Demineralized bone matrix to augment tendon-bone healing:a systematic review

BACKGROUND: Following injury to the rotator cuff and anterior cruciate ligament, a direct enthesis is not regenerated, and healing occurs with biomechanically inferior fibrous tissue. Demineralized bone matrix (DBM) is a collagen scaffold that contains growth factors and is a promising biological material for tendon and ligament repair because it can regenerate a direct fibrocartilaginous insertion via endochondral ossification. Purpose: To provide a comprehensive review of the literature investigating the use of DBM to augment tendon-bone healing in tendon repair and anterior cruciate ligament reconstruction (ACLR). Study Design: Systematic review. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for preclinical and clinical studies that evaluated the use of DBM in tendon repair and ACLR. Search terms included the following: ("demineralized bone matrix" OR "demineralized cortical bone") AND ("tissue scaffold" OR "tissue engineering" OR "ligament" OR "tendon" OR "anterior cruciate ligament" OR "rotator cuff"). Peer-reviewed articles written in English were included, and no date restriction was applied (searches performed February 10, 2017). Methodological quality was assessed with peer-reviewed scoring criteria. RESULTS: The search strategy identified 339 articles. After removal of duplicates and screening according to inclusion criteria, 8 studies were included for full review (tendon repair, n = 4; ACLR, n = 4). No human clinical studies were identified. All 8 studies were preclinical animal studies with good methodological quality. Five studies compared DBM augmentation with non-DBM controls, of which 4 (80%) reported positive findings in terms of histological and biomechanical outcomes. CONCLUSION: Preclinical evidence indicates that DBM can improve tendon-bone healing, although clinical studies are lacking. A range of animal models of tendon repair and ACLR showed that DBM can re-create a direct fibrocartilaginous enthesis, although the animal models are not without limitations. Before clinical trials are justified, research is required that determines the best source of DBM (allogenic vs xenogenic) and the best form of DBM (demineralized cortical bone vs DBM paste) to be used in them

Mesenchymal stromal cells and platelet-rich plasma promote tendon allograft healing in ovine anterior cruciate ligament reconstruction

Purpose The effect of bone marrow mesenchymal stromal cells (BMSCs) and platelet-rich plasma (PRP) on tendon allograft maturation in a large animal anterior cruciate ligament (ACL) reconstruction model was reported for the first time. It was hypothesised that compared with non-augmented ACL reconstruction, BMSCs and PRP would enhance graft maturation after 12 weeks and this would be detected using magnetic resonance imaging (MRI). Methods Fifteen sheep underwent unilateral tendon allograft ACL reconstruction using aperture fixation and were randomised into three groups (n = 5). Group 1 received 10 million allogeneic BMSCs in 2 ml fibrin sealant; Group 2 received 12 ml PRP in a plasma clot injected into the graft and bone tunnels; and Group 3 (control) received no adjunctive treatment. At autopsy at 12 weeks, a graft maturation score was determined by the sum for graft integrity, synovial coverage and vascularisation, graft thickness and apparent tension, and synovial sealing at tunnel apertures. MRI analysis (n = 2 animals per group) of the signal–noise quotient (SNQ) and fibrous interzone (FIZ) was used to evaluate intra-articular graft maturation and tendon–bone healing, respectively. Spearman’s rank correlation coefficient (r) of SNQ, autopsy graft maturation score and bone tunnel diameter were analysed. Results The BMSC group (p = 0.01) and PRP group (p = 0.03) had a significantly higher graft maturation score compared with the control group. The BMSC group scored significantly higher for synovial sealing at tunnel apertures (p = 0.03) compared with the control group. The graft maturation score at autopsy significantly correlated with the SNQ (r = − 0.83, p < 0.01). The tunnel diameter of the femoral tunnel at the aperture (r = 0.883, p = 0.03) and mid-portion (r = 0.941, p = 0.02) positively correlated with the SNQ. Conclusions BMSCs and PRP significantly enhanced graft maturation, which indicates that orthobiologics can accelerate the biologic events in tendon allograft incorporation. Femoral tunnel expansion significantly correlated with inferior maturation of the intra-articular graft. The clinical relevance of this study is that BMSCs and PRP enhance allograft healing in a translational model, and biological modulation of graft healing can be evaluated non-invasively using MRI

Augmentation of Anterior Cruciate Ligament Reconstruction Graft Healing using Demineralised Bone Matrix, Mesenchymal Stromal Cells and Platelet-Rich Plasma

Successful anterior cruciate ligament reconstruction (ACLR) relies on graft healing, which consists of ligamentisation and tendon-bone healing. Orthopaedic biologics (orthobiologics) can potentially enhance ACLR and the effect of demineralised bone matrix (DBM), bone marrow mesenchymal stromal cells (BMSCs) and platelet-rich plasma (PRP) have been investigated in small animal models with some positive results. These treatments have not been investigated in a translational large animal model that utilises graft fixation techniques similar to those used in humans. The aim of this thesis was to investigate the hypothesis that DBM, BMSCs and PRP will each improve graft healing in an ovine model of ACLR. The hypothesis was initially investigated by developing an ovine model for ACLR using demineralised bone. The tensile strength of ovine demineralised cortical bone (DCB) strips from femur and tibia, taken from different aged donors, was investigated, and followed by measuring the strength of DCB in a cadaveric model of ovine ACLR. DCB derived from young tibia had the greatest strength but owing to inferior tensile properties when compared with ACLR using a tendon graft, was not used in an ovine model. Instead, allogenic DBM paste was used in the in vivo ovine model to augment graft healing with an allogenic superficial digital flexor tendon. After 12 weeks in vivo ACLR augmented with either DBM paste, allogenic BMSCs and autologous PRP were compared with non-augmented controls. DBM was associated with significantly improved tendon-bone healing in the femoral tunnel, as evidenced by increase bone formation on µCT and a morphologically superior insertion on histology. No significant differences were seen with BMSCs and PRP compared with the control, except in the macroscopic appearance of the intraarticular graft at autopsy. It was concluded that, although the effect was limited to healing in the femoral tunnel, only DBM treatment significantly improved graft healing

Characterisation of the tensile properties of Demineralised Cortical Bone when used as an anterior cruciate ligament allograft

Background: Graft choice in anterior cruciate ligament (ACL) reconstruction remains controversial and some grafts fail due to inadequate osteointegration. Demineralised cortical bone (DCB) is an osteoinductive collagen-based scaffold. The aim of this study was to measure the tensile properties of DCB from different locations and from different ages, and determine its compatibility with current ACL fixation systems. Methods: The tensile properties of DCB manufactured from femur and tibia of young (9 month) and old (2–3 years) sheep was measured to determine the most appropriate graft choice. The ultimate load and stiffness of DCB allograft using two fixation systems, interference screws and sutures tied around screw posts, was measured ex vivo in an ovine ACL reconstruction model. Comparison was made with superficial digital flexor tendon (SDFT) and ovine ACL. Results: DCB derived from young tibia had the highest ultimate load and stiffness of 67.7 ± 10.6 N and 130.2 ± 64.3 N/mm respectively. No DCB fixation system reached the published peak in vivo force through the ovine ACL of 150 N. SDFT fixation with interference screws (308.2 ± 87.3 N) did reach the in vivo threshold but was significantly weaker than ovine ACL (871.0 ± 64.2 N). Conclusion: The tensile properties of DCB were influenced by the donor age and bone. Owing to inferior tensile properties and incompatibility with suspensory fixation devices, this study indicates DCB is inferior to current tendon grafts options for ACL reconstruction