Mechanistic insights into polyphosphate-mediated osteoinduction.

对聚磷酸盐介导的骨诱导的机制见解。

• 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
• 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

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.

项目摘要 迫切需要创建具有成本效益的生物材料来在情况下促进成骨 如果受伤的骨骼受到生物学损害（例如非工会或临界大小缺陷）或成骨的何时 在通常没有骨骼的组织中所需的（例如脊柱融合）。目前使用的生物材料包括自体移植 同种异体移植，合成矩阵和骨诱导生物制剂。自体植物是黄金标准；但是，它的数量 有限，在收获过程中会导致疼痛，并增加护理成本。破骨合金和合成的合成 有或不添加骨诱导因子（例如BMP2）的矩阵已被不同 结果和可疑的成本效益。理由：我们已经确定陶瓷的合成类似物 血小板多磷酸盐纳米颗粒（息肉NP，链长60-120重复单位）促进骨化体内 - 体内 - 令人惊讶地通过内软骨骨化而不是原发性膜内骨化 用重组BMP2（RBMP2）观察到。目的/方法：在这里，我们旨在确定最佳属性， 骨化机制以及绝对可用的息肉NP60-120的潜在毒性，并比较 骨诱导效率和对RBMP2的毒性。我们将执行一项旨在的系统性投资 最大化陶瓷息肉NP60-120（AIM 1）的骨诱导特性，以确定软骨发生是否为 对于它们的血管生成和骨诱导特性至关重要（AIM 2），并评估是否有毒激活 凝结和炎症随着它们的使用而发生（AIM 3）。骨感应和有害特性将是 与RBMP2相比。所有实验都将在体内采用骨诱导模型进行体内进行 将实验材料植入鼠腹骨肌肉中的地方。预期的结果：我们 预计陶瓷息肉NP60-120至少具有等效的骨诱导潜力，即rbmp2 软骨发生对于息肉-NP60-120介导的骨诱导至关重要，而不是可分配的 在RBMP2介导的骨诱导中观察到，息肉NP60-120会导致局部但不会导致全身性， 凝血和炎症的激活。影响：如果发现的话，这些结果将表明陶瓷息肉 - NP60-120可能代表RBMP22的绝佳替代方法。 NP60-120通过软骨细胞中间体，这将是有利的，因为软骨细胞是相等的 生存并产生骨气诱导因子，包括VEGF和BMP2，在血管中无处不在的环境中 例如需要骨移植的临床情况。此外，鉴于其通过合成的相对可用性 陶瓷息肉NP60-120路线也可能代表比孤立或重组更具成本效益的替代方案 骨诱导因子，例如RBMP2。