Polysaccharide putty formulations for tissue regeneration

用于组织再生的多糖腻子配方

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案的广泛、长期目标是增强纤维素基生物材料的实用性通过开发和评估解决当前局限性的新型创新复合材料来修复组织。细菌纤维素水凝胶和细胞外基质在以下方面表现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特性所需的骨修复等特定应用，并且存储、处理和灭菌的选择有限。植物- 衍生纤维素醋酸酯 (CA) 形式的衍生纤维素能够产生机械性能多孔支架可有效促进骨再生。然而，具有规定尺寸的预制 CA 支架，形状和孔隙特性对适应复杂的骨缺损提出了挑战。另外，相对纤维素/CA 的缓慢降解速度会限制其控制因子释放和愈合骨骼的能力。结合CA 邻苯二甲酸酯 (CAP) 和纳米粘土 (NC) 的组合有可能解决其中一些弱点。这纤维素基复合材料形成腻子，可以模制成复杂的形状，并且随着它的形成而变得坚固变硬，使其能够适应不同的骨缺损。在生理条件下，CAP 在降解较慢的 CA 基质，实现生成互连孔和可调的动态系统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具有不同作用的生物活性因子：在CA内用于早期、持续释放；在 CAP 内进行脉冲释放；和/或进入嵌入 CA/CAP 内的 NC 中，以实现延迟、持续释放。这也使得因素得以释放并行和/或顺序。这种纤维素生物材料的详细、长期的体外和体内表征，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，仍然推进这一变革性天然生物材料平台的知识差距。根据现有知识，据推测，这种动态纤维素基腻子将带来与成分相关的强度变化 3D 微环境中的侵蚀和侵蚀导致不同的生物活性因子释放速率、脉管系统发育、以及骨修复过程中的组织向内生长。这将在四个具体目标中进行测试：目标 1：表征新型纤维素衍生物和组合物的体外理化和释放特性。目标 2：评估体内皮下植入模型中释放分子的生物相容性和生物活性。目标 3：评估具有早期到长期释放曲线的腻子配方对颅骨扁平骨愈合的细胞影响缺点。目标 4：评估油灰配方的早期至长期释放曲线对骨愈合的影响兔尺骨临界尺寸长骨缺损的承载部位。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。如果这种赋能腻子技术成功的话，可能会对该领域具有变革意义，并适应骨骼的其他修复挑战以及生物医学涂层植入物。