Surgical site infections (SSIs) are a persistent clinical challenge. Local antimicrobial delivery may reduce the risk of SSI by increasing drug concentrations and distribution in vulnerable surgical sites compared to what is achieved using systemic antimicrobial prophylaxis alone. In this work, we describe a comprehensive in vivo evaluation of the safety and efficacy of poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ], an injectable temperature-responsive hydrogel carrier for antimicrobial delivery in surgical sites. Biodistribution data indicate that PNDJ is primarily cleared via the liver and kidneys following drug delivery. Antimicrobial-loaded PNDJ was generally well-tolerated locally and systemically when applied in bone, muscle, articulating joints, and intraperitoneal space, although mild renal toxicity consistent with the released antimicrobials was identified at high doses in rats. Dosing of PNDJ at bone-implant interfaces did not affect normal tissue healing and function of orthopedic implants in a transcortical plug model in rabbits and in canine total hip arthroplasty. Finally, PNDJ was effective at preventing recurrence of implant-associated MSSA and MRSA osteomyelitis in rabbits, showing a trend toward outperforming commercially available antimicrobial-loaded bone cement and systemic antimicrobial administration. These studies indicate that antimicrobial-loaded PNDJ hydrogels are well-tolerated and could reduce incidence of SSI in a variety of surgical procedures.

中文翻译：

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载有温度响应抗菌剂的 PNIPAAm 水凝胶用于预防手术部位感染的体内评价

手术部位感染 (SSI) 是一项持续存在的临床挑战。与单独使用全身抗菌药物预防所达到的效果相比，局部抗菌药物给药可以通过增加药物在易受伤害的手术部位的浓度和分布来降低 SSI 的风险。在这项工作中，我们描述了聚（ N-异丙基丙烯酰胺-co-二甲基丁内酯丙烯酰胺-co的安全性和有效性的综合体内评估-Jeffamine M-1000 acrylamide) [PNDJ]，一种可注射的温度响应水凝胶载体，用于手术部位的抗菌药物输送。生物分布数据表明 PNDJ 主要在给药后通过肝脏和肾脏清除。当应用于骨骼、肌肉、关节和腹膜腔时，载有抗菌素的 PNDJ 通常具有良好的局部和全身耐受性，尽管在大鼠中发现高剂量时与释放的抗菌素一致的轻度肾毒性。PNDJ 在骨植入物界面的给药不会影响正常组织愈合和骨科植入物在兔经皮层栓塞模型和犬全髋关节置换术中的功能。最后，PNDJ 可有效预防兔种植体相关 MSSA 和 MRSA 骨髓炎的复发，显示出优于市售抗菌骨水泥和全身抗菌给药的趋势。这些研究表明，载有抗菌素的 PNDJ 水凝胶具有良好的耐受性，可以降低各种外科手术中 SSI 的发生率。