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The prevalence of burnout and depressive symptoms is high among physician trainees.

Background: In the quest for sustainable energy materials, new donor and acceptor materials are being designed, synthesized and tested for photovoltaic (PV) applications. In this context, conjugated organic polymers have received significant interests in the last few decades. Objective: In the present work, we synthesized an organic poly-yne P and assessed its efficiency as donor with a rylene acceptor EP-PTC. Methods: The organic poly-yne P was synthesised via Sonogashira coupling and characterized by analytical and spectroscopic techniques. The PV performance of blends composed of different amounts of polymer P and acceptor EP-PTC was assessed. Computational studies were undertaken at DFT level to determine the geometry, dipole moment, Mulliken charge and energy level. Results: A soluble blue low band-gap (1.72 eV) π-conjugated co-polymer consisting of dioctyloxyphenylene unit linked via ethynylene to 2,3-diphenylthieno[3,4-b]pyrazine has been synthesized and characterized. Blends of P and a soluble organic dye EP-PTC showed good PV performance with broad photocurrent spectra. The copoly-yne/dye-based solar cell with high EP-PTC content shows significantly higher external quantum efficiency (EQE) compared to the single material-based devices. However, a decrease in EQE was observed upon thermal annealing. DFT calculations showed convergence of the experimental results. Conclusion: We have synthesized and characterized a thienopyrazine-based organic co-polyyne and showed that blends of co-polymer P and the perylene dye EP-PTC possess high EQE up to 5.5% for the 90:10 EPPTC: P blend at wavelengths between 350 nm and 710 nm.

Meniscal injury is a common problem among sportsmen and increasingly seen in the older and more active population. The traditional treatment options include a partial meniscectomy, which provides good mechanical and pain relief to the patient. However, the focus of treatment is shifting towards repairing meniscal tears where possible and replacement of the lost meniscal tissue where appropriate. Replacement can be total or partial. Total meniscal replacement using an allograft, is usually reserved for young patients, who meet certain criteria and who have undergone several subtotal meniscectomies or a single stage total meniscectomy and are still symptomatic. Partial meniscal replacement can be utilized in conjunction with a partial meniscectomy to fill the resulting space left by the resection. Collagen based implants and synthetic scaffolds have entered the European market but have demonstrated mixed results in clinical trials. Tissue engineering to create an implant that mimics the biomechanical properties holds much potential for future research.

Aim: The aim was to look at current evidence for treating non-unions or delayed fracture healing in regard to novel methods applying mesenchymal stem cells (MSCs) and growth factors (GF). Methods: Pre-clinical and clinical trials focusing on the use of Mesenchymal Stem Cells and Growth Factors for fracture healing were included in this review. Published articles were identified using specific search terms in Medline, Cochrane Library, PubMed, Scopus and Web of Science. Results: Of the 580 articles found, 82 met my selection criteria and were included, with 39 papers involving trials on the effects of GFs and MSCs on non-unions or bone repair. These included 11 articles on MSCs, 10 on Bone Morphogenetic Proteins, 2 on Vascular-Endothelial GF, 5 on Insulin like-GF, 4 on Transforming-GF-β, 4 on Platelet-Rich Plasma, 1 on Platelet Derived-GF and 2 on Fibroblast-GF, with the other articles included qualitatively. Overall results were positive with the addition of MSCs, Bone Morphogenetic Proteins, VEGF, IGF and TGF-β in aiding fracture healing compared to controls, with mixed results for other factors. Conclusion: Overall this review shows promising results regarding the use of MSCs and various Growth factors in the treatment of fractures and non-unions, as well as synergistic effects observed when combined together. However more research is indicated as these methods are still in the early stages of development.

Mechanical stimulation is a key factor in articular cartilage generation and maintenance. Bioreactor systems have been designed and built in order to deliver specific types of mechanical stimulation. The focus has been twofold, applying a type of preconditioning in order to stimulate cell differentiation, and to simulate in vivo conditions in order to gain further insight into how cells respond to different stimulatory patterns. Due to the complex forces at work within joints, it is difficult to simulate mechanical conditions using a bioreactor. The aim of this review is to gain a deeper understanding of the complexities of mechanical stimulation protocols by comparing those employed in bioreactors in the context of tissue engineering for articular cartilage, and to consider their effects on cultured cells. Allied and Complementary Medicine 1985 to 2016, Ovid MEDLINE[R] 1946 to 2016, and Embase 1974 to 2016 were searched using key terms. Results were subject to inclusion and exclusion criteria, key findings summarised into a table and subsequently discussed. Based on this review it is overwhelmingly clear that mechanical stimulation leads to increased chondrogenic properties in the context of bioreactor articular cartilage tissue engineering using human cells. However, given the variability and lack of controlled factors between research articles, results are difficult to compare, and a standardised method of evaluating stimulation protocols proved challenging. With improved standardisation in mechanical stimulation protocol reporting, bioreactor design and building processes, along with a better understanding of joint behaviours, we hope to perform a meta-analysis on stimulation protocols and methods.

Orthopaedic surgery lends itself well to advances in technology. An area of interest and ongoing research is that of the production of scaffolds for use in trauma and elective surgery. 3D printing provides unprecedented accuracy in terms of micro- and macro-structure and geometry for scaffold production. It can also be utilised to construct scaffolds of a variety of different materials and more recently has allowed for the construction of bio-implants which recapitulate bone and cartilage tissue. This review seeks to look at the various methods of 3DP, the materials used, elements of functionality and design, as well as modifications to increase the biomechanics and bioactivity of 3DP scaffolds.

Diffuse alveolar hemorrhage (DAH) is described as the collection of blood in alveolar spaces caused by damaged pulmonary vasculature. It often presents as a life-threatening medical emergency that requires urgent medical intervention along with timely diagnosis and management of the underlying cause. We hereby report a 19-year-old female who presented with clinical and radiological characteristics consistent with DAH. Laboratory workup studies revealed a diagnosis of systemic lupus erythematosus (SLE) as well as Mycobacterium tuberculosis (MTB) infection. This report describes an extremely unusual case of undiagnosed SLE and coexistent tuberculosis presenting as DAH. This leads to an interesting possibility of risks in patients with immune-mediated vasculitis towards developing severe pulmonary disease in the setting of pulmonary mycobacterial infection.

Tissue engineering has emerged as a promising scientific field potentially yielding in vitro developed tissue to replace degenerative or injured tissues in vivo, thus avoiding the donor site morbidity associated with reconstructive surgery. Integral to the process is the role of scaffolds and the biomaterials used to form them. This review explores the concept of scaffold based tissue engineering and design considerations. The scaffold needs to have certain mechanical and architectural properties, it needs to be biocompatible and biodegradable, and allow combination with bioactive molecules. We also discuss scaffolding techniques, different biomaterial options and fabrication technologies, and future areas of development.

The non-enzymatic reaction (glycation) of reducing sugars with proteins has received increased interest in dietary and therapeutic research lately. In the present work, the impact of glycation on structural alterations of camel serum albumin (CSA) by different glucose metabolites was studied. Glycation of CSA was evaluated by specific fluorescence of advanced glycation end-products (AGEs) and determination of available amino groups. Further, conformational changes in CSA during glycation were also studied using 8-analino 1-nephthlene sulfonic acid (ANS) binding assay, circular dichroism (CD) and thermal analysis. Intrinsic fluorescence measurement of CSA showed a 22 nm red shift after methylglyoxal treatment, suggesting glycation induced denaturation of CSA. Rayleigh scattering analysis showed glycation induced turbidity and aggregation in CSA. Furthermore, ANS binding to native and glycated-CSA reflected perturbation in the environment of hydrophobic residues. However, CD spectra did not reveal any significant modifications in the secondary structure of the glycated-CSA. Thioflavin T (ThT) fluorescence of CSA increased after glycation, illustrated cross β-structure and amyloid formation. Transmission electron microscopy (TEM) analysis further reaffirms the formation of aggregate and amyloid. In summary, glucose metabolites induced conformational changes in CSA and produced aggregate and amyloid structures.

Bioreactors are pivotal to the emerging field of tissue engineering. The formation of neotissue from pluripotent cell lineages potentially offers a source of tissue for clinical use without the significant donor site morbidity associated with many contemporary surgical reconstructive procedures. Modern bioreactor design is becoming increasingly complex to provide a both an expandable source of readily available pluripotent cells and to facilitate their controlled differentiation into a clinically applicable ligament or tendon like neotissue. This review presents the need for such a method, challenges in the processes to engineer neotissue and the current designs and results of modern bioreactors in the pursuit of engineered tendon and ligament.

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.

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.

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.

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.

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-) showing the most significant results in graft healing. Further trials are still required before a definitive conclusion can be reached.

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.

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: 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.

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.

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: 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.

Several artificial biomaterials are available as ligament grafts. No ideal prosthesis mimicking natural human tissue have been found to date. The emerging field of tissue engineering holds the promise to use artificial ligaments as a viable alternative to the patellar or hamstring tendon autografts. Preliminary studies support the idea that these biomaterials have the ability to provide an alternative for autogenous grafts. However, no definitive conclusions have been found. Additionally, the incidence of postoperative complications varies within different studies. Prospective investigations are required to better understand the potential of artificial biomaterials as ligament grafts.

Rotator cuff tear causes a high rate of morbidity. After surgical repair, the presence of a scar tissue reduces tendon biomechanical properties. Emerging strategies for enhancing tendon healing are growth factors, cytokines, gene therapy and tissue engineering. However their efficacy has to be proved. Growth factors help the process of tendon healing by aiding cells chemotaxis, differentiation and proliferation. Numerous growth factors, including the bone morphogenetic proteins and platelet-derived growth factor can be found during the early healing process of a rotator cuff repair. Growth factors are delivered to the repair site using tissue-engineered scaffolding, coated sutures, or dissolved in a fibrin sealant. Platelet-rich plasma is an autologous concentration of platelets and contains an high density of growth factors. There is some evidence that platelet-rich plasma may improve pain and recovery of function in a short time period, but it does not improve healing rates in rotator cuff. Thus the routine use of platelet-rich plasma in rotator cuff repair is not recommended. The addition of mesenchymal stem cells to scaffolds can lead to the production of a better quality healing tissue. Gene therapy is a gene transfer from a cell into another, in order to over-express the gene required. In this way, cultures of stem cells can over-express growth factors. Better understanding of the mechanisms of physiological tendon healing can promote the correct use of these new biological therapies for a better healing tissue.

The emerging field of tissue engineering holds the promise to use bio-materials for meniscus injury repair, namely scaffold or meniscus implant. Many implants have been studied and several studies have been conducted to verify the safety and quality of scaffolds. Preliminary data support the idea that synthetic implants can provide an alternative to menyscectomy helping to preserve the cartilage and preventing arthritis in patient with menisci injuries. However, the prevalence of postoperative complications varies within studies. Further investigations are required to evaluate the role of these materials in the clinical practice.

Tissue engineering and cell therapies are currently being leveraged to find improved treatment strategies in orthopaedics. Adipose stem cells have been considered for their potential to differentiate into different cell lineages. The potential of adipose stem cells to restore chondral, bone and tendon tissue has been demonstrated in vivo and in vitro studies. Recently their capacity to restore cells and extracellular matrix of the intervetebral disc has been also investigated. Treatment of several orthopedic diseases could benefit from the application of adipose stem cells. However, there is still lack of knowledge about their clinical use and further studies are needed to better clarify their potential.

Molecular imprinting is an interesting technique for preparation of molecular recognition materials with discriminating similar molecules from complex systems. In particular, imprinting more than one molecule has immense application in remediation of industrial waste. Major difficulty in molecular imprinting is the selection of suitable polymer precursors. In this article, authors have proposed a new computational approach for combinatorial screening of polymer precursor library to select appropriate polymer precursors to prepare imprinted polymer capable of selectively binding carcinogenic polycyclic aromatic hydrocarbons (PAHs). Molecular Dynamics (MD) and Quantum Mechanics (QM) models were used to compute interaction energy scores between polymer precursors and PAHs in a simulated solvent box. A self-designed virtual library of functional monomers has been prepared, and then used for MD simulations to screen the best functional monomers. Initially, molecules used in the study were geometrically optimized and then interaction energies were computed using density functional theory (DFT) in Becke 3-Parameter Exchange Correlation Function (B3LYP) level with 6-31Gbasis set on Gaussian 4.1 Ver. software. Complimentary to theoretical predictions, selected polymers were prepared in laboratory and compared theoretically computed binding score with the binding capacity of the polymer on spectrofluorimetry. The computer simulations used in this research paper are rapid and reliable for the combinatorial screening of polymer precursors in experimental-free way to design of multi-template imprinted polymers.

Meniscal injuries are among the common sports injuries and their natural healing is limited. Removal of injured meniscus impairs normal knee function and predisposes patients to osteoarthritis. Tissue engineering and replacement strategies provide a novel approach for the treatment of severe meniscus injury. The aim of this article is to review preclinical studies that used approaches for meniscal replacement including growth factors, synthetic and tissue engineered scaffolds and non-meniscal autografts. Medline, EMBASE and UK PubMed search was performed and articles were assessed for inclusion. Included articles were summarised and categorised. Forty seven articles matched the inclusion criteria. The studies were classified according to the approaches used for meniscus replacement. Overall most experiments have shown good tissue integration and biochemical properties of the regenerated tissues. However, only few approaches have demonstrated satisfactory chondroprotective function.

Gene therapy has been successfully used in several areas of medicine as a technique to either alter defective genes or as method to enable delivery of therapeutic proteins. Despite advances in surgical and pharmaceutical interventions for diseases of bone regeneration and healing, results in certain patient groups remain sub-optimal. With this consideration, gene therapy is currently being investigated as a means of facilitating healing and improving outcomes. Two broad techniques which are currently utilised by research teams are discussed in this review; ex vivo and in vivo. The underlying principle is similar in each case; the use of gene therapy to alter target cells to deliver proteins which facilitate bone regeneration. However, whereas ex vivo techniques involve performing genetic manipulations outside the body and then introducing the altered cells to the desired site, in vivo techniques execute genetic manipulations inside the body by the introduction of vectors directly to the desired location. Results from small animal models for both techniques are promising, however, further research is required to demonstrate both safety and efficacy prior to any future clinical application.

Due to the nature of articular cartilage of being poorly vascularized the capabilities of self repair are limited. Mesenchymal stem cells transplantation is a modern technique which has been developed after the high success rates obtained by microfracturing and drilling techniques which promote the release of growth factors and the infiltration of bone marrow derived cells in the lesion. In order to increase the concentration of bone marrow derived cells appropriate devices, the scaffolds, are necessary. These three dimensional constructs mimic the physiological ambient of chondrogenesis. The race for new scaffold materials, which will show high biocompatibility to prevent inflammatory response, high cellular adhesion properties with three dimensional architecture, high bioactivity to deliver growth factor appropriately and possibly high biodegrability has just begun. New studies will concentrate on the role, on the interaction and on the temporal sequence of growth factors to improve ostheocondral differentiation, but the necessity to increase the number of clinical studies with more patients and longer follow ups seems mandatory. The aim of this review is to update and summarise the evidence-based knowledge of treatment of talus chondral defect with new tissue engineering techniques.

Background: The management and treatment of bone defects caused by trauma, non-union, tumors and disease poses a major clinical problem. Limitations with autograft and allograft have led to research into tissue engineering of bone graft using scaffolds and mesenchymal stem cells. Objectives: This systematic review aims to examine and summarize the pre clinical in-vivo studies and the limited clinical studies on the use of scaffolds in the treatment of critical size bony defects. Data sources: Databases: PubMed, Medline, OVID, Scopus and Cochrane library. The following key words and search terms were used: scaffolds, bone repair, bone regeneration, mesenchymal stem cells, and tissue engineering and musculoskeletal. Methods: A total of 503 articles were reviewed. 23 articles were identified as relevant for the purpose of this systematic literature review. Results: Three tables of studies were constructed: pre clinical biological scaffolds, pre clinical synthetic scaffolds and clinical scaffolds. Conclusions: There is a lot of pre clinical evidence that the use of scaffold combined with mesenchymal stem cells enhances osteogenesis when treating bone defects. There is limited clinical evidence at this early stage that scaffolds can be used safely and effectively in tissue engineered grafts to repair bone defects with no RCTs as yet having been conducted. The limited clinical series reported have however produced promising results.

The management of extensive bone defects in the setting of fracture repair, non-union and revision arthroplasty are challenging problems. The supply of harvestable autologous bone graft is limited, with an associated morbidity, and therefore a need exists for a better solution in large defects. The use of stem cells is an evolving field of research, with different potential applications, ranging from simple injection of cells to tissue engineering using osteogenic cells seeded onto a scaffold. This systematic review aims to collate the published preclinical and clinical studies investigating the potential use of stem cells for bone repair.

In orthopaedic tissue engineering, scaffolds may be viewed as a substitute for the extra-cellular matrix. Factors that contribute to an ideal scaffold include strength, degradation rate, porosity, surface property and immune response. Scaffolds may be composed of natural or synthetic polymers, each with its advantages and disadvantages. Composite scaffolds are utilised to alleviate the inherent issues with natural polymers whilst maintaining its benefits as well. This article reviews biomaterials and scaffolds in orthopaedic tissue engineering and covers clinical applications of scaffolds with particular emphasis on bone and cartilage tissue engineering.

Background: Bone healing is a complex process. Whilst the majority of fractures heal with conventional treatment, open fractures, large bone defects and non unions still provide great challenges to Orthopaedic Surgeons. Whilst autologous bone graft is seen as the gold standard, the use of growth factors is a growing area of research to find an effective alternative with lower side effects such as donor site morbidity and the finite amount available. Objectives: This systematic review aims to summarize the pre clinical in-vivo studies and examine the clinical studies on the use of growth factors in bone healing. Data sources: Databases: PubMed, Medline, OVID, and Cochrane library. The following key words and search terms were used: Growth Factors, Bone Healing, Bone Morphogenic Protein, Transforming Growth Factor Beta, Insulin Like Growth Factor, Platelet Derived Growth Factor, Fracture. Methods: All articles were screened based on title with abstracts and full text articles reviewed as appropriate. Reference lists were reviewed from relevant articles to ensure comprehensive and systematic review. Results: Three tables of studies were constructed focussing on Bone Morphogenic Proteins, Platelet Rich Plasma and Growth Factors and Tissue Engineering. Conclusions: Bone Morphogenic Proteins and Platelet Rich Plasma, which contains multiple growth factors, have been shown in preclinical and clinical trials to be an effective alternative to autologous bone graft. Bone Morphogenic Proteins have been shown to be effective in fracture non union, and in open tibial fractures. Platelet Rich Plasma has shown promise in preclinical trials and some small clinical trials, however numbers are limited. Bone Morphogenic Proteins have been shown to be superior to Platelet Rich Protein in one trial. Combining these growth factors with tissue engineering techniques is the focus of ongoing research, and through further clinical trials the most effective techniques for enhancing bone healing will be revealed.

Cartilage tissue engineering is concerned with developing in vitro cartilage implants that closely match the properties of native cartilage, for eventual implantation to replace damaged cartilage. The three components to cartilage tissue engineering are cell source, such as in vitro expanded autologous chondrocytes or mesenchymal progenitor cells, a scaffold onto which the cells are seeded and a bioreactor which attempts to recreate the in vivo physicochemical conditions in which cartilage develops. Although much progress has been made towards the goal of developing clinically useful cartilage constructs, current constructs have inferior physicochemical properties than native cartilage. One of the reasons for this is the neglect of mechanical forces in cartilage culture. Bioreactors have been defined as devices in which biological or biochemical processes can be re-enacted under controlled conditions e.g. pH, temperature, nutrient supply, O2 tension and waste removal. The purpose of this review is to detail the role of bioreactors in the engineering of cartilage, including a discussion of bioreactor designs, current state of the art and future perspectives.

Mesenchymal stem cells (MSCs) have a great capacity for use in regenerative medicine and other clinical applications. However, one question creating curiosity of their use, is how they are affected by ageing. As we now live within an ageing population, the prevalence of age related disorders is increasing, so it is important to investigate how effectively MSCs from older patients can be expanded and differentiated in vitro before their use in autologous cell transplantation. This paper will look at how ageing effects proliferation potential, differentiation potential and cell surface characterisation of human mesenchymal stem cells.

The term tissue engineering is the technology that combines cells, engineering and biological/synthetic material in order to repair, replace or regenerate biological tissues such as bone, muscle, tendons and cartilage. The major human applications of tissue engineering are: skin, bone, cartilage, corneas, blood vessels, left mainstem bronchus and urinary structures. In this systematic review several criteria were identified as the most desirable characteristics of an ideal scaffold. These state that an ideal scaffolds needs to be biodegradable, possess mechanical strength, be highly porous, biocompatible, non-cytotoxic, non antigentic, stuitable for cell attachment, proliferation and differentiation, flexible and elastic, three dimensional, osteoconductive and support the transport of nutrients and metabolic waste. Subsequently, studies reporting on the various advantages and disadvantages of using collagen based scaffolds in musculoskeletal and cartilage tissue engineering were identified. The purpose of this review is to 1) provide a list of ideal characteristics of a scaffold as identified in the literature 2) identify different types of biological protein-based collagen scaffolds used in musculoskeletal and cartilage tissue engineering 3) assess how many of the criteria each scaffold type meets 4) weigh different scaffolds against each other according to their relative properties and shortcomings. The rationale behind this approach is that the ideal scaffold material has not yet been identified. Hence, this review will define how many of the identified ideal characteristics are fulfilled by natural collagen-based scaffolds and address the shortcomings of its use as found in the literature.

Mesenchymal stem cells isolated from amnion/amniotic fluid, umbilical cord blood, placental tissue, umbilical cord vein and the Wharton’s Jelly are promising candidates for musculoskeletal tissue engineering of bone and cartilage tissues. The extracorporeal nature of this source avoids the ethical concerns that plague the isolation of embryonic stem cells. Moreover, the harvesting does not require the invasive and discomfort extraction procedures as well as patient risks that attend adult stem cell isolation. Current preclinical studies support the application of these cell-based therapies for the regeneration of musculoskeletal tissues. We performed a review of the literature to focus on actual knowledge and the future perspectives of the stem cells deriving from umbilical cord and placenta for musculoskeletal tissue engineering.

Conditions affecting cartilage through damage or age-related degeneration pose significant challenges to individual patients and their healthcare systems. The disease burden will rise in the future as life expectancy increases. This has resulted in vigorous efforts to develop novel therapies to meet current and future needs. Due to the limited regenerative capacity of cartilage, in vitro tissue engineering techniques have emerged as the favoured technique by which to develop replacements. Tissue engineering is mainly concerned with developing cartilage replacements in the form of chondrocyte suspensions and three-dimensional scaffolds seeded with chondrocytes. One major limiting factor in the development of clinically useful cartilage constructs is our understanding of the process by which cartilage is formed, chondrogenesis. For example, techniques of culturing chondrocytes in vitro have been used for decades, resulting in chondrocytelike cells which produce an extracellular matrix of similar composition to native cartilage, but with inferior physical properties. It has now been realised that one aspect of chondrogenesis which had been ignored was the physical context in which cartilage exists in vivo. This has resulted in the development of bioreactor systems which aim to introduce various physical stresses to engineered cartilage in a controlled environment. This has resulted in some improvements in the quality of tissue engineered cartilage. This is but one example of how the knowledge of chondrogenesis has been translated into research practice. This paper aims to review what is currently known about the process of chondrogenesis and discusses how this knowledge can be applied to tissue engineering.

Chondrogenesis is a vital part of adult life, as cartilage is important not only for articulation of joints but also maintenance functions of the body. Chondrogenesis is a five way process of intricate events controlled by specific genes and cell-cell interactions which has been documented over recent years. This review highlights the current literature regarding the process of endochondral ossification and covers the different level of control at agent level. Due to the proliferative nature of chondrogenesis and using chondrocytes for self renewal and repair, current research involves finding ways in which to improve and replicate expansion of chondrocytes. The review summarises ways in which ex vitro expansion can be manipulated using growth factors, external sources and scaffolds.

The menisci are important fibrocartilaginous structures which give lubrication, shock absorption, nutrition and stabilisation to the knee joint, and also help transfer load. The meniscus extracellular matrix possesses a complex architecture which is not uniform throughout the tissue. The inner third of the meniscus is composed of hyaline cartilage and the outer meniscus is composed of fibrocartilage. In a mature meniscus only the outer 10-25 is vascularised. There are various types of pathology associated with the meniscus. Previously, surgical techniques used to be considered as conventional treatment for meniscal lesions. However lesions in the avascular regions of the meniscus would rarely heal appropriately. It has been found that total menisectomies in patients may increase their chance of suffering from osteoarthritis in the future. Meniscal tissue engineering has been developed in an attempt to help improve the healing potential of avascular meniscal regions. Many different concepts and approaches have been tried and tested, such as the application of natural and synthetic scaffolds, mesenchymal stem cells, growth factors, fibrin glue and more. The objective of this review is to summarise the different approaches that have been used in the development of meniscal tissue engineering. The focus of this review is to evaluate the strengths and weaknesses of the studies that have been carried out, and from there determine what we have learnt from them in order to further the development in meniscal tissue engineering.

As our population demographics change, osteoarthritis and cartilage defects are becoming more prevalent. The discovery of stems cells and their ability for indefinite regeneration has revolutionised the way cartilage problems are viewed. Tissue engineering has been shown to be the ideal way of repairing articular cartilage lesions, i.e. back to native tissue. Cartilage is an ideal tissue engineering target as it is avascular, aneural and alymphatic. The two main types of stem cells being investigated in chondrogenesis are embryological and mesenchymal stem cells. Research into embryological stem cells has been surrounded by controversy because of ethical, religious and social concerns. We discuss the use of embryological and mesenchymal stem cells in cartilage repair and the various factors involved in the differentiation into chondrocytes. We also discuss commonly used mesenchymal stem cell markers and their limitations.

Bone defects resulting from trauma or resorption, whether physiological or pathological, remain a major challenge in the management of patients. The limits of bone regeneration still result in many people never recovering fully their function and quality of life; with all the social, financial and psychological implications. The aim of this review is to present the current level of possible applications of stem cells and tissue engineering in bone repair. From animal models to human trials, the knowledge surrounding the use of mesenchymal stem cells in manipulating bone healing, where normal physiological procedures have failed, are presented in chronological order. The possibilities in clinical applications of mesenchymal stem cells are evident and exciting. The efficacy, including long-term, of such treatment options still requires further knowledge and appropriately conducted clinical trials, with adequate patient numbers. Once these techniques are properly mastered and perfected, the benefits to regenerative medicine will be immense.

Tissue engineering of bone has the potential to overcome the limitations of using autologous, allogeneic or synthetic bone grafts to treat extensive bone defects. It involves culturing of osteogenic cells within appropriate scaffold materials under conditions that optimize bone development. Stem cells, progenitor cells, terminally differentiated cells or genetically modified cells may be used. Scaffold materials include polymers, ceramics or composites which are used to maintain the desirable characteristics of the individual materials. Preclinical and clinical studies on the use of growth factors such as bone morphogenetic proteins to increase bone formation have had promising results. This review discusses the approaches to and the challenges associated with producing tissue engineered bone.