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Objective A local anesthetic that provides analgesia lasting at least three days could significantly improve postoperative pain management. This study evaluated the analgesic efficacy and safety of an extended-release formulation of bupivacaine based on the injectable hydrogel carrier poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) (PNDJ). Methods The efficacy of PNDJ containing 4% bupivacaine (SBG004) given by peri-incisional subcutaneous injection (SBG004 SC) or wound filling instillation (SBG004 WF) was evaluated compared to saline, liposomal bupivacaine, bupivacaine collagen sponge, bupivacaine-meloxicam polyorthoester, and bupivacaine HCl in a porcine skin and muscle incision model. Mechanical allodynia was assessed by withdrawal from application of von Frey filaments, and local tolerance was evaluated by histology. Bupivacaine pharmacokinetics for SBG004 SC were measured in rabbits (16.5 mg bupivacaine/kg). Results Animals demonstrated less mechanical allodynia at incisions receiving SBG004 SC for up to 96 hours postoperatively. Incisions treated with SBG004 SC tolerated more force without a withdrawal indicative of pain compared to saline for 96 hours, and compared to SBG004 WF and all active controls at 24, 48, and 72 hours except bupivacaine-meloxicam polyorthoester at 72 hours. By 49 days, SBG004 was histologically absent and was replaced with granulation tissue infiltrated with immune cells in some areas. In rabbits, Cmax was 41.6 ± 9.7 ng/mL with t 1/2 82.0 ± 35.8 hours (mean ± SD). Conclusions Peri-incisional SBG004 SC provided extended release of bupivacaine sufficient to reduce sensation of incisional pain for 96 hours, in vivo bupivacaine delivery for at least 7 days, and a favorable local and systemic toxicity profile. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recovery of live cells from three-dimensional (3D) culture would improve analysis of cell behaviors in tissue engineered microenvironments. In this work, we developed a temperature responsive hydrogel to enable transient 3D culture of human glioblastoma (GBM) cells. N-isopropylacrylamide was copolymerized with hydrophilic grafts and functionalized with the cell adhesion peptide RGD to yield the novel copolymer poly(N-isopropylacrylamide-co-Jeffamine® M-1000 acrylamideco-hydroxyethylmethacrylate-RGD), or PNJ-RGD. This copolymer reversibly gels in aqueous solutions when heated under normal cell culture conditions (378C). Moreover, these gels redissolve within 70 s when cooled to room temperature without out the addition of any agents to degrade the synthetic scaffold, thereby enabling rapid recollection of viable cells after 3D culture. We tested the efficiency of cell recovery following extended 3D culture and were able to recover more than 50% of viable GBM cells after up to 7 days in culture. These data demonstrate the utility of physically crosslinked PNJ-RGD hydrogels as a platform for culture and recollection of cells in 3D. [ABSTRACT FROM AUTHOR]