Wang Hai, Agarwal Pranay, Xiao Yichao, Peng Hao, Zhao Shuting, Liu Xuanyou, Zhou Shenghua, Li Jianrong, Liu Zhenguo, He Xiaoming
Department of Biomedical Engineering, Comprehensive Cancer Center, Davis Heart and Lung Research Institute, and Division of Cardiovascular Medicine, and Department of Veterinary Biosciences, The Ohio State University, Columbus, Ohio 43210, United States.
Department of Burns and Plastic Surgery, The Third Xiangya Hospital and Department of Cardiology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China.
ACS Cent Sci. 2017 Aug 23;3(8):875-885. doi: 10.1021/acscentsci.7b00213. Epub 2017 Jul 19.
Stem cell therapy holds great potential for treating ischemic diseases. However, contemporary methods for local stem cell delivery suffer from poor cell survival/retention after injection. We developed a unique multiscale delivery system by encapsulating therapeutic agent-laden nanoparticles in alginate hydrogel microcapsules and further coentrapping the nano-in-micro capsules with stem cells in collagen hydrogel. The multiscale system exhibits significantly higher mechanical strength and stability than pure collagen hydrogel. Moreover, unlike nanoparticles, the nano-in-micro capsules do not move with surrounding body fluid and are not taken up by the cells. This allows a sustained and localized release of extracellular epidermal growth factor (EGF), a substance that could significantly enhance the proliferation of mesenchymal stem cells while maintaining their multilineage differentiation potential via binding with its receptors on the stem cell surface. As a result, the multiscale system significantly improves the stem cell survival at 8 days after implantation to ∼70% from ∼4-7% for the conventional system with nanoparticle-encapsulated EGF or free EGF in collagen hydrogel. After injecting into the ischemic limbs of mice, stem cells in the multiscale system facilitate tissue regeneration to effectively restore ∼100% blood perfusion in 4 weeks without evident side effects.
干细胞疗法在治疗缺血性疾病方面具有巨大潜力。然而，当代局部干细胞递送方法存在注射后细胞存活率/滞留率低的问题。我们开发了一种独特的多尺度递送系统，将负载治疗剂的纳米颗粒包裹在藻酸盐水凝胶微胶囊中，然后将这种纳米微胶囊与干细胞一起共包埋在胶原蛋白水凝胶中。该多尺度系统表现出比纯胶原蛋白水凝胶显著更高的机械强度和稳定性。此外，与纳米颗粒不同，纳米微胶囊不会随周围体液移动，也不会被细胞摄取。这使得细胞外表皮生长因子（EGF）能够持续且局部释放，EGF通过与干细胞表面的受体结合，可显著增强间充质干细胞的增殖，同时维持其多向分化潜能。结果，该多尺度系统在植入后8天时将干细胞存活率从使用纳米颗粒包裹EGF或胶原蛋白水凝胶中游离EGF的传统系统的约4 - 7%显著提高到约70%。将该多尺度系统注射到小鼠缺血肢体后，其中的干细胞促进组织再生，在4周内有效恢复约100%的血液灌注，且无明显副作用。
