Mechanistic insights into polyphosphate-mediated osteoinduction.

对聚磷酸盐介导的骨诱导的机制见解。

基本信息

批准号：
10634500
负责人：
JASON R. McCARTHY
金额：
$ 19.31万
依托单位：
MASONIC MEDICAL RESEARCH LABORATORY, INC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-03 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10634500
关键词：
Ablation Allografting Autologous Transplantation BMP2 gene Biocompatible Materials Biological Process Biological Products Blood Coagulation Disorders Blood Platelets Blood Vessels Bone Growth Bone Injury Bone Transplantation Cations Ceramics Chondrocytes Chondrogenesis Clinical Coagulation Process Collagen Defect Deposition Diphtheria Toxin Distant Electrons Environment Enzyme-Linked Immunosorbent Assay Fibrin Formulation Fracture Gastrocnemius Muscle Growth Factor Harvest Hemorrhage Histology Image Impairment Inflammation Inflammatory Inflammatory Response Investigation Kidney Length Libraries Lung Measurement Measures Mediating Microfils Microscopic Modeling Mus NF-kappa B Nature Normal tissue morphology Oral Surgical Procedures Organ Osteogenesis Pain Particle Size Pathway interactions Physiologic Ossification Plasma Plasmin Polymers Polyphosphates Polyps Property Public Health Recombinants Reporter Route Spinal Fusion Systemic Inflammatory Response Syndrome Techniques Thrombin Toxic effect Vascular Endothelial Growth Factors Work X-Ray Medical Imaging aggrecan analog angiogenesis bone care costs cost effective cost effectiveness design experimental study implant material in vivo innovation insight intramembranous bone formation nanoparticle oral surgery specialty osteoinductive factor response tissue regeneration tissue repair

项目摘要

PROJECT SUMMARY There is an urgent need for the creation of cost-effective biomaterials to promote osteogenesis in situations where injured bone is biologically impaired (e.g. non-union or critical sized defects) or when osteogenesis is desired in tissue normally devoid of bone (e.g. spinal fusion). Currently used biomaterials include autograft, allografts, synthetic matrices, and osteoinductive biologics. Autograft is the gold standard; however, its quantity is limited, causes pain during harvesting, and increases cost of care. Osteoconductive allografts and synthetic matrices with or without the addition of osteoinductive factors (e.g. BMP2), have been employed with varying results and questionable cost-effectiveness. Rationale: We have determined that synthetic analogs of ceramic platelet polyphosphate nanoparticles (polyP-NP, chain length 60-120 repeat units) promote ossification in-vivo - surprisingly through endochondral ossification as opposed to primarily intramembranous ossification, as is observed with recombinant BMP2 (rBMP2). Aims/Approach: Here, we aim to determine the optimal properties, mechanism of ossification, and potential toxicity of the abundantly available polyP-NP60-120 and to compare the osteoinductive efficacy and toxicity to rBMP2. We will perform a definitive systematic investigation designed to maximize the osteoinductive properties of ceramic polyP-NP60-120 (Aim 1), to determine if chondrogenesis is essential for their angiogenic and osteoinductive properties (Aim 2), and assess whether toxic activation of coagulation and inflammation occurs with their use (Aim 3). Osteoinductive and deleterious properties will be compared to rBMP2. All experiments will be conducted in vivo employing the ‘Urist’ model of osteoinduction where experimental materials are implanted into the murine gastrocnemius muscle. Anticipated results: We anticipate that ceramic polyP-NP60-120 will possess at least equivalent osteoinductive potential as rBMP2, that chondrogenesis is essential for polyP-NP60-120 -mediated osteoinductivity as opposed to being dispensable, as is observed in rBMP2-mediated osteoinductivity, and that polyP-NP60-120 will cause local, but not systemic, activation of coagulation and inflammation. Impact: If found true, these results would indicate that ceramic polyP- NP60-120 may represent an excellent alternative to rBMP2. Specifically, if the osteoinductive properties of polyP- NP60-120 are through a chondrocyte intermediate, it would be advantageous as chondrocytes are well equipped to survive and produce osteoinductive factors, including VEGF and BMP2, in a vascularly devoid environments such as the clinical situations requiring bone grafting. Additionally, given its relative availability through synthetic routes, ceramic polyP-NP60-120 may also represent a more cost-effective alternative than isolated or recombinant osteoinductive factors, such as rBMP2.

项目概要迫切需要创造具有成本效益的生物材料来促进成骨受伤的骨骼受到生物学损伤（例如不愈合或严重大小的缺陷）或成骨过程受到影响时通常缺乏骨骼的组织（例如脊柱融合）所需的当前使用的生物材料包括自体移植物，同种异体移植物、合成基质和骨诱导生物制剂是黄金标准。是有限的，会在采集过程中引起疼痛，并增加骨传导同种异体移植物和合成物的护理成本。添加或不添加骨诱导因子（例如 BMP2）的基质已被用于不同的用途结果和值得怀疑的成本效益理由：我们已经确定陶瓷的合成类似物。血小板多磷酸纳米颗粒（polyP-NP，链长60-120个重复单元）促进体内骨化 - 令人惊讶的是，通过软骨内骨化而不是主要的膜内骨化，用重组 BMP2 (rBMP2) 进行观察目的/方法：在这里，我们的目标是确定最佳特性，骨化机制和丰富的聚P-NP60-120的潜在毒性，并比较我们将进行一项明确的系统研究，旨在确定 rBMP2 的骨诱导功效和毒性。最大化陶瓷 PolyP-NP60-120 的骨诱导特性（目标 1），以确定软骨形成是否有效对于其血管生成和骨诱导特性至关重要（目标 2），并评估是否有毒性激活使用它们时会发生凝血和炎症（目标 3）。与 rBMP2 相比，所有实验都将采用“Urist”骨诱导模型在体内进行。实验材料被植入小鼠腓肠肌中预期结果：我们。预计陶瓷 PolyP-NP60-120 至少具有与 rBMP2 相当的骨诱导潜力，即软骨形成对于 PolyP-NP60-120 介导的骨诱导性至关重要，而不是可有可无的，因为在 rBMP2 介导的骨诱导性中观察到，polyP-NP60-120 会引起局部而非全身性，凝血和炎症的激活影响：如果发现属实，这些结果将表明陶瓷聚P-。 NP60-120 可能是 rBMP2 的绝佳替代品，具体来说，如果聚 P- 具有骨诱导特性。 NP60-120是通过软骨细胞中间体，这将是有利的，因为软骨细胞装备精良在缺乏血管的环境中生存并产生骨诱导因子，包括 VEGF 和 BMP2 比如临床上需要植骨的情况。路线，陶瓷 PolyP-NP60-120 也可能是比分离或重组更具成本效益的替代方案骨诱导因子，例如rBMP2。