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.

项目摘要 在过去的几十年中，糖尿病的患病率迅速增长，以惊人的速度和超过54.9 预计到2030年，有百万美国人（占人口的15.3％）患有糖尿病。糖尿病患者是 高度容易受到骨骼感染（骨髓炎）的影响，骨骼再生能力差，将其放置在 截肢的风险极大地影响了生活质量。即使骨髓炎是最古老的 人类历史上的疾病，现有的治疗感染骨骼的医学方法仍然存在严重的局限性 遇到新的挑战。当前骨骼清创术的治疗方法的有效性 其次是抗生素的应用受到（a）形成强烈组装细菌（生物膜）的严重限制 很难去除，（b）细菌对现有抗生素的耐药性的进化，以及（3）不可降解性 聚合甲基丙烯酸酯（PMMA）骨水泥的含量，用于局部提供抗生素，但需要 此后的其他手术将其去除，并具有未反应单体潜在毒性的生物渗透剂。所以， 对于下一代抗生素的开发和先进的医疗需求很大 可以有效治愈感染并改善骨组织的恢复的抗生素输送系统。 为了解决这个重要的问题，在这个项目中，我们旨在开发基于创新的药物设备组合 在一种新型的双靶向抗生素上，可以有效地阻碍细菌耐药性和晚期生物降解 纳米结构的骨水泥可以诱导持续释放抗生素并增强骨骼再生。 我们建议（1）使用Whitloctite（WH）纳米颗粒来发展下一代可生物降解的骨水泥， 利用WH纳米颗粒的出色骨再生能力和生物降解性。 WH也有一个 高度功能化的表面，可以形成纳米结构水泥，可以为 抗生素； （2）合理发展下一代抗生素以增强杀菌能力和 通过计算机辅助设计和多个筛选过程，与我们新的可降解骨水泥兼容。 这是当前使用的抗生素的重大进展，最初从未为骨骼开发 感染或从骨水泥传递。我们已经证明了我们的双重动作初步模型 抗生素可以显着阻碍细菌耐药性的演变，并有效地抵抗生物膜。 （3） 在糖尿病患者中验证我们的双靶向抗生素浸渍的WH骨水泥的治疗功效 骨髓炎模型在体内通过评估骨再生率并进行全面的毒理学 测试。我们设想该项目将产生第一个合理设计的抗生素降解的可生物降解 可以治疗生物膜，克服耐药性并再生骨骼的水泥，从而解决了一个主要 临床需求。这项研究也将有助于抑制一般骨科手术的感染和 因此，可以导致骨骼感染治疗的范式转移。