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: 9762080
• 负责人: Paula T Hammond
• 金额: $ 54.01万
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9762080
• 关键词: 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; Dimensions; Dose; Electrostatics; Evaluation; Face; Film; Formulation; Generations; Gold; Growth; Growth Factor; Harvest; 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; Stem cells; Structure; Surface; System; Technology; Testing; Thinness; Time; Tissues; Transfection; Trauma; Traumatic injury; Vascular Endothelial Growth Factors; Vascularization; Work; Wound Healing; 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; tissue regeneration; tissue repair

 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）：出生缺陷或创伤造成的大颅骨和面部骨缺陷的影响可能导致毁灭性的功能损伤和身体变化，而颅颌面（CMF）重建是骨再生最具挑战性的领域之一。调节修复可导致骨组织再生，同时维持或重现面部结构，并在儿科病例中实现适应性生长重塑。目前的方法依赖于使用患者或供体骨骼，并存在骨可用性不足和发病率的问题。在合理的时间内获得健康、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塑造新组织的机械性能或适形性。面部轮廓，或者以有助于生成新骨组织的速率可控地释放生物活性剂的能力，调节患者天然干细胞向骨的分化并实现骨组织的血管化的生长因子的释放提供了机会。巨大的潜力对于该区域，但大多数现有系统充当以大剂量释放蛋白质的储存库，并且需要异常高的装载量，结果是由于从局部感兴趣区域清除了大部分蛋白质以及风险而大大降低了功效。在这项工作中，我们试图从可降解支架中以生理上适当的剂量水平释放这些有效的生物活性剂，以将天然骨前体细胞招募到愈合部位，并实现新骨前体细胞和新骨前体细胞的完全整合。原生骨。该方法不需要从患者或捐赠者身上共同植入干细胞，这可能需要痛苦且昂贵的骨髓提取，并且依赖于患者或捐赠者的健康状况、可用性和/或兼容性。使用模块化无细胞系统，将机械支架的特性与生物活性释放系统隔离，该纳米级静电层携带活性生长因子，在易于适应的时间尺度上洗脱，以重现伤口愈合级联和快速诱导骨修复。多孔的可降解的聚合物膜。支架的刚性或高度柔性可以通过选择底层聚合物基质来调整。生长因子和活性剂从纳米层涂层中洗脱出来，该涂层很薄，粘附良好且与基质的特征共形。由于这些系统的释放缓慢但持续，清除率有限，并且可以使用少量的生长因子来诱导骨形成的显着增加。该系统是模块化的，能够掺入具有不同释放特性的单一或双重生长因子，例如血管生成因子其次是骨诱导因子，我们研究了这种方法的潜力，并用大鼠下颌缺损模型对其作为颅颌面骨组织修复和恢复的可调节、现成的无细胞选择进行了评估。