Trehalose-based coacervates for biomolecular and cellular delivery to improve wound healing in spinal cord injury

ABSTRACT Traumatic spinal cord injury (SCI) leads to lifelong paralysis and complications affecting cardiovascular, respiratory, bladder, bowel, and sexual function. Because damaged neural tissue does not spontaneously regenerate, hundreds of thousands of individuals live with SCI and current treatments are limited to supportive measures. Therapeutic strategies involving bioactive molecular delivery and cell grafting hold promise for improving functional recovery outcomes after SCI by directing regeneration-supportive glia repair at lesion cores. However, there are challenges that still need to be addressed for clinical translation of these therapeutic approaches; one of the central challenges that remains is mitigating the deleterious effects of lesion environments on the bioactivity of delivered molecules and the survival, localization and function of grafted cells. Coacervates are an emerging biomaterial class that have a unique set of properties suitable to address these challenges. I have developed an innovative method to prepare tunable coacervates composed of trehalose, a non-reducing disaccharide excipient that can stabilize proteins and cell membranes under stress conditions, to confer coacervates with bioactive support functions. I have previously shown that trehalose coacervates (1) enable local, bioactive protein delivery to the mouse central nervous system (CNS), (2) that coacervates are highly tunable for spatial and temporal controlled release of biomacromolecules, and (3) that coacervate injection is non-disruptive to CNS tissue and does not evoke a strong foreign body response. Given this, I hypothesize that coacervate-based molecular delivery and cell grafting in coacervate carriers will attenuate negative lesion effects on delivered therapeutics, and thus augment wound repair processes in lesion environments, leading to improved outcomes after SCI in mice. To explore this hypothesis, I will investigate (1) coacervate-based molecular co-delivery to enhance proliferation of endogenous injury-responsive astrocytes after SCI, and (2) coacervate-based enzymatic debridement and cell grafting strategies for a two-step approach for exogenous glia-based wound repair in chronic SCI. This work will contribute important technical innovations necessary for developing effective biomaterial-based therapeutic strategies for SCI and further our understanding of key biological mechanisms that determine and modulate wound responses after SCI.