Mesenchymal Stem Cells in BTB allograft ACL reconstruction:A Prospective Randomized Controlled Trial

Abstract

Biologic adjuncts have shown promise in improving clinical outcomes following ACL reconstruction (ACLR). Post-operative ligament construct healing is a slow process that involves graft incorporation into bone tunnel sites and intra-articular graft ligamentization, during which failure load and stiffness of grafts decreases. Radiologic imaging has been shown to correspond with histological changes related to the ligamentization process (Hakozaki et al.). The purpose of this study is to evaluate the effects of bone marrow-aspirate concentrate (BMAC), containing mesenchymal stem cells (MSCs), on graft healing, maturation, and integration in patients, as well as patient reported outcome measures (PROMs), undergoing ACL reconstruction with bone-patellar tendon-bone (BTB) allografts. : IRB approval was obtained for a single-blinded randomized controlled trial on patients undergoing ACLR utilizing BTB allografts. Patients were randomized to receive either MSC injection into the ACL allograft or a sham incision with no BMAC harvest or graft injection. Bone marrow aspirate was harvested from the anterior superior iliac crest and concentrated via centrifuge. A minimum of 1.25mL of BMAC was injected into the tendinous/ligamentous portion of the BTB allograft at proximal, middle, and distal sites, with 0.5 mL reserved for post-operative ELISA assay and receptor testing for validation of MSCs within the BMAC harvest. Post-operatively, patients underwent identical standard, accelerated rehabilitation protocols. Outcomes were collected at 6 weeks, 3 months, 6 months, 9 months, 12 months, and 24 months. Knee range of motion, pivot-shift test, anterior-posterior translation, and patient reported outcomes using the KOOS Jr, IKDC, Lysholm surveys, and PROMIS scores including physical function, pain interference, and depression were assessed at the above time points. MRI was performed at 3 months and 9 months. The T2-weighted MRI Signal Intensity Ratio (SIR) of the reconstructed ACL was calculated and standardized to the intensity of the PCL by a musculoskeletal radiologist. A total of 60 patients have been enrolled (54% female, 57% BMAC). The mean age for BMAC and control groups was 34.9 and 35.8, respectively (p=0.7). Mean graft soaking time was 15.9 minutes. Mean time from injury to surgery was 3.7±3.7 months for control and 6.8±14.6 months for BMAC patients (p=0.305). Signal intensity ratios at 3 months revealed significant improvement in the BMAC cohort as compared to control (3.47 and 1.78, respectively, p<0.05). Analysis of secondary clinical outcomes demonstrated that the BMAC cohort significantly outperformed control in degrees of flexion (133º vs. 128º, p=0.02), International Knee Documentation Committee (IKDC) score (64.2 vs. 61.7, p=0.04), and VR12 Mental Health (57.0 vs. 54.7, p=0.002) at 9 months postoperatively. MSC injection into BTB ACL allograft reconstructions demonstrated significantly superior signal intensity ratio on radioimaging during the early ligamentization process. We also observed improved PROMs during the early post-operative period in patients receiving BMAC. This study provides a basis and rationale for continued investigation and application of biologic augmentation of ACLR allograft constructs. Future studies may further elucidate the impact of BMAC on the ligamentization process, clinical outcomes, and PROMs.