Novel Small Molecule for Improved Dental Implant Osseointegration

项目摘要/摘要 口腔种植体在牙科医学中被广泛接受，作为一种修复修复的选择 因先天性牙齿发育不全、牙周病或受伤而缺牙。虽然小鼠的存活率 据报道，经过10年的观察，在完全无牙的颌骨中，植入物的比例超过90%。 在一些患者中，由于骨质疏松等各种骨密度问题，种植体确实会失败。因此，一个 牙种植体治疗的主要临床挑战是改善和加速机械支抗 钛植入颌骨，便于早期功能加载。虽然不同的修改 种植体表面有助于种植体的骨整合，骨合成代谢剂将增加 许多骨密度问题的阳性反应的可预测性，尤其是在老年骨质疏松症患者中 部分的或完全的无牙齿。开曼化学公司发现并申请了一系列EP4 受体激动剂的设计，合成和筛选的目标效力和选择性，细胞活性和 代谢和理化性质符合局部所需的快速全身清除 行政管理。该系列的先导化合物KMN-159在项目第一阶段进行了测试， 体外成骨分化能力和体内骨再生潜能。 大鼠严重骨不连骨折模型及颅骨修复。此外，我们还证明了KMN-159 与rhBMP-2的护理标准相反，不会诱导异位骨形成。在第二阶段的 我们将评估KMN-159-胶原水凝胶组合作为牙种植促进剂的效果 2D和3D体外系统(AIM 1a)和体内大鼠实验性牙槽骨的骨整合 缺陷模型(Aim1b)。目标2将采用最有效的配方剂量KMN-159 证明植入物的生物力学强度得到了提高。最后，一批KMN-159的演示批次在 GMP条件和Helistat可吸收胶原海绵配方将用于测试有效性和安全性 在FDA接受的GLP兔植入模型中。所有的活体研究都旨在将性行为视为一种 生物变量。总之，开曼的目标是为牙医提供一种新颖、有效、安全、经济和易于- 使用小分子药物(KMN-159)-装置组合将提高种植率 骨整合以及骨-种植体界面的强度。这种稳定的、预先包装的、即用即用的 灵活且易于安装的骨整合促进剂将增强骨骼的自然修复过程，并可以 从而便于更早地加载种植体，并与接受植入的种植体相比减少了种植体失败的次数 只有植入物。

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.