Nanostructured degradable bone cement for delivering novel antibiotics

项目总结 在过去的几十年里，糖尿病的患病率以惊人的速度迅速上升，超过54.9 到2030年，预计将有100万美国人(占总人口的15.3%)患有糖尿病。糖尿病患者 对骨感染(骨髓炎)高度敏感，骨再生能力差，将他们安置在 截肢的风险极大地影响了生活质量。尽管骨髓炎是最古老的 在人类历史上，现有的治疗感染骨骼的医学方法仍然有严重的局限性 遇到新的挑战。当前骨清理术治疗方法的有效性 其次是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 (B)细菌对现有抗生素的抗药性的进化；(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 之后进行额外的手术将其移除，并且是生物惰性的，具有未反应单体的潜在毒性。因此， 开发下一代抗生素和先进的抗生素有着巨大的未得到满足的医学需求 抗生素输送系统，能有效治愈感染，促进骨组织恢复。 为了解决这一重要问题，在本项目中，我们的目标是开发一种创新的药物-装置组合 一种新型有效延缓细菌耐药性的双靶向抗生素和一种先进的可生物降解的抗生素 纳米骨水泥可以诱导抗生素的持续释放，并增强骨再生。 我们建议(1)使用白锁石(WH)纳米颗粒来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。万洲国际也有一个 高度功能化的表面，并可以形成纳米结构的水泥，可以提供大量的结合部位 (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种筛选过程，与我们的新型可降解骨水泥兼容。 与目前使用的抗生素相比，这是一个重大的进步，这些抗生素最初从未被开发用于骨骼 感染或从骨水泥中分娩。我们已经证明了我们的双重作用的初步模型 抗生素可显著延缓细菌耐药性的演变，对生物被膜有效；及 验证我们的双靶向抗生素植入的WH骨水泥治疗糖尿病的疗效 评价骨再生率并进行综合毒理学研究的体内骨髓炎模型 测试。我们预计，这个项目将产生第一个合理设计的抗生素--提供可生物降解的 可以治疗生物膜、克服抗药性和再生骨骼的水泥，从而解决主要的 临床需要。这项研究也将有利于抑制普通骨科手术中的感染和 因此，可以导致骨感染治疗的范式转变。

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.