The goal of this study was to develop an aggressive running regimen for modeling osteoarthritis (OA) in rats. Twelve Wistar rats were randomly placed into either a running group or a non‐running group to serve as the control. The running rats used a motorized treadmill to run either 30 km in 3 weeks or 55 km in 6 weeks. Each week, the prints of hind paws were obtained when rats were made to walk through a tunnel. The resulting prints were digitalized for analyses of stride length and step angle. The histology of the knees was examined at 3 and 6 weeks and the OA pathology in the knees was quantified by Mankin's score. Osteoarthritic pathology developed in the knees of the running rats, including decreased proteoglycan content, uneven type II collagen distribution in the cartilage matrix, increased MMP‐13 expression, expanded calcified cartilage zone, and clefts and defects in articular cartilage. The pathology worsened from running for 3 to 6 weeks. Gait analysis revealed an inverse correlation between paw angle and the grades of OA pathology. In conclusion, excessive running induces joint degeneration and a unique gait pattern in rats. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1604–1610, 2012

Objective: Biologics are increasingly used for cartilage repair and osteoarthritis (OA) treatment. This study aimed to provide an overview of the clinical trials conducted on this subject. Design: Two-word combinations of two sets of key words “cartilage”; “joint”; “osteoarthritis” and “biologics”; “stem cells”; “cell implantation” were used to search the database of ClinicalTrials.gov and supplemented with searches of PubMed and EMbase. The registered trials were analyzed for clinical conditions, completion status, phases, and investigated biologics. Recently completed trials with posted/published results were summarized. Results: From 2000 to 2022, a total of 365 clinical trials were registered at ClinicalTrials.gov to use biologics for cartilage repair and OA treatment. Since 2006, the number of registered trials accelerated at an annual rate of 16.4%. Of the 265 trials designated with a phase, 72% were early Phase 1, Phase 1, and Phase 2. Chondrocytes and platelet-rich plasma (PRP) were studied in nearly equal number of early- and late-stage trials. Mesenchymal stem/stromal cells (MSCs) were the most commonly investigated biologics (38%) and mostly derived from bone marrow and adipose tissue (70%). In last 5 years, 32 of the 72 completed trials posted/published results, among which seven Phase 3 trials investigated chondrocytes, PRP, bone marrow aspirate concentrate, hyaluronic acid, collagen membrane, and albumin. Conclusions: There was a rapid increase in the number of registered clinical trials in recent years, using a variety of biologics for cartilage repair and OA treatment. Majority of the biologics still require late-stage trials to validate their clinical effectiveness.

Objectives: Circulating mesenchymal stem cells (MSCs) participate in fracture healing and can be used to enhance fracture healing. This study investigated how CD271-selected MSCs travel in circulation and when is the optimal time to apply MSCs intravenously during fracture healing. Methods: Based on the expression of CD271, MSCs were isolated from human bone marrow and labeled with cypate, a near-infrared fluorochrome. A unilateral closed fracture was created at the femur in immunodeficient mice. The cypate-labeled MSCs were injected into the tail vein of the mice at days 1 and 3 after fracture and were tracked by near-infrared imaging. The mice were euthanized at 3 weeks after fracture. Immunohistochemistry was performed to detect human MSCs at the fracture sites. Migration of CD271-selected MSCs, under the influence of stem cell–derived factor-1, was assessed in vitro. Results: Intravenously injected at day 1, but not day 3, after fracture, CD271-selected MSCs accumulated at the fracture sites significantly and lasted for at least 7 days. All fractures, with or without MSC injections, healed in 3 weeks. Human cells were localized at the fracture sites in mice by immunohistochemistry. CD271-selected MSCs migrated toward the medium contained stem cell–derived factor-1 in vitro. Conclusions: After intravenous injection, CD271-selected MSCs were recruited to the fracture sites. The stages of fracture healing influenced the homing of culture-expanded MSCs. In mice, an optimal window of intravenous injection of MSCs was around 24 hours after fracture. Clinical Relevance: Intravenous application of MSCs may serve as a practical route to deliver stem cells for the treatment of fracture nonunion and delayed union. Levels of Evidence: Level I.

Background: The Trabecular Metal Total Ankle Implant differs from other newer-generation implants in the transfibular approach, multiplanar external frame for alignment, tantalum trabecular metal interfaces, curved geometry, and shallow resection depths. The primary aim of this study was to report midterm clinical and radiographic results, as well as survivorship and adverse events at a minimum of 5-year follow-up. Methods: A total of 83 ankles (81 patients, average age 60.6 years old, 50.6% females) with average 6.3 years’ (range, 5.0-10.1) follow-up were included. Postoperative patient-reported outcome measures (PROMs) included SF-12 physical (PCS) and mental component summary (MCS) scores, Ankle Osteoarthritis Scale (AOS), pain visual analog scale (VAS). Radiographic outcomes included postoperative range of motion (ROM) and coronal/sagittal alignment. Adverse events were reported using the Canadian Orthopaedic Foot and Ankle Society Reoperation Coding System (CROCS). Results: Preoperative tibiotalar coronal deformity included 27 valgus (10 degrees, range 2-20 degrees) and 25 varus ankles (−9 degrees, range −2 to −25 degrees), corrected to neutral postoperatively. Postoperative tibiopedal ROM was 17.8 degrees dorsiflexion and 21.8 degrees plantarflexion. Adverse events occurred at average 28.7 months, most commonly gutter debridement (n = 17, 16.7%) and subsequent operative treatment unrelated to metal components (n = 10, 12.0%). There were 2 cases (2.4%) of acute deep infection treated with irrigation and debridement, polyethylene exchange, and retention of metal components without recurrence of infection. There were no cases of fibular nonunion, septic or aseptic loosening, or implant subsidence. Postoperative PROMS included SF-12 PCS: 40.4; SF-12 MCS: 56.0; VAS: 2.3; AOS Pain: 17.0; and AOS Disability: 24.9. Overall implant survival, defined by retention of the metal components, was 100% at final follow-up. Conclusion: At a minimum of 5 years, patients who underwent TM TAA reported minimal ankle pain and regained neutral ankle alignment and mobility, without septic or aseptic implant loosening. Although having certain limitations, this study suggests that TM TAA is a viable option for the treatment of end-stage ankle arthritis.

Background: While most total ankle arthroplasty (TAA) procedures utilize an anterior approach for implantation, the Zimmer Biomet Trabecular Metal implant is unique in that it utilizes a lateral transfibular approach. We present the largest mid-term study to date to analyze the implant survivorship and clinical and radiographic outcomes of transfibular TAA at a minimum 5-year follow-up. Methods: We retrospectively identified and evaluated 130 ankles (122 patients; mean age, 60.8 years; 50% female) with a mean follow-up of 5.9 years (range, 5.0 to 10.1 years) after primary TAA performed between October 2012 and December 2018. Patient-reported outcome measures (PROMs) included the 12-item Short Form Health Survey (SF-12) Physical Component Summary (PCS) and Mental Component Summary (MCS), Ankle Osteoarthritis Scale (AOS) for pain and disability, and visual analog scale (VAS) for pain. Radiographic measurements for range of motion, coronal and sagittal alignment, and implant subsidence were evaluated. The presence of periprosthetic radiolucency was determined using a 12-zone classification system. Adverse events were reported using the Canadian Orthopaedic Foot and Ankle Society (COFAS) Reoperation Coding System (CROCS). Results: The cohort had mean postoperative values of 41.5 for the SF-12 PCS, 54.9 for the SF-12 MCS, 2.3 for VAS pain, 19.1 for AOS pain, and 28.5 for AOS disability. The postoperative tibiotalar range of motion was 7.5° of dorsiflexion and 17.3° of plantar flexion. A total of 42 valgus ankles (mean coronal tibiotalar angle, 10.4°; range, 1.0° to 25.3°) and 44 varus ankles (mean, −9.1°; range, −1.0° to −25.0°) were corrected to neutral. Twenty-six ankles (20%) had 1 zone of radiolucency, and none of the ankles had >7 zones. There were 3 cases of cysts (2.3%) and 0 cases of subsidence, septic or aseptic loosening, or fibular nonunion. Adverse events occurred in 47 ankles (36.2%) at a mean of 26.7 months, with the most common reoperation being medial gutter debridement (22 ankles; 16.9%). There were 2 ankles (1.5%) with acute infection treated with debridement, antibiotics, and polyethylene exchange with metal component retention. Overall implant survivorship, defined as retention of the metal components, was 100% at the time of final follow-up. Conclusions: The clinical and radiographic data in this study suggest that transfibular TAA is an effective and durable treatment option for end-stage ankle arthritis, with excellent mid-term implant survivorship. Periprosthetic radiolucency was limited and did not lead to implant subsidence or loosening. The most common reoperation was medial gutter debridement. Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.