Environmentally-responsive, layer-by-layer coatings for the on-demand delivery of therapeutic growth factors and antibiotics to repair craniomaxillofacial bone defects

需要颅颌面(CMF)手术来处理先天性出生缺陷和创伤 脸和下巴。CMF重建是骨再生最具挑战性的领域之一，因为它需要 调节性修复，在保持或重塑面部结构的同时，导致组织再生。此外， 这些面部骨骼重建通常会受到细菌感染的影响，从而阻碍愈合过程。许多 表现出可降解性和最小毒性的不同聚合物支架材料已被开发为 骨空洞填充物能促进大块CMF骨缺损的组织再生，但总的来说这些材料不能 本质上促进新骨生长或防止感染。为此，涂覆了聚合物支架植入物 利用聚电解质聚合物的静电逐层(LBL)组件，促愈合生长因子蛋白， 可以促进骨骼再生的抗生素已经被开发出来。然而，目前的聚电解质- 基于构造的构造物被设计为通过非特定的水解来降解，并且对速率的响应最小 组织修复和骨骼再生或细菌感染。因此，需要具有以下特性的LBL系统 更好地在骨愈合过程的整个生命周期内提供治疗，并能够对差异愈合做出反应 细菌感染率和突发事件。该项目旨在开发涂有涂层的生物材料植入物 载药、环保的LBL纳米膜将选择性地将药物有效载荷释放到 在感染的、临界大小的CMF骨缺损中产生更强大的愈合反应。细胞响应性 构建物可以选择性地释放促进愈合的治疗药物，以响应新的组织生长或感染，从而 创造了一种可以按需输送修复药物的材料脚手架系统。据预测，将有更多 明确控制治疗分子从植入材料的释放将延长有效 药物传递窗口通过仅保存药物直到需要时才保存，从而提高 体内治疗。因此，由细胞产生的活性氧专门降解的LBL涂层 与骨愈合有关的物种(ROS)和基质金属蛋白酶(MMP)酶将是 专为释放促进愈合的生长因子而创建，以促进CMF损伤的愈合。一旦这些 响应性生长因子释放系统得到优化，它们将与含有抗生素的LBL结合 有选择地释放药物有效载荷以应对细菌感染的涂层。这项工作预计将 在LBL系统中建立一个有效的平台来促进细胞介导的药物传递，并有可能 在CMF修复和再生医学的各种应用中改善治疗结果。

Craniomaxillofacial (CMF) surgery is required to address congenital birth defects and traumatic injuries to the face and jaw. CMF reconstruction is one of the most challenging areas for bone regeneration, as it requires modulated repair that leads to tissue regeneration while maintaining or recapitulating facial structure. Moreover, these facial bone reconstructions often suffer from bacterial infections that stall the healing process. Many different polymeric scaffold materials that exhibit degradability and minimal toxicity have been developed as bone void fillers to promote tissue regeneration in large CMF bone defects, but in general these materials do not intrinsically promote new bone growth or protect against infection. To this end, polymeric scaffold implants coated with electrostatic layer-by-layer (LbL) assemblies of polyelectrolyte polymers, pro-healing growth factor proteins, and antibiotics that can enhance bone regeneration have been developed. However, current polyelectrolyte- based constructs are engineered to degrade by non-specific hydrolysis and are minimally-responsive to the rate of tissue repair and bone regeneration or bacterial infection. Consequently, there is a need for LbL systems that better deliver therapies over the entire lifetime of the bone healing process and can respond to differential healing rates and flare-ups of bacterial infection. This project seeks to develop biomaterial implants coated with drug-loaded, environmentally-responsive LbL nanofilms that will selectively release drug payloads to generate a more robust healing response in infected, critically-sized CMF bone defects. Cell-responsive constructs can selectively release pro-healing therapeutics in response to new tissue growth or infection, thus creating a material scaffold system that can deliver reparative drugs “on-demand”. It is predicted that more specifically controlling the release of therapeutic molecules from implanted materials will prolong the effective drug delivery window by conserving the drug only until it is needed, thereby increasing the relative efficiency of the treatment in vivo. Therefore, LbL coatings that are specifically degraded by cell-generated reactive oxygen species (ROS) and matrix metalloproteinase (MMP) enzymes, signals both associated with bone healing, will be created to specifically release pro-healing growth factors to improve the healing of CMF injuries. Once these responsive growth factor release systems are optimized, they will be combined with antibiotic-containing LbL coatings that selectively release their drug payload in response to bacterial infection. This work is anticipated to establish an effective platform for promoting cell-mediated drug delivery in LbL systems and has the potential to improve treatment outcomes in both CMF repair and across a variety of applications in regenerative medicine.