Pre-clinical Models of Odontic Analogs by Endogenous Stem Cells

描述(由申请人提供)：牙科内源性干细胞类似物的临床前模型项目摘要牙齿丢失是最常见的器官衰竭。在许多野生动物物种中，牙齿完全脱落等同于生命的终结。对于人类来说，牙齿脱落会对自尊产生负面影响，并损害包括咀嚼、消化和/或言语在内的多种生理功能。在此应用程序中，该应用程序是专门为响应 根据PA-10-009，生物工程研究资助(BRG)，我们建议在临床前模型中开发基于天然牙根形状和尺寸的生物材料支架的牙科类似物。目前，假牙或牙科种植体是部分或完全无牙患者的首选治疗方法。然而，假牙和牙科植入物也存在一些缺点，包括失败、金属过敏和成本过高。在我们的初步数据中，我们证明了在体内植入解剖学上正确的3D生物材料支架后，牙根类似物由假定的牙周韧带和牙槽骨再生。R01提案的总体目标是在临床前模型中生成概念验证数据，这是进一步开发负担得起的技术走向最终临床应用的必要步骤。与以往总是涉及干细胞移植的有益方法的牙齿再生研究不同，拟议的实验被设计为包括两种主要的创新方法。首先，所有拟议的研究都将基于细胞学线索对宿主内源性干细胞的归巢。不会移植任何细胞。干细胞归巢再生如果在临床前模型和未来的临床试验中被证明有效，可能会避免与体外细胞培养相关的过长时间和成本、潜在的污染和肿瘤形成等问题。其次，我们采用了一种新的方法来确定支架生物材料的物理性质如何影响内源性干细胞/祖细胞的招募和分化，这一方法在牙齿再生中尚未被研究过。如果根据生物支架的各种性质在体内开发牙科类似物，而不需要提供细胞趋化线索或细胞，临床翻译可以进一步加快。这些在临床前模型中提出的研究代表了关于牙根再生的最严格的翻译努力， 缺乏只有在临床前研究和FDA和IRB批准后才能进行的人体临床试验。

DESCRIPTION (provided by applicant): Pre-clinical Models of Odontic Analogs by Endogenous Stem Cells Project summary Tooth loss is the most common organ failure. Complete tooth loss in many wildlife species equates to the end of life. For humans, tooth loss negatively impacts one's self-esteem and impairs multiple physiological functions including mastication, digestion and/or speech. In this application that is specifically designed in response to PA-10-009, Bioengineering Research Grants (BRG), we propose to develop odontic analogs based on biomaterial scaffolds in the shape and dimensions of native tooth roots in a preclinical model. Currently, dentures or dental implants are the treatments of choice for patients who are partially or completely edentulous. However, a number of drawbacks are associated with dentures and dental implants, including failure, metal allergy and excessive cost. We demonstrate in our preliminary data that a tooth root analog regenerated with putative periodontal ligament and alveolar bone upon implantation of anatomically correct 3D biomaterial scaffold in vivo. The overall goal of this R01 proposal is to generate proof-of-concept data in a preclinical model that represents an obligatory step for further development of an affordable technology towards eventual clinical applications. As a departure from previous tooth regeneration studies that invariably involve the meritorious approach of stem cell transplantation, the proposed experiments are designed to include two primary innovative approaches. First, all the proposed studies will be based on the homing of host endogenous stem cells by cytotatic cues. No cells will be transplanted. Regeneration by stem cell homing, if proven effective in pre-clinical models and future clinical trials, may circumvent issues such as excessive time and cost in association with ex vivo cell culture, potential contamination and tumoerigenesis. Second, we take a novel approach to determine how physical properties of scaffold biomaterials affect the recruitment and differentiation of endogenous stem/progenitor cells, an approach that has not been investigated in tooth regeneration. If odontic analogs are developed in vivo as a function of various properties of bioscaffolds and without the delivery of cytotactic cues or cells, clinical translation can be further accelerated. These proposed studies in a preclinical model represent the most rigorous translational effort on tooth root regeneration, short of a human clinical trial that can only be conducted after a preclinical study and after FDA and IRB approvals.