Genome-wide analysis identifies differential promoter methylation of Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12 in murine tendinopathy.

We have used a murine Achilles tendinopathy model to investigate whether tissue changes (such as collagen disorganization, chondroid metaplasia, and loss of tensile properties) which are broadly characteristic of human tendinopathies, are accompanied by changes in the expression of chromatin-modifying enzymes and the methylation status of promoter regions of tendon cell DNA. Tendinopathy was induced by two intra-tendinous TGF-ß1 injections followed by cage activity or treadmill running for up to 28 days. Activation of DNA methyltransferases occurred at 3 days after the TGF-ß1 injections and also at 14 days, but only with treadmill activity. Genome-wide Methyl Mini-Seq™ analysis identified 19 genes with differentially methylated promoters, five of which perform functions with an apparent direct relevance to tendinopathy (Leprel2, Foxf1, Mmp25, Igfbp6, and Peg12). The functions of the genes identified included collagen fiber assembly and pericellular interactions, therefore their perturbation could play a role in the characteristic disorganization of fibers in affected tendons. We postulate that a study of the functional genomics of these genes in animal and human tendon could further delineate the pathogenesis of this multi-factorial complex disease. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:947-955, 2017.

Heterotopic Ossification Prophylaxis After Total Hip Arthroplasty: Randomized Trial of 400 vs 700 cGy.

BACKGROUND: Heterotopic ossification (HO) is a known complication following total hip arthroplasty. Radiation is an effective prophylaxis, but an optimal protocol has yet to be determined. We performed a randomized, double-blinded clinical trial in high-risk patients to determine the efficacy of 400 vs 700 cGy doses of radiation. METHODS: One hundred forty-seven patients undergoing total hip arthroplasty and at high risk for HO at an urban medical center were randomized to receive either a single 400 or 700 cGy dose of radiation postoperatively. High risk was defined as a diagnosis of diffuse idiopathic skeletal hyperostosis, hypertrophic osteoarthritis, ankylosing spondylitis, or history of previous HO. Radiation was administered on the first or second postoperative day. A single blinded reviewer graded radiographs taken immediately postoperatively and at a minimum of 6 months postoperatively using the Brooker classification. Progression was defined as an increase in Brooker classification. Operative data including surgical approach, implant fixation, revision surgery, and postoperative range of motion data were also collected. RESULTS: A significantly greater portion of patients who received the 400 cGy dose demonstrated progression of HO than patients who received the 700 cGy dose. There were no wound complications. No preoperative factors were associated with a higher rate of progression. Patients who progressed had less flexion on physical examination than patients who did not progress, but this was not clinically significant. CONCLUSION: Seven hundred centigray was superior to 400 cGy in preventing HO formation following total hip arthroplasty in high-risk patients and may be the more effective treatment in this population. Further studies comparing 700 cGy to dosages between 400 and 700 cGy may help to clarify if a more optimal dose can be identified.

Degenerative Suspensory Ligament Desmitis (DSLD) in Peruvian Paso Horses Is Characterized by Altered Expression of TGFß Signaling Components in Adipose-Derived Stromal Fibroblasts.

Equine degenerative suspensory ligament desmitis (DSLD) in Peruvian Paso horses typically presents at 7-15 years and is characterized by lameness, focal disorganization of collagen fibrils, and chondroid deposition in the body of the ligament. With the aim of developing a test for disease risk (that can be used to screen horses before breeding) we have quantified the expression of 76 TGFß-signaling target genes in adipose-derived stromal fibroblasts (ADSCs) from six DSLD-affected and five unaffected Paso horses. Remarkably, 35 of the genes showed lower expression (p<0.05) in cells from DSLD-affected animals and this differential was largely eliminated by addition of exogenous TGFß1. Moreover, TGFß1-mediated effects on expression were prevented by the TGFßR1/2 inhibitor LY2109761, showing that the signaling was via a TGFßR1/2 complex. The genes affected by the pathology indicate that it is associated with a generalized metabolic disturbance, since some of those most markedly altered in DSLD cells (ATF3, MAPK14, ACVRL1 (ALK1), SMAD6, FOS, CREBBP, NFKBIA, and TGFBR2) represent master-regulators in a wide range of cellular metabolic responses.

Recent Scientific Advances Towards the Development of Tendon Healing Strategies.

There exists a range of surgical and non-surgical approaches to the treatment of both acute and chronic tendon injuries. Despite surgical advances in the management of acute tears and increasing treatment options for tendinopathies, strategies frequently are unsuccessful, due to impaired mechanical properties of the treated tendon and/or a deficiency in progenitor cell activities. Hence, there is an urgent need for effective therapeutic strategies to augment intrinsic and/or surgical repair. Such approaches can benefit both tendinopathies and tendon tears which, due to their severity, appear to be irreversible or irreparable. Biologic therapies include the utilization of scaffolds as well as gene, growth factor, and cell delivery. These treatment modalities aim to provide mechanical durability or augment the biologic healing potential of the repaired tissue. Here, we review the emerging concepts and scientific evidence which provide a rationale for tissue engineering and regeneration strategies as well as discuss the clinical translation of recent innovations.

ADAMTS5 is required for biomechanically-stimulated healing of murine tendinopathy.

A recently developed murine model of tendinopathy, induced by TGF-ß1 injection, has been used to examine the reparative capacity of tendinopathic Achilles in Adamts5(-/-) mice. After TGF-ß1 injection and 2 weeks of treadmill exercise, the Achilles from Adamts5(-/-) mice exhibited a reduction in maximum tensile stress of approximately 60%. However, in contrast to wild type mice previously characterized by this model, Adamts5(-/-) mice subjected to further treadmill exercise were unable to reverse this biomechanical deficit. This nonreparative phenotype was accompanied by a major deficiency, relative to wild-type, in expression of Col1a1 and Col3a1 and an abnormally elevated expression of a wide range of integrins. In addition, the tendinopathic Adamts5(-/-) mice showed a persistent accumulation of chondrogenic cells in the tendon body and an aggrecan-rich fibrocartilaginous matrix within disorganized collagen fiber bundles. Moreover, consistent with the compromised biomechanical properties of the Achilles in the Adamts5(-/-) mice, in vivo gait analysis revealed a strong trend (p = 0.07) towards increased swing time of the injected limb in Adamts5(-/-) relative to wild-type mice. These findings demonstrate that a deficiency in ADAMTS5 promotes a chondrogenic response to TGF-ß1 injection that is not reversed by treadmill exercise. Hence, repair of biomechanically compromised tendons exhibiting midsubstance chondroid accumulation requires ADAMTS5.

Ten-year outcome of serum metal ion levels after primary total hip arthroplasty: a concise follow-up of a previous report*.

We previously reported on the metal ion concentrations of cobalt, chromium, and titanium that were found in the serum of patients three years after they had undergone primary total hip arthroplasty as compared with the concentrations found in the serum of control patients who did not have an implant. This study is a concise update on the serum metal levels found in a cohort of these patients ten years after the time of hip implantation. Of the original seventy-five subjects, metal ion levels were available for forty patients (53%). Ten patients (hybrid group) had received a hybrid total hip replacement that consisted of a modular cobalt-alloy femoral stem with a cobalt-alloy femoral head that had been inserted with cement and a titanium acetabular socket that had been inserted without cement. Nine patients (cobalt-chromium [CoCr] group) had received an implant with an extensively porous-coated modular cobalt-alloy femoral stem and femoral head along with a titanium acetabular socket; the femoral and acetabular components had each been inserted without cement. Eight patients (titanium group) had undergone insertion of a proximally porous-coated modular titanium-alloy femoral stem with a cobalt-alloy femoral head and a titanium acetabular socket; the femoral and acetabular components had each been inserted without cement. Thirteen patients (control group) from the original control group of patients who had not received an implant served as control subjects. Serum metal levels were measured with use of high-resolution sector field inductively coupled plasma mass spectrometry. The hybrid total hip arthroplasty group had mean cobalt levels that were 3.2 times higher at 120 months than they were at baseline, and the cobalt levels in that group were significantly higher than those in the titanium total hip arthroplasty group at thirty-six, sixty, eighty-four, ninety-six, and 120 months (p < 0.01). The hybrid group had mean chromium levels that were 3.9 times higher at 120 months than they were at baseline, and the CoCr total hip arthroplasty group had chromium levels that were 3.6 times higher at 120 months than they were at baseline. The serum titanium levels were higher in the titanium group at all follow-up time intervals as compared with the levels in all other groups, and the level in the titanium group at 120 months was eighteen times higher than it was at baseline (p < 0.01). Patients with well-functioning primary metal-on-polyethylene total hip replacements had elevated serum metal levels for as many as ten years postoperatively. Furthermore, metal release at the modular femoral head-neck junctions, rather than passive dissolution from porous ingrowth surfaces, was likely the dominant source of serum cobalt and chromium.

Long-term survivorship and failure modes of unicompartmental knee arthroplasty.

BACKGROUND: In a previously reported series of 51 patients with 62 cemented, fixed-bearing unicompartmental knee arthroplasties, we reported a 10-year, 98% survival rate with an average knee score of 92 points. The survivorship and modes of failure past 10 years are incompletely understood. QUESTIONS/PURPOSES: At 15-year followup we sought to determine (1) the overall durability and survivorship of this design; (2) modes of failure; and (3) the progression of arthritis in the nonresurfaced compartments. METHODS: Nineteen knees in 16 patients were available for study with 34 patients lost to death and one lost to followup. At 15 years, we analyzed the Kaplan-Meier survivorship as well as durability with regard to radiographic loosening and knee scores, determined modes of failure, and assessed radiographs for degeneration in the nonresurfaced compartments. RESULTS: Fifteen-year survivorship was 93% and 20-year survivorship was 90%. Four of 62 knees were revised to total knee arthroplasty at a mean of 144 months. One knee was revised for patellofemoral and lateral compartment degeneration, one for lateral compartment degeneration, one for polyethylene disengagement and metallosis, and one for pain of unclear etiology. No patients had aseptic loosening or osteolysis. The mean knee score was 78 at latest followup. Arthritic progression in the nonresurfaced compartments was common although symptomatic in only two patients. CONCLUSIONS: With this cemented, fixed-bearing design, the failure rates were low, there were no cases of failure secondary to wear or loosening, and the survivorship was similar to that reported for total knee arthroplasty.

Successful long-term fixation and progression of osteolysis associated with first-generation cementless acetabular components retrieved post mortem.

BACKGROUND: Primary cementless acetabular reconstruction has shown durable long-term fixation. Late failures secondary to aseptic loosening are rare but may occur in patients with previously well-fixed components. In the present study, the histopathological characteristics of postmortem specimens were correlated with wear damage and radiographic data in an attempt to better understand the long-term events in the periacetabular tissue around well-functioning devices. METHODS: Seventeen primary cementless Harris-Galante I acetabular components with adjacent tissues were harvested after a mean of eleven years (range, four to twenty-five years) from patients whose implants were well functioning at the time of death. Undecalcified and paraffin sections were used to quantify the extent of bone and soft tissues within the porous coating and at the interface between the coating and the surrounding bone. Wear particles were identified with use of polarized light microscopy and energy-dispersive x-ray analysis. Bearing-surface volumetric wear and backside wear damage of the polyethylene liner were assessed. RESULTS: All of the components were fixed by bone ingrowth (mean extent, 33% ± 21%). Particle-induced granulomas were present in the porous coating and along the interface and progressed through screw holes, ballooning into the retroacetabular bone in the longer-term specimens. Particles of femoral and acetabular origin were identified in the granulomas. Bearing-surface volumetric wear (mean, 41.6 mm3/year) increased with duration and correlated with increasing extent of granuloma in the porous coating and the increasing size of pelvic granulomas. Radiolucencies on radiographs correlated with the extent of bone and fibrous tissue ingrowth. Of the six pelvic granulomas that were identified histologically, only one was apparent on routine radiographs. CONCLUSIONS: Acetabular fixation by bone ingrowth can be successful into the third decade after implantation. Osteolysis and secondary replacement of bone with particle-induced granuloma are commonly seen in the presence of excellent clinical function. Strategies designed to minimize bearing-surface wear and backside damage are important to maintain long-term bone ingrowth fixation.

Surface damage versus tibial polyethylene insert conformity: a retrieval study.

BACKGROUND: Surface damage of the tibial polyethylene insert in TKA is thought to diminish with increasing conformity, based on computed lower contact stresses. Added constraint from higher conformity may, however, result in greater forces in vivo. QUESTIONS/PURPOSES: We therefore determined whether increased conformity was associated with increased surface pitting, delamination, creep, and polishing in a group of retrieved tibial inserts. METHODS: We compared 38 inserts with a dished articular surface (conforming group) with 31 inserts that were unconstrained and nonconforming in the sagittal plane (less conforming group). The two groups had identical polyethylene composition and processing history. The articulating surfaces were scored for pitting, delamination, deformation/creep, and polishing. Evidence of edge loading and the presence of embedded bone cement were also recorded. RESULTS: The conforming inserts were associated with higher delamination and pitting scores but lower polishing scores, even after adjusting for the effects of sex, age, insert thickness, and implantation duration. Long implantation duration and male sex were also associated with increased delamination, pitting, and polishing, whereas long shelf life was associated only with increased delamination. The conforming group also had approximately a fourfold greater prevalence of edge loading and approximately a threefold greater prevalence of embedded bone cement. The latter was associated with higher scores and proportions of delamination and pitting. CONCLUSIONS: These findings suggest more conformity may increase surface fatigue damage in TKA. Higher constraint-induced stresses during secondary motions and more possibility for edge loading and bone cement capture on a dished surface may account for these results. CLINICAL RELEVANCE: The selection of materials with high fatigue resistance may be particularly important for high-conformity/constraint tibial inserts. In addition, awareness of the benefits and trade-offs with conformity may allow better matching of TKA design to patient.

Murine tendon function is adversely affected by aggrecan accumulation due to the knockout of ADAMTS5.

The present study examined the effect of ADAMTS5 (TS5) knockout on the properties of murine flexor digitorum longus (FDL) and Achilles tendons. FDL and Achilles tendons were analyzed using biomechanical testing, histology, and immunohistochemistry; further characterization of FDL tendons was conducted using transmission electron microscopy (collagen fibril ultrastructure), SDS-PAGE (collagen content and type), fluorescence-assisted carbohydrate electrophoresis for chondroitin sulfate and hyaluronan, and Western blotting for aggrecan, versican, and decorin abundance and distribution. FDL tendons of TS5(-/-) mice showed a 33% larger cross-sectional area, increased collagen fibril area fraction, and decreased material properties relative to those of wild type mice. In TS5(-/-) mice, aggrecan accumulated in the pericellular matrix of tendon fibroblasts. In Achilles tendons, cross-sectional area, stress relaxation, and structural properties were similar in TS5(-/-) and wild type mice; however, the TS5(-/-) tendons exhibited a higher tensile modulus and a weakened enthesis. These results demonstrate that TS5 deficiency disturbs normal tendon collagen organization and alters biomechanical properties. Hence, the role of ADAMTS5 in tendon is to remove pericellular and interfibrillar aggrecan to maintain the molecular architecture responsible for normal tissue function.

Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter-alpha-trypsin-inhibitor in equine degenerative suspensory ligament desmitis.

We describe analysis of suspensory ligaments from horses with advanced degenerative suspensory ligament desmitis (DSLD) to identify the major proteoglycans (PGs), ADAMTS-aggrecanases and inter-alpha-trypsin inhibitor (IαI) components associated with ligament degeneration. Specific anatomical regions of suspensory ligaments from two normal horses and four diagnosed with DSLD were analyzed by Western blot and immunohistochemistry for the following: aggrecan, aggrecan fragments, decorin, ADAMTS4, ADAMTS5, and IαI components. When compared to normal, DSLD ligaments showed about a 15-fold increase (P < 0.0014) in aggrecan levels and markedly enhanced staining with Safranin O. The aggrecan was composed of two distinct high molecular weight core protein species. The largest species was found only in DSLD samples and it co-migrated with aggrecan synthesized by equine mesenchymal stem cells (MSC). Many of the DSLD samples also contained abnormally high concentrations of ADAMTS4, ADAMTS5, and IαI. Notably, the ADAMTS5 in DSLD samples, but not normals, was present largely as a high molecular weight complex. We conclude that ligament degeneration in DSLD is associated with matrix changes characteristic of an inflammatory nonhealing wound, specifically containing chondrogenic progenitor cells. Since aggrecan accumulation is a major feature of incomplete healing in tendon and skin of the ADAMTS5 knockout mouse, we propose that ligament failure in DSLD results from a process involving tissue inflammation and the complexation of ADAMTS5.

Time course and extent of functional recovery during the first postoperative year after minimally invasive total hip arthroplasty with two different surgical approaches--a randomized controlled trial.

UNLABELLED: While others have reported short-term comparisons between various minimally invasive surgical (MIS) approaches to total hip arthroplasty (THA) and their conventional analogues, longer-term data is lacking, as is information indicating whether MIS approaches to THA provide a biomechanically complete recovery. Furthermore, different MIS approaches have not been compared. Our approaches of interest were a one-incision modified Watson-Jones, and a two-incision approach. HYPOTHESES: (1) There are significant differences in gait recovery patterns between the two surgical groups and (2) THA subjects have significant differences in function one year after surgery compared to control subjects. To test these hypotheses, THA candidates (n=26) were randomized to receive one of these MIS approaches and evaluated preoperatively, and postoperatively at 3 weeks, and at 3, 6 and 12 months. Evaluations included three-dimensional gait analysis and 24-hour step-counts. The same data were obtained from 25 control subjects. Recovery time-course was assessed using repeated measures ANOVA. T-tests were used to compare controls with the pooled group of THA subjects. We found no differences between the two THA surgical groups regarding the time-course of recovery (p≥0.591). Although recovery was statistically complete by 3 months postoperatively for all variables, there were significant differences from controls at 12 months. Most notably, the external hip adduction moment, which reflects hip abductor function, was more than one standard deviation below normal (p<0.001). THA subject inactivity could not explain the gait differences, since one year after surgery daily step counts were not significantly different from controls (p=0.346). More work is necessary to determine ways to improve biomechanical outcomes for today's patients with high expectations for function and implant longevity.

Posterior cruciate ligament-retaining total knee arthroplasty in patients with rheumatoid arthritis: a concise follow-up of a previous report.

7We previously reported the minimum eight-year follow-up results of cruciate-retaining total knee arthroplasty in a consecutive series of seventy-two knees in patients with rheumatoid arthritis. In the present study, we evaluated the longer-term outcomes after twenty to twenty-five years of follow-up. Since the publication of our original study, ten knees have been revised: three because of periprosthetic fracture, three because of infection, two because of patellofemoral failure, and two because of posterior instability. The rate of implant survival at twenty years after surgery was 69% (95% confidence interval [CI], 56% to 79%) with revision for any reason as the end point, 81% (95% CI, 69% to 89%) with femoral or tibial component revision for any reason as the end point, and 93% (95% CI, 83% to 97%) with posterior instability as the end point. These long-term results demonstrate that posterior cruciate ligament insufficiency with instability was rarely the cause of failure following cruciate-retaining total knee arthroplasty in patients with rheumatoid arthritis.

Cruciate-retaining TKA using a third-generation system with a four-pegged tibial component: a minimum 10-year followup note.

BACKGROUND: A third-generation TKA system was designed to address problems encountered with earlier designs including a high rate of patellofemoral complications. At a minimum of 5 years, we previously reported survivorship of 98.7% using revision for any reason as the endpoint for a cohort that includes the patients described in this report. That cohort was unique in that a tibial component that uses four short pegs for fixation was used in a subset of patients undergoing cruciate-retaining TKA and the tibial and femoral components were precoated with polymethylmethacrylate. QUESTIONS/PURPOSES: We now report the survival rate, postoperative function, complications, radiographic loosening, and osteolysis at a minimum of 10 years postoperatively. PATIENTS AND METHODS: We retrospectively reviewed 161 patients who underwent 179 TKAs. The patella was resurfaced in all cases and all components were cemented. Patients were evaluated clinically and radiographically for evidence of component loosening and osteolysis. Forty of the 161 patients (with 44 TKAs) had died and eight patients (nine knees) were lost to followup. For the remaining 113 patients (126 knees), the minimum followup was 10 years (mean, 11.7 years; range, 10.0-13.9 years). RESULTS: Survivorship at a minimum of 10 years postoperatively using revision for any reason and revision for aseptic loosening were 97.7% and 100%, respectively. Three knees were revised: one for infection, one for periprosthetic fracture, and one for postoperative arthrofibrosis. There were no reoperations for patellar component maltracking, wear or loosening, tibiofemoral polyethylene wear, osteolysis, or aseptic loosening. Hospital for Special Surgery scores improved from a mean of 47.7 (range, 23-78) preoperatively to 85.4 (range, 33-100). CONCLUSIONS: This cruciate-retaining design had a low risk of implant failure or revision and the design changes eliminated the patellar failures seen with earlier iterations at up to 10 years. LEVEL OF EVIDENCE: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Primary total hip arthroplasty with a porous-coated acetabular component. A concise follow-up, at a minimum of twenty years, of previous reports.

We previously reported the seven and fifteen-year results of the use of a porous-coated acetabular metal shell inserted without cement in a consecutive series of 204 primary total hip arthroplasties. In the present study, we evaluated the longer-term outcomes of these arthroplasties at a minimum follow-up time of twenty years. One hundred and fourteen (92%) of the 124 hips available for study had retained the original acetabular metal shell. A total of five acetabular components had been revised for aseptic loosening or had radiographic evidence of definite loosening. Fourteen hips with well-fixed acetabular shells required a change of the modular acetabular liner because of excessive wear and/or for the treatment of osteolysis, and liner changes have been recommended for another eight hips. The twenty-year rate of survival of the metal shell, with failure defined as revision because of loosening or radiographic evidence of loosening, was 96% (95% confidence interval, 94% to 98%). Cementless acetabular reconstruction continues to provide durable fixation at twenty years postoperatively. Wear-related complications continue to be the major mode of failure.

Revision of the acetabulum with a contemporary cementless component.

We evaluated the performance of a contemporary cementless acetabular component at a minimum of 5 years postoperatively. One hundred eighty-seven consecutive acetabular component revisions were performed using a hemispherical porous-coated component. Patients were followed prospectively with radiographs and Harris hip scores. Twenty patients died, leaving 158 patients (166 hips) available for follow-up at a mean of 91 months. No patients were lost. Eleven acetabular components (7%) required repeated revision, including 4 (2%) for aseptic loosening. Seven of the 145 unrevised acetabular components with radiographic follow-up (5%) were loose. The results of acetabular revision with this contemporary acetabular component were good but inferior to those of earlier-generation implants. This difference is likely multifactorial.

Revision of the acetabular component without cement. A concise follow-up, at twenty to twenty-four years, of a previous report.

We previously reported the results of the use of a cementless acetabular shell for revision total hip arthroplasty in 138 hips at a minimum of three, seven, and fifteen years postoperatively. The current report presents the long-term outcomes of this group at a minimum follow-up of twenty years. Since the last report, two additional hips required repeat revision, both for infection; no additional acetabular shell was loose. In the entire series to date, repeat acetabular revision was performed in twenty-one (15%) of the original 138 hips. Twenty of the twenty-one shells were well fixed at the time of repeat revision, and one had become aseptically loose. The most common reasons for repeat revision were infection (eight hips) and recurrent instability (eight hips). In the metal shells that were well fixed, an isolated liner change for polyethylene wear and/or osteolysis was performed in a total of six hips; four of these liner exchanges were performed since the time of our last report. A liner change had been recommended because of severe wear in four additional hips; thus, 18% of the fifty-six unrevised metal shells were associated with polyethylene wear-related problems. Survivorship, with revision of the shell for aseptic loosening or radiographic evidence of loosening as the end point, was 95% at twenty years (95% confidence interval, 83% to 98%). Reoperations for wear and osteolysis were first seen at approximately twelve years postoperatively. At the time of the present long-term follow-up, the reoperation rate for polyethylene wear and/or osteolysis had increased. We continue to use a hemispherical, titanium metal shell with multiple screws for fixation in the majority of acetabular revisions.

How have alternative bearings (such as metal-on-metal, highly cross-linked polyethylene, and ceramic-on-ceramic) affected the prevention and treatment of osteolysis?

Osteolysis is a multifactorial process dependent on surgical technique, implant design, patient factors, and material composition. Alternative bearing surfaces, such as highly cross-linked polyethylene, ceramic-on-ceramic, and metal-on-metal articular surfaces, have been introduced in an attempt to reduce wear and osteolysis following total hip arthroplasty. Intermediate-term follow-up data available suggest that the prevalence and severity of osteolysis may be reduced with these materials compared with conventional metal-on-polyethylene bearing surface couples. However, long-term data are presently unavailable; the future performance of these bearings awaits clinical validation.

Role of fibroblasts and fibroblast-derived growth factors in periprosthetic angiogenesis.

The periprosthetic granulomatous soft tissue [designated iterfacial membrane (IFM) in this study] exhibits heterogeneous histopathological features, in which highly vascularized areas with dense cellularity alternate with fibrotic and pseudocapsule-like tissue structures. Although macrophage/monocyte activation is a prominent event in the periprosthetic environment, fibroblasts also phagocytose particulate wear debris both in vivo and in vitro. Particulate wear debris and/or cytokines/growth factors alone or in combination (e.g., in conditioned media of explant cultures of IFMs) stimulated normal synovial and IFM fibroblasts to express inflammatory mediators and growth factors such as interleukin (IL)-1beta, IL-6, IL-8, three isoforms of vascular endothelial growth factor (VEGF), monocyte/macrophage chemoattractant protein-1 (MCP-1), macrophage-colony-stimulating factor (M-CSF), cycloxygenases (Cox-1 and Cox-2), acid- and basic-fibroblast growth factors (FGF-1 and FGF-2), leukemia inhibitory factor-1 (LIF-1), transforming growth factor beta-1 (TGF-beta1), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG). Thus, the fibroblast is capable of expressing a wide array of angiogenic and osteoclastogenic factors which are involved in the detrimental processes of the periprosthetic osteolysis.