Tendons are specialized connective tissues that transmit load between bone and muscle, and whose microstructural and compositional features underlie their function. The biological solution to the problem of connecting relatively compliant tendon to stiffer (∼2 orders of magnitude) bone is a gradient interface zone ∼100μm wide. Over the tendon-bone-junction (TBJ) a linear transition takes place in the ECM inorganic:organic (mineral:collagen) ratio as well as mineral crystallinity from that of tendon to bone. While small TBJ injuries can heal via regeneration, severe defects undergo repair-mediated healing characterized by fibrocartilagenous scar tissue with inferior biomechanical and functional properties. Severe TBJ injuries are common in athletes, the elderly, and following severe craniofacial and extremity trauma. Many tendon injuries (i.e. supraspinatus injuries), particularly those associated with acute trauma, are prone to occur at the TBJ due to high levels of region-specific stress concentrations; rotator cuff tendons injuries, one of the most common TBJ injuries, exhibit re-tears at rates as high as 94%. The scale of such defects and current poor clinical results suggest the need for a biomaterial solution that can mimic the dynamic heterogeneities of the native insertion and tendon body to induce rapid, functional regeneration. Three-dimensional collagen-GAG (CG) scaffolds have been successfully used clinically to regenerate large soft tissue defects (skin, peripheral nerves); they act by mimicking the native extracellular matrix (ECM) of the damaged tissue to prevent wound contraction and scar tissue synthesis. However these scaffolds have not traditionally been used for orthopedics due to an inability to recapitulate two critical features of orthopedic tissues: multiscale structural complexity, biomechanical properties. While the multi-scale properties of tendon itself cannot be currently replicated, nature provides an alternative paradigm: core-shell composites. Plant stems combine a porous core with a dense shell to aid osmotic transport (core) while maintaining sufficient tensile/bending stiffness (shell); many bird beaks use core-shell designs to efficiently enhance compressive strength. Here we describe development of three biomaterial engineering approaches to create the next generation of regeneration templates for tendon insertion injuries: composite, spatially patterned CG biomaterials.

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