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

Elizabeth P Wellings; Tony Chieh-Ting Huang; Jialun Li; Timothy E Peterson; Alexander W Hooke; Andrew Rosenbaum; Chunfeng D Zhao; Atta Behfar; Steven L Moran; Matthew T Houdek

doi:10.1177/23259671211062929

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

Orthop J Sports Med. 2021 Dec 17;9(12):23259671211062929. doi: 10.1177/23259671211062929. eCollection 2021 Dec.

Authors

Affiliations

¹ Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota, USA.
² Division of Plastic Surgery, Mayo Clinic, Rochester, Minnesota, USA.
³ Department of Regenerative Medicine, Mayo Clinic, Rochester, Minnesota, USA.
⁴ Van Cleve Cardiac Regeneration Medicine Program, Mayo Clinic, Rochester, Minnesota, USA.
⁵ Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota, USA.

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.

Keywords: exosomes; growth factors/healing enhancement; injury prevention; tendon biomechanics; tendon healing; tissue engineering.