Musculoskeletal tissues are critical to the normal functioning of an individual and following damage or degeneration they show extremely limited endogenous regenerative capacity. The future of regenerative medicine is the combination of advanced biomaterials, structures, and cues to re-engineer/guide stem cells to yield the desired organ cells and tissues. Tissue engineering strategies were ideally suited to repair damaged tissues; however, the substitution and regeneration of large tissue volumes and multi-level tissues such as complex organ systems integrated into a single phase require more than optimal combinations of biomaterials and biologics. We highlight bioinspired advancements leading to novel regenerative scaffolds especially for musculoskeletal tissue repair and regeneration. Tissue and organ regeneration relies on the spatial and temporal control of biophysical and biochemical cues, including soluble molecules, cell-cell contacts, cell-extracellular matrix contacts, and physical forces. Strategies that recapitulate the complexity of the local microenvironment of the tissue and the stem cell niche play a crucial role in regulating cell self-renewal and differentiation. Biomaterials and scaffolds based on biomimicry of the native tissue will enable convergence of the advances in materials science, the advances in stem cell science, and our understanding of developmental biology. 1. Introduction Incidents of tissue loss or organ failure due to accidents, injuries, and disease are debilitating and have led to increased health care costs the world over [1]. Current standard of care includes organ and tissue transplantation, allografts, biofactors, and replacements composed of metals, polymers, and ceramics. However, each strategy suffers from a number of？limitations. For example, autografts and allografts are often associated with limited availability and risks of immunogenicity, respectively. Tissue engineering was developed as an alternative strategy to repair and regenerate living tissues and to provide a viable tissue substitute. Bioengineer Fung first proposed the term “tissue engineering” at a 1987 meeting of the National Science Foundation [2], where it was defined as the use of isolated cells or cell substitutes, tissue-inducing substances, and cells placed on or in matrices to repair and regenerate tissue [3, 4]. Early medical devices were physician-driven and made using off-the-shelf materials such as Teflon, high-density polyethylene, poly(methyl methacrylate), stainless steel, polyurethane, titanium, and silicone elastomers. Over the
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