Novel Small Molecule for Improved Dental Implant Osseointegration

用于改善牙种植体骨整合的新型小分子

基本信息

批准号：
10257506
负责人：
MARIA INES MORANO
金额：
$ 79.38万
依托单位：
CAYMAN CHEMICAL COMPANY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-16 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10257506
关键词：
3-Dimensional Acceleration Address Agonist Alveolar ridge Anabolic Agents Biological Biomechanics Bone Density Bone Regeneration Calvaria Caymans Cells Chemicals Clinical Clinical Research Collagen Defect Dental Dental Implants Dentists Development Devices Dose EP4 receptor Edentulous Mouth Evaluation Failure Formulation Fracture Funding Goals Grant Hydrogels Implant In Vitro Injury Jaw Lead Legal patent Mechanics Medicine Metabolic Methods Modeling Modification Oral Oryctolagus cuniculus Osseointegration Osteogenesis Osteoporosis Patients Periodontal Diseases Pharmaceutical Preparations Pharmacologic Substance Phase Porifera Process Property Rattus Reporting Safety Series Sum Surface Survival Rate System Testing Titanium Tooth structure bone bone strength design edentulism efficacy study efficacy testing first-in-human flexibility improved in vivo meetings novel novel therapeutics older patient osteogenic programs recombinant human bone morphogenetic protein-2 reconstruction regeneration potential repaired response safety study sex small molecule standard of care three-dimensional modeling

3-Dimensional Acceleration Address Agonist Alveolar ridge Anabolic Agents Biological Biomechanics Bone Density Bone Regeneration Calvaria Caymans Cells Chemicals Clinical Clinical Research Collagen Defect Dental Dental Implants Dentists Development Devices Dose EP4 receptor Edentulous Mouth Evaluation Failure Formulation Fracture Funding Goals Grant Hydrogels Implant In Vitro Injury Jaw Lead Legal patent Mechanics Medicine Metabolic Methods Modeling Modification Oral Oryctolagus cuniculus Osseointegration Osteogenesis Osteoporosis Patients Periodontal Diseases Pharmaceutical Preparations Pharmacologic Substance Phase Porifera Process Property Rattus Reporting Safety Series Sum Surface Survival Rate System Testing Titanium Tooth structure bone bone strength design edentulism efficacy study efficacy testing first-in-human flexibility improved in vivo meetings novel novel therapeutics older patient osteogenic programs recombinant human bone morphogenetic protein-2 reconstruction regeneration potential repaired response safety study sex small molecule standard of care three-dimensional modeling

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项目摘要

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.

项目摘要/摘要口服牙齿在牙科医学中被广泛接受为重建治疗选择，以替代由于先天性牙齿产生，牙周疾病或受伤，缺失牙齿。虽然生存率据报道，牙齿在10年中的观察中的牙齿均高于90％的下颌，由于各种骨密度问题，例如骨质疏松症，牙齿确实在某些患者中确实失败了。那，牙科植入疗法的主要临床挑战是改善和加速机械锚固钛将其伸入颚骨，以促进早期的功能载荷。而各种修改植入物表面有助于骨化的骨整合，骨合成代谢剂会增加对于许多骨密度问题的正反应可预测性，尤其是在老年患者中部分或完整的社论。开曼化学公司（Cayman Chemical Company，Inc。）已发现并申请了一系列EP4 接收器激动剂设计，合成和筛选目标效力和选择性，细胞活动和适用于当地的快速全身清除的代谢和物理特性行政。该系列的铅化合物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及其体内骨再生潜力大鼠临界缺陷模型的非工会裂缝和钙修复。此外，我们证明了KMN-159 与护理RHBMP-2的标准相反，不会诱导生态骨形成。在第二阶段项目我们将评估KMN-159-胶原水凝胶组合的影响，作为牙科植入物的加速 2D和3D体外系统（AIM 1A）和大鼠实验性肺泡脊中的骨整合（AIM 1A）缺陷模型（AIM1B）。 KMN-159的最有效剂量将在AIM 2中聘请证明植入物的生物力学强度提高。最后，在 GMP条件并在可吸收胶原蛋白海绵中配制的GMP条件将用于测试效率和安全性在FDA接受的GLP兔植入物模型中。所有的体内研究旨在将性视为生物变量。总而言之，开曼的目标是为牙医提供一种新颖，有效，安全，经济且易于 - 使用小分子药物（KMN-159） - 将剂量组合提高牙齿植入率骨整合以及骨植入界面的强度。这个稳定的，预包装的，现成的，柔性且易于拟合的骨整合会加速会增加骨骼的自然修复过程，并且可以因此，与接收的人相比，早期植入物负载并减少植入物失败数单独植入。