CAREER: Network Topology Design in Polypeptide Hydrogels for Tough and Transparent Biomaterials

Non-technical abstract Natural materials such as muscle and wood are strong and durable, but they are not transparent. They block light, making it difficult to see what is happening inside them. In contrast, biomaterials made from these natural components, such as collagen or fibrin gels, can be clear and allow light to pass through, but they are often fragile and easily damaged during handling or experiments. This trade-off makes it difficult to both manipulate biological samples and observe them at high resolution at the same time. Overcoming this challenge would open new opportunities in biotechnology, where materials need to both support living components and allow scientists to see how they function in three-dimensional environments. Polypeptides are built from amino acids, the same building blocks found in proteins. They offer a promising solution because they provide precise control at the molecular level. This research develops a new class of polypeptide-based biomaterials by controlling both the amino acid sequence in a single polypeptide and how these polypeptides are connected and organized in space. By combining advanced material synthesis with structural characterization and modeling, the research identifies how key design features (including amino acid sequence, cross-linking density, and network architecture) govern the formation of nanoscale structures within the material. These nanostructures directly determine how light passes through the material and how strong and durable it is. By elucidating how molecular sequence and network architecture work together to control material behavior, this research will establish general design principles for creating biomaterials that are both tough and transparent. These advances will enable new biotechnology applications, including real-time imaging of living cells and organoids in three-dimensional environments, providing new ways to study how cells grow, organize, and respond to their surroundings. In the long term, this research will support innovations in engineered tissue scaffolds for regeneration, as well as improved platforms for disease modeling and personalized diagnostics. This project also integrates education and outreach to broaden engagement and participation in STEM. Activities include hands-on training modules in biomaterials and biomanufacturing, engagement with K-12 students through summer programs, and university–industry partnerships that prepare students for careers in the growing biotechnology workforce. Technical abstract This CAREER project introduces network topology as a new design dimension to regulate phase separation in polypeptide networks, with the goal of simultaneously achieving high optical transparency and mechanical toughness. Phase separation in polypeptides is controlled by the interplay between intermolecular interactions (enthalpy) and chain configurational freedom (entropy). In un-cross-linked systems, high entropy enables chain rearrangement and the formation of large aggregates, which scatter light and reduce transparency. In contrast, introducing cross-linking through network topology imposes entropic constraints that limit chain mobility, suppress domain growth, and enable the formation of small, uniformly distributed structures that enhance both optical clarity and mechanical robustness. This topology-mediated entropic constraint offers a powerful mechanism to control phase-separated domain morphology and enables the design of biomaterials that balance toughness and transparency. By integrating polypeptide network synthesis, advanced structural characterization, and thermodynamic modeling, this project will establish fundamental relationships between network topology, phase separation behavior, and material performance. The research will (i) elucidate how network topology governs phase separation in polypeptide systems; (ii) resolve the trade-off between optical and mechanical properties through topology-mediated struct NSF Award ID: 2542949 | Program: 01002930DB NSF RESEARCH & RELATED ACTIVIT,01002627DB NSF RESEARCH & RELATED ACTIVIT,01003031DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Xinyue Liu | Institution: Michigan State University, EAST LANSING, MI | Award Amount: $388,454 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2542949 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2542949.html