Flow patterns through vascular graft models with and without cuffs.

The shape of a bypass graft plays an important role on its efficacy. Here, we investigated flow through two vascular graft designs-with and without cuff at the anastomosis. We conducted Digital Particle Image Velocimetry (DPIV) measurements to obtain the flow field information through these vascular grafts. Two pulsatile flow waveforms corresponding to cardiac cycles during the rest and the excitation states, with 10% and without retrograde flow out the proximal end of the native artery were examined. In the absence of retrograde flow, the straight end-to-side graft showed recirculation and stagnation regions that lasted throughout the full cardiac cycle with the stagnation region more pronounced in the excitation state. The contoured end-to-side graft had stagnation region that lasted only for a portion of the cardiac cycle and was less pronounced. With 10% retrograde flow, extended stagnation regions under both rest and excitation states for both bypass grafts were eliminated. Our results show that bypass graft designers need to consider both the type of flow waveform and presence of retrograde flow when sculpting an optimal bypass graft geometry.

Flow bioreactor design for quantitative measurements over endothelial cells using micro-particle image velocimetry.

Mechanotransduction in endothelial cells (ECs) is a highly complex process through which cells respond to changes in hemodynamic loading by generating biochemical signals involving gene and protein expression. To study the effects of mechanical loading on ECs in a controlled fashion, different in vitro devices have been designed to simulate or replicate various aspects of these physiological phenomena. This paper describes the design, use, and validation of a flow chamber which allows for spatially and temporally resolved micro-particle image velocimetry measurements of endothelial surface topography and stresses over living ECs immersed in pulsatile flow. This flow chamber also allows the study of co-cultures (i.e., ECs and smooth muscle cells) and the effect of different substrates (i.e., coverslip and∕or polyethylene terepthalate (PET) membrane) on cellular response. In this report, the results of steady and pulsatile flow on fixed endothelial cells seeded on PET membrane and coverslip, respectively, are presented. Surface topography of ECs is computed from multiple two-dimensional flow measurements. The distributions of shear stress and wall pressure on each individual cell are also determined and the importance of both types of stress in cell remodeling is highlighted.

Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation.

Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule-encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease.

Convergence of nanotechnology and cardiovascular medicine : progress and emerging prospects.

Advances in the emergence of biological probes, materials, and analytical tools limited to the nanoscale size range, collectively referred to as 'nanotechnology', are increasingly being applied to the understanding and treatment of the major pathophysiological problems in cardiovascular medicine. Analytical techniques based on high-resolution microscopy and molecular-level fluorescence excitation processes capable of detecting nanoscale interactions have been used to elucidate cardiovascular pathology. Nanotechnology has also significantly impacted diagnostic intervention in cardiology, with the use of nanoparticles as contrast agents, for targeted biomedical imaging of vulnerable plaques, for detection of specific pathologic targets signaling the onset of atherosclerosis, and for tracking inflammatory events. Real-time nanoscale biosensors can be used to measure cardiovascular biomarkers, and nanopore sequencing has the potential to speed up the analysis of gene expression in cardiovascular disease. Potential therapeutic applications include the use of nanomaterials in cardiovascular devices, for delivery of drugs and bioactive molecules, or in novel technologies for reducing cholesterol accumulation and for dissolving clots.

Iodine inhibits antiadhesive effect of PEG: implications for tissue engineering.

BACKGROUND: The success of a biomaterial implant may be affected by the surface chemistry's impact on protein adsorption. We have developed a series of poly(ethylene glycol) (PEG) containing, tyrosine-derived polycarbonates, which have been rendered radio-opaque by the iodination of tyrosine units in the copolymer backbone for use in resorbable biomedical implants including vascular stents and grafts. We tested the hypothesis that protein adsorption along with seeding, growth, and migration of human aortic smooth muscle cells (SMC) and human aortic endothelial cells (EC) will be modified by the presence of iodine and PEG within the polymer composition. METHODS: Thin films of these polymers were prepared for the protein-material and cell-material interaction studies. Dot blot, SDS-PAGE, and XPS were used to evaluate relative protein adsorption. Cell adhesion and growth studies were performed using an MTS assay. Cell migration was evaluated using an injury model. RESULTS: The presence of PEG attenuated protein adsorption, cell adhesion, and growth. With the subsequent incorporation of iodine, protein adsorption markedly increased while the antiadhesive effect of PEG was counteracted by iodine for EC and SMC adhesion and SMC growth. CONCLUSION: Iodine incorporation into the polymer resulted in increased protein adsorption thus counteracting the effect of PEG.

Inhibition of apoptosis prevents shear-induced detachment of endothelial cells.

BACKGROUND: Biomaterials placed into the vasculature in man fail to develop an endothelial lining. Attempts to seed endothelial cells (ECs) on prosthetic vascular grafts have failed due to flow-induced detachment. The mechanism of flow-induced detachment of ECs from biomaterials is undefined. We hypothesize that endothelial detachment from biomaterials is caused by flow-induced apoptosis related to the inability of human ECs to adapt to and withstand mechanical loading. MATERIALS AND METHODS: Human aortic endothelial cells were cultured on Dacron membranes, incubated in the presence or absence of a caspase inhibitor (Z-VAD-FMK), and exposed to 0, 1, 10, 20, or 30 dynes/cm(2) of shear stress for 2, 6, 12, and 24 h in a parallel plate bioreactor. The percent of ECs detached was determined and compared with no-flow controls. Apoptosis was determined by analyzing nuclear morphology and identifying cells with caspase activity using FAM-VAD-FMK. The actin cytoskeleton of cells was visualized with fluorescein phalloidin. RESULTS: Increasing shear stress resulted in detachment of ECs from the Dacron membranes, which was associated with increased apoptosis of the residual cells adherent to the membrane determined by both nuclear morphology and caspase activity. Significantly, treatment with the caspase inhibitor Z-VAD-FMK resulted in improved EC retention following exposure to high shear stress (20 and 30 dynes/cm(2)). The majority of apoptosis and detachment were determined to occur after 6 h. CONCLUSIONS: We have demonstrated that high shear stress-induced EC detachment from Dacron is an apoptosis-dependent phenomenon that can be pharmacologically inhibited by a pan-caspase inhibitor.

Implementation of a novel web-based objective structured clinical evaluation.

BACKGROUND: This study was performed to identify factors that impact student performance on a web-based objective structured clinical evaluation (OSCE) that was developed to improve the evaluation process of students who complete a fourth-year surgical clerkship in trauma-critical care. METHODS: We created a multiple-choice OSCE with commercially available software. Clinical cases were developed for incorporation into 7 quizzes that were assembled to appear as 1 examination. Students used intensive care unit flow sheets to review data, to develop a systems-based problem list and differential diagnoses, and to produce treatment recommendations. RESULTS: No difference was noted in a comparison of the mean scores that were achieved by students on a previous paper (essay format) OSCE and the new web OSCE. There was a correlation of student performance on the web OSCE to the National Board of Medical Examiners (NBME) subject examination that had been completed the previous year (r = 0.60; P < .0001). Performance on the NBME subject examination was the only independent factor that affected reporter, interpreter, and manager skills that were assessed by the OSCE (P < .01). CONCLUSION: Implementation of a web OSCE resulted in similar performance of the class as compared with performance on the previous paper OSCE. Correlation of student achievement on the web OSCE to the NBME subject examination supported the construct validity of this institutional examination beyond the areas of face and content validity in which OSCEs may excel.

Factors impacting functional health and resource utilization following abdominal aortic aneurysm repair by open and endovascular techniques.

We assessed the impact on patient outcomes of comorbidities and type of aneurysm repair, open vs. endovascular aortic repair (EVAR). Functional health status was measured prospectively using the Short Form 36 (SF-36) Health Survey. Length of stay (LOS) and need for postdischarge resources (nursing and rehabilitation) were compared between groups. We reviewed the records of 218 patients (126 open, 92 EVAR) who underwent intervention between 1998 and 2003. The SF-36 was completed preoperatively and at intervals ranging from 2 weeks to 1 year after intervention. To identify factors impacting outcome, univariate and multivariate analyses were performed. Overall mortality was 1.9%: 3.2% for open repair and 0% for EVAR (p = 0.13). Physical and mental health were higher during the 3 months following EVAR compared with open repair: physical function (PF) (65.2 +/- 4.1 vs. 54.0 +/- 4.1), vitality (VT) (55.5 +/- 2.5 vs. 44.9 +/- 3.4), and emotional role (ER) (74.9 +/- 5.0 vs. 51.4 +/- 6.7) (analysis of variance p < 0.05). Women following EVAR had decreased physical summary scores (PSS) (34.8 +/- 2.5 vs. 40.4 +/- 1.1, p < 0.05) compared with men postprocedure despite no difference preoperatively. Congestive heart failure (CHF) was an independent factor that negatively impacted PF, body pain (BP), and PSS. EVAR was associated with improved VT and ER. Differences among open repair and EVAR diminished over time. LOS (in days) was greater for open vs. EVAR (9.2 +/- 0.78 vs. 2.0 +/- 0.17) and in women following both open (11.8 +/- 1.5 vs. 8.0 +/- 0.9) and EVAR (3.2 +/- 0.9 vs. 1.8 +/- 0.1) procedures (p < 0.05). Factors that adversely affected LOS were open repair, age, renal insufficiency, pulmonary disease, CHF, and female gender. Following EVAR, patients were less likely to require home care or transfer to a rehabilitation facility than after open repair (14.1 vs. 36.0%, p < 0.05). Women were significantly more likely to require postdischarge care after open repair (48.7 vs. 30.1%) and EVAR (41.7 vs. 10.0%) (p < 0.05). Logistic regression identified female gender, open repair, advanced age, and pulmonary disease as independent predictors of need for postdischarge care. Those patients undergoing abdominal aortic aneurysm (AAA) repair by open technique (compared to EVAR) had significantly impaired functional health with regard to PF, VT, and ER in the first 3 months after surgery. CHF and hypertension also significantly impaired individual functional health scores. Of significance was that female gender was associated with increased LOS and increased utilization of postdischarge nursing and rehabilitation resources following both open and endovascular surgery for AAA.

Resource utilization and outcomes: effect of transfer on patients with ruptured abdominal aortic aneurysms.

We evaluated the transfer of patients with the diagnosis of a ruptured AAA (rAAA) from community centers to a tertiary care center. Our purpose was to identify factors associated with mortality and outcomes following the open repair of rAAA and to evaluate the differences between transferred and nontransferred patients. All patients who underwent repair of rAAA at our institution between 1995 and 2002 were retrospectively reviewed. Univariate and multivariate analysis was performed to identify patient specific factors on presentation and intraoperatively. Fifty-two patients underwent repair of rAAA, 20 patients were transferred to our institution. The overall mortality rate was 67%. The mortality rates for nontransferred and transferred groups were 69% and 65%, respectively. The incidence of mortality within 24 hr of surgery was significantly higher in the patients who were not transferred, 10 vs. 41% (p < 0.05). Patient-specific factors assessed for impact on survival by logistic regression included decreased body temperature on arrival to our institution (p = 0.02) and free rupture (p = 0.05). Of intraoperative factors tested, low systolic blood pressure was significantly associated with mortality (p = 0.05). No difference in total length of stay was noted. Transfer patients' length of stay in the intensive care unit was significantly greater than that of nontransferred patients (18.8 +/- vs. 7.3 +/- days, p < 0.05). The difference in ICU cost was dollar 36,000 among groups. We found the acceptance of transfer patients from community centers with rAAA did not adversely affect patient survival. Transferred patients had an over twofold increases in ICU days used. The identification of hypothermia was the single independent factor associated with poor survival and may be a marker for transfer selection. Given reduced reimbursements and increased utilization, tertiary care centers will need to consider the economic ramifications of accepting transfer patients with rAAA.

Perirenal fixation as an independent factor in aortic remodeling after endovascular aortic aneurysm repair.

The purpose of our study was to evaluate the influence of perirenal fixation of endovascular aortic grafts on the rate of endoleak and aortic sac remodeling. Retrospective analysis of all patients (pts.) after undergoing endovascular aortic aneurysm repair (EVAR) at our institution was performed. Pre- and postoperative aortic dimensions were obtained from CT scans and angiograms. Intraoperative angiograms were reviewed and patients grouped by the proximity of the graft to the lowest renal arteries: group I: flush with the lowest renal artery; group II: < or = 5 mm distal to lowest renal artery; and group III: >5 mm distal to lowest renal artery. Of the 96 grafts placed between 2000 and 2002, 44 were AneuRx (Medtronic, Santa Rosa, CA) and 52 were Ancure (Guidant, Menlo Park, CA) devices. There were 39 pts. in group I, 42 in group II, and 11 in group III (data on 5 pts. were not obtained). At 6 months, the mean decrease in sac diameter for all groups was 0.42 +/- 0.08 cm (1: 0.56 +/- 0.11 cm; 11: 0.38 +/- 0.11 cm; III: 0.6 +/- 0.15 cm). There was no significant difference between each group. When perirenal fixation (group I) was compared with nonperirenal fixation (groups II and III), there was a significant difference in sac shrinkage at 6 months (p < 0.05, ANOVA). Group I had shorter necks and smaller aneurysms (2.2 +/- 0.1 cm and 5.3 +/- 0.1 cm) than those of groups II and III (2.7 +/- 0.1 cm and 5.7 +/- 0.1 cm, p < 0.05, ANOVA). There was no difference in aortic neck diameter or in aortic neck diameter to graft ratio. When controlled for the variables studied (AAA diameter, length of neck, diameter of neck, diameter of neck to graft ratio, and any endoleak by 6 months), logistic regression analysis identified perirenal fixation as the only significant factor in aortic sac shrinkage of >0.4 cm by 6 months (odds ratio = 16, p < 0.01). With the same variables, a linear regression model also identified perirenal fixation as the only predictive factor in aortic shrinkage (regression coefficient = 0.46, p < 0.05). The endoleak-free survival rate with perirenal fixation was 96 +/- 5% and without it was 80 +/- 7% (Kaplan Meier, p = 0.09, log rank). Perirenal placement of endovascular grafts is associated with a trend toward fewer endoleaks, and improved aortic sac shrinkage independent of aortic neck length, AAA diameter, diameter of neck, and endoleak. Failure to achieve perirenal placement of EVAG increased the likelihood of reduced or failed aortic sac shrinkage in this series.

Efficacious use of nitinol stents in the femoral and popliteal arteries.

OBJECTIVE: To evaluate the performance and identify predictors of outcome after the use of self-expanding nitinol stents in the treatment of femoropopliteal arterial occlusive disease. METHODS: A retrospective analysis of a prospectively collected database was performed. Outcomes of patients who underwent placement of a nitinol stent in the femoral or above-knee popliteal arteries between 1999 and 2002 were studied. Patency, limb salvage, and patient survival were determined by Kaplan-Meier estimation and intergroup comparisons by log-rank test and Cox proportional hazards model. To define individual factors associated with clinical outcomes, stepwise regression analysis was performed. RESULTS: A total of 41 patients (mean age, 70 +/- 10 years; gender, 26 men and 15 women) underwent percutaneous placement of nitinol stents. Limb salvage was the indication for intervention in 68% of patients. Diabetes was present in 54%, and 36% had end-stage renal disease. Nitinol stents were placed in the superficial femoral (35 patients) or the above-knee popliteal (6 patients) arteries. The mean postprocedural increase in ankle-brachial index was 0.32 +/- 0.19. The 6-month, 1-year, and 2-year primary patency and limb-salvage rates were 95%, 84%, and 84%, and 92%, 89%, and 89%, respectively. Major amputations occurred only in patients undergoing limb-salvage procedures presenting with major tissue loss. No statistically significant differences in patency were seen with regard to diabetes, end-stage renal disease, runoff score, length of vessel stented (median, 80 mm), hypertension, or smoking. CONCLUSIONS: Our initial experience with self-expanding nitinol stents for femoropopliteal occlusive disease appears to demonstrate acceptable patency and limb-salvage rates at these early time points. Further evaluation of clinical outcome with these devices in this and larger groups of patients is warranted.

Effective use of human simulators in surgical education.

BACKGROUND: We initiated a teaching module utilizing a human simulator midway through 2001-2002 to improve student skills specific to the evaluation of patients in shock during a required clerkship in surgery for fourth-year medical students. We tested the hypothesis that student skills would improve after implementation of this module and identified factors that predicted student performance. MATERIALS AND METHODS: Students (n = 86) chose one of two hospital sites for a clerkship that focuses on the care of acutely ill surgical patients. A case-based lecture focusing on the diagnosis and management of a patient in shock was replaced midway through the academic year by a simulator session with a computerized life-sized mannequin. A standardized clinical final evaluation (OSCE) was used to assess student skills. We evaluated the effect of the simulator session and other factors on student exam performance using univariate and multivariate analysis. RESULTS: The site of the clerkship and the simulator session were significant factors affecting the OSCE score identified by ANOVA, P < 0.05. A stepwise multiple regression analysis testing the effect of simulator module, site, time of year, prior NBME subject exam, and prior OSCE during the third year clerkship identified that the simulator module was the only independent factor that modeled performance on all shock stations, P < 0.01. CONCLUSIONS: In a clerkship that already emphasized faculty facilitated case-based learning, the use of a teaching module employing a human simulator significantly improved test scores. This study supports the efficacy of human simulators to improve student skills related to the management of complex critically ill patients.

Influence of endovascular training on fellowship and general surgical training.

PURPOSE: As endovascular procedures develop, there is a risk of diminished training of residents and fellows in traditional open surgery. We evaluated the effect of our endovascular program, initiated in 1999 coincident with the Federal Drug Administration's approval of endoluminal vascular aortic grafts, on the number of endovascular procedures and open abdominal aortic aneurysm (AAA) repairs performed in comparison to national trends. METHODS: The experience of vascular fellows and chief residents at completion of training (1996-2002) was reviewed and compared with the national mean case numbers before and after initiation of our endovascular program. RESULTS: The development of an endovascular program increased the total number of aneurysms repaired at the Robert Wood Johnson (RWJ) Medical School from 49 +/- 15 to 92 +/- 8 per year (P < 0.01). The number of vascular operations performed by the RWJ fellow increased from 320 +/- 48 to 553 +/- 155 per year (P < 0.05). The number of operations performed nationally by vascular fellows also increased during the same period, but did not reach statistical significance. There was no change in the number of open AAA repairs performed by the RWJ fellow or nationally. There was also no change in the average number of vascular operations completed by RWJ chief residents or nationally (160 +/- 17 versus 157 +/- 1 and 192 +/- 4 versus 189 +/- 4, respectively; P > 0.05). However, the average number of open AAA repairs performed nationally by general surgical chief residents decreased from 10 +/- 0.3 to 9 +/- 0.4 (P < 0.05). CONCLUSION: An endovascular program can increase the total number of AAA repairs performed without influencing the total number of vascular operations performed by general surgical chief residents. There was a decrease in open AAA repairs performed nationally by general surgical chief residents. The advancement of endovascular therapies may decrease the number of open procedures available for trainees in both general and vascular surgery. Perhaps those that will specialize in the field of vascular surgery should have the benefit of those open procedures.

Predictors of educational outcome: factors impacting performance on a standardized clinical evaluation.

BACKGROUND: To improve student skills specific to the evaluation of radiology studies during a required clerkship in surgery for 4th-year medical students, we initiated a self-study CD-ROM educational module midway through 2000-2001. We hypothesized that student performance would improve after implementation of this module and identified factors that predicted student performance. MATERIALS AND METHODS: Students (n = 98) chose one of two hospital sites for a clerkship that focuses on the care of acutely ill surgical patients. A standardized clinical final evaluation (Objective Structured Clinical Evaluation) contained two components: radiology (R score) and ICU clinical "flow sheet" interpretation (C score). We evaluated the effect of the CD-ROM educational module and other factors on student exam performance using univariate and multivariate analysis. RESULTS: The site of the clerkship and use of the CD-ROM educational module were significant factors affecting the C score identified by ANOVA; P < 0.05. With the R scores from both sites combined, performance improved by 22% from a mean of 29.2 +/- 1.1 to 35.7 +/- 1.1 with use of the module. A stepwise multiple regression analysis testing the effect of site, time of year, educational module, and a prior radiology clerkship on the R score identified that the site and CD-ROM educational module modeled performance; R(2) = 0.30, P < 0.01. The C score was affected by site (A: 72.5 +/- 1.6 vs B: 67.3 +/- 1.9, P < 0.05 by ANOVA). Regression analysis identified that time of year (later associated with increased score) and prior performance on the 3rd-year standardized exams (OSCE and NBME) modeled 4th-year C score; R(2) = 0.20, P < 0.01. CONCLUSIONS: In a clerkship that already emphasized faculty-facilitated case-based learning, including evaluation of radiological studies, the addition of a self-study CD-ROM radiology module significantly improved test score. This study supports the efficacy of directed self-study to improve student skills.