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Biomedical subjects

John Fisher

Publications and source records attributed to John Fisher.

At least 19 recordsLinked to original sources
PubMed2007

Simulation of polyethylene wear in ankle joint prostheses.

The performance of total ankle replacements (TARs) have not been comparable to those of the other major joints of the lower extremity. The aim of this work was to develop a new simulator test to compare the wear of a new mobile bearing TAR (Mobility) with one with a good clinical history, the Buechel Pappas, using kinematic inputs derived from the literature. The wear rate for the Mobility components was lower than that for the Buechel-Pappas ankle joints at all time points. The wear rate for both sets of components increased with the inclusion of an anterior/posterior displacement in the kinematic inputs. This was expected as the components are subjected to higher kinematic demands and reproduces similar effects found in knee prostheses. This study has demonstrated that it is possible to study wear of TARs in a modified simulator originally designed for total knee replacements. It was also shown that the new Mobility ankle compares favorably with the Buechel Pappas ankle, which has a successful clinical history, under the simulator test conditions described.

Ankle Joint↗
PubMed2007

Friction of total hip replacements with different bearings and loading conditions.

Metal-on-ultra-high molecular weight polyethylene (UHMWPE) total hip replacements have been the most popular and clinically successful implants to date. However, it is well documented that the wear debris from these prostheses contributes to osteolysis and ultimate failure of the prosthesis, hence alternative materials have been sought. A range of 28 mm diameter bearings were investigated using a hip friction simulator, including conventional material combinations such as metal-on-UHWMPE, ceramic-on-ceramic (CoC), and metal-on-metal (MoM), as well as novel ceramic-on-metal (CoM) pairings. Studies were performed under different swing-phase load and lubricant conditions. The friction factors were lowest in the ceramic bearings, with the CoC bearing having the lowest friction factor in all conditions. CoM bearings also had low friction factors compared with MoM, and the trends were similar to CoC bearings for all test conditions. Increasing swing phase load was shown to cause an increase in friction factor in all tests. Increased serum concentration resulted in increased friction factor in all material combinations, except MoM, where increased serum concentration produced a significant reduction in friction factor.

Biocompatible Materials↗
PubMed2006

Characterisation of wear particles produced by metal on metal and ceramic on metal hip prostheses under standard and microseparation simulation.

The failure of metal on polyethylene total hip replacements due to wear particle induced osteolysis and late aseptic loosening has focused interest upon alternative bearings, such as metal on metal implants. A recent advance in this field has been the development of a novel ceramic on metal implant. The characteristics of the wear particles generated in this low-wearing bearing have not been previously determined. The aims of this study were to characterise metal wear particles from metal on metal and ceramic on metal hips under standard and adverse (microseparation) wear conditions. Accurate characterisation of cobalt-chrome wear particles is difficult since the reactive nature of the particles prevents them from being isolated using acids and bases. A method was developed to isolate the metal wear particles using enzymes to digest serum containing lubricants from metal on metal and ceramic on metal hip simulations. High resolution scanning electron microscopy was then used to characterise the wear particles generated by both metal on metal and ceramic on metal implants under standard and microseparation wear conditions. The wear particles isolated from all simulations had a mean size of less than 50 nm with a rounded and irregular morphology. No significant difference was found between the size of wear particles generated under any conditions.

Ceramics↗
PubMed2006

Development and characterisation of a full-thickness acellular porcine bladder matrix for tissue engineering.

The aim of this study was to produce a natural, acellular matrix from porcine bladder tissue for use as a scaffold in developing a tissue-engineered bladder replacement. Full-thickness, intact porcine bladders were decellularised by distention and immersion in hypotonic buffer containing 0.1% (w/v) SDS and nuclease enzymes. Histological analysis of the resultant matrices showed they were completely acellular; that the major structural proteins had been retained and that there were some residual poorly soluble intracellular proteins. The amount of DNA per mg dry weight of fresh porcine bladder was 2.8 (+/-0.1) microg/mg compared to 0.1 (+/-0.1) microg/mg in decellularised bladder and biochemical analysis showed proportional differences in the hydroxyproline and glycosaminoglycan content of the tissue before and after decellularisation. Uniaxial tensile testing indicated that decellularisation did not significantly compromise the ultimate tensile strength of the tissue. There was, however, an increase in the collagen and elastin phase slopes indicating decreased extensibility. Cytotoxicity assays using porcine smooth muscle cell cultures excluded the presence of soluble toxins in the biomaterial. In summary, a full-thickness natural acellular matrix retaining the major structural components and strength of the urinary bladder has been successfully developed. The matrix is biocompatible with bladder-derived cells and has potential for use in urological surgery and tissue-engineering applications.

Animals↗
PubMed2006

The effect of hyaluronic acid and phospholipid based lubricants on friction within a human cartilage damage model.

The lubricating abilities of different formulations of high molecular weight hyaluronic acid (HA), dipalmitoyl phosphatidylcholine (DPCC) and mixtures of both HA and DPCC were assessed in an in vitro model. Levels of start-up friction were determined using an osteoarthritis (OA) damaged human cartilage model set within a specially designed friction rig. To examine the long term benefits of HA, the extent of penetration of HA into cartilage tissue was investigated using fluorescently labelled HA and confocal microscopy. It was found that in this model, all formulations of HA and the majority of DPCC lubricants reduced friction (HA 5 and 10 mg ml(-1), DPPC 200 mg ml(-1) reductions of 51.9%, 46.7% and 46.5% respectively), compared to a Ringers solution control. Lubrication was found not to be concentration dependent for HA formulations, but concentration was key for DPCC lubrication (100 mg ml(-1) reduced friction by only 15.9%). By combining HA and DPCC (HA/DPPC; 5 mg ml(-1)/100 mg ml(-1) and 10 mg ml(-1)/200 mg ml(-1)), a further improvement was noted (69.5% and 61.9%, respectively) as the mean levels of friction were reduced by up to a further 17% than the most effective individual formulation (HA 5 mg ml(-1)). Penetration of HA into bovine cartilage by up to 300 microm from the surface was observed over a 48 h period. It was observed that HA specifically targeted the chondrocytes as it was primarily found within the lacunae surrounding the cells.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed2006

A Bayesian model for joint segmentation and registration.

A statistical model is presented that combines the registration of an atlas with the segmentation of magnetic resonance images. We use an Expectation Maximization-based algorithm to find a solution within the model, which simultaneously estimates image artifacts, anatomical labelmaps, and a structure-dependent hierarchical mapping from the atlas to the image space. The algorithm produces segmentations for brain tissues as well as their substructures. We demonstrate the approach on a set of 22 magnetic resonance images. On this set of images, the new approach performs significantly better than similar methods which sequentially apply registration and segmentation.

Artifacts↗
PubMed2006

Synthesis and structure-activity relationship of 3,4'-bispyridinylethylenes: discovery of a potent 3-isoquinolinylpyridine inhibitor of protein kinase B (PKB/Akt) for the treatment of cancer.

Structure-based design and synthesis of the 3,4'-bispyridinylethylene series led to the discovery of 3-isoquinolinylpyridine 13a as a potent PKB/Akt inhibitor with an IC(50) of 1.3nM against Akt1. Compound 13a shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to marginal selectivity against closely related kinases in the AGC and CMGC families. Moreover, 13a demonstrates potent cellular activity comparable to staurosporine, with IC(50) values of 0.42 and 0.59microM against MiaPaCa-2 and the Akt1 overexpressing FL5.12-Akt1, respectively. Inhibition of phosphorylation of the Akt downstream target GSK3 was also observed in FL5.12-Akt1 cells with an EC(50) of 1.5microM. The X-ray structures of 12 and 13a in complex with PKA in the ATP-binding site were determined.

Antineoplastic Agents↗
PubMed2006

Self-assembling peptides as injectable lubricants for osteoarthritis.

The self-assembly of peptides is explored as an alternative route towards the development of new injectable joint lubricants for osteoarthritis (OA). The versatility of the peptide chemistry allows the incorporation of behavior reminiscent of hyaluronic acid (HA), while the triggered in situ self-assembly provides easy delivery of the samples by injection due to the low viscosity of the peptide solutions (that are initially monomeric). Using design criteria based on the chemical properties of HA, a range of de novo peptides were prepared with systematic alterations of charge and hydrophilicity that self-assembled into nematic fluids and gels in physiological solution conditions. The frictional characteristics of the peptides were evaluated using cartilage on cartilage sliding contacts along with their rheological characteristics. Peptide P(11)-9, whose molecular, mesoscopic, and rheological properties most closely resembled HA was found to be the most effective lubricant amongst the peptides. In healthy static and dynamic friction testing (corresponding to healthy joints) P(11)-9 at 20-40 mg/mL performed similar to HA at 10 mg/mL. In friction tests with damaged cartilage (corresponding to early stage OA) P(11)-9 was a less efficient lubricant than HA, but still the best among all the peptides tested. The results indicate that de novo self-assembling peptides could be developed as an alternate therapeutic lubricant for early stage OA.

Amino Acid Sequence↗
PubMed2006

Wear of crosslinked polyethylene under different tribological conditions.

Ultra high molecular weight polyethylene (UHMWPE) wear debris has been shown to be a major cause of long term failure of total joint replacements. Recently, crosslinking has been extensively introduced to reduce the wear of UHMWPE. In this study the wear of non-crosslinked and crosslinked UHMWPE were compared under a range of conditions. The materials examined were UHMWPE GUR 1050, non-crosslinked, moderately crosslinked--5MRad, and highly crosslinked--10MRad. The wear was examined on a multidirectional pin on plate rig. The effect of counterface roughness on wear under different kinematics was examined. The results from the different counterface conditions showed that highly crosslinked UHMWPE had significantly lower wear against both smooth and scratched counterfaces. However the reduction in wear for crosslinked polyethylene was less for scratched counterfaces. The second part of the study showed that all the UHMWPE's produced lower wear rates under lower multidirectionality because of reduced cross shear frictional forces and work. These findings are relevant to the consideration of the use of crosslinked polyethylene in the knee, where the kinematics have lower levels of cross shear and in the hip and knee against roughened metallic counterfaces.

Biomechanical Phenomena↗
PubMed2006

Production of an acellular amniotic membrane matrix for use in tissue engineering.

A clinical need exists for an immunologically compatible surgical patch with a wide range of uses including soft tissue replacement, body wall repair, cardiovascular applications, and as a wound dressing. This study aimed to produce an acellular matrix from human amniotic membrane for future assessment as a surgical patch and a delivery system for epithelial cells. A novel detergent-based protocol was modified to remove all cellular components from amnion to render it non-immunogenic. Amnion was harvested within 24 h after elective caesarean section (n = 12). One sample group remained fresh, whereas the other was treated with 0.03% (w/v) sodium dodecyl sulphate, with hypotonic buffer and protease inhibitors, nuclease treatment, and terminal sterilization, using peracetic acid (0.1% v/v). Fresh and treated amnion was analyzed histologically for the presence of cells, deoxyribonucleic acid (DNA), collagen, glycosaminoglycans (GAGs), and elastin. Quantitative analysis was performed to determine levels of GAGs, elastin, hydroxyproline, denatured collagen, and DNA. The biomechanical properties of the membrane were determined using uniaxial tensile testing to failure. Histological analysis of treated human amnion showed complete removal of cellular components from the tissue; the histoarchitecture remained intact. All major structural components of the matrix were retained, including collagen type IV and I, laminin, and fibronectin. Differences were observed between fresh and decellularized amnion in matrix hydroxyproline (34.7 microg/mg vs 49.7 microg/mg), GAG (42.5 microg/mg vs 85.4 microg/mg), denatured collagen (2.2 microg/mg vs 1.7 microg/mg), and elastin (359.2 microg/mg vs 490.8 microg/mg) content. DNA content was diminished after treatment. Acellular matrices were biocompatible, cells grew in contact, and there was no decrease in cell viability after incubation with soluble tissue extracts. In addition, no significant reduction in ultimate tensile strength, extensibility, or elasticity was found after decellularization. Removal of the cellular components should eliminate immunological rejection. The resulting matrix was biocompatible in vitro and exhibited no adverse effects on cell morphology or viability.

Amnion↗
PubMed2006

Review: tissue engineering of the urinary bladder: considering structure-function relationships and the role of mechanotransduction.

A variety of conditions encountered in urology result in bladder dysfunction and the need for bioengineered tissue substitutes. Traditionally, a number of synthetic materials and natural matrices have been used in experimental and clinical settings. However, the production of functional bladder tissue replacements remains elusive. The urinary bladder sustains considerable structural deformation during its normal function and represents an ideal model tissue in which to study the effects of biomechanical simulation on tissue morphogenesis, differentiation, and function. However, the actual role of mechanical forces within the bladder has received little attention. A strategy in which in vitro-generated tissue constructs are conditioned by exposure to the same mechanical forces as they would encounter in vivo could potentially be used both in the development of functional tissue replacements and to further study the role of biomechanical signalling. The purpose of this review is to examine the role and structure-function relationship of the urinary bladder and, through consultation of the literature available on mechanotransduction and tissue engineering of alternative tissues, to determine the factors that need to be considered when biomechanically engineering a functional bladder.

Animals↗
PubMed2006

Development and characterization of an acellular human pericardial matrix for tissue engineering.

This study aimed to produce an acellular human tissue scaffold with a view to recellularization with autologous cells to produce a tissue-engineered pericardium that can be used as a patch for cardiovascular repair. Human pericardia from cadaveric donors were treated sequentially with hypotonic buffer, SDS in hypotonic buffer, and a nuclease solution. Histological analysis of decellularized matrices showed that the human pericardial tissue retained its histioarchitecture and major structural proteins. There were no whole cells or cell fragments. There were no significant differences in the hydroxyproline (normal and denatured collagen) and glycosaminoglycan content of the tissue before and after decellularization (p > 0.05). There were no significant changes in the ultimate tensile strength after decellularization (p > 0.05). However, there was an increased extensibility when the tissue strips were cut parallel to the visualized collagen bundles (p = 0.005). No indication of contact or extract cytotoxicity was found when using human dermal fibroblasts and A549 cells. In summary, successful decellularization of the human pericardium was achieved producing a biocompatible matrix that retained the major structural components and strength of the native tissue.

Adenosine Triphosphate↗
PubMed2006

Tribology of alternative bearings.

The tribological performance and biological activity of the wear debris produced has been compared for highly cross-linked polyethylene, ceramic-on-ceramic, metal-on-metal, and modified metal bearings in a series of in vitro studies from a single laboratory. The functional lifetime demand of young and active patients is 10-fold greater than the estimated functional lifetime of traditional polyethylene. There is considerable interest in using larger diameter heads in these high demand patients. Highly cross-linked polyethylene show a four-fold reduction in functional biological activity. Ceramic-on-ceramic bearings have the lowest wear rates and least reactive wear debris. The functional biological activity is 20-fold lower than with highly cross-linked polyethylene. Hence, ceramic-on-ceramic bearings address the tribological lifetime demand of highly active patients. Metal-on-metal bearings have substantially lower wear rates than highly cross-linked polyethylene and wear decreases with head diameter. Bedding in wear is also lower with reduced radial clearance. Differential hardness ceramic-on-metal bearings and the application of ceramic-like coatings reduce metal wear and ion levels.

Aluminum Oxide↗
PubMed2006

Wear-simulation analysis of rotating-platform mobile-bearing knees.

The wear and wear debris from rotating-platform mobile-bearing knees and fixed-bearing knees were compared in knee joint-simulator studies. The wear rate of the fixed-bearing knees was found to increase as the kinematics were increased because of an increase in internal-external rotation and an increase in anterorposterior (AP) translation. The wear rate of the rotating-platform mobile-bearing knees was found to be significantly lower than that of the fixed-bearing knees. The rotating-platform mobile-bearing knee was able to decouple the complex kinematics to pure rotation at the inferior tibial articulating surface and linear flexion-extension and AP sliding at the superior femoral articulating interface, substantially reducing cross-shear and wear. No difference was found in the wear debris between the rotating-platform and fixed-bearing knees. This resulted in a substantially reduced functional biological activity or osteolytic potential for the rotating-platform mobile-bearing knees due to the lower wear rates.

Knee Prosthesis↗
PubMed2005

Effect of swing phase load on metal-on-metal hip lubrication, friction and wear.

There is renewed interest in metal-on-metal (MOM) total hip replacements (THRs), however, variable wear rates have been observed clinically. It is hypothesised that changes in soft tissue tensioning during surgery may alter loading of THRs during the swing phase of gait leading to changes in fluid film lubrication, friction and wear. This study aimed to assess the effect of swing phase load on the lubrication, friction and wear of MOM hip replacements. Theoretical lubrication modelling was carried out using elastohydrodynamic theory. All the governing equations were solved numerically for the lubricant film thickness between the articulating surfaces under the transient dynamic conditions with low and high swing phase loads. Friction testing was completed using a single axis pendulum simulator, simplified loading cycles were applied with low and high swing phase loads. MOM hip replacements were tested in a hip simulator, modified to provide different swing phase loading regimes; a low (100 N) and a high load (as per ISO 14242-1; 280 N). Results demonstrated that the performance of MOM bearings is highly dependent on swing phase load. Hence, changes in the tension of the tissues at surgery and variations in muscle forces may increase swing phase load, reduce lubrication, increase friction and accelerate wear. This may explain some of the variations that have been observed with clinical wear rates.

Arthroplasty, Replacement, Hip↗
PubMed2005

Biphasic surface amorphous layer lubrication of articular cartilage.

The biphasic nature of articular cartilage has been acknowledged for some time and is known to play an important role in many of the biomechanical functions performed by this unique tissue. From the lubrication point of view however, a simple biphasic model is unable to account for the extremely low friction coefficients that have been recorded experimentally, particularly during start-up. In addition, research over the last decade has indicated the presence of a surface amorphous layer on top of articular cartilage. Here, we present results from a finite element model of articular cartilage that includes a thin, soft, biphasic surface amorphous layer (BSAL). The results of this study show that a thin BSAL, with lower elastic modulus, dramatically altered the load sharing between the solid and liquid phases of articular cartilage, particularly in the near-surface regions of the underlying bulk cartilage and within the surface amorphous layer itself where the fluid load support exceeded 85%. By transferring the load from the solid phase to the fluid phase, the biphasic surface layer improves lubrication and reduces friction, whilst also protecting the underlying cartilage surface by 'shielding' the solid phase from elevated stresses. The increase in lubrication effectiveness is shown to be greatest during short duration loading scenarios, such as shock loads.

Biomechanical Phenomena↗
PubMed2005

Direct agonist/antagonist functions of dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA) exhibits peak adrenal secretion in the fetus at term and around age 30 yr in the adult. Levels then progressively decline, which is associated with decreased levels of testosterone, dihydrotestosterone, and estrogen in peripheral tissues. DHEA supplementation in postmenopausal women increases bone formation and density, an effect mainly attributed to peripheral conversion to sex hormones. In this study, we tested DHEA for direct effects on the androgen (AR) and estrogen (ER) receptors. DHEA bound to AR with a Ki of 1 microM, which was associated with AR transcriptional antagonism on both the mouse mammary tumor virus and prostate-specific antigen promoters, much like the effects of bicalutamide. Unlike bicalutamide, DHEA stimulated, rather than inhibited, LNCaP cell growth, suggesting possible interaction with other hormone receptors. Indeed DHEA bound to ERalpha and ERbeta, with Ki values of 1.1 and 0.5 microM, respectively. Despite the similar binding affinities, DHEA showed preferential agonism of ERbeta with an EC50 of approximately 200 nm and maximal activation at 1 microM. With ERalpha we found 30-70% agonism at 5 microM, depending on the assay. Physiological levels of DHEA are approximately 30 nM and up to 90 nM in the prostate. DHEA at 30 nM is actually sufficient to activate ERbeta transcription to the same degree as estrogen at its circulating concentration, and additive effects are seen when the two were combined. Taken together, DHEA has the potential for physiologically relevant direct activation of ERbeta. With peak levels at term and age 30 yr, there is also a potential for antagonist effects on AR and partial agonism of ERalpha.

Androgen Receptor Antagonists↗