Knee osteoarthritis radiographic progression and associations with pain and function prior to knee arthroplasty: a multicenter comparative cohort study.

OBJECTIVES: We determined the radiographic osteoarthritic worsening rate prior to knee arthroplasty (TKA) and whether this worsening was associated with worsening pain and function as compared to a non-surgical matched sample. METHODS: We used the Osteoarthritis Initiative 5-year datasets. Extent of knee OA 2 years prior to total knee arthroplasty (TKA) was matched to knees of persons who did not undergo TKA. Western Ontario and McMaster Universities Arthritis Index (WOMAC) Function and Knee injury and Osteoarthritis Outcome Score (KOOS) Pain scales were used to quantify functional deficit and functionally relevant pain respectively. A total of 167 persons with isolated TKA and 300 persons with matched symptomatic knee OA but no TKA were studied. RESULTS: During the 2 years prior to TKA, worsening by at least one Kellgren and Lawrence (KL) grade occurred in 27.4% (95% CI = 20.6-34.2) of the surgical knees compared to 6.6% (95% CI = 3.8-9.4) of matched non-surgical knees. Osteoarthritis radiographic progression was strongly associated with WOMAC Function and KOOS Pain worsening (P < 0.001) in the 2 years prior to TKA. KL worsening was strongly associated with future arthroplasty (Odds ratio = 5.0, 95% CI = 2.6-9.8) after adjustment for potential confounders. CONCLUSIONS: Persons undergoing TKA 2 years later had substantial worsening pain and function over the 2-year pre-operative period as compared to a non-surgical sample matched based on KL grades. Almost 30% of persons who elect to undergo TKA undergo rapid disease progression and symptom worsening during the 2 years prior to TKA.

Recommendations of the OARSI FDA Osteoarthritis Devices Working Group.

Osteoarthritis (OA) is the most common type of arthritis and a major cause of chronic musculoskeletal pain and functional disability. While both pharmacologic and non-pharmacologic modalities are recommended in the management of OA, when patients with hip or knee OA do not obtain adequate pain relief and/or functional improvement, joint replacement surgery or other surgical interventions should be considered. Total joint arthroplasties are reliable and cost-effective treatments for patients with significant OA of the hip and knee. Evidence from cohort and observational studies has confirmed substantial improvements in pain relief with cumulative revision rates at 10 years following total hip (THA) and total knee arthroplasties (TKA) at 7% and 10%, respectively. Joint replacements have been used in most every synovial joint, although results for joints other than hip and knee replacement have not been as successful. The evolution of new device designs and surgical techniques highlights the need to better understand the risk to benefit ratio for different joint replacements and to identify the appropriate methodology for evaluating the efficacy and optimal outcomes of these new devices, designed to treat OA joints.

Simultaneous labeling of mast cell proteases and protease mRNAs at the bone-implant interface of aseptically loosened hip implants.

Human mast cells (MC) exhibit two distinct phenotypes based on the protease content of their secretory granules. MC(TC) cells express tryptase, chymase, cathepsin G, and mast cell carboxypeptidase, while MC(T) cells express only tryptase. Both mast cell phenotypes were assessed near regions of osteolysis in uninfected failed joint implants by immunohistochemistry with antibodies to tryptase and chymase, and by in situ hybridization with anti-sense RNA probes for the respective mRNA molecules. Specimens from the interface membrane of 32 aseptically loosened total hip implants were studied, 28 of which had mast cells of the MC(TC) type. Most of these mast cells were aligned along the bone-prosthesis interface adjacent to loosened implants, suggesting involvement in the chronic inflammatory response that leads to bone resorption. Further ultrastructural evidence of mast cells in tissues from failed joint interface membranes was shown by transmission electron microscopy, and detection by staining after magnetic activated cell sorting. The presence of MC at the periprosthetic interface of eroded bone suggests MC degranulation and activity are associated with osteolysis in failed joint prostheses.

Late loosening of press-fit cementless acetabular components.

Between January 1987 and September 1990, 67 consecutive cementless total hip arthroplasties were implanted in 59 patients by one surgeon. The mean age of the patients at surgery was 57 years (range, 23-80 years). All acetabular components were plasma-sprayed titanium hemispheric cups with four peripheral rim fins, but additional screw fixation was not used. The mean followup was 10.4 years (range, 8.8-12.5 years). With revision as the endpoint, the failure rate of this acetabular component at a mean of 10.4 years was 28% (19/67). Of the 56 patients (56 hips) with radiographic followup, loosening of the acetabular shell occurred in 10 hips in 10 patients (18%). Seventy percent of these loosened cups failed by tilt which occurred in a rapid manner; all of the patients required revision surgery. We examined the manner of loosening of a press-fit acetabular component after early (5-year) results showed high hip scores and a low failure rate.

pN collagen type III within tendon grafts used for anterior cruciate ligament reconstruction.

This study measured the amount of immature collagen type III present in tendon rafts obtained from anterior cruciate ligament (ACL) reconstructions. These values were compared with those obtained from control grafts typically used for reconstruction--Achilles, patellar, and fascia lata--and also to the normal ACL. Analyses were performed using a commercially available radioimmunoassay (RIA). The RIA made use of a rabbit polyclonal antibody specific to the amino terminus of procollagen type III. The specificity of the Ab was confirmed by a western blot. Fibril diameter of each of the above samples was measured by transmission electron microscopy (TEM). We thus were able to determine if there was a relationship between pN collagen III content and fibril diameter. The mean amount of pN collagen type III in the normal tendon control group was 0.8 +/- 0.3 ng/microg total protein (range 0.0-2.5 ng/microg). There was significantly greater pN collagen III (16 +/- 3.7 ng/microg total protein) in the grafts containing an average fibril diameter <55 nm than in the normal tendons or ACL (P < 0.05). Grafts with an average fibril diameter >55 nm had similar levels of pN collagen III (1.0 +/- 0.79 ng/microg) as the controls. There was also significantly less pN-collagen III within the functional grafts (5.3 +/- 1.9 ng/microg) as compared to failed grafts, (21.6 +/- 5.1 ng/microg, P < 0.05). These results indicate that incomplete processing of procollagen III may be responsible for some of the ultrastructural alterations seen in tendon grafts. Since ultrastructural organization is believed to influence mechanical properties of these tissues. pN collagen III levels may be a possible indicator of ligament or tendon weakness.

Mechanical comparison of fixation techniques for the tibial tubercle osteotomy.

Tibial tubercle osteotomies currently are used as an exposure technique for revision total knee arthroplasty and for distal patellofemoral realignment. A review of the literature reveals no biomechanical studies that evaluate methods of osteotomy fixation in terms of static strength. This study evaluates the fixation strength of common techniques used to repair tibial tubercle osteotomies. Bevel and stepcut tibial tubercle osteotomies were created in 36 anatomic specimen knees and were repaired with either two 4.5-mm cortical screws or 18-gauge stainless steel cerclage wire. The failure load for the bevelcut osteotomies repaired with two-screws was 1,654 +/- 359 N; for the bevelcut osteotomies repaired with three cerclage wires, 622 +/- 283 N; for the stepcut osteotomies repaired with three cerclage wires, was 984 +/- 441 N; and for the stepcut osteotomy repaired with four cerclage wires, 1,099 +/- 632 N. This study shows that two bicortical screws provide the greatest static fixation strength for repairing tibial tubercle osteotomies. When repairing tibial tubercle osteotomies for distal patellofemoral realignment, screw fixation would provide the most reliable fixation. However, the placement of screws around the stem of a revision arthroplasty tibial component is difficult. Cerclage wires are easier to place and provide solid static fixation, especially with the addition of a proximal stepcut osteotomy.

A comparison of the midvastus and paramedian approaches for total knee arthroplasty.

This prospective, double-blinded evaluation of 24 osteoarthritic patients undergoing bilateral total knee replacement compared the midvastus and standard parapatellar approaches. The midvastus approach was found to offer an early advantage in terms of less pain and earlier return to function. There were no significant complications associated with the midvastus approach. This approach should be a part of the knee surgeon's armamentarium.

Differences in mRNA expression patterns between patellar tendons and anterior cruciate ligaments of immature pigs.

The patellar tendon is the most commonly used graft source in reconstruction of the anterior cruciate ligament. The performance of a patellar tendon graft in such a reconstruction is largely related to the structural and functional differences between patellar tendons and anterior cruciate ligaments. From a genetic point of view, the structural and functional differences are ultimately decided by the differential patterns of gene expression between the two tissues. In the present study, the genetic differences between normal patellar tendons and normal anterior cruciate ligaments were explored by screening a large number of mRNA species to detect the species unique to each tissue. Of the approximately 1,000 mRNAs screened, 20 differentially expressed mRNA species were detected. Eight were unique to patellar tendons, and 12 were unique to anterior cruciate ligaments. Of these 20 unique mRNA species, 12 did not match any of the known sequences in gene databases and were probably novel genes. Transcriptional control is a major step in the genetic pathway; therefore, the variations found between patellar tendons and anterior cruciate ligaments at this level of gene expression indicate that the differences between the two tissues are likely more extensive than previously thought. These differences probably influence the survival of patellar tendon autografts and should be explored further.

Macrophage activation results in bone resorption.

Monocytes or macrophages from important accessory cells in the regulation of bone metabolism and destruction. Cells of the mononuclear phagocyte lineage form the precursor cells of the osteoclasts. Soluble products produced by activated macrophages regulate progenitor cell proliferation, recruitment, differentiation, and activity of osteoblasts and osteoclasts. After osteoclasts are removed from the resorption site, macrophages process bone surfaces and create a cement line before osteoblasts enter to form new bone. Although osteolysis associated with normal bone remodeling is seen as an osteoclast driven process, it may be that in chronic inflammation macrophage activation and vascular derangements lead to low pH, local bone demineralization (acid attack), and H+ mediated stimulation of the primary afferent nociceptive nerve fibers (bone pain). Osteoclasts are not able to attach to demineralized bone or to osteoid surfaces. However, if macrophages degrade the demineralized organic bone matrix, chemotactic factors and attachment sites for osteoclasts are produced. In such a scenario, the osteoclast-osteoblast mediated activation, resorption, and formation cycle would be secondarily activated. Such events may play a role in the most common orthopaedic problem related to macrophage activation, aseptic loosening of orthopaedic joint implants, which is secondary to a chronic foreign body reaction and to micromovement.

Differential messenger ribonucleic acid expression in aggressive versus linear periprosthetic osteolysis.

Osteolysis is a radiographic term used to describe bone resorption adjacent to prosthetic implants. This process involves a spectrum of radiographic presentations, from small generalized linear patterns (linear osteolysis) to larger erosive patterns (aggressive osteolysis). The tissue from aggressive osteolytic lesions from five patients were compared with a series of linear osteolytic lesions from five additional patients. Total ribonucleic acid was extracted from these tissue samples, followed by reverse transcription and amplification by the polymerase chain reaction using a series of primers intended to amplify all ribonucleic acid species. The polymerase chain reaction products were separated by gel electrophoresis and compared by side by side analysis (differential display techniques). Transcription initiation factor IIB and cytokine receptor CRFB4 messenger ribonucleic acid were expressed in four of five patients with aggressive osteolytic lesions, as compared with none of five patients with linear osteolytic lesions. Conversely, nonmuscle myosin heavy chain messenger ribonucleic acid was expressed in five of five patients with linear osteolysis, and in none of the five patients with aggressive osteolysis. Thus, there is a difference in cell behavior between linear and aggressive osteolytic lesions that likely accounts for differences in radiographic appearance. This disparity is likely attributable to differences in local conditions (greater amounts of debris, increasing instability of the implant, or increased fluid pressures within the osteolytic lesions), and differences in host response.

Transforming growth factor-beta 1 and 2 in the synovial-like interface membrane between implant and bone in loosening of total hip arthroplasty.

OBJECTIVE: Development of a synovial-like membrane in the implant-bone or cement-bone interface has been linked to aseptic loosening of total hip arthroplasties (THA). This tissue consists of a fibrous stroma containing blood vessels and macrophages, but with relatively few lymphocytes, compared to "autoimmune" rheumatoid synovitis. Our aim was to examine transforming growth factor-beta (TGF-beta) in the synovial-like membrane of the interface and pseudocapsular tissue of loose THA and compare it to control knee synovial membrane. METHODS: Twenty samples obtained from 10 patients with loose THA at revisions performed for aseptic loosening and 10 samples of knee synovial membrane as controls were analyzed for TGF-beta expression using rabbit antihuman TGF-beta 1 and TGF-beta 2 IgG in immunohistochemical staining. Results were quantitated by a semi-automatic VIDAS image analysis system. RESULTS: Immunoperoxidase staining disclosed TGF-beta in macrophages and fibroblasts and also in some vascular endothelial cells and in occasional lymphocytes. Image analysis showed an increased number of positive cells/mm2 of both TGF-beta 1 (2327 +/- 212 vs 946 +/- 136; p < 0.01) and TGF-beta 2 (2292 +/- 594 vs 311 +/- 113; p < 0.01) compared to the control tissue. Increased expression of both TGF-beta 1 and TGF-beta 2 was also shown in the pseudocapsule (3210 +/- 585 and 1796 +/- 214). Use of cement or type of alloy did not seem to have any great effect on local expression of TGF-beta. CONCLUSION: Profibrotic and immunosuppressive TGF-beta are increased in the synovial-like membrane in periprosthetic tissues around loose hip prostheses. They may play a role in the formation, maintenance, and growth of the interface tissue, and thus in the aseptic loosening of THA.

Periprosthetic femoral osteolysis around an uncemented nonmodular Moore prosthesis.

Periprosthetic osteolysis is a major problem in total joint arthroplasty surgery today. The particulate debris from ultrahigh-molecular-weight polyethylene, polymethyl methacrylate, and corrosion products from modular connections have been implicated in this process. A case of femoral osteolysis at the tip of a nonmodular Moore prosthesis, in the absence of polyethylene, polymethyl methacrylate, and modular connections, is reported. In the area of osteolysis, histochemical and in situ hybridization techniques established the expression of messenger ribonucleic acid encoding for certain cytokines implicated in bone resorption, preferentially in the area of osteolysis. This case illustrates that the etiology of periprosthetic osteolysis is multifactorial and can occur in the absence of polyethylene, methacrylate, or modular components. All joint implants should be monitored for the development of this complication.

Biochemical and molecular homogeneity in the patellar tendon of the immature pig.

Patellar tendon is widely used for reconstruction of the anterior cruciate ligament. However, few studies have investigated the tendon's homogeneity, a characteristic often assumed of it in experiments. In this study, the assumption that the patellar tendon is homogeneous was tested by dividing the central half of the tendon into six sections along its length and width and comparing commonly measured biochemical parameters and patterns of gene expression among these sections. No significant differences were found between the sections for any of the studied parameters: water content (p > 0.5), DNA content (p > 0.9), total collagen content (p > 0.8), amount of type I collagen (p > 0.7) or type-III collagen (p > 0.7), or expression of mRNA (p > 0.9). For all parameters, the minimum power value for statistical analyses was greater than 0.80. It was concluded that the central half of the tendon is homogeneous in terms of all of the measured parameters. The results provide important information for the many experiments that sample part of the patellar tendon to infer the characteristics of the whole tendon, e.g., biopsy studies.

Tissue response to particulate polymethylmethacrylate in mice with various immune deficiencies.

We examined the tissue response to subcutaneous injections of particulate polymethylmethacrylate powder in fully immunocompetent C3Hf/Sed mice as well as three strains of mice with different levels of lymphocyte dysfunction. Five weeks after the injection, we found clearly demarcated granulomas. Histological and immunohistochemical studies showed that these granulomas were similar among all strains, with either paucity or absence of lymphoid cells. In situ hybridization with use of complementary RNA probes indicated that macrophages were synthesizing interleukin-1 beta messenger RNA (mRNA), a marker of macrophage activation, and a cytokine implicated in pathological bone resorption. We concluded that, in mice, there is a lymphocyte-independent pathway of macrophage activation in response to particulate polymethylmethacrylate. This suggests that the foreign-body response to particulate orthopaedic biomaterials is macrophage-initiated and maintained and that lymphocytes are not essential to this response, although they may modulate it.

Platelet-derived growth factor in fibrous musculoskeletal disorders: a study of pathologic tissue sections and in vitro primary cell cultures.

Despite the great variability in the clinical behavior of fibrous lesions of the musculoskeletal system, they are composed of cytologically similar fibrocytes. Receptors for estrogen or progesterone, or both, are present in some of these lesions and some increase their rate of growth during periods of high levels of sex steroid hormones. The platelet-derived growth factor-B (PDGF-B) proto-oncogene encodes the B chain of PDGF, a mitogen for fibrocytes. Tissue from aggressive fibromatosis, fibrous dysplasia, plantar fibromatosis, and recurrent plantar fibromatosis was analyzed with use of the polymerase chain reaction and in situ hybridization for the expression of PDGF-B and PDGF beta receptor. Cell culture was used to determine if estrogen and progesterone stimulation modulated the expression of PDGF-B. Aggressive fibromatosis, fibrous dysplasia, and recurrent plantar fibromatosis expressed PDGF-B; plantar fibromatosis, normal plantar fascia, normal fascia lata, and mature scar did not. All of the tissues expressed PDGF beta receptor. The level of expression in aggressive fibromatosis and fibrous dysplasia was four times that in the recurrent plantar fibromatosis. Estrogen and progesterone stimulation in aggressive fibromatosis resulted in an increase in the level of expression. Therefore, the detection of PDGF-B may be an adjunct in the pathologic identification of locally invasive lesions. Its production may be a common mechanism leading to a fibroproliferative response through deregulation of the control of growth by both paracrine and autocrine mechanisms.

The expression of platelet-derived growth-factor gene in Dupuytren contracture.

Dupuytren contracture is a disease of the palmar fascia characterized by nodular fibroblastic proliferation; its etiology and pathogenesis are poorly understood. Growth factors are polypeptides that regulate cell growth and differentiation and extracellular matrix production. Platelet-derived growth factor is known to cause fibroblastic proliferation, and it may be involved in the pathogenesis of Dupuytren contracture. The purpose of this study was to determine if the gene for the B chain of platelet-derived growth factor is expressed in Dupuytren contracture. Tissue from patients who had Dupuytren disease was examined immunohistochemically with the 5B5 antibody, which is a marker for fibroblasts. Polymerase chain reaction, gel electrophoresis, Southern blotting, and in situ hybridization were also used to study gene expression in the tissue as well as in normal fascia, A172 cells, and MRC5 cells. Total cellular RNA was extracted from tissue and cells. Polymerase chain reaction was done with oligonucleotide primers complementary to a portion of the platelet-derived growth-factor-B and platelet-derived growth-factor-receptor genes. The platelet-derived growth-factor-B gene was expressed in all six specimens from the patients who had Dupuytren contracture as well as in the A172 cells, but not in the normal fascia lata or the MRC5 cells. These results were confirmed with Southern blotting of the products of the reaction with a platelet-derived growth-factor-B probe. The gene for the platelet-derived growth-factor receptor was expressed by all tissues and cells studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Etiology of osteolysis around porous-coated cementless total hip arthroplasties.

The prosthetic components and tissues retrieved from 12 hips with osteolysis in association with well-fixed cementless porous-coated total hip prostheses (5 Porous Coated Anatomic, 6 Harris-Galante Porous, and 1 Omniflex) were examined using a variety specific techniques including electron microscopy, standard histology, immunohistochemistry, and particle identification. The patients were young and active. Extensive osteolysis developed in all 12 femurs and 3 acetabula between 36 and 84 months after arthroplasty (mean, 63 months). All of the polyethylene liners were noted to be worn substantially (mean volumetric wear, 1140 +/- 810 mm3). The wear was unrelated to the head diameter in this small number of cases. In all 12 cases, the articulating surfaces were wear polished and contained numerous fine multidirectional scratches, suggesting 3-body abrasive wear mechanisms in addition to adhesive wear liberating very small (micron to submicron) wear particles. In 4 cases, surface delamination and flaking of polyethylene were also found, suggesting fatigue wear liberating larger wear particles. Nine of 10 cobalt alloy heads showed numerous fine scratches with sharp edges presumably from 3-body abrasive wear. Corrosion and fretting at the femoral head-neck junction in 5 cases, burnishing of the femoral stem against bone in 4 cases, and metal staining of tissues opposite the porous coatings in 7 cases provided evidence for the liberation of fine metal particles from outside the articulation. Histologic and immunohistochemical studies of tissue in the regions of osteolysis in all cases showed numerous focal aggregates of KP1 antibody positive activated macrophages containing large amounts of submicron intracellular particles of polyethylene (presumably related to the 3-body abrasive wear polishing) and giant cells within a fibrous stroma. In 5 cases, some of the macrophages also contained submicron metal particles but smaller in numbers. T lymphocytes, plasma cells, and mast cells that might indicate hypersensitivity were found in 4 of the 12 cases (33%), and none of the cases had B lymphocytes. These data suggest that abrasive wear at the articulation leads to the liberation of abundant fine particulate wear debris of polyethylene into the tissues around cementless prostheses. Small amounts of particulate metal debris are also liberated from corrosion and fretting of the metal components and can contribute to accelerated 3-body abrasive wear at the articulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Osteolysis around uncemented acetabular components of cobalt-chrome surface replacement hip arthroplasty.

Ten cases of major osteolysis were identified in patients with hemispherical cobalt chrome acetabular components of cementless resurfacing total hip prostheses at follow-up examinations ranging from two to five years. All components were porous coated with cobalt chrome spheres and were stabilized initially with screws. Five patients were women and five were men, with ages ranging from 20 to 59 years. The radiolucent cystic lesions with peripheral rims of reactive bone formation appeared one to five years after the operation. They measured from 1.5 to 6 cm in the largest diameter and were most often found adjacent to the screws used to secure the acetabular components to the skeleton. On the radiographs, none of the components appeared to be loose. Three patients had revision surgery. In two of the three cases, the implants were found to be firmly fixed. There was no clinical or bacteriologic evidence of infection. The polyethylene articulating surface showed signs of wear in all three cases and in one of the three it dislocated from the metal shell. Granulation tissue was found in the regions of osteolysis, and the diseased tissue contained numerous macrophages and giant cells. Lymphocytes and plasma cells were rare. Numerous small particles of phagocytosed polyethylene and metal in the cells were noted in two cases, whereas only polyethylene was found in the third.(ABSTRACT TRUNCATED AT 250 WORDS)

Production of cytokines around loosened cemented acetabular components. Analysis with immunohistochemical techniques and in situ hybridization.

The chronic inflammatory response to wear particles from orthopaedic joint implants is believed to cause osteolysis and to contribute to prosthetic loosening. Previous in vitro experiments have demonstrated that particulate debris from joint implants causes cells in culture to release products that have been implicated in this pathological bone resorption. The purpose of the current study was to investigate the in vivo features of this complex process in patients who had had a total hip replacement. Membraneous tissue was obtained from the cement-bone interface of ten polyethylene acetabular components that had been revised for aseptic loosening in ten patients. The immunoperoxidase technique, which involves the use of specific antibodies for each cell type, showed that macrophages were the predominant cellular constituents but also that fibroblasts, many of which were not identified on plain histological study, were present and were actively producing collagen. T lymphocytes were present variably, but they generally composed less than 10 percent of the cells. Particulate debris (polyethylene, methylmethacrylate, and metal) was present in all membrane specimens but was intracellular only in macrophages and multinucleated giant cells. 35S-labeled nucleic-acid probes, complementary to human interleukin-1-beta and to platelet-derived growth-factor-2 messenger RNA (mRNA), were hybridized with serial tissue sections. Hybridization demonstrated interleukin-1-beta mRNA predominantly in macrophages, and not in fibroblasts or in T lymphocytes to any major extent. In contrast, immunolocalization demonstrated interleukin-1-beta protein on both macrophages and fibroblasts, suggesting that macrophages release interleukin-1-beta, which then binds to both fibroblasts and macrophages. Platelet-derived growth-factor transcripts were found in both macrophages and fibroblasts.

Acrylic fragmentation in total hip replacements and its biological consequences.

Loosening of total joint prostheses is in part related to the fragmentation of the acrylic cement mantle surrounding the prosthesis and the biologic consequences to the particulate acrylic. Fractographic studies of femoral cement mantles retrieved at revision surgery and autopsy showed frequent fractures in varying stages of development in the cement and wear at the fracture surfaces. Defects in the cement mantle, thin mantles, sharp corners on the prosthesis, separation at the cement mantle interface, and pores in the cement were frequently associated with cement fractures. The progressive fractures and wear led to the liberation of particulate acrylic debris into the surrounding tissues. The tissues at the bone-cement interface removed at revision surgery showed that a macrophage, giant-cell foreign-body granulomatous reaction occurs in response to the particulate, but not bulk cement. This tissue can produce a variety of chemical mediators of inflammation and bone resorption, and can resorb bone in organ cultures. A granulomatous tissue reaction with a very similar appearance can be produced in experimental animals using particulate-form polymethylmethacrylate (PMMA), but not the bulk form of PMMA. The tissue reaction is not mediated by the classic cell or humeral immune mechanisms. Subcutaneous injection of particulate PMMA powder into fully immunocompetent C3Hf/SED mice as well as three strains of mice with progressive immunologic deficiencies (nude/nude, SCID, and triple deficient Nu-bg-XID/SED mice) led to a foreign-body reaction in all strains at five weeks as shown by histologic and immunohistochemical examination despite the differences in immune deficiency. This, along with the scarcity of lymphocytes in the human tissues, suggests that the biologic reactions to fragmented cement can be produced and sustained by nonimmune phagocytosis and activation by macrophages and giant cells without significant contribution by the immune system.