A mathematical model of signalling molecule-mediated processes during regeneration of osteochondral defects after chondrocyte implantation.

Treating bone-cartilage defects is a fundamental clinical problem. The ability of damaged cartilage to self-repair is limited due to its avascularity. Left untreated, these defects can lead to osteoarthritis. Details of osteochondral defect repair are elusive, but animal models indicate healing occurs via an endochondral ossification-like process, similar to that in the growth plate. In the growth plate, the signalling molecules parathyroid hormone-related protein (PTHrP) and Indian Hedgehog (Ihh) form a feedback loop regulating chondrocyte hypertrophy, with Ihh inducing and PTHrP suppressing hypertrophy. To better understand this repair process and to explore the regulatory role of signalling molecules on the regeneration process, we formulate a reaction-diffusion mathematical model of osteochondral defect regeneration after chondrocyte implantation. The drivers of healing are assumed to be chondrocytes and osteoblasts, and their interaction via signalling molecules. We model cell proliferation, migration and chondrocyte hypertrophy, and matrix production and conversion, spatially and temporally. We further model nutrient and signalling molecule diffusion and their interaction with the cells. We consider the PTHrP-Ihh feedback loop as the backbone mechanisms but the model is flexible to incorporate extra signalling mechanisms if needed. Our mathematical model is able to represent repair of osteochondral defects, starting with cartilage formation throughout the defect. This is followed by chondrocyte hypertrophy, matrix calcification and bone formation deep inside the defect, while cartilage at the surface is maintained and eventually separated from the deeper bone by a thin layer of calcified cartilage. The complete process requires around 48 months. A key highlight of the model demonstrates that the PTHrP-Ihh loop alone is insufficient and an extra mechanism is required to initiate chondrocyte hypertrophy, represented by a critical cartilage density. A parameter sensitivity study reveals that the timing of the repair process crucially depends on parameters, such as the critical cartilage density, and those describing the actions of PTHrP to suppress hypertrophy, such as its diffusion coefficient, threshold concentration and degradation rate.

Assessment of the effectiveness of weight-adjusted antibiotic administration, for reduced duration, in surgical prophylaxis of primary hip and knee arthroplasty.

BACKGROUND: Prophylactic antibiotics have significantly led to a reduction in the risk of post-operative surgical site infections (SSI) in orthopaedic surgery. The aim of using antibiotics for this purpose is to achieve serum and tissue drug levels that exceed, for the duration of the operation, the minimum inhibitory concentration of the likely organisms that are encountered. Prophylactic antibiotics reduce the rate of SSIs in lower limb arthroplasty from between 4% and 8% to between 1% and 3%. Controversy, however, still surrounds the optimal frequency and dosing of antibiotic administration. AIM: To evaluate the impact of introduction of a weight-adjusted antibiotic prophylaxis regime, combined with a reduction in the duration of administration of post-operative antibiotics on SSI incidence during the 2 years following primary elective total hip and knee arthroplasty. METHODS: Following ethical approval, patients undergoing primary total hip arthroplasty (THA)/total knee arthroplasty (TKA) with the old regime (OR) of a preoperative dose [cefazolin 2 g intravenously (IV)], and two subsequent doses (2 h and 8 h), were compared to those after a change to a new regime (NR) of a weight-adjusted preoperative dose (cefazolin 2 g IV for patients < 120 kg; cefazolin 3g IV for patients > 120 kg) and a post-operative dose at 2 h. The primary outcome in both groups was SSI rates during the 2 years post-operatively. RESULTS: A total of n = 1273 operations (THA n = 534, TKA n = 739) were performed in n = 1264 patients. There was no statistically significant difference in the rate of deep (OR 0.74% (5/675) vs NR 0.50% (3/598); fishers exact test P = 0.72), nor superficial SSIs (OR 2.07% (14/675) vs NR 1.50% (9/598); chi-squared test P = 0.44) at 2 years post-operatively. With propensity score weighting and an interrupted time series analysis, there was also no difference in SSI rates between both groups [RR 0.88 (95%CI 0.61 to 1.30) P = 0.46]. CONCLUSION: A weight-adjusted regime, with a reduction in number of post-operative doses had no adverse impact on SSI incidence in this population.

Midterm outcome of superior capsular reconstruction using doubled acellular human dermal allograft for irreparable rotator cuff tear.

BACKGROUND: Thicker (folded) facia lata autografts have been shown to be superior to thinner grafts and single-layered acellular human dermal (HD) allografts for superior capsular reconstruction (SCR) in biomechanical studies. The aim of this study was to evaluate the midterm clinical outcomes following SCR for irreparable supraspinatus tears using doubled (folded) HD allograft. METHODS: Thirty-two patients who had undergone SCR using doubled HD allograft between February 2012 and January 2020 were recruited in a continuous manner in this retrospective study. The inclusion criteria were SCR performed for irreparable supraspinatus tear and a minimum of 2 years' follow-up. The primary outcome measure was the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score. The secondary outcome measures were complications and revision surgery. A subgroup analysis was performed between patients who received a "standard" graft of mean 3-mm thickness or a "thick" graft of mean 4.4-mm thickness. RESULTS: One patient was lost to follow-up. A total of 31 patients (31 shoulder joints) were analyzed with a mean follow-up duration of 48 months (range, 25-96 months). Following surgery, there was significant improvement in the ASES score from 18.1 ± 14.3 (preoperative) to 76.3 ± 25.1 (postoperative) (P < .001), with a satisfactory clinical outcome obtained in 83.8% of the patients. In a subset of 8 patients completing 5 years' follow-up, the clinical improvements were sustained. The percentage of patients with a clinically successful outcome was higher among those with thick grafts compared to those with standard grafts, although this failed to reach statistical significance (94.4% vs. 69.2%, risk ratio 1.36, 95% confidence interval 0.93-1.99, P = .13). One patient within the standard group underwent revision surgery. CONCLUSION: SCR for irreparable rotator cuff tears with doubled HD allograft results in improved clinical outcomes and low reoperation at midterm follow-up duration.