Development of a Novel Bone Adhesive Scaffold to Accelerate Bone Regeneration and Improve Ridge Height Maintenance for the Treatment of Patients with Residual Ridge Resorption

项目概要/摘要 超过50%的美国45岁以上的成年人有缺牙。牙齿脱落后， 颌骨将在称为残留牙槽嵴再吸收过程中萎缩。虽然牙科种植体支撑的牙冠具有 成为护理标准，市场研究表明，70%的患者必须接受牙槽嵴隆乳 提供足够的骨结构以接受植入物放置的手术。骨移植的市场是高度 零散，表明不存在满足用户需求的理想材料。大多数牙医仍然 由于其具有挑战性的操作性能和较差的可预测性，对现有骨移植物不满意。由于 由于缺乏结构完整性，它们通常需要额外的成本和步骤来放置辅助遏制装置 以防止移植物迁移和纤维组织向内生长，从而阻碍骨再生。因此，一个次要的 30%的病例需要进行隆乳手术，以确保有足够的体积用于种植体植入。 RevBio公司已经开发出一种高度多孔的再生骨移植生物材料，具有粘合性能，称为 Tetranite®牙科骨支架（TN-ADBS）。与目前可用的移植材料不同，TN-ADBS 在应用过程中具有粘性，其独特的粘合性能使其能够保持形状，无需 辅助固定或密封装置。TN-ADBS由O-磷酸-L-丝氨酸（OPLS）组成，其部分地 使其具有独特的粘附性，研究还发现OPLS在其再吸收和局部释放过程中， 骨促进，使该产品产生更可预测和有效的产品。 先前的资金来自美国国立卫生研究院-密歇根州匹兹堡Wyndham再生医学资源中心已被用于 目的：（a）开发TN-ADBS，（B）评价其在用户操作试验中的性能，（c）开发具有 下颌骨临界尺寸缺损，和（d）在该模型中进行初步疗效研究。基于FDA 反馈，TN-ADBS将作为器械主导的组合产品进行监管，其中OPLS是药物成分 促进骨骼再生。以下拟议的第二阶段拨款申请是根据FDA最近的 反馈，以解决以下两个具体目标：（1）评估TN-ADBS（OPLS）的局部/全身效应 新西兰白色家兔在最大使用条件下的药代动力学/药效学（PK/PD） （2）证明TN-ADBS在用于预期动物的关键动物研究中的安全性和有效性 通过（i）显示TN-ADBS治疗的局部或全身副作用， 缺陷不劣于对照，以及（ii）在整个过程中显示出优越的上级脊高度保持 与对照组相比，骨替代物（p<0.05）。 这些转化动物研究的结果与外科医生确认的模拟使用试验互补 和生物安全性评价研究，将用作提交试验用器械豁免的基础 (IDE)进行人体研究RevBio的长期使命是为外科医生提供一种新颖的 骨移植产品，以简化手术和改善临床结果的牙嵴增加。

PROJECT SUMMARY/ABSTRACT Over 50% of US adults over the age of 45 have missing teeth. Following tooth loss, the alveolar portion of the jaw will atrophy in a process known as residual ridge resorption. While dental implant-supported crowns have become the standard of care, market research indicates that 70% of patients must undergo a ridge augmentation procedure to provide adequate bony structure to accept implant placement. The market for bone grafts is highly fragmented, indicating that the ideal material meeting user needs does not exist. Most dentists remain dissatisfied with existing bone grafts due to their challenging handling properties and poor predictability. Due to the lack of structural integrity, they typically require extra costs and steps to place ancillary containment devices to prevent graft migration and fibrous tissue ingrowth that impedes bone regeneration. As a result, a secondary augmentation procedure is required in 30% of cases to ensure sufficient volume for implant placement. RevBio, Inc. has developed a highly porous, regenerative bone graft biomaterial with adhesive properties called Tetranite® Adhesive Dental Bone Scaffold (TN-ADBS). Unlike currently available graft materials, TN-ADBS is cohesive during application and its unique adhesive properties allow it to maintain form, eliminating the need for ancillary fixation or containment devices. TN-ADBS is comprised of O-Phospho-L-Serine (OPLS), which in part makes it uniquely adhesive to bone and studies have also found OPLS during its resorption and local release to be osteopromotive, lending this product to yield a more predictable and efficacious product. Prior funding from the NIH-Michigan Pittsburgh Wyss Regenerative Medicine Resource Center has been used to: (a) develop TN-ADBS, (b) evaluate its performance in user handling trials, (c) develop a canine model with a mandibular critical-sized defect, and (d) conduct preliminary efficacy studies in this model. Based on FDA feedback, TN-ADBS will be regulated as a device-led combination product, where OPLS is the drug constituent promoting bone regeneration. The following proposed Phase II grant application is designed per recent FDA feedback to address the following two Specific Aims: (1) to assess the local/systemic effects of TN-ADBS (OPLS) and pharmacokinetics/pharmacodynamics (PK/PD) under maximal use conditions in a New Zealand white rabbit model and (2) to demonstrate the safety and efficacy of TN-ADBS in a pivotal animal study for the intended clinical use to augment deficient jaw bone by (i) showing local or systemic adverse effects of TN-ADBS treated defects are non-inferior to controls and (ii) by showing superior ridge height maintenance throughout the course of bone substitution in comparison to controls (p<0.05). The results from these translational animal studies, complementary to surgeon-validated simulated use trials and biological safety evaluation studies, will be used as the basis for filing an Investigational Device Exemption (IDE) with the FDA to initiate human studies. Long-term, RevBio’s mission is to provide surgeons with a novel bone grafting product to simplify surgery and improve clinical outcomes for dental ridge augmentation.