Regenerative Engineering Through Biomaterial Design

Advances in the field regenerative medicine require biomaterials that instruct, rather than simply permit, a desired cellular response. A major contemporary motivator in biomaterial design is the complex organization of the tissues in our bodies, which are hierarchical, vary in space and time, and can differ person-to person. However, the future success of regenerative medicine requires more deeply considering aspects of human variation and heterogeneity. For example, considering the role of sex-specific differences in tissue engineering technologies motivates innovative lines of investigation that will become central dogma in the future.<br/><br/>Defects in craniofacial bones of the skull occur congenitally, after high-energy impacts, and during the course of treatment for stroke and cancer. They affect a broad segment of the US population, are large and irregularly shaped, and heal poorly. Contemporary tissue engineering efforts that combine exogenous mesenchymal stem cells (MSCs), morphogens, and biomaterials face challenges due to the cost and time for in vitro MSC expansion and MSC-biomaterial culture as well as the need for supraphysiological morphogen doses. We are developing porous biomaterials that can be shaped precisely and quickly like an alloplastic implant but that work in a regenerative fashion like autologous bone. Specifically, I will describe a class of mineralized collagen scaffold that promotes MSC recruitment and osteogenicity in the absence of osteogenic supplements. We have refined these materials to study MSC-macrophage crosstalk and to promote MSC-osteoprogenitors to secrete osteoprotegerin, a soluble glycoprotein and endogenous inhibitor of osteoclast activity. We showed polymeric meshes can be integrated into the scaffold, à la rebar in concrete, to create composites that can be shaped intraoperatively to aid surgical-practicality and accelerate regeneration. I will also describe scaffold processing approaches to create spatially-graded collagen biomaterials that direct MSC differentiation down multiple musculoskeletal lineages in a spatially-selective manner, along with methods to develop continuous hydrogel zones that link dissimilar musculoskeletal tissue zones (e.g., tendon and bone) to provide mechanical and trophic advantages to accelerate regenerative healing. I will conclude by describing recent efforts to address barriers preventing regeneration, notably the role of sex-differences in regenerative activity. These initiatives demonstrate that understanding sex-specific differences in cell activity is essential in the design of biomaterial system to improve regenerative potential as well as to study disease progression and therapy.