infectionsfor humans at 65%, and are associated with the growth ofbacterial biofilms on device surfaces [1]. The combinationof surface thrombus and biofilm formation that eventuallyinhibits the functionality of the device is collectivelytermed biofouling [2–6]. Severe biofouling of medicaldevices, ultimately resulting in failure, is only effectivelycorrected by the removal and replacement of the devicethrough costly invasive procedures. Given the broad scope
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Corresponding author: Reynolds, M.M. ([email protected]).
140 Trends in Biotechnology, March 2014, Vol. 32, No. 3
of medical device use and the physiological environmentsto which they are exposed makes the design of antifoulingmaterials a challenge requiring multiple avenues ofapproach.
In order to design materials that can combat the nega-tive effects associated with surface biofouling, we mustfirst consider the process involved [7]. Although the exactmechanisms of attachment of biological agents to the sur-face of medical devices is not well understood, physical andchemical surface properties are known to influence thetype and extent of surface fouling [8]. Upon insertion intoa liquid environment, a conditioning layer immediatelyforms, composed of lipids and glycoproteins, on the devicesurface. The composition of the conditioning layer is dic-tated by the device surface properties, including chargeand hydrophilicity, and environmental factors such as pHand temperature. The composition of the conditioninglayer subsequently influences what types of bacterialstrains can colonize the surface and the likelihood ofthrombus formation [8]. Once a suitable environment forattachment is established, bacterial species are capable ofadhering to the surface and proliferating into microcolo-nies, eventually forming biofilms. Biofilms found on blood-contacting devices often include a large portion of hostclotting proteins and immune cells intended to isolate theinfection and prevent the formation of sepsis [5,6].
Bacterial biofilms are encased in a protective shield ofexopolysaccharides, which increases the resistance of bac-teria to antimicrobial agents 1000-fold compared to bac-teria growing in suspension [8,9]. As a result, the failedimmune response results in the additional accumulation ofbiomolecules on the device surface, accentuating the for-mation of thrombus [5,10]. The surface biofouling results inloss of device function, ranging from obstruction to dama-ging surrounding healthy tissues (Figure 1). Ultimately,mature biofilms detach from the surface of the device and
environment.
Biofouling: chronic formation of a biofilm on a medical device surface, causing
the function of the device to be impaired.
Medical device: a material form, intended to serve a mechanical and
physiological function, which is interfaced in a biological system.
Thrombus: aggregation of proteins and platelets on a surface that results in the
formation of a blood clot.
Zwitterion: a neutral molecule that contains both positive and negative
charges.
Func�oningdevice
Device foulingThrombus and/orbacterial biofilm
forma�on
Implanted medical device
Biofouling agent
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Figure 1. Surface biofouling of an implanted medical device due to the adhesion of
bacterial colonies and/or thrombolytic agents.
Review Trends in Biotechnology March 2014, Vol. 32, No. 3
are released as infectious boluses or dangerous emboliassociated with life-threatening complications [8,11].
Materials design for resisting biofoulingMaintaining medical devices in a homeostatic environ-ment with the biological interface is key to their sustainedusage. Complications associated with fouled medicaldevices are often costly to repair for both the patientsand caretakers. According to the old adage, ‘an ounce ofprevention is worth a pound of cure’, the fabrication ofbiomaterials for medical devices has turned towards thedevelopment of materials that can inhibit surface biofoul-ing. The design of next-generation biomedical devices isprimarily aimed at preventing surface fouling throughpassive and active approaches by the manipulation ofphysical and chemical surface properties, respectively(Figure 2). The fabrication of materials is designed asantiadhesive, based on their ability to prevent the adhe-sion of noxious biomolecules, or antimicrobial by denatur-ing infectious microbes and subsequently restricting theproliferation of biofilms. Antimicrobial materials can bedesigned as either passive or active materials. Manipula-tion of surface properties to construct a passive antimicro-bial surface primarily includes functionalization of thesurface with antimicrobial peptides (Figure 2E), whichnot only neutralizes the pathogen, but also prevents theadhesion and subsequent formation of surface biofilms.Active approaches towards antimicrobial action primarilyrely on drug-eluting materials that neutralize pathogens,but only minimally inhibit surface adhesion. Ideally, abiomedical device will facilitate antifouling behavior whilesupporting the integration of the medical device into ahomeostatic state with the surrounding environment. Inthis review, we provide a summary of each technique usedfor resisting surface fouling and also present the concertedapproach that aims for the integration of biomaterials withsurrounding tissues and fluids.
(A)
(D) (E)
(B)
Hydrophillic surface
+ + + + + + + + + + +Ca�onic an�microbial surface
H H H H H H H HH H H H
HHHHHH
O O O O O
O O
Biomolecule funcsurface
Hydrophobic
Figure 2. Surface modification methods for combating device surface fouling using pas
adhesion-resistant coatings (A–C, F) and surfaces with antimicrobial properties (D–F).
Passive materials for resisting biofoulingHydrophilic surfaces
Hydrophilic low-fouling and nonfouling surfaces sharecommon structural and chemical properties such as elec-trical neutrality and the capacity to form hydrogen bonds[12]. Hydrophilic surfaces resist the adhesion of foulingagents to the material surface through the formation of aphysical barrier known as a hydration layer [12,13]. Thehydration layer is formed as a result of hydrogen bondingbetween the functional groups on the device surface andwater molecules in the environment. The preparation ofhydrophilic materials is achieved based on the inclusion ofchemical functionalities capable of forming hydrogenbonds on the monomeric units of the polymer backbone[13]. The effectiveness of the hydrophilic materials is basedon the strength of the hydration layer, which is dictated bythe physiochemical properties of the material, includingmolecular weights of the polymer and the conformation ofthe polymer chains.
The current gold standard material in the preparationof biomedical devices is polyethylene glycol (PEG) [14].PEG is an intrinsically low-fouling surface capable ofresisting nonspecific protein adsorption and cell adhesiondue to the formation of hydration layer with the surround-ing environment. Alternative antifouling materials withan improved resistance to a loss of function currently underconsideration are polyamides, polyurethanes, and natu-rally occurring polysaccharides, including chitosan anddextran [13,15]. Combinatorial synthesis of various mono-mer units incorporating a range of functional groups for theconstruction of superior hydrophilic antifouling surface arealso under exploration. However, prolonged exposure ofhydrophilic materials in a biological environment resultsin the destruction of the hydration layer, due to surfaceoxidation that inhibits the antifouling properties [13].
Hydrophobic surfaces
Rather than relying on the formation of a relatively labilehydration layer, hydrophobic materials are designed torepel the attachment of water and biomolecules alike.Hydrophobic materials are prepared by incorporating func-tional groups that resist hydrogen bonding onto the surfaceof the material. Medical devices with hydrophobic surfacesin the past were considered toxic to the host environmentdue to the inclusion of toxic components in materials coat-ings needed to render the surface hydrophobic. Recently,biocompatible fluorinated hydrophobic coatings have beenreported using silica colloids [16] or through the deposition
(F)
(C)
+ + + + + +-----H HH
H O
O
�onalized Drug elu�ng surface
surface Zwi�erionic adhesionresistant surface
TRENDS in Biotechnology
sive (A–E) and active (F) approaches. These approaches rely on the development of
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of a secondary polymer layer locked in place by a micro/nanoporous substrate termed slippery liquid infused por-ous surfaces (SLIPSs) [17,18]. Both formulation methodsare effective at reducing the adhesion of Staphylococcusaureus and Pseudomonas aeruginosa bacterial colonies onthe surface. The adhesion-resistant character of the sur-face was confirmed as the mode of action of this prepara-tion, based on the lack of biocidal action and minimalcytotoxicity towards healthy cells. Although current workdemonstrates a significant reduction in surface adhesion ofP. aeruginosa, it was noted that differences in the bacterialstrain did permit variability in surface attachment. Assuch, in a clinical setting where an abundance of bacterialstrains and thrombotic agents are present, the effective-ness of hydrophobic materials remains untested.
Zwitterionic charged coatings
Cytoplasmic membranes of cells are composed of zwitter-ionic lipids that create a nonthrombogenic surface [19].Taking a cue from nature, zwitterionic antifouling materi-als are prepared by incorporating positively and negativelycharged species into the polymeric backbone of materialsused in the fabrication of medical devices. The most fre-quently investigated zwitterionic materials are poly(sulfo-betaine) and poly(carboxybetaine) adhered tomethacrylate or acrylamide backbones [20]. Similar tohydrophilic materials, zwitterionic materials prevent non-specific adhesion of biofouling agents by maintaining acharge-neutral surface and forming a hydration layer onthe surface [13]. In contrast to hydrophilic surfaces, forwhich the hydration layer is maintained by weak hydrogenbonds, the hydration layer in zwitterionic materials istightly bound through electrostatic interactions. The moretightly held the hydration layer, the more effective thematerial is at resisting a disruption in the protective sur-face barrier, and therefore resisting the adhesion of foulingagents. As such, polyzwitterionic materials with balancedcharge distribution along the surface inhibit nonspecificadhesion and thereby reduce the incidence of both biofilmand thrombus formation [21,22]. Not unlike hydrophilicmaterials, however, over time the hydration layer of zwit-terionic materials is breached and adhered biomoleculesalter the electronic and chemical surface properties, lead-ing to surface biofouling.
Cationic charged coatings
The fabrication of surfaces with positive charge results inbroad-spectrum antimicrobial activity [23,24]. Althoughthe mechanism of action is still the subject of much debate,the general consensus is that the positive charge disruptsthe lipid membrane of microbes. This disruption causes theinternal contents of the microbes to be expelled, renderingthem in a deactivated state that does not cause an infec-tion. Cationic groups are incorporated onto medical devicesby covalently functionalizing the backbone of polymericmaterials. Polysaccharide materials such as chitosan exhi-bit broad-spectrum antimicrobial activity against bacteria,viruses and fungi, while maintaining a low toxicity towardsmammalian cells [25,26]. The antimicrobial action of chit-osan is attributed to variations in the surface charge of thematerial due to the high nitrogen content of the polymer
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creating a cationic surface [26]. Despite demonstratedsuccess, the use of these materials is ultimately inhibitedby their limited reactivity and processability into func-tional medical devices.
Enhancement of the materials properties of naturallyoccurring polymers has been directed towards processingof the materials as blends with synthetic polymers [27].Concerns over the safety of such materials have beenraised with regards to the possibility that chronic exposureto environmental bacteria may lead to resistance to notonly the material, but also to other antibiotic agents.Furthermore, the incorporation of solely cationic function-alities into the material does not prevent the adhesion ofproteins or bacteria to the surface, which can create aprime environment for surface biofouling. The implemen-tation of materials that can balance antimicrobial activityand adhesion resistance is necessary. Synthetic materialsthat alternate between a cationic and zwitterionic statecan imbue both adhesion resistance and antimicrobialactivity to a surface [28,29].
Functionalization of material surfaces with biomolecules
The controlled deposition of biomolecules on the surface ofthe device can create a physical and chemical barrierbetween fouling agents and the device surface withoutimpairing the functionality of the device [30]. Surfacefunctionalization with biomolecules occurs through thecovalent attachment of proteins or peptides to the poly-meric backbone [31,32]. In some instances, functionalgroups on the polymer backbone are available for directreaction with functional groups on the biomolecule tosecure attachment. An alternative route of surface func-tionalization is through plasma treatment of the surface tocreate reactive radical species that readily react withfunctionalities on biomolecules to secure them to the sur-face [33–36].
Antimicrobial peptides are an innate component of theimmune system with bactericidal, viricidal, fungicidal, andtumoricidal properties [30]. Coating a surface with pep-tides offers certain advantages. Antimicrobial peptides areoften derived from naturally occurring sources, and assuch, they offer the advantage of being inherently biocom-patible and cationic charged peptides can impart antimi-crobial activity. Furthermore, because the surface hasalready been deposited with biomolecules in the form ofpeptides, the additional deposition of biomolecules asso-ciated with fouling to the device surface is inhibited[31,32,34,37]. The use of antimicrobial peptides is effectiveagainst a broad range of microbes including pathogenicbacterial strains of P. aeruginosa, S. aureus, Streptococcusgordonii, Fusobacterium nucleatum, and Porphyromonasgingivalis [31]. Such antimicrobial peptides have demon-strated significant resistance to the formation of biofilmson surfaces without inducing cytotoxicity towards healthycells. Additionally, metal stents coated with antimicrobialpeptide-functionalized polymers also reduce the adhesionof thrombus-forming fibrin by half [33]. However, it wasobserved that biofilm resistance was closely associatedwith the particular peptide being used and that bacterialresistance has been reported for both Gram-negative and -positive bacteria [30].
110°C37°CPBS 24 h
An�-adhesion Contact killing
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Figure 3. Layer by layer assembly of materials with antiadhesive top coatings that degrade over 24 h to leave a cationic antimicrobial fixed layer. Adapted, with permission,
from [44]. Abbreviation: PBS, phosphate-buffered saline.
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Multiple modes of antibiofouling activity in a single
material
Our discussion has focused on methods used for eithercontrolling the adhesion of fouling agents to device sur-faces or the neutralizing biofilm-forming pathogens.Although each approach is effective for the intended appli-cation, the combined activity of antiadhesive and antimi-crobial functionalities into a single material wouldultimately enhance the antifouling properties of medicaldevices [28,38]. The risk for device rejection due to noso-comial infection is greatest immediately following implan-tation, during which time microbes adhere to and colonizeon the surfaces [39,40]. Using a layer by layer approach,antimicrobial agents and antiadhesive components can beincorporated into a single material for improved efficacyagainst surface biofouling. A hydrophilic degradable topcoating traps adhered bacteria and is sloughed off to reveala bottom coating that exhibits both antifouling and anti-microbial activity due to the incorporation of biomoleculeson the surface (Figure 3). After 24 h of exposure, surfaceswithout a degradable top coat exhibit high amounts ofnonspecific adhesion to the surface, whereas degradationof the top coat all but eliminates any adsorbed species onthe surface. Although this approach is advantageous afterremoval of the degradable coatings, the remaining anti-microbial surface remains susceptible to adhesion of foul-ing agents.
Active materials for resisting biofouling: therapeuticeluting materialsSustained use of antibiotics leads to pathogenic resistanceand their ultimate ineffectiveness [41,42]. Rather thanfocusing on the systemic delivery of therapeutics, a moreproactive approach utilizes site-localized delivery frommaterials [43]. The effectiveness of these materials is ratednot only on their efficiency in preventing surface fouling,but also their biocompatibility with surrounding tissues.Chemical inhibition of fouling on device surfaces throughthe elution of a therapeutic incorporated into the polymermatrix has successfully inhibited the formation of biofilmsand thrombi [44–47]. The successful use of drug-elutingmaterials hinges on the controlled elution of the drug fromthe material matrix in order to deliver the proper dosage.The lifetime of use for drug-eluting materials is dependenton the total amount of drug that can be incorporated intothe material [48–50]. The combined use of these types of
materials with the antifouling technology described in theprevious section has successfully demonstrated animprovement in the prevention of device rejection [51–53].
Drug-eluting surfaces
Polymeric materials are known to be effective drug-deliv-ery vehicles based on their capacity for incorporatingtherapeutics into the material matrix as blends and thesubsequent controlled release properties. The incorpora-tion of therapeutic materials including antibiotics, immu-nosuppressants, and antiproliferative drugs into devicematrices is a well-established process with several formu-lations approved for use by the FDA [43,51–53]. Such drug-eluting materials are successful towards the inhibition ofboth biofilm- and thrombus-associated device fouling. Theeffectiveness of these materials is rated not only on theirefficiency in preventing surface fouling, but also theirbiocompatibility with surrounding tissues. Antiprolifera-tive drugs eluted from polymer stent coatings are known tointerfere with the natural vascular healing process, whichcan lead to device failure as a result of non-integration withthe biological environment [54]. Furthermore, the sus-tained use of antibiotics leads to pathogenic resistance,resulting in a decrease in their effectiveness over time[41,42]. In addition, the inclusion of a single antimicrobialagent does not guarantee neutralization of all infectiousagents that can be encountered. The prolonged use of drug-eluting materials is not feasible due to the limited capacityof polymeric materials for incorporating therapeutics intothe device matrix.
NO: a single therapeutic for antimicrobial and
antithrombotic action
Perhaps the most ubiquitous of all biomolecules, NO isgenerated as a part of the healthy function of mostnucleated cells in the human body and is responsible forcellular signaling process in the cardiovascular, immune,and nervous systems [55–60]. The production of NO is aresult of the reaction of L-arginine with NO synthase(NOS), of which there are three: endothelial NOS (eNOS),nervous NOS (nNOS), and immune NOS (iNOS) (Figure 4)[61–63]. The effect of NO is concentration dependent,ranging from proliferative and protective effects at lowconcentrations, to cytotoxic at higher concentrations,and each NOS enzyme is responsible for regulating differ-ent physiological conditions based on the amount of
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Natural homeostasis Immune responsesEndothelial cells and neurons
eNOS,nNOS
Con�nuously expressed
Cell signalingOxida�ve stress Induces apoptosis
iNOS
Vasodila�on
Regulatesplatelet ac�va�on
(1-30nM) (>100nM)Irregulari�es trigger iNOS
Macrophages, platelets, immune cells
Triggered byinfec�ous agents, stress
inflamma�on
L-arginine
NO NO
DNA damageTRENDS in Biotechnology
Figure 4. Role of NO in regulating a homeostatic environment and generating an immune response. Abbreviations: eNOS, endothelial NO synthase; iNOS, immune NO
synthase; nNOS, nervous NO synthase.
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generated NO. Both eNOS and nNOS maintain a lowoutput of NO on cellular surfaces, because normal physio-logical function in healthy hosts and a deficiency in NO areclosely associated with the formation of arterial thrombus[64–66]. However, iNOS is associated with immuneresponses and is the only NOS enzyme in which NOgeneration can be induced as result of inflammation orinfection [67,68]. As such, the levels of NO generated byiNOS are high and aimed at creating cytotoxic and biocidaleffects. Macrophages are the primary sources of NO gen-erated during immune responses, and the subsequentantimicrobial action of NO is thought to occur via themutation of microbial DNA, inhibition of DNA repairand synthesis in the microbe, and neutralization by per-oxynitrite [68].
NO is a biomolecule capable of antimicrobial, thrombo-lytic, and proliferative effects, therefore, NO-releasingmaterials are the subject of extensive investigations forcombating medical device failure. Rather than relying onenzymatic pathways for NO generation, small-moleculeNO donors, such as diazeniumdiolates, can be incorporateddirectly into polymeric matrices of existing devices asblended materials or covalently adhered to the surface[69]. The release of NO from donor molecules is triggeredby the heat and moisture found in physiological conditionsto give a site-localized effect, and the amount can be easilytuned depending on the composition of the donor molecule.The incorporation of NO-releasing groups into medicaldevices has subsequently established effectiveness againstthe formation of thrombi and biofilms [44–46,70,71].
Continuous generation of NO, regulated by eNOS, onthe surface of healthy cells and blood vessels regulates theinteraction of biomolecules with the surface and promotesthe proliferation of healthy blood vessels [66]. The incor-poration of a medical device into a blood-contacting envir-onment leads to areas that are not capable of promoting theproliferation of healthy cells through natural means.Therefore, the sustained release of NO at low dosageson the material surface can mimic the body’s own naturalsignaling processes and protection and proliferation ofhealthy cells. The generation of NO has been linked tothe growth of new healthy blood vessels as a result ofangiogenesis [72]. The angiogenic properties of NO havesuggested potential utility in re-endothelialization inwound-healing applications and reconstruction of blood
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vessels in applications where vascular grafts are used[72,73].
Ideally an NO material will be designed to work sym-biotically with a biological environment. To this end, anideal material will initially release a large bolus of NO(similar to what is expressed by iNOS) to facilitate anti-microbial action against the formation of biofilms, withouttriggering a thrombus that would cause an immuneresponse. After the initial implantation period when therisk for surface biofouling has been minimized, the releaseof NO should be tapered to levels associated with eNOS tofacilitate the proliferation of healthy cells on the materialsurface. Current NO-releasing materials, however, lackthe reservoirs of NO needed for long-term NO generation.Rather than relying on the use of incorporated NO donorsas a source, an alternative approach is to rely on availablesources of NO existing in the bloodstream to facilitate long-term NO generation. To this end, materials have recentlybeen reported that incorporate a NO catalyst into thepolymeric matrix of biomedical devices and are capableof generating NO from bioavailable NO donors foundcirculating in the bloodstream [74,75].
Methods to integrate devices with surrounding tissuesand fluidsCombating biofouling of a medical device is a continuousbattle to preserve the longevity of the device. A medicaldevice that has remained functional for many years cansuddenly fail as a result of late-stage thrombosis or thepresentation of latent infection [76]. Materials are nowbeing designed to integrate better into surrounding tissuesand fluids. The integration of the device into the biologicalenvironment via the adhesion and proliferation of healthycells on the device surfaces facilitates a symbiotic relationbetween the device and its biological environment [77–79].The device retains its functionality and biofouling is pre-vented as a result of healthy functioning of the naturalendothelium.
Concluding remarksMedical device technologies range from simple bandages tocoronary artery stents. Regardless of intended use, materi-als used to fabricate these devices must maintaintheir function over the intended lifetime of the device.Interactions between the material and the biological
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environment result in the deposition of proteins and patho-genic agents that have the potential to render the deviceunusable. In this paper, we summarized the approaches forcountering these effects and reducing the risk of devicefailure. Approaches involve the modification of surface prop-erties in the materials used to fabricate the device or theelution of chemical agents. Significant progress has beenmade for short-term applications. Ongoing research effortsare underway to create regenerative materials for medicaldevice technologies that can integrate with the surroundingtissues and fluids to not only replace the biological function,but also regenerate cells around the implant site.
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