Bettencourt, Jacob W.

AimsContemporary outcomes of total femoral arthroplasties (TFAs) in the non-oncological setting are limited. This study aimed to assess implant survival free from revision and reoperation, clinical outcomes, and radiological results associated with TFAs for non-oncological conditions.MethodsWe identified 24 patients who received TFAs between 1 January 2007 and 31 December 2021 through our institutional total joint registry. The patients’ mean age was 66 years (48 to 83), mean BMI was 33 kg/m2 (21 to 54), and median follow-up was four years (IQR 2 to 5). Bearings used included eight flat-faced polyethylene bearings, seven dual-mobility constructs, six constrained liners, and three face-changing liners. Of the 24 patients, 17 had a previously documented periprosthetic joint infection (PJI) and 12 were treated with chronic antibiotic suppression following their TFAs.ResultsThe two-, five-, and ten-year survivals free of any revision were 66%, 51%, and 34%, respectively. There were 12 revisions: five for hip dislocation, four for PJI, one for aseptic tibial loosening, one for prosthetic knee dislocation, and one for acetabular loosening with pelvic discontinuity. The two-, five-, and ten-year survivals free of any reoperation were 53%, 47%, and 34%, respectively. In addition to the stated TFA revisions, one patient required open reduction of a hip dislocation, and two patients required superficial irrigation and debridement procedures for wound complications. Mean Harris Hip Scores improved from a mean score of 48 to 69 (p = 0.002), and Knee Society Scores improved from a mean score of 56 to 71 (p = 0.110). At final follow-up, 20 patients had TFAs in situ, but four patients had been treated with hip disarticulation due to recalcitrant infection. All but one tibial and all non-revised acetabular components were radiologically well-fixed at final follow-up.ConclusionThe use of TFAs in the non-oncological setting, mostly for salvage of multiply revised hips with previous PJI, had a low five-year survival free from any revision of 51%, mostly for hip dislocation and infection. Nevertheless, clinical outcomes improved in this challenging cohort of patients.Cite this article: Bone Joint J 2025;107-B(4):449–454.

AbstractAdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty‐six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K‐wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16‐week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10‐week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose‐dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals.

AbstractArthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti‐fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFβ1‐mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFβ1‐induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA‐seq analysis corroborated the anti‐myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle‐treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.

AbstractArthrofibrosis, which is characterized by excessive scar tissue and limited motion, can complicate the daily functioning of patients after total knee arthroplasty (TKA). Molecular hallmarks of arthrofibrosis include pathologic accumulation of myofibroblasts and disproportionate collagen deposition. Epigenetic mechanisms, including posttranslation modification of histones, control gene expression and may regulate fibrotic events. This study assessed the role of the bromodomain and extra‐terminal (BET) proteins on myofibroblast differentiation. This group of epigenetic regulators recognize acetylated lysines and are targeted by a class of drugs known as BET inhibitors. RNA‐seq analysis revealed robust mRNA expression of three BET members (BRD2, BRD3, and BRD4) while the fourth member (BRDT) is not expressed in primary TKA knee outgrowth fibroblasts. RT‐qPCR and western blot analyses revealed that BET inhibition with the small molecule JQ1 impairs TGFβ1‐induced expression of ACTA2, a key myofibroblast marker, in primary outgrowth knee fibroblasts. Similarly, JQ1 administration also reduced COL3A1 mRNA levels and collagen deposition as monitored by picrosirius red staining. Interestingly, the inhibitory effects of JQ1 on ACTA2 mRNA and protein expression, as well as COL3A1 expression and collagen deposition, were paralleled by siRNA‐mediated depletion of BRD4. Together, these data reveal that BRD4‐mediated epigenetic events support TGFβ1‐mediated myofibroblast differentiation and collagen deposition as seen in arthrofibrosis. To our knowledge, these are the first studies that assess epigenetic regulators and their downstream events in the context of arthrofibrosis. Future studies may reveal clinical utility for drugs that target epigenetic pathways, specifically BET proteins, in the prevention and treatment of arthrofibrosis.

Aims As has been shown in larger animal models, knee immobilization can lead to arthrofibrotic phenotypes. Our study included 168 C57BL/6J female mice, with 24 serving as controls, and 144 undergoing a knee procedure to induce a contracture without osteoarthritis (OA). Methods Experimental knees were immobilized for either four weeks (72 mice) or eight weeks (72 mice), followed by a remobilization period of zero weeks (24 mice), two weeks (24 mice), or four weeks (24 mice) after suture removal. Half of the experimental knees also received an intra-articular injury. Biomechanical data were collected to measure passive extension angle (PEA). Histological data measuring area and thickness of posterior and anterior knee capsules were collected from knee sections. Results Experimental knees immobilized for four weeks demonstrated mean PEAs of 141°, 72°, and 79° after zero, two, and four weeks of remobilization (n = 6 per group), respectively. Experimental knees demonstrated reduced PEAs after two weeks (p < 0.001) and four weeks (p < 0.0001) of remobilization compared to controls. Following eight weeks of immobilization, experimental knees exhibited mean PEAs of 82°, 73°, and 72° after zero, two, and four weeks of remobilization, respectively. Histological analysis demonstrated no cartilage degeneration. Similar trends in biomechanical and histological properties were observed when intra-articular violation was introduced. Conclusion This study established a novel mouse model of robust knee contracture without evidence of OA. This was appreciated consistently after eight weeks of immobilization and was irrespective of length of remobilization. As such, this arthrofibrotic model provides opportunities to investigate molecular pathways and therapeutic strategies. Cite this article: Bone Joint Res 2023;12(1):58–71.

AbstractArthrofibrosis is characterized by excessive extracellular matrix (ECM) deposition that results in restricted joint motion after total knee arthroplasties (TKAs). Currently, treatment options are limited. Therefore, an in vitro model of knee‐related myofibroblastogenesis is valuable to facilitate investigation of the arthrofibrotic process, diagnostic and therapeutic options. In this study, we obtained intraoperative posterior capsule (PC), quadriceps tendon (QT), and suprapatellar pouch (SP) tissues from the knees of four patients undergoing primary TKAs for osteoarthritis. From these tissues, we isolated primary cells by the outgrowth method and subsequently characterized these cells in the absence and presence of the pro‐myofibroblastic cytokine, transforming growth factor beta 1 (TGFβ1). Light microscopy of knee outgrowth cells revealed spindle‐shaped cells, and immunofluorescence (IF) analysis demonstrated staining for the fibroblast‐specific markers TE‐7 and vimentin (VIM). These knee outgrowth fibroblasts differentiated readily into myofibroblasts as reflected by enhanced α‐smooth muscle actin (ACTA2) mRNA and protein expression and increased mRNA expression of collagen type 1 (COL1A1) and type 3 (COL3A1) with collagenous matrix deposition in the presence of TGFβ1. Outgrowth knee fibroblasts were more sensitive to TGFβ1‐mediated myofibroblastogenesis than adipose‐derived mesenchymal stromal/stem cells (MSCs). While outgrowth knee fibroblasts isolated from three anatomical regions in four patients exhibited similar gene expression, these cells are distinct from other fibroblastic cell types (i.e., Dupuytren's fibroblasts) as revealed by RNA‐sequencing. In conclusion, our study provides an in vitro myofibroblastic model of outgrowth knee fibroblasts derived from patients undergoing primary TKA that can be utilized to study myofibroblastogenesis and assess therapeutic strategies for arthrofibrosis.

Aims Septic arthritis of the hip often leads to irreversible osteoarthritis (OA) and the requirement for total hip arthroplasty (THA). The aim of this study was to report the mid-term risk of any infection, periprosthetic joint infection (PJI), aseptic revision, and reoperation in patients with a past history of septic arthritis who underwent THA, compared with a control group of patients who underwent THA for OA. Methods We retrospectively identified 256 THAs in 244 patients following septic arthritis of the native hip, which were undertaken between 1969 and 2016 at a single institution. Each case was matched 1:1, based on age, sex, BMI, and year of surgery, to a primary THA performed for OA. The mean age and BMI were 58 years (35 to 84) and 31 kg/m2 (18 to 48), respectively, and 100 (39%) were female. The mean follow-up was 11 years (2 to 39). Results The ten-year survival free of any infection was 91% and 99% in the septic arthritis and OA groups, respectively (hazard ratio (HR) = 13; p < 0.001). The survival free of PJI at ten years was 93% and 99% in the septic arthritis and OA groups, respectively (HR = 10; p = 0.002). There was a significantly higher rate of any infection at ten years when THA was undertaken within five years of the diagnosis of septic arthritis compared with those in whom THA was undertaken > five years after this diagnosis was made (14% vs 5%, respectively; HR = 3.1; p = 0.009), but there was no significant difference in ten-year survival free of aseptic revision (HR = 1.14; p = 0.485). The mean Harris Hip Scores at two and five years postoperatively were significantly lower in the septic arthritis group compared with the OA group (p = 0.001 for both). Conclusion There was a ten-fold increased risk of PJI in patients with a history of septic arthritis who underwent THA compared with those who underwent THA for OA with a ten-year cumulative incidence of 7%. The risk of any infection had a strong downward trend as the time interval between the diagnosis of septic arthritis and THA increased, highlighted by a 3.1-fold higher risk when THAs were performed within five years of the diagnosis being made. Cite this article: Bone Joint J 2022;104-B(2):227–234.

Background: Septic arthritis of the native knee often results in irreversible joint damage leading to the need for total knee arthroplasty (TKA). The purpose of the present study was to examine the intermediate-term risk of periprosthetic joint infection (PJI), aseptic revision, and reoperation following primary TKA in patients with a history of septic arthritis of the native knee as compared with primary TKA performed for the treatment of osteoarthritis. Methods: We retrospectively identified 215 primary TKAs performed from 1971 to 2016 at a single institution in patients with a history of septic arthritis of the native knee. Each case was matched 1:1 based on age, sex, body mass index (BMI), and surgical year to a TKA for osteoarthritis. The mean age and BMI were 63 years and 30 kg/m 2 , respectively. The mean duration of follow-up was 9 years. Results: Survivorships free of PJI at 10 years were 90% and 99% for the septic arthritis and osteoarthritis groups, respectively (hazard ratio [HR] = 6.1; p < 0.01). Ten-year survivorships free of any aseptic revisions were 83% and 93% (HR = 2.5; p < 0.01), and survivorships free of any reoperation were 61% and 84% (HR = 2.9; p < 0.01) for the septic arthritis and osteoarthritis groups, respectively. In addition, as time from the diagnosis of native knee septic arthritis to TKA increased, the relative risk of subsequent infection decreased. Preoperative and 2-year postoperative Knee Society scores were similar between the groups (p = 0.16 and p = 0.19, respectively). Conclusions: There was a 6.1-fold increased risk of PJI in patients undergoing TKA with a history of native knee septic arthritis when compared with controls undergoing TKA for the treatment of osteoarthritis, with a cumulative incidence of 9% at 10 years. Subgroup analysis of the septic arthritis cohort revealed a higher risk of any infection in patients who underwent TKA within the first 5 to 7 years after the diagnosis of septic arthritis as compared with those with a greater duration. Moreover, the 10-year rates of survival free of aseptic revision, any revision, and any reoperation were significantly worse in the native knee septic arthritis cohort. Level of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

AbstractExperimental analyses of posttraumatic knee arthrofibrosis utilize a rabbit model as a gold standard. However, a rodent model of arthrofibrosis offers many advantages including reduced cost and comparison with other models of organ fibrosis. This study aimed to characterize the biomechanical, histological, and molecular features of a novel posttraumatic model of arthrofibrosis in rats. Forty eight rats were divided into two equal groups. An immobilization procedure was performed on the right hind limbs of experimental rats. One group was immobilized for 4 weeks and the other for 8 weeks. Both groups were remobilized for 4 weeks. Limbs were studied biomechanically via assessment of torque versus degree of extension, histologically via whole knee specimen, and molecularly via gene expression of posterior capsular tissues. Significant differences were observed between experimental and control limbs at 4 N‐cm of torque in the 4‐week (knee extension: 115° ± 8° vs. 169° ± 17°, respectively; p = 0.007) and 8‐week immobilization groups (knee extension: 99° ± 12° vs. 174° ± 9°, respectively; p = 0.008). Histologically, in each group experimental limbs demonstrated increased posterior capsular thickness and total area of tissue when compared to control limbs (p < 0.05). Gene expression values evaluated in each group were comparable. This study presents a novel rat model of arthrofibrosis with severe and persistent knee contractures demonstrated biomechanically and histologically. Statement of clinical significance: Arthrofibrosis is a common complication following contemporary total knee arthroplasties. The proposed model is reproducible, cost‐effective, and can be employed for translational investigations studying the pathogenesis of arthrofibrosis and efficacy of neoadjuvant pharmacologic agents.