Purpose: Mesenchymal stromal cells (MSCs) are used to treat various inflammatory conditions. In parallel, to mitigate pain associated with inflammation, analgesics or opioids are prescribed, often with significant side effects. Local anesthetics (LAs) offer a promising alternative to these medications. However, their short duration and negative effects on anti-inflammatory MSCs have limited their therapeutic effectiveness. To mitigate these negative effects and to move toward developing a cotherapy, we engineered a sustained release bupivacaine alginate-liposomal construct that enables up to 4 days of LA release. By encapsulating MSC in alginate (eMSC), we demonstrate that we can further increase drug concentration to clinically relevant levels, without compromising eMSC viability or anti-inflammatory function.
Materials and methods: MSCs were freely cultured or encapsulated in alginate microspheres ± TNFα/IFN-γ and were left untreated or dosed with bolus, liposomal, or construct bupivacaine. After 24, 48, and 96 hours, the profiles were assessed to quantify secretory function associated with LA–MSC interactions. To approximate LA exposure over time, a MATLAB model was generated.
Results: eMSCs secrete similar levels of IL-6 and prostaglandin E2 (PGE2) regardless of LA modality, whereas free MSCs secrete larger amounts of IL-6 and lower amounts of anti-inflammatory PGE2. Modeling the system indicated that higher doses of LA can be used in conjunction with eMSC while retaining eMSC viability and function. In general, eMSC treated with higher doses of LA secreted similar or higher levels of immunomodulatory cytokines.
Conclusion: eMSCs, but not free MSC, are protected from LA, regardless of LA modality. Increasing the LA concentration may promote longer and stronger pain mitigation while the protected eMSCs secrete similar, if not higher, immunomodulatory cytokine levels. Therefore, we have developed an approach, using eMSC and the LA construct that can potentially be used to reduce pain as well as improve MSC anti-inflammatory function.

Keywords: MSC cytokine secretion, local anesthetics, encapsulated MSC, drug diffusion model


中文翻译：

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用于布比卡因递送和间充质基质细胞免疫调节协同治疗的藻酸盐封装。

目的：间充质基质细胞 (MSCs) 用于治疗各种炎症。同时，为了减轻与炎症相关的疼痛，镇痛剂或阿片类药物被开具处方，通常具有显着的副作用。局部麻醉剂 (LAs) 为这些药物提供了有希望的替代品。然而，它们的持续时间短和对抗炎 MSCs 的负面影响限制了它们的治疗效果。为了减轻这些负面影响并朝着开发联合疗法的方向发展，我们设计了一种缓释海藻酸布比卡因脂质体结构，可以实现长达 4 天的 LA 释放。通过将 MSC 包裹在海藻酸盐 (eMSC) 中，我们证明我们可以进一步将药物浓度提高到临床相关水平，而不会影响 eMSC 的活力或抗炎功能。
材料和方法： MSCs 自由培养或封装在藻酸盐微球 ± TNFα/IFN-γ 中，不处理或给予推注、脂质体或构建布比卡因。在 24、48 和 96 小时后，评估概况以量化与 LA-MSC 相互作用相关的分泌功能。为了近似 LA 暴露随时间的变化，生成了一个 MATLAB 模型。
结果：无论 LA 模式如何，eMSCs 分泌相似水平的 IL-6 和前列腺素 E2 (PGE2)，而游离 MSCs 分泌更多的 IL-6 和更少的抗炎 PGE2。对该系统进行建模表明，可以将更高剂量的 LA 与 eMSC 结合使用，同时保持 eMSC 的活力和功能。一般来说，用更高剂量的 LA 处理的 eMSC 分泌相似或更高水平的免疫调节细胞因子。
结论：无论 LA 模式如何，eMSCs，但不是免费的 MSC，都受到 LA 保护。增加 LA 浓度可以促进更长时间和更强的疼痛缓解，而受保护的间充质干细胞分泌相似的（如果不是更高的话）免疫调节细胞因子水平。因此，我们开发了一种方法，使用 eMSC 和 LA 结构，可以潜在地用于减轻疼痛以及改善 MSC 抗炎功能。

关键词： MSC细胞因子分泌，局麻药，包封MSC，药物扩散模型