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Micrococcal nuclease-triggered antibiotics release: a prophylactic implant coating against S. aureus infections

微球菌核酸酶触发的抗生素释放：针对金黄色葡萄球菌感染的预防性植入物涂层

基本信息

批准号：
10684948
负责人：
Jie Song
金额：
$ 48.94万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10684948
关键词：
Address Animals Antibiotics Bacteria Biological Assay Bone Cements Bypass Characteristics Chemicals Clinical Debridement Detection Development Dose Engineering Ensure Evaluation Femur Goals Growth Histology Hydrogels Implant In Vitro Incubated Infection Infection prevention Injections Invaded Location Mechanics Methylation Microbial Biofilms Micrococcal Nuclease Modeling Modification Monitor Mus Nucleotides Oligonucleotides Operative Surgical Procedures Organ Orthopedic Surgery Orthopedics Osteomyelitis Pathology Pharmaceutical Preparations Predisposition Prosthesis Prosthesis-Related Infections Rattus Replacement Arthroplasty Safety Saline Second Look Surgery Serum Staphylococcus aureus Staphylococcus aureus infection Surface Surgical Models System Systemic infection Technology Testing Thick Torsion Vancomycin aspirate bioluminescence imaging bone clinical translation clinically relevant comparative efficacy cortical bone drug resistance development efficacy evaluation ethylene glycol implant associated infection implant coating improved in vivo in vivo evaluation infection rate metallicity microbial nuclease operation phosphodiester phosphorothioate prevent prophylactic recurrent infection side effect standard care success surface coating translational potential

项目摘要

PROJECT SUMMARY/ABSTRACT Periprosthetic infections is one of the most serious complications in orthopedic surgeries, occurring in 1-4% of primary total joint replacement and up to 30% of revisions. Infections caused by Staphylococcus aureus (S. aureus), the most prevalent microbial culprit in orthopedic infections, are particularly hard to treat due to their tendency to form biofilms on implant and notorious ability to invade the canalicular network of surrounding bone. Existing prophylactic antibiotic deliveries involve high drug doses that are unsafe yet ineffective and could lead to the development of drug resistance. Utilizing an oligonucleotide linker labile to S. aureus micrococcal nuclease (MN) cleavage, we recently developed a hydrogel capable of on-demand release of covalently tethered vancomycin. When applied as a hydrogel coating to Ti6Al4V intramedullary (IM) pin and inserted to mouse femoral canal inoculated with S. aureus, the MN-triggered release of vancomycin timely killed the bacterial on implant surface and within IM space before they had a chance to colonize or invade surrounding bone, thereby preventing biofilm formation and osteomyelitis development in the 3 weeks examined. The covalent tethering dose of vancomycin in this coating was orders of magnitude lower than the typical prophylactic antibiotic content used clinically. The goal of the proposed study is to further engineer this exciting on-demand drug release system to enhance its serum stability and rigorously examine its efficacy in providing sustained protection against periprosthetic infections using two clinically relevant implant infection models. In Aim 1, the oligonucleotide linker is chemically modified by selective 2'-O-methylation and phosphorothioate modifications to achieved enhanced mammalian serum nuclease stability while maintaining necessary sensitivity to MN cleavage. In Aim 2, the in vitro optimized nucleotide linker will be implemented in MN-sensitive hydrogel coating and applied to Ti6Al4V IM pins for on-demand delivery of vancomycin. The efficacy and safety of this prophylactic coating in providing timely and sustained protection against S. aureus periprosthetic infections will be rigorously evaluated over 6 months using a rat femoral canal infection model. In Aim 3, the efficacy of this on-demand antibiotic release strategy in reducing the high periprosthetic infection rates following surgical debridement of previously infected rat femoral canal will be examined using a rat IM implant revision surgery model. The degree of infections as a function of pin coating and bioluminescent S. aureus inoculation are longitudinally monitored by bioluminescent imaging and µCT quantification of cortical bone thickening at 2 weeks, 1, 2, 3 and 6 months, and by end-point quantification of bacteria on the retrieved pin, torsion test of explanted femur and femoral histology at 1, 3 and 6 months. Long-term safety of the coating is examined by systemic organ pathology at the endpoints. Systemic injections of vancomycin at a dose several hundred-fold higher than that in the prophylactic coating are carried out in a subset of infected animals receiving uncoated IM pins to allow direct comparison of the efficacy of this prophylactic coating vs. that of the standard care. Achieving more sustained protection against periprosthetic infections or recurrent infections than systemic vancomycin injections will be considered a success while achieving extended protection for 6 months without local and systemic side effects will be considered exceptional. If successfully validated, the timely and sustained eradication of bacteria enabled by MN-triggered vancomycin release could bring together safety and efficacy in addressing the daunting challenge of orthopedic implant-associated infections by bypassing the notoriously hard-to-treat biofilms and osteomyelitis.

项目总结/文摘