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Therapeutic potential of exosomes in rotator cuff tendon healing.

ABSTRACT: Rotator cuff tears are common musculoskeletal injuries that can cause significant pain and disability. While the clinical results of rotator cuff repair can be good, failure of tendon healing remains a significant problem. Molecular mechanisms underlying structural failure following surgical repair remain unclear. Histologically, enhanced inflammation, disorganization of the collagen fibers, calcification, apoptosis and tissue necrosis affect the normal healing process. Mesenchymal stem cells (MSCs) have the ability to provide improved healing following rotator cuff repair via the release of mediators from secreted 30-100 nm extracellular vesicles called exosomes. They carry regulatory proteins, mRNA and miRNA and have the ability to increase collagen synthesis and angiogenesis through increased expression of mRNA and release of proangiogenic factors and regulatory proteins that play a major role in proper tissue remodeling and preventing extracellular matrix degradation. Various studies have shown the effect of exosomes on improving outcome of cutaneous wound healing, scar tissue formation, degenerative bone disease and Duchenne Muscular Dystrophy. In this article, we critically reviewed the potential role of exosomes in tendon regeneration and propose the novel use of exosomes alone or seeded onto biomaterial matrices to stimulate secretion of favorable cellular factors in accelerating the healing response following rotator cuff repair.

SUBMITTER: Connor DE

PROVIDER: S-EPMC6830879 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Therapeutic potential of exosomes in rotator cuff tendon healing.

Connor Denton E DE Paulus Jordan A JA Dabestani Parinaz Jila PJ Thankam Finosh K FK Dilisio Matthew F MF Gross R Michael RM Agrawal Devendra K DK

Journal of bone and mineral metabolism 20190601 5

Rotator cuff tears are common musculoskeletal injuries that can cause significant pain and disability. While the clinical results of rotator cuff repair can be good, failure of tendon healing remains a significant problem. Molecular mechanisms underlying structural failure following surgical repair remain unclear. Histologically, enhanced inflammation, disorganization of the collagen fibers, calcification, apoptosis and tissue necrosis affect the normal healing process. Mesenchymal stem cells (M ...[more]

PMID: 31154535

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Project description:BackgroundMore than 450,000 rotator cuff repairs are performed annually, yet healing of tendon to bone often fails. This failure is rooted in the fibrovascular healing response, which does not regenerate the native attachment site. Better healing outcomes may be achieved by targeting inflammation during the early period after repair. Rather than broad inhibition of inflammation, which may impair healing, the current study utilized a molecularly targeted approach to suppress IKKβ, shutting down only the inflammatory arm of the nuclear factor κB (NF-κB) signaling pathway.PurposeTo evaluate the therapeutic potential of IKKβ inhibition in a clinically relevant model of rat rotator cuff repair.Study designControlled laboratory study.MethodsAfter validating the efficacy of the IKKβ inhibitor in vitro, it was administered orally once a day for 7 days after surgery in a rat rotator cuff repair model. The effect of treatment on reducing inflammation and improving repair quality was evaluated after 3 days and 2, 4, and 8 weeks of healing, using gene expression, biomechanics, bone morphometry, and histology.ResultsInhibition of IKKβ attenuated cytokine and chemokine production in vitro, demonstrating the potential for this inhibitor to reduce inflammation in vivo. Oral treatment with IKKβ inhibitor reduced NF-κB target gene expression by up to 80% compared with a nontreated group at day 3, with a subset of these genes suppressed through 14 days. Furthermore, the IKKβ inhibitor led to enhanced tenogenesis and extracellular matrix production, as demonstrated by gene expression and histological analyses. At 4 weeks, inhibitor treatment led to increased toughness, no effects on failure load and strength, and decreases in stiffness and modulus when compared with vehicle control. At 8 weeks, IKKβ inhibitor treatment led to increased toughness, failure load, and strength compared with control animals. IKKβ inhibitor treatment prevented the bone loss near the tendon attachment that occurred in repairs in control.ConclusionPharmacological inhibition of IKKβ successfully suppressed excessive inflammation and enhanced tendon-to-bone healing after rotator cuff repair in a rat model.Clinical relevanceThe NF-κB pathway is a promising target for enhancing outcomes after rotator cuff repair.

Project description:ObjectiveThe purpose of this study was to investigate the effect of hyaluronic acid (HA) in the tendon-bone healing process after rotator cuff repair in a rabbit model.MethodsIn vitro, rat bone marrow stromal cells (rBMSCs) were cultured in media for cartilage-related and inflammation-related gene expression levels examination at 1.0 mg/mL of HA. In vivo, 48 New Zealand white rabbits underwent rotator cuff repair surgery, and they were randomly divided into three groups: (1) control group (n = 16), (2) microfracture (MF) group accepting MF treatment (n = 16) and (3) MF/HA group accepting MF with HA treatment (n = 16). Four rabbits from each group were sacrificed at 6 and 12 weeks postoperatively for histological evaluation and biomechanical testing.ResultsIn vitro experiments reveal that HA significantly decreased inflammation-related mRNA expression (IL-1, TNF?) compared with the control group. At 6 weeks after surgery, there was no significant difference of load-to-failure between groups. At 12 weeks after surgery, the mean failure load of the MF/HA group was significantly higher than that of the control group (100.5 ± 10.1 N vs. 68.0 ± 6.2 N; p = 0.0115). The mean failure load of the MF group appeared higher than that of the control group, whereas there was no significant difference (p > 0.05). Histologically, more chondrocytes were clustered at the tendon-bone interface, and more extracellular matrixes were produced in the MF/HA group. The interface of the MF/HA group appeared similar with the normal tendon-bone interface.ConclusionHA may play a crucial role in the acceleration of tendon-to-bone healing which might be through inhibiting inflammation. Rotator cuff repair using MF along with HA led to better tendon-bone healing and a subsequent increase of biomechanical strength at the repair site.The translational potential of this articleHA injection is very common for patients with rotator cuff disease because of its antiinflammatory action and adhesion prevention preoperatively. The HA injection during surgery provides an antiinflammatory effect during tendon-bone healing process and leads to better tendon-bone healing postoperatively.

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Therapeutic potential of exosomes in rotator cuff tendon healing.

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Therapeutic potential of exosomes in rotator cuff tendon healing.

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