Intrinsic Tendon Regeneration After Application of Purified Exosome Product: An In Vivo Study

Abstract

Background: Tendons are primarily acellular, limiting their intrinsic regenerative capabilities. This limited regenerative potential contributes to delayed healing, rupture, and adhesion formation after tendon injury. Purpose: To determine if a tendon’s intrinsic regenerative potential could be improved after the application of a purified exosome product (PEP) when loaded onto a collagen scaffold. Study Design: Controlled laboratory study. Methods: An in vivo rabbit Achilles tendon model was used and consisted of 3 groups: (1) Achilles tenotomy with suture repair, (2) Achilles tenotomy with suture repair and collagen scaffold, and (3) Achilles tenotomy with suture repair and collagen scaffold loaded with PEP at 1 × 1012 exosomes/mL. Each group consisted of 15 rabbits for a total of 45 specimens. Mechanical and histologic analyses were performed at both 3 and 6 weeks. Results: The load to failure and ultimate tensile stress were found to be similar across all groups ( P ≥ .15). The tendon cross-sectional area was significantly smaller for tendons treated with PEP compared with the control groups at 6 weeks, which was primarily related to an absence of external adhesions ( P = .04). Histologic analysis confirmed these findings, demonstrating significantly lower adhesion grade both macroscopically ( P = .0006) and microscopically ( P = .0062) when tendons were treated with PEP. Immunohistochemical staining showed a greater intensity for type 1 collagen for PEP-treated tendons compared with collagen-only or control tendons. Conclusion: Mechanical and histologic results suggested that healing in the PEP-treated group favored intrinsic healing (absence of adhesions) while control animals and animals treated with collagen only healed primarily via extrinsic scar formation. Despite a smaller cross-sectional area, treated tendons had the same ultimate tensile stress. This pilot investigation shows promise for PEP as a means of effectively treating tendon injuries and enhancing intrinsic healing. Clinical Relevance: The production of a cell-free, off-the-shelf product that can promote tendon regeneration would provide a viable solution for physicians and patients to enhance tendon healing and decrease adhesions as well as shorten the time required to return to work or sports.

Dose–response analysis after administration of a human platelet‐derived exosome product on neurite outgrowth in vitro

“…While the neuroregenerative effect of exosomes has recently been highlighted and their application in tissue regeneration (i.e., bone, wound, and tendon) has been increasingly investigated, little is known about the mechanisms of action of exosomes (Ikumi et al, 2021;Kisby et al, 2021;Ren et al, 2021;Shi et al, 2021Shi et al, , 2023Wellings et al, 2021). In this study, a PEP dose-response analysis was successfully investigated and examined effects of neurite outgrowth in vitro.…”

“…The exosomes are lyophilized and stored as a stabilized powder cake in glass vials at RT. PEP may have a great potential to enhance tissue repair and regeneration (Ikumi et al, 2021;Kisby et al, 2021;Ren et al, 2021;Shi et al, 2021Shi et al, , 2023Wellings et al, 2021) protein-1, hepatocyte growth factor, and vascular endothelial growth factor (Ikumi et al, 2021). Peripheral nerve basic science research using MSCs has been greatly studied over the past decades.…”

The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration

“…More organized and denser collagenous tissue and fewer inflammatory cells were also displayed at the tendon-bone interface after rotator cuff repair in the TISSEEL–PEP group [ 90 ]. Wellings et al demonstrated significantly fewer external adhesions and improved mechanical functions with the application of PEP loaded onto a collagen scaffold, indicating that the off-the-shelf PEP product favored intrinsic healing instead of extrinsic healing [ 91 ].…”

“…Based on the mechanisms, many studies have established bio-engineered exosomal products that show benefits to soft tissue wound healing as listed in Figure 1 (right). Among them, PEP can significantly enhance both tendon [ 74 , 91 ] and peripheral nerve [ 184 ] regeneration, but has not been studied on skeletal muscles. Future studies regarding PEP’s effects on muscle repair can be useful.…”

Application of Orthobiologics in Achilles Tendinopathy: A Review

“…Supplementation of collagen with purified exosome product demonstrated intrinsic healing in tendon disorder. Application of exosomes for tendon injury show less microscopic and macroscopic circumferential adhesions [ 143 ]. BM-MSC-derived exosomes loaded with fibrin glue enhance the expression of tenomodulin and type 1 collagen, improve the biomechanical properties of neotendon, and facilitate the differentiation and proliferation of resident stem cells into local TSCs in vivo [ 144 ].…”