Polysaccharide putty formulations for tissue regeneration

用于组织再生的多糖腻子配方

• 批准号: 10627055
• 负责人: Sangamesh Gurappa Kumbar
• 金额: $ 37.35万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627055
• 关键词: 3-Dimensional; Acetates; Address; Biocompatible Materials; Biological Assay; Bone Density; Bone Matrix; Bone Regeneration; Bone Tissue; Bone Transplantation; Calvaria; Cell Culture Techniques; Cellulose; Cephalic; Ceramics; Clinical; Complement; Complex; Coupled; Defect; Development; Diffusion; Drug or chemical Tissue Distribution; Economic Burden; Enabling Factors; Ensure; Equilibrium; Excipients; Extracellular Matrix; FDA approved; Formulation; Fracture; Future; Generations; Growth; Growth Factor; Hydrogels; Impaired healing; In Vitro; Knowledge; Mechanics; Mesenchymal Stem Cells; Modeling; Molds; Nanotubes; Natural regeneration; Oryctolagus cuniculus; Osteoblasts; Osteoclasts; Osteogenesis; Pharmaceutical Preparations; Physiologic pulse; Physiological; Plants; Polymers; Polymethyl Methacrylate; Polysaccharides; Porosity; Property; Proteins; Research; Shapes; Site; Solubility; Sterilization; System; Technology; Temperature; Testing; Time; Time Factors; Tissues; Variant; Vascularization; Vertebral column; Weight-Bearing state; Work; biomaterial compatibility; bone; bone engineering; bone healing; bone repair; bone strength; calcium phosphate; cell behavior; clay; comparison control; cortical bone; craniofacial; demineralization; design; dynamic system; efficacy testing; flat bone; flexibility; halloysite; implantable device; implantation; in vivo; innovation; long bone; mouse model; nano; novel; phthalates; release factor; repaired; scaffold; stem cell delivery; subcutaneous; three dimensional structure; tissue regeneration; tissue repair; ulna

Project Summary/Abstract The broad, long-term objectives of this proposal are to enhance the utility of cellulose-based biomaterials for tissue repair by developing and evaluating a new and innovative composite that address current limitations. Bacterial cellulose hydrogels and extracellular matrices have shown excellent regeneration capabilities in multiple tissue types. However, these materials lack mechanical strength and degradation features needed for specific applications such as bone repair, and have limited options for storage, handling, and sterilization. Plant- derived cellulose in its derivative cellulose acetate (CA) form is capable of creating mechanically competent porous scaffolds that are effective in bone regeneration. However, premade CA scaffolds with defined sizes, shapes, and pore properties present challenges in adapting to complex bone defects. Additionally, the relatively slow degradation rate of cellulose/CA can limit its ability to control factor release and heal bone. Combining CA with CA phthalate (CAP) and nanoclay (NC) has the potential to address some of these weaknesses. This cellulose-based composite forms a putty that can be molded into complex shapes and becomes strong as it hardens, making it adaptable to diverse bone defects. Under physiologic conditions, CAP erodes before the slower-degrading CA matrix, enabling a dynamic system that generates interconnected pores and tunable growth factor release profiles and degradation. A CA/CAP/NC composite allows flexible incorporation of multiple bioactive factors for varied effects: within CA for early, sustained release; within CAP for pulsed release; and/or into NC embedded within the CA/CAP for delayed, sustained release. This also allows factors to be released in parallel and/or sequentially. Detailed, long-term in vitro and in vivo characterizations of this cellulose biomaterial, including its ability to balance strength and porosity and the effects of osteoclasts on its degradation, remain knowledge gaps for advancing this transformative and natural biomaterial platform. Based on current knowledge, it is hypothesized that this dynamic cellulose-based putty will impart composition-dependent changes of strength and erosion in 3D microenvironments leading to varied bioactive factor release rates, vasculature development, and tissue ingrowth during bone repair. This will be tested in four Specific Aims: Aim 1: Characterize physicochemical and release properties of novel cellulose derivatives and compositions in vitro. Aim 2: Evaluate biocompatibility and bioactivity of released molecules in an in vivo subcutaneous implantation model. Aim 3: Evaluate cellular effects of putty formulations with early to long-term release profiles on a cranial flat-bone healing defect. Aim 4: Assess putty formulations with early to long-term release profiles on bone healing at a load- bearing site in a critical-sized long-bone defect in rabbit ulna. These studies will address several knowledge gaps for using cellulose biomaterials in bone healing. If this enabling putty technology is successful, it may be transformative to the field and adapted for other repair challenges in bone as well as a coating for biomedical implants.

项目总结/摘要 该提案的广泛的长期目标是提高纤维素基生物材料的实用性， 通过开发和评估一种新的创新复合材料来修复组织，以解决当前的局限性。 细菌纤维素水凝胶和细胞外基质已经显示出优异的再生能力， 多种组织类型。然而，这些材料缺乏机械强度和降解所需的特征， 例如骨修复的特定应用，并且对于储存、处理和灭菌具有有限的选择。植物- 以其衍生物醋酸纤维素（CA）形式的衍生纤维素能够产生机械上胜任的 多孔的支架，在骨再生中有效。然而，具有限定尺寸的预制CA支架， 形状和孔隙性质对适应复杂的骨缺损提出了挑战。此外，相对 纤维素/CA缓慢降解速率可限制其控制因子释放和愈合骨的能力。组合CA 具有邻苯二甲酸CA（CAP）和纳米粘土（NC）的聚合物具有解决这些弱点中的一些的潜力。这 纤维素基复合材料形成一种腻子，可以塑造成复杂的形状，并变得强大，因为它 硬化，使其能够适应各种骨缺损。在生理条件下，CAP在 缓慢降解的CA基质，使动态系统能够产生互连的孔和可调的 生长因子释放曲线和降解。CA/CAP/NC复合材料允许灵活地结合多种 用于不同效果的生物活性因子：在CA内用于早期、持续释放;在CAP内用于脉冲释放;和/或 进入嵌入CA/CAP内的NC中，用于延迟持续释放。这也使得因子可以在 并行和/或顺序地。这种纤维素生物材料的详细、长期体外和体内表征， 包括其平衡强度和孔隙率的能力以及破骨细胞对其降解的影响， 知识差距，以推进这一变革性和天然的生物材料平台。根据目前的知识， 据推测，这种动态纤维素基腻子将赋予组合物依赖的强度变化， 和侵蚀，导致不同的生物活性因子释放速率，脉管系统发育， 和组织向内生长。这将在四个具体目标中进行测试：目标1：表征 本发明提供了新型纤维素衍生物和组合物在体外的物理化学和释放性质。目标2：评估 在体内皮下植入模型中释放的分子的生物相容性和生物活性。目标3： 评价具有早期至长期释放特征的油灰制剂对颅骨扁平骨愈合的细胞效应 缺损目的4：评估在负荷下具有对骨愈合的早期至长期释放曲线的油灰制剂- 兔尺骨关键尺寸长骨缺损的承载部位。这些研究将解决几个知识差距 在骨愈合中使用纤维素生物材料。如果这种使能腻子技术是成功的，它可能是 对该领域具有变革性，适用于骨修复的其他挑战以及生物医学涂层。 植入物.