Erythromycin-doped nanofiber coating to increase implant longevity

掺红霉素的纳米纤维涂层可延长植入物的使用寿命

• 批准号: 9294197
• 负责人: WEIPING REN
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294197
• 关键词: Adhesions; Anti-Bacterial Agents; Antibiotics; Architecture; Biological; Blood; Bone Marrow; Bone Matrix; Caliber; Cell Adhesion; Clinical; Collagen Type I; Complication; Cultured Cells; Data; Differentiation and Growth; Dimensions; Disease; Elderly; Encapsulated; Erythromycin; FDA approved; Failure; Family suidae; Fiber; Formulation; Glycolic-Lactic Acid Polyester; Goals; Growth; Health Status; Healthcare; Hydroxyapatites; Implant; In Vitro; Incidence; Infection; Infection prevention; Longevity; Measures; Mechanics; Medical Device; Mental Health; Microbial Biofilms; Modeling; Morphology; Nature; Operative Surgical Procedures; Orthopedics; Osseointegration; Osteoblasts; Osteoclasts; Osteogenesis; Pain; Patients; Pharmaceutical Preparations; Physiology; Polymers; Polyvinyl Alcohol; Population; Preparation; Property; Quality of life; Rattus; Recovery of Function; Rehabilitation therapy; Replacement Arthroplasty; Research; Sampling; Savings; Services; Shapes; Solid; Staphylococcus aureus; Stromal Cells; Surface; System; Testing; Time; Titanium; Ursidae Family; Veterans; Work; X-Ray Computed Tomography; bactericide; base; biomaterial compatibility; bone; bone healing; compare effectiveness; controlled release; cost; expectation; experience; experimental study; high risk; hydrophilicity; implant coating; implantation; improved; in vivo; innovation; joint injury; mechanical behavior; nanofiber; nanoscale; osteogenic; physical conditioning; prevent; response; retinal rods; sample fixation; success; tibia

Failure of osseointegration (direct anchorage of an implant by bone formation at the bone-implant surface) and implant infection are the two main causes of implant failure and loosening. There is an urgent need for orthopedic implants that both promote rapid osseointegration and prevent bacterial colonization, particularly when placed in bone compromised by disease or the physiology of the patients. The goal of this study is to develop a bactericidal “bone-like” nanofiber (NF) coating to enhance osseointegration while preventing implant infection. To imitate the architecture of the natural bone matrix, we developed coaxial electrospun NFs composed of poly (lactide-co-glycolide) (PLGA) and polyvinyl alcohol (PVA) polymers arranged in a core- sheath configuration. PLGA is a FDA-approved co-polymer with long clinical experience as a carrier for sustained drug release. Type I collagen (Col) was embedded in the PLGA to form a bioactive PLGACol sheath fiber. PVA has a good fiber-forming capability and will be used to encapsulate nanoscale hydroxyapatite (HA) to form a hydrophilic PVAHA core fiber. The PLGACol/PVAHA NFs are biocompatible and biodegradable with appropriate fiber diameter, pore size and mechanical strength, leading to enhanced cell adhesion, proliferation and differentiation of bone marrow stromal cells (BMSCs). In the proposed study, we will embed erythromycin (EM, bactericidal and anti-osteoclastic) into PLGACol/PVAHA NFs. We hypothesize that NFs will mimic the biological, structural and mechanical behaviors of natural bone, and enhance the adhesion, growth and differentiation of BMSCs. We propose that the embedding of EM in the PLGACol/PVAHA NFs will inhibit bacterial colonization and promote implant osseointegration because of its stimulatory activity of bone healing. We will test our hypothesis by pursuing three Aims: Aim 1: Develop an optimal PLGACol/PVAHA NF formulation for titanium (Ti) implant coating: (a) Define an optimal NF formulation based on the cellular response (viability, proliferation and osteogenic differentiation of rat BMSCs, and (b) Further optimize the bonding strength of NF coating to the Ti implant in an ex vivo porcine bone implantation model; Aim 2: Characterize the effects of EM doping of PLGACol/PVAHA NFs on the cellular response, bacterial growth and biofilm formation in vitro. We propose that EM doping will change the physiochemical nature of NFs (morphology, surface topology, degradation, mechanical strength and EM release dynamics, Aim 2a), which will impact on the cellular response (viability, proliferation and osteogenic differentiation of rat BMSCs, Aim 2b), and bacterial growth and biofilm formation (adhesion, viability and biofilm formation of Staphylococcus aureus, S. aureus, Aim 2c), and Aim 3: Determine the effects of EM doping of PLGACol/PVAHANFs on infection inhibition and osseointegration in a rat S. aureus- infected tibia implantation model. We will determine whether the EM-NF coating is sufficient to inhibit implant infection (bacterial culture, biofilm formation) and enhance osseointegration (pullout test, bone histomorphometry, and micro computed tomography, CT). We expect that a sustained release of EM from NF coating will inhibit implant infection and further promote osseointegration due to its proven osteogenic and bactericidal activities. The proposed work is innovative, because it capitalizes on a new strategy of implant surface fabrication by providing a “bone-like” nanoscale topology and a reservoir of controllable sustained drug release. It is our expectation that the resultant approach will provide solid evidence favoring the advantages of the proposed NF coated medical devices over those currently available. These results will be significant, because they are expected to improve the success of total joint replacement and increase implant longevity. It should not appreciably increase the cost of the implant. This will improve the quality of life for these patients and provide a significant healthcare savings.

骨整合失败（通过骨种植体表面的骨形成直接锚定种植体） 种植体感染和种植体感染是种植体失败和松动的两个主要原因，迫切需要种植体修复。 既能促进快速骨整合又能防止细菌定植的骨科植入物，特别是 当放置在因疾病或患者生理机能受损的骨骼中时。 开发一种杀菌“类骨”纳米纤维（NF）涂层，以增强骨整合，同时防止 为了模仿天然骨基质的结构，我们开发了同轴静电纺丝纳米纤维。 由排列在核心中的聚丙交酯乙交酯 (PLGA) 和聚乙烯醇 (PVA) 聚合物组成 PLGA 是 FDA 批准的共聚物，作为载体具有长期的临床经验。 I型胶原蛋白（Col）嵌入PLGA中，形成具有生物活性的PLGACol鞘。 PVA具有良好的成纤能力，将用于封装纳米级羟基磷灰石（HA）。 形成亲水性 PVAHA 芯纤维，PLGACol/PVAHA NF 具有生物相容性和可生物降解性。 适当的纤维直径、孔径和机械强度，导致细胞粘附、增殖增强 在拟议的研究中，我们将嵌入红霉素。 （EM、杀菌和抗破骨）到 PLGACol/PVAHA NF 中，我们认为 NF 会模仿 PLGACol/PVAHA NF。 天然骨的生物、结构和机械行为，并增强粘附、生长和 我们认为将 EM 嵌入 PLGACol/PVAHA NF 中会抑制 BMSC 的分化。 由于其刺激骨愈合的活性，可以抑制细菌定植并促进种植体骨整合。 我们将通过追求三个目标来检验我们的假设： 目标 1：开发最佳的 PLGACol/PVAHA NF 钛 (Ti) 植入物涂层的配方：(a) 根据细胞定义最佳 NF 配方 反应（大鼠 BMSC 的活力、增殖和成骨分化，以及（b）进一步优化 离体猪骨植入模型中 NF 涂层与钛植入物的结合强度；目标 2： 表征 PLGACol/PVAHA NF 的 EM 掺杂对细胞反应、细菌生长的影响 我们认为 EM 掺杂将改变 NF 的理化性质。 （形态、表面拓扑、降解、机械强度和电磁释放动力学，目标 2a），其中 将影响细胞反应（大鼠 BMSC 的活力、增殖和成骨分化，目标 2b）， 细菌生长和生物膜形成（金黄色葡萄球菌的粘附、活力和生物膜形成， 金黄色葡萄球菌，目标 2c) 和目标 3：确定 PLGACol/PVAHANF 的 EM 掺杂对感染的影响 我们将确定大鼠金黄色葡萄球菌感染的胫骨植入模型中的抑制和骨整合。 EM-NF 涂层是否足以抑制种植体感染（细菌培养、生物膜形成）以及 增强骨整合（拔出试验、骨组织形态计量学和显微计算机断层扫描 (CT)）。 预计 NF 涂层持续释放的 EM 将抑制种植体感染并进一步促进 由于其已被证明的成骨和杀菌活性而具有骨整合作用。 所提出的工作具有创新性，因为它利用了种植体表面制造的新策略 通过提供“骨状”纳米级拓扑结构和可控持续药物释放的储存库，这就是我们的。 期望由此产生的方法将提供有利于所提议的优点的坚实证据 与现有的 NF 涂层医疗设备相比，这些结果将意义重大，因为它们是 预期可以提高全关节置换术的成功率并延长植入物的寿命。 明显增加植入物的成本，这将改善这些患者的生活质量并提供治疗。 节省大量医疗费用。