BioPulp: Bioengineeering approaches for dental pulp regeneration

描述(申请人提供)：牙髓是牙齿中央核心的软结缔组织，作为生物可行的器官维持牙齿的动态平衡。当龋齿或创伤涉及牙髓时，需要进行牙髓治疗。在不可逆性牙髓炎中，牙医或牙髓医生拔除牙髓，并用生物惰性材料堵塞预备好的根管。仅在美国，每年就有大约1600万例牙髓治疗手术，每年的总支出约为150亿至250亿美元。虽然根管治疗被认为是成功的牙科治疗之一，但文献中反复记录了并发症。由于冠状渗漏或未被发现的副根管引起的继发感染并不少见，并给患者和牙医带来额外的痛苦。在根管治疗过程中，大量的牙齿结构被移除，导致牙齿折断的发生率增加。根管治疗的牙齿缺乏神经支配和牙髓感觉，因此失去了检测继发性感染的能力。对于乳牙或根尖形成不完全的年轻恒牙，根管治疗要么是相反的，要么可能导致牙根发育停止。科学地说，这些并发症可能归因于当前根管治疗的最终结果，导致失活的牙齿失去了天然牙齿的动态平衡和宿主防御机制。我们的初步数据表明，在小鼠体内异位种植整个人牙后，通过细胞因子诱导的细胞归巢途径，经根管治疗的人牙在体内可以重新细胞化和重新血运。这些发现提供了概念的证据，即经根管治疗的人牙齿的牙髓可以在体内原位再血管化和再细胞化。因此，我们的总体假设是，牙髓的各种成分，包括血管生成、成牙本质细胞和神经元，可以通过细胞因子诱导的细胞归巢再生。这项为期6个月的SBIR/第一阶段计划的总体目标是在生物相容材料支架中制备单一和组合细胞因子的配方，以促进牙髓再生。我们的长期目标有两个：1)在小动物和大动物模型中确定基于生物的牙髓再生的有效性和安全性；2)在牙髓患者中进行随机对照的多中心临床试验，并确定基于生物的牙髓治疗的有效性和安全性。我们设想，基于生物的治疗将再生牙髓患者的牙髓。 与公共卫生相关：这个SBIR/第一阶段项目将为因感染或创伤而导致的牙髓再生的生物工程疗法开发原型。仅在美国，每年大约有1600万例牙髓治疗手术。目前的根管治疗存在并发症，如继发性感染、术后牙齿断裂以及对乳牙或年轻恒牙无效等。我们的初步数据表明，在活体内，经过根管治疗的人的牙齿可以重新细胞化和血运重建。我们设计了跨学科的方法，具有在人类牙齿中再生牙髓的强大潜力。

DESCRIPTION (provided by applicant): Dental pulp is soft connective tissue in the central core of a tooth, and maintains homeostasis of the tooth as a biologically viable organ. When caries or trauma involves dental pulp, endodontic therapies are indicated. In irreversible pulpitis, the dentist or endodontist extirpates dental pulp, and obturates the instrumented root canal with bioinert materials. A total of approximately 16 million endodontic procedures are performed each year in the United States alone, with an annual total expenditure of approximately $15 to $25 billion dollars. Whereas root canal therapy is considered one of the successful dental treatments, complications have been repeatedly documented in the literature. Secondary infections due to coronal leakage or undetected accessory root canals are not uncommon, and cause additional distress to both patients and dentists. A substantial amount of tooth structure is removed during root canal treatment, leading to increased incidences of tooth fracture. Root canal treated teeth are devoid of innervation and pulpal sensation, and thus are deprived of the ability to detect secondary infections. In deciduous teeth or young permanent teeth with incomplete root apex formation, endodontic treatment is either contra-indicated or may lead to the cessation of root development. Scientifically, these complications may be attributed to the end result of the current root canal treatment leading to a devitalized tooth that has lost the mechanisms for homeostasis and host defense of a native tooth. Our preliminary data demonstrate that endodontically treated human teeth are recellularized and revascularized in vivo upon cytokine- induced cell homing approaches following in vivo ectopic implantation of the entire human teeth in mice. These findings provide the proof of concept that dental pulp of endodontically treated human tooth may be revascularized and recellularized orthotopically in vivo. Accordingly, our overall hypothesis is that various elements of dental pulp, including the angiogenic, odontoblastic and neuronal, can be regenerated by cytokine-induced cell homing. The overall goal of this 6-month SBIR/Phase-I proposal is to prepare formulations of singular and combinatory cytokines in biocompatible material scaffolds towards dental pulp regeneration. Our long-term goal is twofold: 1) to determine the efficacy and safety of biologically based dental pulp regeneration in small and large animal models, and 2) to perform randomized and controlled, multi-center clinical trials in endodontic patients, and determine the efficacy and safety of biologically based endodontic therapies. We envision that biologically based therapies will regenerate dental pulp in endodontic patients. PUBLIC HEALTH RELEVANCE: This SBIR/Phase I project will develop prototypes for bioengineered therapies for the regeneration of dental pulp resulting from infection or trauma. A total of approximately 16 million endodontic procedures are performed each year in the United States alone. Current root canal therapy has complications such as secondary infections, post-operative tooth fracture, and a lack of efficacy in deciduous teeth or young permanent teeth. Our preliminary data demonstrate that endodontically treated human teeth are recellularized and revascularized in vivo. We have designed interdisciplinary approaches with a strong potential to regenerate dental pulp in human teeth.