可塑性纳米羟基磷灰石/聚羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇释药系统治疗兔骨髓炎

背景：现有的局部药物缓释系统多为块状，不能任意塑形，难以与骨腔完全贴敷，易导致骨髓炎复发，且药物爆释作用明显、载药量不大、释放时间短、有一定抗原性。为此，课题组与华南理工大学合作研制一种新型的可塑性局部药物缓释系统，以期为骨髓炎的治疗提供更好方法。 目的：观察可塑性纳米羟基磷灰石/聚羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇[nanohydroxyapatite/poly (3-hydroxybutyrate- hydroxyvalerate)- polyethylene glycol, nano-HA/PHBV-PEG]载硫酸庆大霉素(gentamicin，GM)局部药物释放系统对骨髓炎的治疗作用。 方法：制备兔胫骨近端骨髓炎模型，于胫骨近端骨窗内注入金黄色葡萄球菌后2周，行病灶清除。Ⅰ组植入1 mL可塑性nano-HA/PHBV-PEG-GM局部药物释放系统；Ⅱ组植入可塑性nano-HA/PHBV-PEG 1 mL及23.2 mg硫酸庆大霉素粉；Ⅲ组植入1 mL可塑性nano-HA/PHBV-PEG并肌注硫酸庆大霉素5 d，共23.2 mg；Ⅳ组植入1 mL可塑性nano-HA/PHBV-PEG；Ⅴ组无任何植入。术后8周进行放射学、组织学、细菌学检查。 结果与结论：Ⅰ组细菌计数及改良X射线Norden 骨髓炎评分极低，明显小于其他各组(P < 0.01)，其组织学观察无明显骨髓炎表现。Ⅱ、Ⅲ、Ⅳ组细菌计数逐渐增大，差异有显著性意义(P < 0.01)。但3组间改良X射线Norden 骨髓炎评分差异无显著性意义(P > 0.05)，组织学观察骨髓炎表现也无本质差别。Ⅱ、Ⅲ、Ⅳ组细菌计数及改良X射线Norden 骨髓炎评分均较高,明显大于Ⅴ组(P < 0.01或0.05)；其组织学显示出严重骨髓炎表现。结果提示：①在病灶清除后，一期将可塑性nano-HA/PHBV-PEG-DDS植入残留的感染性骨缺损，能快速有效地治疗骨髓炎。②传统的全身抗生素应用或单纯局部应用抗生素方法虽然较不用抗生素好，但不能确保一期植骨有效治疗慢性骨髓炎。③在不用药、传统全身用药或单纯局部用药条件下，一期植骨反而会加重骨髓炎。

Treatment of osteomyelitis in rabbits with plastic nanohydroxyapatite/poly (3-hydroxybutyrate-hydroxyvalerate)-polyethylene glycol drug delivery system

BACKGROUND: Existing local drug delivery system is mostly massive, cannot arbitrary moulding and is difficult to completely sticking with the bone cavity, which easily lead to recurrence of osteomyelitis, and obvious effect of drug burst release, small amount of drug loading, short releasing time, and certain antigenicity. Therefore, a new type of plastic local drug delivery system was developed by task force and South China University of Technology, in order to provide a better method of treatment of osteomyelitis. OBJECTIVE:To investigate the therapeutic effect of the plastic nanohydroxyapatite/poly (3-hydroxybutyrate-hydroxyvalerate)-polyethylene glycol-gentamicin local drug delivery system (nano-HA/PHBV-PEG-GM-DDS) on osteomyelitis. METHODS: Proximal tibia osteomyelitis model of rabbits was prepared. Staphylococcus aureus was injected into proximal tibia bone window after 2 weeks and underwent debridement. The plastic nano-HA/PHBV-PEG-GM-DDS of 1 mL was implanted into groupⅠ, the plastic nano- HA/PHBV-PEG of 1 mL mixed gentamicin power of 23.2 mg into group Ⅱ, the plastic nano- HA/PHBV-PEG of 1 mL in conjunction with intramuscle gentamicin into group Ⅲ 5 days, a total of 23.2 mg, the plastic nano-HA/PHBV-PEG of 1 mL without antibiotic in group Ⅳ, and nothing into group Ⅴ. Specimens were harvestd 8 weeks after the above procedures and then were subjected to radiological, histological and bacteriological examinations. RESULTS AND CONCLUSION:In groupⅠ, the bacteria counting and X-ray Norden scoring were by far the smallest among all 5 groups (P < 0.01)，with no histological manifestation of osteomyelitis. In groupⅡ, Ⅲ, and Ⅳ, the bacteria counting gradually increased and there was significant difference among three groups (P < 0.01). However, there was no significant difference in improved X-ray Norden scoring among 3 groups (P > 0.05); histological manifestation had also no essential difference. The bacteria counting and Norden scoring as well as the histological manifestation in groupⅡ, Ⅲ, and Ⅳ were significantly higher than those in group Ⅴ (P < 0.01 or 0.05), its histology showed severe osteomyelitis manifestation. The results showed that the plastic nano- HA/PHBV-PEG-GM-DDS could be implanted as primary graft into the remaining infected defect after debridement to effectively treat osteomyelitis. Conventional systemic antibiotic or simple local antibiotic following debridement was not effective in treating chronic osteomyelitis. Primary bone grafting would rather make the condition worse, under without any antibiotic or conventional systemic antibiotic or simple local antibiotic.