Evans, Christopher

Abstract The Fracture Nonunion Symposium presented at the 2024 Orthopaedic Trauma Association Basic Science Focus Forum featured invited speakers who discussed current perspectives on this topic. Clinical approaches, diagnostic advancements, basic science perspectives, and novel treatment strategies were discussed. This symposium was curated to highlight this common and challenging clinical problem faced by orthopaedic and musculoskeletal practitioners from around the globe.

Abstract Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced posttraumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the 2 models. At the nexus of the 3 aging hallmarks, advanced glycation end product (AGE)/receptor for AGE (RAGE) emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE–RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE–RAGE signaling as a sex-dependent driver of age-related KOA.

Objectives: To develop and validate an unbiased, accurate, convenient, and inexpensive means of determining when an osseous defect has healed and recovered sufficient strength to allow weight bearing. Methods: A novel image processing software algorithm was created to analyze the radiographic images and produce a metric designed to reflect the bone strength. We used a rat femoral segmental defect model that provides a range of healing responses from complete union to nonunion. Femora were examined by x-ray, micro–computed tomography and mechanical testing. Accurate simulated radiographic images at different incident x-ray beam angles were produced from the micro–computed tomography data files. Results: The software-generated metric (SC) showed high levels of correlation with both the mechanical strength (τMech) and the polar moment of inertia (pMOI), with the mechanical testing data having the highest association. The optimization analysis yielded optimal oblique angles θB of 125 degrees for τMech and 50 degrees for pMOI. The Pearson R2 values for the optimized model were 0.71 and 0.64 for τMech and pMOI, respectively. Further validation using true radiographs also demonstrated that the metric was accurate and that the simulations were realistic. Conclusions: The preliminary findings suggest a very promising methodology to assess bone fracture healing using conventional radiography. With radiographs acquired at appropriate incident angles, it proved possible to accurately calculate the degree of healing and the mechanical strength of the bone. Further research is necessary to refine this approach and determine whether it translates to the human clinical setting.

Osteoarthritis is a painful, chronic disease with widespread burden on patients, communities, health and social care systems. Conservative therapies, such as nonpharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, disease control often remains inadequate. Recent advances in osteoarthritis management have aimed to provide greater variety of treatment options. Here, we summarize a targeted literature review evaluating efficacy and safety of intra-articular therapies for osteoarthritis. Injections of intra-articular therapies directly into the joint avoid conventional barriers to joint entry, increase bioavailability and lower systemic toxicity. Intra-articular corticosteroids and hyaluronic acid are established United States Food and Drug Administration (US FDA)/European Medicines Agency (EMA)-approved treatments; however, concerns exist regarding effect duration, safety, effectiveness across populations and heterogeneity. Newer therapies, such as autologous blood products and mesenchymal stem cells, are in development. Benefits of autologous blood products (e.g. platelet-rich plasma, autologous conditioned serum) include an expected improved safety profile and direct targeting of osteoarthritis-related pathophysiology. Autologous conditioned serum is cell-free and manufactured by a standardized process, whereas platelet-rich plasma composition and characteristics can vary. Currently, only limited efficacy comparisons between these biological treatments can be drawn; long-term clinical and safety studies are needed to increase the efficacy evidence base and earn consideration in treatment frameworks.

Background: Reverse dynamization is a technology for enhancing the healing of osseous defects. With use of an external fixator, the axial stiffness across the defect is initially set low and subsequently increased. The purpose of the study described in this paper was to explore the efficacy of reverse dynamization under different conditions. Methods: Rat femoral defects were stabilized with external fixators that allowed the stiffness to be modulated on living animals. Recombinant human bone morphogenetic protein-2 (rhBMP-2) was implanted into the defects on a collagen sponge. Following a dose-response experiment, 5.5 μg of rhBMP-2 was placed into the defect under conditions of very low (25.4-N/mm), low (114-N/mm), medium (185-N/mm), or high (254-N/mm) stiffness. Reverse dynamization was evaluated with 2 different starting stiffnesses: low (114 N/mm) and very low (25.4 N/mm). In both cases, high stiffness (254 N/mm) was imposed after 2 weeks. Healing was assessed with radiographs, micro-computed tomography (μCT), histological analysis, and mechanical testing. Results: In the absence of dynamization, the medium-stiffness fixators provided the best healing. Reverse dynamization starting with very low stiffness was detrimental to healing. However, with low initial stiffness, reverse dynamization considerably improved healing with minimal residual cartilage, enhanced cortication, increased mechanical strength, and smaller callus. Histological analysis suggested that, in all cases, healing provoked by rhBMP-2 occurred by endochondral ossification. Conclusions: These data confirm the potential utility of reverse dynamization as a way of improving bone healing but indicate that the stiffness parameters need to be selected carefully. Clinical Relevance: Reverse dynamization may reduce the amount of rhBMP-2 needed to induce healing of recalcitrant osseous lesions, reduce the time to union, and decrease the need for prolonged external fixation.