Mesh Infection and Hernia Repair: A Review

Abstract

Background:

The use of a prosthetic mesh to repair a tissue defect may produce a series of post-operative complications, among which infection is the most feared and one of the most devastating. When occurring, bacterial adherence and biofilm formation on the mesh surface affect the implant's tissue integration and host tissue regeneration, making preventive measures to control prosthetic infection a major goal of prosthetic mesh improvement.

Methods:

This article reviews the literature on the infection of prosthetic meshes used in hernia repair to describe the in vitro and in vivo models used to examine bacterial adherence and biofilm formation on the surface of different biomaterials. Also discussed are the prophylactic measures used to control implant infection ranging from meshes soaked in antibiotics to mesh coatings that release antimicrobial agents in a controlled manner.

Results:

Prosthetic architecture has a direct effect on bacterial adherence and biofilm formation. Absorbable synthetic materials are more prone to bacterial colonization than non-absorbable materials. The reported behavior of collagen biomeshes, also called xenografts, in a contaminated environment has been contradictory, and their use in this setting needs further clinical investigation. New prophylactic mesh designs include surface modifications with an anti-adhesive substance or pre-treatment with antibacterial agents or metal coatings.

Conclusions:

The use of polymer coatings that slowly release non-antibiotic drugs seems to be a good strategy to prevent implant contamination and reduce the onset of resistant bacterial strains. Even though the prophylactic designs described in this review are mainly focused on hernia repair meshes, these strategies can be extrapolated to other implantable devices, regardless of their design, shape or dimension.

The repair of an abdominal wall defect by prosthetic mesh implant is today a common procedure with more than a million such surgical interventions per year conducted in the United States [1]. Since the first synthetic materials described by Usher et al. at the end of the 1950s, [2 –5], along with those later proposed by Lichtenstein for his method of tension-free repair [6], the use of a biomaterial for hernia repair has become standard procedure for this type of surgery. The benefits of prosthetic mesh implant over the traditional repair procedures of autoplasty or sutures include a substantial reduction in the incidence of hernia recurrence [7 –10].

The basic requirements of a prosthetic material for hernia repair were described in the 1950s [11]. Since then, research efforts have been targeted at designing and developing the ideal prosthetic material. Thus, a prosthetic mesh for hernia repair should induce minimal host inflammatory reactions and adhesions, good vascularization, good host tissue incorporation, and be resistant to infection [12 –14]. It should also be chemically inert, non-carcinogenic or allergenic, easily sterilized, and should adapt well to the defect under repair [15]. The use of such a material, however, is not completely exempt of complications. It has been well established that the foreign body reaction triggered in the host in response to the implant of a prosthetic material can give rise to a series of complications such as dehiscence and implant migration [16], seroma [17], adhesions and fistulas [18 –21], chronic pain [22 –24], intestinal obstruction [25], and infection [26 –28], among others.

Prosthetic infection is among the most devastating complications for the patient and is also a burden for the health care system. For open operations, incidences of infection have been estimated at 2% to 4% for inguinal hernia repair and 6% to 10% for incisional hernia repair [29]. For laparoscopic incisional hernia repair procedures, this incidence drops to 3.6% [15,30]. Overall, the prevalence of biomaterial infection is greater in incisional hernia, generally much more complex than inguinal hernia (e.g., hernia size, surgery duration). This is further supported that in many cases, the formation of incisional hernias has been facilitated by surgical site infection prior to hernia appearance. The risk of infection is also greater when surgery pursues the treatment of an incarcerated or strangulated hernia with or without bowel resection. The presence of microorganisms in the implanted mesh and surrounding tissues will modify the natural tissue repair and can jeopardize the remodeling process. This increases the risk of a patient suffering a hernia recurrence requiring a second surgery, thus raising rates of morbidity and mortality with the corresponding impacts on healthcare costs [31].

Stages of Prosthetic Infection

In every implanted biomaterial, whether it is used for hernia repair or not, the infection usually occurs at the moment of the implantation because of the entry of a small number of microorganisms through the surgical wound, mainly from the skin and mucosa of the patient, the hands of hospital staff, or the environment [32]. Once inside the organism, bacteria colonize the biomaterial surface and adjacent tissues [33]. In the presence of bacterial infection, the implanted mesh induces a reduction in the phagocytic activity of immune system cells against the infecting microorganisms, triggering the expression of protection mechanisms in metabolically active bacteria [34].

Bacterial adherence to the surface of a prosthetic mesh takes place in two stages: (a) one of rapid and reversible interaction between the microorganisms and mesh surface mediated by physico-chemical factors (gravitation and Van der Waals forces, electrostatic charge, hydrophobic interactions, chemotaxis, etc.), and (b) irreversible adherence of microorganisms to the substrate mediated by cell and molecular factors (adhesion proteins called adhesins and their coding genes) [35,36].

Once adherence takes place, some bacteria have the capacity to interact with others to form complex communities of sessile microorganisms strongly bound to the substrate known as biofilms [37]. Most of biofilms are composed of multiple bacterial strains and conduct to a polymicrobial infection [38]. One of the main features of a biofilm is the presence in their structure of an amorphous capsule composed of polysaccharide substances and extracellular matrix proteins secreted by the bacteria themselves that acts as a protection barrier for the microorganisms, increasing their resistance to the actions of drugs and immune system cells [39]. Within the biofilm, bacteria undergo a series of phenotypic modifications that differentiate them from their free counterparts [40,41], conferring the biofilm even more resistance, which may be between 10 and 1000 times greater than that shown by planktonic bacteria [42,43]. These aspects determine that prosthetic infections associated with biofilms are particularly difficult to eradicate, and usually require removal of the infected mesh and complete debridement of the implant site [44].

The development of a biofilm is controlled by a self-induced mechanism known as quorum sensing. This intra-cellular signaling pathway allows bacteria to communicate with surrounding microorganisms and is conditioned by environmental characteristics and the density of microorganisms present [39]. Other routes of communication exist among the microorganisms comprising the biofilm such as channels for the flow of water, nutrients, oxygen, and waste products. These channels determine that environmental conditions (osmotic pressure, pH, nutrient concentrations, concentrations of oxygen, debris, etc.) vary between the different zones of a single biofilm [45] and bacteria occur in different metabolic states depending on the zone inhabited [46]. Hence, the more metabolically active bacteria are found in the outermost regions of the biofilm where they are closer to a source of oxygen and nutrient flow. These microorganisms have the capacity to detach from the polysaccharide matrix and migrate to other implant regions where they become attached once again, and the cycle recommences, consolidating the infection [36]. In contrast, bacteria occupying deeper biofilm zones generally show anoxic habitats and a latent metabolism. This confers these microorganisms a slow proliferation rate, scarce metabolic activity, and greater resistance to antibiotics [46].

Some biofilm-forming bacteria have been closely associated with hospital-acquired and surgical site infections (SSI). These include Staphylococcus aureus and Staphylococcus epidermidis, two of the main microorganisms responsible for prosthetic infection [47,48]. Together with these, several bacteria of the genera Streptococcus and Enterobacter play a key role in the pathogenesis of infections associated with hernia repair meshes [27].

Biomaterials and Bacterial Adherence

The environment that surrounds the implanted biomaterial may favor bacterial adherence to its surface [49]. Given the damp nature of the environment, small protein-rich (fibronectin, fibrinogen, collagen, etc.) aqueous films form around the implant and adjacent tissues. These films, designated conditioning films, facilitate bacterial adhesion to the material, thus increasing the risk of prosthetic infection [31] and affecting the scarring process [50].

Prosthetic architecture is determined by a series of factors such as chemical composition, electrical charge, hydrophobicity, and the surface area, the topography—such as the roughness—of the material [51,52]. The type of biomaterial, i.e. synthetic, biological; its structure, e.g., laminar, reticular (meshes), composite; pore size (macroporous, microporous, non-porous); and, in addition, for woven or knitted materials, yarn configuration, i.e., monofilament, multi-filament, play a key role in bacterial adherence [31,41,53]. The more complex its architecture, the greater the risk the biomaterial may be colonized by microorganisms [54].

There is currently a great diversity of prosthetic materials for hernia repair. The classification of Amid, proposed in 1997 [55], has always been a reference and set the guidelines indicating the different materials to be used for hernia repair. However, the recent introduction of several materials has expanded clinical applications, and new classification schemes have been proposed [56]. The most recent scheme [57] classifies prosthetic materials into two large groups: Polymer-based and natural. In turn, polymer materials are divided into reticular, laminar, and composite. Finally, natural biomaterials include biological materials otherwise known as bioprostheses. The most representative characteristics of all these meshes regarding bacterial colonization are summarized in Table 1.

Table 1.

Classification of the Most Relevant Materials Utilized to Repair Abdominal Wall Defects and Their Susceptibility to Bacterial Contamination

Type of mesh	Most representative materials	Susceptibility to bacterial contamination
Polymer-Based (Synthetic) Meshes
Reticular (monofilament, multifilament)	Non-absorbable (PP, PE, PVDF)	High risk of adhesion at the mesh nodes. Multifilament > Monofilament. PE > PP, PVDF.
	Absorbable (PLA, PGA, TMC)	Absorbable > Non-absorbable.Hydrophilic components increase the risk of bacterial adhesion.
Laminar (microporous, non-porous)	Non absorbable (PTFE, ePTFE)	Wide surface prone to be colonized.Microporous > Non-porous.
	Absorbable (TMC)	Infrequent use due to the combination of a wide surface plus absorbable material.
Composites	Integrating material: Non-absorbable (PP, PE)	Barrier components provide a wide surface prone to be colonized by bacteria.
	Barrier: Absorbable (PEG, HA, PDS, cellulose, PCG) or non-absorbable (PTFE, ePTFE)	Absorbable barrier > Non-absorbable.

Type of mesh	Degradation of the collagen matrix	Sensitivity to bacterial contamination
Biologic Meshes (Biomeshes)
Crosslinked (allogenic, xenogenic)	Slow degradation of the collagen matrix	Controversial use in contaminated fields; lack of consensus.
Non-crosslinked (allogenic, xenogenic)	Fast degradation of the collagen matrix	Crossliking could enhance the bacterial adhesion to the mesh surface.
		Bacterial metalloproteases enhance the degradation of the biomesh.

ePTFE = expanded polytetrafluoroethylene; HA = hyaluronic acid; PDS = polydioxanone; PE = polyester; PEG = poly(ethylene glycol); PGA = poly(glycolic acid); PGC = poliglecaprone; PLA = poly(lactic acid); PP = polypropylene; PTFE = polytetrafluoroethylene; PVDF = polyvinylidene fluoride; TMC = trimethylene carbonate.

Synthetic meshes

Synthetic meshes, either knitted or woven, make up a large proportion of all the prosthetic materials used in hernia repair. The synthetic materials most commonly used are non-absorbable and include meshes made of polypropylene (PP), polyester (PE), or polyvinylidenfluoride (PVDF) yarns. Among the absorbable materials, we should mention polyesters made of lactic acid, glycolic acid, and trimethyl carbonate (TMC). These materials may be woven or knitted out of one or several filaments and have different-sized pores [58]. The behavior of meshes when exposed to bacterial infection varies according to the material implanted. There is clinical data to support the non-use of prosthetic material in a contaminated surgical field. In this condition, meshes made of fast degrading materials such as polyglactin may even provide less structural support and confer a greater risk of abdominal sepsis than non-absorbable meshes [59]. It has been suggested that, given their greater contact surface area, multi-filament meshes are more susceptible to biofilm development than monofilament prostheses [15,27,28,31,34,41,49,51 –54,58,62 –65]. This is further supported that meshes composed of PE, generally made of multi-filament yarns, are more sensitive to bacterial adherence than those made of PP or PVDF, essentially in monofilament configuration [27,31,53,60,61]. Pore size is also an influencing factor, such that meshes with large pores, also referenced as lightweight meshes, have a reduced contact area and may be therefore less prone to bacterial colonization than prosthetic meshes with smaller pores, also called heavyweight meshes [49,66].

Laminar synthetic materials

The laminar, or sheet, prostheses most used are of the non-absorbable type and are composed of polytetrafluoroethylene (PTFE) or expanded PTFE (ePTFE). Absorbable TMC sheet prosthetic meshes are less frequently employed. Sheet materials are generally microporous (pore size less than 10 mcm), though non-porous materials also exist [67]. All laminar materials have a large surface area susceptible to colonization. Despite this, several studies have shown that the risk of infection of these meshes is influenced by the presence of micropores, as bacteria are able to settle in these structures where they are protected against the actions of macrophages, which cannot penetrate the biomaterial [28,68 –70]. In contrast, non-porous sheet materials show a markedly reduced risk of infection and could be appropriate for use in contaminated fields [67].

Composite synthetic materials

Composite prostheses are composed of two or more materials. Generally, a main component is a tissue integrating material (reticular—woven or knitted—non-absorbable) and a second component acts as a barrier (absorbable or non-absorbable), preventing post-operative tissue attachment to the surgical site [71]. Despite the wide variety of available composites, there is evidence to suggest that these materials can provide an adequate environment for bacterial adherence, niche formation, and biofilm development due essentially to the large surface area provided by the barrier sheet, thus precluding their use in contaminated surgical fields [15,51 –54,64,66].

Biological materials

Biological prostheses, bioprostheses or tissue grafts, are composed of decellularized and delipidated tissues rich in collagen, such as dermis and small intestinal submucosa (allogenic or xenogenic grafts). These materials are by definition biodegradable and may be classified into two groups according to whether they have or not covalent bonds between collagen molecules as crosslinked or non-crosslinked, respectively. Crosslinks protect biomeshes from their degradation mediated by matrix metalloproteases [72] and lengthen the mesh's reabsorption time in the host [73]. There is currently debate regarding the use of a biomesh in a contaminated setting [74,75], and so far there is insufficient evidence to support the efficacy of these materials in the presence of infection [15]. Some authors have proposed that the presence of decellularized blood vessel channels in the biomesh structure confers the prosthesis an inherent advantage over synthetic materials because these channels promote rapid implant vascularization and the early arrival of macrophages in the case of bacterial infection [76]. Although there are experimental [76 –78] and clinical [12,59,79,80] data to suggest the good behavior of a biomesh when faced with infection, numerous studies have also revealed the high susceptibility of these materials to bacterial colonization [30,67,81 –84]. Clinical studies have also shown that the presence of crosslinks could induce bacterial adherence to biological materials [83]. Other studies [85] reported that crosslinked biological prostheses were safe with relatively low rates of recurrence, for the treatment of complex hernia. The lack of consensus reached along with the elevated costs of these materials and lack of official recommendation by the US's Food and Drug Administration (FDA) [15], have meant that collagen biomeshes are not recommended for use in a contaminated setting [86].

Besides the type of implanted material, a prosthetic infection will be conditioned by the contaminating microorganisms because not all bacteria have the same adherence properties and this will affect the affinity of each bacterial strain towards a given biomaterial [53]. For example, S. aureus was found to show a greater adherence affinity towards metal-type materials than S. epidermidis, which in turn adhered more to synthetic materials [31], especially those with a hydrophilic surface [64]. Similarly, biofilms formed by gram-negative bacteria such as Escherichia coli and Pseudomonas aeruginosa seem to be slightly less affected by the prosthetic implant's characteristics than are biofilms composed of gram-positive bacteria such as S. aureus [41].

Experimental Models of Prosthetic Infection

Given the great impacts of prosthetic infection for healthcare, it is essential that we determine the mechanisms that promote and favor bacterial adherence to the biomaterial surface to generate a sufficiently large body of data on which to base the best prophylactic or therapeutic strategy for each individual case [42]. To this end, in vitro and in vivo experimental models are useful. Results arising from such models along with those of retrospective and prospective clinical trials provide a large volume of information about the behavior of the different materials in the presence of bacterial infection. In the field of hernia repair, numerous studies have addressed prosthetic infection in the absence of antimicrobial treatment in an effort to establish the susceptibility of the different biomaterials to bacterial adherence and biofilm formation.

In vitro experimental models

One of the most rapid and economic ways of assessing bacterial adherence to the biomaterial surface is through the design of in vitro experimental models. These models allow for the easy control of a high number of parameters (substrate, temperature, pH, environmental conditions, flow, etc.) and the behavior of biomaterials exposed to one [47,54,62] or several bacterial strains [41,49,53,64,66,69,82,87] and to different concentrations of bacteria [88] can be simultaneously examined. It is also possible to use several culture media (liquid or solid) as the substrate for seeding and to vary the study time to examine the different stages of bacterial contamination and biofilm formation [42].

To adequately evaluate the vulnerability of the different prosthetic materials, it is important to select a suitable bacterial strain, preferably a biofilm former or a catalogued strain such as those belonging to collections such as the American Type Culture Collection (ATCC), which guarantee a good reproducibility of results [89]. Similarly, the dose employed to establish the prosthetic infection is an important variable if results are to be translated to human clinical practice. Studies have shown that in a bacterial contaminated environment, the presence of an implanted material will notably reduce the number of microorganisms necessary to trigger a prosthetic infection, such that a bacterial dose of only 10² CFU could be sufficient to establish a SSI [54,88].

Additionally, when the aim of the study is to evaluate the effectiveness of any antimicrobial treatment, it is common to carry out antibiotic susceptibility tests, as well as to determine the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of such treatments. These procedures should always be performed under standardized procedures, such as those protocols regulated by the European Committee of Antimicrobial Susceptibility Testing (EUCAST) or the U.S. Clinical and Laboratory Standards Institute (NCCLS) [90]. The choice of the standardized procedures to be used depends on the nature and composition of the implant. For example, the international standard method for the determination of antibacterial activity of antibacterial finished textiles products (ISO 20743) is applicable to all textile products. Other normalized test methods, as the American Standard Methods (ASTM), have been developed to evaluate non-leachable antimicrobial agents (ASTM E2149) or present on hydrophobic material (ASTM E2180).

The flexibility of in vitro studies contrasts with their main limitation: Poorly mimicking clinical contamination situations. For example, neither the materials tested nor the contaminating microorganisms are in contact with the complex network of immunological, cellular or biochemical mediators present in the host organism. Accordingly, in vivo experimental models are an ideal complement to such studies.

In vivo experimental models

Experimental animals can be used to analyze the effects of prosthetic infection on the tissue integration and vascularization of an implant along with the behavior of the different biomaterials in the presence of bacterial contamination. All procedures involving experimental animals need to be conducted under current directives relative to laboratory animal welfare, and require the approval of an institutional review board, or ethics committee, according to the ethics principles of reduction, replacement, and refinement (known as the three “Rs”) [91,92]. When designing in vivo models, it is highly recommended to include adequate control groups in order to properly evaluate the performance of the experimental groups in terms of bacterial adherence and effectiveness of the antimicrobial treatments. Furthermore, the sample size of each group should be optimized to obtain statistically relevant data [93].

The selection of the experimental animal is crucial to guarantee the utility and reliability of the results. The closer the morphological and physiological characteristics of the animal to those of human beings, the more translatable to clinical practice will be the data obtained. The rabbit has proved useful for models of hernia repair because of similarities with human beings in terms of the elasticity of the abdominal wall [94] and the structure and composition of the omentum [95]. Further, the rabbit shows good sensitivity to bacterial infection [67,89] and its body size is appropriate for creating medium hernial defects [89]. This animal has been used to address the repair of such defects in acute infection [67,68,70] and bowel infection [96] conditions. Because of their smaller size compared with the rabbit and easy housing, rodents have been often used to examine prosthetic mesh infection in models of ventral hernia [30], acute chronic hernia [51,84,97], and peritonitis [63,78,98]. Rodents have also been used in models of subcutaneous implantation [35,86], in which neither the biomaterial or contaminating bacteria make contact with the fascia and muscle planes of the abdominal wall.

Interventions in this type of experimental model are aggressive as the use of antibiotics would interfere with the prosthetic infection induced. We therefore recommend subjecting the animals to regular follow up exams to obtain data on health state and infection signs and thus establish trial end points for the more aggressive procedures, in full compliance with animal welfare guidelines and directives.

Once the study has ended, animals are euthanized so that biological specimens can be obtained for their processing and evaluation [89]. At this time point, visual inspection of the recovered biomaterial provides key information on both the behavior of the material in the presence of infection and the effect of the infection itself on host tissue incorporation. The efficacy of any antimicrobial treatment given can also be assessed. These observations will also serve to assess the performance of prosthetic meshes treated with an antimicrobial before implant compared with non-treated meshes. Table 2 lists some of the parameters that should be evaluated in an experimental model of hernia repair in infection conditions.

Table 2.

Macroscopic Observations Related to Contaminated Implants That Can Be Recorded Immediately after Animal Euthanasia

Infection Assessment—Main Features
Skin necrosis	Absence			Presence
Fistula	Absence			Presence
Swelling/Edema	Absence	Soft.Moderate area	Soft.Large area	Hard.Moderate area	Hard.Large area
Purulent material	Absence	A few sites along the suture line	All around the implant	Covering < 50% of surface	Covering > 50% of surface

Infection Assessment—Secondary Features
Vascularization	Normal	Moderate	Severe
Thrombosis	Absence	Moderate	Severe

Tissue Integration Assessment
Encapsulation	Absence	Moderate	Severe
Tissue integration	Complete	Partial integration	Delamination

Bacterial adherence

The methods used to assess bacterial adherence to the prosthetic surface span from the more traditional techniques to complex analysis systems using computer tools. Scanning electron microscopy (SEM) is among the most employed classic methods [49,62,64,67,69,87,88]. This imaging technique magnifies the surface of the contaminated biomaterial so that the implant zones that are most susceptible to bacterial colonization can be observed, such as the nodes of woven and knitted meshes, micropores of laminar prostheses [69], interstices of multi-filament meshes [64], and hydrophilic films of composites [64].

Bacterial growth on the prosthetic surface can be examined using techniques that determine in a semi-quantitative manner the expansion of the bacterial population after a given time of contamination. For this purpose, turbidimetric assays [47] and cell viability tests such as MTT [47], resazurin [82], or LIVE/DEAD^® [41] are often employed.

The total number of bacteria adhered to the prosthetic surface can be quantified using techniques that induce the detachment of microorganisms without destroying them so that they can be later counted as colonies growing on agar plates. To this end, prosthetic meshes are subjected to washing with vigorous agitation [53,62,64] or preferably to sonication in an ultrasound bath [54,66]. Using this latter method, it is possible to quantitatively recover bacteria adhered to a biomaterial surface [86]. For prosthetic materials of an intricate architecture or explanted meshes from experimental animals with host tissue remnants, samples may be subjected to scraping or homogenized in a stomacher prior to agitation or sonication. This mechanical process can lead to a loss of a proportion of the initial bacterial population and this needs to be taken into account when analyzing results [99].

The presence of biofilms on the surface of the prosthesis and tissues can be assessed by seeding the biomaterial with bacterial strains that have been genetically transformed to express fluorescent proteins that can be detected by fluorimetry and/or confocal laser microscopy [54]. Although attractive, the technology for this method, however, is not always available.

The use of immunohistochemical and histological procedures [67,69] is a useful strategy to examine the presence of bacterial biofilms on the prosthetic surface. Immunolabeling of bacteria, fluorescent in situ hybridization (FISH) and specific staining techniques (gram, methyl blue) provide valuable information of the spatial position of biofilms in prosthetic implants and tissues. Through the more conventional histological staining techniques (hematoxylin-eosin, Masson trichrome) it may be determined how infection affects the integration of a mesh within host tissue, and the presence of inflammatory cells can also be detected.

Polymerase chain reaction (PCR) is a molecular biology-based tool that specifically amplifies gene sequences, frequently utilized to identify the microorganisms responsible for the infection and to evaluate which genes are activated in the bacteria within the biofilm [100]. The high specificity of the PCR is enhanced when combined with other tools; it was recently demonstrated that the combination of both PCR and mass spectrometry the (Ibis T5000 technology) allowed the detection of a wide broad of bacteria in meshes explanted from patients who underwent SSI after ventral hernia repair [101]. Because of the high sensitivity and the possibility of evaluating several tissue samples simultaneously, the utilization of technologies such as Ibis T5000 for clinical diagnose is of great interest [100].

Design of Prophylactic Materials

To avoid a possible prosthetic infection, pre-operative prophylaxis with systemic antibiotics is common and especially recommended in high-risk patients [65]. Unfortunately, the prophylactic use of antibiotics cannot fully guarantee the prevention of post-operative infection will be prevented [28] and though there is evidence that antibiotic prophylaxis reduces the rate of SSI by almost 50% [102], clinical data suggest that this strategy, for example, is unable to prevent an infection following surgery for an inguinal hernia [103,104]. Moreover, data from clinical studies suggest that the antibiotic prophylaxis has a substantial impact on avoiding the mesh infection in open inguinal hernia repair, but not in laparoscopic or endoscopic procedures [105]. Such controversy suggests a need for other preventive measures applied at the time of surgery to avoid or at least minimize the risk of a prosthetic infection.

One of the most promising strategies developed so far is the use of prosthetic materials endowed with antimicrobial properties that prevent bacterial adherence and the formation of a biofilm on the implant surface [106]. The design of a prosthetic mesh resistant to infection is based on modifying its surface by coating the mesh with anti-adhesive substances [107,108], antimicrobial agents, essentially antiseptics or antibiotics [27,32], metals or metal ions [31,48,108] (summarized in Table 3), or inhibitors of the mechanisms that promote bacterial adherence [32]. These modifications should always involve absorbable, non-toxic materials of controlled degradation rate that do not affect the biomechanical properties or tissue integration of the implant [13].

Table 3.

Summary of the Most Representative Agents Utilized to Prevent Bacterial Contamination of Surgical Devices

Agent [type]	Used as	Bacterial strain [exp. model]	Ref.
Poly(ethylene glycol) [AA]	Compound	Staphylococcus aureus, Staphylococcus epidermidis [iv, IV]	[107]
Poly(ethylene oxide) [AA]	Compound	S. aureus, S. epidermidis [iv, IV]	[107]
Polysilazane-based polymers [AF]	Compound	Marine bacteria strains [iv]	[111]
Gentamicin [AB]	Dipping	S. aureus [iv]	[65]
	Dipping	Post-mesh herniorrhaphy infection [cs]	[113]
	Polymer coating	S. aureus, S. epidermidis, Escherichia coli [iv]	[119,120]
Vancomycin [AB]	Dipping	MRSA [IV]	[52]
	Polymer coating	S. aureus [IV]	[13]
	Polymer coating	S. aureus, S. epidermidis [iv, IV]	[123]
Vancomycin [AB] + allicin [AS]	Joint lavage	S. epidermidis [IV]	[133]
Ofloxacin [AB]	Polymer coating	E. coli [iv]	[14]
Ofloxacin + Rifampicin [ABs]	Polymer coating	Gram positive and negative strains [iv]	[124]
Ofloxacin + Amoxicillin [ABs]	Polymer coating	E. coli [IV]	[125]
Ciprofloxacin [AB]	Polymer coating	S. aureus, S. epidermidis, E. coli [IV]	[126]
Lysostaphin [EP]	Mesh coating	S. aureus [iv]	[129]
	Mesh coating	S. aureus [IV]	[130,131]
PHACOS [BP]	Mesh coating	MRSA [iv, IV]	[132]
Chlorhexidine [AS]	Dipping	Gram positive and negative strains [review]	[32]
Chlorhexidine [AS] + Silver [M]	Mesh coating	Gram positive and negative strains [iv,IV,cs]	[30,44]
Triclosan [AS]	Suture coating	Surgical site infections [cs]	[136]
	Mesh coating	S. aureus [IV]	[137]
Quaternary ammonium salts [AS]	Compound	Gram positive and negative strains [iv]	[138]
Nitric oxide [QC]	Mesh coating	S. aureus [IV]	[142,143]
Silver [M]	Nanoparticles	S. aureus [iv,IV]	[147]
	Mesh coating	E. coli [iv,IV]	[148]
Titanium [M]	Mesh coating	Gram-positive and negative strains [ic,IV]	[34,41]
Gold + palladium [Ms]	Mesh coating	S. epidermidis [iv, IV]	[48]

AA = antiadhesive; AB = antibiotic; AF = antifouling; AS = antiseptic; BP = biopolymer; cs = case report; EP = endopeptidase; iv = in vitro; IV = in vivo; M = metal; MRSA = methicillin-resistant S. aureus; QC = chemical compound.

Anti-adhesive substances

Anti-adhesive substances are utilized to prevent the biofouling formation on the surface of the biomaterials and host tissue, through modifying the interactions between the prosthetic material and the bacteria and the protein deposits present in the conditioning film that surrounds the implant [32]. Anti-adhesive coatings such as polyvinylpyrrolidone [109], poly(ethylene glycol) [107] and poly(ethylene oxide) [107], are usually hydrophobic and lead to a substantial reduction in the number of microorganisms adhered to the prosthetic surface as well as to the strength of adherence [110]. Polysilazane-based polymers are often utilized as anti-fouling compounds [111]. Additionally, anti-adhesive coatings such as poly(dimethylsiloxane) are used not only to control the bacterial adhesion to the mesh surface, but also to prevent the adhesion formation when the mesh is placed in direct contact with the visceral loops [112].

Antibiotic agents

Antibiotics are the antimicrobial agents most used in prosthetic coatings. During hernia repair surgery it is common to dip or soak the prosthetic mesh in an antibiotic solution such as gentamicin [33,65,113] or vancomycin [52] immediately before its implant. This simple, economic technique allows for the administration of an antibiotic at the local level. However, although this measure is often adopted, there is some controversy over its efficacy [52,114,115]. Despite data indicating that the measure serves to control a prosthetic infection [116], experimental studies [117] and clinical evidence [118] suggest that soaking a prosthetic mesh in an antibiotic solution offers no benefits over the systemic use of the antibiotic, due probably to the rapid diffusion and dilution of the antibiotic in the organism [62].

As an alternative to supplementing a prosthetic material with antibiotics, biomaterials may be coated with polymer systems that achieve the controlled and local release of drugs [27]. Immobilizing the antibiotic in the polymer coating offers several advantages with respect to the dipping or soaking method: The diffusion of the antibiotic is delayed, hereby eventually providing a greater efficacy of treatment at the local level and allowing the use of lower drug concentrations, thus minimizing toxicity and the risk of inducing bacterial resistance [14]. However, these coatings also have their limitations. The first is that it is not easy to evenly coat the biomaterial, and there is a risk of reducing pore diameter and modifying the mechanical properties of the prosthesis [14]. Secondly, not all coatings are able to release the drug in a slow and linear fashion, thus reducing its efficacy in a few hours [13]. Polymer coating thickness is also a crucial factor. The rate of drug release increases with decreasing coating thickness and its greater thickness will enhance the stiffness of the implanted material [13,14]. Ideally, prosthetic coatings should achieve the controlled release of antimicrobial agents over at least the first 3–4 d after mesh implant [14].

Several antibiotics have been used in polymer coatings for hernia repair materials. Junge et al. assessed the in vitro antibacterial efficacy of PVDF meshes coated with a polymer loaded with gentamicin [119,120], and host tissue ingrowth in these implants in in vivo experimental models in the absence of bacterial contamination [119 –122]. These prostheses proved effective against all strains tested but gentamicin-resistant E. coli, and featured good biocompatibility with no adverse effects. Other vancomycin-loaded polymer systems have been successfully used to coat PE meshes in an S. aureus–contaminated subcutaneous model [13] and PP meshes in a hernia repair model of acute S. aureus and S. epidermidis infection [123]. Other authors have examined in vitro the coating of PP meshes with polymers loaded with different concentrations of ofloxacin [14] or ofloxacin-rifampicin combinations [124]. These studies have shown that these meshes have great activity against gram positive and negative microorganisms along with minimal cytotoxicity. Ofloxacin used with amoxicillin in PP mesh polymer coatings has proved effective in a model of incisional hernia in the presence of E. coli [125]. Others have demonstrated in vitro the efficacy of ciprofloxacin coatings against S. aureus, S. epidermidis, and E. coli [126].

The extended use of antibiotics goes hand in hand with the appearance of new bacterial strains resistant to these agents [127] and determines a need to restrict the design and commercialization of antibiotic-releasing medical devices. Currently marketed in the United States, the AIGIS_RX ST^® Antibacterial Soft Tissue Repair Device (TYRX Inc., New Jersey, USA) is a lightweight PP material with an absorbable polymer coating for the controlled post-operative release of rifampicin and monocycline.

Antiseptic agents and other antimicrobial agents

The use of antibacterial agents of natural origin for prosthetic coatings reduces the risk of resistant strains emerging [128]. Natural peptides with inherent antimicrobial activity have been used in coatings for medical devices such as catheters [32], but few studies have examined their use with hernia repair prosthetics. Lysostaphin is a bacterial endopeptidase that specifically acts against bacteria of the genus Staphylococcus. This antibacterial agent has been successfully used in coatings applied to PP meshes contaminated in vitro [129] and to collagen biomeshes in a contaminated subcutaneous implant model [130,131]. The use of polymers of bacterial origin (biopolymers) to control the formation of methicillin-resistant Staphylococcus aureus (MRSA) biofilms on polythene terephthalate (PET) materials has been recently described [132]. Another antibacterial agent is allicin. This natural compound has been reported to inhibit the formation of biofilms of S. epidermidis in orthopedic devices [133].

Solutions of antiseptics such as chlorhexidine may also be used to pretreat a prosthetic material. These agents are mainly employed to clean the surgical zone though several medical devices impregnated in chlorhexidine exist including vascular catheters [32]. Also available is an ePTFE mesh impregnated with chlorhexidine diacetate-silver carbonate, the DualMesh^® Plus (W. L. Gore & Associates Inc., Delaware, USA). This hernia repair material approved by the FDA [62] has a wide antimicrobial spectrum against gram positive and negative bacteria [30,62], though it seems to show no substantial effect on methicillin-resistant strains [51]. Moreover, its use in patients has been linked to non-infectious fever [44] and to allergic reactions because of hypersensitivity to chlorhexidine [44], maybe because of the too fast local release of chlorhexidine, at high, cytotoxic concentrations.

The antiseptic triclosan is used in the manufacture of surgical suture thread with antimicrobial properties [134,135]. In a recent retrospective study including patients undergoing digestive tract surgery, the use of Vicryl^® Plus (Ethicon Endo-Surgery Inc., Ohio, USA), an absorbable polyglactin 910 suture material coated with triclosan, was observed to notably reduce the incidence of SSIs compared with non-coated sutures [136]. This antiseptic has also been successfully used in PP mesh coatings [137].

Polymer systems loaded with quaternary ammonium biocides are yet another option for prosthetic coatings [138,139]. These compounds, widely employed as disinfectants [140], have proved effective against several strains of gram positive and negative microorganisms [132,138,141]. Because of their antibacterial efficacy, their use as preventive coatings for medical devices has been proposed [138], though some authors argue that more work is needed to confirm that quaternary ammonium salts do not induce bacterial resistance [140].

Nitric oxide

Coating a prosthetic material with an agent that induces or potentiates the activity of immune cells such as nitric oxide (NO) is another strategy that can appreciably reduce bacterial adherence to the prosthetic surface [142]. Nitric oxide acts as an immune response modulator [143]. Activated macrophages synthesize large amounts of NO, the reactive intermediates of which (e.g., peroxynitrite, dinitrogen trioxide) have highly acute cytotoxic and cytostatic effects on pathogenic microorganisms [143,144]. Given the short half-life of NO, its use in prosthetic coatings could guarantee a good local antibacterial effect with minimal toxicity for the cells of the host organism [142].

Despite their good performance in vitro [142,143], it has been argued that NO-releasing polymer coatings may not be appropriate for macroporous meshes, because following implant macrophages are able to penetrate through the mesh pores and produce large quantities of NO thus canceling out the NO releasing effect of the implanted material [143].

Metals

Although without understanding the underlying mechanisms, the antibacterial effects of some metals have been known since ancient times [145]. Several studies have examined the possible applications of metals in the design of medical devices [108,144]. A recent study compared the efficacy of 23 antimicrobial coatings currently marketed in the European Union used on steel or glass contaminated with E. coli [146]. Its results indicate that coatings containing silver nanoparticles may be as effective as conventional antiseptics such as triclosan and quaternary ammonium, in in vitro conditions, although the authors of this study recognize that the ecotoxicological impacts of the use of such coatings need to be assessed.

In the field of hernia repair prosthetics, the efficacy of silver in combination with chlorhexidine has been demonstrated by the antibacterial mesh DualMesh^® Plus. Other prosthetic materials have also been used to test the antimicrobial efficacy of silver-containing treatments. Zhou et al. [147] designed a biomesh composed of porcine intestinal submucosa containing silver nanoparticles and assessed its in vitro behavior in the presence of several gram positive and negative bacteria and performance in an in vivo S. aureus–contaminated abdominal wall defect model. The results of this study revealed the optimal behavior of the biomaterial design, which was able to efficiently fight the bacterial contamination and was biocompatible with the host tissue. The efficiency of a macroporous PP prototype containing silver nanoparticles (C. R. Bard Inc., New Jersey, USA), has also been observed in an experimental model of incisional hernia in the presence of E. coli [148]. This prototype showed good antimicrobial behavior though its biocompatibility was altered with delayed healing when compared with the uncoated PP behavior, suggesting the need to address the issue of possible silver toxicity in the coating of this prosthetic prototype.

The prosthetic hernia repair material TiMESH^® (pfm Medical AG, Cologne, Germany) is composed of lightweight monofilament PP coated with titanium. Its antibacterial efficacy has been assessed in experimental conditions in vitro [41,49,62] and in vivo [34,63,119] with contradictory results. Although there is clinical evidence to suggest that the TiMESH implant may have benefits over the more conventional PP materials [149], the results of experimental studies indicate the opposite [49,63,119]. Further, it has been reported that the antimicrobial capacity of TiMESH is markedly reduced over that of DualMesh Plus [49].

The potential use of gold for coating prosthetics has also been addressed. Studies conducted in vitro have shown that fixing gold nanoparticles to the surface of PP does not alter the biomaterial's physico-chemical properties [150]. Saygun et al. [48] developed an innovative method of coating PP meshes with gold and gold-palladium alloys employing a metallizer used in SEM preparation techniques, and tested the actions of these coatings on S. epidermidis both in vitro and in vivo. These authors observed that both coatings gave rise to substantial reductions in bacterial adherence and biofilm formation, especially those containing gold-palladium. However, although these results are promising, palladium ions are known to affect the cell cycle in eukaryotic cells [151], such that the use of this metal in prosthetic coatings needs to be carefully assessed.

Future Perspectives

Work so far in the field of prosthetic infection has revealed some of the mechanisms involved in bacterial adherence and biofilm formation on the biomaterial surface and served to identify some of the features that will increase the susceptibility of a given material to its colonization by bacteria. However, despite these advances, the ideal prosthetic for use in a setting of infection remains to be developed.

Today the search for this ideal biomaterial has been aided by a multidisciplinary approach, such as the incorporation of new emerging disciplines such as nanoengineering or microinformatics, for the design and development of intelligent devices [106]. These tools can be used in highly innovative strategies to prevent SSIs or infections associated with prosthetic implants. An example would be the implant of biosensors to monitor certain physiological parameters in a patient as possible indicators of post-operative infection [152]. Even more futuristic is the development of prosthetic materials equipped with sensors that detect the early adherence of microorganisms and send a signal to a reservoir to initiate the local release of drugs to avoid implant contamination [106].

In the future, these intelligent devices could mean a great advance in the control of prosthetic infection, offering a way of rapidly and locally delivering antibiotics or other drugs although reducing the systemic toxicity of treatment and risk of new resistant strains emerging [153]. Clinicians could telemetrically follow each implant [154] so that any signs of prosthetic infection could prompt the appropriate treatment before the infection is consolidated.

Today several prototype devices exist based on such technological developments. Films have been designed to release highly controlled doses of gentamicin in response to an electrical stimulus [155] along with hip prostheses fitted with microelectromechanical systems capable of detecting the presence of bacteria and activating the release of antibiotics [106,153]. A recent design is a molecular diagnosis electronic device designated NanoCHIP^® Infection Control Panel (Savyon Diagnostics, Israel). This device rapidly and simultaneously identifies MRSA, vancomycin-resistant Enterococcus and Klebsiella pneumoniae carbapenemase-producing bacteria in samples obtained from patients at risk of infection [156].

Although highly promising, the development of these devices is costly given their complex design and manufacture and the need for multidisciplinary research groups in which scientists and clinicians work together. Further, their efficacy and potential use in the design of prophylactic prosthetic materials also requires multiple experimental studies [153].

Conclusions

Infections involving prosthetic implants are a devastating post-operative complication, not only in the case of hernia repair but also in all the surgical procedures entailing the implantation of any biomaterial into the patient's body. The most frequently used ways of preventing implant contamination are: (a) the prophylactic administration of antimicrobial agents via the systemic route, (b) local antimicrobial agent application by irrigating the surgical site or the implant of a material capable of the controlled release of an antimicrobial, or (c) combined systemic/local prophylaxis.

The use of a prosthetic material that releases antibacterial substances in a local controlled manner is a good preventive strategy to control infections associated with implants because it reduces the systemic toxicity of treatment. To optimize the performance of these materials, the drugs released should be non-antibiotic so that the emergence of resistant bacterial strains is minimized. In the foreseeable future, the incorporation of sensors in prosthetics to detect the presence of bacteria and activate the release of drugs before a biofilm develops will mean a huge advance in the design of prosthetic devices resistant to infection.

Footnotes

Acknowledgments

We thank Dr. Audrey Robyns for her careful reading of the manuscript and her comments.

Author Disclosure Statement

Drs. Pérez-Köhler, Bayon, and Bellón declare no conflict of interest.

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