Arun S. Shanbhag

Composition and morphology of wear debris in failed uncemented total hip replacement

Interfacial membranes collected at revision from 11 failed uncemented Ti-alloy total hip replacements were examined. Particles in the membranes were characterised by electron microscopy, microchemical spectroscopy and particle size analysis. Most were polyethylene and had a mean size of 0.53 micron +/- 0.3. They were similar to the particles seen in the base resin used in the manufacture of the acetabular implants. Relatively few titanium particles were seen. Fragments of bone, stainless steel and silicate were found in small amounts. Most of the polyethylene particles were too small to be seen by light microscopy. Electron microscopy and spectroscopic techniques are required to provide an accurate description of this debris.

Inhibition of Wear Debris Mediated Osteolysis in a Canine Total Hip Arthroplasty Model

In this study the efficacy of an oral bisphosphonate therapy to inhibit wear debris mediated bone resorption was evaluated in a canine total hip replacement model. Adult canines were randomized to three groups (n = 8 each) with a right uncemented total hip replacement performed on each animal. Group I (control) received no particulate debris. In Groups II and III, a mixture of 1 x 10(9) particles were introduced into the proximal femoral gap intraoperatively. The particle mixture consisted of fabricated ultra high molecular weight polyethylene (mean 2.3 microns, 90% by number), titanium alloy (mean 3.1 microns, 5%), and cobalt chrome alloy (mean 0.8 micron, 5%). Group III canines additionally received oral drug therapy (5 mg once a day, alendronate sodium) which was begun on postoperative Day 7 and continued until the time of sacrifice. Postoperatively, all animals were allowed 24 weeks of full ambulation before euthanasia. Radiographs obtained preoperatively, postoperatively, and at time of sacrifice were evaluated for periprosthetic osteolysis. Interfacial tissues were examined histologically and placed in organ culture and the supernatants were assayed for prostaglandin E2 and interleukin-1. One animal receiving debris (Group II) suffered a periprosthetic fracture and was sacrificed from the study. Radiographically, one of eight Group I (control) and six of seven canines from Group II (debris) had periprosthetic radiolucencies with endosteal scalloping develop. In contrast, only one of eight animals from Group III (debris + alendronate) had periprosthetic radiolucencies develop. Whereas tissues from control animals were mostly fibrous and acellular, tissues from both experimental groups had significant macrophage infiltration. Levels of prostaglandin E2 and interleukin-1 were elevated significantly in periprosthetic tissues from both experimental groups compared with controls. Continuous administration of alendronate effectively inhibited bone lysis for the 24-week duration of the study. This is consistent with the literature indicating that alendronate is incorporated in the mineralizing matrix making it refractory to osteoclastic resorption. This report has significant clinical implications for controlling the most common cause of implant failure.

Wear Debris in Total Joint Replacements.

&NA; In vivo degradation of prosthetic implant materials is increasingly recognized as a major factor limiting the durability of total joint arthroplasty. In vivo degradation occurs primarily by means of wear processes that can generate large quantities of particulate debris. This debris can stimulate an adverse local host response leading to periprosthetic bone loss, which can compromise implant fixation and bone stock. The authors review the basic mechanisms of implant degradation and the host response to particulate degradation products, particularly in the context of the pathogenesis of osteolysis. Submicron polyethylene particles (mean size, 0.5 &mgr;m) are the dominant type of wear particle present in periprosthetic tissues associated with uncemented hip replacements. Polyethylene wear can be minimized by improving the quality of the polyethylene, avoiding use of large‐diameter (greater than 28 mm) femoral heads in total hip arthroplasty, and improving the design and fabrication of modular connections, which can be important sources of threebody wear particles. Advances in the understanding of the basic mechanisms of osteolysis are critical to the development of preventive measures that will minimize the clinical impact of this phenomenon.

PATHOGENESIS OF BONE LOSS AFTER TOTAL HIP ARTHROPLASTY

Bone loss with or without evidence of aseptic loosening is a long term complication after total hip arthroplasty (THA). It occurs with all materials and in all prosthetic systems in use or that have been used to date. Bone loss after THA can be a serious problem in revision surgery because bone deficiencies may limit reconstructive options, increase the difficulty of surgery, and necessitate autogenous or allogenic bone grafting. There are three factors adversely affecting maintenance of bone mass after THA: (1) bone loss secondary to particulate debris; (2) adaptive bone remodeling and stress shielding secondary to size, material properties, and surface characteristics of contemporary prostheses; and (3) bone loss as a consequence of natural aging. This chapter reviews the mechanisms of the primary causes of bone loss after THA.

The role of adsorbed endotoxin in particle-induced stimulation of cytokine release.

Numerous in vitro models have demonstraed the capacity of wear particles to stimulate the release of soluble pro‐inflammatory products with the ability to induce local bone resorption. Recent observations have demonstrated that binding of lipopolysaccharide (LPS) to particulate wear deris can significantly modulate the pattern of cell response in the in vitro models. These findings raise concerns over the possible role of LPS in the athogenesis of aseptic looseing after total joint replacements, and also indicates the importance of controlling for possible confounding effects of LPS contamination in the in vitro models used to study the reactive nature of wear debris. Our studies were undertaken to rigorously analyze the effects of particle‐associated LPS on cell responses and to assess the efficacy ofdifferent treatment protocols to inactivate LPS associated with different particulate materials. Particles of cobalt‐chrome alloy, titanium‐6‐aluminum‐4‐vanadium, titanium nitride and silica were pretreated with LPS and exposed to multiple treatment protocols. When cells were treated with „as‐received”︁ particles prepared by washing in ethanol, small amounts of TNF‐α, IL‐1β, and IL‐1α were detected. In contrast, all particle species pretreated with LPS produced marked increases in TNF‐α, IL‐1α, and IL‐1β release, as well as upregulation of corresponding mRNa levels even after ethanol washing. Boiling the LPS‐pretreated particles in 1% acetic acid or autoclaving and baking the particles also markedly reduced and in some instances abolished the effect of the LPS‐pretreatment. This indicates that LPS binds to the surface of particles of diverse composition and that the bound LPS is biologically active. Treatment protocols to inactivate particle‐associated LPS demonstrated significant differences in effcacy. When the most rigorous treatments were utilized, essentially all LPS activity could be eliminated. Particles treated with these methods retained some capacity to stimulated cytokine release, but activities were markedly reduced. These results provide further evidnce indicating that LPS contamination of particulate materials can markedly enhance their biological activity. This potential confounding effect needs to be carefully monitored and controlled in the in vitro model systems systems used to evaluate wear particles. Furthermore, the presence of particle‐associated endotoxin at the bone‐implant interface in vivo could markedly enhance the adverse biological activity of particulate wear debris.

Macrophage response to cross-linked and conventional UHMWPE

To prevent wear debris-induced osteolysis and aseptic loosening, cross-linked ultra-high molecular weight polyethylenes (UHMWPE) with improved wear resistance have been developed. Hip simulator studies have demonstrated very low wear rates with these new materials leading to their widespread clinical use. However, the biocompatibility of this material is not known. We studied the macrophage response to cross-linked UHMWPE (XLPE) and compared it to conventional UHMWPE (CPE) as well as other clinically used orthopaedic materials such as titanium-alloy (TiAlV) and cobalt-chrome alloy (CoCr). Human peripheral blood monocytes and murine macrophages, as surrogates for cells mediating peri-implant inflammation, were cultured onto custom designed lipped disks fabricated from the test materials to isolate cells. Culture supernatants were collected at 24 and 48h and analyzed for cytokines such as IL-1alpha, IL-1beta, TNF-alpha and IL-6. Total RNA was extracted from adherent cells and gene expression was analyzed using qualitative RT-PCR. In both in vitro models, macrophages cultured on cross-linked and conventional polyethylene released similar levels of cytokines, which were also similar to levels on control tissue culture dishes. Macrophages cultured on TiAlV and CoCr-alloy released significantly higher levels of cytokines. Human monocytes from all donors varied in the magnitude of cytokines released when cultured on identical surfaces. The variability in individual donor responses to TiAlV and CoCr surfaces may reflect how individuals respond differently to similar stimuli and perhaps reveal a predisposed sensitivity to particular materials.

Effects of Particles on Fibroblast Proliferation and Bone Resorption In Vitro

An in vitro study was conducted to determine the ability of particle challenged human peripheral monocytes to modulate fibroblast proliferation and bone resorption. The effects of commercially pure titanium, titanium-aluminum-vanadium, and ultrahigh molecular weight polyethylene wear debris, either fabricated or retrieved from patients with failed total hip arthroplasties, were examined as a function of the composition, size, and dose of particles. In vitro generated particles were selected to be matched closely in particle size distribution to that found in vivo. Dosages were controlled by standardizing the ratio of particle surface area to mean monocyte surface area. The results support the hypothesis that, in vitro, challenge of monocytes by particulate wear debris results in a biphasic dose response. For the metal particles, fibrogenesis was observed over the range of 1x to 10x surface area ratio (the surface area of particles to the surface area of cells), although for metallic and polyethylene particles, saturated doses of 10x surface area ratio were required to stimulate bone resorption. In addition, metallic particles were able to stimulate fibrogenesis at doses at which simulated and retrieved polyethylene were ineffective. Although there may be a nonosteolytic chronically tolerable annual dose of ultrahigh molecular weight polyethylene wear debris corresponding to approximately 1x surface area ratio, lower doses, especially of metallic debris, may produce reactive fibroblast proliferation and fibroplasia that may contribute to implant loosening and failure.

Evaluation of porous polyethylene for external ear reconstruction

Autogenous rib cartilage and silicone rubber are materials currently used for ear reconstruction. Increased morbidity and operative time with rib cartilage grafts and a high rate of extrusion with silicone implants render them less than ideal for reconstruction of the human ear. The purpose of the current investigation is to determine the efficacy of porous polyethylene as an alternative synthetic material for ear reconstruction. Porous polyethylene and silicone rubber discs of equal sizes in two thicknesses were implanted in lieu of the cartilage in the external ear of eight baboons. Histological evaluation of the sites after nine weeks revealed excellent anchorage of the thin porous polyethylene implants (1.5 mm) in the surrounding tissues. Silicone rubber implants, however, were encapsulated in a thickened granulation tissue capsule. When thicker implants (3.0 mm) were used, exposure or extrusion occurred in all cases. Porous polyethylene implants demonstrated only partial exposure; half of the silicone rubber implants were extruded; and the other two silicone rubber implants were almost completely extruded. Porous polyethylene was thus better incorporated into the soft tissues than silicone rubber as long as the overlying soft tissues were not stressed by an oversized implant or inadequate soft tissue coverage.

Nitric oxide release by macrophages in response to particulate wear debris

At the interface between a prosthetic implant and bone, macrophage interaction with particulate wear debris is a key event in the initiation of localized bone resorption, leading to aseptic loosening of the prostheses. Numerous investigators have reported that macrophages release a variety of cytokines and mediators including tumor necrosis factor, interleukin-1, prostaglandin E2, and interleukin-6 when they are stimulated with particulate wear debris. In this study, we have demonstrated that macrophages stimulated with particulate debris are also capable of releasing in copious amounts a key inflammatory chemical, nitric oxide. This release of nitric oxide was dependent upon the period of culture and the type and dosage of the challenging particles. Titanium-alloy particles were the most stimulatory, followed by commercially pure titanium and polymethyl-methacrylate. While the role of nitric oxide in osteolysis is not clearly understood, the literature suggests that it may be a key mediator in inhibiting DNA synthesis, in cell proliferation, and in stimulating PGE2 release. This finding enhances our understanding of the sequence of events occurring at the bone-implant interface during wear debris-mediated osteolysis, and exposes potential avenues to interrupt this sequence.

Particulate-Induced, Prostaglandin- and Cytokine-Mediated Bone Resorption in an Experimental System and in Failed Joint Replacements.

Total hip arthroplasty (THA) has provided dramatic pain relief and improvement in function for millions of patients with end-stage arthritis; however, periprosthetic osteolysis following THA has become increasingly recognized as a major clinical problem in both cemented and cementless reconstructions. An aggressive granulomatous tissue (interfacial membrane) consisting predominantly of fibroblasts, aggregates of macrophages, and foreign body giant cells develops at the interface of bone/prostheses or bone/cement. It is believed that particulate wear debris from prosthetic materials and/or bone cement are phagocytized by histiocytic cells of interfacial membrane and then these cells produce inflammatory mediators and proteolytic enzymes to provoke a cascade of osteolytic events. In this paper, we studied in vitro responsiveness of various cell types to particulate wear debris. Although titanium and titanium alloys demonstrate excellent biocompatibility in bulk form, titanium in particulate form can provoke a variety of cellular responses. We have found that small-sized Ti particles of phagocytosable size, a commonly encountered particle species in the periprosthetic tissues of failed THAs, stimulate macrophages to secrete various mediators of bone resorption (prostaglandin E2, interleukin-1, interleukin-6, and tumor necrosis factor-α from macrophages and cause bone resorption in organ culture. In addition, we have shown that phagocytosable titanium particles stimulate fibroblasts to up-regulate the expression of matrix metalloproteinases (stromelysin and collagenase) without a substantial effect on the tissue inhibitor of these enzymes (TIMP). Titanium particulates also have a suppressive effect on procollagen synthesis by an osteoblast-like cell line. Thus, titanium particulates have the capacity to stimulate bone resorption and inhibit bone matrix formation. In this series of experiments, we have also shown in vitro inhibitory effect of certain pharmaceutical components (indomethacin, misoprostol) upon bone resorption in organ culture, which may indicate a potential therapeutic intervention to prevent or treat particulate-induced pathological bone resorption in total joint arthroplasties.