“pH值响应式抗生素智能控释”多级孔氧化硅/碳纤维复合材料的研发及在关节假体周围感染翻修中的应用研究

Periprosthetic joint infection remains one of the leading causes of revision following hip or knee arthroplasty. The two-stage revision procedure is currently the “gold standard” for the treatment of prosthetic joint infections. However, the re-infection rate after two-stage revision has been reported to be as high as 25%. .The antibiotic-loaded cement spacer plays a critical role in the eradication of bacteria in the two-stage revision, since the bacteria embedded in the biofilm require up to 1000-fold of minimal inhibitory concentration (MIC) of antibiotic for elimination, which usually is inaccessible for systemic antibiotic therapy, and theoretically can only be achieved by local delivery of the antibiotic. However, the antibiotic-loaded cement spacer has lots of disadvantages, such as less than 10% of the loaded antibiotics can be released from the spacer in most cases; the antibiotic shows “burst” release after implantation, which lasts for only several hours and can not maintain sufficient antimicrobial concentration for long enough duration for the eradication of infection; even worse, the bacteria can colonize on the surface of spacer after local antimicrobial levels have fallen below the therapeutic level. The above defects of the antibiotic-loaded cement spacer may be the major causes for the failure of the two-stage revision..Targeting at the above problems, the current research will utilize the cutting-edge technologies in the relevant areas, to develop a new intelligent hybrid biomaterial—“hierarchical porous silica/ carbon fibre” with the function of “pH-responsive controlled release of antibiotic”. The new material has the following advantages:Ⅰ) The material can be loaded with large volume of antibiotics, continuously release the antibiotics and maintain the effective antimicrobial concentration for more than 4 weeks to eradicate the residual bacteria; Ⅱ) The material can accurately sense the change of pH value of the local environment. Under normal physiological environment, the material does not release antibiotics and serve as “storage depot” of the antibiotics. When the pH value of the environment dramatically decreases to around 6 due to the bacterial infections, the material will start continuously releasing antibiotics, until the bacteria completely disappear; Ⅲ) Besides to serve as spacers for the two-stage revision, the material can also be made as porous absorbable bone substitute material with intelligent anti-infection function, which could be used to fill bone defects with osteomylitis.

二期翻修术目前是治疗关节假体周围感染的“金标准”，但术后再感染率可达25%。二期翻修术的核心环节--抗生素骨水泥间隔物的以下缺陷可能是导致翻修失败的重要原因：载药量小；仅不到10%的抗生素可被释放；爆发性释放，不能维持有效杀菌浓度和时间，难以杀灭残留菌；一次性释放，且无论有无细菌均释放抗生素，无法对抗迟发感染。针对该问题，本研究将利用国际前沿进展，研发新型“pH值响应式抗生素智能控释”多级孔氧化硅/碳纤维骨科生物材料，具有以下优势：1）载药量倍增，并可持续释放有效浓度抗生素4周以上，彻底杀灭残留菌；2）可准确感知环境酸碱状态，正常生理环境下材料作为储存抗生素的“药库”不释放抗生素，当环境pH值因细菌感染而出现降低时才大量释放抗生素，直至细菌彻底消失，可有效对抗迟发感染；3）除可制备成具有一定强度的间隔物用于二期翻修，也可制成具有智能抗感染能力的可吸收骨替代材料，实现感染环境下骨缺损的修复。

二期翻修术目前是治疗关节假体周围感染的“金标准”，但术后再感染率可达25%。 二期翻修术的核心环节--抗生素骨水泥间隔物的以下缺陷可能是导致翻修失败的重要原因:载药量小，仅不到10%的抗生素可被释放;爆发性释放，不能维持有效杀菌浓度和时间，难以杀灭残留菌；一次性释放，且无论有无细菌均释放抗生素，无法对抗迟发感染。针对该问题本研究基于介孔二氧化硅纳米材料(Mesoporous silica nanoparticle，MSN)的靶向骨组织和靶向细菌的纳米生物材料，使得抗生素在假体周围有效大量持续释放，达到治疗假体周围感染；同时研究了小分子非甾体类抗炎药药物（氟芬那酸）在细菌感染中的应用及细菌感染对骨量和骨生物力学影响。本课题体通过合成具有细菌靶向、骨靶向和pH响应的尺寸可控的介孔氧化硅纳米颗粒然后药物负载，体外体内研究了MSN载药、细菌靶向与骨靶向修饰及其在治疗假体周围感染中的性能。研究表明骨与细菌双靶向MSN体外具有很好地生物相容性和细菌及骨靶向性，体外负载万古霉素包封率为46±2.3%，载药量为48±3.4%，体外可以达到一周的可控释放。体外抗菌实验表明双靶向介孔二氧化硅纳米材料具有优异的细菌清除能力和抑制生物膜形成。体内假体周围感染治疗实验，相比单纯万古霉素，双靶向介孔纳米材料负载万古霉素在治疗植入物相关感染效果较好。因此我们体外构建了一个细菌与骨双靶向的介孔二氧化硅纳米载体，能很的负载万古霉素并靶向假体周围感染部位，在感染部位持续释放万古霉素，有效治疗假体周围感染。在药物治疗假体周围感染方面我们课题组研究出氟芬那酸能够有效抑制耐药金葡菌感染。实验证明，氟芬那酸可以显著抑制耐甲氧西林金葡菌的生长，破坏细菌壁的超微结构，并恢复耐药菌对传统β-内酰胺类抗生素的敏感性。同时高浓度的葡萄球菌相比于无菌性骨溶解，会导致了更低的骨量和骨生物力学特性，因此，在翻修手术的围手术期，更需要预防微骨折的发生。研究成果有望对假体周围感染的治疗提供理论依据和新手段。