Adipose-Derived Stem Cell Sheets Improve Early Biomechanical Graft Strength in Rabbits After Anterior Cruciate Ligament Reconstruction

Abstract

Background: Although various reconstruction techniques are available for anterior cruciate ligament (ACL) injuries, a long recovery time is required before patients return to sports activities, as the reconstructed ACL requires time to regain strength. To date, several studies have reported use of mesenchymal stem cells in orthopaedic surgery; however, no studies have used adipose-derived stem cell (ADSC) sheets in ACL reconstruction (ACLR). Hypothesis: ADSC sheet transplantation can improve biomechanical strength of the autograft used in ACLR. Study Design: Controlled laboratory study. Methods: A total of 68 healthy Japanese white rabbits underwent unilateral ACLR with a semitendinosus tendon autograft after random enrollment into a control group (no sheet; n = 34) and a sheet group (ADSC sheet; n = 34). At 2, 4, 8, 16, and 24 weeks after surgery, rabbits in each group were sacrificed to evaluate tendon-bone healing using histological staining, micro–computed tomography, and biomechanical testing. At 24 weeks, scanning transmission electron microscopy of the graft midsubstance was performed. Results: The ultimate failure load for the control and sheet groups, respectively, was as follows: 17.2 ± 5.5 versus 37.3 ± 10.3 ( P = .01) at 2 weeks, 28.6 ± 1.9 versus 47.4 ± 10.4 ( P = .003) at 4 weeks, 53.0 ± 14.3 versus 48.1 ± 9.3 ( P = .59) at 8 weeks, 66.2 ± 9.3 versus 95.2 ± 43.1 ( P = .24) at 16 weeks, and 66.7 ± 27.3 versus 85.3 ± 29.5 ( P = .39) at 24 weeks. The histological score was also significantly higher in the sheet group compared with the control group at early stages up to 8 weeks. On micro–computed tomography, relative to the control group, the bone tunnel area was significantly narrower in the sheet group at 4 weeks, and the bone volume/tissue volume of the tendon-bone interface was significantly greater at 24 weeks. Scanning transmission electron microscopy at 24 weeks indicated that the mean collagen fiber diameter in the midsubstance was significantly greater, as was the occupation ratio of collagen fibers per field of view, in the sheet group. Conclusion: ADSC sheets improved biomechanical strength, prevented bone tunnel enlargement, and promoted tendon-bone interface healing and graft midsubstance healing in an in vivo rabbit model. Clinical Relevance: ADSC sheets may be useful for early tendon-bone healing and graft maturation in ACLR.

A Cross-Sectional Survey Of Availability And Technical Feasibility Of Basic Medical Equipment To Run Community-Based Clinical Trial Sites, In Cross River State, Nigeria

“…Matsumoto et. al., [114] had similar findings indicating improved early biomechanical strength and tendon-bone healing. In their study they also used a rabbit model undergoing ACLR with ST autograft.…”

Bioactive Decellularized Tendon-Derived Stem Cell Sheet for Promoting Graft Healing After Anterior Cruciate Ligament Reconstruction

“…41 The same group later showed that BMP 2–transduced ACL-derived CD34 + cells further improved graft osteointegration and tensile strength of the reconstructed complex. 25 Cell sheets formed by adipose-derived stromal cells 39 were also reported to improve the biomechanical strength of the reconstructed complex at the early stage after ACLR. Although these cell sheets all showed regenerative capacity, ligament-derived stem cells/TDSCs showed high proliferation, clonogenicity, and multilineage differentiation potential, including ligamentous/tenogenic differentiation potential, and hence may have better potential for tendon and tendon-bone junction repair.…”

“…Considering the biocompatibility of scaffolds and inhomogeneous injection of cells, the cell sheet approach is developing rapidly. 25,39,41 The connective tissue growth factor and ascorbic acid–treated tendon-derived stem cell (TDSC) sheet has been shown to promote tendon healing after acute injury and graft healing after ACLR in animal models. 37,38 However, the need to maintain cell viability and stability and the potential uncontrolled actions of transplanted cells are key issues to be solved for the clinical translation of all stem cell–based therapies.…”

Tackling the Challenges of Graft Healing After Anterior Cruciate Ligament Reconstruction—Thinking From the Endpoint

“…In preclinical studies, osteoinductive factors, such as bone morphogenetic protein-2 (BMP-2) ( Crispim et al, 2018 ), α-fibroblast growth factor (α-FGF) ( Lu et al, 2018 ), basic fibroblast growth factor (bFGF) ( Kimura et al, 2008 ), granulocyte colony-stimulating factor (G-CSF) ( Sasaki et al, 2008 ), and transforming growth factor-β1 (TGF-β1) ( Yamazaki et al, 2005 ) enhanced tunnel bone formation and, hence, promoted tendon graft-to-bone tunnel healing after ACLR ( Table 2 ). Besides, cells like ACL-derived CD34 + cell ( Mifune et al, 2012 ; Mifune et al, 2013 ), tendon-derived stem cells (TDSCs) ( Lui et al, 2014c ), bone marrow-derived MSCs (BMSCs) ( Hur et al, 2019 ), and adipose-derived stem cells (ADSCs) ( Matsumoto et al, 2021 ) had been applied directly or made into cell sheets for the enhancement of bone formation after ACLR. These cells could release osteogenic factors and promote osteogenesis at the graft–bone interface.…”