BETA HAIRPIN PEPTIDE HYDROGELS FOR LIVER REGENERATION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们正在开发一种水凝胶化策略，基于肽的触发自组装，以帮助癌症切除手术后的肝再生。我们将设计水凝胶，可以封装细胞在体外，随后可以在体内注射。我们设计了肽，当溶解在水溶液中时， 溶液形成无规卷曲构象的集合，使它们完全可溶。然而，当我们加入一种外源刺激，如细胞培养基，肽折叠成一个<$-发夹构象。这些折叠的肽经历快速自组装，形成高度交联的水凝胶。当自我组装 在肝细胞存在的情况下，水凝胶化机制触发水凝胶化，凝胶变得充满细胞。这些凝胶的一个独特特征是，当施加适当的剪切应力时，凝胶将剪切变稀，成为粘性凝胶。然而，在停止施加剪切之后，粘性凝胶快速自愈合，产生具有与剪切稀化之前的原始水凝胶几乎相同的机械刚度的凝胶。凝胶的材料性质，例如凝胶化动力学、机械刚性和剪切稀化后的恢复动力学，将通过肽设计进行调整，以使它们能够通过注射器递送。通过注射器递送，所得凝胶/细胞构建体可以剪切稀递送到靶组织，在那里它们快速恢复，采用与伤口部位互补的形状。递送后，凝胶保持在应用点的局部（例如，它们不流动）。我们将研究凝胶的细胞相容性和生物相容性，以及凝胶/细胞结构在空间上递送的能力。 大鼠肝组织局部化的方式。我们将测试它们帮助切除的大鼠肝脏再生的能力。我们已经召集了以下团队来解决这个提案的目标：辛迪·法拉奇-卡森，细胞和分子生物学家，乔·班尼特博士，一位肝癌外科医生，水凝胶材料专家Darrin Pochan，以及肽设计、合成和材料专家Joel Schneider。总体而言，该团队的专业知识涵盖材料设计、表征、体外细胞相容性和体内生物相容性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are developing a hydrogelation strategy, based on the triggered self-assembly of peptides, to aid in liver regeneration after cancer resection surgery. We will design hydrogels that can encapsulate cells in vitro that can be subsequently injected in vivo. We have designed peptides that, when dissolved in aqueous solutions, form an ensemble of random coil conformations rendering them fully soluble. However, when we add an exogenous stimulus, such as cell culture media, the peptides fold into a ¿-hairpin conformation. These folded peptides undergo rapid self-assembly forming a highly crosslinked hydrogel. When the selfassembly mechanism triggers hydrogelation in the presence of hepatocytes, gels become impregnated with cells. A unique characteristic of these gels is that when an appropriate shear stress is applied, the gel will shear-thin, becoming a viscous gel. However, after the application of shear has stopped, the viscous gel quickly self-heals producing a gel with mechanical rigidity nearly identical to the original hydrogel before shear-thinning. The gels' material properties, such as the gelation kinetics, mechanical rigidity and recovery kinetics after shear-thinning, will be tuned via peptide design to enable them to be delivered via syringe. With syringe delivery, the resulting gel/cell constructs can be shear-thin-delivered to targeted tissue where they quickly recover, adopting a shape that compliments the wound site. After delivery, the gels remain localized at the point of application (e.g. they do not run). We will investigate the cytocompatibility and biocompatibility of the gels, as well as the ability of the gel/cell constructs to be delivered in a spatially localized manner to rat liver tissue. We will test their ability to aid in the regeneration of resected rat liver. We have assembled the following team to address the aims of this proposal: Cindy Farach-Carson, a cell and molecular biologist, Dr. Joe Bennett M.D., a liver cancer surgeon, Darrin Pochan, an expert in hydrogel materials, and Joel Schneider, an expert in peptide design, synthesis and materials. Collectively, the expertise of the team spans material design, characterization, in vitro cell compatibility, and in vivo biocompatibility.