Preclinical Studies on Biomaterial Scaffold use in Knee Ligament Regeneration: A Systematic Review.

BACKGROUND: Knee joint trauma may result in damage of the intra-articular ligaments, with rupture of the anterior cruciate ligament (ACL) a common and troublesome injury due to poor capabilities for spontaneous regeneration. Autograft and allograft surgical reconstructions are the mainstay of treatment, but have associated risks of failure, therefore tissue-engineering techniques aiming to regenerate the native ACL are being researched as a potential alternative treatment. OBJECTIVES: This article aims to review the current evidence produced by ex vivo and in vivo studies investigating biomaterial scaffolding and mesenchymal stem cell (MSC) techniques in orthopaedic tissue engineering of ACL injuries. METHODS: Databases searched were Ovid MEDLINE, Cochrane Library, Embase, Elsevier Scopus, Web of Science and NCBI PubMed, with search terms 'ligament', 'scaffold', 'mesenchymal stem cell' and 'tissue engineering'. RESULTS: 1132 articles were identified, with 19 articles suitable for review inclusion. Of the eligible studies, 10 used biologic scaffold material, 6 used synthetic constructs, and hybrid scaffolds were employed in the remaining 3 studies. CONCLUSIONS: A large amount of preclinical evidence for viability of MSC seeded biomaterial scaffolds in ACL regeneration exists. Studies show that with stimulation, MSCs adhere and proliferate well on various scaffold materials ranging from silk to engineered polymers. Hybrid scaffolds are particularly promising, and with further research, the best features from strong natural substances such as silk, and biologically inert synthetic materials could be combined. Currently, there are few plans to begin human clinical trials, but preclinical studies are moving into larger animal models.

A Systematic Review And Meta-Analysis of Clinical Trials of Mesenchymal Stem Cell Therapy for Cartilage Repair.

BACKGROUND: Osteoarthritis (OA) is a major global burden creating significant morbidity worldwide. Current curative therapies are expensive, challenging to access and have significant risks, making them infeasible and difficult in many cases. Mesenchymal stem cells (MSCs) can be applied to joints and may regenerate the cartilage damaged in OA, this therapy may be advantageous to existing treatments. OBJECTIVE: We systematically reviewed clinical trials of MSCs for cartilage repair and provide an overview of the literature in this area here. MEDLINE, Embase, CENTRAL, clinicaltrials.gov and Open- Grey were searched for controlled trials and case series with >5 patents involving MSC therapy for cartilage repair. The controlled trials were meta-analysed and the primary outcome measure was improvement in pain over the control group. A narrative synthesis was composed for the case series. RESULTS: A significant reduction in pain was found with the use of MSCs over controls: Standardised mean difference=-1.27 (95% Confidence intervals -1.95 to -0.58). However, the data was extremely heterogeneous with I2=95%, this may be attributed to differing therapies, clinical indication for treatment and joints treated amongst others. Case series showed improvements in treated patients with a variety of differing treatments and by many outcomes. There were no severe adverse outcomes found across all studies that could be attributed to MSCs, implying their safety. CONCLUSION: We conclude that MSCs have significant potential for the treatment of OA, however, larger, more consistent trials are needed for conclusive analysis.

A Systematic Review of Clinical Studies Investigating Mesenchymal Stem Cells for Fracture Non-Union and Bone Defects.

BACKGROUND: Fracture non-union is a significant problem with a wide range demographic and massive socioeconomic elements, as well as the clinical difficulties it presents. Conventional treatments with autograft and allograft bone grafting pose serious difficulties, thus, it is necessary to develop novel techniques with our ever increasing knowledge of bioengineering using natural materials. OBJECTIVE: To search for current evidence regarding the treatment of fracture non-union or bone defects using mesenchymal stem cells (MSCs). RESULTS: The results presented in this review show that the use of mesenchymal stem cells for the treatment of non-union and bone defects is optimistic. Several papers had positive outcomes to report. There is a need for higher level evidence. CONCLUSION: A strong need of clinical results is required to further progress in cell therapy. Launched trials will hopefully provide this information in the near future. If clinical trials are positive, further development of complex tissue engineering techniques may be developed to treat large bone defects.

Knee Ligament Injury and the Clinical Application of Tissue Engineering Techniques: A Systematic Review.

BACKGROUND: The incidence of knee ligament injury is increasing and represents a significant cost to healthcare providers. Current interventions include tissue grafts, suture repair and non-surgical management. These techniques have demonstrated good patient outcomes but have been associated graft rejection, infection, long term immobilization and reduced joint function. The limitations of traditional management strategies have prompted research into tissue engineering of knee ligaments. OBJECTIVE: This paper aims to evaluate whether tissue engineering of knee ligaments offers a viable alternative in the clinical management of knee ligament injuries. A search of existing literature was performed using OVID Medline, Embase, AMED, PubMed and Google Scholar, and a manual review of citations identified within these papers. RESULTS: Silk, polymer and extracellular matrix based scaffolds can all improve graft healing and collagen production. Fibroblasts and stem cells demonstrate compatibility with scaffolds, and have been shown to increase organized collagen production. These effects can be augmented using growth factors and extracellular matrix derivatives. Animal studies have shown tissue engineered ligaments can provide the biomechanical characteristics required for effective treatment of knee ligament injuries. CONCLUSION: There is a growing clinical demand for a tissue engineered alternative to traditional management strategies. Currently, there is limited consensus regarding material selection for use in tissue engineered ligaments. Further research is required to optimize tissue engineered ligament production before clinical application. Controlled clinical trials comparing the use of tissue engineered ligaments and traditional management in patients with knee ligament injury could determine whether they can provide a cost-effective alternative.

A Systematic Review of Mesenchymal Stem Cells in Spinal Cord Injury, Intervertebral Disc Repair and Spinal Fusion.

Spinal surgery presents a challenge for both neurosurgery and orthopaedic surgery. Due to the heterogeneous differentiation potential of mesenchymal stem cells, there is much interest in the treatment of spine surgery. Animal and human trials focussing on the efficacy of mesenchymal stem cells in spinal cord injury, spine fusion and disc degeneration were included in this systematic review. Published articles up to January 2016 from MEDLINE, PubMed and Ovid were used by searching for specific terms. Of the 2595 articles found, 53 met the selection criteria and were included for analysis (16 on spinal cord injury, 28 on intervertebral disc repair and 9 on spinal fusion). Numerous studies reported better results when the mesenchymal stem cells were used in co-culture with other cells or used in scaffolds. Mesenchymal stem cells were also found to have an immune-modulatory role, which can improve surgical outcome. This systematic review suggests that mesenchymal stem cells can be used safely and effectively for these spinal surgery treatments. Whilst, in certain studies, mesenchymal stem cells did not necessarily show improved results from existing treatments, they provide an alternative option. This can reduce morbidity that arises from current surgical treatment.

Tissue Engineering in Achilles Tendon Reconstruction: A Systematic Review of Preclincal Studies.

BACKGROUND: Tissue engineering is now being used in Achilles tendon (AT) repair in animal models. There are many preclinical studies that have used different types of stem cells for AT repair. However, there are no systematic reviews that evaluate all these studies to see which type of stem cell provides the most improvement for AT repair in animal models. Sahni V et al.,(1) divided the multiple stem cell types into three broad categories; Tendon derived stem cells (TDSCs), mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs). These three categories have been used in this systematic review to group the different stem cell types together and to also see which category of stem cells provide superior enhancement of AT repair. METHOD: All studies that have focused on using different types of stem cells in animal models for AT repair and have also included an outcome measure to identify any improvement made with stem cells have been included in this systematic review. Online published articles from 1946 to January 2016 were searched using Ovid MEDLINE (R) and PubMed databases. RESULTS: Of the 181 articles found and assessed for eligibility, 15 articles met predefined selection criteria and were included in this systematic review. Stem cells can either augment current methods of surgical repair or can provide an alternative route for tendon regeneration because of their unique ability of improving histological characteristics and biomechanical properties. CONCLUSION: This systematic review shows that stem cells can provide an improvement in AT repair in animal models. Histological analysis of the tendon tissue as well as biomechanical tests such as ultimate failure load have been used to show this improvement in AT repair. Nevertheless, we do not know which type of stem cell, from the three broad categories, provides a superior enhancement of AT regeneration in animal models. Our results underscore a need for a head-to-head comparison of the different types of stem cells used in AT repair with or without current methods of surgical repair.

The Effects of Ageing on Differentiation and Characterisation of Human Mesenchymal Stem Cells.

BACKGROUND: Mesenchymal stem cells (MSC) are unique in their ability to self-renew and differentiate into one of many lineage possibilities. It is therefore integral to preserve these qualities to prevent the far reaching effects of a defective stem cell. Human mesenchymal stem cells (hMSC) are precursors for and can differentiate into osteoblasts, adipocytes and chondrocytes. They were originally found in the bone marrow, but have also been located in the umbilical cord, adipose tissue and muscle. Few studies have been conducted into the in vivo effects of age on these cells. This contribution reviews current knowledge surrounding the effects of age on the characteriation and differentiation of human mesenchymal stem cells. METHOD: 471 articles were found using a combination of Online published articles from January 1983 to January 2016 were searched using the Cochrane Library, PubMed, Medline, Scopus, Web of Science and Science Direct databases. There were no existing systematic reviews on this research topic. RESULTS: Nine studies were identified that met the predefined selection criteria. Three studies were used to assess the effects of ageing on characterisation of hMSC with no conclusive results. The cumulative results of these studies show that the effect of ageing on characterisation of hMSC remains inconclusive. Seven studies were used to assess the differentiation potentials of hMSC showing that age either decreased or altered lineage preference in hMSC differentiation. CONCLUSION: There is indication that ageing affects hMSC characterisation and differentiation, however it is not conclusive. There are not enough high quality controlled clinical trials to make reliable conclusions.

A Systemic Review of Adult Mesenchymal Stem Cell Sources and their Multilineage Differentiation Potential Relevant to Musculoskeletal Tissue Repair and Regeneration.

BACKGROUND: Adult mesenchymal stem cells (MSCs) were first isolated from bone marrow by Friedenstein in 1976. These cells were clonogenic, non-haematopoietic, and able to replicate extensively in vitro. The fields of regenerative medicine and tissue engineering have grown dramatically since their inception. In the decades since, MSCs have been identified from mesoderm-, endoderm- and ectoderm-derived tissues. In light of our ageing population, the need for effective cell-based therapies for tissue repair and regeneration is ever-expanding. OBJECTIVES: The purpose of this systematic review was to summarise evidence from the most recent studies outlining different sources of adult MSCs and their suitability in musculoskeletal applications. METHODS: Online published articles were searched for using the PubMed/MEDLINE and Ovid databases, and relevant articles fulfilling the pre-defined eligibility criteria were analysed. RESULTS: To date, MSCs have been isolated from a number of adult tissues, including trabecular bone, adipose tissue, bone marrow, synovium, dermis, periodontal ligament, dental pulp, bursa and the umbilical cord. Bone marrow MSCs are currently considered the gold standard, with which newly discovered sources are compared on the basis of their renewal capabilities and multipotency. Furthermore, MSCs have been successful in the regeneration of osteonecrosis, osteoarthritis, bony defects, fracture remodeling and so on. CONCLUSION: Unfortunately, significant hurdles remain and will need to be overcome before tissue engineering using MSCs becomes routine in clinical practice. Thus, further research and understanding are required into the safe and effective sourcing and application of mesenchymal stem cells in musculoskeletal applications.

The Use of Growth Factors and Mesenchymal Stem Cells in Orthopaedics: In particular, their use in Fractures and Non-Unions: A Systematic Review.

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-ß, 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-ß 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 Protocols of Human Derived Cells in Articular Cartilage Tissue Engineering - A Systematic Review.

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.

Pilon fracture: a case report of a 45-year-old dental technician.

Pilon fractures are complex and difficult-to-treat fractures of the lower extremity that account for about 1% of all lower extremity fractures and up to 10% of tibial fractures. The injury is caused by high energy axial load either from motor vehicle accidents or a fall from height. The treatment of these fractures has caused controversy among surgeons due to mixed outcomes. Here we report a case of pilon fracture in a 45 year old male patient who has sustained the injury as a result of a fall from a height of approximately 12 feet. We describe why it is absolutely crucial that the patient is treated with external fixation initially and evaluate its merits and drawbacks as well as ways to minimize the complications associated with external fixation of open intra-articular distal tibial fractures.

Orthopaedic approaches to proximal humeral fractures following trauma.

Proximal humeral fractures have been a topic of discussion in medical literature dating back as far as 3rd century BC. Today, these fractures are the most common type of humeral fractures and account for about 5-6% of all fractures in adults with the incidence rising rapidly with age. In broad terms the management of proximal humeral fractures can be divided into two categories: conservative versus surgical intervention. The aim of treatment is to stabilize the fracture, aid better union and reduce pain during the healing process. Failure to achieve this can result in impairment of function, and significantly weaken the muscles inserting onto the proximal humerus. With the rising incidence of proximal humeral fractures, especially among the elderly, the short and long term burden for patients as well as the wider society is increasing. Furthermore, there is a lack of consistency in the definitive treatment and management of displaced fractures. This systematic review of literature compares the surgical treatment of proximal humeral fractures with their conservative management, by evaluating the available randomised controlled trials on this topic.

Evaluation of biological protein-based collagen scaffolds in cartilage and musculoskeletal tissue engineering--a systematic review of the literature.

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.

Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis.

Human ether-a-go-go-related gene (hERG) potassium channels are critical determinants of cardiac repolarization. Loss of function of hERG channels is associated with Long QT Syndrome, arrhythmia, and sudden death. Acidosis occurring as a result of myocardial ischemia inhibits hERG channel function and may cause a predisposition to arrhythmias. Acidic pH inhibits hERG channel maximal conductance and accelerates deactivation, likely by different mechanisms. The mechanism underlying the loss of conductance has not been demonstrated and is the focus of the present study. The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance. Abolition of inactivation, by the mutation S620T, also did not affect the proton sensitivity of channel conductance. Instead, voltage-dependent channel inhibition (δ = 0.18) indicative of pore block was observed. Consistent with a fast block of the pore, hERG S620T single channel data showed an apparent reduction of the single channel current amplitude at low pH. Furthermore, the effect of protons was relieved by elevating external K(+) or Na(+) and could be modified by charge introduction within the outer pore. Taken together, these data strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.