Liang Qiuzhen, Song Xinghua, She Shengli, Wang Zhen, Wang Chong, Jiang Dawei
Department of Orthopaedics, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830054, China,
Drug Des Devel Ther. 2019 Jan 18;13:373-384. doi: 10.2147/DDDT.S190696. eCollection 2019.
Low drug concentration in the tuberculosis (TB) lesion and bone defects or nonunion after debridement are two major problems that occur in the course of treating osteo-articular TB. Thus, the combination of drug-delivery system and bone tissue repair appears to be the most promising option for osteoarticular TB treatment.
Herein, we report a novel anti-TB dual delivery system based on rifapentine polylactic acid microspheres (RPMs) to treat infections, with the addition of adipose-derived mesenchymal stem cells (ASCs) seeded in hydroxyapatite/tricalcium phosphate (HA/TCP) to promote bone formation. Cell proliferation, osteogenesis, and apoptosis were performed to investigate the effects of rifapentine on ASCs. The RPMs were synthesized by emulsion-solvent evaporation method, and then the monolayer composite (ASC + RPM) and three-dimensional (3D) composite scaffold (ASC + RPM + HA/TCP) were constructed, respectively. The alkaline phosphatase (ALP) activity and real-time PCR were used for determining the osteogenic differentiation. The concentrations of rifapentine resulting from the composites were detected.
The results showed that rifapentine has no influence on ASCs proliferation and osteogenesis when the drug concentration was below 20 µg/mL, which was significantly higher than minimal inhibitory concentration. The drug loading and encapsulation efficiency of RPMs were 40.56%±2.63% and 70.24%±2.18%, respectively. The proliferation of the cells in monolayer was higher than that in 3D composite, and the addition of RPMs slightly increased the proliferation. The ALP activity and gene expression of osteocalcin and osteopontin were higher in the 3D composite than those in the monolayer. Good biocompatibility was observed by microscopic image and H&E stain. The release tests revealed that the 3D composite exhibited sustained release profiles of rifapentine for 76 days. The dual delivery systems in 3D composite could moderate the burst release and extend the length of release time when compared to single delivery in monolayers.
In conclusion, such dual delivery antituberculotic scaffold represents a potential new strategy for TB infections and bone defects.
结核病灶内药物浓度低以及清创术后骨缺损或骨不连是骨与关节结核治疗过程中出现的两个主要问题。因此，药物递送系统与骨组织修复相结合似乎是治疗骨与关节结核最有前景的选择。
在此，我们报告一种基于利福喷丁聚乳酸微球（RPMs）的新型抗结核双递送系统用于治疗感染，并添加接种于羟基磷灰石/磷酸三钙（HA/TCP）中的脂肪间充质干细胞（ASCs）以促进骨形成。进行细胞增殖、成骨和凋亡实验以研究利福喷丁对ASCs的影响。通过乳液-溶剂蒸发法合成RPMs，然后分别构建单层复合物（ASC + RPM）和三维（3D）复合支架（ASC + RPM + HA/TCP）。采用碱性磷酸酶（ALP）活性和实时定量PCR检测成骨分化情况。检测复合物中利福喷丁的浓度。
结果表明，当药物浓度低于20μg/mL时，利福喷丁对ASCs增殖和成骨无影响，该浓度显著高于最低抑菌浓度。RPMs的载药量和包封率分别为40.56%±2.63%和70.24%±2.18%。单层细胞的增殖高于3D复合物中的细胞，添加RPMs可轻微增加增殖。3D复合物中ALP活性以及骨钙素和骨桥蛋白的基因表达高于单层复合物。通过显微镜图像和苏木精-伊红染色观察到良好的生物相容性。释放试验表明，3D复合物呈现利福喷丁76天的缓释曲线。与单层单一递送相比，3D复合物中的双递送系统可缓解突释并延长释放时间。
总之，这种双递送抗结核支架代表了一种针对结核感染和骨缺损的潜在新策略。
