The promise of cell therapy for repair and restoration of damaged tissues or organs relies on administration of large dose of cells whose healing benefits are still limited and sometimes irreproducible due to uncontrollable cell loss and death at lesion sites. Using a large amount of therapeutic cells increases the costs for cell processing and the risks of side effects. Optimal cell delivery strategies are therefore in urgent need to enhance the specificity, efficacy, and reproducibility of cell therapy leading to minimized cell dosage and side effects. Here, we addressed this unmet need by developing injectable 3D microscale cellular niches (microniches) based on biodegradable gelatin microcryogels (GMs). The microniches are constituted by in vitro priming human adipose-derived mesenchymal stem cells (hMSCs) seeded within GMs resulting in tissue-like ensembles with enriched extracellular matrices and enhanced cell-cell interactions. The primed 3D microniches facilitated cell protection from mechanical insults during injection and in vivo cell retention, survival, and ultimate therapeutic functions in treatment of critical limb ischemia (CLI) in mouse models compared with free cell-based therapy. In particular, 3D microniche-based therapy with 10(5) hMSCs realized better ischemic limb salvage than treatment with 10(6) free-injected hMSCs, the minimum dosage with therapeutic effects for treating CLI in literature. To the best of our knowledge, this is the first convincing demonstration of injectable and primed cell delivery strategy realizing superior therapeutic efficacy for treating CLI with the lowest cell dosage in mouse models. This study offers a widely applicable cell delivery platform technology to boost the healing power of cell regenerative therapy.

中文翻译：

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Primed 3D 可注射微孔板可实现对严重肢体缺血的低剂量细胞治疗。

用于修复和修复受损组织或器官的细胞疗法的前景依赖于施用大剂量的细胞，这些细胞的愈合益处仍然有限，有时由于无法控制的细胞损失和损伤部位的死亡而无法重现。使用大量治疗细胞会增加细胞处理的成本和副​​作用的风险。因此，迫切需要优化细胞递送策略以提高细胞治疗的特异性、功效和可重复性，从而最大限度地减少细胞剂量和副作用。在这里，我们通过开发基于可生物降解明胶微冷冻凝胶 (GMs) 的可注射 3D 微型细胞壁龛 (microniches) 解决了这一未满足的需求。Microniche 由体外引发人类脂肪来源的间充质干细胞 (hMSCs) 组成，这些细胞接种在 GMs 中，产生具有丰富细胞外基质和增强细胞间相互作用的组织样集合。与基于游离细胞的治疗相比，在注射和体内细胞保留、存活和治疗小鼠模型中的严重肢体缺血 (CLI) 过程中，启动的 3D 微孔促进细胞保护免受机械损伤。特别是，10(5) hMSCs 的基于 3D microniche 的治疗比 10(6) 自由注射 hMSCs 的治疗实现了更好的缺血肢体挽救，这是文献中治疗 CLI 具有治疗效果的最小剂量。据我们所知，这是第一个令人信服的可注射和致敏细胞递送策略的演示，它在小鼠模型中以最低的细胞剂量实现了治疗 CLI 的卓越疗效。这项研究提供了一种广泛适用的细胞递送平台技术，以提高细胞再生疗法的治愈能力。