Direct electrospinning of 3D auricle-shaped scaffolds for tissue engineering applications.

Thirty-two poly(ε)caprolactone (PCL) scaffolds have been produced by electrospinning directly into an auricle-shaped mould and seeded with articular chondrocytes harvested from bovine ankle joints. After seeding, the auricle shaped constructs were cultured in vitro and analysed at days 1, 7, 14 and 21 for regional differences in total DNA, glycosaminoglycan (GAG) and collagen (COL) content as well as the expression of aggrecan (AGG), collagen type I and type II (COL1/2) and matrix metalloproteinase 3 and 13 (MMP3/13). Stress-relaxation indentation testing was performed to investigate regional mechanical properties of the electrospun constructs. Electrospinning into a conductive mould yielded stable 3D constructs both initially and for the whole in vitro culture period, with an equilibrium modulus in the MPa range. Rapid cell proliferation and COL accumulation was observed until week 3. Quantitative real time PCR analysis showed an initial increase in AGG, no change in COL2, a persistent increase in COL1, and only a slight decrease initially for MMP3. Electrospinning of fibrous scaffolds directly into an auricle-shape represents a promising option for auricular tissue engineering, as it can reduce the steps needed to achieve an implantable structure.

Role of alternative interventional procedures when endo- and epicardial catheter ablation attempts for ventricular arrhythmias fail.

BACKGROUND Ventricular tachycardia (VT) refractory to antiarrhythmic drugs and standard percutaneous catheter ablation techniques portends a poor prognosis. We characterized the reasons for ablation failure and describe alternative interventional procedures in this high-risk group. METHODS AND RESULTS Sixty-seven patients with VT refractory to 4±2 antiarrhythmic drugs and 2±1 previous endocardial/epicardial catheter ablation attempts underwent transcoronary ethanol ablation, surgical epicardial window (Epi-window), or surgical cryoablation (OR-Cryo; age, 62±11 years; VT storm in 52%). Failure of endo/epicardial ablation attempts was because of VT of intramural origin (35 patients), nonendocardial origin with prohibitive epicardial access because of pericardial adhesions (16), and anatomic barriers to ablation (8). In 8 patients, VT was of nonendocardial origin with a coexisting condition also requiring cardiac surgery. Transcoronary ethanol ablation alone was attempted in 37 patients, OR-Cryo alone in 21 patients, and a combination of transcoronary ethanol ablation and OR-Cryo (5 patients), or transcoronary ethanol ablation and Epi-window (4 patients), in the remainder. Overall, alternative interventional procedures abolished ≥1 inducible VT and terminated storm in 69% and 74% of patients, respectively, although 25% of patients had at least 1 complication. By 6 months post procedures, there was a significant reduction in defibrillator shocks (from a median of 8 per month to 1; P<0.001) and antiarrhythmic drug requirement although 55% of patients had at least 1 VT recurrence, and mortality was 17%. CONCLUSIONS A collaborative strategy of alternative interventional procedures offers the possibility of achieving arrhythmia control in high-risk patients with VT that is otherwise uncontrollable with antiarrhythmic drugs and standard percutaneous catheter ablation techniques.

Ablation of ischemic ventricular tachycardia: evidence, techniques, results, and future directions

PURPOSE OF REVIEW This article summarizes current understanding of the arrhythmia substrate and effect of catheter ablation for infarct-related ventricular tachycardia, focusing on recent findings. RECENT FINDINGS Clinical studies support the use of catheter ablation earlier in the course of ischemic disease with moderate success in reducing arrhythmia recurrence and shocks from implantable defibrillators, although mortality remains unchanged. Ablation can be lifesaving for patients presenting with electrical storm. Advanced mapping systems with image integration facilitate identification of potential substrate, and several different approaches to manage hemodynamically unstable ventricular tachycardia have emerged. Novel ablation techniques that allow deeper lesion formation are in development. SUMMARY Catheter ablation is an important therapeutic option for preventing or reducing episodes of ventricular tachycardia in patients with ischemic cardiomyopathy. Present technologies allow successful ablation in the majority of patients, even when the arrhythmia is hemodynamically unstable. Failure of the procedure is often because of anatomic challenges that will hopefully be addressed with technological progress.

Future glucose-lowering drugs for type 2 diabetes

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.

The development and investigation of a novel pulsatile heart assist device

Cardiovascular diseases (CVD) contributed to almost 30% of worldwide mortality; with heart failure being one class of CVD. One popular and widely available treatment for heart failure is the intra-aortic balloon pump (IABP). This heart assist device is used in counterpulsation to improve myocardial function by increasing coronary perfusion, and decreasing aortic end-diastolic pressure (i.e. the resistance to blood ejection from the heart). However, this device can only be used acutely, and patients are bedridden. The subject of this research is a novel heart assist treatment called the Chronic Intermittent Mechanical Support (CIMS) which was conceived to offer advantages of the IABP device chronically, whilst overcoming its disadvantages. The CIMS device comprises an implantable balloon pump, a percutaneous drive line, and a wearable driver console. The research here aims to determine the haemodynamic effect of balloon pump activation under in vitro conditions. A human mock circulatory loop (MCL) with systemic and coronary perfusion was constructed, capable of simulating various degrees of heart failure. Two prototypes of the CIMS balloon pump were made with varying stiffness. Several experimental factors (balloon inflation/deflation timing, Helium gas volume, arterial compliance, balloon pump stiffness and heart valve type) form the factorial design experiments. A simple modification to the MCL allowed flow visualisation experiments using video recording. Suitable statistical tests were used to analyse the data obtained from all experiments. Balloon inflation and deflation in the ascending aorta of the MCL yielded favourable results. The sudden balloon deflation caused the heart valve to open earlier, thus causing longer valve opening duration in a cardiac cycle. It was also found that pressure augmentation in diastole was significantly correlated with increased cardiac output and coronary flowrate. With an optimum combination (low arterial compliance and low balloon pump stiffness), systemic and coronary perfusions were increased by 18% and 21% respectively, while the aortic end-diastolic pressure (forward flow resistance) decreased by 17%. Consequently, the ratio of oxygen supply and demand to myocardium (endocardial viability ratio, EVR) increased between 33% and 75%. The increase was mostly attributed to diastolic augmentation rather than systolic unloading.

Novel bioactive scaffolds incorporating nanogels as potential drug eluting devices

Big advances are being achieved in the design of new implantable devices with enhanced properties. For example, synthetic porous three-dimensional structures can mimic the architecture of the tissues, and serve as templates for cell seeding. In addition, polymeric nanoparticles are able to provide a programmable and sustained local delivery of different types of biomolecules. In this study novel alternative scaffolds with controlled bioactive properties and architectures are presented. Two complementary approaches are described. Firstly, scaffolds with nanogels as active controlled release devices incorporated inside the three-dimensional structure are obtained using the thermally induced phase separation (TIPS) method. Secondly, a novel coating method using the spraying technique to load these nanometric crosslinked hydrogels on the surface of two-dimensional (2D) and three-dimensional (3D) biodegradable scaffolds is described. The scanning electron microscopy (SEM) images show the distribution of the nanogels on the surface of different substrates and also inside the porous structure of poly-a-hydroxy ester derivative foams. Both of them are compared in terms of manufacturability, dispersion and other processing variables.

Cell exclusion in couette flow:evaluation through flow visualisation and mechanical forces

Cell exclusion is the phenomenon whereby the hematocrit and viscosity of blood decrease in areas of high stress. While this is well known in naturally occurring Poiseuille flow in the human body, it has never previously been shown in Couette flow, which occurs in implantable devices including blood pumps. The high-shear stresses that occur in the gap between the boundaries in Couette flow are known to cause hemolysis in erythrocytes. We propose to mitigate this damage by initiating cell exclusion through the use of a spiral-groove bearing (SGB) that will provide escape routes by which the cells may separate themselves from the plasma and the high stresses in the gap. The force between two bearings (one being the SGB) in Couette flow was measured. Stained erythrocytes, along with silver spheres of similar diameter to erythrocytes, were visualized across a transparent SGB at various gap heights. A reduction in the force across the bearing for human blood, compared with fluids of comparable viscosity, was found. This indicates a reduction in the viscosity of the fluid across the bearing due to a lowered hematocrit because of cell exclusion. The corresponding images clearly show both cells and spheres being excluded from the gap by entering the grooves. This is the first time the phenomenon of cell exclusion has been shown in Couette flow. It not only furthers our understanding of how blood responds to different flows but could also lead to improvements in the future design of medical devices.

Laparoscopic greater curvature plication in morbidly obese women with type 2 diabetes:effects on glucose homeostasis, postprandial triglyceridemia and selected gut hormones

Background: Laparoscopic greater curvature plication (LGCP) is an emerging bariatric procedure that reduces the gastric volume without implantable devices or gastrectomy. The aim of this study was to explore changes in glucose homeostasis, postprandial triglyceridemia, and meal-stimulated secretion of selected gut hormones [glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), ghrelin, and obestatin] in patients with type 2 diabetes mellitus (T2DM) at 1 and 6 months after the procedure. Methods: Thirteen morbidly obese T2DM women (mean age, 53.2 ± 8.76 years; body mass index, 40.1 ± 4.59 kg/m2) were prospectively investigated before the LGCP and at 1- and 6-month follow-up. At these time points, all study patients underwent a standardized liquid mixed-meal test, and blood was sampled for assessment of plasma levels of glucose, insulin, C-peptide, triglycerides, GIP, GLP-1, ghrelin, and obestatin. Results: All patients had significant weight loss both at 1 and 6 months after the LGCP (p≤0.002), with mean percent excess weight loss (%EWL) reaching 29.7 ;plusmn2.9 % at the 6-month follow-up. Fasting hyperglycemia and hyperinsulinemia improved significantly at 6 months after the LGCP (p<0.05), with parallel improvement in insulin sensitivity and HbA1c levels (p<0.0001). Meal-induced glucose plasma levels were significantly lower at 6 months after the LGCP (p<0.0001), and postprandial triglyceridemia was also ameliorated at the 6-month follow-up (p<0.001). Postprandial GIP plasma levels were significantly increased both at 1 and 6 months after the LGCP (p<0.0001), whereas the overall meal-induced GLP-1 response was not significantly changed after the procedure (p ;gt0.05). Postprandial ghrelin plasma levels decreased at 1 and 6 months after the LGCP (p<0.0001) with no significant changes in circulating obestatin levels. Conclusion: During the initial 6-month postoperative period, LGCP induces significant weight loss and improves the metabolic profile of morbidly obese T2DM patients, while it also decreases circulating postprandial ghrelin levels and increases the meal-induced GIP response. © 2013 Springer Science+Business Media New York.

Microporous polycaprolactone matrices for drug delivery and tissue engineering:the release behaviour of bioactives having extremes of aqueous solubility

Microporous polycaprolactone (PCL) matrices loaded with hydrophobic steroidal drugs or a hydrophilic drug - pilocarpine hydrochloride - were produced by precipitation casting using solutions of PCL in acetone. The efficiency of steroid incorporation in the final matrix (progesterone (56 %) testosterone (46 %) dexamethasone (80 %)) depended on the nature of the drug initially co-dissolved in the PCL solution. Approximately 90 % w/w of the initial load of progesterone, 85 % testosterone and 50 % dexamethasone was released from the matrices in PBS at 37°C over 8 days. Pilocarpine hydrochloride (PH)-loaded PCL matrices, prepared by dispersion of powder in PCL solution, released 70-90 % of the PH content over 12 days in PBS. Application of the Higuchi model revealed that the kinetics of steroid and PH release were consistent with a Fickian diffusion mechanism with corresponding diffusion coefficients of 5.8 × 10-9 (progesterone), 3.9 × 10 -9 (testosterone), 7.1 × 10-10 (dexamethasone) and 22 × 10-8 cm2/s (pilocarpine hydrochloride). The formulation techniques described are expected to be useful for production of implantable, insertable and topical devices for sustained delivery of a range of bioactive molecules of interest in drug delivery and tissue engineering.

Electro and Magneto-Electropolished Surface Micro-Patterning on Binary and Ternary Nitinol

In this study, an Atomic Force Microscopy (AFM) roughness analysis was performed on non-commercial Nitinol alloys with Electropolished (EP) and Magneto-Electropolished (MEP) surface treatments and commercially available stents by measuring Root-Mean-Square (RMS) , Average Roughness (Ra), and Surface Area (SA) values at various dimensional areas on the alloy surfaces, ranging from (800 x 800 nm) to (115 x 115µm), and (800 x 800 nm) to (40 x 40 µm) on the commercial stents. Results showed that NiTi-Ta 10 wt% with an EP surface treatment yielded the highest overall roughness, while the NiTi-Cu 10 wt% alloy had the lowest roughness when analyzed over (115 x 115 µm). Scanning Electron Microscopy (SEM) and Energy Dispersive Spectroscopy (EDS) analysis revealed unique surface morphologies for surface treated alloys, as well as an aggregation of ternary elements Cr and Cu at grain boundaries in MEP and EP surface treated alloys, and non-surface treated alloys. Such surface micro-patterning on ternary Nitinol alloys could increase cellular adhesion and accelerate surface endothelialization of endovascular stents, thus reducing the likelihood of in-stent restenosis and provide insight into hemodynamic flow regimes and the corrosion behavior of an implantable device influenced from such surface micro-patterns.

Vacuum brazing of alumina ceramic to titanium for biomedical implants using pure gold as the filler metal

One of the many promising applications of metal/ceramic joining is in biomedical implantable devices. This work is focused on vacuum brazing of C.P titanium to 96% alumina ceramic using pure gold as the filler metal. A novel method of brazing is developed where resistance heating of C.P titanium is done inside a thermal evaporator using a Ta heating electrode. The design of electrode is optimized using Ansys resistive heating simulations. The materials chosen in this study are biocompatible and have prior history in implantable devices approved by FDA. This research is part of Boston Retinal implant project to make a biocompatible implantable device (www.bostonretina.org). ^ Pure gold braze has been used in the construction of single terminal feedthrough in low density hermetic packages utilizing a single platinum pin brazed to an alumina or sapphire ceramic donut (brazed to a titanium case or ferrule for many years in implantable pacemakers. Pure gold (99.99%) brazing of 96% alumina ceramic with CP titanium has been performed and evaluated in this dissertation. Brazing has been done by using electrical resistance heating. The 96% alumina ceramic disk was manufactured by high temperature cofired ceramic (HTCC) processing while the Ti ferrule and gold performs were purchased from outside. Hermetic joints having leak rate of the order of 1.6 × 10-8 atm-cc/ sec on a helium leak detector were measured. ^ Alumina ceramics made by HTCC processing were centreless grounded utilizing 800 grit diamond wheel to provide a smooth surface for sputtering of a thin film of Nb. Since pure alumina demonstrates no adhesion or wetting to gold, an adhesion layer must be used on the alumina surface. Niobium (Nb), Tantalum (Ta) and Tungsten (W) were chosen for evaluation since all are refractory (less dissolution into molten gold), all form stable oxides (necessary for adhesion to alumina) and all are readily thin film deposited as metals. Wetting studies are also performed to determine the wetting angle of pure gold to Ti, Ta, Nb and W substrates. Nano tribological scratch testing of thin film of Nb (which demonstrated the best wetting properties towards gold) on polished 96% alumina ceramic is performed to determine the adhesion strength of thin film to the substrate. The wetting studies also determined the thickness of the intermetallic compounds layers formed between Ti and gold, reaction microstructure and the dissolution of the metal into the molten gold.^

Developing a high density platinum/alumina hermetic feedthrough

Typically, hermetic feedthroughs for implantable devices, such as pacemakers, use a alumina ceramic insulator brazed to a platinum wire pin. This combination of material has a long history in implantable devices and has been approved by the FDA for implantable hermetic feedthroughs. The growing demand for increased input/output (I/O) hermetic feedthroughs for implantable neural stimulator applications could be addressed by developing a new, cofired platinum/alumina multilayer ceramic technology in a configuration that supports 300 plus I/Os, which is not commercially available. Seven platinum powders with different particle sizes were used to develop different conductive cofire inks to control the densification mismatch between platinum and alumina. Firing profile (ramp rate, burn- out and holding times) and firing atmosphere and concentrations (hydrogen (wet/dry), air, neutral, vacuum) were also optimized. Platinum and alumina exhibit the alloy formation reaction in a reduced atmosphere. Formation of any compound can increase the bonding of the metal/ceramic interface, resulting in enhanced hermeticity. The feedthrough fabricated in a reduced atmosphere demonstrated significantly superior performance than that of other atmospheres. A composite structure of tungsten/platinum ratios graded thru the via structure (pure W, 50/50 W/Pt, 80/20 Pt/W and pure Pt) exhibited the best performance in comparison to the performance of other materials used for ink metallization. Studies on the high temperature reaction of platinum and alumina, previously unreported, showed that, at low temperatures in reduced atmosphere, Pt 3Al or Pt8Al21 with a tetragonal structure would be formed. Cubic Pt3Al is formed upon heating the sample to temperatures above 1350 °C. This cubic structure is the equilibrium state of Pt-Al alloy at high temperatures. The alumina dissolves into the platinum ink and is redeposited as a surface coating. This was observed on both cofired samples and pure platinum thin films coated on a 99.6 Wt% alumina and fired at 1550 °C. Different mechanisms are proposed to describe this behavior based on the size of the platinum particle

Optimization of wireless power transfer via magnetic resonance in different media

A wide range of non-destructive testing (NDT) methods for the monitoring the health of concrete structure has been studied for several years. The recent rapid evolution of wireless sensor network (WSN) technologies has resulted in the development of sensing elements that can be embedded in concrete, to monitor the health of infrastructure, collect and report valuable related data. The monitoring system can potentially decrease the high installation time and reduce maintenance cost associated with wired monitoring systems. The monitoring sensors need to operate for a long period of time, but sensors batteries have a finite life span. Hence, novel wireless powering methods must be devised. The optimization of wireless power transfer via Strongly Coupled Magnetic Resonance (SCMR) to sensors embedded in concrete is studied here. First, we analytically derive the optimal geometric parameters for transmission of power in the air. This specifically leads to the identification of the local and global optimization parameters and conditions, it was validated through electromagnetic simulations. Second, the optimum conditions were employed in the model for propagation of energy through plain and reinforced concrete at different humidity conditions, and frequencies with extended Debye's model. This analysis leads to the conclusion that SCMR can be used to efficiently power sensors in plain and reinforced concrete at different humidity levels and depth, also validated through electromagnetic simulations. The optimization of wireless power transmission via SMCR to Wearable and Implantable Medical Device (WIMD) are also explored. The optimum conditions from the analytics were used in the model for propagation of energy through different human tissues. This analysis shows that SCMR can be used to efficiently transfer power to sensors in human tissue without overheating through electromagnetic simulations, as excessive power might result in overheating of the tissue. Standard SCMR is sensitive to misalignment; both 2-loops and 3-loops SCMR with misalignment-insensitive performances are presented. The power transfer efficiencies above 50% was achieved over the complete misalignment range of 0°-90° and dramatically better than typical SCMR with efficiencies less than 10% in extreme misalignment topologies.

C-MEMS Based Micro Enzymatic Biofuel Cells

Miniaturized, self-sufficient bioelectronics powered by unconventional micropower may lead to a new generation of implantable, wireless, minimally invasive medical devices, such as pacemakers, defibrillators, drug-delivering pumps, sensor transmitters, and neurostimulators. Studies have shown that micro-enzymatic biofuel cells (EBFCs) are among the most intuitive candidates for in vivo micropower. In the fisrt part of this thesis, the prototype design of an EBFC chip, having 3D intedigitated microelectrode arrays was proposed to obtain an optimum design of 3D microelectrode arrays for carbon microelectromechanical systems (C-MEMS) based EBFCs. A detailed modeling solving partial differential equations (PDEs) by finite element techniques has been developed on the effect of 1) dimensions of microelectrodes, 2) spatial arrangement of 3D microelectrode arrays, 3) geometry of microelectrode on the EBFC performance based on COMSOL Multiphysics. In the second part of this thesis, in order to investigate the performance of an EBFC, behavior of an EBFC chip performance inside an artery has been studied. COMSOL Multiphysics software has also been applied to analyze mass transport for different orientations of an EBFC chip inside a blood artery. Two orientations: horizontal position (HP) and vertical position (VP) have been analyzed. The third part of this thesis has been focused on experimental work towards high performance EBFC. This work has integrated graphene/enzyme onto three-dimensional (3D) micropillar arrays in order to obtain efficient enzyme immobilization, enhanced enzyme loading and facilitate direct electron transfer. The developed 3D graphene/enzyme network based EBFC generated a maximum power density of 136.3 μWcm-2 at 0.59 V, which is almost 7 times of the maximum power density of the bare 3D carbon micropillar arrays based EBFC. To further improve the EBFC performance, reduced graphene oxide (rGO)/carbon nanotubes (CNTs) has been integrated onto 3D mciropillar arrays to further increase EBFC performance in the fourth part of this thesisThe developed rGO/CNTs based EBFC generated twice the maximum power density of rGO based EBFC. Through a comparison of experimental and theoretical results, the cell performance efficiency is noted to be 67%.