BETA HAIRPIN PEPTIDE HYDROGELS FOR LIVER REGENERATION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们正在开发一种基于触发的多肽自组装的水凝胶策略，以帮助癌症切除手术后的肝脏再生。我们将设计一种可以在体外包裹细胞的水凝胶，随后可以在体内注射。我们设计的多肽，当溶解在水中时 溶液，形成一个随机卷曲构象的系综，使它们完全溶解。然而，当我们加入外源刺激时，如细胞培养液，多肽折叠成发夹构象。这些折叠的多肽经历快速的自组装，形成高度交联的水凝胶。当自组装件 机制在肝细胞存在的情况下触发水凝胶，凝胶变得浸透细胞。这些凝胶的一个独特特征是，当施加适当的剪切力时，凝胶将剪切变薄，成为粘性凝胶。然而，在剪切作用停止后，粘性凝胶迅速自我愈合，产生与剪切变稀前的原始水凝胶几乎相同的机械硬度的凝胶。凝胶的材料特性，如凝胶化动力学、机械刚性和剪切变稀后的恢复动力学，将通过多肽设计进行调整，使其能够通过注射器输送。通过注射器输送，产生的凝胶/细胞结构可以剪切稀薄地输送到目标组织，在那里它们迅速恢复，采用与伤口部位相辅相成的形状。交付后，凝胶在涂抹时仍保持局部(例如，它们不运行)。我们将研究凝胶的细胞相容性和生物相容性，以及凝胶/细胞结构在空间上传递的能力 对大鼠肝组织的定位方式。我们将测试它们帮助切除的大鼠肝脏再生的能力。我们组建了以下团队来解决这项提案的目标：细胞和分子生物学家辛迪·法拉赫-卡森、肝癌外科医生乔·班尼特·M.D.、水凝胶材料专家达林·波坎和多肽设计、合成和材料专家乔尔·施奈德。总的来说，该团队的专业知识涵盖材料设计、表征、体外细胞兼容性和体内生物兼容性。

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.