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

环境响应型逐层涂层，用于按需输送治疗性生长因子和抗生素，以修复颅颌面骨缺损

• 批准号: 9927495
• 负责人: John Robert Martin
• 金额: $ 1.48万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2020-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927495
• 关键词: Address; Alkynes; Amines; Antibiotics; Area; Bacteria; Bacterial Infections; Biocompatible Coated Materials; Biocompatible Materials; Biological; Birth trauma; Bone Growth; Bone Injury; Bone Regeneration; Bone remodeling; Calvaria; Cations; Cells; Chemistry; Complex; Congenital Abnormality; Defect; Drug Delivery Systems; Electrostatics; Engineering; Enzymes; Evaluation; Exhibits; Face; Facial Injuries; Family; Fibrinogen; Filler; Film; Flare; Fostering; Gentamicins; Growth; Growth Factor; Hydrolysis; Implant; In Vitro; Infection; Injury; Jaw; Mandible; Matrix Metalloproteinases; Measures; Mediating; Modeling; Operative Surgical Procedures; Peptides; Pharmaceutical Preparations; Physiological; Polymers; Process; Proteins; Rattus; Reactive Oxygen Species; Recovery; Regenerative Medicine; Series; Signal Transduction; Staphylococcus aureus infection; Structure; System; Therapeutic; Toxic effect; Traumatic injury; Treatment outcome; Work; base; biodegradable polymer; bone; bone healing; bone morphogenetic protein 2; bone morphogenic protein; catalyst; craniomaxillofacial; crosslink; cytotoxicity; density; drug release kinetics; face bone structure; healing; implant material; improved; in vivo; monomer; oxidation; reconstruction; regenerative; release factor; repaired; response; scaffold; tissue regeneration; tissue repair

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.

需要进行颅骨颌面（CMF）手术，以解决先天性的先天缺陷和创伤性伤害 脸和下巴。 CMF重建是骨骼再生最挑战的领域之一，因为它需要 调制修复，导致组织再生，同时维持或概括面部结构。而且， 这些面部骨骼重建通常患有细菌感染，使愈合过程停滞不前。许多 暴露于降解性和最小毒性的不同聚合物支架材料已开发为 骨骼空隙填充剂以促进大CMF骨缺陷的组织再生，但通常这些材料不会 内在促进新的骨骼生长或预防感染。为此，聚合物脚手架覆盖了 与聚电解质聚合物的逐层静电（LBL）组件，促愈合生长因子蛋白， 并且已经开发了可以增强骨再生的抗生素。但是，当前的聚电解质 - 基于非特异性水解的基于基于的构建体是为了降低的，并且对速率具有最小的响应性 组织修复和骨再生或细菌感染。因此，需要LBL系统 在骨骼愈合过程的整个生命周期中，更好地提供疗法，可以响应差异治疗 细菌感染的发生率和爆发。该项目旨在开发包含的生物材料工具 负载的，具有环境响应的LBL纳米膜，将有选择地将药物有效载荷释放到 在受感染的，严重的CMF骨缺陷中产生更强大的愈合反应。细胞响应 结构可以选择性地释放促愈合疗法，以应对新的组织生长或感染，从而 创建一个材料脚手架系统，该系统可以“按需”提供修复性药物。可以预测更多 专门控制植入材料中治疗分子的释放将延长有效 药物输送窗口仅通过保存药物为止，直到需要，从而提高了相对效率 体内治疗。因此，通过细胞生成的活性氧特异性降解的LBL涂层 物种（ROS）和基质金属蛋白酶（MMP）酶，都与骨骼愈合相关的信号 创建的是专门释放亲治疗增长因子以改善CMF损伤的愈合。一旦这些 响应式生长因子释放系统优化，它们将与含抗生素的LBL结合 选择性地释放其针对细菌感染的药物有效载荷的涂层。预计这项工作将 建立一个有效的平台来促进LBL系统中的细胞介导的药物输送，并有可能 改善CMF修复和各种再生医学应用中的治疗结果。