Highly Tunable Brush-Like Polymer Architectures to Control Therapeutic Delivery and Cell-Material Interactions

My laboratory’s research projects combine my expertise in polymer science and biology to develop precise synthetic tools for problems at biomaterial interfaces. We approach these problems by designing materials from the “bottom up,” which is the idea that macroscale properties arise from the collection of interactions that occur at the molecular scale, nanoscale, and microscale. Our projects seek to program precise macroscale properties by controlling molecular assembly, and we then use the new substrates to ask questions about muscle, immune, and connective tissue biology using in vitro tissue culture and in vivo models. As an example, our ongoing work advances this goal by synthesizing cytocompatible liquid crystalline substrates to ask questions about how variations in viscoelasticity at subcellular, cellular, and supercellular length scales impact cellular responses. This MIRA program is motivated by the idea that brush-like polymer surfaces have significant and untapped potential as biomaterials. The concept features the spatially-controlled growth of polymers from natural biomaterial surfaces using synthetic methods to control the composition, connectivity, and morphology of the polymers. At a minimum, the projects will establish a new synthetic platform for brush-like polymers on silk fibroin substrates (films and particles) and will use the platform to generate new knowledge of brush-brush and brush- cell associations to tune interactions with implanted materials. In addition, the projects are unified in their goals to develop the brush-like polymer architecture for local drug delivery with specific focus on the anesthetic bupivacaine. Bupivacaine solutions are often applied directly at a surgical site to treat post-operative pain. While many bupivacaine formulations have been tested, nearly all rely on the diffusion of free drug or drug encapsulated in a polymer. No formulation achieves the sustained release required for postoperative pain, and repeat bupivacaine administration is prohibited due to cardiac toxicity, creating a critical treatment gap. These projects build upon our recent successes generating high degrees of functionalization on purified silk fibroin, a protein whose composition and secondary structure often frustrate modification efforts. Over the next five years, we will synthesize brush-like polymers of varying composition to quantify how the brush morphology and connectivity with neighbors affect the loading and release of varying drugs. Using release data to generate pharmacokinetic models and statistical analysis, we will rationally design multi-composition brushes for the phased release of local anesthetic to establish the brushes’ delivery efficacy and impact on tissues in an in vivo mouse model of surgical pain. Finally, injectable brush formulations will be generated on particles of varying shapes and sizes to establish how the polymer architecture impacts phagocytosis, targeting of specific cell types, and efficacy in a nerve block model. Ultimately, we will build upon our efforts to discover new, well-controlled polymer designs that alter protein interactions and cellular responses to feed into our lab’s broader goals to use materials to engineer immune responses and enhance integration with surrounding tissues.