Mesenchymal stem cell exosomes in bone regenerative strategies-a systematic review of preclinical studies.

The ability of bone for regeneration has long been recognized. However, once beyond a critical size, spontaneous regeneration of bone is limited. Several studies have focused on enhancing bone regeneration by applying mesenchymal stromal/stem cells (MSCs) in the treatment strategies. Despite the therapeutic efficacy of MSCs in bone regeneration, cell-based therapies are impeded by several challenges in maintaining the optimal cell potency and viability during expansion, storage, and final delivery to patients. Recently, there has been a paradigm shift in therapeutic mechanism of MSCs in tissue repair from one based on cellular differentiation and replacement to one based on secretion and paracrine signaling. Among the broad spectrum of trophic factors, extracellular vesicles â€‹particularly the exosomes have been reported to be therapeutically efficacious in several injury/disease indications, including bone defects and diseases. The current systematic review aims to summarize the results of the existing animal studies which were conducted to evaluate the therapeutic efficacy of MSC exosomes for bone regeneration. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis â€‹guidelines, the PubMed and The Cochrane Library database were searched for relevant controlled preclinical animal studies. A total of 23 studies were identified, with the total sample size being 690 rats or mice and 38 rabbits. Generally, MSC exosomes were found to be efficacious for bone regeneration in animal models of bone defects and diseases such as osteonecrosis and osteoporosis. In these studies, MSC exosomes promoted new bone formation with supporting vasculature â€‹and displayed improved morphological, biomechanical, and histological outcomes, coupled with positive effects on cell survival, proliferation, and migration, osteogenesis, and angiogenesis. Unclear-to-low risk in bias and incomplete reporting in the primary studies highlighted the need for standardization in outcome measurements and reporting. Further studies in large animal models to establish the safety and efficacy would provide useful information on guiding the design of clinical trials.

Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration.

OBJECTIVE: Clinical and animal studies have demonstrated the efficacy of mesenchymal stem cell (MSC) therapies in cartilage repair. As the efficacy of many MSC-based therapies has been attributed to paracrine secretion, particularly extracellular vesicles/exosomes, we determine here if weekly intra-articular injections of human embryonic MSC-derived exosomes would repair and regenerate osteochondral defects in a rat model. METHODS: In this study, osteochondral defects were created on the trochlear grooves of both distal femurs in 12 adult rats. In each animal, one defect was treated with 100 µg exosomes and the contralateral defect treated with phosphate buffered saline (PBS). Intra-articular injections of exosomes or PBS were administered after surgery and thereafter weekly for a period of 12 weeks. Three unoperated age-matched animals served as native controls. Analyses were performed by histology, immunohistochemistry, and scoring at 6 and 12 weeks after surgery. RESULTS: Generally, exosome-treated defects showed enhanced gross appearance and improved histological scores than the contralateral PBS-treated defects. By 12 weeks, exosome-treated defects displayed complete restoration of cartilage and subchondral bone with characteristic features including a hyaline cartilage with good surface regularity, complete bonding to adjacent cartilage, and extracellular matrix deposition that closely resemble that of age-matched unoperated control. In contrast, there were only fibrous repair tissues found in the contralateral PBS-treated defects. CONCLUSION: This study demonstrates for the first time the efficacy of human embryonic MSC exosomes in cartilage repair, and the utility of MSC exosomes as a ready-to-use and 'cell-free' therapeutic alternative to cell-based MSC therapy.

Enhancement of meniscal repair in the avascular zone using mesenchymal stem cells in a porcine model.

We hypothesised that meniscal tears treated with mesenchymal stem cells (MSCs) together with a conventional suturing technique would show improved healing compared with those treated by a conventional suturing technique alone. In a controlled laboratory study 28 adult pigs (56 knees) underwent meniscal procedures after the creation of a radial incision to represent a tear. Group 1 (n = 9) had a radial meniscal tear which was left untreated. In group 2 (n = 19) the incision was repaired with sutures and fibrin glue and in group 3, the experimental group (n = 28), treatment was by MSCs, suturing and fibrin glue. At eight weeks, macroscopic examination of group 1 showed no healing in any specimens. In group 2 no healing was found in 12 specimens and incomplete healing in seven. The experimental group 3 had 21 specimens with complete healing, five with incomplete healing and two with no healing. Between the experimental group and each of the control groups this difference was significant (p < 0.001). The histological and macroscopic findings showed that the repair of meniscal tears in the avascular zone was significantly improved with MSCs, but that the mechanical properties of the healed menisci remained reduced.

Mesenchymal stem cells in musculoskeletal tissue engineering: a review of recent advances in National University of Singapore.

A key factor in the tissue engineering approach to tissue repair and regeneration is the use of appropriate cells. Mesenchymal stem cells (MSCs) are derived from bone marrow stroma or connective tissues and they have the potential to differentiate into various mesenchymal cell lines in vitro and in vivo. These cells hold great promise for musculoskeletal tissue engineering. This review is based mainly on the work which has been done in the National University of Singapore on the use of MSCs for engineering cartilage, growth plate, bone and tendon/ligament as well as the clinical trail of autologous chondrocyte implantation. It can help to shape future research on musculoskeletal tissue engineering.

Spinal fusion and instrumentation for paediatric neuromuscular scoliosis: retrospective review.

PURPOSE: A retrospective study was conducted to review the surgical results among 24 patients with neuromuscular scoliosis, who were treated with spinal instrumentation and fusion at the Department of Orthopaedic Surgery, National University Hospital, Singapore between March 1993 and December 1998. METHODS: We examined complete hospital records of patients who had scoliosis due to aetiologies such as spinal muscular atrophy, cerebral palsy, Duchenne muscular dystrophy, and congenital myopathies. The mean age of patients was 10.6 years (range, 6-14 years) and the mean follow-up duration was 5.5 years. RESULTS: 18 patients had posterior surgery alone, whereas 4 had an anterior release with posterior instrumentation, and 2 had an anterior fusion with instrumentation. The mean length of stay in the intensive care unit was 2 days and the mean duration of hospital stay was 11 days. The mean correction in scoliosis angle ranged from 75.6 degrees to 25.7 degrees. All patients could at least sit without support postoperatively. The one-second forced expiratory volume and forced vital capacity were, in general, maintained throughout the follow-up. There were 2 major complications and 2 minor ones; these were pseudarthrosis with rod breakage requiring revision, deep infection necessitating hardware removal, superficial infection that responded to antibiotics, and urinary tract infection requiring 3 weeks of antibiotic treatment. There were no deaths or any neurological complications after instrumentation. CONCLUSION: Spinal stabilisation and fusion in children with neuromuscular scoliosis is a safe and effective treatment modality. The effect of surgery on long-term pulmonary function, however, remains controversial and needs to be addressed.