Localized SDF-1α Delivery Increases Pro-Healing Bone Marrow-Derived Cells in the Supraspinatus Muscle Following Severe Rotator Cuff Injury

Abstract

To examine how the chemotactic agent stromal cell-derived factor-1alpha (SDF-1α) modulates the unique cellular milieu within rotator cuff muscle following tendon injury, we developed an injectable, heparin-based microparticle platform to locally present SDF-1α within the supraspinatus muscle following severe rotator cuff injury. SDF-1α loaded, degradable, N-desulfated heparin-based microparticles were fabricated, injected into a rat model of severe rotator cuff injury, and were retained for up to 7 days at the site. The resultant inflammatory cell and mesenchymal stem cell populations were analyzed compared to uninjured contralateral controls and, after 7 days, the fold-change in anti-inflammatory, M2-like macrophages (CD11b+CD68+CD163+, 4.3X fold-change) and mesenchymal stem cells (CD29+CD44+CD90+, 3.0X, respectively) was significantly greater in muscles treated with SDF-1α loaded microparticles than unloaded microparticles or injury alone. Our results indicate that SDF-1α loaded microparticles may be a novel approach to shift the cellular composition within the supraspinatus muscle and create a more pro-regenerative milieu, which may provide a platform to improve muscle repair following rotator cuff injury in the future.

Full‐thickness rotator cuff tear in rat results in distinct temporal expression of multiple proteases in tendon, muscle, and cartilage

“…). However, our laboratory has previously shown significant fibrous infiltration of the supraspinatus muscle in this animal model at 3 weeks post‐injury and maintenance of similar levels of fibrous tissue up to 6 weeks, which aligns with other groups using similar animal models of rotator cuff injuries …”

“…In the supraspinatus muscle, significant upregulation of cathepsin L (associated with muscle atrophy in rats) is observed at 1 week before obvious muscle fibrosis/atrophy could be observed at 3 weeks (Fig. ).…”

“…Rotator cuff injury was induced using a method previously established . This animal model was chosen as muscle degeneration, an outcome we aim to characterize in this study, does not occur to a large degree in other models, such as tendon transection only, in rats .…”

“…Due to the acute injury of the tendon, we expected to observe damage to this tissue soon after injury and chose 1 week to capture effects of acute inflammation . For muscle, we have previously shown significant fibrous tissue infiltration (indicative of muscle degeneration) 3 weeks following tendon injury . In our previous studies with tendon overuse injuries, we have observed concomitant humeral head cartilage damage by 12 weeks after tendon injury onset.…”

Affinity Effects on the Release of Non-Conventional Antifibrotics from Polymer Depots

“…Future work could incorporate multiple different binding sites to improve the delivery of drug cocktails for various wound-healing and anti-fibrotic applications (e.g., from the current results, a co-polymer with both β-CD and dextran domains may result in better co-delivery of RIF and MTP than either β-CD or dextran alone). Incorporating native structures, such as albumin or heparin, in future devices could allow for co-delivery of growth factors, cytokines, or other signaling molecules for improved efficacy [27,47]. Furthermore, the diisocyanate-crosslinked CD polymer depots are known to be refillable in vivo [15,48], even through biofilms and in the presence of serum molecules [10,26], yet the effects of fibrotic processes such as collagen deposition and immune system activity on drug refilling into cyclodextrin polymer depots have yet to be determined.…”