Nanostructured degradable bone cement for delivering novel antibiotics

用于输送新型抗生素的纳米结构可降解骨水泥

• 批准号: 10717850
• 负责人: Hae Lin Jang
• 金额: $ 69.78万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717850
• 关键词: Address; American; Amputation; Anti-Bacterial Agents; Antibiotics; Area; Bacteria; Bacterial DNA; Binding; Binding Sites; Biochemistry; Biomedical Engineering; Bone Cements; Bone Regeneration; Bone Tissue; Cementation; Chemicals; Chronic; Clinical; Computer-Aided Design; DNA Gyrase; Data; Debridement; Defect; Derivation procedure; Development; Devices; Diabetes Mellitus; Diabetic Foot; Disease; Divalent Cations; Drug resistance; Effectiveness; Electrons; Engineering; Evolution; Excision; Experimental Designs; Formulation; Goals; Health; Heel; Hospitals; Human; Hydroxyapatites; Impairment; Implant; In Vitro; Incidence; Infection; Injectable; Local Therapy; Maintenance; Medical; Methods; Microbial Biofilms; Minerals; Modeling; Mutate; Nanostructures; Natural regeneration; Nature; Necrosis; Operative Surgical Procedures; Orthopedic Surgery; Orthopedics; Osteogenesis; Osteomyelitis; Outcome; Pain; Patient Admission; Patients; Penetration; Pharmaceutical Preparations; Polymethyl Methacrylate; Population; Predisposition; Prevalence; Process; Quality of life; Quinolones; Recording of previous events; Recovery; Regenerative capacity; Research; Resistance; Resistance development; Risk; Site; Skeleton; Surface; System; Testing; Toxic effect; Toxicology; Treatment Efficacy; Vertebral column; angiogenesis; antibiotic design; bacterial resistance; bactericide; biomaterial compatibility; bone; bone loss; chronic infection; diabetic; diabetic patient; diabetic rat; drug release profile; efficacy testing; improved; in silico; in vivo; in vivo Model; innovation; mechanical properties; monomer; nanoparticle; next generation; novel; pharmacophore; rational design; regenerative; resistant strain; screening; synergism; systemic toxicity

PROJECT SUMMARY The prevalence of diabetes has rapidly risen during the last decades at an alarming rate, and more than 54.9 million Americans (15.3% of the population) are predicted to suffer from diabetes by 2030. Diabetic patients are highly susceptible to bone infections (osteomyelitis) and have poor bone regeneration capacity, placing them at a risk of amputations that dramatically impacts the quality of life. Even though osteomyelitis is one of the oldest diseases in human history, the existing medical approach to treat infected bone still has serious limitations while encountering new challenges. The effectiveness of the current treatment approach of debridement of the bone followed by antibiotics application is critically limited by (a) the formation of strongly assembled bacteria (biofilm) that are difficult to remove, (b) evolution of bacterial resistance to existing antibiotics, and (3) non-degradability of polymethylmethacrylate (PMMA) bone cement, which is used to locally deliver antibiotics but requires additional surgery to remove it afterward and is bioinert with potential toxicity of unreacted monomers. Therefore, there is a significant unmet medical need for the development of a next-generation antibiotic and an advanced antibiotic delivering system that can effectively cure the infection and improve the recovery of bone tissue. To solve this important problem, in this project, we aim to develop an innovative drug-device combination based on a novel dual-targeting antibiotic that can effectively retard bacteria resistance and an advanced biodegradable nanostructured bone cement that can induce a sustained release of antibiotics and enhance bone regeneration. We propose (1) to use whitlockite (WH) nanoparticles to develop a next-generation biodegradable bone cement, leveraging the excellent bone regeneration capacity and biodegradability of WH nanoparticles. WH also has a highly functionalized surface and can form nanostructured cement that can provide a large binding site for antibiotics; (2) to rationally develop next-generation antibiotics to have enhanced bactericidal capacity and compatible with our new degradable bone cement via computer-aided design and multiple screening processes. This is a significant advance from currently used antibiotics, which were originally never developed for bone infection or delivery from bone cement. We have already demonstrated that our preliminary model of dual-action antibiotics can significantly retard the evolution of bacterial resistance and is effective against biofilms; and (3) to validate the therapeutic efficacy of our dual-targeting antibiotic-impregnated WH bone cement in a diabetic osteomyelitis model in vivo by evaluating bone regeneration rate and conducting a comprehensive toxicological test. We envisage that this project will generate the first rationally designed antibiotic-delivering biodegradable cement that can treat biofilms, overcome drug resistance and regenerate the bone, thereby addressing a major clinical need. This research will also be beneficial for inhibiting infections in general orthopedic surgeries and thus, can lead to a paradigm shift in the treatment of bone infection.

项目概要 过去几十年来，糖尿病患病率以惊人的速度迅速上升，超过 54.9 预计到 2030 年，将有 100 万美国人（占总人口的 15.3%）患有糖尿病。糖尿病患者 极易受到骨感染（骨髓炎）且骨再生能力差，使他们处于 严重影响生活质量的截肢风险。尽管骨髓炎是最古老的疾病之一 人类历史上的疾病中，现有治疗骨感染的医学方法仍然存在严重的局限性 遇到新的挑战。目前骨清创治疗方法的有效性 其次，抗生素的应用受到以下因素的严重限制：(a) 强组装细菌（生物膜）的形成 难以去除，(b) 细菌对现有抗生素耐药性的进化，以及 (3) 不可降解性 聚甲基丙烯酸甲酯 (PMMA) 骨水泥，用于局部输送抗生素，但需要 随后需要进行额外的手术将其去除，并且具有生物惰性，未反应的单体具有潜在毒性。所以， 开发下一代抗生素和先进药物的医疗需求尚未得到满足 抗生素输送系统可以有效治愈感染并促进骨组织的恢复。 为了解决这个重要问题，在这个项目中，我们的目标是开发一种基于创新的药物-设备组合 研究一种新型双靶向抗生素，可有效延缓细菌耐药性和先进的可生物降解 纳米结构骨水泥可以诱导抗生素持续释放并增强骨再生。 我们建议（1）使用辉石（WH）纳米颗粒开发下一代可生物降解骨水泥， 利用WH纳米颗粒优异的骨再生能力和生物降解性。 WH还有​​一个 高度功能化的表面，可以形成纳米结构的水泥，可以为 抗生素； (2)合理开发新一代抗生素，增强杀菌能力 通过计算机辅助设计和多重筛选流程，与我们新型可降解骨水泥兼容。 与目前使用的抗生素相比，这是一个重大进步，抗生素最初从未针对骨骼开发 感染或骨水泥输送。我们已经证明了我们的双作用初步模型 抗生素可以显着延缓细菌耐药性的进化，并且对生物膜有效；和（3） 验证我们的双靶向抗生素浸渍 WH 骨水泥对糖尿病患者的治疗效果 通过评估骨再生率并进行全面的毒理学研究建立体内骨髓炎模型 测试。我们预计该项目将产生第一个设计合理、可生物降解的抗生素递送药物 可以治疗生物膜、克服耐药性和再生骨骼的水泥，从而解决主要问题 临床需要。这项研究也将有利于抑制普通骨科手术和 因此，可以导致骨感染治疗的范式转变。