Novel Small Molecule for Improved Dental Implant Osseointegration

项目总结/摘要 口腔种植体在牙科医学中被广泛接受为替代牙种植体的重建治疗选择。 因先天性牙齿发育不全、牙周病或受伤而缺牙。虽然存活率 据报道，在10年的观察中，牙植入物在完全无牙颌中的比例高于90%， 由于各种骨密度问题如骨质疏松症，牙科植入物在一些患者中确实失效。因此 牙种植体治疗的主要临床挑战是改善和加速牙种植体的机械锚定。 将钛植入颌骨以促进早期功能负荷。虽然各种修改 植入物表面有助于植入物的骨整合，骨合成代谢剂将增加 对于许多骨密度问题，尤其是老年患者的骨密度问题， 部分或完全缺牙。开曼化学公司发现了一系列EP 4并获得专利 受体激动剂的设计，合成和筛选的目标效力和选择性，细胞活性， 代谢和物理化学性质适合于局部所需的快速全身清除 局该系列的先导化合物KMN-159在项目的第一阶段进行了测试， 证明了其体外成骨分化能力以及体内骨再生潜力， 骨不连和颅骨修复的大鼠临界缺损模型。此外，我们证明KMN-159 与标准治疗rhBMP-2相比，其不诱导异位骨形成。在第二阶段， 本研究将评估KMN-159-胶原水凝胶组合物作为牙种植促进剂的效果 体外系统（Aim 1a）和大鼠实验性牙槽嵴骨体内的2D和3D骨整合 缺陷模型（Aim 1b）。KMN-159的最有效制剂剂量将用于目标2， 证明植入物的生物力学强度得到改善。最后，将KMN-159的演示批次在以下条件下制备： GMP条件和Helistat可吸收胶原蛋白海绵配制将用于测试有效性和安全性 在FDA认可的GLP家兔植入模型中。所有的体内研究都是将性别作为一种 生物变量总而言之，Cayman的目标是为牙医提供一种新颖，有效，安全，经济，易于操作的 使用小分子药物（KMN-159）-器械组合，这将增加牙科植入率 骨整合以及骨-种植体界面的强度。这种稳定的，预先包装好的，即用型的， 一种灵活且易于安装的骨整合促进剂将增强骨的自然修复过程， 因此与那些接受植入物的患者相比 单独植入。

PROJECT SUMMARY/ABSTRACT Oral implants are widely accepted in dental medicine as a reconstructive treatment option for replacement of missing teeth because of congenital tooth agenesis, periodontal diseases, or injury. Although the survival rate of dental implants over a 10-year observation has been reported to be higher than 90% in totally edentulous jaws, dental implants do fail in some patients due to a variety of bone density problems such as osteoporosis. Thus, a major clinical challenge for dental implant therapy is improving and accelerating the mechanical anchorage of the titanium implants into the jawbone to facilitate earlier functional loading. While various modifications of implant surfaces have helped osseointegration of implants, a bone anabolic agent would increase the predictability of a positive response for many of the bone density problems seen especially in older patients with partial or complete edentulism. Cayman Chemical Company, Inc. had discovered and patented a series of EP4 receptor agonists designed, synthesized, and screened for target potency and selectivity, cell activity, and metabolic and physicochemical properties amenable to the rapid systemic clearance desirable for local administration. The lead compound of the series, KMN-159, was tested during Phase I of the project and demonstrated its in vitro osteogenic differentiation capacity as well as its in vivo bone regeneration potential in rat critical defect models of non-union fracture and calvarial repair. Moreover, we demonstrated that KMN-159 does not induce ectopic bone formation in contrast to the standard of care rhBMP-2. During Phase II of the project we will evaluate the effects of KMN-159-collagen hydrogel combination as an accelerant of dental implant osseointegration in 2D and 3D in vitro systems (Aim 1a) and in vivo in a rat experimental alveolar ridge bone defect model (Aim1b). The most efficacious formulation dose of KMN-159 will be employed in Aim 2 to demonstrate improved biomechanical strength of the implant. Finally, a Demo Batch of KMN-159 prepared under GMP conditions and formulated in Helistat absorbable collagen sponges will be used to test efficacy and safety in a GLP rabbit implant model accepted by the FDA. All the in vivo studies were designed to consider sex as a biological variable. In sum, Cayman’s goal is to offer dentists a novel, effective, safe, economical, and easy-to- use small molecule drug (KMN-159)-device combination that will increase the rate of dental implant osseointegration as well as the strength of the bone-implant interface. This stable, prepackaged, ready-to-use, flexible and easily-fitted osseointegration accelerant would augment the bone’s natural repair process and could thus facilitate earlier implant loading and decrease the number of implant failures as compared to those receiving implants alone.