Creating an Optimal In Vivo Environment to Enhance Outcomes Using Cell Therapy to Repair/Regenerate Injured Tissues of the Musculoskeletal System

Abstract

Following most injuries to a musculoskeletal tissue which function in unique mechanical environments, an inflammatory response occurs to facilitate endogenous repair. This is a process that usually yields functionally inferior scar tissue. In the case of such injuries occurring in adults, the injury environment no longer expresses the anabolic processes that contributed to growth and maturation. An injury can also contribute to the development of a degenerative process, such as osteoarthritis. Over the past several years, researchers have attempted to use cellular therapies to enhance the repair and regeneration of injured tissues, including Platelet-rich Plasma and mesenchymal stem/medicinal signaling cells (MSC) from a variety of tissue sources, either as free MSC or incorporated into tissue engineered constructs, to facilitate regeneration of such damaged tissues. The use of free MSC can sometimes affect pain symptoms associated with conditions such as OA, but regeneration of damaged tissues has been challenging, particularly as some of these tissues have very complex structures. Therefore, implanting MSC or engineered constructs into an inflammatory environment in an adult may compromise the potential of the cells to facilitate regeneration, and neutralizing the inflammatory environment and enhancing the anabolic environment may be required for MSC-based interventions to fulfill their potential. Thus, success may depend on first eliminating negative influences (e.g., inflammation) in an environment, and secondly, implanting optimally cultured MSC or tissue engineered constructs into an anabolic environment to achieve the best outcomes. Furthermore, such interventions should be considered early rather than later on in a disease process, at a time when sufficient endogenous cells remain to serve as a template for repair and regeneration. This review discusses how the interface between inflammation and cell-based regeneration of damaged tissues may be at odds, and outlines approaches to improve outcomes. In addition, other variables that could contribute to the success of cell therapies are discussed. Thus, there may be a need to adopt a Precision Medicine approach to optimize tissue repair and regeneration following injury to these important tissues.

Osteoarthritis as an Umbrella Term for Different Subsets of Humans Undergoing Joint Degeneration: The Need to Address the Differences to Develop Effective Conservative Treatments and Prevention Strategies

“…Interestingly, in preclinical models, administration of anti-inflammatory drugs such as corticosteroids immediately after PTOA-inducing surgery can diminish the inflammation and progression to OA-like disease in sheep and rabbits [ 47 , 48 , 49 , 50 ], as well as pigs [ 51 ]. Some uptake of this concept has occurred in the clinical literature as well (discussed in [ 4 ]). Certainly, such a catabolic and inflammatory environment should be controlled if other interventions such as stem cell injections, tissue-engineered construct implantation, or the use of anabolic interventions are contemplated [ 4 , 28 ].…”

“…Some uptake of this concept has occurred in the clinical literature as well (discussed in [ 4 ]). Certainly, such a catabolic and inflammatory environment should be controlled if other interventions such as stem cell injections, tissue-engineered construct implantation, or the use of anabolic interventions are contemplated [ 4 , 28 ]. However, controlling inflammation alone will not address the mechanical dysfunction in PTOA, so a multimodal approach is needed.…”

“…If only 12% of human knee OA is due to PTOA, that means other initiating mechanisms must be entertained to address the remaining ~88% of cases. Some other options for potential initiators of knee OA include metabolic dysregulation such as that accompanying obesity, a post-menopausal phenotype to account for the increase of non-PTOA incidence in the post-menopausal female population, variation in lower extremity set points that arise during growth and maturation that are impacted by the aging process (discussed in [ 4 , 28 ]), and of course, genetic and epigenetic factors that could be independent contributors to risk for OA development or contribute to one of the previously mentioned options.…”

“…Until the last few decades, OA was commonly thought of as a disease of cartilage as that is the tissue that is most affected by the disease processes. Cartilage is aneural and avascular, so it is compromised when self-healing is considered (discussed in [ 4 ]). However, OA is now considered a disease of the whole joint [ 5 , 6 ], and thus, the multitude of components that make up a joint such as the knee, are involved [cartilage, ligaments, tendons, menisci, synovium, capsule and muscle].…”

“…While the term osteoarthritis implies that the degenerative process involves inflammation, for many years it was considered solely a degenerative process ascribed to aging-related “wear and tear” or due to injury that disturbed the relationship between the components of a joint leading to the demise of the “weakest link”-cartilage [ 7 ]. However, it is now fairly clear that inflammatory processes are involved in OA progression [ 4 , 8 , 9 , 10 , 11 , 12 ], but it is not clear whether inflammation is part of the initiation process leading to overt OA in different subsets of the condition.…”