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

 描述(申请人提供)：出生缺陷或创伤造成的巨大颅面部骨缺损可导致破坏性的功能损害和生理变化，但颅颌面(CMF)重建是骨再生最具挑战性的领域之一。它需要有规律的修复，导致骨组织再生，同时保持或重塑面部结构，并在儿科病例中实现适应性生长重塑。目前的方法依赖于患者或供体骨的使用，存在骨可获得性不足、骨供体部位的发病率或供体骨不相容的问题。在合理的时间范围内获得健康、高度血管化和发育良好的骨组织的能力仍然有限。设计用于骨再生的新型合成或混合材料通常缺乏机械性能或整形新组织以适应面部轮廓的能力，也缺乏以有助于产生新骨组织的速度可控地释放生物活性物质的能力。生长因子的释放调节患者的天然干细胞向骨的分化，并使骨组织的血管形成为这一领域提供了巨大的潜力，但大多数现有的系统作为仓库，以大剂量释放蛋白质，需要异常高的负荷。其结果是，由于从感兴趣的局部区域清除了大部分蛋白质，导致疗效大大降低，以及因大量系统性暴露这些因子而产生不良副作用的风险。在这项工作中，我们试图以生理上合适的剂量从可降解的支架中释放这些有效的生物活性物质，将天然骨前体细胞招募到愈合部位，实现新骨和天然骨的完全整合。这种方法不需要患者或捐赠者的干细胞共植入，这可能需要痛苦和昂贵的骨髓提取，并取决于患者或捐赠者的健康、可用性和/或兼容性。在拟议的工作中，我们使用了一个模块化的无细胞系统，将机械支架的特性与生物活性释放系统隔离开来。携带活性生长因子的纳米静电层可在易于适应的时间尺度上洗脱，以重现伤口愈合级联反应并诱导快速骨修复，用于覆盖多孔性可降解聚合物膜。支架的刚性或柔韧性可以通过选择底层聚合物基材进行调整。生长因子和活性物质从纳米层状涂层中洗脱出来，该涂层薄，附着力好，与衬底的特征高度适形。由于从这些系统释放缓慢但持续，清除是有限的，少量的生长因子可以用来诱导显著增加骨形成。该系统是模块化的，能够加入具有不同释放特性的单一或双生长因子，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，并用大鼠下颌骨缺损模型评估了它作为一种可调的、现成的、无细胞的颅颌面骨组织修复和修复的选择。

 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.