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Biomedical subjects

J E Sanders

Publications and source records attributed to J E Sanders.

At least 19 recordsLinked to original sources
PubMed2002

Tissue response to microfibers of different polymers: polyester, polyethylene, polylactic acid, and polyurethane.

Tissue response to single polymer microfibers of polyester (PET), polyethylene (PE), poly(L-lactic acid) (PLA), and polyurethane (PU) was assessed using a rat subcutaneous model. Fibers of diameters ranging from 1 to 15 microm were aligned parallel to each other on polycarbonate frames and implanted in the subcutaneous dorsum in the subscapular region. After 5 weeks of implantation, fibrous capsule thickness was significantly less for fibers of diameters 1-5 than for those of 11-15 microm for all polymers tested. For PET and PU, 75.0 and 71.4% respectively of the 1-5 microm fibers had no capsule, while for PE and PLA only 45.5 and 56.3% respectively had no capsule. For 1-5 microm fibers, PE had significantly thicker capsules than PET and PU. Reducing fiber diameters from 6-10 to 1-5 microm induced a greater reduction in capsule thickness than changing polymers among PET, PE, and PLA. PU showed the least encapsulation of all polymers, demonstrating significantly thinner capsules than PET, PE, and PLA for 6-10 and 11-15 microm fibers.

Animals↗
PubMed2002

Control of in vivo microvessel ingrowth by modulation of biomaterial local architecture and chemistry.

We developed a method for controlling local architecture and chemistry simultaneously in biomaterial implants to control microvessel ingrowth in vivo. Porous polypropylene disks (5 mm in diameter and 40 microm thick) were plasma-coated with a fluoropolymer and then laser-drilled with 50-microm-diameter holes through their thickness. We then oxidized the disks to create hydroxyl functionality on the exposed polypropylene (inside the holes). Acrylamide was grafted to the hydroxyl groups through polymerization in the presence of activating ceric ions. Staining with toluidine blue O demonstrated that grafting occurred only inside the holes. We used the Hoffman degradation reaction to convert the amide groups of acrylamide to amine groups, and then we used ethylene glycol diglycidyl ether to attach biomolecules of interest inside the holes: secreted protein acidic and rich in cysteine (SPARC) peptide Lys-Gly-His-Lys (KGHK; angiogenic), thrombospondin-2 (TSP; antiangiogenic), or albumin (rat; neutral). In vivo testing in a rat subcutaneous dorsum model for a 3-week interval demonstrated a greater vessel surface area (p = 0.032) and a greater number of vessels (p = 0.043) in tissue local to the holes with KGHK-immobilized disks than with TSP-immobilized disks. However, differences between KGHK-immobilized and albumin-immobilized disks were less significant (p = 0.120 and p = 0.289 for the vessel surface area and number of vessels, respectively). The developed methods have potential applications in biomaterial design applications for which selective neovascularization is desired.

Animals↗
PubMed2002

Use of vascular explants for ex vivo neovascularization of biomaterials.

Biomaterial polymers have been proposed as scaffolds for cell assembly in vascular bioengineering. We describe here a new method for the neovascularization of polyurethane meshes from explants of rat aorta. Aortic rings embedded in collagen-permeated polyurethane meshes and cultured in medium supplemented with fetal bovine serum and vascular endothelial growth factor generated florid microvascular outgrowths that efficiently vascularized the available spaces between polyurethane fibers. The neovessels could be identified in the live cultures by phase-contrast microscopy, and in formalin-fixed preparations by the ABC peroxidase procedure, using the endothelial-specific Griffonia isolectin B4. The aortic outgrowths were successfully labeled with the intravital fluorescent dyes Calcein AM or SPDiOC(18), which are nontoxic and can be used for tracking studies. This study shows that artificial biomaterial meshes can be colonized ex vivo with histotypic microvascular networks, and provides the proof of concept for the future development of stably vascularized devices for in vivo implantation.

Animals↗
PubMed2002

Busulfan concentration and graft rejection in pediatric patients undergoing hematopoietic stem cell transplantation.

We retrospectively analyzed the relationship between busulfan average steady-state plasma concentration (C(SS)) and graft rejection in 53 children receiving busulfan/cyclophosphamide (BU/CY) preparative regimens prior to hematopoietic stem cell transplantation (HSCT). Patients received a total oral busulfan dose of 11 to 28 mg/kg followed by a total cyclophosphamide dose of 120 to 335 mg/kg in preparation for allogeneic grafts (HLA-matched or HLA partially matched sibling, parent or unrelated donor). Graft rejection occurred in eight (15%) patients. Busulfan C(SS) (P = 0.0024) was the only statistically significant predictor of rejection on univariate logistic regression analysis, with the risk of rejection decreasing with an increase in busulfan C(SS). Severe (grade 3 or 4) regimen-related toxicity (RRT) occurred in four patients. Ten patients (19%) had a busulfan C(SS) higher than 900 ng/ml, one of whom had severe RRT. Higher and variable doses of cyclophosphamide may explain the lack of a relationship between busulfan C(SS) and RRT in children. It may be possible to improve the outcome of HSCT in pediatric patients receiving the BU/CY regimen through optimization of busulfan C(SS) and better definition of the contribution of activated cyclophosphamide metabolites to toxicity.

Adolescent↗
PubMed2002

Interface pressure and shear stress changes with amputee weight loss: case studies from two trans-tibial amputee subjects.

Interface pressures and shear stresses were measured at monthly intervals on two trans-tibial amputee subjects who lost more than 12% of their body weight over the course of the study. For one subject interface pressures and shear stresses during the weight-acceptance phase of gait decreased over the study interval at all 13 sites monitored, while the other subject experienced increased pressures distally but decreased pressures proximally. Subjects' stumps appeared to atrophy over the study interval, increasing distal end and patellar tendon loading, but not increasing interface shear stresses at other locations. Adding socks at the end of the study did not return interface pressures to first session values at all sites. It is expected that local stump shape changes occurred, causing a non-uniform change in interface stress patterns.

Amputees↗
PubMed2001

Administration of cyclosporine for 24 months compared with 6 months for prevention of chronic graft-versus-host disease: a prospective randomized clinical trial.

This study compared the incidence of clinical extensive chronic graft-versus-host disease (GVHD), transplantation-related mortality, survival, and relapse-free survival among recipients randomly assigned to receive a 24-month or a 6-month course of cyclosporine prophylaxis after transplantation of allogeneic marrow from an HLA-identical sibling or alternative donor. Patients who did not have clinical manifestations of chronic GVHD on day 80 after transplantation were eligible for the study if they previously had acute GVHD or if a skin biopsy showed histologic evidence of chronic GVHD. Clinical extensive chronic GVHD developed in 35 of the 89 patients (39%) in the 24-month group and 37 of the 73 patients (51%) in the 6-month group. The hazard of developing chronic GVHD was not significantly different in the 2 groups (hazard ratio = 0.76; 95% confidence interval, 0.48-1.21; P =.25). In addition, there were no significant differences between the 2 groups in transplantation-related mortality, survival, or disease-free survival.

Adult↗
PubMed2001

The role of NF-kappa B in TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of melanoma cells.

Previous studies have shown that activation of NF-kappaB can inhibit apoptosis induced by a number of stimuli. It is also known that TNF-related apoptosis-inducing ligand (TRAIL) can activate NF-kappaB through the death receptors TRAIL-R1 and TRAIL-R2, and decoy receptor TRAIL-R4. In view of these findings, we have investigated the extent to which activation of NF-kappaB may account for the variable responses of melanoma lines to apoptosis induced by TRAIL and other TNF family members. Pretreatment of the melanoma lines with the proteasome inhibitor N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal (LLnL), which is known to inhibit activation of NF-kappaB, was shown to markedly increase apoptosis in 10 of 12 melanoma lines with death receptors for TRAIL. The specificity of results for inhibition of NF-kappaB activation was supported by an increase of TRAIL-induced apoptosis in melanoma cells transfected with a degradation-resistant IkappaBalpha. Furthermore, studies with NF-kappaB reporter constructs revealed that the resistance of melanoma lines to TRAIL-induced apoptosis was correlated to activation of NF-kappaB in response to TRAIL. TRAIL-resistant sublines that were generated by intermittent exposure to TRAIL were shown to have high levels of activated NF-kappaB, and resistance to TRAIL could be reversed by LLnL and by the superrepressor form of IkappaBalpha. Therefore, these results suggest that activation of NF-kappaB by TRAIL plays an important role in resistance of melanoma cells to TRAIL-induced apoptosis and further suggest that inhibitors of NF-kappaB may be useful adjuncts in clinical use of TRAIL against melanoma.

Apoptosis↗
PubMed2001

Collagen fibril diameters increase and fibril densities decrease in skin subjected to repetitive compressive and shear stresses.

Understanding microstructural changes that occur in skin subjected to repetitive mechanical stress is crucial towards the development of therapies to enhance skin adaptation and load tolerance in patients at risk of skin breakdown (e.g. prosthesis users, wheelchair users). To determine if collagen fibril diameter, collagen fibril density, dermal thickness, epidermal thickness, basement membrane length, and dermal cell density changed in response to repetitive stress application, skin subjected to moderate cyclic compressive and shear stresses for 1h/d, 5d/week, for 4 weeks was compared with skin from an unstressed contralateral control. The lateral aspects of the hind limbs of 12 Landrace/Yorkshire pigs were used. Skin from under the stressed site and a contralateral control site was processed for electron microscopy and light microscopy analysis. Electron microscopy results demonstrated significant (p<0.01) increases in collagen fibril diameter of 15.9%, 22.4%, and 22.9% for the upper, mid, and lower layers of the dermis, respectively, for the stressed skin compared with the control skin. Collagen fibril density (fibrils/unit cross-sectional area) decreased significantly for stressed vs. control by 19.8%, 29.2%, and 31.8% for the upper, mid, and lower layers, respectively. Light microscopy results demonstrated trends of a decrease in dermal thickness and an increase in cell density for stressed vs. control samples, but the differences were not significant. Differences in epidermal thickness and basement membrane length were not significant. These results demonstrate that quantifiable changes occur in collagen fibril architecture but not in the gross tissue morphology following in vivo cyclic loading of pig skin.

Animals↗
PubMed2001

Standing interface stresses as a predictor of walking interface stresses in the trans-tibial prosthesis.

Interface pressures and shear stresses within the socket, in standing and walking, were measured for two unilateral, male, trans-tibial amputee subjects, during two sessions each. The ratios of equal weight-bearing standing stresses to peak walking stresses showed regional variation, ranging from 0.24:1 for pressure over the anterior region to 1.01:1 for resultant interface shear stress over the lateral region. Interface stresses in standing were only moderate predictors of peak walking stresses. The best correlation coefficient between standing in full weight-bearing and peak walking stress was 0.88 for pressure over the lateral region. As the amputees progressed from minimal to full weight-bearing in standing, and then to walking, the interface stresses increased in a nonlinear fashion, consistent with the assumption that the anterior tibia provides much resistance to the bending moment in the sagittal plane during walking.

Adult↗
PubMed2001

A device to apply user-specified strains to biomaterials in culture.

An apparatus was developed to apply user-specified displacements to biomaterial samples in culture. The device allowed cyclic waveforms of bandwidth 0 Hz to 20 Hz to be applied under physiologic thermal (37.5 degrees C) and [CO2] (5%) conditions. For a 0 Hz to 20 Hz bandwidth signal similar in shape to a ventricular pressure waveform, the mean displacement error was 0.26% of the full-scale output. The maximum overshoot was 0.700%. Environmental system evaluation tests demonstrated a specimen cartridge temperature of 37.20 +/- 0.15 degrees C during cyclic loading and 37.23 +/- 0.21 degrees C during static conditions. [CO2] was 5.29 +/- 0.54% during cyclic loading and 5.25 +/- 0.61% during static conditions. Laminar flow applied at the loading rod entrances to the specimen cartridge ensured the sample remained sterile during testing. As a preliminary evaluation, polyurethane samples were seeded with fetal foreskin fibroblasts and subject to intermittent cyclic displacements. Results demonstrated enhanced cell proliferation and increased [PGE2] for samples subjected to 10% strain compared with unstrained controls. A next step will be to evaluate cell response sensitivity to strain magnitude, duration, direction, and frequency. The long-term intent is to establish mechanical loading configurations that induce acceptable or adaptation-inducing responses for use in implant design and tissue engineering applications.

Animals↗
PubMed2000

Thalidomide for treatment of patients with chronic graft-versus-host disease.

In a randomized, placebo-controlled, double-blind trial, thalidomide or placebo together with glucocorticoids and either cyclosporine or tacrolimus was administered as initial therapy for clinical extensive chronic graft-versus-host disease (cGVHD). All patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per day, followed by a gradual increase to 800 mg/d if side effects were tolerable. Treatment with the study drug was discontinued before resolution of cGVHD in 23 (92%) of the 25 patients who received thalidomide and in 17 (65%) of the 26 patients who received placebo (P =.02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short to assess its efficacy in controlling cGVHD. (Blood. 2000;96:3995-3996)

Actuarial Analysis↗
PubMed2000

Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types.

Resistance of normal cells to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis is believed to be mediated by expression of two decoy receptors. Here we show that the expression and localisation of TRAIL receptors (TRAIL-Rs) vary between different cells and that resistance to TRAIL is mediated by different mechanisms. The decoy receptor, TRAIL-R3, appeared important in protection of endothelial cells, whereas lack of surface death receptor expression and as yet unknown intracellular inhibitor(s) of apoptosis downstream of caspase-3 may play a major role in protection of melanocytes and fibroblasts from TRAIL induced apoptosis, respectively. Differential subcellular location of decoy receptors may be an important determinant of their effectiveness in different types of normal cells.

Apoptosis↗
PubMed2000

Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Multicenter investigation of bone marrow transplantation for sickle cell disease.

Fifty children who had symptomatic sickle cell disease received matched sibling marrow allografts between September 1991 and March 1999, with Kaplan-Meier probabilities of survival and event-free survival of 94% and 84%, respectively. Twenty-six patients (16 male, 10 female) had at least 2 years of follow-up after transplantation and were evaluated for late effects of transplantation and for its impact on sickle cell-related central nervous system (CNS) and pulmonary disease. Patients ranged between 3.3 and 14.0 (median, 9. 4) years of age and had a median follow-up of 57.9 (range 38-95) months after transplantation. Among 22 of 26 patients who had stable donor engraftment, complications related to sickle cell disease resolved, and none experienced further episodes of pain, stroke, or acute chest syndrome. All 10 engrafted patients with a prior history of stroke had stable or improved cerebral magnetic resonance imaging results. Pulmonary function tests were stable in 22 of the 26 patients, worse in two, and not studied in two. Seven of eight patients transplanted for recurrent acute chest syndrome had stable pulmonary function. Linear growth measured by median height standard deviation score improved from -0.7 before transplantation to -0.2 after transplantation. An adverse effect of busulfan conditioning on ovarian function was demonstrated in five of seven evaluable females who are currently at least 13 years of age. None of the four males tested had elevated serum gonadotropin levels. These data confirm that allogenic bone marrow transplantation establishes normal erythropoiesis and is associated with improved growth and stable CNS imaging and pulmonary function in most patients. (Blood. 2000;95:1918-1924)

Adolescent↗
PubMed2000

Phase I topotecan preparative regimen for high-risk neuroblastoma, high-grade glioma, and refractory/recurrent pediatric solid tumors.

We evaluated the toxicity and maximum tolerated dose of topotecan in a novel myeloablative regimen as treatment for high-risk pediatric tumors. Patients received an assigned topotecan dosage in combination with fixed doses of carboplatin and thiotepa, followed by autologous hematopoietic stem cells infusion. Topotecan dose was escalated in cohorts of four patients until the maximum tolerated dose of topotecan was defined or until accrual of 30 patients. Pharmacokinetics of topotecan were examined, and event-free survival was estimated. We describe preliminary results following treatment of 25 pediatric patients with high-risk solid tumors.

Antineoplastic Agents↗
PubMed2000

Tissue response to single-polymer fibers of varying diameters: evaluation of fibrous encapsulation and macrophage density.

An in vivo study was conducted to assess the sensitivity of fibrous capsule thickness and macrophage density to polymer fiber diameter. Single polypropylene fibers of diameters ranging from 2.1 to 26.7 microm were implanted in the subcutaneous dorsum of Sprague-Dawley rats. Results at 5 weeks demonstrated reduced fibrous capsule thickness for small fibers. Capsule thickness was 0.6 (+/-1.8) microm, 11.7 (+/-12.0) microm, 20.3 (+/-11.6) microm, and 25.5 (+/-10.0) microm for fibers in the ranges of 2.1 to 5.9, 6.5 to 10.6, 11.1 to 15.8, and 16.7 to 26.7 microm, respectively. Fibers very near to blood vessels had smaller capsules than did those with local vasculature further away. The macrophage density in tissue with fiber diameters 2.1 to 5.9 microm (23.03 +/- 8.67%) was comparable to that of unoperated contralateral control skin (18.72+/-10.06%). For fibers with diameters in the ranges of 6.5 to 10.6, 11.1 to 15.8, and 16.7 to 26.7 microm, macrophage densities were 33.90+/-13.08%, 34.40+/-15.77%, and 41.68+/-13.98%, respectively, all of which were significantly larger (p<0.002) than that for the control. The reduced fibrous capsule thickness and macrophage density for small fibers (<6 microm) compared with large fibers could be due to the reduced cell-material contact surface area or to a curvature threshold effect that triggers cell signaling. A next step will be to extend the analysis to meshes to evaluate fiber-spacing effects on small-fiber biomaterials.

Animals↗
PubMed2000

Characterisation of three-dimensional anatomic shapes using principal components: application to the proximal tibia.

The objective of the research is to determine if principal component analysis (PCA) provides an efficient method to characterise the normative shape of the proximal tibia. Bone surface data, converted to analytical surface descriptions, are aligned, and an auto-associative memory matrix is generated. A limited subset of the matrix principal components is used to reconstruct the bone surfaces, and the reconstruction error is assessed. Surface reconstructions based on just six (of 1452) principal components have a mean root-mean-square (RMS) reconstruction error of 1.05% of the mean maximum radial distance at the tibial plateau. Surface reconstruction of bones not included in the auto-associative memory matrix have a mean RMS error of 2.90%. The first principal component represents the average shape of the sample population. Addition of subsequent principal components represents the shape variations most prevalent in the sample and can be visualised in a geometrically meaningful manner. PCA offers an efficient method to characterise the normative shape of the proximal tibia with a high degree of dimensionality reduction.

Adult↗