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Biomedical subjects

Thomas D Brown

Publications and source records attributed to Thomas D Brown.

At least 19 recordsLinked to original sources
PubMed2007

Nonidentical and outlier duty cycles as factors accelerating UHMWPE wear in THA: a finite element exploration.

Wear rate and wear direction vary considerably within total hip arthroplasty (THA) patient cohorts. Third body effects and wide-ranging differences in patient activity levels are two factors suspected of contributing to wear variability. A sliding-distance-coupled contact finite element formulation was used to test the hypothesis that nonidentical duty cycles (differing activities, or change of third body challenge) produce accelerations in polyethylene wear. Effects of nonidentical duty cycles, time-variant femoral head roughening, and outlier gait inputs were investigated. Without femoral head roughening, combination walk/stair-climb wear simulations did not result in appreciably higher volumetric wear than a walk-only simulation, but when a roughened zone was included, walk/stair-climb volumetric wear increased by approximately 57% above that of a similarly roughened walk-only simulation. To investigate time-variant femoral head roughening, wear simulations were begun with femoral head roughening at one location on the femoral head, switching to another location halfway through the simulation. Results varied depending on roughening sites, but cases of substantial increase in wear involved a transient jump in wear rate shortly after the change of head roughening location. Outlier duty cycles were simulated by increasing or decreasing the joint contact force and range of motion inputs, to levels at the 97.5th and 2.5th percentiles of a population of normal subjects. The resulting wear showed an increase or decrease closely proportional to the percentage by which each input (force or range of motion) was changed.

Arthroplasty, Replacement, Hip↗
PubMed2007

Stability of fused versus nonfused THA femoral impaction grafts.

Impaction grafting for THA involves compacting morselized cancellous bone (MCB) into a cavitary defect to build up bone stock. Ideally, the MCB subsequently remodels into a new contiguous cancellous lattice. A recent laboratory model of MCB fusion allows simulating an impaction graft construct in this ideal eventual clinical state. The purpose of the present study was to determine the relative stability of femoral impaction graft constructs in which the MCB has fused versus that for MCB in the freshly impacted nonfused condition. Cemented femoral impaction graft constructs were created in composite femurs. For fused constructs, the MCB was mixed with an amine epoxy that causes the MCB to set up into a contiguous structure biomechanically comparable to intact cancellous bone in compression. The constructs were loaded with 500,000 physiologic gait cycles. Three-dimensional motion was measured between the femur and the stem. The fused femoral impaction grafts were much more stable than the nonfused grafts at the proximal stem location, but MCB fusion had only a modest effect on distal stem stability. These results indicate that most of the opportunity to reduce femoral stem micromotion and migration lies proximal, and that steps to enhance impaction graft remodeling and fusion are most effectively focused proximally.

Arthroplasty, Replacement, Hip↗
PubMed2006

Phase II study of capecitabine (Xeloda) and concomitant boost radiotherapy in patients with locally advanced rectal cancer.

PURPOSE: The aim of this study was to determine the efficacy of capecitabine (Xeloda), an oral fluoropyrimidine, as a radiosensitizer in the neoadjuvant treatment of locally advanced rectal cancer (LARC). METHODS AND MATERIALS: We conducted a phase II study of capecitabine (825 mg/m2 orally, twice daily continuous) with radiotherapy (52.5 Gy/30 fractions to the primary tumor and perirectal nodes) in 54 patients with LARC (node-negative > or = T3 or any node-positive tumor) staged by endoscopic ultrasound (EUS). The primary endpoint was pathologic response rate; secondary endpoints included toxicity profiles and survival parameters. RESULTS: Of the 54 patients (median age, 56.7 years; range, 21.3-78.7 years; male:female ratio, 1.7; Eastern Cooperative Oncology Group performance status 0-1: 100%), 51 patients (94%) had T3N0 or T3N1 disease by EUS. Surgery was not performed in 3 patients; 2 of these patients had metastatic disease, and the third patient refused after a complete clinical response. Of the 51 patients evaluable for pathologic response, 9 patients (18%) achieved complete response, and 12 patients (24%) had microscopic residual disease (< 10% viable cells). In addition, 26 patients of all 54 patients (51%) achieved T-downstaging, and 15 patients of 29 patients (52%) achieved N-downstaging. Grade 3/4 toxicities were radiation dermatitis (9%) and diarrhea (2%). Sphincter preservation rate for tumor < or = 5 cm from the anal verge was 67% (18/27). CONCLUSION: This regimen of radiotherapy plus capecitabine is well tolerated and is more convenient than protracted venous infusion of 5-FU. The pathologic response rate is comparable to our previous experience using protracted venous infusion 5-FU for LARC.

Adult↗
PubMed2006

Intra-articular contact stress distributions at the ankle throughout stance phase-patient-specific finite element analysis as a metric of degeneration propensity.

A contact finite element (FE) formulation is introduced, amenable to patient-specific analysis of cumulative cartilage mechano-stimulus attributable to habitual functional activity. CT scans of individual human ankles are segmented to delineate bony margins. Each bone surface is projected outward to create a second surface, and the intervening volume is then meshed with continuum hexahedral elements. The tibia is positioned relative to the talus into a weight-bearing apposition. The articular members are first engaged under light preload, then plantar-/dorsi-flexion kinematics and resultant loadings are input for serial FE solutions at 13 instants of the stance phase of level walking gait. Cartilage stress histories are post-processed to recover distributions of cumulative stress-time mechano-stimulus, a metric of degeneration propensity. Consistency in computed contact stress exposures presented for seven intact ankles stood in contrast to the higher magnitude and more focal exposures in an incongruously reduced tibial plafond fracture. This analytical procedure provides patient-specific estimates of degeneration propensity due to various mechanical abnormalities, and it provides a platform from which the mechanical efficacy of alternative surgical interventions can be estimated.

Ankle Injuries↗
PubMed2006

Comparison of cellular strain with applied substrate strain in vitro.

Strain magnitudes within tenocytes undergoing substrate tensile strain are not well defined. It was hypothesized that strain magnitudes at the cellular level would reflect those of the applied substrate (equibiaxial or uniaxial) strain. A vacuum-operated device was used to apply equibiaxial or uniaxial tension to a flexible substrate upon which tenocytes were cultured in monolayer. Images of tenocytes labeled with Fura-2, to detect free intracellular calcium ions, and MitoFluor Green, to detect mitochondria, were taken prior to strain and for 20 min during application of static strain. A custom-written, texture correlation program computed strain magnitudes in the cell based on the change in pixel pattern displacements between images of non-strained and strained cells. On average, cellular strain was approximately 37+/-8% and 63+/-11% of the applied equibiaxial and uniaxial substrate strain, respectively. The largest cell strains were detected in cells oriented parallel to the direction of applied uniaxial tensile strain. However, strain magnitudes within a cell were heterogeneous. The variance in strain magnitude within and among tenocytes is dependent on cell orientation, cell stiffness, cytoskeleton organization, subcellular organelles, or placement and type of cell-substrate contacts. Results of the present study indicate that cultured tenocytes experience a moderate fraction of the applied substrate strain.

Animals↗
PubMed2006

Subtotal hepatectomy following neoadjuvant chemotherapy for a previously unresectable hepatocellular carcinoma.

An awareness of variant hepatic vascular anatomy provides vital information in the preoperative evaluation of patients with hepatocellular carcinoma. The authors present a patient with unresectable hepatocellular carcinoma who responded to combination systemic and regional chemotherapy. Because of the presence of an enlarged inferior right hepatic vein, the patient subsequently underwent successful subtotal hepatectomy with resection of all three main hepatic veins. This case illustrates that the combination of innovative neoadjuvant chemotherapy and well-planned surgical approaches may benefit a small number of patients previously deemed unresectable.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Design factors influencing performance of constrained acetabular liners: finite element characterization.

Constrained acetabular liners are utilized to deal with the infrequent but devastating problem of recurrent dislocation. While an encouraging treatment of last resort, the clinical performance of contemporary constrained liners has been somewhat mixed. There are multiple factors contributing to this variability, one of which is the limited understanding of the intrinsic mechanical characteristics of these specialty devices. To address this issue, a three-dimensional, materially nonlinear, multi-surface contact finite element model of a representative constrained liner was created. The model was physically validated, and then used for parametric testing to explore the effects of individual design features. The model was exercised for both intra-operative assembly and lever-out dislocation. It was found that the coefficient of friction between the femoral head and the liner substantially affected both the force required to seat the femoral head into the liner during assembly, and the peak moment resisting dislocation (226% increase in assembly force for friction coefficients of 0.2 versus 0.0; 49% reduction in dislocation moment for friction coefficients of 0.013 versus 0.135). As expected, the cup opening radius also had a dominant effect on both maneuvers: decreasing the opening radius from 13.9 to 13.6 mm increased assembly force by 506 N and increased the dislocation moment by over 3.5 N-m, whereas the influence of other design parameters was much more modest.

Acetabulum↗
PubMed2006

Problematic sites of third body embedment in polyethylene for total hip wear acceleration.

A computational model was developed to identify the sites of third body particle embedment in a total hip acetabular component surface that are most problematic in terms of roughening the overpassing regions of the femoral head counterface, leading in turn to most severely accelerated polyethylene wear. The analytical approach used was to calculate loci of acetabular sites that, during the gait cycle, overpass previously documented regions of kinetically most critical femoral head roughening. Instantaneous local contact stress and sliding distance were postulated as factors contributing to the severity of the femoral head scratching/roughening which would be expected, due to otherwise-similar particles embedded along each such acetabular overpass locus. The computational results showed that the location of debris embedment was a potent determinant of the amount of polyethylene wear acceleration expected. The data also showed that the supero-lateral aspect of the acetabular cup is consistently and by far the most problematic area for third body particle embedment.

Acetabulum↗
PubMed2006

Contribution of articular surface geometry to ankle stabilization.

BACKGROUND: Passive ankle stability under weight-bearing conditions has been found to depend substantially on the role of the articular surface geometry. In the present study, it was hypothesized that, in the ankle under axial loading, contact-stress changes in response to alterations of external load involve reproducible and specific patterns to maintain ankle stability. METHODS: Six cadaver ankles with the peri-ankle ligaments intact were tested. Each specimen, held at several predetermined ankle positions under a primary one-body-weight axial force, was subjected to an additional secondary load. The secondary load-specifically, anterior/posterior shear force, inversion/eversion torque, or internal/external rotation torque-was applied independently, while motion associated with the two other secondary loading directions was unconstrained. Contact stress in the tibiotalar articulation was monitored by a real-time contact-stress sensor. Site-specific stress changes solely due to secondary loading at each load/position were identified by subtraction of the corresponding axial-force-only baseline distribution. The role of these stress changes in ankle stabilization was studied for each specimen by analyzing the data with a computer model of ankle geometry. RESULTS: In the cadaver experiment, anterior and posterior shear forces caused reproducible positive changes in articular contact stresses on the anterior and posterior regions, respectively. Similar changes with version torques occurred on the medial and lateral regions. Positive changes with internal/external rotation torques occurred at two diagonal locations: anterolateral and posteromedial, or anteromedial and posterolateral. In the model analysis, these stress-change patterns were found to be effective in ankle stabilization, and the levels of contribution by the articular surface were calculated as accounting for approximately 70% of anterior/posterior stability, 50% of version stability, and 30% of internal/external rotation stability. CONCLUSIONS: The documented changes in contact stress illustrate the major role of articular geometry in passive ankle stabilization. The levels of contribution by the articular surface that we calculated are consistent with those reported in the literature. These findings support the conceptual mechanism of ankle stabilization by redistribution of articular contact stress.

Aged↗
PubMed2006

Impact of comorbidities on the measurement of health in patients with ankle osteoarthritis.

BACKGROUND: Investigators seeking to understand the impact of musculoskeletal disorders commonly use validated outcome instruments to assess the effect of diseases on physical function and quality of life. However, the influence of concomitant systemic or musculoskeletal comorbidities on these scores has not been widely considered in orthopaedic research. The purpose of this study was to determine how morbidity unrelated to the ankle influences the perception of physical function and pain by patients with ankle osteoarthritis. METHODS: Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, Ankle Osteoarthritis Scale (AOS) pain scale scores, demographic data, and systemic and musculoskeletal comorbidities were determined prospectively for 195 patients with ankle osteoarthritis and ninety-five age and gender-matched controls. The effect of systemic and musculoskeletal comorbidities on each of the scores was determined. RESULTS: On the average, patients with ankle osteoarthritis had a relatively normal MCS score (47 +/- 13 points) and a markedly diminished PCS score (32 +/- 8 points). Both of these scores averaged 50 +/- 9 points in the control group. The AOS pain score averaged 61 +/- 23 points in the group with ankle osteoarthritis, whereas it averaged 10 +/- 15 points in the control group. We found the perception of ankle pain by patients with ankle osteoarthritis to be significantly and linearly associated with the number of other musculoskeletal problems (not related to the foot or ankle). CONCLUSIONS: The degree of physical impairment associated with ankle osteoarthritis, as measured with the SF-36, is equivalent to that reported to be associated with severely disabling medical problems including end-stage kidney disease and congestive heart failure. The perception of ankle health status as measured with a validated, patient-oriented, anatomically specific instrument is influenced by the patients' perception of their overall musculoskeletal comorbidity status. The authors of clinical studies using these instruments should adjust for concomitant musculoskeletal disease.

Ankle Joint↗
PubMed2006

Loading and boundary condition influences in a poroelastic finite element model of cartilage stresses in a triaxial compression bioreactor.

BACKGROUND: We developed a poroelastic finite element (FE) model of cartilage in dynamic triaxial compression to parametrically analyze the effects of loading and boundary conditions on a baseline model. Conventional mechanical tests on articular cartilage such as confined and unconfined compression, indentation, etc., do not fully allow for modulation of compression and shear at physiological levels whereas triaxial compression does. A Triaxial Compression Bioreactor, or TRIAX, has been developed to study chondrocyte responses to multi-axial stress conditions under cyclic loading. In the triaxial setting, however, a cartilage explant's physical testing environment departs from the ideal homogeneous stress state that would occur from strict linear superposition of the applied axial and transverse pressure. METHOD OF APPROACH: An axisymmetric poroelastic FE model of a cartilage explant (4 mm diameter, 1.5 mm thick) in cyclic triaxial compression was created. Axial and transverse loads (2 MPa at 1 Hz.) were applied via a platen and containment sheath. Parameters of interest included the rise time and magnitude of the applied load, in addition to the containment sheath modulus and the friction coefficient at the cartilage/platen interfaces. Metrics of interest in addition to whole explant axial strain included axial (surface normal) stress, shear stress, pore pressure, and the fluid load carriage fraction within the explant. RESULTS: Strain results were compared to experimental data from explants tested in the TRIAX under conditions similar to the baseline model. Explant biomechanics varied considerably over numbers of load cycles and parameter values. Cyclic loading caused an increase in accumulated strain for the various loading and boundary conditions. CONCLUSIONS: Unlike what would be expected from linear superposition of the homogeneous stresses from the applied axial and transverse pressure, we have shown that the stress state within the TRIAX is considerably heterogeneous. Both the boundary influences (variation in the sheath modulus and friction coefficient) and the loading history (due to poroelastic material behavior) interact in a highly nonlinear manner to influence that heterogeneity.

Bioreactors↗
PubMed2006

Perspectives on chondrocyte mechanobiology and osteoarthritis.

Osteoarthritis, the clinical syndrome of joint pain and dysfunction due to joint degeneration, is among the most frequent and symptomatic medical problems for middle aged and older people, and it is the most common cause of long term disability in most populations of people over 65. Currently there are no effective methods of preventing or curing osteoarthritis. Post-traumatic OA, the joint degeneration, pain and dysfunction that develop following joint injury, is the form of OA that is most directly related to elevated articular surface contact stress. However, mechanical stress that exceeds the tolerance of the articular surface can cause or accelerate the progression of joint degeneration in all individuals and in all synovial joints. In some patients, decreasing mechanical forces on degenerated joint surfaces stimulates formation of a new biologic articular surface. The advances in understanding of the effects of mechanical forces on chondrocytes and cartilage presented and discussed at the 4th Symposium on Mechanobiology: Cartilage and Chondrocyte will help in the efforts to develop new methods of preventing and treating osteoarthritis.

Aged↗
PubMed2005

Determination of ankle external fixation stiffness by expedited interactive finite element analysis.

Interactive finite element analysis holds the potential to quickly and accurately determine the mechanical stiffness of alternative external fixator frame configurations. Using as an example Ilizarov distraction of the ankle, a finite element model and graphical user interface were developed that provided rapid, construct-specific information on fixation rigidity. After input of specific construct variables, the finite element software determined the resulting tibial displacement for a given configuration in typically 15s. The formulation was employed to investigate constructs used to treat end-stage arthritis, both in a parametric series and for five specific clinical distraction cases. Parametric testing of 15 individual variables revealed that tibial half-pins were much more effective than transfixion wires in limiting axial tibial displacement. Factors most strongly contributing to stiffening the construct included placing the tibia closer to the fixator rings, and mounting the pins to the rings at the nearest circumferential location to the bone. Benchtop mechanical validation results differed inappreciably from the finite element computations.

Ankle↗
PubMed2005

Contact stress transients during functional loading of ankle stepoff incongruities.

Cartilage deformation demonstrates viscoelastic behavior due to its unique structure. However, nearly all contact studies investigating incongruity-associated changes in cartilage surface stresses have been static tests. These tests have consistently measured only modest increases in contact stresses, even with large incongruities. In this study, an experimental approach measuring real-time contact stresses in human cadaveric ankles during quasi-physiologic motion and loading was used to determine how stepoff incongruities of the distal tibia affected contact stresses and contact stress gradients. Peak instantaneous contact stresses, in ankles with stepoffs between 1.0 and 4.0mm of the anterolateral articular surface, increased by between 2.3 x and 3.0 x compared to the corresponding intact ankle values. Peak instantaneous contact stress gradients in stepoff configurations increased by between 1.9 x and 2.6 x the corresponding intact configuration values. Anatomic reduction of the displaced fragment restored intact contact stresses and contact stress gradients. Intact and anatomic configurations demonstrated a heterogeneous population of low-magnitude, randomly oriented contact stress gradient vectors in contrast to high-magnitude, preferentially oriented gradients in stepoff configurations. Peak instantaneous contact stresses may be important pathomechanical determinants of post-traumatic arthritis. Abnormal contact stress gradients could cause regional pathological disturbances in cartilage stress and interstitial fluid distribution. Measuring contact stresses and contact stress gradients during motion allowed potential incongruity-associated pathologic changes in loading that occur over the complete motion cycle to be investigated.

Ankle Joint↗
PubMed2005

Catalytic subunit of human telomerase reverse transcriptase is an independent predictor of survival in patients undergoing curative resection of hepatic colorectal metastases: a multicenter analysis.

PURPOSE: To determine the role of the catalytic subunit of human telomerase reverse transcriptase (hTERT) in predicting survival after resection of hepatic colorectal metastases (CRM). PATIENTS AND METHODS: Two hundred one patients who underwent curative resection of hepatic CRM between 1990 and 2000 were identified from a multicenter database. The CRM were analyzed for hTERT nucleolar expression by standard immunohistochemical techniques. hTERT expression and known clinicopathologic factors of survival were examined. RESULTS: With a median follow-up of 80 months, 152 patients (75.6%) had died; the 5-year overall survival was 30.7%. On univariate analysis, number of metastases greater than two (P = .0005), extrahepatic disease (P = .0054), disease-free interval less than 12 months (P = .006), carcinoembryonic antigen level greater than 200 ng/mL (P = .0071), and positive hTERT nucleolar staining (P < .0001) were associated with decreased survival. On multivariate analysis, three factors independently predicted survival: number of metastases (relative risk [RR] = 1.74; P = .0011); disease-free interval (RR = 1.70; P = .0035); and positive hTERT nucleolar staining (RR = 2.03; P < .0001). Patients with none or one of these factors had a 5-year survival rate of 48%, whereas those with two or three of these factors had a 5-year survival of 15% (P < .0001). CONCLUSION: hTERT nucleolar expression is associated with worse survival after resection of hepatic CRM. hTERT expression in conjunction with number of hepatic metastases and disease-free interval may permit more accurate prediction of survival after resection of hepatic CRM.

Adult↗
PubMed2005

Thalidomide in the treatment of patients with hepatocellular carcinoma: a phase II trial.

BACKGROUND: The treatment of patients with hepatocellular carcinoma (HCC) presents a major challenge, because associated cirrhosis limits the choice of chemotherapeutic agents. However, the abundant vascularity of HCC presents an attractive target for antiangiogenic therapy that potentially may be tolerated by cirrhotic patients. The current study was conducted to assess the antitumor activity, treatment tolerance, treatment-related toxicity, and patient survival after the administration of thalidomide in a Phase II trial. METHODS: Thirty-seven HCC patients were accrued between March, 1999, and March, 2000. Initially, the dose of oral thalidomide was escalated from 400 mg per day during the first week to 1000 mg per day by the fifth week, delivering one-third of the dose in the morning and the remaining two-thirds of the dose in the evening prior to bedtime. Changes in the daily drug administration schedule were allowed based on tolerance. Response was assessed at 8-week intervals. RESULTS: Thirty-two of 37 registered patients were evaluable for response. One patient had a partial response (PR), 1 patient had a minor response (MR), 10 patients had stable disease (SD) (31%; 95% confidence interval [95%CI], 16-51%), and 20 patients) (61%; 95%CI, 42-78%) had disease progression. The most commonly encountered toxicity was somnolence, with Grade 3-4 somnolence (>or= 4 hours of sleep during normal waking hours) in 9 patients (35%) and Grade 2 somnolence ( 800 mg if it was delivered at bedtime. Grade 3-4 skin reactions were observed in 20% of patients, and exfoliative dermatitis was observed in 1 responding patient. The overall median survival was 6.8 months. CONCLUSIONS: With a 5% PR rate, a 5% MR rate, and a 31% SD rate, the results indicate that thalidomide mostly may offer HCC patients disease stabilization. It is possible that, at a different dosage, or combined with other chemotherapy agents, or with the use of a different thalidomide analogue, longer patient survival may be achieved. However, in view of the significant neurologic toxicity encountered among these commonly cirrhotic HCC patients, thalidomide monotherapy at the high doses studied cannot be recommended for the treatment of HCC.

Adult↗