Injectable hydrogels for hiPSC-neuron therapy of spinal cord injury - PROJECT SUMMARY Regenerative medicine cell transplantation strategies are limited by poor transplanted cell survival, retention, and integration. To overcome this, I propose development of an engineered biomaterial that addresses two major causes of transplanted cell death: (i) acute membrane damage during injection and (ii) long-term exposure to a toxic microenvironment, by providing (i) cell encapsulation within an injectable hydrogel and (ii) slow-release of growth factors. To evaluate the preclinical effectiveness of this biomaterial, I will target cervical spinal cord injury (SCI), which results in permanent sensorimotor dysfunction and has no clinically available regenerative therapies. My data demonstrates that transplanting human induced pluripotent stem cell-derived neurons (hiPSC-neurons) significantly improves anatomical and functional outcomes in rat models of cervical SCI; however, this cell type suffers from poor transplanted cell viability, reducing therapeutic efficacy. I have already shown that use of an injectable hydrogel significantly improves the acute viability of encapsulated cells by providing mechanical shielding during injection, which resulted in statistically improved neurite outgrowth and forelimb function. I now hypothesize that tuning the temporal growth factor-release properties of this designer, injectable hydrogel will significantly improve long-term survival of transplanted hiPSC-neurons, leading to significantly improved anatomical and functional outcomes. Specifically, in Aim 1, I will optimize a growth factor- release system in vitro to assist hiPSC-neurons in surviving oxidative stress and excitotoxicity that are present at the injury site. In Aim 2, I perform functional evaluation of this biomaterial/cell therapy in a subacute model of SCI in comparison to standard delivery vehicles (saline and fibrinogen) and appropriate controls. My career goal is to lead a translational laboratory that leverages expertise in biomaterials and stem cell biology to develop regenerative therapies for central nervous system (CNS) injury and to serve as a role model for young female scientists from underrepresented backgrounds. This Career Development Award would enable me to enhance my strong background in CNS neurodegeneration and stem cell biology with new expertise in biomaterial design and translational bioengineering. My career development plan includes (1) formal coursework in materials science and bioengineering, (2) technical training in recombinant biomaterials synthesis and characterization, (3) close mentorship by an outstanding bioengineer with a strong track-record of successful training and collaboration, and (4) career guidance by an Advisory Committee to prepare for my transition to independence. My training plan leverages the outstanding resources available within Stanford University and national and international events to strengthen my scientific network, build on my extensive mentorship and grantsmanship skills, and polish my scientific communication. This plan will position me to submit innovative and interdisciplinary application packets for tenure-track Assistant Professorships in my last year of this award as I embark on an independent career at the intersection of biomaterials science and CNS regeneration.
