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Early Diagnosis of Orthopedic Implant Failure Using Macromolecular Imaging Agents

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ABSTRACT

Purpose

To develop and evaluate diagnostic tools for early detection of wear particle-induced orthopaedic implant loosening.

Methods

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer was tagged with a near infrared dye and used to detect the inflammation induced by polymethylmethacrylate (PMMA) particles in a murine peri-implant osteolysis model. It was established by inserting an implant into the distal femur and challenging with routine PMMA particles infusion. The osteolysis was evaluated by micro-CT and histological analysis at different time points.

Results

Significant peri-implant osteolysis was found 3-month post PMMA particle challenge by micro-CT and histological analysis. At 1-month post challenge, when there was no significant peri-implant bone loss, the HPMA copolymer-near infrared dye conjugate was found to specifically target the femur with PMMA particles deposition, but not the contralateral control femur with phosphate buffered saline (PBS) infusion.

Conclusion

The results from this study demonstrate the feasibility of utilizing the macromolecular diagnostic agent to detect particle-induced peri-implant inflammation prior to the development of detectable osteolysis. Recognition of this early pathological event would provide the window of opportunity for prevention of peri-implant osteolysis and subsequent orthopaedic implant failure.

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Abbreviations

APMA:

N-(3-aminopropyl)methacrylamide

BS/TV:

Bone surface density

BV:

Bone volume

BV/TV:

Bone volume/tissue volume

ELVIS:

Extravasation through leaky vasculature and inflammatory cell-mediated sequestration

H&E:

Hematoxylin and eosin

HPMA:

N-(2-Hydroxypropyl)methacrylamide

i.S:

Intersection surface

MMI:

Mean polar moment of inertia

PBS:

Phosphate buffered saline

P-IRDye:

PMA copolymer-near infrared dye conjugate

PMMA:

Poly (methyl methacrylate)

ROI:

Region of interest

TRAP:

Tartrate-resistant acid phosphatase

TV:

Tissue volume

VOI:

Volume of interest

REFERENCES

  1. Teeny SM, York SC, Mesko JW, Rea RE. Long-term follow-up care recommendations after total hip and knee arthroplasty: results of the American Association of Hip and Knee Surgeons’ member survey. J Arthroplast. 2003;18(8):954–62.

    Article  Google Scholar 

  2. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am Vol. 2007;89(4):780–5.

    Article  Google Scholar 

  3. Meijer MF, Reininga IH, Boerboom AL, Stevens M, Bulstra SK. Poorer survival after a primary implant during revision total knee arthroplasty. Int Orthop. 2013;37(3):415–9.

    Article  PubMed Central  PubMed  Google Scholar 

  4. Amstutz HC, Campbell P, Kossovsky N, Clarke IC. Mechanism and clinical significance of wear debris-induced osteolysis. Clin Orthop Relat Res. 1992;276:7–18.

    PubMed  Google Scholar 

  5. Hallab NJ, Jacobs JJ. Biologic effects of implant debris. Bull NYU Hosp Jt Dis. 2009;67(2):182–8.

    PubMed  Google Scholar 

  6. Holt G, Murnaghan C, Reilly J, Meek RM. The biology of aseptic osteolysis. Clin Orthop Relat Res. 2007;460:240–52.

    CAS  PubMed  Google Scholar 

  7. Purdue PE, Koulouvaris P, Potter HG, Nestor BJ, Sculco TP. The cellular and molecular biology of periprosthetic osteolysis. Clin Orthop Relat Res. 2007;454:251–61.

    Article  PubMed  Google Scholar 

  8. Ingham E, Fisher J. The role of macrophages in osteolysis of total joint replacement. Biomaterials. 2005;26(11):1271–86.

    Article  CAS  PubMed  Google Scholar 

  9. Stulberg BN, Della Valle AG. What are the guidelines for the surgical and nonsurgical treatment of periprosthetic osteolysis? J Am Acad Orthop Surg. 2008;16 Suppl 1:S20–5.

    PubMed  Google Scholar 

  10. Talmo CT, Shanbhag AS, Rubash HE. Nonsurgical management of osteolysis: challenges and opportunities. Clin Orthop Relat Res. 2006;453:254–64.

    Article  PubMed  Google Scholar 

  11. Malchau H, Potter HG. How are wear-related problems diagnosed and what forms of surveillance are necessary? J Am Acad Orthop Surg. 2008;16 Suppl 1:S14–9.

    PubMed  Google Scholar 

  12. Beck RT, Illingworth KD, Saleh KJ. Review of periprosthetic osteolysis in total joint arthroplasty: an emphasis on host factors and future directions. J Orthop Res Off Publ Orthop Res Soc. 2012;30(4):541–6.

    Article  Google Scholar 

  13. Saleh KJ, Thongtrangan I, Schwarz EM. Osteolysis: medical and surgical approaches. Clin Orthop Relat Res. 2004;427:138–47.

    Article  PubMed  Google Scholar 

  14. Potter HG, Nestor BJ, Sofka CM, Ho ST, Peters LE, Salvati EA. Magnetic resonance imaging after total hip arthroplasty: evaluation of periprosthetic soft tissue. J Bone Joint Surg Am Vol. 2004;86-A(9):1947–54.

    Google Scholar 

  15. Looney RJ, Boyd A, Totterman S, Seo GS, Tamez-Pena J, Campbell D, et al. Volumetric computerized tomography as a measurement of periprosthetic acetabular osteolysis and its correlation with wear. Arthritis Res. 2002;4(1):59–63.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Puri L, Wixson RL, Stern SH, Kohli J, Hendrix RW, Stulberg SD. Use of helical computed tomography for the assessment of acetabular osteolysis after total hip arthroplasty. J Bone Joint Surg Am Vol. 2002;84-A(4):609–14.

    Google Scholar 

  17. Ren K, Purdue PE, Burton L, Quan LD, Fehringer EV, Thiele GM, et al. Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates. Mol Pharm. 2011;8(4):1043–51.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Rao AJ, Nich C, Dhulipala LS, Gibon E, Valladares R, Zwingenberger S, et al. Local effect of IL-4 delivery on polyethylene particle induced osteolysis in the murine calvarium. J Biomed Mater Res A. 2012;101:1926–34.

    PubMed Central  PubMed  Google Scholar 

  19. Zhang X, Morham SG, Langenbach R, Young DA, Xing L, Boyce BF, et al. Evidence for a direct role of cyclo-oxygenase 2 in implant wear debris-induced osteolysis. J Bone Miner Res Off J Am Soc Bone Miner Res. 2001;16(4):660–70.

    Article  CAS  Google Scholar 

  20. Yang SY, Yu H, Gong W, Wu B, Mayton L, Costello R, et al. Murine model of prosthesis failure for the long-term study of aseptic loosening. J Orthop Res: Off Publ Orthop Res Soc. 2007;25(5):603–11.

    Article  Google Scholar 

  21. Epstein NJ, Warme BA, Spanogle J, Ma T, Bragg B, Smith RL, et al. Interleukin-1 modulates periprosthetic tissue formation in an intramedullary model of particle-induced inflammation. J Orthop Res: Off Publ Orthop Res Soc. 2005;23(3):501–10.

    Article  CAS  Google Scholar 

  22. Zhang T, Yu H, Gong W, Zhang L, Jia T, Wooley PH, et al. The effect of osteoprotegerin gene modification on wear debris-induced osteolysis in a murine model of knee prosthesis failure. Biomaterials. 2009;30(30):6102–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Kopeček JBH. Poly[N-(2-hydroxypropyl)methacrylamide]—I. Radical polymerization and copolymerization. Eur Polym J. 1973;9(1):7–14.

    Article  Google Scholar 

  24. Lai JT, Filla D, Shea R. Functional polymers from novel carboxyl-terminated trithiocarbonates as highly efficient RAFT agents. Macromolecules. 2002;35(18):6754–6.

    Article  CAS  Google Scholar 

  25. Omelyanenko V, Kopeckova P, Gentry C, Kopecek J. Targetable HPMA copolymer-adriamycin conjugates. Recognition, internalization, and subcellular fate. J Control Release Off J Control Release Soc. 1998;53(1–3):25–37.

    Article  CAS  Google Scholar 

  26. WH MSaS. A modified ninhydrin reagent for the photometric determination of amino acids and related compounds. J Biol Chem. 1954;211(2):907–13.

    Google Scholar 

  27. Yang SY, Mayton L, Wu B, Goater JJ, Schwarz EM, Wooley PH. Adeno-associated virus-mediated osteoprotegerin gene transfer protects against particulate polyethylene-induced osteolysis in a murine model. Arthritis Rheum. 2002;46(9):2514–23.

    Article  CAS  PubMed  Google Scholar 

  28. Noordin S, Masri B. Periprosthetic osteolysis: genetics, mechanisms and potential therapeutic interventions. Can J Surg J Can Chir. 2012;55(6):408–17.

    Article  Google Scholar 

  29. Revell PA. The combined role of wear particles, macrophages and lymphocytes in the loosening of total joint prostheses. J R Soc Interface R Soc. 2008;5(28):1263–78.

    Article  CAS  Google Scholar 

  30. Leopold SS, Rosenberg AG, Bhatt RD, Sheinkop MB, Quigley LR, Galante JO. Cementless acetabular revision. Evaluation at an average of 10.5 years. Clin Orthop Relat Res. 1999;369:179–86.

    Article  PubMed  Google Scholar 

  31. Ren W, Wu B, Peng X, Hua J, Hao HN, Wooley PH. Implant wear induces inflammation, but not osteoclastic bone resorption, in RANK(−/−) mice. J Orthop Res: Off Publ Orthop Res Soc. 2006;24(8):1575–86.

    Article  CAS  Google Scholar 

  32. Quan LD, Purdue PE, Liu XM, Boska MD, Lele SM, Thiele GM, et al. Development of a macromolecular prodrug for the treatment of inflammatory arthritis: mechanisms involved in arthrotropism and sustained therapeutic efficacy. Arthritis Res Ther. 2010;12(5):R170.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Yuan F, Quan LD, Cui L, Goldring SR, Wang D. Development of macromolecular prodrug for rheumatoid arthritis. Adv Drug Deliv Rev. 2012;64(12):1205–19.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Shimizu T, Mehdi R, Yoshimura Y, Yoshikawa H, Nomura S, Miyazono K, et al. Sequential expression of bone morphogenetic protein, tumor necrosis factor, and their receptors in bone-forming reaction after mouse femoral marrow ablation. Bone. 1998;23(2):127–33.

    Article  CAS  PubMed  Google Scholar 

  35. Ma T, Huang Z, Ren PG, McCally R, Lindsey D, Smith RL, et al. An in vivo murine model of continuous intramedullary infusion of polyethylene particles. Biomaterials. 2008;29(27):3738–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Vermeirsch H, Nuydens RM, Salmon PL, Meert TF. Bone cancer pain model in mice: evaluation of pain behavior, bone destruction and morphine sensitivity. Pharmacol Biochem Behav. 2004;79(2):243–51.

    Article  CAS  PubMed  Google Scholar 

  37. Bellido M, Lugo L, Roman-Blas JA, Castaneda S, Caeiro JR, Dapia S, et al. Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis. Arthritis Res Ther. 2010;12(4):R152.

    Article  PubMed Central  PubMed  Google Scholar 

  38. Kolari PJ, Airaksinen O. Poor penetration of infra-red and helium neon low power laser light into the dermal tissue. Acupunct Electrother Res. 1993;18(1):17–21.

    CAS  PubMed  Google Scholar 

  39. Mancini DM, Bolinger L, Li H, Kendrick K, Chance B, Wilson JR. Validation of near-infrared spectroscopy in humans. J Appl Physiol. 1994;77(6):2740–7.

    CAS  PubMed  Google Scholar 

  40. Quan LD, Yuan F, Liu XM, Huang JG, Alnouti Y, Wang D. Pharmacokinetic and biodistribution studies of N-(2-hydroxypropyl)methacrylamide copolymer-dexamethasone conjugates in adjuvant-induced arthritis rat model. Mol Pharm. 2010;7(4):1041–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

This study was supported in part by NIH/NIAMS R01 AR053325 and R01 AR062680 to D.W. and an ACR-REF: Within Our Reach Grant to S.R.G. The authors would like to thank Ms. Laura Weber for proof-reading the manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, COP 3026, Omaha, NE, 68198-6025, USA

    Ke Ren, Yijia Zhang & Dong Wang

  2. Department of Internal Medicine/Rheumatology Division, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Anand Dusad

  3. Hospital for Special Surgery, New York, NY, 10021, USA

    P. Edward Purdue & Steven R. Goldring

  4. Department of Orthopaedic Surgery and Rehabilitation, University of Nebraska Medical Center, Omaha, NE, 68198, USA

    Edward V. Fehringer & Kevin L. Garvin

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  1. Ke Ren
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Correspondence to Dong Wang.

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Ren, K., Dusad, A., Zhang, Y. et al. Early Diagnosis of Orthopedic Implant Failure Using Macromolecular Imaging Agents. Pharm Res 31, 2086–2094 (2014). https://doi.org/10.1007/s11095-014-1310-x

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  • DOI: https://doi.org/10.1007/s11095-014-1310-x

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