Tunable Nanolayer-Polymer Composite Patches for Cell-Free CMF Repair

用于无细胞 CMF 修复的可调节纳米层-聚合物复合贴片

• 批准号: 9978810
• 负责人: Paula T Hammond
• 金额: $ 54.03万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2023-01-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978810
• 关键词: 3-Dimensional; Accidents; Address; Angiogenic Factor; Area; Behavior; Birth trauma; Blood Vessels; Bolus Infusion; Bone Marrow; Bone Regeneration; Bone Resorption; Bone Tissue; Bone Transplantation; Calvaria; Cell Differentiation process; Cell Proliferation; Cell-Free System; Cells; Cephalic; Characteristics; Child; Childhood; Clinic; Congenital Abnormality; DNA; Defect; Deformity; Development; Dose; Electrostatics; Evaluation; Face; Film; Formulation; Generations; Gold; Growth; Growth Factor; Harvest; Head Cancer; Head and Neck Cancer; Health; Hybrids; Hydrogels; Implant; In Vitro; Jaw; Lead; Lesion; Mandible; Maxilla; Membrane; Minerals; Modeling; Morbidity - disease rate; Natural regeneration; Operative Surgical Procedures; Oryctolagus cuniculus; Osteogenesis; Outcome; Pain; Pathologic; Patients; Physiological; Plasmids; Platelet-Derived Growth Factor; Polymers; Pre-Clinical Model; Procedures; Production; Proteins; Rattus; Recovery; Risk; Shapes; Site; Structure; Surface; System; Technology; Testing; Thinness; Time; Tissues; Transfection; Trauma; Traumatic injury; Vascular Endothelial Growth Factors; Vascularization; Work; angiogenesis; appropriate dose; assault; base; biodegradable polymer; bone; bone morphogenetic protein 2; calcium phosphate; clinically relevant; craniofacial; craniomaxillofacial; cranium; design; face bone structure; flexibility; functional disability; healing; implantation; in vivo; interest; mechanical properties; nanoscale; nucleic acid delivery; osteoinductive factor; precursor cell; public health relevance; reconstruction; recruit; release factor; repaired; restoration; scaffold; side effect; stem cells; tissue regeneration; tissue repair; wound healing

DESCRIPTION (provided by applicant): The impact of large cranial and facial bone defects from birth defects or trauma can result in devastating functional impairment and physical changes, yet craniomaxillofacial (CMF) reconstruction is one of the most challenging areas for bone regeneration. It requires modulated repair that leads to bone tissue regeneration while maintaining or recapitulating facial structure and enabling adaptive growth remodeling in pediatric cases. Current approaches rely on the use of patient or donor bone and present issues of insufficient bone availability, morbidity at the bone donor site, or incompatibility of donated bone. The ability to gain healthy, highly vascularized and well developed bone tissue over reasonable timeframes remains limited. New synthetic or hybrid materials designed for bone regeneration often lack either the mechanical properties or conformability to shape new tissue to the contours of the face, or the ability to controllably release bioactive agents at rates that hel generate new bone tissue. The release of growth factors that regulate the differentiation of the patient's native stem cells to bone, and enable vascularization of the bone tissue offers great potential for this area, but most existing systems act as depots that release the proteins with a large bolus and need unusually high loadings. The result is a greatly lowered efficacy due to clearance of much of the protein from the local region of interest, and the risk of undesired side effects from large systemic exposure of the factors. In this work, we seek to release these potent bioactive agents in physiologically appropriate dose levels from degradable scaffolds to recruit native bone precursor cells to the healing site, and achieve full integration of new and native bone. This approach does not require the co-implantation of stem cells from the patient or a donor, which can require painful and expensive bone marrow extraction and relies on the health, availability and/or compatibility of the patient or donor. In the proposed work, we use a modular cell-free system that isolates the properties of the mechanical scaffold from the bioactive release system. Nanoscale electrostatic layers carrying active growth factors that elute over readily adapted time scales to recapitulate the wound healing cascade and induce rapid bone repair are used to coat a porous degradable polymer membrane. The rigidity or flexibility of the scaffold can be adapted through the choice of underlying polymer substrate. Growth factors and active agents are eluted from the nanolayered coating, which is thin, well- adhered and highly conformal to the features of the substrate. Because release from these systems is slow but sustained, clearance is limited and small amounts of growth factor can be used to induce significant increases in bone formation. The system is modular, enabling the incorporation of single or dual growth factors introduced with different release characteristics, such as an angiogenic factor followed by an osteoinductive factor. We investigate the potential of this approach and evaluate it with a rat mandibular defect model as a tunable, off-the-shelf, cell-free option for craniomaxillofacial bone tissue repair and restoration.

描述（由申请人提供）：由于出生缺陷或创伤导致的大面积颅骨和面部骨缺损会导致毁灭性的功能损伤和身体变化，然而颅颌面（CMF）重建是骨再生最具挑战性的领域之一。它需要调节修复，导致骨组织再生，同时维持或再现面部结构，使儿童病例适应性生长重塑。目前的方法依赖于使用患者或供体骨，存在骨可用性不足、供体骨发病或供体骨不相容等问题。在合理的时间框架内获得健康、高度血管化和发育良好的骨组织的能力仍然有限。为骨再生设计的新合成或混合材料通常缺乏机械性能或符合面部轮廓的新组织，或者无法控制以帮助生成新骨组织的速率释放生物活性物质。生长因子的释放调节患者原生干细胞向骨的分化，并使骨组织的血管化，为这一领域提供了巨大的潜力，但大多数现有的系统都是作为大量释放蛋白质的仓库，需要异常高的负荷。结果是药效大大降低，因为大部分蛋白质从局部区域清除，以及由于大量全身暴露于这些因素而产生不良副作用的风险。在这项工作中，我们试图从可降解支架中释放这些生理上适当剂量的强效生物活性物质，以招募天然骨前体细胞到愈合部位，并实现新骨和天然骨的完全整合。这种方法不需要同时植入患者或供体的干细胞，后者可能需要痛苦且昂贵的骨髓提取，并且依赖于患者或供体的健康、可用性和/或相容性。在提出的工作中，我们使用模块化的无细胞系统，将机械支架的特性从生物活性释放系统中分离出来。纳米级静电层携带活性生长因子，在容易适应的时间尺度上洗脱以重现伤口愈合级联并诱导快速骨修复，用于覆盖多孔可降解聚合物膜。支架的刚性或柔韧性可以通过选择底层聚合物基底来调整。从纳米层涂层中洗脱出生长因子和活性物质，涂层薄，附着力好，与基底的特性高度符合。因为从这些系统中释放是缓慢但持续的，清除是有限的，少量的生长因子可以用来诱导骨形成的显著增加。该系统是模块化的，可以加入具有不同释放特性的单一或双重生长因子，例如血管生成因子和骨诱导因子。我们研究了这种方法的潜力，并通过大鼠下颌缺损模型来评估它作为颅颌面骨组织修复和修复的可调、现成的、无细胞的选择。