(453a) Improving Stem Cell Transplantation Through Fluid Dynamics and Polymer Physics

Stem cell transplantation is a promising therapy for a myriad of debilitating diseases and injuries; however, current delivery protocols are inadequate. Transplantation by direct injection, which is clinically preferred for its minimal invasiveness, commonly results in less than 5% cell viability, greatly inhibiting clinical outcomes. We demonstrate that a significant cause of cell death occurs during transport through the syringe needle, where extensional stretching forces experienced by the cells results in mechanical membrane disruption. We further demonstrate that a variety of clinically relevant cell types including adipose-derived stem cells (ASC), marrow stromal cells (MSC), and neural progenitor cells (NPC) can be protected from these damaging forces by encapsulation within hydrogels of specific viscoelastic properties. We hypothesize that these shear-thinning hydrogels may undergo plug-flow through the syringe needle, whereby bands of shear-thinned polymer are located at the needle walls and lubricate the flow of individual gel "plugs" through the needle. These gel plugs may serve as transport vehicles for the encapsulated cells, thereby shielding them from disruptive mechanical forces.

            Building on these fundamental studies, we have designed a reproducible, bio-resorbable, customizable hydrogel using protein-engineering technology. In our Mixing-Induced Two-Component Hydrogel (MITCH), network assembly is driven by specific and stoichiometric peptide-peptide binding interactions. By integrating protein science methodologies with polymer physics models, we manipulate the polypeptide chain interactions and demonstrate the direct ability to tune the network crosslinking density, sol-gel phase behavior, and gel mechanics. These MITCH materials enable stem cell and growth factor encapsulation upon simple mixing at constant physiological conditions, making them well suited for use in the surgical suite. In vivo studies in a murine model demonstrate that transplanted ASCs achieve significantly better retention at the subcutaneous injection site compared to cells delivered in collagen, alginate, or saline alone. These results provide mechanistic insight into the role of mechanical forces during cell delivery and support the use of protective hydrogels in future clinical stem cell injection studies.