Search PubMed⌕ Search

Biomedical subjects

S A Goldstein

Publications and source records attributed to S A Goldstein.

At least 73 records · Page 4Linked to original sources
PubMed1998

Finite-element modeling of trabecular bone: comparison with mechanical testing and determination of tissue modulus.

We combined three techniques--mechanical testing, three-dimensional imaging, and finite-element modeling--to distinguish between the contributions of architecture and tissue modulus to mechanical function in human trabecular bone. The objectives of this study were 2-fold. The first was to assess the accuracy of micromechanical modeling of trabecular bone using high-contrast x-ray images of the trabecular architecture. The second was to combine finite-element calculations with mechanical testing to infer an average tissue modulus for the specimen. Specimens from five human L1 vertebrae were mechanically tested along the three anatomic axes. The specimens were then imaged by synchrotron x-ray tomography, and the elastic moduli of each specimen were calculated from the tomographic image by finite-element modeling. We found that 23-microm tomographic images resolved sufficient structural detail such that the calculated anisotropy in the elastic modulus was within the uncertainties of the experimental measurements in all cases. The tissue modulus of each specimen was then estimated by comparing the calculated mean stiffness of the specimen, averaged over the three anatomical directions, with the experimental measurement. The absolute values of the experimental elastic constants could be fitted, again within the uncertainties of the experimental measurements, by a single tissue modulus of 6.6 GPa, which was the average tissue modulus of the five specimens. These observations suggest that a combination of mechanical testing, three-dimensional imaging, and finite-element modeling might enable the physiological variations in tissue moduli to be determined as a function of age and gender.

Aged↗
PubMed1998

Sequence and function of the two P domain potassium channels: implications of an emerging superfamily.

A new superfamily of K+ channels has emerged in the past 2 years. Notable for possessing two pore-forming P domains in each subunit, members of the superfamily have been recognized through phylogeny from micro-organisms to humans. Four subfamilies of two P domain channels have been isolated thus far; among these are the first cloned examples of outward rectifier and open rectifier (or leak) K+ channels. The two P domain K+ channels offer a new perspective from which to glimpse the molecular basis for function and dysfunction of K+-selective ion channels.

Amino Acid Sequence↗
PubMed1998

Single-channel characteristics of wild-type IKs channels and channels formed with two minK mutants that cause long QT syndrome.

IKs channels are voltage dependent and K+ selective. They influence cardiac action potential duration through their contribution to myocyte repolarization. Assembled from minK and KvLQT1 subunits, IKs channels are notable for a heteromeric ion conduction pathway in which both subunit types contribute to pore formation. This study was undertaken to assess the effects of minK on pore function. We first characterized the properties of wild-type human IKs channels and channels formed only of KvLQT1 subunits. Channels were expressed in Xenopus laevis oocytes or Chinese hamster ovary cells and currents recorded in excised membrane patches or whole-cell mode. Unitary conductance estimates were dependent on bandwidth due to rapid channel "flicker." At 25 kHz in symmetrical 100-mM KCl, the single-channel conductance of IKs channels was approximately 16 pS (corresponding to approximately 0.8 pA at 50 mV) as judged by noise-variance analysis; this was fourfold greater than the estimated conductance of homomeric KvLQT1 channels. Mutant IKs channels formed with D76N and S74L minK subunits are associated with long QT syndrome. When compared with wild type, mutant channels showed lower unitary currents and diminished open probabilities with only minor changes in ion permeabilities. Apparently, the mutations altered single-channel currents at a site in the pore distinct from the ion selectivity apparatus. Patients carrying these mutant minK genes are expected to manifest decreased K+ flux through IKs channels due to lowered single-channel conductance and altered gating.

Animals↗
PubMed1998

Use of microcomputed tomography scanning as a new technique for the evaluation of membranous bone.

Previous basic bone studies in cranial bone biology and bone grafting have used calipers, volume displacement, and cephalometric tracings to measure membranous bone and to infer fundamental properties of cranial bone. These tools have limited accuracy and reproducibility. Histomorphometry has also been used in the quantitative analysis of cranial bone; however, two-dimensional histology is unable to capture a precise representation of the three-dimensional structure of bone. For the first time, we have used the advanced technology of three-dimensional microcomputed tomographic (micro-CT) scanning as a highly accurate and automated tool to precisely measure changes in bone stereology, volume and projection, and microarchitecture in the evaluation of membranous bone. The advantages of this technology are numerous and include the rapid and nondestructive three-dimensional analysis of bone microstructure at resolutions between 10 and 75 microns. Measures of "connectivity" in three dimensions and the architectural parameter of "anisotropy" are available through micro-CT imaging but can only be inferred through two-dimensional histological series. We successfully imaged two full-thickness cranial bone specimens and one cancellous iliac bone graft. The images demonstrate a similarity between the two membranous specimens and a marked difference in comparison with the endochondral graft. These differences are borne out by mathematical analysis, and their significance is discussed. The utility of micro-CT in the evaluation of membranous bone was displayed by its ability to rapidly calculate differences in bone stereology and to quantitatively measure morphological changes at an ultrastructural level. We believe the benefits of this system will prove to be extremely useful for investigations into the basic biology of membranous bone, bone grafts, and craniofacial interfaces, and we encourage its use by other scientific investigators in the field of craniofacial surgery as they strive for more scientifically rigorous tools to understand the basic biology of membranous bone.

Animals↗
PubMed1998

Evaluation of the mechanical environment during distraction osteogenesis.

Physical forces have been hypothesized to direct the process of bone regeneration during distraction osteogenesis. However, despite significant clinical experience, relatively little is known about how the mechanics of distraction influence bone formation. This study investigated net fixator forces and strains in the distraction callus during bilateral lengthening of tibiae in New Zealand White rabbits. Distractions yielded a classic viscoelastic response with a sharp increase in fixator force, followed immediately by significant relaxation. Tension acting on mesenchymal gap tissue caused by distraction was estimated to reach more than 30 N by the time full lengthening was achieved. Average maximum cyclic strains within the distraction zone during ambulation were estimated to be 14% to 15% and supported by the results of fluoroscopic imaging. Paradigms for fracture healing have hypothesized that such strains are incompatible with new bone formation. The documented clinical success of distraction osteogenesis at stimulating large volumes of new bone suggests that other mechanisms that warrant additional investigation may be at work during distraction.

Animals↗
PubMed1998

Potential role for direct gene transfer in the enhancement of fracture healing.

This paper describes the use of localized transient gene therapy for the augmentation of fracture healing. It introduces a method involving the delivery of plasmid deoxyribonucleic acid via a three dimensional matrix into a wound, with in vivo transfection of wound repair cells resulting, their subsequent expression of factors that condition the wound site and the promotion of healing. Based on experience with critical and noncritical defect models in small and large animals, the potential advantages of this approach are discussed and experimental evidence of promoting bone formation is provided. The studies show the potential of this technology not only to promote bone healing but also to repair or to regenerate other connective tissues.

Animals↗
PubMed1998

Micromechanics of osteonal cortical bone fracture.

Microcracks have been associated with age-related bone tissue fragility and fractures. The objective of this study was to develop a simple osteonal cortical bone model and apply linear elastic fracture mechanics theory to understand the micromechanics of the fracture process in osteonal cortical bone and its dependence on material properties. The linear fracture mechanics of our composite model of cortical bone, consisting of an osteon and interstitial bone tissue, was characterized in terms of a stress intensity factor (SIF) near the tip of a microcrack. The interaction between a microcrack and an osteon was studied for different types of osteons and various spacing between the crack and the osteon. The results of the analysis indicate that the fracture mechanics of osteonal cortical bone is dominated by the modulus ratio between the osteon and interstitial bone tissue: A soft osteon promotes microcrack propagation toward the osteon (and cement line) while a stiff one repels the microcrack from the osteon (and cement line). These findings suggest that newly formed, low-stiffness osteons may toughen cortical bone tissue by promoting crack propagation toward osteons. A relatively accurate empirical formula also was obtained to provide an easy estimation of the influence of osteons on the stress intensity factor.

Biomechanical Phenomena↗
PubMed1998

Accuracy of two-dimensional echocardiographic planimetry of the mitral valve area before and after balloon valvuloplasty.

The purpose of this study was to assess the accuracy of planimetry after percutaneous balloon mitral valvuloplasty (PBMV). The mitral valve area (MVA) was estimated in 34 patients before and after PBMV, using two-dimensional echocardiographic planimetry, Doppler pressure half-time (PHT), and the Gorlin formula. There was no significant difference in the correlation of planimetry and PHT before (r = 0.53, p = 0.001) and after PBMV (r = 0.56, p < 0.001). A similar correlation was found between planimetry and the Gorlin formula (r = 0.44, p = 0.01 before PBMV, r = 0.37, p = 0.03 after PBMV). The concordance between planimetry, PHT, and the Gorlin formula in classifying patients into mild, moderate, or severe mitral stenosis was not worse after PBMV. Planimetry-derived MVA was not less accurate after PBMV than before PBMV. However, the correlation between the two echocardiographic measurements and the Gorlin formula was only moderate.

Blood Flow Velocity↗
PubMed1998

Systemic over-secretion of growth hormone in transgenic mice results in a specific pattern of skeletal modeling and adaptation.

The effects of growth hormone (GH) over-secretion on bone modeling and remodeling in transgenic mice were investigated using systematic and hierarchical methods. The results showed that continual systemic stimulation of GH over-secretion in mice resulted in an initial increase in bone mass, but its bone quality was not comparable with that of the littermate controls. Further continual over-stimulation of GH resulted in an increase in bone resorption leading to thinner cortices with inferior tissue mechanical properties. Three biological mechanisms following GH over-production are formulated to explain the observed results: GH over-secretion stimulated the production of inferior bone matrices, i.e., woven bone and cartilage, in addition to the production of normal lamellar bone; the increased bone formation stimulated by GH was followed by an exaggerated bone resorption process, resulting in cortical tissue with inferior mechanical properties; and a cortical shift occurred following GH over-stimulation that appeared to be caused by the combined effects of GH over-secretion and a variation in mechanical stimuli in the metallothionein-1 growth hormone regulating hormone transgenic mice. An "Optimal Strain Environment" model is proposed to help explain the observed results. From the results of the present and previous studies, we believe that the primary goal of bone adaptation to a biological perturbation, at least in mice, is to ensure proper mechanical function by maintaining structural integrity. In the process of maintaining a targeted whole bone structural integrity, the mechanical integrity of tissue may be sacrificed.

Adaptation, Physiological↗
PubMed1998

Biomechanical and histological evaluation of a calcium phosphate cement.

It is often difficult to achieve stable fixation of a comminuted fracture associated with a metaphyseal defect. The injection of a resorbable cement into an osseous defect may help to stabilize the fracture and to maintain osseous integrity as the cement is resorbed and replaced by bone. The purpose of the present study was to evaluate the repair of a metaphyseal defect after treatment with an injectable calcium-phosphate cement. The injectable cement undergoes isothermic curing in vivo to form a carbonated apatite (dahllite) with a compressive strength of twenty-five megapascals. Either the cement or allograft bone was placed in proximal tibial metaphyseal and distal femoral metaphyseal defects in seventy-two dogs and was evaluated from twenty-four hours to seventy-eight weeks postoperatively. Histological examination showed that the cement was osteoconductive; nearly the entire surface area was covered with bone two weeks after the injection. The resulting bone-cement composite underwent gradual remodeling over time in a pattern that was qualitatively similar to the remodeling of normal cortical and cancellous bone. Osteoclasts were found to resorb the cement and were usually associated with adjacent new-bone formation. With increasing time in vivo, the cement was penetrated by small blood vessels that became surrounded by circumferential lamellae of bone and that closely resembled evolving haversian systems. This process occurred more rapidly in the cortex than in the medulla. Mechanical testing showed that, by eight weeks, the tibiae that had been treated with cement had reached nearly 100 per cent of the torsional strength of the contralateral, control (intact) tibiae; this finding paralleled the histological observations of bone apposition to the cement and rapid restoration of the cortex. At no time was fibrous tissue present between the cement and the bone, and there was no evidence of acute inflammation. Small particles of cement were present within occasional macrophages during the process of cement resorption, but the macrophages disappeared over time and were not associated with fibrosis or unexpected resorption of bone. Resorption of the cement was incomplete in the medullary area at seventy-eight weeks, but the pattern of cement resorption and bone-remodeling suggested gradual restoration of a physiological proportion of bone and marrow in both the cortical and the medullary region with maintenance of mechanical function.

Animals↗
PubMed1998

Mechanical properties of human trabecular bone lamellae quantified by nanoindentation.

Improved preventive and therapeutic strategies for skeletal diseases such as osteoporosis rely on a better understanding of the mechanical properties of trabecular bone and their influence on cell mediated adaptation processes. The mechanical properties of trabecular bone are determined by composition as well as structural (trabecular architecture), microstructural (trabecular packets) and nanostructural (lamellae) organization. Density is the major predictor of the mechanical properties of trabecular structures and has been extended to the concept of fabric to include architectural anisotropy and improve even further the power of prediction. Recent advances in QCT and MRI technologies allow for precise assessment of 3D trabecular architecture and the mechanical consequences of structural changes can be increasingly well quantified by the means of computational methods. While single trabeculae have been tested using various techniques with contrasting results, little is known about the intrinsic mechanical properties of trabecular bone lamellae on which these computational methods rely. For instance, water and mineral content have a significant effect on the elastic, viscous, yield and postyield properties of bone tissue. In addition, collagen fiber orientation affects the mechanics of single remodeling units. Variations in composition and organization determined by age, accumulated damage or disease may therefore reduce the mechanical integrity of trabecular bone and deserve more attention. The aim of this work was to utilize a nanoindentation technique to quantify elastic modulus and hardness of human trabecular bone lamellae.

Aged↗
PubMed1998

Norian SRS cement augmentation in hip fracture treatment. Laboratory and initial clinical results.

Bone quality, initial fracture displacement, severity of fracture comminution, accuracy of fracture reduction, and the placement of the internal fixation device are important factors that affect fixation stability. New high strength cements that are susceptible to remodeling and replacement for fracture fixation may lead to improved clinical outcome in the treatment of hip fractures. Norian SRS is an injectable, fast setting cement that cures in vivo to form an osteoconductive carbonated apatite of high compressive strength (55 MPa) with chemical and physical characteristics similar to the mineral phase of bone. It can be used as a space filling internal fixation device to facilitate the geometric reconstruction, load transfer, and healing of bone with defects and/or fractures in regions of cancellous bone. Furthermore, this cement can improve the mechanical holding strength of conventional fixation devices. Use of this material potentially could improve fracture stability, retain anatomy during fracture healing and improve hip function, thus achieving better clinical outcomes. In vivo animal studies have shown the material's biocompatibility, and cadaveric studies have shown the biomechanical advantage of its use in hip fractures. Initial clinical experience (in 52 femoral neck fractures and 39 intertrochanteric fractures) showed the potential clinical use of this innovative cement in the treatment of hip fractures.

Aged↗
PubMed1998

Bone regeneration and fracture healing. Experience with distraction osteogenesis model.

The relation between physical forces and the processes of bone regeneration and healing remains incompletely understood. Gaps in understanding of these processes stem in part from models that produce inadequate amounts of new bone for study. Bone created through the use of distraction osteogenesis provides an attractive substrate for the study of mechanical forces and their effects on bone formation because this technique produces large volumes of new bone in a controlled fashion. The optimal mechanical environment in which bone formation occurs clinically has not been fully determined. In laboratory studies, however, the mechanical environment can be manipulated, and resultant changes in bone formation can be measured. To investigate how changes in strain environment influence patterns of bone formation, a bilateral New Zealand White rabbit model of bilateral distraction osteogensis was implemented. When a stiffener was applied to the external distractor, computation analyses predicted a sevenfold to eightfold decrease in all strain measures. These reductions in gap strains appeared to induce significant decreases in bone volume fraction and mean trabecular thickness. When osteotomies were created at a 30 degrees angle to the bony axis to generate more shear within the gap tissue, changes in the distribution of gap strains and resultant new bone architecture were observed. Specific correlations between changes in tissue level strains and the pattern of bone regeneration were seen in both experiments. These results provide direct in vivo evidence that pluripotential gap tissues are sensitive to their physical surroundings. Mechanisms responsible for this sensitivity might include vascularity, stem cell supply, and scaffolding architecture. The process of bone formation in distraction osteogenesis appears to be related to bone formation processes associated with more common conditions. The distraction osteogenesis model described suggests a mechanism for bone formation that seems applicable to other more common processes associated with bone formation, including fracture healing and impaired fracture healing.

Adult↗
PubMed1997

Restoration of pedicle screw fixation with an in situ setting calcium phosphate cement.

STUDY DESIGN: Pedicle screws were pulled out of human cadaveric vertebrae before and after augmentation with polymethylmethacrylate or in situ-setting calcium phosphate cement. The fixation strength of screws augmented with calcium phosphate cement was compared with that of screws augmented with polymethylmethacrylate. OBJECTIVES: To determine whether a new in situ-setting calcium phosphate cement might be suitable for augmenting the fixation of pedicle screws. The principle objective was to compare the pull-out resistance of screws augmented with calcium phosphate cement with the pull-out behavior of screws augmented with polymethylmethacrylate. Polymethylmethacrylate augmentation was chosen as the standard because of its current clinical use. Five types of screws were tested to determine whether screw design had an effect on the efficacy of augmentation. SUMMARY OF BACKGROUND DATA: Although many factors affect the pull-out resistance of pedicle screws, a key determinant of their performance is the strength of their attachment to the spine. In elderly, osteopenic patients, the screw-bone interface is especially at risk for stripping during insertion or pull-out after surgery. In these patients, polymethylmethacrylate has been used to augment pedicle screw fixation, although its use is not without risk. In situ-setting calcium phosphate cements may provide an alternative to polymethylmethacrylate in this application. Like polymethylmethacrylate, calcium phosphate cements can be injected into the prepared screw hole. They have the added advantage of being resorbed and replaced during healing and normal bone remodeling. METHODS: Thirty human lower lumbar vertebrae (L3-L5) were implanted bilaterally with one of five types of pedicle screws (n = 6 for each screw type). The screws were pulled out 3.0 mm at 0.25 mm/sec with a servohydraulic materials testing machine. The 3.0-mm pull-out distance, which was slightly longer than one thread pitch, was designed to strip the screw-bone interface but to leave the pedicle otherwise intact. After the initial testing, the screws in each vertebrae were removed, and the screw tracks were filled with 2.0 cc of polymethylmethacrylate (one side) or calcium phosphate cement (contralateral side). After augmentation, the screws were reinserted, and the cements were allowed to harden for 24 hours. Postaugmentation testing followed the protocols for preaugmentation testing, and the pull-out resistance of screws augmented with calcium phosphate cement was compared with the pull-out resistance of screws augmented with polymethylmethacrylate. RESULTS: Mechanically, calcium phosphate cement compared favorably with polymethylmethacrylate for augmenting pedicle screws. Both restored the strength of the screw-bone interface: across all screw types, the average increase in pull-out strength was 147% with polymethylmethacrylate augmentation and 102% with calcium phosphate cement. There were no significant differences because of screw type with either type of augmentation. CONCLUSIONS: The in situ-setting calcium phosphate cement investigated in this study compared favorably with polymethylmethacrylate in a single-cycle, pull-out test of augmented pedicle screws in senile trabecular bone. With further evaluation, this cement may offer an alternative to polymethylmethacrylate for the enhancement of pedicle screw fixation clinically.

Bone Cements↗
PubMed1997

A minK-HERG complex regulates the cardiac potassium current I(Kr).

MinK is a widely expressed protein of relative molecular mass approximately 15K that forms potassium channels by aggregation with other membrane proteins. MinK governs ion channel activation, regulation by second messengers, and the function and structure of the ion conduction pathway. Association of minK with a channel protein known as KvLQT1 produces a voltage-gated outward K+ current (I[sK]) resembling the slow cardiac repolarization current (I[Ks]). HERG, a human homologue of the ether-a-go-go gene of the fruitfly Drosophila melanogaster, encodes a protein that produces the rapidly activating cardiac delayed rectifier (I[Kr]). These two potassium currents, I(Ks) and I(Kr), provide the principal repolarizing currents in cardiac myocytes for the termination of action potentials. Although heterologously expressed HERG channels are largely indistinguishable from native cardiac I(Kr), a role for minK in this current is suggested by the diminished I(Kr) in an atrial tumour line subjected to minK antisense suppression. Here we show that HERG and minK form a stable complex, and that this heteromultimerization regulates I(Kr) activity. MinK, through the formation of heteromeric channel complexes, is thus central to the control of the heart rate and rhythm.

Animals↗
PubMed1997

MinK potassium channels are heteromultimeric complexes.

MinK is a transmembrane protein of 130 amino acids found in the kidney, heart, and vestibular system of mammals. Its expression in Xenopus laevis oocytes induces a voltage-dependent potassium current similar to that seen in vivo. Indirect evidence has fueled speculation that function requires association of MinK and another protein endogenous to oocytes and native tissues. In this report, we show that direct covalent modification of an oocyte membrane protein alters properties of the MinK ion conduction pore; modified channels exhibit decreased potassium conduction and increased permeability to sodium and cesium. The modifying reagents, two membrane-impermeant, sulfhydryl-specific methanethiosulfonate derivatives, react only from the extracellular solution at rates that are determined by the conformational state of the channel. These findings indicate that MinK is intimately associated with an oocyte protein whose exposure to the external solution changes during channel gating and which acts with MinK to establish ion conduction pore function.

Animals↗
PubMed1997

Structure and function of embryonic growth plate in the absence of functioning skeletal muscle.

Normal growth and development of the skeleton require the presence of viable, actively contracting skeletal muscle throughout the fetal period. A chick embryo model of midgestation chemical paralysis and secondary muscle atrophy was used to test the hypothesis that functioning muscle stimulates the growth of long bones by influencing the proliferation, differentiation, and hypertrophy of chondrocytes in cartilage of the epiphysis and growth plate. Paralysis did not alter the overall developmental stage of the long bone or the organization of the growth plate. Compared with controls, however, uptake of bromodeoxyuridine in the paralyzed chick was reduced by 27-55% in the chondroepiphysis and uppermost zone of the tibial growth plate, indicating reduced proliferation of chondrocytes. A specific reduction in the size of the proliferative zone and a reduced number of proliferating cells were also observed. By contrast, in the second, post-proliferative zone of the growth plate, the height of the zone was unchanged and its area was only slightly reduced compared with controls. Finally, median hypertrophic cell profile area, a measure of cell size, was not significantly affected by paralysis, although frequency analysis revealed modest numerical reductions in the population of the largest hypertrophic chondrocytes in the paralyzed group. These data suggest that the role of functioning fetal muscle in maintaining proper skeletal growth may be mediated primarily through specific stimulation of the recruitment or proliferation of immature chondrocytes, or of both.

Animals↗