Multidomain Peptides for Inflammation and Angiogenic Mediated Tissue Regeneration

描述(申请人提供)：最近开发的多结构域肽(MDP)可以被触发自组装成纳米纤维水凝胶。考虑到这些短链氨基酸序列提供的简单性和多功能性，物理和生物反应是可以调节的。将细胞降解位点结合到氨基酸骨架中，可以使多肽水凝胶被渗透的细胞分解。同样，将细胞结合域工程到 多肽序列提供了一种允许细胞黏附和增殖的方法。总之，可降解和不可降解多肽的混合物将允许随时间变化的酶分解和细胞渗透。水凝胶可以很容易地吸入注射器并通过针头输送，并具有机械回收功能。这将使细胞因子和生长因子有效地输送到生物支架或病理损伤中--例如在根管期间挖空的牙齿。任何手术或植入物(包括根管)都会引起炎症反应。虽然其他人试图避免这种炎症反应，但我们的目标是调节渗透的免疫细胞对愈合反应的反应，而不是慢性炎症/植入排斥反应。这一点已经被特定的细胞因子所证实，这些细胞因子可以引导炎症细胞达到愈合和消退的表型。虽然没有尝试牙齿再生，但之前的研究已经显示出在神经再生和血管组织工程等模型中的有效性。此外，添加一种有助于血管形成的分子将有助于创建活组织。这些添加剂将在体外用免疫细胞、血管细胞和牙齿干细胞进行测试。这项工作将在体内应用这些细胞因子/生长因子负载的凝胶--其中炎症细胞将被引导消炎，浸润性细胞将形成血管，并用天然的活组织取代纳米纤维支架。这个项目被组织成三个目标。目的1确定MDP的降解，以及细胞因子/生长因子的加载和释放。目的2阐明免疫细胞、血管细胞和牙髓干细胞在负载MDP纳米纤维中的细胞行为。目的3将在伤口愈合和牙髓再生的动物模型中确定负载的MDP纳米纤维的生物相容性和免疫反应。在展示牙齿再生的适用性的同时，负载的多肽支架可以量身定制，以适应组织工程和转化医学的各种其他应用。

DESCRIPTION (provided by applicant): Recently developed Multidomain Peptides (MDP) can be triggered to self-assemble into nanofiber hydrogels. Given the simplicity and versatility offered by these short chain amino acid sequences, the physical and biological responses can be tuned. Incorporation of cell degradation sites into the amino acid backbone allow for peptide hydrogels to be broken down by infiltrating cells. Similarly, engineering cell binding domains into the peptide sequence, offer a method to allow cell adhesion and proliferation. Together, mixtures of degradable and non-degradable peptides will allow time-dependent enzymatic breakdown with cellular infiltration. Hydrogels can be easily aspirated into a syringe and delivered via needle, with mechanical recovery. This will allow cytokines and growth factors to effectively be delivered into biological scaffolds or pathologic lesions - such as hollowed out teeth during a root canal. Any procedure or implant (including a root canal) will induce an inflammatory reaction. While others have tried to obviate this inflammatory response, we aim to modulate the infiltrating immune cells' response to one of healing as opposed to chronic inflammation/implant rejection. This has been demonstrated with specific cytokines that guide inflammatory cells to a healing and resolution phenotype. While not attempted with dental regeneration, prior studies have shown efficacy in models including nerve regeneration and vascular tissue engineering. Further, addition of a molecule that aids in blood vessel formation will help in creating living tissue. These additives will be tested in vitro with immune cells, cels from blood vessels and dental stem cells. The work will culminate with in vivo application of these cytokine/ growth factor loaded gels - where inflammatory cells will be guided to resolve inflammation, infiltrating cells will develop blood vessels and replace the nanofiber scaffolding with native living tissue. This project is organized into 3 aims. Aim 1 will determine the degradation of MDP, and loading and release of cytokines / growth factors. Aim 2 will elucidate the cellular behavior of immune cells, blood vessel cells and dental pulp stem cells in loaded MDP nanofibers. Aim 3 will determine biocompatibility and immune response of loaded MDP nanofibers in an animal model of wound healing and dental pulp regeneration. While showcasing applicability for dental regeneration, loaded peptide scaffolds can be tailored to a variety of other applications for tissue engineering and translational medicine.