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Meniscal repair is widely used as a treatment for meniscus injury. However, where meniscal damage has progressed such that repair is not possible, approaches for partial meniscus replacement are now being developed which have the potential to restore the functional role of the meniscus, in stabilising the knee joint, absorbing and distributing stress during loading, and prevent early degenerative joint disease. One attractive potential solution to the current lack of meniscal replacements is the use of decellularised natural biological scaffolds, derived from xenogeneic tissues, which are produced by treating the native tissue to remove the immunogenic cells. The current study investigated the effect of decellularisation on the biomechanical tensile and compressive (indentation and unconfined) properties of the porcine medial meniscus through an experimental–computational approach. The results showed that decellularised medial porcine meniscus maintained the tensile biomechanical properties of the native meniscus, but had lower tensile initial elastic modulus. In compression, decellularised medial porcine meniscus generally showed lower elastic modulus and higher permeability compared to that of the native meniscus. These changes in the biomechanical properties, which ranged from less than 1% to 40%, may be due to the reduction of glycosaminoglycans (GAG) content during the decellularisation process. The predicted biomechanical properties for the decellularised medial porcine meniscus were within the reported range for the human meniscus, making it an appropriate biological scaffold for consideration as a partial meniscus replacement.

In order to pre-clinically evaluate the performance and efficacy of novel osteochondral interventions, physiological and clinically relevant whole joint simulation models, capable of reproducing the complex loading and motions experienced in the natural knee environment are required. The aim of this study was to develop a method for the assessment of tribological performance of osteochondral grafts within an in vitro whole natural joint simulation model. The study assessed the effects of osteochondral allograft implantation (existing surgical intervention for the repair of osteochondral defects) on the wear, deformation and damage of the opposing articular surfaces. Tribological performance of osteochondral grafts was compared to the natural joint (negative control), an injury model (focal cartilage defects) and stainless steel pins (positive controls). A recently developed method using an optical profiler (Alicona Infinite Focus G5, Alicona Imaging GmbH, Austria) was used to quantify and characterise the wear, deformation and damage occurring on the opposing articular surfaces. Allografts inserted flush with the cartilage surface had the lowest levels of wear, deformation and damage following the 2 h test; increased levels of wear, deformation and damage were observed when allografts and stainless steel pins were inserted proud of the articular surface. The method developed will be applied in future studies to assess the tribological performance of novel early stage osteochondral interventions prior to in vivo studies, investigate variation in surgical precision and aid in the development of stratified interventions for the patient population.

The use of nanoparticles in medicine is ever increasing, and it is important to understand their targeted and non-targeted effects. We have previously shown that nanoparticles can cause DNA damage to cells cultured below a cellular barrier without crossing this barrier. Here, we show that this indirect DNA damage depends on the thickness of the cellular barrier, and it is mediated by signalling through gap junction proteins following the generation of mitochondrial free radicals. Indirect damage was seen across both trophoblast and corneal barriers. Signalling, including cytokine release, occurred only across bilayer and multilayer barriers, but not across monolayer barriers. Indirect toxicity was also observed in mice and using ex vivo explants of the human placenta. If the importance of barrier thickness in signalling is a general feature for all types of barriers, our results may offer a principle with which to limit the adverse effects of nanoparticle exposure and offer new therapeutic approaches. Indirect DNA damage to cells cultured below a cellular barrier caused by nanoparticles occurs across barriers containing two or more layers, but not monolayer barriers, suggesting that the thickness of the cell barrier is important in signalling.

Vascular endothelial growth factor (VEGF) is a potent angiogenic factor with a key role in several pathological processes, including tumour vascularization. Our preliminary observations indicated higher VEGF concentrations in serum samples than in matched plasma samples. We have now demonstrated that this difference is due to the presence of VEGF within platelets and its release upon their activation during coagulation. In eight healthy volunteers, serum VEGF concentrations ranged from 76 to 854 pg ml(-1) and were significantly higher (P < 0.01) than the matched citrated plasma VEGF concentrations, which ranged from < 9 to 42 pg ml(-1). Using platelet-rich plasma, mean (s.d.) platelet VEGF contents of 0.56 (0.36) pg of VEGF 10(-6) platelets were found. Immunocytochemistry demonstrated the cytoplasmic presence of VEGF within megakaryocytes and other cell types within the bone marrow. From examination of the effects of blood sample processing on circulating VEGF concentrations, it is apparent that for accurate measurements, citrated plasma processed within 1 h of venepuncture should be used. Serum is completely unsuitable. The presence of VEGF within platelets has implications for processes involving platelet and endothelial cell interactions. e.g. wound healing, and in tumour metastasis, when platelets adhering to circulating tumour cells may release VEGF at points of adhesion to endothelium, leading to hyperpermeability and extravasation of cells.

Hemiarthroplasty is a potentially attractive alternative to knee replacement for young, active patients, as it allows preservation of more bone stock for potential revisions. However, there has been limited success with hemiarthroplasty or spacers to date. The wear and degradation of the biomaterial–cartilage interface is of paramount importance in the design and success of hemiarthroplasties. A comprehensive understanding of the tribological performance of hemiarthroplasty implants in the natural joint is required. The objective of this study was to investigate the tribological response of bovine medial compartmental knees, both natural and hemiarthroplasty replaced, under physiological loads and motion. The conformity of these metallic hemiarthroplasties was varied (conforming plates with radius of 50 mm and radius of 100 mm and a flat plate design), in order to examine the effects of conformity and contact stress, on the friction, friction shear stress and cartilage degeneration. With decreasing conformity of hemiarthroplasty bearings, an increase in contact stress was found, which resulted in elevated friction, elevated friction shear stress and increased cartilage degeneration. A strong correlation was found between contact stress and wear and between friction shear stress and wear. This new and unique in vitro tribological simulation has shown the direct elevation of friction, surface fibrillation and biomechanical wear of cartilage, upon replacing the tibia with a hemiarthroplasty, particularly when using low conformity hemiarthroplasty designs.

Many of the decellularised dermis products on the market at present are aspectically produced. NHS Blood and Transplant Tissue Services have developed a method of producing a dCELL human dermis which has been terminally sterilised by gamma irradiation. The terminally sterilised decellularised dermis was compared with cellular tissue and examined for histology, residual DNA content, biomechanical and biochemical properties, in vitro cytotoxicity and in vivo implantation in a mouse model. No alterations in morphology as viewed by light microscopy were observed and DNA removal was 99 %. There were no significant changes in ultimate tensile stress or evidence for collagen denaturation or cytotoxicity. The in vivo studies did not indicate any adverse tissue reactions in the mouse model and demonstrated incorporation of dCELL human dermis into the host. Decellularisation, followed by terminal sterilisation with gamma irradiation, is an appropriate method to produce a human dermis allograft material suitable for transplantation.

The aims of this study were to develop a biological large diameter vascular graft by decellularisation of native human aorta to remove the immunogenic cells whilst retaining the essential biomechanical, and biochemical properties for the ultimate benefit of patients with infected synthetic grafts. Donor aortas (n = 6) were subjected to an adaptation of a propriety decellularisation process to remove the cells and acellularity assessed by histological analysis and extraction and quantification of total DNA. The biocompatibility of the acellular aortas was determined using standard contact cytotoxicity tests. Collagen and denatured collagen content of aortas was determined and immunohistochemistry was used to determine the presence of specific extracellular matrix proteins. Donor aortas (n = 6) were divided into two, with one half subject to decellularisation and the other half retained as native tissue. The native and decellularised aorta sections were then subject to uniaxial tensile testing to failure [axial and circumferential directions] and suture retention testing. The data was compared using a paired t-test. Histological evaluation showed an absence of cells in the treated aortas and retention of histoarchitecture including elastin content. The decellularised aortas had less than 15 ng mg−1 total DNA per dry weight (mean 94% reduction) and were biocompatible as determined by in vitro contact cytotoxicity tests. There were no gross changes in the histoarchitecture [elastin and collagen matrix] of the acellular aortas compared to native controls. The decellularisation process also reduced calcium deposits within the tissue. The uniaxial tensile and suture retention testing revealed no significant differences in the material properties (p > 0.05) of decellularised aorta. The decellularisation procedure resulted in minimal changes to the biological and biomechanical properties of the donor aortas. Acellular donor aorta has excellent potential for use as a large diameter vascular graft.

Tissue-engineering approaches to cardiac valve replacement have made considerable advances over recent years and it is likely that this application will realize clinical success in the near future. Research in this area has been driven by the inadequacy of the currently available cardiac valve prostheses for younger patients who require multiple reoperations as they grow and develop. Tissue engineering has the potential to provide a valve capable of the same growth, repair, and regeneration as a natural valve and could improve outcomes for patients of all ages. Owing to the function and physical environment of the cardiac valve, the development of tissue-engineered replacements is unusual in that the biomechanical properties of the construct must dominate the biological properties in order for the valve to be functional at the time of implantation. As a result of this, conventional tissue-engineering scaffolds based on biodegradable polymers or collagen may not at present be suitable in this situation because of their initial limited strength. Research into the use of acellular xenogeneic and allogeneic matrices for tissue-engineered heart valves has consequently become extremely popular since the biomechanical properties of the valve can potentially be preserved with an optimal decellularization technique that removes the cells without damaging the matrix. A number of acellular scaffolds have already been tested clinically both unseeded and preseeded with cells and these have met with variable results. This article reviews the concepts involved and the advantages and disadvantages of the different approaches to tissue engineering a living cardiac valve.

The current wear-testing standard (ISO18192-1) for total disc replacement (TDR) requires only four degrees of freedom (DOF) inputs: axial load, flexion–extension, lateral bending and axial rotation. The study aim was to assess the effect of an additional DOF, anterior–posterior (AP) shear on the wear of the ProDisc-L TDR. A 5DOF simulator was used to test ProDisc-L implants under 4DOF and 5DOF conditions. The 4DOF conditions were defined by ISO18192-1 whilst the 5DOF used ISO18192-1 conditions with the addition of an AP load of +175 and −140 N (anterior and posterior, respectively), extrapolated from in vivo data. The implants were mounted such that the polyethylene insert could be removed for gravimetric measurements. Tests were run using bovine serum (15 g/l protein concentration) as a lubricant for five million cycles (MC), with measurements repeated every 1 MC. The mean wear rate in the 4DOF test was 12.7 ± 2.1 mg/MC compared to 11.6 ± 1.2 mg/MC in the 5DOF test. There were marked differences in the wear scars between 4DOF and 5DOF simulations. With 4DOF, wear scars were centralised on the dome of the insert, whilst 5DOF scars were larger, breaching the anterior rim of the dome causing deformation at the edge. The 4DOF wear test showed similar gravimetric wear rates to previously published ISO-tested TDRs. The addition of AP load was found to have no significant effect on the overall wear rate. However, there were pronounced differences in the respective wear scars, which highlights the need for more research in order to understand the factors that influence wear of TDR.

Application of a high-level decontamination or sterilisation procedure and cell removal technique to tendon allograft can reduce the concerns of disease transmission, immune reaction, and may improve remodelling of the graft after implantation. The decellularised matrix can also be used as a matrix for tendon tissue engineering. One such sterilisation factor, Peracetic acid (PAA) has the advantage of not producing harmful reaction residues. The aim of this study was to evaluate the effects of PAA treatment and a cell removal procedure on the production of tendon matrix. Human patellar tendons, thawed from frozen were treated respectively as: Group 1, control with no treatment; Group 2, sterilised with PAA (0.1 % (w/v) PAA for 3 h) Group 3, decellularised (incubation successively in hypotonic buffer, 0.1 % (w/v) sodium dodecyl sulphate, and a nuclease solution); Group 4, decellularised and PAA sterilised. Histological analysis showed that no cells were visible after the decellularisation treatment. The integrity of tendon structure was maintained after decellularisation and PAA sterilisation, however, the collagen waveform was slightly loosened. No contact cytotoxicity was found in any of the groups. Determination of de-natured collagen showed no significant increase when compared with the control. This suggested that the decellularisation and sterilisation processing procedures did not compromise the major properties of the tendon. The sterilised, decellularised tendon could be suitable for clinical use.