Abstract
BackgroundThe clinical outcomes following intrasynovial flexor tendon repair are highly variable. Excessive inflammation is a principal factor underlying the formation of adhesions at the repair surface and affecting matrix regeneration at the repair center that limit tendon excursion and impair tendon healing. A previous in-vitro study revealed that adipose-derived mesenchymal stromal cells (ASCs) modulate tendon fibroblast response to macrophage-induced inflammation. The goal of the current study was therefore to explore the effectiveness of autologous ASCs on the inflammatory stage of intrasynovial tendon healing in vivo using a clinically relevant animal model.MethodsZone II flexor tendon transections and suture repairs were performed in a canine model. Autologous ASC sheets were delivered to the surface of repaired tendons. Seven days after repair, the effects of ASCs on tendon healing, with a focus on the inflammatory response, were evaluated using gene expression assays, immunostaining, and histological assessments.ResultsASCs delivered via the cell sheet infiltrated the host tendon, including the repair surface and the space between the tendon ends, as viewed histologically by tracking GFP-expressing ASCs. Gene expression results demonstrated that ASCs promoted a regenerative/anti-inflammatory M2 macrophage phenotype and regulated tendon matrix remodeling. Specifically, there were significant increases in M2-stimulator (IL-4), marker (CD163 and MRC1), and effector (VEGF) gene expression in ASC-sheet treated tendons compared with nontreated tendons. When examining changes in extracellular matrix expression, tendon injury caused a significant increase in scar-associated COL3A1 expression and reductions in COL2A1 and ACAN expression. The ASC treatment effectively counteracted these changes, returning the expression levels of these genes closer to normal. Immunostaining further confirmed that ASC treatment increased CD163+ M2 cells in the repaired tendons and suppressed cell apoptosis at the repair site.ConclusionsThis study provides a novel approach for delivering ASCs with outcomes indicating potential for substantial modulation of the inflammatory environment and enhancement of tendon healing after flexor tendon repair.
Highlights
The clinical outcomes following intrasynovial flexor tendon repair are highly variable
The Type 2 macrophage phenotype (M2) phenotype may be induced through the immunoregulatory function of adipose-derived mesenchymal stromal cells (ASCs). In addition to their easy accessibility and tenogenic potential [14], we recently reported that Adipose-derived mesenchymal stromal cell (ASC) protect tendon fibroblasts (TFs) from the negative effects of Type 1 macrophage phenotype (M1) macrophages by inducing an M1 to M2 phenotypic switch in vitro [15]
These results demonstrated that viable cells were successfully delivered to the tendon repair site using ASC sheets held in place by HA
Summary
The clinical outcomes following intrasynovial flexor tendon repair are highly variable. Modulation of the early inflammatory response that initiates the repair process may be necessary for a satisfactory recovery of tendon function. Within the first 2–3 days, gene expression levels of proinflammatory cytokines increase by many thousand-fold at the wound site [6] Such increases are accompanied by the infiltration of large numbers of inflammatory cells, including monocytes and neutrophils [6]. The initial postrepair cellular response, which often leads to adhesion formation, matrix degradation, and cell death [6, 7, 10], is largely detrimental to tendon healing. Careful modulation of the inflammatory cascade is necessary to improve tendon healing, by suppressing negative features such as tendon cell death and matrix degradation and by enhancing positive features associated with tendon cell proliferation and matrix synthesis
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