Infrapatellar Fat Pad Mesenchymal Stromal Cell–Derived Exosomes Accelerate Tendon-Bone Healing and Intra-articular Graft Remodeling After Anterior Cruciate Ligament Reconstruction

Abstract

Background: Exosomes derived from mesenchymal stromal cells (MSCs) reportedly enhance the healing process. However, no studies have investigated the effect of exosomes from infrapatellar fat pad (IPFP) MSCs on tendon-bone healing and intra-articular graft remodeling after anterior cruciate ligament reconstruction (ACLR). Purpose: To evaluate the in vivo effect of exosomes from IPFP MSCs on tendon-bone healing and intra-articular graft remodeling in a rat model of ACLR. Study Design: Controlled laboratory study. Methods: A total of 90 skeletally mature male Sprague Dawley rats underwent unilateral ACLR using an autograft. All rats were randomly divided into 3 groups: sham injection (SI) group (n = 30), control injection (CI) group (n = 30), and IPFP MSC–derived exosome injection (IMEI) group (n = 30). At 2, 4, and 8 weeks postoperatively, tendon-bone healing and intra-articular graft remodeling were evaluated via biomechanical testing, micro–computed tomography, and histological analysis; macrophage polarization was evaluated using immunohistochemical staining. Results: Biomechanical testing demonstrated a significantly higher failure load and stiffness in the IMEI group than in the SI and CI groups at 4 and 8 weeks postoperatively. Moreover, a thinner graft-to-bone healing interface with more fibrocartilage was observed in the IMEI group at both time points. Micro–computed tomography revealed greater new bone ingrowth in the IMEI group than in the other groups, as demonstrated by smaller mean bone tunnel areas and a larger bone volume/total volume ratio. Additionally, more cellular infiltration was observed in the intra-articular graft in the IMEI group than in the other groups at 4 weeks, followed by more regularly organized fibers with mature collagen at 8 weeks. Notably, similar trends of macrophage polarization were found at both the graft-to-bone interface and the intra-articular graft in the IMEI group, with significantly fewer proinflammatory M1 macrophages and larger numbers of reparative M2 macrophages than in the SI and CI groups. Conclusion: IPFP MSC–derived exosomes accelerated tendon-bone healing and intra-articular graft remodeling after ACLR, which may have resulted from the immunomodulation of macrophage polarization. Clinical Relevance: The IPFP can be easily harvested by most orthopaedic surgeons. Exosomes from IPFP MSCs, constituting a newly emerging cell-free approach, may represent a treatment option for improving tendon-bone healing and intra-articular graft remodeling after ACLR.

Therapeutic potential and mechanisms of mesenchymal stem cell-derived exosomes as bioactive materials in tendon–bone healing

“…Similarly, Huang et al discovered that BMSC-Exos promoted tendon–bone healing after RC reconstruction in rats by inhibiting M1 macrophage polarization and M1 macrophage secretion of pro-inflammatory cytokines to suppress inflammation [ 102 ]. Consistent with these findings, a recent study has shown that IPFP MSC–derived exosomes accelerated tendon–bone healing and intra-articular graft remodeling in a rat model of ACL construction, which may have resulted from the immunomodulation of macrophage polarization, leading to decreasing M1 infiltration while promoting M2 infiltration [ 104 ]. In general, such features of exosomes make them promising tools for attenuating early inflammatory response, which is the prior condition for successful tissue healing processes [ 120 ].…”

“…Similarly, in a rat RC model, Fu et al reported that ASC-Exo loaded with hydrogels markedly enhanced osteogenic tenogenic and chondrogenic differentiation of tendon stem cells [ 103 ]. Consistent with these findings, a recent study has indicated that infrapatellar fat pad (IPFP) MSC–derived exosomes loaded in a sodium alginate hydrogel promoted tendon–bone healing and intra-articular graft remodeling in a rat ACL construction model [ 104 ]. This may provide a new therapeutic option for the application of exosomes.…”

NAMPT encapsulated by extracellular vesicles from young adipose-derived mesenchymal stem cells treated tendinopathy in a “One-Stone-Two-Birds” manner

“…The results of this study provide supportive data for ADMSC young -EVs in tendinopathy therapy and highlight their effects on both tenocytes and macrophages. Two previous studies on ADMSC-derived EVs in tendon repair did not provide the age of donors [ 31 , 32 ]; however, it was natural to conjecture that no ADMSCs from aged mice or humans were used in their studies. Thus, our data were consistent with previous studies, and additional knowledge was provided for future studies.…”

Biomechanical and Histological Results of Dual-Suspensory Reconstruction Using Banded Tendon Graft to Bridge Massive Rotator Cuff Tears in a Chronic Rabbit Model

“…At 6 and 12 weeks postoperatively, 12 rabbits in each group were sacrificed via a CO 2 overdose, 54 and the cuff-graft-humerus (C-G-H) complexes were carefully dissected for gross examination in bursal- and articular-sided views. The qualitative gross observations were performed by an experienced investigator (W.S.)…”