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      The Biologic Response to Polyetheretherketone (PEEK) Wear Particles in Total Joint Replacement: A Systematic Review

      research-article
      , MSc, , MSc, , PhD, , PhD
      Clinical Orthopaedics and Related Research
      Springer US

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          Abstract

          Background

          Polyetheretherketone (PEEK) and its composites are polymers resistant to fatigue strain, radiologically transparent, and have mechanical properties suitable for a range of orthopaedic applications. In bulk form, PEEK composites are generally accepted as biocompatible. In particulate form, however, the biologic response relevant to joint replacement devices remains unclear. The biologic response to wear particles affects the longevity of total joint arthroplasties. Particles in the phagocytozable size range of 0.1 µm to 10 µm are considered the most biologically reactive, particularly particles with a mean size of < 1 µm. This systematic review aimed to identify the current evidence for the biologic response to PEEK-based wear debris from total joint arthroplasties.

          Questions/purposes

          (1) What are the quantitative characteristics of PEEK-based wear particles produced by total joint arthroplasties? (2) Do PEEK wear particles cause an adverse biologic response when compared with UHMWPE or a similar negative control biomaterial? (3) Is the biologic response affected by particle characteristics?

          Methods

          Embase and Ovid Medline databases were searched for studies that quantified PEEK-based particle characteristics and/or investigated the biologic response to PEEK-based particles relevant to total joint arthroplasties. The keyword search included brands of PEEK (eg, MITCH, MOTIS) or variations of PEEK types and nomenclature (eg, PAEK, CFR-PEEK) in combination with types of joint (eg, hip, knee) and synonyms for wear debris or immunologic response (eg, particles, cytotoxicity). Peer-reviewed studies, published in English, investigating total joint arthroplasty devices and cytotoxic effects of PEEK particulates were included. Studies investigating devices without articulating bearings (eg, spinal instrumentation devices) and bulk material or contact cytotoxicity were excluded. Of 129 studies, 15 were selected for analysis and interpretation. No studies were found that isolated and characterized PEEK wear particles from retrieved periprosthetic human tissue samples.

          Results

          In the four studies that quantified PEEK-based particles produced using hip, knee, and spinal joint replacement simulators, the mean particle size was 0.23 µm to 2.0 µm. The absolute range reported was approximately 0.01 µm to 50 µm. Rod-like carbon particulates and granular-shaped PEEK particles were identified in human tissue by histologic analysis. Ten studies, including six animal models (rat, mouse, and rabbit), three cell line experiments, and two human tissue retreival studies, investigated the biologic response to PEEK-based particles. Qualitative histologic assessments showed immunologic cell infiltration to be similar for PEEK particles when compared with UHMWPE particles in all six of the animal studies identified. However, increased inflammatory cytokine release (such as tumor necrosis factor-α) was identified in only one in vitro study, but without substantial suppression in macrophage viability. Only one study tested the effects of particle size on cytotoxicity and found the largest unfilled PEEK particles (approximately 13 µm) to have a toxic effect; UHMWPE particles in the same size range showed a similar cytotoxic effect.

          Conclusions

          Wear particles produced by PEEK-based bearings were, in almost all cases, in the phagocytozable size range (0.1–10 µm). The studies that evaluated the biologic response to PEEK-based particles generally found cytotoxicity to be within acceptable limits relative to the UHMWPE control, but inconsistent when inflammatory cytokine release was considered.

          Clinical Relevance

          To translate new and advanced materials into clinical use more quickly, the clinical relevance and validity of preclinical tests need to be improved. To achieve this for PEEK-based devices, human tissue retrieval studies including subsequent particle isolation and characterization analyses are required. In vitro cell studies using isolated wear particles from tissue or validated joint replacement simulators, instead of manufactured particles, are also required.

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          Most cited references46

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          Polyethylene particles of a 'critical size' are necessary for the induction of cytokines by macrophages in vitro.

          Particulate wear debris from total hip prosthetic components can stimulate macrophages to produce mediators of osteolysis which may cause aseptic implant loosening. This study evaluated the in vitro response of murine peritoneal macrophages to polyethylene particles of definitive size distributions at varying volume doses. Ceridust 3615 polyethylene particles with a mean size of 0.21, 0.49, 4.3 and 7.2 microm and GUR 120 polyethylene resin with a mean size of 88 microm were co-cultured with C3H murine peritoneal macrophages at volume (microm)3 to cell number ratios of 100:1, 10:1, 1:1 and 0.1: 1. The secretion of IL-6, IL-1beta and TNF-alpha was determined by ELISA. Significantly elevated levels of TNF-alpha and IL-1beta were determined at 100:1 ratios when the macrophages were challenged with particles with a mean size of 0.49, 4.3 and 7.2 microm, and at 10:1 ratios for particles with a mean size of 0.49 and 4.3 microm. IL-6 production was significantly elevated at 100:1 ratios for mean particle sizes of 0.49 and 4.3 microm. Particles outside this range produced considerably less cytokine suggesting that both the size and volume (or number) of polyethylene particles are critical factors in macrophage activation. Therefore particles in the phagocytosable size range of 0.3-10 microm appear to be the most biologically active.
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            Wear particles, periprosthetic osteolysis and the immune system.

            The immune system modulates many key biological processes in humans. However, the exact role of the immune system in particle-associated periprosthetic osteolysis is controversial. Human tissue retrieval studies, in vivo and in vitro experiments suggest that the immune response to polymer particles is non-specific and macrophage-mediated. Lymphocytes may modulate this response. However direct lymphocyte activation by polymer particle-protein complexes seems unlikely. However, metallic byproducts may complex with serum proteins and lead to a Type IV, lymphocyte-mediated immune reaction. In predisposed individuals, this reaction may rarely lead to persistent painful joint effusions, necessitating debridement and excision of the bearing surfaces of the prosthesis. In these patients, retrieved periprosthetic tissues exhibit histological evidence of perivascular lymphocytic cuffing. These findings are worrisome, given the fact that increasing numbers of metal-on-metal joint implants are being implanted in younger more active individuals worldwide.
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              The biology of aseptic osteolysis.

              Total hip arthroplasty is one of the most commonly performed and successful elective orthopaedic procedures. However, numerous failure mechanisms limit the long-term success including aseptic osteolysis, aseptic loosening, infection, and implant instability. Aseptic osteolysis and subsequent implant failure occur because of a chronic inflammatory response to implant-derived wear particles. To reduce particulate debris and their consequences, implants have had numerous design modifications including high-molecular-weight polyethylene sockets and noncemented implants that rely on bone ingrowth for fixation. Surgical techniques have improved cementation with the use of medullary plugs, cement guns, lavage of the canal, pressurization, centralization of the stem, and reduction in cement porosity. Despite these advances, aseptic osteolysis continues to limit implant longevity. Numerous proinflammatory cytokines, such as interleukin-1, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2, have proosteoclastogenic effects in response to implant-derived wear particles. However, none of these cytokines represents a final common pathway for the process of particle-induced osteoclast differentiation and maturation. Recent work has identified the fundamental role of the RANKL-RANK-NF-kappaB pathway not only in osteoclastogenesis but also in the development and function the immune system. Thus, the immune system and skeletal homeostasis may be linked in the process of osteoclastogenesis and osteolysis.
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                Author and article information

                Contributors
                J.L.Tipper@leeds.ac.uk
                Journal
                Clin Orthop Relat Res
                Clin. Orthop. Relat. Res
                Clinical Orthopaedics and Related Research
                Springer US (New York )
                0009-921X
                1528-1132
                18 July 2016
                18 July 2016
                November 2016
                : 474
                : 11
                : 2394-2404
                Affiliations
                Institute of Medical and Biological Engineering, School of Mechanical Engineering, University of Leeds, Leeds, LS2 9JT UK
                Article
                4976
                10.1007/s11999-016-4976-z
                5052196
                27432420
                86f1a797-9b8f-4eec-8fc1-41f78f53d9aa
                © The Author(s) 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 20 November 2015
                : 6 July 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000266, Engineering and Physical Sciences Research Council;
                Award ID: EP/500513/1
                Categories
                Symposium: Advances in PEEK Technology
                Custom metadata
                © The Association of Bone and Joint Surgeons® 2016

                Orthopedics
                Orthopedics

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