# Extracellular Vesicles for Regenerative Medicine Applications
###### Abstract  
Tissue engineering and regenerative medicine (TERM) may be defined as a translational discipline focused on the development of novel techniques, devices, and materials to replace or repair injured or diseased tissue and organs. The main approaches typically use cells, scaffolds, and signaling molecules, either alone or in combination, to promote repair and regeneration. Although cells are required to create new functional tissue, the source of cells, either from an exogenous allogeneic or autologous source or through the recruitment of endogenous (autologous) cells, is technically challenging and risks the host rejection of new tissue. Regardless of the cell source, these approaches also require appropriate instruction for proliferation, differentiation, and in vivo spatial organization to create new functional tissue. Such instruction is supplied through the microenvironment where cells reside, environments which largely consist of the extracellular matrix (ECM). The specific components of the ECM, and broadly the extracellular space, responsible for promoting tissue regeneration and repair, are not fully understood, however extracellular vesicles (EVs) found in body fluids and solid phases of ECM have emerged as key mediators of tissue regeneration and repair. Additionally, these EVs might serve as potential cell-free tools in TERM to promote tissue repair and regeneration with minimal risk for host rejection and adverse sequelae. The past two decades have shown a substantial interest in understanding the therapeutic role of EVs and their applications in the context of TERM. Therefore, the purpose of this review is to highlight the fundamental characteristics of EVs, the current pre-clinical and clinical applications of EVs in TERM, and the future of EV-based strategies in TERM.  
tissue engineering; regenerative medicine; extracellular vesicle +
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matrix (ECM) [5; 6]. The ECM is a complex, three-dimensional network of proteins, proteoglycans, and glycosaminoglycans that provides cells and tissues with both structural and physiologic support [5]. In addition, the ECM hosts an abundant landscape of sequestered growth factors, morphogens, cryptic peptides, and extracellular vesicles (EVs), all of which function to regulate normal cell physiology and promote tissue regeneration and repair [6].  
The specific components of the ECM, and broadly the extracellular space, responsible for promoting tissue regeneration and repair are not fully understood, but EVs found in body fluids and solid phases of ECM have emerged as key mediators of tissue regeneration and repair [7]. Given their potential as therapeutic mediators of tissue repair in a wide variety of pathophysiological conditions [8], EVs are being explored as a cell-free approach to supporting tissue regeneration and repair through influencing host cell phenotype and function entirely independent of a requirement for cell source or scaffold material. This approach could potentially mitigate the issues of cell and scaffold rejection by the host, a major concern for the translational application of TERM therapies [9]. Over the past two decades, there has been substantial interest in understanding the therapeutic role of EVs and their applications in the context of TERM. Therefore, the purpose of this review is to highlight the fundamental characteristics of EVs, the current pre-clinical and clinical applications of EVs in TERM and other disciplines, and the future of EV-based strategies in TERM.