Diabetic foot ulcers are a major health care concern with limited effective therapies. Mesenchymal stem cell (MSC)‐based therapies are promising treatment options due to their beneficial effects of immunomodulation, angiogenesis, and other paracrine effects. We investigated whether a bioengineered scaffold device containing hypoxia‐preconditioned, allogeneic human MSCs combined with the beta‐adrenergic antagonist timolol could improve impaired wound healing in diabetic mice. Different iterations were tested to optimize the primary wound outcome, which was percent of wound epithelialization. MSC preconditioned in 1 μM timolol at 1% oxygen (hypoxia) seeded at a density of 2.5 × 10⁵ cells/cm² on Integra Matrix Wound Scaffold (MSC/T/H/S) applied to wounds and combined with daily topical timolol applications at 2.9 mM resulted in optimal wound epithelialization 65.6% (24.9% ± 13.0% with MSC/T/H/S vs 41.2% ± 20.1%, in control). Systemic absorption of timolol was below the HPLC limit of quantification, suggesting that with the 7‐day treatment, accumulative steady‐state timolol concentration is minimal. In the early inflammation stage of healing, the MSC/T/H/S treatment increased CCL2 expression, lowered the pro‐inflammatory cytokines IL‐1B and IL6 levels, decreased neutrophils by 44.8%, and shifted the macrophage ratio of M2/M1 to 1.9 in the wound, demonstrating an anti‐inflammatory benefit. Importantly, expression of the endothelial marker CD31 was increased by 2.5‐fold with this treatment. Overall, the combination device successfully improved wound healing and reduced the wound inflammatory response in the diabetic mouse model, suggesting that it could be translated to a therapy for patients with diabetic chronic wounds.

中文翻译：

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真皮基质、人间充质干细胞和噻吗洛尔的组合产物促进小鼠糖尿病伤口愈合。

糖尿病足溃疡是一个主要的医疗保健问题，有效的治疗方法有限。基于间充质干细胞 (MSC) 的疗法因其免疫调节、血管生成和其他旁分泌作用的有益作用而成为有前景的治疗选择。我们研究了含有缺氧预处理的同种异体人 MSCs 与 β-肾上腺素能拮抗剂噻吗洛尔相结合的生物工程支架装置是否可以改善糖尿病小鼠受损的伤口愈合。测试不同的迭代以优化主要伤口结果，即伤口上皮化的百分比。MSC 在 1 μM 噻吗洛尔中预处理，1% 氧（缺氧），密度为 2.5 × 10 ^{5 个} 细胞/cm ²在 Integra 基质伤口支架 (MSC/T/H/S) 上应用于伤口并结合每日局部使用 2.9 mM 噻吗洛尔导致最佳伤口上皮形成 65.6%（24.9% ± 13.0% MSC/T/H/S vs 41.2 % ± 20.1%，在控制中）。噻吗洛尔的全身吸收低于 HPLC 定量限，表明在 7 天的治疗中，累积稳态噻吗洛尔浓度最小。在愈合的早期炎症阶段，MSC/T/H/S 治疗增加了 CCL2 表达，降低了促炎细胞因子 IL-1B 和 IL6 水平，中性粒细胞减少了 44.8%，并将 M2/M1 的巨噬细胞比率转变为1.9 在伤口中，表现出抗炎作用。重要的是，这种治疗使内皮标志物 CD31 的表达增加了 2.5 倍。总体，