Infections associated with medical device use can have serious consequences for patients. Such healthcare-associated infections are often challenging to treat because of the persistence of microbial biofilms and the presence of antimicrobial-resistant microorganisms. The risks of device-associated infections can be reduced by using medical devices with antimicrobial effects. In this Review, we discuss preclinical performance testing of medical devices with antimicrobial effects, including in vitro strategies, animal models and computational modelling. We examine the clinical performance of antimicrobial bone cements, urinary catheters, venous catheters and wound dressings. Rational preclinical test strategies are needed to obtain information to estimate how well a device will benefit the patient in clinical use. We outline the potential of ex vivo models, microphysiological systems, organoids and medical devices-on-chips as complementary testing strategies. To move preclinical tests from the bench to the bedside, we propose a systems approach to address the many interrelated aspects of medical device interactions using a question-based rubric.
Infections associated with medical devices are a major public health challenge that could be mitigated in part by devices with antimicrobial effects.
Microbial biofilm plays an important part in the pathogenesis of device-associated infections and is a key target of devices with antimicrobial effects.
Preclinical performance testing is essential for the understanding of antimicrobial performance and safety of medical devices.
In vitro antimicrobial performance testing of medical devices can be improved through a systems approach to develop a testing strategy, and the development of improved formats, such as ex vivo tissue models, microphysiological systems, organoids and medical devices-on-chips.
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Magill, S. S. et al. Multistate point-prevalence survey of health care-associated infections. N. Engl. J. Med. 370, 1198–1208 (2014).
Phillips, K. S., Wang, Y., Jayan, G. & Patwardhan, D. Antimicrobial and anti-biofilm medical devices: public health and regulatory science challenges in Antimicrobial Coatings And Modifications On Medical Devices (eds Zhang, Z. & Wagner, V. E.) 37–65 (Springer Publishing, 2017).
Grainger, D. W. et al. Critical factors in the translation of improved antimicrobial strategies for medical implants and devices. Biomaterials 34, 9237–9243 (2013).
Carnicer-Lombarte, A., Chen, S. T., Malliaras, G. G. & Barone, D. G. Foreign body reaction to implanted biomaterials and its impact in nerve neuroprosthetics. Front. Bioeng. Biotechnol. 9, 622524 (2021).
Vroman, L., Adams, A. L., Fischer, G. C. & Munoz, P. C. Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces. Blood 55, 156–159 (1980).
Krystel-Whittemore, M., Dileepan, K. N. & Wood, J. G. Mast cell: a multi-functional master cell. Front. Immunol. 6, 620 (2015).
Yang, J., Zhang, L., Yu, C., Yang, X. F. & Wang, H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res. 2, 1 (2014).
Prame Kumar, K., Nicholls, A. J. & Wong, C. H. Y. Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease. Cell Tissue Res. 371, 551–565 (2018).
Martin, C. J., Peters, K. N. & Behar, S. M. Macrophages clean up: efferocytosis and microbial control. Curr. Opin. Microbiol. 17, 17–23 (2014).
Arango Duque, G. & Descoteaux, A. Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 5, 491 (2014).
Ni Choileain, N. & Redmond, H. P. Cell response to surgery. Arch. Surg. 141, 1132–1140 (2006).
Lewis, K. Riddle of biofilm resistance. Antimicrob. Agents Chemother. 45, 999–1007 (2001).
Wood, T. K., Knabel, S. J. & Kwan, B. W. Bacterial persister cell formation and dormancy. Appl. Environ. Microbiol. 79, 7116–7121 (2013).
Nodzo, S. R. et al. Conventional diagnostic challenges in periprosthetic joint infection. J. Am. Acad. Orthop. Surg. 23, S18–S25 (2015).
Osmon, D. R. Microbiology and antimicrobial challenges of prosthetic joint infection. J. Am. Acad. Orthop. Surg. 25, S17–S19 (2017).
Parvizi, J. Orthopedic infections: no one is denying anymore that we have a problem! Knee Surg. Relat. Res. 31, 17 (2019).
Dapunt, U., Prior, B., Kretzer, J. P., Giese, T. & Zhao, Y. Bacterial biofilm components induce an enhanced inflammatory response against metal wear particles. Ther. Clin. Risk Manag. 16, 1203–1212 (2020).
Stickler, D. J. Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done. J. Intern. Med. 276, 120–129 (2014).
Rieger, U. M. et al. Bacterial biofilms and capsular contracture in patients with breast implants. Br. J. Surg. 100, 768–774 (2013).
Junaid, T., Wu, X., Thanukrishnan, H. & Venkataramanan, R. in Clinical Pharmacy Education, Practice And Research (ed. Thomas, D.) 425–436 (Elsevier, 2019).
Phillips, K. S., Patwardhan, D. & Jayan, G. Biofilms, medical devices, and antibiofilm technology: key messages from a recent public workshop. Am. J. Infect. Control. 43, 2–3 (2015).
Leigh, B. L. et al. Antifouling photograftable zwitterionic coatings on PDMS substrates. Langmuir 35, 1100–1110 (2019).
Souza, J. G. S. et al. Targeting pathogenic biofilms: newly developed superhydrophobic coating favors a host-compatible microbial profile on the titanium surface. ACS Appl. Mater. Interf. 12, 10118–10129 (2020).
Lee, S. W. et al. Biofilm removal by reversible shape recovery of the substrate. ACS Appl. Mater. Interf. 13, 17174–17182 (2021).
Lee, S. W., Phillips, K. S., Gu, H., Kazemzadeh-Narbat, M. & Ren, D. How microbes read the map: effects of implant topography on bacterial adhesion and biofilm formation. Biomaterials 268, 120595 (2021).
Cyphert, E. L. & von Recum, H. A. Emerging technologies for long-term antimicrobial device coatings: advantages and limitations. Exp. Biol. Med. 242, 788–798 (2017).
Gimeno, M. et al. A controlled antibiotic release system to prevent orthopedic-implant associated infections: an in vitro study. Eur. J. Pharm. Biopharm. 96, 264–271 (2015).
Williams, D. & Ashton, N. Therapeutic delivery device. US Patent US10744313B2 (2020).
Abdul-Aziz, M. H., Lipman, J., Mouton, J. W., Hope, W. W. & Roberts, J. A. Applying pharmacokinetic/pharmacodynamic principles in critically ill patients: optimizing efficacy and reducing resistance development. Semin. Respir. Crit. Care Med. 36, 136–153 (2015).
Gandhi, A., Matta, M., Garimella, N., Zere, T. & Weaver, J. Development and validation of a LC-MS/MS method for quantitation of fosfomycin — application to in vitro antimicrobial resistance study using hollow-fiber infection model. Biomed. Chromatogr. 32, e4214 (2018).
Wang, Y., Guan, A., Wickramasekara, S. & Phillips, K. S. Analytical chemistry in the regulatory science of medical devices. Annu. Rev. Anal. Chem. 11, 307–327 (2018).
US Food and Drug Administration. Appropriate use of voluntary consensus standards in premarket submissions for medical devices. FDA.gov https://www.fda.gov/media/71983/download (2018).
Wang, H., Garg, A., Kazemzadeh-Narbat, M., Urish, K. L. & Phillips, K. S. Moving toward meaningful standards for preclinical performance testing of medical devices and combination products with antimicrobial effects. In Antimicrobial Combination Devices 17–25 (ASTM International, 2020).
Wang, H. et al. An ex vivo model of medical device-mediated bacterial skin translocation. Sci. Rep. 11, 5746 (2021).
Bechert, T., Steinrucke, P. & Guggenbichler, J. P. A new method for screening anti-infective biomaterials. Nat. Med. 6, 1053–1056 (2000).
Ceri, H. et al. The Calgary biofilm device: new technology for rapid determination of antibiotic susceptibilities of bacterial biofilms. J. Clin. Microbiol. 37, 1771–1776 (1999).
Stepanovic, S., Vukovic, D., Dakic, I., Savic, B. & Svabic-Vlahovic, M. A modified microtiter-plate test for quantification of staphylococcal biofilm formation. J. Microbiol. Methods 40, 175–179 (2000).
Djordjevic, D., Wiedmann, M. & McLandsborough, L. A. Microtiter plate assay for assessment of Listeria monocytogenes biofilm formation. Appl. Env. Microbiol. 68, 2950–2958 (2002).
Bjarnsholt, T. et al. The impact of mental models on the treatment and research of chronic infections due to biofilms. APMIS 129, 598–606 (2021).
US Food and Drug Administration. General considerations for animal studies for medical devices. FDA.gov https://www.fda.gov/media/93963/download (2015).
Andes, D. R. & Lepak, A. J. In vivo infection models in the pre-clinical pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents. Curr. Opin. Pharmacol. 36, 94–99 (2017).
Petty, W., Spanier, S. & Shuster, J. J. Prevention of infection after total joint replacement. Experiments with a canine model. J. Bone Joint Surg. Am. 70, 536–539 (1988).
Lebeaux, D., Chauhan, A., Rendueles, O. & Beloin, C. From in vitro to in vivo models of bacterial biofilm-related infections. Pathogens 2, 288–356 (2013).
Moriarty, T. F. et al. Recommendations for design and conduct of preclinical in vivo studies of orthopedic device-related infection. J. Orthop. Res. 37, 271–287 (2019).
Bjarnsholt, T. et al. The in vivo biofilm. Trends Microbiol. 21, 466–474 (2013).
Lovati, A. B., Bottagisio, M., de Vecchi, E., Gallazzi, E. & Drago, L. Animal models of implant-related low-grade infections. A twenty-year review. Adv. Exp. Med. Biol. 971, 29–50 (2017).
Guiton, P. S., Hung, C. S., Hancock, L. E., Caparon, M. G. & Hultgren, S. J. Enterococcal biofilm formation and virulence in an optimized murine model of foreign body-associated urinary tract infections. Infect. Immun. 78, 4166–4175 (2010).
Witsø, E., Hoang, L., Løseth, K. & Bergh, K. Establishment of an in vivo rat model for chronic musculoskeletal implant infection. J. Orthop. Surg. Res. 15, 23 (2020).
Raju, D. R., Jindrak, K., Weiner, M. & Enquist, I. F. A study of the critical bacterial inoculum to cause a stimulus to wound healing. Surg. Gynecol. Obstet. 144, 347–350 (1977).
Netuschil, L., Auschill, T. M., Sculean, A. & Arweiler, N. B. Confusion over live/dead stainings for the detection of vital microorganisms in oral biofilms–which stain is suitable? BMC Oral. Health 14, 2 (2014).
England, M. R., Stock, F., Gebo, J. E. T., Frank, K. M. & Lau, A. F. Comprehensive evaluation of compendial USP <71>, BacT/Alert Dual-T, and Bactec FX for detection of product sterility testing contaminants. J. Clin. Microbiol. https://doi.org/10.1128/JCM.01548-18 (2019).
International Organization for Standardization. Sterilization of health care products — Microbiological methods — Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process. ISO.org https://www.iso.org/standard/70801.html (2019).
Pham, L. H. P. et al. Dissolvable alginate hydrogel-based biofilm microreactors for antibiotic susceptibility assays. Biofilm 5, 100103 (2023).
Shanks, N., Greek, R. & Greek, J. Are animal models predictive for humans? Phil. Ethics Human. Med. 4, 2 (2009).
van der Worp, H. B. et al. Can animal models of disease reliably inform human studies? PLoS Med. 7, e1000245 (2010).
von Herrath, M. G. & Nepom, G. T. Lost in translation: barriers to implementing clinical immunotherapeutics for autoimmunity. J. Exp. Med. 202, 1159–1162 (2005).
Reizner, W. et al. A systematic review of animal models for Staphylococcus aureus osteomyelitis. Eur. Cell Mater. 27, 196–212 (2014).
King, J. D., Hamilton, D. H., Jacobs, C. A. & Duncan, S. T. The hidden cost of commercial antibiotic-loaded bone cement: a systematic review of clinical results and cost implications following total knee arthroplasty. J. Arthroplasty 33, 3789–3792 (2018).
Kleppel, D., Stirton, J., Liu, J. & Ebraheim, N. A. Antibiotic bone cement’s effect on infection rates in primary and revision total knee arthroplasties. World J. Orthop. 8, 946–955 (2017).
Farhan-Alanie, M. M., Burnand, H. G. & Whitehouse, M. R. The effect of antibiotic-loaded bone cement on risk of revision following hip and knee arthroplasty. Bone Joint J. 103-B, 7–15 (2021).
Zheng, H. et al. Control strategies to prevent total hip replacement-related infections: a systematic review and mixed treatment comparison. BMJ Open 4, e003978 (2014).
Balato, G. et al. Bacterial biofilm formation is variably inhibited by different formulations of antibiotic-loaded bone cement in vitro. Knee Surg. Sports Traumatol. Arthrosc. 27, 1943–1952 (2019).
Tunney, M. M. et al. Biofilm formation by bacteria isolated from retrieved failed prosthetic hip implants in an in vitro model of hip arthroplasty antibiotic prophylaxis. J. Orthop. Res. 25, 2–10 (2007).
Pestrak, M. J. et al. Investigation of synovial fluid induced Staphylococcus aureus aggregate development and its impact on surface attachment and biofilm formation. PLoS One 15, e0231791 (2020).
Knott, S. et al. Floating biofilm formation and phenotype in synovial fluid depends on albumin, fibrinogen, and hyaluronic acid. Front. Microbiol. 12, 655873 (2021).
Foster, A. L. et al. Single-stage revision of MRSA orthopedic device-related infection in sheep with an antibiotic-loaded hydrogel. J. Orthop. Res. 39, 438–448 (2021).
Johnson, J. R., Kuskowski, M. A. & Wilt, T. J. Systematic review: antimicrobial urinary catheters to prevent catheter-associated urinary tract infection in hospitalized patients. Ann. Intern. Med. 144, 116–126 (2006).
Lam, T. B., Omar, M. I., Fisher, E., Gillies, K. & MacLennan, S. Types of indwelling urethral catheters for short-term catheterisation in hospitalised adults. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD004013.pub4 (2014).
Mandakhalikar, K. D. et al. Restriction of in vivo infection by antifouling coating on urinary catheter with controllable and sustained silver release: a proof of concept study. BMC Infect. Dis. 18, 370 (2018).
Centers for Disease Control and Prevention. Guideline for prevention of catheter-associated urinary tract infections (2009). CDC.gov https://www.cdc.gov/infectioncontrol/guidelines/cauti/background.html (2015).
Wang, H. et al. Effectiveness of antimicrobial-coated central venous catheters for preventing catheter-related blood-stream infections with the implementation of bundles: a systematic review and network meta-analysis. Ann. Intensive Care 8, 71 (2018).
Chong, H. Y., Lai, N. M., Apisarnthanarak, A. & Chaiyakunapruk, N. Comparative efficacy of antimicrobial central venous catheters in reducing catheter-related bloodstream infections in adults: abridged Cochrane systematic review and network meta-analysis. Clin. Infect. Dis. 64, S131–S140 (2017).
Allan, N. D., Giare-Patel, K. & Olson, M. E. An in vivo rabbit model for the evaluation of antimicrobial peripherally inserted central catheter to reduce microbial migration and colonization as compared to an uncoated PICC. J. Biomed. Biotechnol. 2012, 921617 (2012).
US Food and Drug Administration. Classification of wound dressings combined with drugs. FDA.gov https://www.fda.gov/media/100005/download (2016).
Alves, D. R. et al. Development of a high-throughput ex-vivo burn wound model using porcine skin, and its application to evaluate new approaches to control wound infection. Front. Cell. Infect. Microbiol. https://doi.org/10.3389/fcimb.2018.00196 (2018).
Yang, Q. et al. Development of a novel ex vivo porcine skin explant model for the assessment of mature bacterial biofilms. Wound Repair. Regen. 21, 704–714 (2013).
Zilberman, M. et al. Hybrid wound dressings with controlled release of antibiotics: structure-release profile effects and in vivo study in a guinea pig burn model. Acta Biomater. 22, 155–163 (2015).
Mana, T. S. C. et al. Preliminary analysis of the antimicrobial activity of a postoperative wound dressing containing chlorhexidine gluconate against methicillin-resistant Staphylococcus aureus in an in vivo porcine incisional wound model. Am. J. Infect. Control. 47, 1048–1052 (2019).
Kazemzadeh-Narbat, M. et al. Strategies for antimicrobial peptide coatings on medical devices: a review and regulatory science perspective. Crit. Rev. Biotechnol. 41, 94–120 (2021).
Sanz-Ruiz, P., Matas-Diez, J. A., Sanchez-Somolinos, M., Villanueva-Martinez, M. & Vaquero-Martin, J. Is the commercial antibiotic-loaded bone cement useful in prophylaxis and cost saving after knee and hip joint arthroplasty? The transatlantic paradox. J. Arthroplasty 32, 1095–1099 (2017).
Schwarz, E. M. et al. 2018 International Consensus meeting on musculoskeletal infection: research priorities from the general assembly questions. J. Orthop. Res. 37, 997–1006 (2019).
Bargon, R. et al. General Assembly, research caveats: proceedings of international consensus on orthopedic infections. J. Arthroplasty 34, S245–S253.e241 (2019).
Jackson, S., Hitchins, D. & Eisner, H. What is the systems approach? INSIGHT 13, 41–43 (2010).
US Food and Drug Administration. Leveraging real world evidence in regulatory submissions of medical devices. FDA.gov https://www.fda.gov/news-events/fda-voices/leveraging-real-world-evidence-regulatory-submissions-medical-devices (2021).
Mummery, C., van de Stolpe, A., Roelen, B. & Clevers, H. in Stem Cells: Scientific Facts And Fiction 2nd edn, 343–361 (Academic Press, 2014).
Guan, A. et al. Medical devices on chips. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-017-0045 (2017).
Ribet, D. & Cossart, P. How bacterial pathogens colonize their hosts and invade deeper tissues. Microbes Infect. 17, 173–183 (2015).
Sauer, M. M. et al. Catch-bond mechanism of the bacterial adhesin FimH. Nat. Commun. 7, 10738 (2016).
Emody, L., Kerenyi, M. & Nagy, G. Virulence factors of uropathogenic Escherichia coli. Int. J. Antimicrob. Agents 22, 29–33 (2003).
Shaked, H. et al. Unusual “flesh-eating” strains of Escherichia coli. J. Clin. Microbiol. 50, 4008–4011 (2012).
van Burik, J. A. & Magee, P. T. Aspects of fungal pathogenesis in humans. Annu. Rev. Microbiol. 55, 743–772 (2001).
Broekhuizen, C. A. et al. Staphylococcus epidermidis is cleared from biomaterial implants but persists in peri-implant tissue in mice despite rifampicin/vancomycin treatment. J. Biomed. Mater. Res. A 85, 498–505 (2008).
Niederholtmeyer, H., Chaggan, C. & Devaraj, N. K. Communication and quorum sensing in non-living mimics of eukaryotic cells. Nat. Commun. 9, 5027 (2018).
Anderson, M. J. et al. Efficacy of skin and nasal povidone-iodine preparation against mupirocin-resistant methicillin-resistant Staphylococcus aureus and S. aureus within the anterior nares. Antimicrob. Agents Chemother. 59, 2765–2773 (2015).
Wang, Y., Tan, X., Xi, C. & Phillips, K. S. Removal of Staphylococcus aureus from skin using a combination antibiofilm approach. npj Biofilms Microbiomes 4, 16 (2018).
Wang, Y., Leng, V., Patel, V. & Phillips, K. S. Injections through skin colonized with Staphylococcus aureus biofilm introduce contamination despite standard antimicrobial preparation procedures. Sci. Rep. 7, 45070 (2017).
Moreau-Marquis, S., Redelman, C. V., Stanton, B. A. & Anderson, G. G. Co-culture models of Pseudomonas aeruginosa biofilms grown on live human airway cells. J. Vis. Exp. https://doi.org/10.3791/2186 (2010).
Pedersen, R. M. et al. A method for quantification of epithelium colonization capacity by pathogenic bacteria. Front. Cell Infect. Microbiol. 8, 16 (2018).
Bucior, I., Tran, C. & Engel, J. Assessing Pseudomonas virulence using host cells. Methods Mol. Biol. 1149, 741–755 (2014).
Wang, Y. et al. Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell Mol. Gastroenterol. Hepatol. 5, 113–130 (2018).
Engevik, K. A., Matthis, A. L., Montrose, M. H. & Aihara, E. Organoids as a model to study infectious disease. Methods Mol. Biol. 1734, 71–81 (2018).
Kim, J., Hegde, M. & Jayaraman, A. Co-culture of epithelial cells and bacteria for investigating host-pathogen interactions. Lab Chip 10, 43–50 (2010).
van Oosten, M. et al. Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin. Nat. Commun. 4, 2584 (2013).
Konjufca, V. & Miller, M. J. Two-photon microscopy of host-pathogen interactions: acquiring a dynamic picture of infection in vivo. Cell Microbiol. 11, 551–559 (2009).
Felix, L. P., Perez, J. E., Contreras, M. F., Ravasi, T. & Kosel, J. Cytotoxic effects of nickel nanowires in human fibroblasts. Toxicol. Rep. 3, 373–380 (2016).
Cheng, G. et al. Detection of mitochondria-generated reactive oxygen species in cells using multiple probes and methods: potentials, pitfalls, and the future. J. Biol. Chem. 293, 10363–10380 (2018).
Li, W., Wang, J., Ren, J. & Qu, X. Endogenous signalling control of cell adhesion by using aptamer functionalized biocompatible hydrogel. Chem. Sci. 6, 6762–6768 (2015).
Ho, E., Karimi Galougahi, K., Liu, C. C., Bhindi, R. & Figtree, G. A. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol. 1, 483–491 (2013).
Morgenstern, M. et al. The value of quantitative histology in the diagnosis of fracture-related infection. Bone Joint J. 100-B, 966–972 (2018).
Sanders, W. E. Jr. & Sanders, C. C. Toxicity of antibacterial agents: mechanism of action on mammalian cells. Annu. Rev. Pharmacol. Toxicol. 19, 53–83 (1979).
US Food and Drug Administration. Use of international standard ISO 10993-1, “Biological evaluation of medical devices — part 1: Evaluation and testing within a risk management process”. FDA.gov https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and (2016).
Guan, A., Wang, Y., Phillips, K. S. & Li, Z. A contact-lens-on-a-chip companion diagnostic tool for personalized medicine. Lab Chip 16, 1152–1156 (2016).
Occhetta, P. et al. Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model. Nat. Biomed. Eng. 3, 545–557 (2019).
Polini, A. et al. Towards the development of human immune-system-on-a-chip platforms. Drug Discov. Today 24, 517–525 (2019).
Ramadan, Q. & Gijs, M. A. In vitro micro-physiological models for translational immunology. Lab Chip 15, 614–636 (2015).
Zaatreh, S. et al. Co-culture of S. epidermidis and human osteoblasts on implant surfaces: an advanced in vitro model for implant-associated infections. PLoS One 11, e0151534 (2016).
Jauregui, R. G. et al. IL-1β promotes Staphylococcus aureus biofilms on implants in vivo. Front. Immunol. 10, 1082 (2019).
Purwada, A. et al. Ex vivo engineered immune organoids for controlled germinal center reactions. Biomaterials 63, 24–34 (2015).
Henriksen, K. et al. P. aeruginosa flow-cell biofilms are enhanced by repeated phage treatments but can be eradicated by phage-ciprofloxacin combination. Pathog. Dis. https://doi.org/10.1093/femspd/ftz011 (2019).
Sandbakken, E. T. et al. Highly variable effect of sonication to dislodge biofilm-embedded Staphylococcus epidermidis directly quantified by epifluorescence microscopy: an in vitro model study. J. Orthop. Surg. Res. 15, 522 (2020).
Alhede, M. et al. Phenotypes of non-attached Pseudomonas aeruginosa aggregates resemble surface attached biofilm. PLoS One 6, e27943 (2011).
Haaber, J., Cohn, M. T., Frees, D., Andersen, T. J. & Ingmer, H. Planktonic aggregates of Staphylococcus aureus protect against common antibiotics. PLoS One 7, e41075 (2012).
Macias-Valcayo, A. et al. in Advances In Microbiology, Infectious Diseases And Public Health Vol. 15 (ed. Donelli, G.) 81–90 (Springer International Publishing, 2021).
Gupta, T. T. et al. Staphylococcus aureus aggregates on orthopedic materials under varying levels of shear stress. Appl. Environ. Microbiol. https://doi.org/10.1128/AEM.01234-20 (2020).
Gupta, T. T., Gupta, N. K., Burback, P. & Stoodley, P. Free-floating aggregate and single-cell-initiated biofilms of Staphylococcus aureus. Antibiotics 10, 889 (2021).
Alfa, M. J. & Howie, R. Modeling microbial survival in buildup biofilm for complex medical devices. BMC Infect. Dis. 9, 56 (2009).
Allan, J. M., Jacombs, A. S. W., Hu, H., Merten, S. L. & Deva, A. K. Detection of bacterial biofilm in double capsule surrounding mammary implants: findings in human and porcine breast augmentation. Plast. Reconstr. Surg. 129, 578e–580e (2012).
Arciola, C. R., Campoccia, D. & Montanaro, L. Implant infections: adhesion, biofilm formation and immune evasion. Nat. Rev. Microbiol. 16, 397–409 (2018).
Niu, W. A., Rivera, S. L., Siegrist, M. S. & Santore, M. M. Depletion forces drive reversible capture of live bacteria on non-adhesive surfaces. Soft Matter https://doi.org/10.1039/D1SM00631B (2021).
Moriarty, T. F., Grainger, D. W. & Richards, R. G. Challenges in linking preclinical anti-microbial research strategies with clinical outcomes for device-associated infections. Eur. Cell Mater. 28, 112–128 (2014).
Hossainy, S. & Prabhu, S. A mathematical model for predicting drug release from a biodurable drug-eluting stent coating. J. Biomed. Mater. Res. A 87, 487–493 (2008).
Tzafriri, A. R., Groothuis, A., Price, G. S. & Edelman, E. R. Stent elution rate determines drug deposition and receptor-mediated effects. J. Control. Rel. 161, 918–926 (2012).
Xu, Y., Kim, C.-S., Saylor, D. M. & Koo, D. Polymer degradation and drug delivery in PLGA-based drug–polymer applications: a review of experiments and theories. J. Biomed. Mater. Res. B 105, 1692–1716 (2017).
Saylor, D. M., Forrey, C., Kim, C. S. & Warren, J. A. Diffuse interface methods for modeling drug-eluting stent coatings. Ann. Biomed. Eng. 44, 548–559 (2016).
McGinty, S. & Pontrelli, G. A general model of coupled drug release and tissue absorption for drug delivery devices. J. Control. Rel. 217, 327–336 (2015).
McDermott, M. K. et al. Microstructure and elution of tetracycline from block copolymer coatings. J. Pharm. Sci. 99, 2777–2785 (2010).
Saylor, D. M., Kim, C. S., Patwardhan, D. V. & Warren, J. A. Modeling microstructure development and release kinetics in controlled drug release coatings. J. Pharm. Sci. 98, 169–186 (2009).
Saylor, D. M., Soneson, J. E., Kleinedler, J. J., Horner, M. & Warren, J. A. A structure-sensitive continuum model of arterial drug deposition. Int. J. Heat Mass Transf. 82, 468–478 (2015).
Levin, A. D., Vukmirovic, N., Hwang, C.-W. & Edelman, E. R. Specific binding to intracellular proteins determines arterial transport properties for rapamycin and paclitaxel. Proc. Natl Acad. Sci USA 101, 9463–9467 (2010).
Creel, C. J., Lovich, M. A. & Edelman, E. R. Arterial paclitaxel distribution and deposition. Circ. Res. 86, 879–884 (2000).
Saylor, D. M. et al. Strategies for rapid risk assessment of color additives used in medical devices. Toxicol. Sci. https://doi.org/10.1093/toxsci/kfz179 (2019).
Saylor, D. M., Chandrasekar, V., Elder, R. M. & Hood, A. M. Advances in predicting patient exposure to medical device leachables. Med. Devices Sensors 3, e10063 (2020).
Saylor, D. M., Adidharma, L., Fisher, J. W. & Brown, R. P. A biokinetic model for nickel released from cardiovascular devices. Regul. Toxicol. Pharmacol. 80, 1–8 (2016).
Saylor, D. M. et al. Predicting patient exposure to nickel released from cardiovascular devices using multi-scale modeling. Acta Biomater. 70, 304–314 (2018).
Sjollema, J. et al. In vitro methods for the evaluation of antimicrobial surface designs. Acta Biomater. 70, 12–24 (2018).
Griffiths, R., Lewis, A. & Jeffrey, P. in Models For Assessing Drug Absorption And Metabolism (eds Borchardt, R. T., Smith, P. L. & Wilson, G.) 67–84 (Springer Publishing, 1996).
Schierholz, J. M. & Beuth, J. Implant infections: a haven for opportunistic bacteria. J. Hospital Infect. 49, 87–93 (2001).
Tan, L. et al. Engineered probiotics biofilm enhances osseointegration via immunoregulation and anti-infection. Sci. Adv. https://doi.org/10.1126/sciadv.aba5723 (2020).
Vertes, A., Hitchins, V. & Phillips, K. S. Analytical challenges of microbial biofilms on medical devices. Anal. Chem. 84, 3858–3866 (2012).
US Food and Drug Administration. Public workshop — orthopedic device-related infections. FDA.gov https://www.fda.gov/medical-devices/workshops-conferences-medical-devices/public-workshop-orthopedic-device-related-infections-11132020-11132020 (2020).
International Organization for Standardization. ISO/TC 150 implants for surgery. ISO.org https://www.iso.org/committee/53058.html.
Centers for Disease Control and Prevention. Biggest threats and data. CDC.gov https://www.cdc.gov/drugresistance/biggest-threats.html (2021).
Foxman, B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am. J. Med. 113, 5S–13S (2002).
Gandelman, G. et al. Intravascular device infections: epidemiology, diagnosis, and management. Cardiol. Rev. 15, 13–23 (2007).
Maki, D. G., Kluger, D. M. & Crnich, C. J. The risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. Mayo Clin. Proc. 81, 1159–1171 (2006).
Koenig, S. M. & Truwit, J. D. Ventilator-associated pneumonia: diagnosis, treatment, and prevention. Clin. Microbiol. Rev. 19, 637–657 (2006).
Kurtz, S. M., Lau, E., Watson, H., Schmier, J. K. & Parvizi, J. Economic burden of periprosthetic joint infection in the United States. J. Arthroplasty 27, 61–65.e61 (2012).
Nguyen, A. K. et al. Effects of subcytotoxic exposure of silver nanoparticles on osteogenic differentiation of human bone marrow stem cells. Appl. Vitro Toxicol. 5, 10 (2019).
Zisi, A. P., Exindari, M. K., Siska, E. K. & Koliakos, G. G. Iodine-lithium-alpha-dextrin (ILαD) against Staphylococcus aureus skin infections: a comparative study of in-vitro bactericidal activity and cytotoxicity between ILαD and povidone-iodine. J. Hosp. Infect. 98, 134–140 (2018).
The Antimicrobial Index KnowledgeBase: gentamicin. Antibiotics.Toku-E.com https://antibiotics.toku-e.com/antimicrobial_664_9.html (2015).
Kovacik, A. et al. In vitro assessment of gentamicin cytotoxicity on the selected mammalian cell line (Vero cells). Adv. Res. Life Sci. https://doi.org/10.1515/arls-2017-0018 (2017).
Odore, R., Colombatti Valle, V. & Re, G. Efficacy of chlorhexidine against some strains of cultured and clinically isolated microorganisms. Vet. Res. Commun. 24, 229–238 (2000).
Lessa, F. C. et al. Toxicity of chlorhexidine on odontoblast-like cells. J. Appl. Oral. Sci. 18, 50–58 (2010).
The Antimicrobial Index KnowledgeBase: vancomycin. Antibiotics.Toku-E.com https://antibiotics.toku-e.com/antimicrobial_1182_32.html (2015).
Sofian, Z. M. et al. Cytotoxicity evaluation of vancomycin and its complex with beta-cyclodextrin on human glial cell line. Pak. J. Pharm. Sci. 25, 831–837 (2012).
Zhou, C. et al. In vitro synergistic activity of antimicrobial combinations against blaKPC and blaNDM-producing enterobacterales with blaIMP or mcr genes. Front. Microbiol. https://doi.org/10.3389/fmicb.2020.533209 (2020).
Yorganci, K., Krepel, C., Weigelt, J. A. & Edmiston, C. E. In vitro evaluation of the antibacterial activity of three different central venous catheters against Gram-positive bacteria. Eur. J. Clin. Microbiol. Infect. Dis. 21, 379–384 (2002).
Desai, D. G., Liao, K. S., Cevallos, M. E. & Trautner, B. W. Silver or nitrofurazone impregnation of urinary catheters has a minimal effect on uropathogen adherence. J. Urol. 184, 2565–2571 (2010).
Sams-Dodd, J. & Sams-Dodd, F. Time to abandon antimicrobial approaches in wound healing: a paradigm shift. Wounds 30, 345–352 (2018).
Fitzgerald, D. J. et al. Cadexomer iodine provides superior efficacy against bacterial wound biofilms in vitro and in vivo. Wound Repair. Regen. 25, 13–24 (2017).
Neacsu, I. et al. Novel hydrogels based on collagen and ZnO nanoparticles with antibacterial activity for improved wound dressings. Romanian Biotechnol. Lett. 24, 317–323 (2019).
Halstead, F. D. et al. In vitro activity of an engineered honey, medical-grade honeys, and antimicrobial wound dressings against biofilm-producing clinical bacterial isolates. J. Wound Care 25, 93–94 (2016).
Kostenko, V., Lyczak, J., Turner, K. & Martinuzzi, R. J. Impact of silver-containing wound dressings on bacterial biofilm viability and susceptibility to antibiotics during prolonged treatment. Antimicrob. Agents Chemother. 54, 5120–5131 (2010).
Cataldi, V. et al. In vitro activity of Aloe vera inner gel against microorganisms grown in planktonic and sessile phases. Int. J. Immunopathol. Pharmacol. 28, 595–602 (2015).
Rezvanian, M., Ahmad, N., Mohd Amin, M. C. & Ng, S. F. Optimization, characterization, and in vitro assessment of alginate-pectin ionic cross-linked hydrogel film for wound dressing applications. Int. J. Biol. Macromol. 97, 131–140 (2017).
Mohseni, M. et al. A comparative study of wound dressings loaded with silver sulfadiazine and silver nanoparticles: in vitro and in vivo evaluation. Int. J. Pharm. 564, 350–358 (2019).
Zhou, D., Yang, T. & Luo, G. Preparation of chitin-lysozyme anti-infective eco-friendly dressing and its effect on wound healing. AIP Conf. Proc. 2058, 020012 (2019).
Laverdiere, M., Boisvert, C., Auclair, C. & Elie, R. in vitro activity of framycetin sulfate (sofratulle) and chlorhexidine acetate (bactigras) tulle dressings against microorganism commonly found in wound infections. Curr. Ther. Res. 33, 6 (1983).
Bakhsheshi-Rad, H. R. et al. In vitro and in vivo evaluation of chitosan-alginate/gentamicin wound dressing nanofibrous with high antibacterial performance. Polym. Test. 82, 106298 (2020).
Boot, W. et al. An antibiotic-loaded hydrogel demonstrates efficacy as prophylaxis and treatment in a large animal model of orthopaedic device-related infection. Front. Cell Infect. Microbiol. 12, 826392 (2022).
Roche, E. D. et al. Cadexomer iodine effectively reduces bacterial biofilm in porcine wounds ex vivo and in vivo. Int. Wound J. 16, 674–683 (2019).
US Food and Drug Administration. Mission possible: how FDA can move at the speed of science. FDA.gov https://www.fda.gov/media/93524/download (2015).
US Food and Drug Administration. Factors to consider when making benefit-risk determinations in medical device premarket approval and de novo classifications. FDA.gov https://www.fda.gov/regulatory-information/search-fda-guidance-documents/factors-consider-when-making-benefit-risk-determinations-medical-device-premarket-approval-and-de (2019).
US Food and Drug Administration. Combination products. FDA.gov https://www.fda.gov/combination-products (2018).
US Food and Drug Administration. Frequently asked questions about combination products. FDA.gov https://www.fda.gov/combination-products/about-combination-products/frequently-asked-questions-about-combination-products#OCP (2020).
Kramer, D. B., Tan, Y. T., Sato, C. & Kesselheim, A. S. Ensuring medical device effectiveness and safety: a cross–national comparison of approaches to regulation. Food Drug Law J. 69, 1–23 (2014).
Maak, T. G. & Wylie, J. D. Medical device regulation: a comparison of the United States and the European Union. J. Am. Acad. Orthop. Surg. 24, 537–543 (2016).
Van Norman, G. A. Drugs devices: comparison of European and U.S. approval processes. JACC Basic. Transl. Sci. 1, 399–412 (2016).
Rocco, P., Musazzi, U. M. & Minghetti, P. Medicinal products meet medical devices: classification and nomenclature issues arising from their combined use. Drug Discov. Today 27, 103324 (2022).
US Food and Drug Administration. Tripartite biocompatibility guidance. FDA.gov http://www.clinicaldevice.com/VintageGuidances/1987-04%20G87-1_Tripartite_Bio_Guidance_from_FDA_REQUEST.pdf (1987).
US Food and Drug Administration. Recognized consensus standards. FDA.gov https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfstandards/search.cfm (2022).
The authors thank reviewers from the Center for Devices and Radiological Health — CDRH/OSEL/DBCMS, CDRH/OPEQ/OHT6 and CDRH/OPEQ/OHT4 — for critical feedback on the manuscript.
The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services. The findings and conclusions in this paper have not been formally disseminated by the US Food and Drug Administration and should not be construed to represent any agency determination or policy. The authors have no other competing interests to disclose.
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Wang, H., Chediak, J.A., Belmont, P.J. et al. Preclinical performance testing of medical devices with antimicrobial effects. Nat Rev Bioeng 1, 589–605 (2023). https://doi.org/10.1038/s44222-023-00060-6