Diversity Supplement for Angiogenic and anti-microbial supports for pulp regeneration

项目摘要：牙髓是牙齿中至关重要的微环境，它蕴藏着血管和 神经，更不用说与牙本质小管连接的成牙本质细胞了。创伤或细菌感染可能 使牙髓发炎，造成极度疼痛。拔除发炎的牙髓(并有可能用惰性牙髓取代它 材料)可以缓解疼痛，但手术后会留下一颗失活的牙齿。对于青少年来说，另一种选择是可能的 患者，称为过度器械(OI)。在OI期间，牙髓腔暴露在周围循环中 牙髓摘除术后。只要根尖乳头完好无损，牙髓管中就会发生一些组织再生。 随后--尽管这种杂乱无章的组织并不模仿天然软组织。尤其是在成年人中，OI 导致无功能的牙髓骨化。牙髓治疗过程中的另一个问题是发生/复发 口腔细菌的定植。这种感染可能会延长并加剧牙髓炎症。一种材料- 建议的基础配方可以(A)促进牙髓中的血管化软组织再生，而(B) 抵抗细菌感染。我们的策略依赖于自组装多肽水凝胶--一类超分子 可以在体内注射的材料，同时保持其凝胶状特性。这些材料由规范的 氨基酸和生物相容。这种材料需要提供机械支持和生物线索。 用于组织向内生长。有些与直觉相反的是，一种自组装的多肽水凝胶，没有额外的生长 因素或外源性细胞，在犬牙髓切除模型中显示血管化软组织的形成 28天。在另一项研究中，属于同一平台的另一种阳离子两亲性水凝胶显示 通过膜通透性抑制细菌生长的效果。在这项提议中，一种组合治疗 将对该模式在实现上述双重目标方面的有效性进行测试。机械之谜 这些项目将帮助解决渗透细胞的谱系/来源和细胞环境的进化 在牙髓摘除和软性仿生水凝胶植入后的牙髓管内。刻画了长- 由这种水凝胶促进的血管化软组织的成熟是另一个目标。多种多样- 在这项生物工程研究资助申请中提出的学科项目将汇集一位化学家 和生物工程师(PiV.A.K.，一名早期研究员)，口腔细菌菌落专家(co-I C.C.)，以及 牙髓医生(co-I E.S.)，以解决一个持久的挑战：修复后再生仿生血管软组织 牙髓切除手术。体外机制分析、浸润性细胞的体内特征和组织学/放射学 牙髓软组织和牙髓-牙本质复合体的长期演变的鉴定将建立在发表的基础上 研究和大量的初步数据。即使拟议的实验只取得了部分成功，我们也会 了解牙髓中的组织-材料相互作用。AIMS的成功将产生 无细胞、无生长因子、现成的材料配方的引人注目的数据，适用于 为数百万需要牙髓摘除的患者提供牙髓治疗环境和改善临床结果。

Project Summary: The dental pulp is the vital microenvironment in the tooth, harboring blood vessels and nerves, not to mention odontoblasts that interface with the dentinal tubules. Trauma or bacterial infection may inflame the dental pulp, creating extreme pain. Extirpating the inflamed pulp (and potentially replacing it with inert materials) ameliorates the pain, but the procedure leaves a devitalized tooth. An alternative is possible in juvenile patients, called over-instrumentation (OI). During OI, the pulpal chamber is exposed to the peripheral circulation post-pulpectomy. As long as the apical papilla is intact, some tissue regeneration takes place in the pulpal canal subsequently — although the disorganized tissue does not mimic native soft tissue. In adults in particular, OI results in non-functional pulpal ossification. Another concern in endodontic procedures is occurrence/recurrence of colonization by oral bacteria. Such infections may prolong and exacerbate pulpal inflammation. A material- based formulation is proposed that can (a) promote vascularized soft-tissue regeneration in the pulp, while (b) resisting bacterial infection. Our strategy rests on self-assembling peptide hydrogels — a class of supramolecular materials that can be injected in vivo while keeping their gel-like properties. The materials consist of canonical amino acids and are biocompatible. Such materials need to provide both mechanical support and biological cues for tissue ingrowth. Somewhat counter-intuitively, a self-assembling peptide hydrogel, without added growth factors or exogenous cells, demonstrated formation of vascularized soft-tissue in a canine pulpectomy model in 28 days. In a separate study, a different cationic amphiphilic hydrogel belonging to the same platform, showed efficacy in inhibiting bacterial growth via membrane permeabilization. In this proposal, a combinatorial treatment modality will be tested for its effectiveness in achieving the dual goals described above. A mechanistic puzzle that these projects would help solve is the lineage/source of infiltrating cells and evolution of the cellular milieu in the pulpal canal after pulpectomy and implantation of soft biomimetic hydrogels. Characterization of the long- term maturation of the vascularized soft tissue promoted by such hydrogels is another target. The multi- disciplinary project proposed in this Bioengineering Research Grant application would bring together a chemist and bioengineer (PI V.A.K., an early-stage investigator), a specialist in oral bacterial colonies (co-I C.C.), and an endodontist (co-I E.S.), to solve an enduring challenge: regenerating biomimetic vascularized soft tissue post- pulpectomy. In vitro mechanistic analyses, in vivo characterization of infiltrating cells, and histologic/radiographic identification of long-term evolution of the pulpal soft tissue and the pulp-dentin complex would build on published studies and extensive preliminary data. Even if the proposed experiments are only partially successful, we would learn about tissue-material interaction in the context of dental pulp. Success of the aims would produce compelling data for a cell-free, growth-factor-free, off-the-shelf material formulation ideal for application in endodontic settings and improve clinical outcomes in millions of patients needing pulpectomy.