Current Stem Cell Research & Therapy - Volume 10, Issue 1, 2015

In this review, we analysed the role of stem cell and growth factor therapy on rotator cuff tendon repair. The injury to the rotator cuff tendons can be sustained in numerous ways and generally causes significant pain and disability to the affected individual. Following surgical repair of ruptured rotator cuff tendons re-rupture rates can be as high as 20-60%. In order to augment this repair process and to decrease the re-rupture rates tissue engineering methods can be used. These include the use of stem cells and growth factors. Mesenchymal stem cells are stem cells which can differentiate into a variety of connective tissue cell types and can therefore be utilised in repairing tendons. So far there has only been one human study using stem cells in rotator cuff tendon repair. This study has produced a positive result but consisted of only 14 patients and lacks a control group for comparison. Similar work has also been done using growth factors. Both individual and combination growth factor therapy have been used to improve rotator cuff tendon repair. However, the results so far have been disappointing with growth factors. For the purpose of future studies better techniques should be explored with regards to the delivery of stem cells and growth factors as well as the possibility of combining growth factor and stem cell therapy to improve repair rates.

Background: The management and treatment of ligamentous injuries within an orthopaedic population has continued to evolve throughout the last several decades. Limitations with autograft, allograft and synthetics have led to research into tissue engineering using scaffolds and mesenchymal stem cells. Objectives: This systematic review aims to examine and summarise the pre clinical in-vivo studies and limited clinical studies on the use of scaffolds in the treatment of ligamentous injuries Data sources: Databases: PubMed, CINAHL, Web of science, Medline, Cochrane library and Embase. The following key words and search terms were used: scaffolds, ligament, mesenchymal stem cells, tissue engineering, clinical, and preclinical. Methods: A total of 118 articles were reviewed. 19 articles were identified as relevant for the purpose of this systematic literature review. An additional 2 articles were sourced from the reference list of reviewed articles. Results: Three tables of studies were constructed: pre clinical biological scaffolds, pre clinical synthetic scaffolds and clinical scaffolds. Conclusions: There is a large body of pre clinical evidence that the use of scaffolds combined with mesenchymal stem cells can be a viable option in the regeneration of ligamentous structures with biological and mechanical properties suitable for function. There is, however, limited clinical evidence supporting the use of recently developed scaffolds and historical evidence of synthetic scaffolds failing in the management of anterior cruciate ligament repairs. There appears to be no consensus in the literature as to the nature of the scaffold material that is most suitable for clinical trials. No randomised control trials have yet been conducted.

Platelet Rich Plasma (PRP) and growth factors have had encouraging results in several surgical specialties. Their use in orthopaedics is increasing and has been trialed in fracture management, spinal fusion and tendon and ligament healing. Anterior cruciate ligament (ACL) injuries are a significant economic burden and often require surgical reconstruction. This review article used laboratory and clinical studies to evaluate the effectiveness of PRP and growth factors as an adjunct to ACL reconstruction. Overall, the results of studies to date have been disappointing especially given the success in other specialties. PRP has been relatively successful in improving vascularization within the tibial tunnel but less so in the femoral tunnels. The targeting of specific growth factors seems to show more promise than generic PRP injections with vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and transforming growth factor-beta (TGF-β) showing the most significant results in graft healing. Further trials are still required before a definitive conclusion can be reached.

Tendon and ligament injuries are common, and repair slowly with reduced biomechanical properties. With increasing financial demands on the health service and patients to recover from tendon and ligament injuries faster, and with less morbidity, health professionals are exploring new treatment options. Tissue engineering may provide the answer, with its unlimited source of natural cells that in the correct environment may improve repair and regeneration of tendon and ligament tissue. Mesenchymal stem cells have demonstrated the ability to self renew and have multilineage differentiation potential. The use of bone marrow-derived mesenchymal stem cells has been reported, however significant in vitro culture expansion is required due to the low yield of cells, which has financial implications. Harvesting of bone marrow cells also has associated morbidity. Several studies have looked at alternative sources for mesenchymal stem cells. Reports in literature from animal studies have been encouraging, however further work is required. This review assesses the potential sources of mesenchymal stem cells for tissue engineering in tendons and ligaments.

Achilles tendon injuries are common but complex in nature. Healing occurs via scar tissue formation leading to poor patient outcomes. Currently surgical and non-surgical treatment leads to suboptimal tendon healing and has complications. Tissue engineering is an advancing field that can either augment surgical repair or provide an alternative method for Achilles tendon repair. This article will explore the principles behind tissue engineering in Achilles tendon repair. Furthermore it will describe the current literature regarding the different types of stem cells used in Achilles tendon repair, how different growth factors augment tendon repair, as well as the role of biomaterials in tissue engineering.

Bone tissue engineering is a promising therapeutic option to enhance tissue regeneration and repair. The development of bone tissue engineering is directly related to changes in materials technology. While the inclusion of material requirements is standard in the design process of engineered bone substitutes, it is critical to incorporate clinical requirements in order to engineer a clinically relevant device. This review focuses on the potentials of bone marrow derived mesenchymal stem cells (BM-MSCs) in trauma and orthopaedics and presents the need for bone tissue-engineered alternatives.

Purpose: This systematic review analyzes histological scoring systems for degenerative tendon-enthesis changes, ex vivo tendon-enthesis repair and tissue-engineered tendon-enthesis repair. A secondary aim is to establish the validity and applicability of these scores to find a comprehensive and validated histological scoring system for the evaluation of tendon-enthesis tissue. Methods: We performed a systematic review of the literature by analyzing the following databases: PubMed, Embase, Medline, CINAHL, and Cochrane. The methodology of the study was developed according to the PRISMA guidelines. Results: Twenty-seven articles, describing a total of 9 scores for tendinopathy, 6 scores for tendon ruptures, and 12 scores for tendon regeneration were included. For enthesis changes, 4 studies describe a total of 3 scores for enthesopathy and 1 scores for enthesis regeneration. The Movin score and its modifications seem be the more comprehensive to assess the degenerative changes; the Soslowsky score, the Watkins score, the Novel scoring system and the Burssens score seem be the more comprehensive to assess tendon repair process. Only the Matthys score assesses the histological changes in enthesopathies, and the modified Watkins score has been well applied to assess enthesis repair. Conclusion: The assessment of tendon-enthesis structure can be performed with several histological scoring systems previously published in literature. However, no studies have been performed to validate these score in research settings. Further experimental and clinical studies should be developed to provide a comprehensive and validated scoring system for the histological assessment of tendon-enthesis repair.

Purpose: In the last decades, new evidences supported the relationship polymorphisms and the susceptibility to develop ligament and tendon injuries. We performed a review of the genetic factors involved in tendon and ligament injuries. Methods: A review of the literature has been performed in a systematic fashion by using the terms “sports”, “ligaments”, “injuries”, “tendon” and “genetics”. PubMed, Embase, CINAHL, Cochrane, Medline and Google Scholar databases were screened over the years 1984–2014. Results: The genes currently associated with tendon and ligament injuries include gene encoding for collagen, tenascin, matrix metallopeptidase, and growth factors. Conclusions: Tendon and ligament injuries do not have a single genetic cause. Predictive genomics DNA profiling for athletic performance and sport injuries allows to understand what genetic advantages have to be exploited, and which genetic barriers have to be overcome. Although these findings could explain why an individual is able to excel in one sport discipline rather than in a different one, and why an individual develops more injuries than another one, many other factors should be taken into account. Indeed, environment and lifestyle play a critical role in combination with gene profile in determing tendon and ligament injuries.

Background: Fibronectin, a large dimeric plasma glycoprotein found only in vertebrates, is a core component of several extracellular matrices. Integrin receptors regulate different cell activities. Fibronectin expression patterns in intervertebral disc have not been extensively studied. The aim of this study was to evaluate the distribution of fibronectin in the different regions of the intervertebral disc, and in intervertebral discs of different levels of monkeys. Methods: Spines of nine 3-4 year-old cynomolgus monkeys (Macaca fascicularis) were studied. From every spine, 5 vertebral motion segments were sectioned (C5-C6, T3-T4, T9-T10, L2-L3, L4-L5) producing forty-five vertebral motion segments. These were bisected in the sagittal plane. Immunohistochemical studies were performed using specific antibodies to detect fibronectin. Results: A positive immunoreaction for fibronectin was found in the endplates, in the peripheral annulus fibrosus, and in the longitudinal ligaments. There was no fibronectin immunoreactivity in the nucleus pulposus and in the central annular region close to the nucleus pulposus. There were no differences in immunoreactivity to fibronectin among discs of different levels and discs of different monkeys. Conclusions: Fibronectin may exert a role in the organization of the extracellular matrix of the intervertebral discs. Identifying the structural features of the intervertebral disc extracellular matrix may help to understand the mechanisms of intervertebral disc pathology.

Objective: To evaluate the effects of VEGF, BMP-7, MatrigelTM, hyaluronic acid, in vitro cultured chondrocytes and trephination to promote and enhance the healing process of avascular meniscal tears in an animal model. Methods: A longitudinal tear was produced in the inner avascular part of the meniscus of 24 sheeps. Each tear was treated with trephination technique and suture. The animals were divided into 6 groups to receive a different treatment: control (I); VEGF, BMP-7, MatrigelTM, hyaluronic acid, in vitro cultured chondrocytes. At 8 weeks from surgery, meniscal samples were explanted and analyzed by histology, immunohistochemistry, and histomorphometry. Results: At the histological examination, Group IV and VI showed a partial closure of the meniscal lesion, whereas Group I, II, III, and V did not show any evidence of healing. In the group IV, the healed tissue represented the 22.95% of the lesion area. In the group VI, the healed tissue represented the 43.75% of the lesion area. Conclusions: Autologous chondrocytes and BMP-7 associated with trephination and suture techniques enhanced healing process of meniscal tears in the avascular inner third of the meniscus in ovine model.

Purpose: The aim of the present study was to compare the potential for cartilage repair of fresh amniotic membrane (AM), cryopreserved AM and cryopreserved AM previously cultured with bone marrow mesenchymal stem cells (BM-MSCs) in an in vivo sheep animal model. Methods: A full-thickness cartilage defect was surgically produced in 12 adult sheep, in the bearing region of the lateral femoral condyle. The animals were randomized into 4 groups (n=3): no treatment of the defect (G1); filling with fresh AM (G2); with cryopreserved AM previously cultivated with BM-MSCs (G3); with cryopreserved AM alone (G4). Postoperatively, the full load was possible. At two months, the animals were euthanized. The quality of the new synthesized tissue was evaluated with the macroscopic, by using International Cartilage Repair Society (ICRS) scale, and histological analyses, by using O'Driscoll scale. Results: The control samples showed an ICRS grade III (abnormal); while the samples of Groups 2, 3 and 4 reported a grade II (similar to healthy cartilage). The mean value of O'Driscoll scale in the control group (3.3) was significantly lower compared to the treatment groups (G2: 10.7; G3: 8; G4: 11.3) (P <0.05). No significant differences were found between the experimental groups. Conclusion: AM could be a suitable material for the management of articular cartilage defects. Stem cells within AM demonstrated to be able to differentiate in chondrocytes in vivo. Fresh AM, cryopreserved AM and cryopreserved AM previously cultivated with BM-MSCs showed similar regenerative properties.

One of Nature’s gifts to mankind is mesenchymal stem cells (MSC’s). They are multipotent in nature and are present literally in every tissue. Since, they possess certain characteristics of stem cells such as self-renewal and differentiation they are known to be one of the key players in normal tissue homeostasis. This novel function of mesenchymal stem cells has been explored by scientists in the field of regenerative medicine. This review gives an insight of the various sources of mesenchymal stem cells available for tissue engineering with regard to tendon and ligament and the mechanism involved during regeneration.