Perspective: Optimizing Host Environments to Enhance MSK Tissue Repair and Complement Use of Cellular Therapies Is Critical for Improving Outcome Success—An Unmet Need

Since the discovery and characterization of mesenchymal stem cells (MSC) some 40 years ago and the development of induced pluripotent stem cells (iPSC), opportunities to advance repair and potentially regenerate injured or diseased connective tissues of the musculoskeletal (MSK) system have been intensely investigated. While some advances have been made with some tissues, progress has not been as great as was hoped following the availability of such stem-like cells. Optimizing cell-biomaterial composites in vitro for features such as cell state or extracellular vesicle cargo, structure, composition, biomechanical integrity are likely to be only part of the story and optimizing the environments where such composites have been implanted has not received the same attention. Thus, implanting optimized or near optimized cell-biomaterial composites in acutely or chronically affected implantation sites can compromise the efficacy of such composites to effectively repair/regenerate MSK tissues. This may be due to inflammatory processes, alterations to the remaining tissues in the injury site during development of chronicity, waiting too long to repair residual tissue, or other host factors. Thus, success in realizing the potential of MSC and iPSC may depend, in significant part, on the environment at the implantation site. Further attention to optimizing the implantation site may enhance outcome success with long-term return to tissue function. Furthermore, heterogeneity in patient populations regarding natural factors influencing healing outcomes after injury may also require changes to clinical trial design to assess efficacy of cell therapies.