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'Mechanogenetics,' a new field at the convergence of mechanobiology and synthetic biology, presents an innovative strategy to treat, repair, or restore diseased cells and tissues by harnessing mechanical signal transduction pathways to control gene expression. While the role of mechanical forces in regulating development, homeostasis, and disease is well established, only recently have we identified the specific mechanosensors and downstream signaling pathways involved in these processes. Simultaneously, synthetic biological systems are developing increasingly sophisticated approaches of controlling mammalian cellular responses. Continued mechanistic refinement and identification of how cellular mechanosensors respond to homeostatic and pathological mechanical forces, combined with synthetic tools to integrate and respond to these inputs, promises to extend the development of new therapeutic approaches for treating disease., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Immunoengineering continues to revolutionize healthcare, generating new approaches for treating previously intractable diseases, particularly in regard to cancer immunotherapy. In joint diseases, such as osteoarthritis (OA) and rheumatoid arthritis (RA), biomaterials and anti-cytokine treatments have previously been at that forefront of therapeutic innovation. However, while many of the existing anti-cytokine treatments are successful for a subset of patients, these treatments can also pose severe risks, adverse events and off-target effects due to continuous delivery at high dosages or a lack of disease-specific targets. The inadequacy of these current treatments has motivated the development of new immunoengineering strategies that offer safer and more efficacious alternative therapies through the precise and controlled targeting of specific upstream immune responses, including direct and mechanistically-driven immunoengineering approaches. Advances in the understanding of the immunomodulatory pathways involved in musculoskeletal disease, in combination with the growing emphasis on personalized medicine, stress the need for carefully considering the delivery strategies and therapeutic targets when designing therapeutics to better treat RA and OA. Here, we focus on recent advances in biomaterial and cell-based immunomodulation, in combination with genetic engineering, for therapeutic applications in joint diseases. The application of immunoengineering principles to the study of joint disease will not only help to elucidate the mechanisms of disease pathogenesis but will also generate novel disease-specific therapeutics by harnessing cellular and biomaterial responses. STATEMENT OF SIGNIFICANCE: It is now apparent that joint diseases such as osteoarthritis and rheumatoid arthritis involve the immune system at both local (i.e., within the joint) and systemic levels. In this regard, targeting the immune system using both biomaterial-based or cellular approaches may generate new joint-specific treatment strategies that are well-controlled, safe, and efficacious. In this review, we focus on recent advances in immunoengineering that leverage biomaterials and/or genetically engineered cells for therapeutic applications in joint diseases. The application of such approaches, especially synergistic strategies that target multiple immunoregulatory pathways, has the potential to revolutionize our understanding, treatment, and prevention of joint diseases., Competing Interests: Declaration of Competing Interest Farshid Guilak is an employee of Cytex Therapeutics, Inc. No other others have competing interests., (Copyright © 2021. Published by Elsevier Ltd.)