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

 描述（由申请人提供）：出生缺陷或创伤导致的大型颅骨和面部骨缺损的影响可能导致破坏性的功能障碍和身体变化，但颅颌面（CMF）重建是骨再生最具挑战性的领域之一。它需要调节修复，导致骨组织再生，同时保持或重现面部结构，并使适应性生长重塑儿科病例。目前的方法依赖于患者或供体骨的使用，并且存在骨可用性不足、骨供体部位的发病率或供体骨的不相容性的问题。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合成或混合材料通常缺乏使新组织成形为面部轮廓的机械性能或适形性，或者缺乏以有助于产生新骨组织的速率可控地释放生物活性剂的能力。调节患者的天然干细胞分化成骨并使骨组织血管化的生长因子的释放为该领域提供了巨大的潜力，但大多数现有系统用作以大剂量释放蛋白质的储库，并且需要异常高的负载。结果是由于从感兴趣的局部区域清除了大部分蛋白质而大大降低了功效，并且由于因子的大量全身暴露而存在不期望的副作用的风险。在这项工作中，我们试图从可降解支架中以生理学上合适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，并实现新骨和天然骨的完全整合。这种方法不需要来自患者或供体的干细胞的共植入，这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。在所提出的工作中，我们使用模块化的无细胞系统，该系统将机械支架的特性与生物活性释放系统隔离。携带活性生长因子的纳米级静电层被用于涂覆多孔可降解聚合物膜，所述活性生长因子在容易适应的时间尺度上聚集以重现伤口愈合级联并诱导快速骨修复。支架的刚性或柔性可以通过选择下面的聚合物基底来调整。生长因子和活性剂从纳米层涂层洗脱，所述纳米层涂层是薄的、良好粘附的并且与基底的特征高度共形。因为从这些系统释放缓慢但持续，清除是有限的，少量的生长因子可用于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，然后是骨诱导因子。我们研究了这种方法的潜力，并评估它与大鼠下颌骨缺损模型作为一个可调的，现成的，无细胞的选择颅颌面骨组织修复和恢复。

 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.