A 100-V Withstanding Analog-Front-End for High-Resolution Intravascular Ultrasound Imaging.

Intravascular Ultrasound ultrasonic imaging (IVUS) can microscopically image blood vessels and reveal tissue layers from within the blood vessel lumen. It has high tissue penetration ability for lesion classification and can image through blood. Compared to optical techniques, however, IVUS has lower resolution arising from low acoustic bandwidths which cannot resolve sharp edges. The presented 100-V withstanding Analog-Front-End (AFE) was developed to enable a high resolution, low cost IVUS system using a high-bandwidth focused polymer transducer with 40-MHz center frequency. The fabricated AFE interfaced with the transducer with minimal insertion loss, could withstand and duplex 100-V high voltage pulses and echo signal, and had a total signal chain gain of 9.8 dB. The AFE achieved a signal-to-noise ratio (SNR) of 20.1 dB including the insertion loss of the high-impedance transducer. AFE SNR was limited by input impedance required for high-voltage pulse clamping circuitry, but was sufficient for IVUS echo reception.Clinical Relevance- This work has the potential to enable much higher resolution, and potentially cheaper, IVUS imaging in blood vessels by integrating low-cost acoustic transducers with interface amplifiers directly on the catheter.

Microfluidic chip for graduated magnetic separation of circulating tumor cells by their epithelial cell adhesion molecule expression and magnetic nanoparticle binding.

The enumeration of circulating tumor cells (CTCs) in the peripheral bloodstream of metastatic cancer patients has contributed to improvements in prognosis and therapeutics. There have been numerous approaches to capture and counting of CTCs. However, CTCs have potential information beyond simple enumeration and hold promise as a liquid biopsy for cancer and a pathway for personalized cancer therapy by detecting the subset of CTCs having the highest metastatic potential. There is evidence that epithelial cell adhesion molecule (EpCAM) expression level distinguishes these highly metastatic CTCs. The few previous approaches to selective CTC capture according to EpCAM expression level are reviewed. A new two-stage microfluidic device for separation, enrichment and release of CTCs into subpopulations sorted by EpCAM expression level is presented here. It relies upon immunospecific magnetic nanoparticle labeling of CTCs followed by their field- and flow-based separation in the first stage and capture as discrete subpopulations in the second stage. To fine tune the separation, the magnetic field profile across the first stage microfluidic channel may be modified by bonding small Vanadium Permendur strips to its outer walls. Mathematical modeling of magnetic fields and fluid flows supports the soundness of the design.

The P387 thrombospondin-4 variant promotes accumulation of macrophages in atherosclerotic lesions.

Thrombospondin-4 (TSP4) is a pro-angiogenic protein that has been implicated in tissue remodeling and local vascular inflammation. TSP4 and, in particular, its SNP variant, P387 TSP4, have been associated with cardiovascular disease. Macrophages are central to initiation and resolution of inflammation and development of atherosclerotic lesions, but the effects of the P387 TSP4 on macrophages remain essentially unknown. We examined the effects of the P387 TSP4 variant on macrophages in cell culture and in vivo in a murine model of atherosclerosis. Furthermore, the levels and distributions of the two TSP4 variants were assessed in human atherosclerotic arteries. In ApoE-/- /P387-TSP4 knock-in mice, lesions size measured by Oil Red O did not change, but the lesions accumulated more macrophages than lesions bearing A387 TSP4. The levels of inflammatory markers were increased in lesions of ApoE-/- /P387-TSP4 knock-in mice compared to ApoE-/- mice. Lesions in human arteries from individuals carrying the P387 variant had higher levels of TSP4 and higher macrophage accumulation. P387 TSP4 was more active in supporting adhesion of cultured human and mouse macrophages in experiments using recombinant TSP4 variants and in cells derived from P387-TSP4 knock-in mice. TSP4 supports the adhesion of macrophages and their accumulation in atherosclerotic lesions without changing the size of lesions. P387 TSP4 is more active in supporting these pro-inflammatory events in the vascular wall, which may contribute to the increased association of P387 TSP4 with cardiovascular disease.

Towards safe operation of an active retinal prosthesis during functional MRI and diffusion tensor imaging.

OBJECTIVE: To determine if the Argus II retinal prosthesis can operate during functional MRI (fMRI) and diffusion tensor imaging (DTI) acquisitions and if currents induced in the prosthesis by imaging are at safe levels. MATERIALS AND METHODS: One Argus II retinal prosthesis was modified to enable current measurements during imaging. Active electronics were modified to enable operation during scans. Induced current was measured during diagnostic scans, which were previously shown to be safe for implanted patients, and during fMRI and DTI scans. All measurements were performed using an ASTM phantom to ensure reproducible placement. RESULTS: The prosthesis was able to maintain communication with the external RF coil during the fMRI and DTI scans except briefly during pre-scans. Current levels induced during fMRI and DTI scans were consistently below those measured during diagnostic scans. CONCLUSIONS: fMRI and DTI may be safely performed while the Argus II retinal prosthesis is operating.

Artificial Intelligence in Intracoronary Imaging.

PURPOSE OF REVIEW: This paper investigates present uses and future potential of artificial intelligence (AI) applied to intracoronary imaging technologies. RECENT FINDINGS: Advances in data analytics and digitized medical imaging have enabled clinical application of AI to improve patient outcomes and reduce costs through better diagnosis and enhanced workflow. Applications of AI to IVUS and IVOCT have produced improvements in image segmentation, plaque analysis, and stent evaluation. Machine learning algorithms are able to predict future coronary events through the use of imaging results, clinical evaluations, laboratory tests, and demographics. The application of AI to intracoronary imaging holds significant promise for improved understanding and treatment of coronary heart disease. Even in these early stages, AI has demonstrated the ability to improve the prediction of cardiac events. Large curated data sets and databases are needed to speed the development of AI and enable testing and comparison among algorithms.

Catheter-Mounted CMOS Front-Ends for Broadband Intravascular Ultrasonic Imaging.

Intravascular ultrasonic (IVUS) imaging catheters currently use ceramic piezoelectric transducers to form radial images of blood vessel walls. Further improvements in image quality may be enabled through Capacitive and Piezoelectric Micromachined Ultrasonic Transducers (CMUTs and PMUTs). Polymer PMUTs offer many benefits in imaging quality, however, the low acoustic sensitivity and high electrical impedance of polymer PMUTs prevents unbuffered use with 50-Ω IVUS cables. Here, we present the design and optimization of an integrated CMOS front-end specifically designed to be integrated on a 0.8-mm imaging catheter. A series-duplexer topology with active limiter was selected for simplicity of integration, and compatibility with conventional high-voltage IVUS pulser-receiver systems. Noise optimization of the front-end revealed that an impedance-matching optimum exists, which balances the system parasitic capacitances relative to the transducer complex impedance. Optimized design equations compared favorably to simulation results in predicting front-end bandwidth and transducer-referred SNR. Large-signal transient simulation showed that the front-end can withstand 100-V pulses while recovering in 240 ns for echo reception. The integrated front-end occupied 0.74 × 1.8 mm die area (including large solder-bump bond pads), with an estimated transducer-referred noise floor of 6.5 n V R M S / H z over a 100-MHz imaging bandwidth.

Inductive passive sensor for intraparenchymal and intraventricular monitoring of intracranial pressure.

Accurate measurement of intracranial hypertension is crucial for the management of elevated intracranial pressure (ICP). Catheter-based intraventricular ICP measurement is regarded as the gold standard for accurate ICP monitoring. However, this method is invasive, time-limited, and associated with complications. In this paper, we propose an implantable passive sensor that could be used for continuous intraparenchymal and intraventricular ICP monitoring. Moreover, the sensor can be placed simultaneously along with a cerebrospinal fluid shunt system in order to monitor its function. The sensor consists of a flexible coil which is connected to a miniature pressure sensor via an 8-cm long, ultra-thin coaxial cable. An external orthogonal-coil RF probe communicates with the sensor to detect pressure variation. The performance of the sensor was evaluated in an in vitro model for intraparenchymal and intraventricular ICP monitoring. The findings from this study demonstrate proof-of-concept of intraparenchymal and intraventricular ICP measurement using inductive passive pressure sensors.

Biocompatibility evaluation of a thermoplastic rubber for wireless telemetric intracranial pressure sensor coating.

This study investigated the biocompatibility of the experimental thermoplastic rubber Arbomatrix(™) that will be used as the protective coating on a novel intracranial pressure (ICP) sensor silicon chip. Arbomatrix(™) was benchmarked against biocompatible commercial silicone rubber shunt tubing in the brain via a rat model with 60-day implant duration. A bare silicon chip was also implanted. The results showed similar cellular distribution in the brain-implant boundary and surrounding tissues. Quantitative analysis of neuron and glia density did not show significant difference between implants. Through histological and immunohistochemical evaluation we conclude that Arbomatrix(™) is well tolerated by the brain. Due to its exceptional barrier properties Arbomatrix(™) has already been shown to be an excellent protective coating for new ICP monitoring chip.

Response of bone marrow derived connective tissue progenitor cell morphology and proliferation on geometrically modulated microtextured substrates.

Varying geometry and layout of microposts on a cell culture substrate provides an effective technique for applying mechanical stimuli to living cells. In the current study, the optimal geometry and arrangement of microposts on the polydimethylsiloxane (PDMS) surfaces to enhance cell growth behavior were investigated. Human bone marrow derived connective tissue progenitor cells were cultured on PDMS substrates comprising unpatterned smooth surfaces and cylindrical post microtextures that were 10 µm in diameter, 4 heights (5, 10, 20 and 40 µm) and 3 pitches (10, 20, and 40 µm). With the same 10 µm diameter, post heights ranging from 5 to 40 µm resulted in a more than 535 fold range of rigidity from 0.011 nNµm⁻¹ (40 µm height) up to 5.888 nNµm⁻¹(5 µm height). Even though shorter microposts result in higher effective stiffness, decreasing post heights below the optimal value, 5 µm height micropost in this study decreased cell growth behavior. The maximum number of cells was observed on the post microtextures with 20 µm height and 10 µm inter-space, which exhibited a 675 % increase relative to the smooth surfaces. The cells on all heights of post microtextures with 10 µm and 20 µm inter-spaces exhibited highly contoured morphology. Elucidating the cellular response to various external geometry cues enables us to better predict and control cellular behavior. In addition, knowledge of cell response to surface stimuli could lead to the incorporation of specific size post microtextures into surfaces of implants to achieve surface-textured scaffold materials for tissue engineering applications.

A low-cost automated streaming potential measurement system.

Surface charge characterization is important in the design and testing of coatings and membranes for biological and industrial applications, but commercial zeta potential meters are expensive and difficult to adapt to a variety of membrane designs. We combined inexpensive off-the-shelf components, a test mount fabricated with a conventional rapid prototyping system, and software written using a no-cost integrated development environment to implement a low-cost, automated streaming potential meter. Software written in Visual C# managed a USB data acquisition and control pod to regulate the transmembrane pressure while simultaneously reading transmembrane voltages from a digital multimeter with 0.1-nV precision. The streaming potential was measured through a commercially available polyethersulfone membrane with repeatable results for transmembrane pressures between -15 and 15 kPa. The transmembrane voltages for each set of six pressures were linear, with R (2) values greater than 0.9995. The zeta potentials calculated from the measured streaming potentials are in agreement with previous results for the same commercial membrane previously reported in the literature. The material cost for the system is less than $4000.

Three-dimensional in vitro follicle growth: overview of culture models, biomaterials, design parameters and future directions.

In vitro ovarian follicle culture is a new frontier in assisted reproductive technology with tremendous potential, especially for fertility preservation. Folliculogenesis within the ovary is a complex process requiring interaction between somatic cell components and the oocyte. Conventional two-dimensional culture on tissue culture substrata impedes spherical growth and preservation of the spatial arrangements between oocyte and surrounding granulosa cells. Granulosa cell attachment and migration can leave the oocyte naked and unable to complete the maturation process. Recognition of the importance of spatial arrangements between cells has spurred research in to three-dimensional culture system. Such systems may be vital when dealing with human primordial follicles that may require as long as three months in culture. In the present work we review pertinent aspects of in vitro follicle maturation, with an emphasis on tissue-engineering solutions for maintaining the follicular unit during the culture interval. We focus primarily on presenting the various 3-dimensional culture systems that have been applied for in vitro maturation of follicle:oocyte complexes. We also try to present an overview of outcomes with various biomaterials and animal models and also the limitations of the existing systems.

A microfluidic bioreactor with integrated transepithelial electrical resistance (TEER) measurement electrodes for evaluation of renal epithelial cells.

We have developed a bilayer microfluidic system with integrated transepithelial electrical resistance (TEER) measurement electrodes to evaluate kidney epithelial cells under physiologically relevant fluid flow conditions. The bioreactor consists of apical and basolateral fluidic chambers connected via a transparent microporous membrane. The top chamber contains microfluidic channels to perfuse the apical surface of the cells. The bottom chamber acts as a reservoir for transport across the cell layer and provides support for the membrane. TEER electrodes were integrated into the device to monitor cell growth and evaluate cell-cell tight junction integrity. Immunofluorescence staining was performed within the microchannels for ZO-1 tight junction protein and acetylated α-tubulin (primary cilia) using human renal epithelial cells (HREC) and MDCK cells. HREC were stained for cytoskeletal F-actin and exhibited disassembly of cytosolic F-actin stress fibers when exposed to shear stress. TEER was monitored over time under normal culture conditions and after disruption of the tight junctions using low Ca(2+) medium. The transport rate of a fluorescently labeled tracer molecule (FITC-inulin) was measured before and after Ca(2+) switch and a decrease in TEER corresponded with a large increase in paracellular inulin transport. This bioreactor design provides an instrumented platform with physiologically meaningful flow conditions to study various epithelial cell transport processes.

Demonstration of second-harmonic IVUS feasibility with focused broadband miniature transducers.

Focused broadband miniature polyvinylidene fluoride-trifluoroethylene (PVDF TrFE) ultrasonic transducers were investigated for intravascular (IVUS) second-harmonic imaging. Modeling and experimental studies demonstrated that focused transducers, unlike conventional flat transducers, build up second harmonic peak pressures faster and stronger, leading to an increased SNR of second harmonic content within the coronary geometry. Experimental results demonstrated that focused second harmonic pressures could be controlled to occur at specific depths by controlling the f-number of the transducer. The experimental results were in good agreement with the modeled results. Experiments were conducted using three imaging modalities: fundamental 20 MHz (F20), second harmonic 40 MHz (H40), and fundamental 40 MHz (F40). The lateral resolutions for a 1-mm transducer (f-number 3.2) at F20, F40, and H40 were experimentally measured to be 162, 123, and 124 microm, respectively, which agreed well with the theoretical calculations with <<8% error. Lateral resolution was further characterized in the three modes, using a micromachined phantom consisting of fixed bars and spaces with widths ranging from 20 to 160 microm. H40 exhibited better lateral resolution, clearly displaying 40- and 60-microm bars with about 4 dB and 7 dB greater signal strength compared with F20. Ex vivo human aorta images were obtained in the second-harmonic imaging mode to show the feasibility of high resolution second-harmonic IVUS using focused transducers.

Permeability - Selectivity Analysis for Ultrafiltration: Effect of Pore Geometry.

The effects of pore size on the performance of ultrafiltration membranes are fairly well understood, but there is currently no information on the impact of pore geometry on the trade-off between the selectivity and permeability for membranes with pore size below 100 nm. Experimental data are presented for both commercial ultrafiltration membranes and for novel silicon membranes having slit-shaped nanopores of uniform size fabricated by photolithography using a sacrificial oxide technique. Data are compared with theoretical calculations based on available hydrodynamic models for solute and solvent transport through membranes composed of a parallel array of either cylindrical or slit-shaped pores. The results clearly demonstrate that membranes with slit-shaped pores have higher performance, i.e., greater selectivity at a given value of the permeability, than membranes with cylindrical pores. Theoretical calculations indicate that this improved performance becomes much less pronounced as the breadth of the pore size distribution increases. These results provide new insights into the effects of pore geometry on the performance of ultrafiltration membranes.

Design and analysis of MEMS based PVDF ultrasonic transducers for vascular imaging.

Polyvinilidene fluoride (PVDF) single-element transducers for high-frequency (>30 MHz) ultrasound imaging applications have been developed using MEMS (Micro-electro-Mechanical Systems) compatible techniques. Performance of these transducers has been investigated by analyzing the sources and effects of on-chip parasitic capacitances on the insertion-loss of the transducers. Modeling and experimental studies showed that on-chip parasitic capacitances degraded the performance of the transducers and an improved method of fabrication was suggested and new devices were built. New devices developed with minimal parasitic effects were shown to improve the performance significantly. A 1-mm aperture PVDF device developed with minimal parasitic effects has resulted in a reduction of insertion loss of 21 dB compared with devices fabricated using a previous method.

Post microtextures accelerate cell proliferation and osteogenesis.

The influence of surface microtexture on osteogenesis was investigated in vitro by examining the proliferation and differentiation characteristics of a class of adult stem cells and their progeny, collectively known as connective tissue progenitor cells (CTPs). Human bone marrow-derived CTPs were cultured for up to 60 days on smooth polydimethylsiloxane (PDMS) surfaces and on PDMS with post microtextures that were 10 microm in diameter and 6 microm in height, with 10 microm separation. DNA quantification revealed that the numbers of CTPs initially attached to both substrates were similar. However, cells on microtextured PDMS transitioned from lag phase after 4 days of culture, in contrast to 6 days for cells on smooth surfaces. By day 9 cells on the smooth surfaces exhibited arbitrary flattened shapes and migrated without any preferred orientation. In contrast, cells on the microtextured PDMS grew along the array of posts in an orthogonal manner. By days 30 and 60 cells grew and covered all surfaces with extracellular matrix. Western blot analysis revealed that the expression of integrin alpha5 was greater on the microtextured PDMS compared with smooth surfaces. Real time reverse transcription-polymerase chain reaction revealed that gene expression of alkaline phosphatase had decreased by days 30 and 60, compared with that on day 9, for both substrates. Gene expression of collagen I and osteocalcin was consistently greater on post microtextures relative to smooth surfaces at all time points.

A three-dimensional scaffold with precise micro-architecture and surface micro-textures.

A three-dimensional (3D) structure comprising precisely defined micro-architecture and surface micro-textures, designed to present specific physical cues to cells and tissues, may provide an efficient scaffold in a variety of tissue engineering and regenerative medicine applications. We report a fabrication technique based on microfabrication and soft lithography that permits for the development of 3D scaffolds with both precisely engineered architecture and tailored surface topography. The scaffold fabrication technique consists of three key steps starting with microfabrication of a mold using an epoxy-based photoresist (SU-8), followed by dual-sided molding of a single layer of polydimethylsiloxane (PDMS) using a mechanical jig for precise motion control; and finally, alignment, stacking, and adhesion of multiple PDMS layers to achieve a 3D structure. This technique was used to produce 3D Texture and 3D Smooth PDMS scaffolds, where the surface topography comprised 10 microm diameter/height posts and smooth surfaces, respectively. The potential utility of the 3D microfabricated scaffolds, and the role of surface topography, were subsequently investigated in vitro with a combined heterogeneous population of adult human stem cells and their resultant progenitor cells, collectively termed connective tissue progenitors (CTPs), under conditions promoting the osteoblastic phenotype. Examination of bone-marrow derived CTPs cultured on the 3D Texture scaffold for 9 days revealed cell growth in three dimensions and increased cell numbers compared to those on the 3D Smooth scaffold. Furthermore, expression of alkaline phosphatase mRNA was higher on the 3D Texture scaffold, while osteocalcin mRNA expression was comparable for both types of scaffolds.

High-Performance Silicon Nanopore Hemofiltration Membranes.

Silicon micromachining provides the precise control of nanoscale features that can be fundamentally enabling for miniaturized, implantable medical devices. Concerns have been raised regarding blood biocompatibility of silicon-based materials and their application to hemodialysis and hemofiltration. A high-performance ultrathin hemofiltration membrane with monodisperse slit-shaped pores was fabricated using a sacrificial oxide technique and then surface-modified with poly(ethylene glycol) (PEG). Fluid and macromolecular transport matched model predictions well. Protein adsorption, fouling, and thrombosis were significantly inhibited by the PEG. The membrane retained hydraulic permeability and molecular selectivity during a 90 hour hemofiltration experiment with anticoagulated bovine whole blood. This is the first report of successful prolonged hemofiltration with a silicon nanopore membrane. The results demonstrate feasibility of renal replacement devices based on these membranes and materials.

Modulating human connective tissue progenitor cell behavior on cellulose acetate scaffolds by surface microtextures.

Soft lithography techniques are used to fabricate cellulose acetate (CA) scaffolds with surface microtextures to observe growth characteristics of the progeny of human marrow-derived connective tissue progenitor cells (CTPs). Human CTPs were collected and cultured on CA scaffolds comprised postmicrotextures and smooth surfaces for up to 30 days. Cells on the smooth surfaces migrated without any preferred orientation for up to 30 days. On microtextures, cells tended to direct their processes toward posts and other cells on day 9. By day 30, cells on microtextures covered the surface with extracellular matrix. DNA quantification revealed approximately threefold more cells on microtextures than on the smooth surfaces. The alkaline phosphatase (AP) mRNA expression was slightly higher on smooth surfaces on day 9. However, by day 30, AP mRNA showed higher expression on microtextures. The mRNA expression of collagen type I was increased on microtextures by day 30, whereas smooth surfaces demonstrated similar expression. The osteocalcin mRNA expression was increased on postmicrotextures relative to smooth surfaces by day 30.