Pharmacologic Mobilization and Chemokine-Directed Recruitment of Mesenchymal Stromal Cells to the Surgically Repaired Rotator Cuff

Abstract

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.