A fully functional drug-eluting joint implant

Abstract

Despite advances in orthopaedic materials, the development of drug-eluting bone and joint implants that can sustain the delivery of the drug and maintain the necessary mechanical strength to withstand loading has remained elusive. Here, we demonstrate that modifying the eccentricity of drug clusters and the percolation threshold in ultra-high molecular weight polyethylene (UHMWPE) results in maximized drug elution and 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 the absence of detectable systemic effects. We argue that the antibiotic-eluting UHMWPE joint implant is a promising candidate for clinical trials.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Highly eccentric drug-eluting polyethylene.
Figure 2: Highly eccentric drug cluster morphology influences the mechanical and elution properties of the implant material.
Figure 3: Influence of the highly eccentric morphology of modified UHMWPE on its drug elution and mechanical properties.
Figure 4: In vivo evaluation of VPE in joint infection model.
Figure 5: In vitro evaluation of RVPE.
Figure 6: In vivo evaluation of RVPE in a lapine joint infection model.

References

  1. 1

    National Hospital Discharge Survey 777–782 (Centers for Disease Control and Prevention/National Center for Health Statistics, 2010).

  2. 2

    Paxton, E. W., Inacio, M., Slipchenko, T. & Fithian, D. C. The Kaiser Permanente National Total Joint Replacement Registry. Perm. J. 12, 12–16 (2008).

    Article  Google Scholar 

  3. 3

    Hip and Knee Arthroplasty: Annual Report 2015 (Australian Orthopaedic Association National Joint Replacement Registry, 2015).

  4. 4

    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 (2012).

    Article  Google Scholar 

  5. 5

    Kubista, B. et al. Reinfection after two-stage revision for periprosthetic infection of total knee arthroplasty. Int. Orthop. 36, 65–71 (2012).

    Article  Google Scholar 

  6. 6

    Lentino, J. R. Prosthetic joint infections: bane of orthopedists, challenge for infectious disease specialists. Clin. Infect. Dis. 36, 1157–1161 (2003).

    Article  Google Scholar 

  7. 7

    Segawa, H., Tsukuyama, D. T., Kyle, R. F., Becker, D. A. & Gustilo, R. B. Infection after total knee arthroplasty. A retrospective study of the treatment of eighty-one infections. J. Bone Joint Surg. Am. 81, 1434–1445 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Spellberg, B. & Lipsky, B. A. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin. Infect. Dis. 54, 393–407 (2012).

    Article  Google Scholar 

  9. 9

    Pioletti, D. P. et al. Orthopedic implant used as drug delivery system: clinical situation and state of research. Curr. Drug Deliv. 5, 59–63 (2008).

    CAS  Article  Google Scholar 

  10. 10

    Duncan, C. P. & Masri, B. A. The role of antibiotic-loaded cement in the treatment of an infection after a hip replacement. Instr. Course Lect. 44, 305–313 (1995).

    CAS  PubMed  Google Scholar 

  11. 11

    Radin, S., Campbell, J. T., Ducheyne, P. & Cuckler, J. M. Calcium phosphate ceramic coatings as carriers of vancomycin. Biomaterials 18, 777–782 (1997).

    CAS  Article  Google Scholar 

  12. 12

    Lin, S. S. et al. Development of a biodegradable antibiotic delivery system. Clin. Orthop. Relat. R. 362, 240–250 (1999).

    Article  Google Scholar 

  13. 13

    Burnett, R. S., Kelly, M., Hanssen, A. D. & Barrack, R. L. Technique and timing of two-stage exchange for infection in TKA. Clin. Orthop. Relat. R. 464, 164–178 (2007).

    Google Scholar 

  14. 14

    Jung, J., Schmid, N. V., Kelm, J., Schmitt, E. & Anagnostakos, K. Complications after spacer implantation in the treatment of hip joint infections. Int. J. Med. Sci. 6, 265–273 (2009).

    Article  Google Scholar 

  15. 15

    Kühn, K.-D. Bone Cements: Up-to-Date Comparison of Physical and Chemical Properties of Commercial Materials 89–93 (Springer, 2000).

    Google Scholar 

  16. 16

    Lee, C. in The Well-Cemented Total Hip Arthroplasty: Theory and Practice (eds Breusch, S. & Malchau, H. ) 60–66 (Springer, 2005).

    Google Scholar 

  17. 17

    Cho, C. H. et al. Elasto-plastic contact analysis of fatigue wear behaviour of UHMWPE tibial components. Japan. J. Clin. Biomech. 23, 373–379 (2002).

    Google Scholar 

  18. 18

    Korhonen, R. K., Kostinen, A., Konttinen, Y. T., Santavirta, S. S. & Lapallainen, R. The effect of geometry and abduction angle on the stresses in cemented UHMWPE acetabular cups – finite element simulations and experimental tests. BioMed. Eng. Online 4, 32 (2005).

    Article  Google Scholar 

  19. 19

    Lilikakis A & Sutcliffe, M. P. F. The effect of vancomycin addition to the compression strength of antibiotic-loaded bone cements. Int. Orthop. 33, 815–819 (2009).

    Article  Google Scholar 

  20. 20

    Meyer, J., Piller, G., Spiegel, C. A., Hetzel, S. & Squire, M. Vacuum-mixing significantly changes antibiotic elution characteristics of commercially available antibiotic-impregnated bone cements. J. Bone Joint Surg. Am. 93, 2049–2056 (2011).

    Article  Google Scholar 

  21. 21

    Thomes, B., Murray, P. & Bouchier-Hayes, D. Development of resistant strains of Staphylococcus epidermidis on gentamicin-loaded bone cement in vivo. J. Bone Joint Surg. Br. 84, 758–760 (2002).

    CAS  Article  Google Scholar 

  22. 22

    Xie, Z. et al. Gentamicin-loaded borate bioactive glass eradicates osteomyelitis due to Escherichia coli in a rabbit model. Antimicrob. Agents Ch. 57, 3293–3298 (2013).

    CAS  Article  Google Scholar 

  23. 23

    Fan, J. B., Huang, C., Jiang, L. & Wang, S. Nanoporous microspheres: from controllable synthesis to healthcare applications. J. Mater. Chem. B. 2013, 2222–2235 (2013).

    Article  Google Scholar 

  24. 24

    Bawa, R., Siegel, R., Marasca, B., Karel, M. & Langer, R. S. An explanation for the controlled release of macromolecules from polymers. J. Control. Release 1, 259–267 (1985).

    CAS  Article  Google Scholar 

  25. 25

    Guo, Q. H., Guo, S. & Wang, Z. M. Estimation of 5-fluorouracil-loaded ethylene-vinyl acetate stent coating based on percolation threshold. Int. J. Pharm. 333, 95–102 (2007).

    CAS  Article  Google Scholar 

  26. 26

    Yi, Y. B. & Sastry, A. M. Analytical approximation of the percolation threshold for overlapping ellipsoids of revolution. Proc. R. Soc. Lond. A 460, 2353–2380 (2004).

    Article  Google Scholar 

  27. 27

    Plumlee, K. P. & Schwartz, C. J. Development of porous UHMWPE morphologies for fixation of gel-based materials. J. Appl. Poly. Sci. 114, 2555–2563 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Amin, T. J., Lamping, J. W., Hendriks, K. J. & McIff, T. E. Increasing the elution of vancomycin from high-dose antibiotic-loaded bone cement: a novel preparation technique. J. Bone Joint Surg. Am. 94, 1946–1951 (2012).

    Article  Google Scholar 

  29. 29

    Collier J. P. et al. Comparison of cross-linked polyethylene materials for orthopaedic applications. Clin. Orthop. Relat. R. 414, 289–304 (2003).

    Article  Google Scholar 

  30. 30

    Ertl, P., Rohde, B. & Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties. J. Med. Chem. 43, 3714–3717 (2000).

    CAS  Article  Google Scholar 

  31. 31

    Laverty, G., Alkawareek, M. Y. & Gilmore, B. F. The in vitro susceptibility of biofilm forming medical device related pathogens to conventional antibiotics. Dataset Papers Sci. 2014, 250694 (2014).

    Article  Google Scholar 

  32. 32

    Goldman, M., Gronsky, R. & Pruitt, L. The influence of sterilization technique and ageing on the structure and morphology of medical-grade ultra-high molecular weight polyethylene. J. Mater. Sci.-Mater. M. 9, 207–212 (1998).

    CAS  Article  Google Scholar 

  33. 33

    Kurtz, A. & Patel, J. D. in UHMWPE Biomaterials Handbook 3rd edn (ed. Kurtz, S. M. ) 57–71 (Elsevier, 2016).

    Google Scholar 

  34. 34

    Besemer D. C. et al. Evidence of vitamin E grafting to polyethylene. In Orthopaedic Research Society 2013 Annual Meeting Poster 1055 (Orthopaedic Research Society, 2013).

  35. 35

    Cui, Q., Mihalko, W. M., Shields, J. S., Ries, M. & Saleh, K. J. Antibiotic-impregnated cement spacers for the treatment of infection associated with total hip or knee arthroplasty. J. Bone Joint Surg. Am. 89, 871–882 (2007).

    PubMed  Google Scholar 

  36. 36

    Mellor, J. A., Kingdom, J., Cafferkey, M. & Keane, C. T. Vancomycin toxicity: a prospective study. J. Antimicrob. Chemoth. 15, 773–780 (1985).

    CAS  Article  Google Scholar 

  37. 37

    Glaudemas, A. W. J. M., Galli, F., Pacilio, M. & Signore, A. Leukocyte and bacteria imaging in prosthetic joint infection. Eur. Cell. Mater. 25, 61–77 (2013).

    Article  Google Scholar 

  38. 38

    Rose, W. E. & Poppens, P. T. Impact of biofilm on the in vitro activity of vancomycin alone and in combination with tigecycline and rifampicin against Staphylococcus aureus. J. Antimicrob. Chemoth. 63, 485–488 (2008).

    Article  Google Scholar 

  39. 39

    Yee, Y. C., Kisslinger, B., Yu, V. L & Jin, D. J. A mechanism of rifamycin inhibition and resistance in Pseudomonas aeruginosa. J. Antimicrob. Chemoth. 38, 133–137 (1996).

    CAS  Article  Google Scholar 

  40. 40

    Bradley, J. S. & Scheld, W. M. The challenge of penicillin-resistant Streptococcus pneumoniae meningitis: current antibiotic therapy in the 1990s. Clin. Infect. Dis. 24 (Suppl. 2), S213–S221 (1997).

    CAS  Article  Google Scholar 

  41. 41

    Oral, E. et al. A surface cross-linked UHMWPE stabilized by vitamin E with low wear and high fatigue strength. Biomaterials 31, 7051–7060 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Lauderdale, K. J., Malone, C. L., Boles, B. R., Morcuende, J. & Horswill, A. R. Biofilm dispersal of community-associated methicillin-resistant Staphylococcus aureus on orthopedic implant material. J. Orthop. Res. 28, 55–61 (2010).

    CAS  PubMed  Google Scholar 

  43. 43

    Isefuku, S., Joyner, C. J. & Simpson, A. H. Toxic effect of rifampicin on human osteoblast-like cells. J. Orthop. Res. 19, 950–954 (2010).

    Article  Google Scholar 

  44. 44

    Moses, M. A., Brem, H. & Langer, R. Advancing the field of drug delivery: taking aim at cancer. Cancer Cell 4, 337–341 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Ambrose, C. G. et al. Effective treatment of osteomyelitis with biodegradable microspheres in a rabbit model. Clin. Orthop. Relat. R. 421, 203–299 (2004).

    Article  Google Scholar 

  46. 46

    Surdam, J. W., Licini, D. J., Baynes, N. T. & Arce, B. R. The use of exparel (liposomal bupivacaine) to manage postoperative pain in unilateral total knee arthroplasty patients. J. Arthroplasty 30, 325–329 (2015).

    Article  Google Scholar 

  47. 47

    Meyer, F. et al. Effects of lactic acid and glycolic acid on human osteoblasts: a way to understand PLGA involvement in PLGA/calcium phosphate composite failure. J. Orthop. Res. 30, 864–871 (2012).

    CAS  Article  Google Scholar 

  48. 48

    Bohner, M. in Injectable Biomaterials: Science and Applications (ed. Vernon, B. ) 24–39 ( Woodhead, 2011).

    Google Scholar 

  49. 49

    Hua, X. et al. Experimental validation of finite element modelling of a modular metal-on-polyethylene total hip replacement. Proc. Inst. Mech. Eng. H 228, 682–692 (2014).

    Article  Google Scholar 

  50. 50

    Neut, D. et al. Biomaterial-associated infection of gentamicin-loaded PMMA beads in orthopaedic revision surgery. J. Antimicrob. Chemoth. 47, 885–891 (2001).

    CAS  Article  Google Scholar 

  51. 51

    van de Belt, H. et al. Staphylococcus aureus biofilm formation on different gentamicin-loaded polymethylmethacrylate bone cements. Biomaterials 22, 1607–1611 (2001).

    CAS  Article  Google Scholar 

  52. 52

    Antoci, V. et al. Vancomycin covalently bonded to titanium alloy prevents bacterial colonization. J. Orthop. Res. 25, 858–866 (2007).

    CAS  Article  Google Scholar 

  53. 53

    Stewart, S. et al. Vancomycin-modified implant surface inhibits biofilm formation and supports bone-healing in an infected osteotomy model in sheep. J. Bone Joint Surg. Am. 94, 1406–1415 (2012).

    Article  Google Scholar 

  54. 54

    Castaneda, P., McLaren, A., Tavaziva, G. & Overstreet, D. Biofilm antimicrobial susceptibility increases with antimicrobial exposure time. Clin. Orthop. Relat. R. 474, 1659–1664 (2016).

    Article  Google Scholar 

  55. 55

    Xiong, Y. Q. et al. Real-time in vivo bioluminescent imaging for evaluating the efficacy of antibiotics in a rat Staphylococcus aureus endocarditis model. Antimicrob. Agents Ch. 49, 380–387 (2005).

    CAS  Article  Google Scholar 

  56. 56

    Kadurugamuw, J. L. et al. Rapid direct method for monitoring antibiotics in a mouse model of bacterial biofilm infection. Antimicrob. Agents Ch. 47, 3130–3137 (2003).

    Article  Google Scholar 

  57. 57

    Zhang, Q. et al. Acceleration of emergence of bacterial antibiotic resistance in connected microenvironments. Science 333, 1764–1767 (2011).

    CAS  Article  Google Scholar 

  58. 58

    Gullberg, E. et al. Selection of resistant bacteria at very low antibiotic concentrations. PLoS Pathog. 7, e1002158 (2011).

    CAS  Article  Google Scholar 

  59. 59

    Pardo-Alonso, S., Vicente, J., Solorzano, E., Rodriguez-Perez, M. A. & Lehmhus, D. Geometrical tortuosity 3D calculations in infiltrated aluminium cellular materials. Proc. Mater. Sci. 4, 145–150 (2014).

    Article  Google Scholar 

  60. 60

    Ortez, J. H. in Manual of Antimicrobial Susceptibility Testing (ed. Coyle M. B. ) 39–52 (American Society for Microbiology, 2005).

    Google Scholar 

Download references

Acknowledgements

We are grateful to G. Wojkiewicz and B. Tricot from the Center for Systems Biology, Massachusetts General Hospital (MGH) for their assistance with the bioluminescence imaging. This work was performed in part at the Center for Nanoscale Systems (CNS), a member of the National Nanotechnology Infrastructure Network (NNN), which is supported by the National Science Foundation (NSF) under NSF award no. ECS-0335765. The CNS is part of Harvard University. This study was supported in part by the Harris Orthopedics Lab Sundry Fund, MGH Orthopedics Departmental Fund, US National Institutes of Health grants P01-HL120839 and P41-EB015903.

Author information

Affiliations

Authors

Contributions

V.J.S., D.A.B, E.O., O.K.M., H.R., A.A.F., H.M., S.J.J.K. and S.H.Y. designed the experiments. V.J.S., D.A.B. and S.J.J.K. performed the experiments. All authors were involved in the analyses and interpretation of the data. V.J.S., D.A.B., S.J.J.K., E.O. and O.K.M. wrote the paper, with the help of the co-authors.

Corresponding author

Correspondence to E. Oral.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary discussion, figures and tables. (PDF 1736 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Suhardi, V., Bichara, D., Kwok, S. et al. A fully functional drug-eluting joint implant. Nat Biomed Eng 1, 0080 (2017). https://doi.org/10.1038/s41551-017-0080

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing