Medical device biomaterials and antimicrobial resistance: exploring an overlooked research interface

Modern healthcare depends heavily on polymer-based medical devices (1). Among these, polyvinyl chloride (PVC) is widely used in has become the predominant material used in a wide range of single-use medical devices such as intravenous fluid bags, blood storage bags, urinary catheters, endotracheal tubes, and dialysis circuits.Over six decades, PVC has accounted for an estimated 40%a substantial proportion of medical plastics worldwide, valued for its flexibility, durability, transparency, chemical resistance and relatively low cost (2).However, in clinical practice, PVC-based medical devices are not compositionally or functionally uniform.Medical-grade PVC is formulated with different plasticizerplasticisers (e.g. DEHP, TOTM, DINCH), stabiliszers, and additives, and undergoes diverse manufacturing and steriliszation processes, surface treatment, geometry, fluid contact and duration of clinical use. Throughout this article, we therefore refer to specific PVC-based device types and formulations where possible , and we treat any generalised claims about "PVC" as provisional and device-dependent.While these devices have transformed patient care, they are also implicated incentral to the epidemiology of healthcare-associated infections (HAIs). Indwelling devices, including urinary and vascular catheters and devices used for respiratory support, can provide surfaces for microbial attachment and biofilm formation and are associated with important device-related infectious complicationsIndwelling devices such as urinary catheters, central venous catheters and ventilator circuits account for a substantial amount of device-associated infections, prolonged hospitalization, increased antimicrobial use and excess mortality (3). These infections can prolong hospitalisation and necessitate antimicrobial treatment, placing device-associated infection at an important intersection between infection prevention and antimicrobial use. However, the established risk associated with device use should be distinguished from the question of whether the biomaterial itself independently modifies infection or AMR-related outcomes.Consequently, device-associated infections sit at an important intersection between infection prevention and antimicrobial resistance (AMR).AMR has simultaneously emerged as one of the greatest threats to global health., An estimated 1.14 million deaths were attributable to bacterial AMR globally in 2021, with the burden projected to increase substantially over coming decadescausing an estimated 1.27 million deaths annually (4), and some analyses project that, if current trends continue, deaths from antibiotic-resistant bacteria could surpass those from cancer (5). In response, global efforts to combat AMR have expanded considerably, centered on antimicrobial stewardship, One Health surveillance, infection prevention and control. Within this broader agenda, however, the potential relevance of medical-device biomaterial characteristics to processes associated with AMR has received comparatively limited investigation. Biomaterials interact directly with microorganisms, host tissues and administered drugs, raising questions about whether material-specific properties could influence intermediate processes relevant to infection or antimicrobial exposure. Whether these interactions translate into clinically meaningful AMR outcomes remains uncertain.Despite these advances, one aspect of healthcare has received remarkably little attention within the AMR discourse: the materials through which care is delivered.In this article, we examine three potential pathways through which medical-device biomaterials, with particular attention to PVC, could intersect with processes relevant to AMR. We distinguish established material-and device-related phenomena from indirect or hypothesis-generating downstream links to AMR and identify the principal evidence gaps requiring further investigation. Rather than proposing PVC or other biomaterials as established determinants of AMR, we use these pathways as a framework for examining an underexplored research interface and for considering priorities for future microbiological, pharmacological and clinical research.We propose that medical device biomaterials represent an overlooked upstream component of the AMR ecosystem. Using PVC-based medical devices as an illustrative case because of their widespread use, we aimed to examine four biologically plausible pathways through which biomaterial properties could influence processes associated with resistance. These pathways are mechanistically distinct, but each represents a route through which the device material, rather than the microorganism alone, could plausibly influence infection or resistance outcomes. Although current evidence is insufficient to establish a definitive causal link, this hypothesis warrants further investigation to inform future research, infection prevention strategies and global AMR policy. Table 1 summarises selected device categories, their principal exposure routes and the most relevant biological interactions.PlausiblePotential PathwaysBefore considering biofilms as a potential pathway relevant to AMR, it is essential to distinguish resistance from tolerance and persistence. between AMR, tolerance, and persistence, as these terms describe related but mechanistically distinct phenomena. AMR refers to heritable genetic changes that enable microorganisms to grow or survive at antimicrobial concentrations that would inhibit susceptible strains, typically reflected as an increased minimum inhibitory concentration (MIC), using meansthrough mechanisms including target alteration, enzymatic degradation of drugs, permeability alteration, and efflux pumps (5). Antimicrobial tolerance allows bacterial populations to survive transient exposure to bactericidal antibiotics without an increase in MIC, whereas persistence describes the survival of a small phenotypic subpopulation that can resume growth once antimicrobial pressure is removed (5,6). These distinctions are particularly important in biofilms, where enhanced survival during antimicrobial exposure does not necessarily represent heritable resistance. is the survival of bacteria exposed to bactericides but without a modification of the MIC due to reasons including growth retardation, stress response, or residing in the extracellular polymeric substances (EPS) of a biofilm (6). Persistence represents a related but distinct phenomenon in which a small subpopulation of phenotypically tolerant cells transiently survives antimicrobial exposure without genetic change and can regrow once treatment pressure is removed (7).Biofilm formation provides one of the more biologically plausible pathways through which medical-device biomaterials could influence processes relevant to AMR. Environmental studies have shown that plastic surfaces can support microbial communities and facilitate interactions relevant to antimicrobial resistance.However, environmental microplastics differ substantially from indwelling medical devices in host exposure, flow conditions, microbial ecology, dwell time and antimicrobial pressure, limiting direct extrapolation to clinical settings (5,(8)(9)(10). Moreover, PVC-based devices encounter distinct protein conditioning films, flow regimes, microbial communities, and dwell times (5). These contextual factors strongly influence biofilm formation, leaching, and drug sorption.Medical dDevice surfaces can support microbial adhesion and biofilm development, providing a biologically plausible pathway through which biomaterial properties could influence processes relevant to AMR. but the magnitude and clinical significance of material-related differences depend on Ssurface chemistry, hydrophobicity, roughness, conditioning films, fluid flow conditions, device geometry, microorganism, and duration of use can all influence bacterial attachment and biofilm development (7)(8)(9)(10). (8,9); materialassociated biofilm behaviour is further shaped by bacterial physiology and the stage of biofilm development itself (8). Comparative studies have, for example, reported greater bacterial adhesion to some hydrophobic materials, including PVC, silicone and stainless steel, than to hydrophilic surfaces such as glass. However, these effects are highly context-dependent and vary according to the microorganism, surface characteristics and experimental conditions (8,9). Current evidence therefore supports material-dependent differences in microbial adhesion but does not establish that PVC carries a greater biofilm-or AMR-related risk than alternative medical-device materials. Evidence that PVC specifically increases resistance-gene transfer or clinical AMR outcomes relative to alternative device materials remains lacking.Evidence from environmental plastics further suggests that plastic-associated microbial communities can provide conditions favorable to microbial interactions relevant to AMR (11). However, environmental microplastics differ substantially from indwelling medical devices in host exposure, flow conditions, microbial ecology, dwell time and antimicrobial pressure, limiting direct extrapolation to clinical PVC devices (11)(12)(13)(14).Such evidence therefore supports biological plausibility but should not be interpreted as evidence of a PVCspecific clinical AMR effect.Once established, biofilms can enhance bacterial survival during antimicrobial exposure through mechanisms including reduced antimicrobial penetration, altered metabolic activity, stress responses and the formation of persister cells (15)(16)(17). These mechanisms predominantly represent antimicrobial tolerance and persistence rather than heritable resistance. Nevertheless, enhanced survival within biofilms may contribute to persistent or recurrent device-associated infections and repeated or prolonged antimicrobial exposure. These distinct biofilmassociated survival mechanisms are summarized in figure 1.A separate but related consideration is Within this conceptual framework of PVC-AMR pathways, PVC-based medical devices are most clearly implicated in promoting biofilm-associated tolerance and providing micro-environments in which horizontal gene transfer (HGT). The close spatial organization, high cell density and extracellular matrix within biofilms can create conditions conducive to the transfer of mobile genetic elements, including those carrying antimicrobial resistance genes (18). However, this evidence relates to HGT within biofilms generally and does not establish a PVC-specific effect. There is currently no direct comparative clinical evidence demonstrating that PVC-based medical devices increase HGT relative to alternative biomaterials or that PVC-associated biofilms result in increased clinical AMR. HGT therefore represents a biologically plausible link between device-associated biofilms and the dissemination of resistance determinants, but its specific contribution within PVC medical devices remains unconfirmed.A further hypothesis-generating consideration is co-selection between AMR and resistance to other selective agents. Environmental studies have demonstrated associations between metal resistance and antibiotic resistance genes, including co-occurrence on mobile genetic elements, while experimental evidence from microplasticassociated biofilms suggests that combined antibiotic and metal pressures can influence the abundance and coselection of resistance determinants (19)(20)(21). However, these findings derive predominantly from environmental systems and cannot be directly extrapolated to medical-device biofilms. Whether comparable co-selection processes occur on PVC or other device materials in vivo, and whether they influence clinically relevant AMR, remains unknown.Overall, the evidence is strongest for the ability of medical-device surfaces to support biofilm formation and for established biofilm-associated tolerance and persistence. Evidence linking these processes specifically to PVC is more limited, while the downstream progression from PVC-associated biofilm formation to HGT and clinically relevant AMR remains indirect and hypothesis-generating. Rather than directly generating resistance, PVC and other device biomaterials may provide microenvironments in which processes relevant to antimicrobial survival and the dissemination of resistance determinants can occur. Whether these effects differ meaningfully between biomaterials and translate into clinical AMR outcomes remains an important research gap.of existing resistance genes may occur, rather than directly generating de novo heritable resistance (12). The progression from PVC-associated biofilms and tolerance to clinically relevant AMR emergence is therefore best regarded as a conditional, hypothesis-generating pathway that depends on multiple ecological and clinical factors, including antibiotic exposure patterns, host immunity, and the surrounding microbial community. Evidence from deviceassociated infection and biomaterials research is therefore more relevant to assessing whether material properties influence microbial adhesion and biofilm development in medical devices.The formation of biofilm starts with the adhesion of microorganisms to the surface of the device, which is influenced by the nature of the surface material, its hydrophobicity and surface texture. Experimental studies suggest that these surface characteristics can influence bacterial attachment, although the extent to which PVC differs from other materials varies by microorganism, device type and clinical context (12). Comparative adhesion studies have reported higher colonization on hydrophobic materials such as PVC, stainless steel, and silicone than on hydrophilic glass. However, broader reviews indicate that this effect is highly conditiondependent and may be confounded by factors such as surface roughness, charge, porosity, rinsing protocols, and flow conditions (13)(14)(15). Recent reviews of biofilms across catheters, ventilator circuits, dialysis devices and prostheses similarly describe these communities as structured and strongly shaped by surface and flow conditions, without attributing device-associated risk to any single material (16). Device-surface biofilms are also exposed in situ to sub-inhibitory concentrations of catheter lock and flush solutions. In vitro studies of specific lock-solution components, including sodium citrate and heparin, show that such sub-inhibitory concentrations can increase rather than decrease biofilm formation in some staphylococcal strains, highlighting that these exposures can influence biofilm behavior in unpredictable ways (14,17). Whether this effect contributes specifically to AMR, rather than to biofilm quantity alone, has not been directly tested.Once attachment occurs, the substrate may influence not only the amount of biofilm formed but also its internal architecture. The extracellular polymeric substance of biofilms is a dynamic structural matrix whose composition and organization determine biofilm protection and morphology, and substrate chemistry can affect both adhesion kinetics and microcolony structure (15,17). To our knowledge, no study has systematically examined this question for PVC in a clinical device context. We therefore highlight it as a research priority rather than an established effect.However, once the biofilm is formed, it can increase the chances of survival of the bacteria when exposed to antimicrobials due to processes like decreased penetration, changes in metabolic status, and formation of persister cells. These effects primarily represent antimicrobial tolerance or persistence rather than heritable resistance (18,19). They may nevertheless prolong infection and increase the need for repeated or extended antimicrobial treatment. These distinct biofilm-associated survival mechanisms are summarised in Figure 1.A separate and mechanistically distinct consideration is horizontal gene transfer. The close spatial organisation and high cell density within biofilms can create conditions conducive to the exchange of mobile genetic elements, including those carrying antimicrobial resistance determinants (20). To our knowledge, no direct comparative clinical studies have shown that PVC-based medical devices increase horizontal gene transfer relative to alternative biomaterials or that such material-dependent effects contribute to antimicrobial resistance in vivo. We therefore consider this a plausible but unconfirmed pathway linking biomaterial-associated biofilms to antimicrobial resistance processes, rather than an established causal relationship specific to PVC.A second, more indirect pathway concerns additives plasticisers used in some flexible PVC-based medical devices. To achieve the flexibility needed for clinical use, these devices require chemical additives called plasticizers. Di(2-Ethylhexyl) Phthalate or DEHP has historically been extensively one of the most usedwidely used plasticisers in PVC medical products, although alternative plasticisers are increasingly used in some devices and regions. for many years as a plasticizer in numerous medical products made from PVC though it is now dominant only in particular devices depending on the geographic location, where plasticizers other than DEHP have started to be used. Because DEHP is not covalently bonded to the PVC polymer, it can migrate from medical devices into blood, intravenous fluids and other solutions in contact with the device (22). The extent of migration varies according to the device formulation and conditions of use, including the contacting fluid, flow rate and duration of exposure (23) Comparative studies illustrate this variability. Tokhadze and colleagues (27) examined evaluated plasticised PVC and several alternative infusion-tubing materials under simulated clinical conditions and found observed substantial material-dependent differences in drug loss (30). Diazepam showed marked absorption into some PVC-based systems, whereas insulin loss was predominantly attributable to surface adsorption and paracetamol showed demonstrated little or no measurable sorption. Importantly, alternative polymers were not uniformly superior to PVC; the direction and magnitude of drug loss depended on the specific drug-material combination (27). Similarly,Other studies of diazepam and tacrolimus have reported greater sorption with some PVC tubing than with alternative materials, although the magnitude of the effect depended on the drug, tubing material and infusion conditions similarly demonstrate that sorption varies across PVC and non-PVC administration tubing and according to the mode and conditions of infusion (31,32). These findings establish that PVC and other polymeric administration systems can alter delivery of selected drugs, but they do not demonstrate a general effect across all medications.The relevance of this phenomenon to antimicrobial therapy is less well established. Much of the available PVC sorption literature concerns non-antimicrobial drugs, particularly lipophilic such as diazepam and Evidence cannot therefore be directly extrapolated to many of which have different properties and may with PVC administration studies suggest that interactions are rather than evidence that PVC infusion systems systematically antimicrobial delivery is currently of drug loss within an administration does not necessarily indicate from tubing is not to of clinically important relevance depends on the proportion of drug the administered infusion the protein and whether the exposure a of drug interactions with plasticised PVC further supports the plausibility of adsorption and absorption at the interface while studies of delivery through other systems similarly demonstrate that device materials can alter delivery of selected and reviews of behaviour in other delivery routes However, these do not establish clinically antimicrobial both illustrate that material interactions can alter exposure for lipophilic or but literature is specific to intravenous and treatment or resistance in downstream with AMR is therefore hypothesis-generating. a specific antimicrobial undergoes substantial sorption within a particular administration reduced drug delivery could target antimicrobial exposure is an established in antimicrobial therapy more however, direct evidence demonstrating that PVC-associated sorption antimicrobial treatment or for is currently sorption should therefore be regarded as a consideration rather than an established through which PVC medical devices contribute to directly antimicrobial target and clinical outcomes across PVC and alternative administration systems are needed to determine whether this pathway has clinical of these interactions to antimicrobial therapy is less a specific antimicrobial undergoes clinically meaningful sorption within a particular administration the and target could be However, direct evidence demonstrating that drug loss from PVC-based infusion systems clinically antimicrobial treatment or for antimicrobial resistance remains We therefore consider drug-material sorption a plausible pathway that warrants investigation rather than an established linking PVC-based medical devices to devices are and evaluated on the of and clinical These have substantially reduced the risk of infections from manufacturing or AMR has over the The on AMR surveillance, infection antibiotic use, and in The on AMR further the on One Health surveillance, antimicrobial use, research and Within these medical-device biomaterials are not generally as distinct in AMR should not be interpreted as a in existing AMR but rather as the limited evidence that material-specific differences translate into clinically meaningful AMR One Health AMR and all within this biomaterials, however, are not as within AMR or policy. should not be interpreted as evidence that current are it the limited evidence available on whether material-specific differences influence or of material and device In the pathways, including the where consider device and while biological of materials is within a framework by such as In the to the and biological properties of medical devices and the prevention or of infection and microbial should also consider populations with high device exposure or increased to outcomes. and for example, may prolonged or repeated exposure to intravenous circuits, or other medical devices. may have systems that influence responses to chemical These may therefore be particularly populations for studies examining exposure, biofilm formation and drug-material However, to one pathway should not be to to all pathways, and should be evaluated an is of device materials and comparative of clinically relevant biomaterials, and of material-specific into pharmacological and studies would determine whether the pathways have measurable clinical or responses should rather than evidence demonstrating that particular biomaterials or formulations meaningfully influence antimicrobial exposure or AMR-related than proposing we an that biomaterial into research, and systematically device materials and plasticizers in clinical and infection comparative studies of infection and outcomes across different device materials, and that and consider available evidence on biofilm formation, leaching, and sorption. evidence can inform future if PVC-associated pathways are shown to influence pathways are to affect all and both the exposure to medical devices, such as prolonged intravenous or and the to for antibiotic or altered of such as care, where prolonged exposure to PVC devices with and systems, particular attention in future comparative risk may substantially the exposure and risk by these device biomaterials represent a relevant but of the broader AMR has examined three pathways through which properties of PVC and other device materials could intersect with processes relevant to AMR. Evidence supports several upstream of these pathways, including device-associated biofilm formation, migration and patient exposure, and drug-material However, evidence increasingly indirect when these phenomena are to downstream AMR and a causal relationship between PVC or other biomaterials and clinical AMR has not been been overlooked within the AMR their in healthcare and their direct interface with microorganisms and the used to treat priority is therefore not to AMR risk to particular biomaterials but to determine whether material-specific differences translate into clinically meaningful effects on antimicrobial exposure or outcomes. Comparative studies under conditions, with more of device composition and be essential to this evidence biomaterial characteristics into microbiological, pharmacological and clinical research could whether medical-device materials represent a within the determinants of AMR if provide an evidence for future or have four mechanistically distinct, biologically plausible Although current evidence is insufficient to establish a causal link between medical device biomaterials in and AMR, the biological plausibility of several pathways and the of investigation further research, with particular attention to patient may exposure or the AMR evidence to biomaterial may identify to infection prevention and that future are by a more of the factors AMR. evidence be particularly in where the burden of AMR is greatest and to healthcare-associated infections can have substantial