Background: Soft tissue allografts are essential for revision and multiple ligament surgeries in the knee, where donor-site morbidity is an issue. However, the use of allografts is associated with a higher failure rate of osteointegration. Mesenchymal stem cells (MSCs) are investigated as potential agents to enhance bone tunnel and tendon healing. Purpose: This study was conducted to analyze the effect of coating allografts with MSCs on the quality and rate of osteointegration at the allograft tendon and bone interface, and the biomechanical properties of these enhanced anterior cruciate ligament (ACL) grafts compared with controls. Study Design: Descriptive laboratory study. Methods: Bilateral ACL reconstructions using Achilles tendon allografts were performed in 36 rabbits. On 1 limb, the graft was coated with autogenous MSCs in a fibrin glue carrier, while the contralateral limb served as a control with no MSCs. The reconstructions were assessed histologically and biomechanically at 2, 4, and 8 weeks. Results: At 8 weeks, histologic analysis of the controls revealed the development of mature scar tissue resembling Sharpey fibers spanning the tendon-bone interface. In contrast, the MSC-enhanced reconstructions showed a mature zone of fibrocartilage blending from bone to the allograft, strongly resembling a normal ACL insertion. On biomechanical testing, the MSC-enhanced grafts had significantly higher load-to-failure rates than controls. However, the stiffness and Young's modulus were lower in the treatment group. Conclusions: The application of MSCs at the allograft tendon-bone interface during ACL reconstruction results in the development of an intervening zone of fibrocartilage. The use of MSCs to enhance allograft osteointegration is a novel method offering the potential of more physiologic and earlier healing, although further investigation must be conducted to improve the biomechanical strength. Clinical Relevance: Mesenchymal stem cells can improve the biologic properties of soft tissue allograft healing. Combined with the decrease in donor-site morbidity, allografts are a viable choice for the sports medicine surgeon.

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 ​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 ​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 ​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.

This study evaluates the ability of MSCs isolated from different origins--bone marrow, periosteum, or fat--to treat partial growth arrest in immature (6-week-old) New Zealand White rabbits. Up to 50% of the medial half of the proximal physis of the tibia was excised in these New Zealand White rabbits. Three weeks later, the bony bridge was excised, and fibrin glue with and without MSCs were transferred into the physeal defect of different rabbits. Contralateral tibias, without undergoing operation, served as self-control. Four groups of rabbits were involved in the study. Each group was injected separately with bone marrow-derived MSCs (group I), periosteum-derived MSCs (group II), fat-derived MSCs (group III), and fibrin glue alone (control, group IV). The rabbits were killed 8 and 16 weeks postoperatively. Clinical, radiological, and histological analyses were subsequently performed. Similar proliferative rates for three MSCs were demonstrated on days 4, 7, and 11 of primary culture. However, MSCs derived from bone-marrow and periosteum appeared to be more homogeneous than that from fat. All MSCs demonstrated chondrogenic and osteogenic differentiation potentials in vitro. The tibias in groups I and II showed significant correction of varus angulation at 16 weeks. However, the varus angulation in group III remained significantly obvious when compared with group I (p < 0.05). The length discrepancies between operated and normal tibiae in groups I, II, and III were significantly corrected compared with control (p < 0.01). In conclusion, bone-marrow and periosteum yielded more homogenous MSCs than fat, providing better correction of physeal arrest in rabbits. The source of MSCs itself could influence the success in the treatment of growth arrest.

The treatment of osteochondral defects (OCD) remains challenging. Among currently available surgical treatments for OCDs, scaffold-based treatments are promising to regenerate the osteochondral unit. However, there is still no consensus regarding the clinical effectiveness of these scaffold-based therapies for OCDs. Previous reviews have described the gradient physiological characteristics of osteochondral tissue and gradient scaffold design for OCD, tissue engineering strategies, biomaterials, and fabrication technologies. However, the discussion on bridging the gap between the clinical need and preclinical research is still limited, on which we focus in the present review, providing an insight into what is currently lacking in tissue engineering methods that failed to yield satisfactory outcomes, and what is needed to further improve these techniques. Currently available surgical treatments for OCDs are firstly summarized, followed by a comprehensive review on experimental animal studies in recent 5 years on osteochondral tissue engineering. The review will then conclude with what is currently lacking in these animal studies and the recommendations that would help enlighten the community in developing more clinically relevant implants. This review is attempting to summarize the lessons from clinical and preclinical failures, providing an insight into what is currently lacking in TE methods that failed to yield satisfactory outcomes, and what is needed to further improve these implants.

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.

To investigate the feasibility of using chitin, a natural polymer, as a scaffold to repair large growth plate defects (50% of physis) in immature rabbits, mesenchymal stem cells (MSCs) were harvested from periosteum. The compatibilities of chitin with the MSCs were investigated in vitro using immunohistochemistry and fluorescence confocal microscopy. The results showed high compatibilities of chitin. An experimental model of growth arrest was created by excising the medial half of the proximal growth plate of the tibia in 6-week-old New Zealand White rabbits. The physeal defect after excision of the bony bridge was transplanted either with no interposition (group 1), chitin alone (group 2), or chitin with MSCs (group 3). In groups 2 and 3, both angulatory deformities and length discrepancies of the tibia were corrected. The differences between group 3 and group 1 were greater than those between group 2 and group 1.