Exosomes Derived From Kartogenin-Preconditioned Mesenchymal Stem Cells Promote Cartilage Formation and Collagen Maturation for Enthesis Regeneration in a Rat Model of Chronic Rotator Cuff Tear

Abstract

Background: Poor tendon-to-bone healing in chronic rotator cuff tears (RCTs) is related to unsatisfactory outcomes. Exosomes derived from mesenchymal stem cells reportedly enhance rotator cuff healing. However, the difficulty in producing exosomes with a stronger effect on enthesis regeneration must be resolved. Purpose: To study the effect of exosomes derived from kartogenin (KGN)-preconditioned human bone marrow mesenchymal stem cells (KGN-Exos) on tendon-to-bone healing in a rat model of chronic RCT. Study Design: Controlled laboratory study. Methods: Exosome-loaded sodium alginate hydrogel (SAH) was prepared. Moreover, exosomes were labeled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR) or 1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine perchlorate (Dil) for in vivo tracking. Bilateral rotator cuff repair (RCR) was conducted in an established chronic RCT rat model. A total of 66 rats were randomized to control, untreated exosome (un-Exos), and KGN-Exos groups to receive local injections of pure SAH, un-Exos, or KGN-Exos SAH at the repaired site. The presence of DiR/Dil-labeled exosomes was assessed at 1 day and 1 week, and tendon-to-bone healing was evaluated histologically, immunohistochemically, and biomechanically at 4 and 8 weeks. Results: Both un-Exos and KGN-Exos exhibited sustained release from SAH for up to 96 hours. In vivo study revealed that un-Exos and KGN-Exos were localized to the repaired site at 1 week. Moreover, the KGN-Exos group showed a higher histological score and increased glycosaminoglycan and collagen II expression at 4 and 8 weeks. In addition, more mature and better-organized collagen fibers with higher ratios of collagen I to collagen III were observed at 8 weeks in the tendon-to-bone interface compared with those in the control and un-Exos groups. Biomechanically, the KGN-Exos group had the highest failure load (28.12 ± 2.40 N) and stiffness (28.57 ± 2.49 N/mm) among the 3 groups at 8 weeks. Conclusion: Local injection of SAH with sustained KGN-Exos release could effectively promote cartilage formation as well as collagen maturation and organization for enthesis regeneration, contributing to enhanced biomechanical properties after RCR. Clinical Relevance: KGN-Exos injection may be used as a cell-free therapeutic option to accelerate tendon-to-bone healing in chronic RCT.

Three‐dimensional printed Zn2SiO4/sodium alginate composite scaffold with multiple biological functions for tendon‐to‐bone repair

“…Sodium alginate (SA) is a polysaccharide extracted from seaweed, known for its excellent biocompatibility, biodegradability, and controllability 6,7 . Consequently, SA has been employed as a delivery vehicle for growth factors, stem cells, or exosomes in the treatment of tendon–bone interface injuries 8–11 . Nonetheless, the extant body of literature scarcely documents instances of concurrent enhancement of both tendon and bone regeneration, primarily attributed to the deficiency in bioactivity exhibited by traditional scaffolds.…”

Sequential intervention of anti-inflammatory and osteogenesis with silk fibroin coated polyethylene terephthalate artificial ligaments for anterior cruciate ligament reconstruction

“…Tendon/ligament injuries are debilitating musculoskeletal diseases in sports medicine. [1][2][3] Among them, an anterior cruciate ligament (ACL) tear is a common sports injury. Annually, around 200 000 ACL tear occurs in America.…”

An extracellular matrix mimicking alginate hydrogel scaffold manipulates an inflammatory microenvironment and improves peripheral nerve regeneration by controlled melatonin release

“…14 There is potential for a wide range of alginate applications in many bio-related fields such as implants, wound healing, drug and protein delivery, regenerative medicine or tissue engineering, and research to understand the basis of the body and disease. 15–27…”

“…14 There is potential for a wide range of alginate applications in many bio-related fields such as implants, wound healing, drug and protein delivery, regenerative medicine or tissue engineering, and research to understand the basis of the body and disease. [15][16][17][18][19][20][21][22][23][24][25][26][27] Nevertheless, hydrogels do not provide a certain level of mechanical support. It becomes a very crucial constraint for its usage in neural repair.…”