CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome

Non-technical Abstract Stem cells hold tremendous promise for the field of regenerative medicine due to their potential to repair injured and diseased tissues. However, the promise of stem cells has not been fully realized, as the majority of stem cells transplanted into the body after injury die rapidly after transplantation. Despite their fate, these stem cells still often manage to have a small positive impact on the damaged tissues into which they are transplanted. This healing response is partly due to the proteins secreted by the stem cells into the surrounding injury environment, which can reduce inflammation and make the environment more hospitable for the infiltration of host cells to regenerate the injured tissue. However, proteins typically also do not remain within the injury site for long periods of time, making their effects short-lived. The goal of this CAREER proposal is to develop biomaterials to capture and concentrate these potent cell-secreted proteins to enhance and prolong their therapeutic effects beyond the initial period of stem cell survival. These biomaterials will be engineered to only capture specific proteins of interest from a complex mixture of cell-secreted proteins, thereby allowing them to act as sieves – enriching therapeutic proteins without trapping ineffective proteins. Toward broad societal impact, the ability to selectively enrich regenerative proteins from complex mixtures could transform the therapeutic potential of stem cell transplantation with implications for treating many diseases and injuries, including musculoskeletal injuries, cardiovascular disease, and spinal cord injury. This highly interdisciplinary project requires participation by students interested in bioengineering, chemistry, biology, and human physiology, and will engage students across multiple departments at the University of Oregon in both bioengineering research and education. An inclusive bioengineering education course will be developed to give students from a variety of disciplines the skills necessary to develop sustainable bioengineering outreach activities that can, in turn, be used to promote pathways to bioengineering for K-12 students in science, technology, engineering, and math (STEM). By increasing access to bioengineering curriculum at multiple levels (K-12, undergraduate, and graduate students), the proposed work will diversify the pool of talented scientists and engineers with the skills and desire to engage in interdisciplinary bioengineering research. Technical Abstract Mesenchymal stem/stromal cells (MSCs) secrete proteins that can mediate the immune response to injury and stimulate tissue repair. However, poor viability of transplanted MSCs can limit long-term therapeutic effects. Harnessing the regenerative potential of stem cells through the proteins they secrete (i.e., the “secretome”) represents a recent paradigm shift in the field of tissue engineering. Biomaterials can be used to sequester and prolong the presentation of secreted proteins beyond the initial period of cell survival. Yet, current biomaterials have a limited ability to selectively sequester specific target proteins from complex protein mixtures. The goal of this CAREER proposal is to develop a library of affinity-based biomaterials that can selectively sequester and present therapeutic proteins secreted by MSCs. Several key innovations will be employed herein, including the use of directed evolution to identify high-specificity affinity interactions between target proteins and materials, and the use of bio-transport modeling to predict the effects of protein-material affinity interactions and protein secretion rates on overall protein sequestration, thereby enabling the optimization of biomaterials for protein sequestration. This highly interdisciplinary project requires participation by trainees interested in bioengineering, chemistry, biology, and human physiology, and will engage students across multiple departments at the University of Oregon in both bioengineering research and education. An inclusive bioengineering education course will be developed to increase access to bioengineering curriculum and give students from a variety of disciplines the professional and pedagogical skills to develop sustainable bioengineering outreach activities that can, in turn, be used to promote pathways to bioengineering for K-12 students in STEM. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.