Injectable Fibrocartilage-Forming Cores Enhance Bone-Tendon Healing in a Rat Rotator Cuff Model.

Abstract

After surgical repair of rotator cuff (RC) tears, the torn tendon heals unsatisfactorily to the greater tuberosity owing to limited regeneration of the bone-tendon (BT) insertion. This situation motivates the need for new interventions to enhance BT healing in the RC repair site. To develop injectable fibrocartilage-forming cores by tethering fibroblast growth factor 18 (FGF18) on acellular fibrocartilage matrix microparticles (AFM-MPs) and evaluate their efficacy on BT healing. Controlled laboratory study. We harvested normal fibrocartilage tissue from the porcine RC insertion, after which it was decellularized and then micronized for fabricating AFM-MPs. The collagen-binding domain was fused into the N-terminus of FGF18 to synthesize recombinant FGF18 (CBD-FGF18), which was tethered to the collagen fibers of AFM-MPs to prepare the injectable fibrocartilage-forming cores (CBD-FGF18@AFM-MPs). After examining the influence of the CBD-FGF18@AFM-MPs on the viability and chondrogenic differentiation of bone marrow mesenchymal stem cells in vitro, we determined the function of the CBD-FGF18@AFM-MPs on BT healing in a rat RC tear model. A total of 80 Sprague-Dawley rats with RC injuries were randomly assigned to 4 supplemental treatments during RC repair: saline injection (control group), AFM-MPs injection, natural FGF18@AFM-MPs injection, and CBD-FGF18@AFM-MPs injection. At 4 and 8 weeks postoperatively, the harvested RC specimens were evaluated via micro-computed tomography, histologic staining, and mechanical testing. In vitro, the CBD-FGF18@AFM-MPs were highly biomimetic, suitable for cell growth and proliferation, and superior in stimulating chondrogenesis. In vivo micro-computed tomography results showed that the CBD-FGF18@AFM-MPs group had significantly more new bone formation and better bone remodeling than the other 3 groups. Histologically, at 4 and 8 weeks postoperatively, the CBD-FGF18@AFM-MPs group had the best continuity of the BT insertion with regular collagen alignment and extensive fibrocartilage regeneration. Importantly, at 8 weeks postoperatively, the RC specimens from the CBD-FGF18@AFM-MPs group presented the highest failure load and stiffness. The injectable fibrocartilage-forming cores provide a new biological intervention to promote RC healing. The injectable fibrocartilage-forming cores may be a new complementary treatment for surgical repair of RC tears.