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.

项目摘要/摘要 该提案的广泛，长期目标是增强基于纤维素的生物材料的实用性 通过开发和评估解决当前局限性的新的创新综合材料来修复组织。 细菌纤维素水凝胶和细胞外基质表现出极好的再生能力 多种组织类型。但是，这些材料缺乏所需的机械强度和降解功能 特定的应用，例如骨修复，并且可以进行储存，处理和灭菌的选择有限。植物- 其衍生纤维素乙酸纤维素（CA）形式的衍生纤维素能够创建机械胜任 有效骨再生的多孔支架。但是，预制的CA脚手架具有定义的大小， 形状和孔特性在适应复杂的骨缺损方面提出了挑战。另外，相对 纤维素/Ca的降解速率慢，可以限制其控制因子释放和治愈骨骼的能力。结合Ca 邻苯二甲酸酯（CAP）和纳米粘土（NC）具有解决这些弱点的潜力。这 基于纤维素的复合材料形成一个可以模制成复杂形状并在其上变得强大的腻子 硬化，使其适应各种骨骼缺陷。在生理条件下，帽子在 降低降低的Ca矩阵，使一个动态系统能够生成相互连接的毛孔和可调 生长因子释放曲线和降解。 CA/CAP/NC复合材料允许灵活掺入多个 各种影响的生物活性因素：在CA内进行早期，持续释放；在脉冲释放的帽子内；和/或 进入嵌入CA/CAP内的NC，以进行延迟，持续释放。这也允许因素释放 并行和/或顺序。该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，以促进这个变革性和自然的生物材料平台。基于当前的知识 假设这个基于动态纤维素的腻子将赋予强度的组成依赖性变化 3D微环境中的侵蚀导致不同的生物活性因子释放率，脉管系统发育， 和骨修复过程中的组织向内生长。这将以四个特定目的进行测试：目标1：特征 新型纤维素衍生物和组成的物理化学和释放特性。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： 评估具有早期至长期释放曲线的腻子配方对颅骨愈合的细胞效应 缺点。 AIM 4：评估在负载下骨骼愈合的早期至长期释放曲线的腻子配方 - 在兔尺骨中的关键尺寸长骨缺陷中轴承位点。这些研究将解决一些知识差距 用于在骨愈合中使用纤维素生物材料。如果这种启用的油灰技术成功了，则可能是 对田地进行变革，并适应骨骼的其他维修挑战以及生物医学的涂层 植入物。