UC Davis

Tissue engineering aims to combine cells, soluble cues, and biomaterials to repair tissue injuries that surpass the body’s innate healing ability. While physical and chemical aspects of regeneration are well-represented in this paradigm, electrical cues are not. This is a significant oversight, as bioelectricity, voltage-mediated communication between cells, plays a critical role in homeostatic and regenerative events in vivo. To address this shortcoming, researchers have included electrically conductive additives in biomaterials to mimic the electrical activities and environment cells and tissues experience during healing. Cells grown on conductive substrates frequently demonstrate improved behaviors such as proliferation, differentiation, and maturation, even in the absence of electrical stimulation. While these results are promising, their mechanism of action is not well understood. Additionally, the potential for conductive materials to direct cells has drawn attention away from characterizing how a material’s conductivity and biophysical properties influence each other. Examining both characteristics is important since the physical properties of a material are also well-known to orchestrate cell behavior.For this work, we sought to develop an electrically and mechanically tunable hydrogel platform that could be used to interrogate the relationship between these two properties and understand how their interplay influences cells towards regeneration. The studies conducted for this work involve an electrically conductive, synthetic, conjugated polymer, referred to as PEDOT:PSS, and we mixed it with two well-known hydrogel materials, agarose and polyethylene glycol. We established conditions under which the electrical and mechanical properties of these hydrogels were decoupled, then demonstrated mesenchymal stromal cells had improved adhesion and spreading on conductive gels over non-conductive ones. To explain this observation, we used solutions of proteins with different isoelectric points (hence different charged in physiological pH) to understand the hydrogels’ surface characteristics. More proteins adsorbed to conductive gels, suggesting greater surface charge. These studies begin to fill foundational knowledge gaps by providing a high-level understanding of how electroactive materials improve cell behavior, even in the absence of external stimulation. We next investigated how the interplay of conductivity and the physical cue, porosity, facilitated myogenic differentiation for muscle tissue engineering applications. Myoblasts grown in conductive microporous scaffolds had markedly greater myosin heavy chain expression at both the gene and protein level. Upregulation of this late myogenic marker is indicative of maturation, suggesting the importance of both electroactivity and microporosity for muscle generation. These studies help improve our understanding of cell interactions with electrically conductive biomaterials which begin to address important deficits within the field. We hope this work contributes to the development of materials that are intentionally designed to recapitulate the electrical environment of healing or that facilitate communication between endogenous and implanted tissue. We believe such a material would have significant implications for clinical translation and has the potential to improve the quality of life for millions of patients.