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: 10373389
• 负责人: JASON R. McCARTHY
• 金额: $ 25.13万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373389
• 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; Gold; 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; alpha Toxin; 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.

项目总结 迫切需要创造具有成本效益的生物材料来促进在某些情况下的成骨 受伤的骨在生物学上受损(例如，骨不连或严重大小的缺陷)或成骨作用 通常无骨组织(如脊柱融合术)所需的。目前使用的生物材料包括自体移植， 同种异体移植、合成基质和骨诱导生物制品。自体移植是黄金标准；然而，它的数量 有限，在收获期间造成痛苦，并增加护理成本。同种异体骨移植和人工合成 具有或不具有骨诱导因子(例如BMP2)添加的基质已被用于不同的 结果和值得怀疑的成本效益。理论基础：我们已经确定陶瓷的合成类似物 血小板聚磷酸纳米粒(Polyp-NP，链长60-120个重复单位)促进体内骨化- 令人惊讶的是通过软骨内骨化，而不是主要是膜内骨化。 用重组BMP2(RBMP2)观察。目标/方法：在这里，我们的目标是确定最优属性， 丰富的息肉-NP60-120的成骨机制和潜在毒性，并比较 RBMP2的诱导成骨效果和毒性。我们将进行一项决定性的系统调查，旨在 最大化陶瓷息肉-NP60-120的骨诱导性能(目标1)，以确定软骨形成是否 对于血管生成和骨诱导特性是必不可少的(目标2)，并评估毒性激活 使用它们时会发生凝血和炎症(目标3)。诱骨和有害的特性将是 与rBMP2相比。所有的实验都将在活体内进行，使用的是骨诱导的‘urist’模型。 将实验材料植入小鼠的腓肠肌。预期结果：我们 预计陶瓷Polyp-NP60-120将至少具有与rBMP2相同的骨诱导潜能，即 软骨形成对Polyp-NP60-120介导的成骨作用是必不可少的，而不是可有可无的，因为 在rBMP2介导的成骨诱导作用中观察到，Polyp-NP60-120将引起局部的，而不是全身的， 激活凝血和炎症。影响：如果发现属实，这些结果将表明陶瓷息肉- NP60-120可能是rBMP2的一个很好的替代品。具体地说，如果息肉的骨诱导特性- NP60-120是通过软骨细胞中间体，这将是有利的，因为软骨细胞装备良好 在缺乏血管的环境中生存并产生骨诱导因子，包括血管内皮生长因子和骨形成蛋白2 比如需要植骨的临床情况。此外，考虑到其相对可用性，通过合成 与分离或重组相比，陶瓷息肉-NP60-120也可能是一种更具成本效益的替代方案 骨诱导因子，如rBMP2。