Background: Mesenchymal stromal cell (MSC) techniques represent a promising method to enhance the surgical repair of rotator cuff tears. To eliminate the resource-intensive process of cell isolation and culture expansion, a method to recruit endogenous MSCs was investigated in an established rat model of rotator cuff repair. Hypothesis: MSCs can be pharmacologically mobilized from the peripheral blood and recruited to the operative rotator cuff to enhance tendon-bone healing. Study Design: Controlled laboratory study. Methods: The rat model of supraspinatus tendon detachment and acute surgical repair was used to compare the ability of 3 different chemokines (SDF-1β, MIP-3α, and MCP-1) to recruit optically labeled MSCs to the operative shoulder from circulation. Additional experimentation was undertaken to assess the effects of pharmacological MSC mobilization using a combination of a β 3 adrenoreceptor agonist (BRL37344) and a CXCR4 antagonist (AMD3100) on chemokine-directed recruitment to the shoulder. Finally, the effects of this therapeutic strategy on tendon-bone healing were assessed. Results: MCP-1–loaded hydrogels recruited the greatest number of MSCs from circulation. MCP-1–driven MSC recruitment was significantly enhanced by a regimen of subcutaneous BRL37344 and AMD3100. Postmortem micro–computed tomography imaging performed at a 6-week endpoint revealed that local MCP-1 delivery was associated with significant reductions in trabecular spacing and apparent mineral density, and a significant increase in trabecular number, while pharmacological MSC mobilization had no significant effects. MCP-1 delivery was associated with a lower tendon cross-sectional area and a significant increase in percent relaxation ( P = .006). Pharmacological MSC mobilization was associated with significantly increased peak stress ( P = .039), significantly increased elastic modulus ( P = .037), and a nonsignificant increase in both equilibrium stress ( P = .057) and ultimate stress ( P = .058). Local MCP-1 delivery was associated with significant improvements in tenocyte morphology. Conclusion: Endogenous MSCs can be pharmacologically mobilized into peripheral blood and recruited to the site of rotator cuff repair via local delivery of MCP-1. This therapeutic strategy was associated with improvements in the static and dynamic mechanical properties of the tendon-bone interface. Clinical Relevance: The healing of rotator cuff repairs represents an ongoing clinical challenge in orthopaedic surgery. This study demonstrates a method to use endogenous MSCs to enhance healing of the rotator cuff.

中文翻译：

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药物动员和趋化因子定向间充质基质细胞募集到手术修复的肩袖

背景： 间充质基质细胞 （MSC） 技术代表了一种很有前途的增强肩袖撕裂手术修复的方法。为了消除细胞分离和培养扩增的资源密集型过程，在已建立的肩袖修复大鼠模型中研究了一种募集内源性 MSC 的方法。假设：MSC 可以从外周血中药理学动员并募集到手术肩袖以增强肌腱骨愈合。研究设计： 对照实验室研究。方法：采用冈上肌腱脱离和急性手术修复大鼠模型比较 3 种不同趋化因子 （SDF-1β 、 MIP-3α 和 MCP-1） 从循环中将光学标记的 MSC 募集到手术肩部的能力。进行了额外的实验，以评估使用 β 3 肾上腺素受体激动剂 （BRL37344） 和 CXCR4 拮抗剂 （AMD3100） 的组合进行药物 MSC 动员对趋化因子定向募集到肩部的影响。最后，评估了这种治疗策略对肌腱骨愈合的影响。结果：负载 MCP-1 的水凝胶从循环中募集了最多的 MSC。MCP-1 驱动的 MSC 募集通过皮下 BRL37344 和 AMD3100 方案得到显著增强。在 6 周终点进行的尸后显微计算机断层扫描成像显示，局部 MCP-1 递送与小梁间距和表观矿物质密度的显着减少以及小梁数量的显着增加有关，而药理学 MSC 动员没有显着影响。 MCP-1 递送与较低的肌腱横截面积和松弛百分比的显着增加有关 （P = .006）。药理学 MSC 动员与峰值应力显著增加 （P = .039）、弹性模量显著增加 （P = .037） 以及平衡应力 （P = .057） 和极限应力 （P = .058） 均无显著增加相关。局部 MCP-1 递送与肌腱细胞形态的显着改善相关。结论： 内源性 MSC 可以药理学地动员到外周血中，并通过 MCP-1 的局部递送被募集到肩袖修复部位。这种治疗策略与肌腱-骨骼界面的静态和动态机械性能的改善有关。临床相关性： 肩袖修复的愈合代表了骨科手术中持续的临床挑战。本研究展示了一种使用内源性 MSC 来增强肩袖愈合的方法。