Engineering the design of self-assembling, shear-thinning pentapeptide hydrogels to promote neural cell growth and differentiation

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PART 1: NON-TECHNICAL SUMMARYThe brain is central to the human experience, but society poorly understands many of the factors that impact brain cell survival and growth. Hydrogel biomaterials can help address this problem because they behave like human tissues, allowing researchers to model healthy and diseased or injured tissue in a simplified lab setting and better understand human health. While hydrogels can emulate a wide variety of tissues, hydrogels that emulate brain tissue are useful to grow cells derived from the brain. This proposal aims to make new hydrogels similar to human tissue because they are composed of the same raw materials, built from natural amino acids strung together in blocks that are simple and cheap to make. Hydrogels prepared from these amino acid building blocks look and act like brain tissue with behavior controlled by the choice of block and block pattern. The right amino acid sequence may result in blocks that find each other and automatically assemble into a 3-dimensional structure, like a designer microscopic city which builds itself. These interchangeable blocks can come together in different shapes, determining whether the hydrogel behaves more like a liquid or a solid, as well as its suitability for growing cells. Hydrogel properties will be studied in the lab as well as in computer simulations to create and test the best possible block combinations. Given the versatility of blocks and ways in which they assemble, this strategy is expected to result in a new family of hydrogel materials that can automatically rebuild themselves after damage. The hydrogels that best mimic brain tissue will be used to guide the behavior of brain-derived cells and control cell growth. This research will impact education by training students in biology, materials science, computer science, engineering, and neuroscience through laboratory and curricular activities. An outreach program centered on paid high school and college internships for underprivileged youth will nurture interests in engineering, provide research skills, and build experience in diverse student groups through research and science communication.PART 2: TECHNICAL SUMMARYIntegral to realizing functional peptide biomaterials is an understanding of the molecular and macroscopic features that govern assembly, morphology, and biological interactions. This research centers on the rational design and investigation of a new family of peptides that assemble under cytocompatible conditions into a robust extracellular matrix (ECM) hydrogel with structure and bioactivity that drive cell fate. This project seeks to develop a new family of short, rapidly gelling, self-healing peptides that emulate a wide variety of tissues. Using short, 5-amino-acid sequences as gelators simplifies synthesis and maximizes adaptability. These new peptides will address existing peptide hydrogel deficiencies, namely 1) gelation mechanisms that lead to poor survival of sensitive cells, like neurons and neural stem cells, and 2) low mechanical stiffnesses. The proposed approach will involve cytocompatible encapsulation of neural cells as a test bed. To improve the design and discovery process, a computational framework will be integrated with the experimental approach. This design strategy could transform biomaterials development and address the challenges of characterizing the dynamic processes that occur in biological matrices. Computational simulations will provide understanding of peptide assembly and more efficiently identify and predict peptide candidates that will cytocompatably assemble into 3D physical hydrogels. The primary goal is to create, model, and characterize peptides that gel under physiological conditions and drive neural stem cell differentiation. Outcomes of this research project will include amino acid sequences conducive to physiological gelation, an atomistic molecular dynamic model of peptide assembly, and a compliant, dynamic matrix appropriate for neural cell culture. Physiologically relevant hydrogels that gel on-demand will dramatically improve the ease and efficacy of cell culture and study. This project will create a comprehensive high school research internship program for socioeconomically challenged students, and broaden their career and college opportunities. As part of this project the PI will cross train PhD students, work-study college students, and high school interns in biomaterials synthesis, molecular simulations, stem cell biology, and neural tissue engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.