Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, United States.
J Control Release. 2010 Aug 3;145(3):221-30. doi: 10.1016/j.jconrel.2010.04.002. Epub 2010 Apr 9.
Infection is a common complication in open fractures that compromises the healing of bone and can result in loss of limb or life. Currently, the clinical standard of care for treating contaminated open fractures comprises a staged approach, wherein the wound is first treated with non-biodegradable antibiotic-laden poly(methyl methacrylate) (PMMA) beads to control the infection followed by bone grafting. Considering that tissue regeneration is associated with new blood vessel formation, which takes up to 6 weeks in segmental defects, a biodegradable bone graft with sustained release of an antibiotic is desired to prevent the implant from becoming infected, thus allowing the processes of both vascularization and new bone formation to occur unimpeded. In the present study, we utilized biodegradable porous polyurethane (PUR) scaffolds as the delivery vehicle for vancomycin. Hydrophobic vancomycin free base (V-FB) was obtained by precipitating the hydrophilic vancomycin hydrochloride (V-HCl) at pH 8. The decreased solubility of V-FB resulted in an extended vancomycin release profile in vitro, as evidenced by the fact that active vancomycin was released for up to 8 weeks at concentrations well above both the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC). Using PUR prepared from lysine triisocyanate (LTI) (PUR(LTI)), the extended in vitro release profile observed for V-FB translated to improved infection control in vivo compared to V-HCl in a contaminated critical-sized fat femoral segmental defect. The performance of PUR(LTI)/V-FB was comparable to PMMA/V-HCl beads in vivo. However, compared with PMMA, PUR is a biodegradable system which does not require the extra surgical removal step in clinical use. These results suggest that PUR scaffolds incorporating V-FB could be a potential clinical therapy for treatment of infected bone defects.
感染是开放性骨折的常见并发症，会影响骨骼愈合，并导致肢体丧失或死亡。目前，治疗污染性开放性骨折的临床标准护理包括分期治疗方法，即首先用不可生物降解的载抗生素聚甲基丙烯酸甲酯（PMMA）珠来控制感染，然后进行骨移植。考虑到组织再生与新血管形成有关，而在节段性缺损中需要长达 6 周的时间，因此需要具有抗生素持续释放功能的可生物降解骨移植物来防止植入物感染，从而使血管化和新骨形成过程不受阻碍。在本研究中，我们利用可生物降解多孔聚氨酯（PUR）支架作为万古霉素的输送载体。通过将亲水性万古霉素盐酸盐（V-HCl）在 pH8 下沉淀，得到疏水性万古霉素游离碱（V-FB）。V-FB 的溶解度降低导致其在体外的万古霉素释放曲线延长，事实证明，活性万古霉素在浓度高于最低抑菌浓度（MIC）和最低杀菌浓度（MBC）的情况下，可长达 8 周持续释放。使用赖氨酸三异氰酸酯（LTI）（PUR(LTI)）制备 PUR，与 V-HCl 相比，V-FB 在体内观察到的延长体外释放曲线转化为更好的感染控制。PUR(LTI)/V-FB 的性能与 PMMA/V-HCl 珠粒在体内的性能相当。然而，与 PMMA 相比，PUR 是一种可生物降解的系统，在临床使用中不需要额外的手术去除步骤。这些结果表明，含有 V-FB 的 PUR 支架可能是治疗感染性骨缺损的一种潜在临床治疗方法。
