Current Stem Cell Research & Therapy - Volume 8, Issue 3, 2013

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.

Understanding of the biology of bone regeneration has been increasing rapidly, with greater appreciation for the importance of biochemical aspects as well as the mechanical requirements for bone to heal. There are a number of situations where there is difficulty in bone healing such as fracture non-union; or growth such as osteogenesis imperfecta; or a requirement for surplus bone to reconstruct defects such as following surgery for tumour excision or limb lengthening. There is a greater understanding of the complex interplay between osteoblasts and osteoclasts, and the chemical mediators that that provide signalling along complex pathways. Although we have known about substances such as Bone Morphogenic Proteins and Growth Hormones for some time, their application in clinical practice is still not widespread, and we need to study them more to understand their role in bone healing. With newer technologies such as stem cells and gene therapy being developed there is the potential for vast improvement in bone regenerative techniques, although we are not at a stage where we can be confident that these techniques will work. In this review article we discuss the basic healing process of bone and how our understanding of this has led to improved techniques as well as the potential for future developments in new technologies.

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.

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.

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.

Meniscal injuries are one of the common sports injuries and their natural healing is limited. Removal of injured meniscus alters knee biomechanics and predisposes patients to osteoarthritis. Tissue engineered meniscus provides a novel approach for the treatment of severe meniscus injury. The aim of this review is to review preclinical studies that used cell based approaches for tissue engineered meniscus. Studies were assessed for inclusion following a search in PubMed, UK PubMed central and Embase. All preclinical studies that used cell based approaches for meniscus regeneration were included in the study. Nineteen articles that used cellular approaches were reviewed. The cell types used were mesenchymal stem cells (derived from bone marrow or synovium), meniscal fibrochondrocytes, chondrocytes and bone marrow stromal cells. One study used xenogeneic bone marrow derived mesenchymal stem cells. Sixteen out of nineteen studies showed better tissue regeneration with cell based approaches when compared to acellular controls. The review included preclinical studies. The diversity of the studies made it impossible to adhere to full guidelines or perform a meta-analysis. Overall, experiments have demonstrated superior tissue integration and favourable biochemical properties of the regenerated tissues compared to acellular techniques. Few approaches however, have measured the chondroprotective ability at preclinical testing.

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.

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 osteogenic potential of mesenchymal stem cells (MSCs) from umbilical cord blood (UCB) on porous poly lactide-co-glycolide (PLGA) scaffolds have been reported to differentially support osteogenic differentiation based on polymer composition (80:20, 75:25 and 70:30 percent of PLA: PGA, respectively). Along with polymer composition; fused NaCl crystal matrix prior to solvent casting improves the porosity and pore interconnectivity in 3D scaffolds, which has significant impact on cell proliferation. FTIR and XRD studies of PLGA scaffolds also verified the intermolecular interactions, phase distribution and crystallinity in scaffolds. Among three scaffold combinations, sample B (75:25) has showed maximum porosity with optimum water uptake/retention abilities. Impact of polymer composition and porosity on cell proliferation was investigated through MTT assay, where sample B was observed to be supporting better cell proliferation, due to its internal structure. The above results were further confirmed by ALP and Col-I gene expression studies using RT-PCR. Immunofluorescent studies also revealed the extracellular filamentous actin organization over the scaffolds, where cell adhesion and proliferation was found to be higher with increase in PGA content, which is a hydrophilic polymer.

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.