A Fully Functional Drug-Eluting Joint Implant

Despite advances in orthopedic materials, the development of drug-eluting bone and joint implants that can sustain the delivery of the drug and maintain the necessary mechanical strength in order to withstand loading has remained elusive. Here, we demonstrate that modifying the eccentricity of drug clusters and the percolation threshold in ultrahigh molecular weight polyethylene (UHMWPE) results in maximized drug elution and in the retention of mechanical strength. The optimized UHMWPE eluted antibiotic at a higher concentration for longer than the clinical gold standard antibiotic-eluting bone cement while retaining the mechanical and wear properties of clinically used UHMWPE joint prostheses. Treatment of lapine knees infected with Staphylococcus aureus with the antibiotic-eluting UHMWPE led to complete bacterial eradication and to the absence of detectable systemic effects. We argue that the antibiotic-eluting UHMWPE joint implant is a promising candidate for clinical trials.

[1]  John M. Wright,et al.  Effective Treatment of Osteomyelitis with Biodegradable Microspheres in a Rabbit Model , 2004, Clinical orthopaedics and related research.

[2]  C. Spiegel,et al.  Vacuum-mixing significantly changes antibiotic elution characteristics of commercially available antibiotic-impregnated bone cements. , 2011, The Journal of bone and joint surgery. American volume.

[3]  J. Lentino Prosthetic joint infections: bane of orthopedists, challenge for infectious disease specialists. , 2003, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[4]  Robert Langer,et al.  Advancing the field of drug delivery: taking aim at cancer. , 2003, Cancer cell.

[5]  S. Kurtz,et al.  The Clinical Performance of Highly Cross-linked UHMWPE in Hip Replacements , 2016 .

[6]  G. Prosser,et al.  AUSTRALIAN ORTHOPAEDIC ASSOCIATION , 1950 .

[7]  Mahmoud Y. Alkawareek,et al.  The In Vitro Susceptibility of Biofilm Forming Medical Device Related Pathogens to Conventional Antibiotics , 2014 .

[8]  Sara E Cosgrove,et al.  Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[9]  R. Barrack,et al.  Technique and Timing of Two-stage Exchange for Infection in TKA , 2007, Clinical orthopaedics and related research.

[10]  L. Pruitt,et al.  The influence of sterilization technique and ageing on the structure and morphology of medical-grade ultrahigh molecular weight polyethylene , 1998, Journal of materials science. Materials in medicine.

[11]  J. Kingdom,et al.  Vancomycin toxicity: a prospective study. , 1985, The Journal of antimicrobial chemotherapy.

[12]  Francesco Migliavacca,et al.  Contact stresses and fatigue life in a knee prosthesis: comparison between in vitro measurements and computational simulations. , 2004, Journal of biomechanics.

[13]  W. Scheld,et al.  The challenge of penicillin-resistant Streptococcus pneumoniae meningitis: current antibiotic therapy in the 1990s. , 1997, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  F. Kennedy,et al.  Comparison of Cross-Linked Polyethylene Materials for Orthopaedic Applications , 2003, Clinical orthopaedics and related research.

[15]  M. Inacio,et al.  The kaiser permanente national total joint replacement registry. , 2008, The Permanente journal.

[16]  R. Langer,et al.  An explanation for the controlled release of macromolecules from polymers , 1985 .

[17]  V. Yu,et al.  A mechanism of rifamycin inhibition and resistance in Pseudomonas aeruginosa. , 1996, The Journal of antimicrobial chemotherapy.

[18]  Heather N. Watson,et al.  Economic burden of periprosthetic joint infection in the United States. , 2012, The Journal of arthroplasty.

[19]  Chih-kuan Tung,et al.  Acceleration of Emergence of Bacterial Antibiotic Resistance in Connected Microenvironments , 2011, Science.

[20]  P. Zambelli,et al.  Orthopedic implant used as drug delivery system: clinical situation and state of the research. , 2008, Current Drug Delivery.

[21]  G. Tavaziva,et al.  Biofilm Antimicrobial Susceptibility Increases With Antimicrobial Exposure Time , 2016, Clinical orthopaedics and related research.

[22]  S. Kurtz The Clinical Performance of Historical and Conventional UHMWPE in Hip Replacements , 2016 .

[23]  Neil Rushton,et al.  Effects of lactic acid and glycolic acid on human osteoblasts: A way to understand PLGA involvement in PLGA/calcium phosphate composite failure , 2012, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[24]  P. Turner,et al.  Serum concentrations and bioavailability of rifampicin and isoniazid in combination. , 1976, British journal of clinical pharmacology.

[25]  O. Muratoglu,et al.  A surface crosslinked UHMWPE stabilized by vitamin E with low wear and high fatigue strength. , 2010, Biomaterials.

[26]  M. Coyle Manual of Antimicrobial Susceptibility Testing , 2005 .

[27]  W. Rose,et al.  Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus. , 2009, The Journal of antimicrobial chemotherapy.

[28]  Ann Marie Sastry,et al.  Analytical approximation of the percolation threshold for overlapping ellipsoids of revolution , 2004, Proceedings of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[29]  Kevin P. Francis,et al.  Rapid Direct Method for Monitoring Antibiotics in a Mouse Model of Bacterial Biofilm Infection , 2003, Antimicrobial Agents and Chemotherapy.

[30]  Johan Bellemans,et al.  Total knee arthroplasty: a guide to get better performance , 2005 .

[31]  Ruth K Wilcox,et al.  Experimental validation of finite element modelling of a modular metal-on-polyethylene total hip replacement , 2014, Proceedings of the Institution of Mechanical Engineers. Part H, Journal of engineering in medicine.

[32]  C. Joyner,et al.  Toxic effect of rifampicin on human osteoblast‐like cells , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[33]  Benjamin A Lipsky,et al.  Systemic antibiotic therapy for chronic osteomyelitis in adults. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[34]  B. Vernon Injectable Biomaterials: Science and Applications , 2011 .

[35]  P. Selzer,et al.  Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. , 2000, Journal of medicinal chemistry.

[36]  J. V. van Horn,et al.  Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery. , 2001, The Journal of antimicrobial chemotherapy.

[37]  Lisa A. Pruitt,et al.  Conventional and Cross-Linked Polyethylene Properties , 2005 .

[38]  S. Radin,et al.  Calcium phosphate ceramic coatings as carriers of vancomycin. , 1997, Biomaterials.

[39]  Linus Sandegren,et al.  Selection of Resistant Bacteria at Very Low Antibiotic Concentrations , 2011, PLoS pathogens.

[40]  A. Hanssen,et al.  Reinfection after two-stage revision for periprosthetic infection of total knee arthroplasty , 2011, International Orthopaedics.

[41]  A. Lilikakis,et al.  The effect of vancomycin addition to the compression strength of antibiotic-loaded bone cements , 2009, International Orthopaedics.

[42]  J. Higgins,et al.  Taking Aim at Cancer , 2016 .

[43]  R F Kyle,et al.  Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. , 1999, The Journal of bone and joint surgery. American volume.

[44]  V. Saikko,et al.  Advances in tribological testing of artificial joint biomaterials using multidirectional pin-on-disk testers. , 2014, Journal of the mechanical behavior of biomedical materials.

[45]  Klaus-Dieter Kühn,et al.  Bone Cements: Up-to-Date Comparison of Physical and Chemical Properties of Commercial Materials , 2000 .

[46]  G. Waertel The role of antibiotic-loaded cement in the treatment of an infection after a hip replacement. , 1996, The Journal of bone and joint surgery. American volume.

[47]  J. V. van Horn,et al.  Staphylococcus aureus biofilm formation on different gentamicin-loaded polymethylmethacrylate bone cements. , 2001, Biomaterials.

[48]  V. Kraus,et al.  Measurement of synovial fluid volume using urea. , 2007, Osteoarthritis and cartilage.

[49]  Khaled J Saleh,et al.  Antibiotic-impregnated cement spacers for the treatment of infection associated with total hip or knee arthroplasty. , 2007, The Journal of bone and joint surgery. American volume.

[50]  J. Parvizi,et al.  Vancomycin-modified implant surface inhibits biofilm formation and supports bone-healing in an infected osteotomy model in sheep: a proof-of-concept study. , 2012, The Journal of bone and joint surgery. American volume.

[51]  K. Francis,et al.  Real-Time In Vivo Bioluminescent Imaging for Evaluating the Efficacy of Antibiotics in a Rat Staphylococcus aureus Endocarditis Model , 2005, Antimicrobial Agents and Chemotherapy.

[52]  D. Bouchier‐Hayes,et al.  Development of resistant strains of Staphylococcus epidermidis on gentamicin-loaded bone cement in vivo. , 2002, The Journal of bone and joint surgery. British volume.

[53]  Rami K Korhonen,et al.  The effect of geometry and abduction angle on the stresses in cemented UHMWPE acetabular cups – finite element simulations and experimental tests , 2005, Biomedical engineering online.

[54]  Cornie Scheffer,et al.  Contact stresses in a patient-specific unicompartmental knee replacement , 2010, 2010 Annual International Conference of the IEEE Engineering in Medicine and Biology.

[55]  C. Schwartz,et al.  Development of porous UHMWPE morphologies for fixation of gel‐based materials , 2009 .

[56]  J. Kelm,et al.  Complications after spacer implantation in the treatment of hip joint infections , 2009, International journal of medical sciences.

[57]  E. Wickstrom,et al.  Vancomycin covalently bonded to titanium alloy prevents bacterial colonization , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[58]  Lei Jiang,et al.  Nanoporous microspheres: from controllable synthesis to healthcare applications. , 2013, Journal of materials chemistry. B.

[59]  C. Malone,et al.  Biofilm dispersal of community‐associated methicillin‐resistant Staphylococcus aureus on orthopedic implant material , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[60]  E. Graves National Hospital Discharge Survey. , 1989, Vital and health statistics. Series 13, Data from the National Health Survey.

[61]  A. Hanssen,et al.  Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. , 2013, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[62]  S. Ueng,et al.  Development of a biodegradable antibiotic delivery system. , 1999, Clinical orthopaedics and related research.

[63]  Clive T Lee The Mechanical Properties of PMMA Bone Cement , 2005 .

[64]  A. Signore,et al.  Leukocyte and bacteria imaging in prosthetic joint infection. , 2013, European cells & materials.

[65]  M. Bohner Designing ceramics for injectable bone graft substitutes , 2011 .

[66]  Zhong-min Wang,et al.  Estimation of 5-fluorouracil-loaded ethylene-vinyl acetate stent coating based on percolation thresholds. , 2007, International journal of pharmaceutics.

[67]  J. Vicente,et al.  Geometrical Tortuosity 3D Calculations in Infiltrated Aluminium Cellular Materials , 2014 .

[68]  Changqing Zhang,et al.  Gentamicin-Loaded Borate Bioactive Glass Eradicates Osteomyelitis Due to Escherichia coli in a Rabbit Model , 2013, Antimicrobial Agents and Chemotherapy.

[69]  J. Surdam,et al.  The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. , 2015, The Journal of arthroplasty.

[70]  T. McIff,et al.  Increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique. , 2012, The Journal of bone and joint surgery. American volume.