Marwan F. Al-Rjoub

Enhanced Heat Transfer and Thermal Dose Using Magnetic Nanoparticles During HIFU Thermal Ablation—An In-Vitro Study

Avoiding collateral damage to healthy tissues during the high intensity focused ultrasound (HIFU) ablation of malignant tumors is one of the major challenges for effective thermal therapy. Such collateral damage can originate out of the need for using higher acoustic powers to treat deep seated or highly vascularized tumors. The objective of this study is to assess the utility of using magnetic nanoparticles (mNPs) during HIFU procedures to locally enhance heating at low powers, thereby reducing the likelihood of collateral thermal damage and undesired destruction due to cavitation. Tissue phantoms with 0% (control), 1% and 3% mNPs concentrations by volume were fabricated. Each tissue phantom was embedded with four thermocouples (TCs) and sonicated using transducer acoustic powers of 5.15 W, 9.17 W, and 14.26 W. The temperature profiles during the heating and cooling periods were recorded for each embedded TC. The measured transient temperature profiles were used for thermal-dose calculations. The increase in the concentration of mNPs in the tissue phantoms, from 0% to 3%, resulted in the rise in the peak temperatures for all the TCs for each acoustic power. The thermal dose also increased with the rise in the concentration of mNPs in the tissue phantoms. For the highest applied acoustic power (14.26 W), the peak temperature at TC 1 (T1) in tissue phantoms with 1% and 3% mNPs concentrations increased (with respect to tissue phantom with 0% (control) mNPs concentration) by 1.59 and 2.09 , respectively. For an acoustic power of 14.26 W, the time required to achieve cellular necrosis as defined by a 240 equivalent min thermal dose was approximately 75 s in the absence of mNPs, 14 s for the 1% concentration, and 8 s for the 3% concentration. Magnetic nanoparticles have the potential to significantly reduce the time for HIFU thermal-ablation procedures. They can also decrease the likelihood of collateral damage by the propagating beam in HIFU procedures by reducing the intensity required to achieve cellular necrosis. [DOI: 10.1115/1.4027340]

New techniques for determining the longitudinal effects of local hemodynamics on the intima-media thickness in arteriovenous fistulae in an animal model.

Remodeling in the arteriovenous fistulas (AVFs) is believed to be a hemodynamic‐driven process, which results in extreme changes in the diameter and intima‐media thickening (IMT) of vessels over time. This study aims to describe the successful development of techniques that enabled correlation of changes in local and longitudinal wall shear stress (WSS) with the temporal variations of the diameter and IMT in the venous segment of AVFs. An AVF was created between the femoral artery and vein of a 50‐kg pig. We have previously shown the successful use of CT‐scan and ultrasound techniques for anatomical and flow measurements in AVFs, respectively. In this study, we developed new techniques involving markers (both in vivo and ex vivo), casting (ex vivo), and micro‐MRI (ex vivo; 7 Tesla). A radiopaque marker (ROM) was sutured to the AVF at the day of surgery, which was visible in the CT‐scan images, micro‐MRI, and histology sections. Therefore, ROM served as a fixed local reference for both in vivo and ex vivo states of AVFs. Immediately after sacrificing the pig, a procedure was developed to create a cast from the AVF and thus, maintaining the in vivo state of the AVF during the histology process. Then, micro‐MRI and histology techniques were conducted on the AVF to measure IMT in the vein. Along the ROM, the local changes in WSS levels for two cross‐sections were tracked at 2D (D: days) and 28D post surgery. WSS levels reduced from 2D to 28D for both cross‐sections. Also, the recirculation zones, which formed at 2D for both sections, became smaller in size at 28D. These hemodynamic changes were then mapped onto the corresponding IMT measurements from histology and micro‐MRI. It was observed that the recirculation zones at 2D and 28D corresponded to the largest IMT in the two sections. In summary, the new methodologies allowed us to define a fixed local reference at all time points in the AVF, which enabled accurate tracking of local changes in hemodynamics (WSS), configuration (diameter), and structure (IMT) of the venous segment over time. This also empowered study of the interactions between these parameters, which could improve our understanding about the hemodynamic‐driven remodeling in AVFs. From a clinical point of view, this information could be translated into local and early therapeutic interventions for dialysis patients.

Influence of Variable Native Arterial Diameter and Vasculature Status on Coronary Diagnostic Parameters

In current practice, diagnostic parameters, such as fractional flow reserve (FFR) and coronary flow reserve (CFR), are used to determine the severity of a coronary artery stenosis. FFR is defined as the ratio of hyperemic pressures distal (p(rh)) and proximal (p(ah)) to a stenosis. CFR is the ratio of flow at hyperemic and basal condition. Another diagnostic parameter suggested by our group is the pressure drop coefficient (CDP). CDP is defined as the ratio of the pressure drop across the stenosis to the upstream dynamic pressure. These parameters are evaluated by invasively measuring flow (CFR), pressure (FFR), or both (CDP) in a diseased artery using guidewire tipped with a sensor. Pathologic state of artery is indicated by lower CFR (<2). Similarly, FFR lower than 0.75 leads to clinical intervention. Cutoff for CDP is under investigation. Diameter and vascular condition influence both flow and pressure drop, and thus, their effect on FFR and CDP was studied. In vitro experiment coupled with pressure-flow relationships from human clinical data was used to simulate pathophysiologic conditions in two representative arterial diameters, 2.5 mm (N1) and 3 mm (N2). With a 0.014 in. (0.35 mm) guidewire inserted, diagnostic parameters were evaluated for mild (∼64% area stenosis (AS)), intermediate (∼80% AS), and severe (∼90% AS) stenosis for both N1 and N2 arteries, and between two conditions, with and without myocardial infarction (MI). Arterial diameter did not influence FFR for clinically relevant cases of mild and intermediate stenosis (difference < 5%). Stenosis severity was underestimated due to higher FFR (mild: ∼9%, intermediate: ∼ 20%, severe: ∼ 30%) for MI condition because of lower pressure drops, and this may affect clinical decision making. CDP varied with diameter (mild: ∼20%, intermediate: ∼24%, severe: by 2.5 times), and vascular condition (mild: ∼35%, intermediate: ∼14%, severe: ∼ 9%). However, nonoverlapping range of CDP allowed better delineation of stenosis severities irrespective of diameter and vascular condition.

Improved Flow Rate in Electro-Osmotic Micropumps for Combinations of Substrates and Different Liquids With and Without Nanoparticles

A new design for an electro-osmotic flow (EOF) driven micropump was fabricated. Considering thermal management applications, three different types of micropumps were tested using multiple liquids. The micropumps were fabricated from a combination of materials, which included: silicon-polydimethylsiloxane (Si-PDMS), Glass-PDMS, or PDMS-PDMS. The flow rates of the micropumps were experimentally and numerically assessed. Different combinations of materials and liquids resulted in variable values of zeta-potential. The ranges of zeta-potential for Si-PDMS, Glass-PDMS, and PDMS-PDMS were −42.5–−50.7 mV, −76.0–−88.2 mV, and −76.0–−103.0 mV, respectively. The flow rates of the micropumps were proportional to their zeta-potential values. In particular, flow rate values were found to be linearly proportional to the applied voltages below 500 V. A maximum flow rate of 75.9 μL/min was achieved for the Glass-PDMS micropump at 1 kV. At higher voltages nonlinearity and reduction in flow rate occurred due to Joule heating and the axial electro-osmotic current leakage through the silicon substrate. The fabricated micropumps could deliver flow rates, which were orders of magnitude higher compared to the previously reported values for similar size micropumps. It is expected that such an increase in flow rate, particularly in the case of the Si-PDMS micropump, would lead to enhanced heat transfer for microchip cooling applications as well as for applications involving micrototal analysis systems (μTAS).

ENHANCED ELECTRO-OSMOTIC FLOW PUMP FOR MICRO-SCALE HEAT EXCHANGERS

Non-uniform heat flux generated by microchips can create “hot spots” in localized areas on the microchip surface. This research presents an improved design of an active cooling electro-osmotic flow (EOF) based micro-pump for hot spots thermal management. The design of the micro-pump was simpler and more practical for the application compared to designs presented in literature.Most micro-channel heat sink devices presented in literature were silicon based. Though silicon has better thermal conductivity when compared to polymers used in micro-devices fabrication, processes of silicon fabrication are complicated and time consuming. Also, most micro-channel fabrication processes use silicon etching which leads to rough walls within the micro-channel. An improved design, which uses a combination of silicon and Polydimethylsiloxane (PDMS), is being developed and tested. The main idea of this design is to utilize the favorable thermal properties of silicon while achieving both smoother charged surfaces and ease of fabrication of PDMS material.The EOF micro-pump was tested for four cooling fluid namely, DI water, distilled water, borax buffer, and Al2O3 nano-particles suspended in water solution. A maximum flow rate of 31.2 μL/min was achieved using distilled water at 500 V of EOF voltage. Such micro-pump with this flow rate range can be implemented in a closed loop heat rejection system for hot spot thermal management. Moreover, it can be used in Lap-on-chip and uTAS application for sample transport.© 2012 ASME

Improved design and characterization of PLGA/PLA-coated Chitosan based micro-implants for controlled release of hydrophilic drugs

Graphical abstract Figure. No caption available. ABSTRACT Repetitive intravitreal injections of Methotrexate (MTX), a hydrophilic chemotherapeutic drug, are currently used to treat selected vitreoretinal (VR) diseases, such as intraocular lymphoma. To avoid complications associated with the rapid release of MTX from the injections, a Polylactic acid (PLA) and Chitosan (CS)‐based MTX micro‐implant prototype was fabricated in an earlier study, which showed a sustained therapeutic release rate of 0.2–2.0 &mgr;g/day of MTX for a period ˜1 month in vitro and in vivo. In the current study, different combinations of Poly(lactic‐co‐glycolic) acid (PLGA)/PLA coatings were used for lipophilic surface modification of the CS‐MTX micro‐implant, such as PLGA 5050, PLGA 6535 and PLGA 7525 (PLA: PGA – 50:50, 65:35, 75:25, respectively; M.W: 54,400 – 103,000) and different PLA, such as PLA 100 and PLA 250 (MW: 102,000 and 257,000, respectively). This improved the duration of total MTX release from the coated CS‐MTX micro‐implants to ˜3–5 months. With an increase in PLA content in PLGA and molecular weight of PLA, a) the initial burst of MTX and the mean release rate of MTX can be reduced; and b) the swelling and biodegradation of the micro‐implants can be delayed. The controlled drug release mechanism is caused by a combination of diffusion process and hydrolysis of the polymer coating, which can be modulated by a) PLA content in PLGA and b) molecular weight of PLA, as inferred from Korsmeyer Peppas model, Zero order, First order and Higuchi model fits. This improved micro‐implant formulation has the potential to serve as a platform for controlled release of hydrophilic drugs to treat selected VR diseases.

Efficient capture of magnetic microbeads by sequentially switched electroosmotic flow—an experimental study

Magnetophoretic separation is a commonly used immunoassay technique in microfluidic platforms where magnetic microbeads (mMBs) coated with specific epitopes (antibodies) entrap target pathogens by antigen-antibody kinetics. The mMB-cell complexes are then separated from the continuous flow using an external magnetic field. The goal of this study was to design and test a microfluidic device for efficient separation of fluorescence-tagged mMBs driven by electroosmotic flow (EOF) under steady (time invariant) and switched (time varying) electric field conditions. The EOF was driven at electric fields of 100–180 V cm−1. The mMBs were captured by a neodymium (NdFeB) permanent earth magnet. The capture efficiency (η c) of these mMBs was improved by sequential switching of the applied electric field driven-EOF. The fluorescent images of the captured mMBs, obtained using an inverted epifluorescence microscope, were quantified using image processing tools. In steady EOF, induced by constant electric field, the number of captured mMBs decreased by 72.3% when the electric field was increased from 100 V cm−1 to 180 V cm−1. However, alternating the direction of flow through sequential switching of EOF increased the η c by bringing the escaped mMBs back to the capture zone and increasing their residence time in the area of higher magnetic fields. The average increase in η c was 54.3% for an mMB concentration of 1 × 106 beads ml−1 (C 1) and 41.6% for a concentration of 2 × 106 beads ml−1 (C 2). These improvements were particularly significant at higher electric fields where the η c with switching was, on average, ~70% more compared to flow without switching. The technique of sequential switching demonstrates an efficient method for capture of mMBs for application in magnetophoretic immunoassay.

Capture of Magnetic Microspheres in Electrokinetic Flow for Application in Lab-on-Chip Devices

Isolation of bio-molecules, cells and pathogens for immunoassays is a critical component in micro total analysis systems (μTAS). Magnetophoretic technique is often used for separation of such target species, where magnetic beads tagged with specific antibodies against cell surface epitopes, are captured in the microfluidic device. In this study, a numerical model is developed for capture of beads under an external magnetic field in electrokinetically driven flow. The results indicate an increase in the number of beads captured when the magnetic field is higher and the flow is driven by lower electric fields.Copyright

Enhanced Capture of Magnetic Microbeads Using Combination of Reduced Magnetic Field Strength and Sequentially Switched Electroosmotic Flow—A Numerical Study

Magnetophoretic immunoassay is a widely used technique in lab-on-chip systems for detection and isolation of target cells, pathogens, and biomolecules. In this method, target pathogens (antigens) bind to specific antibodies coated on magnetic microbeads (mMBs) which are then separated using an external magnetic field for further analysis. Better capture of mMB is important for improving the sensitivity and performance of magnetophoretic assay. The objective of this study was to develop a numerical model of magnetophoretic separation in electroosmotic flow (EOF) using magnetic field generated by a miniaturized magnet and to evaluate the capture efficiency (CE) of the mMBs. A finite-volume solver was used to compute the trajectory of mMBs under the coupled effects of EOF and external magnetic field. The effect of steady and time varying (switching) electric fields (150-450 V/cm) on the CE was studied under reduced magnetic field strength. During switching, the electric potential at the inlet and outlet of the microchannel was reversed or switched, causing reversal in flow direction. The CE was a function of the momentum of the mMB in EOF and the applied magnetic field strength. By switching the electric field, CE increased from 75% (for steady electric field) to 95% for lower electric fields (150-200 V/cm) and from 35% to 47.5% for higher electric fields (400-450 V/cm). The CE was lower at higher EOF electric fields because the momentum of the mMB overcame the external magnetic force. Switching allowed improved CE due to the reversal and decrease in EOF velocity and increase in mMB residence time under the reduced magnetic field strength. These improvements in CE, particularly at higher electric fields, made sequential switching of EOF an efficient separation technique of mMBs for use in high throughput magnetophoretic immunoassay devices. The reduced size of the magnet, along with the efficient mMB separation technique of switching can lead to the development of portable device for detection of target cells, pathogens, and biomolecules.

Influence of Variable Native Arterial Diameter on Fractional Flow Reserve: An In-Vitro Study

Fractional flow reserve (FFR), the ratio of the pressures distal (Pd) and proximal (Pa) to a stenosis, and coronary flow reserve (CFR), the ratio of flows at maximal vasodilation to the resting condition, are widely used for determining the functional severity of a coronary artery stenosis. However, the diameter of the native artery might influence the FFR values. Therefore, using an in-vitro experimental study, we tested the variation of FFR for two arterial diameters, 2.5 mm (N1) and 3 mm (N2). We hypothesize that FFR is not influenced by native arterial diameter. For both N1 and N2, vasodilation-distal perfusion pressure (CFR-Prh) curves were obtained using a 0.35 mm guidewire by simulating physiologic flows under different blockage conditions: mild (64% area stenosis (AS)), intermediate (80% AS) and severe (90% AS). The FFR values for the two arterial models differed insignificantly, within 3%, for mild and intermediate stenoses but differed appreciably for severe stenosis (~25%). This significant difference in FFR values for severe stenosis can be attributed to relatively larger difference in guidewire obstruction effect at the stenotic throat region of the two native arterial models. These findings confirm that FFR will not differ for the clinically relevant cases of mild and intermediate stenosis for different arterial diameters.