Scaling a Hydraulic Motor for Minimally Invasive Medical Devices.

Aligned with the medical device industry's trend of miniaturization, academic and commercial researchers are constantly attempting to reduce device sizes. Many applications require miniature actuators (2 mm range) to perform mechanical work; however, biocompatible micromotors are not readily available. To that end, a hydraulic motor-driven cutting module that aims to combine cutting and drug delivery is presented. The hydraulic motor prototype developed has an outside diameter (OD) of ~4 mm (twice the target size) and a 1 mm drive shaft to attach a cutter. Four different designs were explored and fabricated using additive manufacturing. The benchtop experimental data of the prototypes are presented herein. For the prototype motor with fluid inlet perpendicular to the blades, the average angular velocity was 10,593 RPM at a flowrate of 3.6 mL/s and 42,597 RPM at 10.1 mL/s. This design was numerically modeled using 3D-transient simulations in ANSYS CFX (version 2022 R2) to determine the performance characteristics and the internal resistance of the motor. Simplified mathematical models were also used to compute and compare the peak torque with the simulation estimates. The viability of current design represents a crucial milestone in scaling the hydraulic motor to a 2 mm OD to power a microcutter.

Design and Modeling of a Miniature Hydraulic Motor for Powering a Cutting Tool for Minimally Invasive Procedures.

Miniaturization of multifunctional instruments is key to evolving less invasive medical procedures. The current work outlines steps towards developing a miniature motor to power a cutting tool of a millimeter-scale robot/device (target outside diameter ~2 mm) for minimally invasive procedures. Multiple motor concepts were explored and ranked using a Pugh matrix. The single-rotor hydraulic design was deemed most viable for prototyping and scale-down to the target size. Prototypes were manufactured to be progressively smaller using additive manufacturing. The smallest prototype fabricated was 2:1 scale of the desired final size with a 2 mm outside diameter (OD) rotor and a device OD of 4 mm. The scaled prototypes with an 8 mm rotor were lab tested and achieved average speeds of 5000-6000 RPM at a flowrate of 15-18 mL/s and 45 PSI water pressure. Ansys CFX was used as a design tool to explore the parameter space and 3D transient simulations were implemented using the immersed solid method. The predicted rotor RPM from the modeling matched the experimental values within 3% error. The model was then used to develop performance curves for the miniature hydraulic motor. In summary, the single-rotor hydraulic design shows promise for miniaturization to the target 2 mm size.

A Spray-On Carbon Nanotube Artificial Neuron Strain Sensor for Composite Structural Health Monitoring.

We present a nanocomposite strain sensor (NCSS) to develop a novel structural health monitoring (SHM) sensor that can be easily installed in a composite structure. An NCSS made of a multi-walled carbon nanotubes (MWCNT)/epoxy composite was installed on a target structure with facile processing. We attempted to evaluate the NCSS sensing characteristics and benchmark compared to those of a conventional foil strain gauge. The response of the NCSS was fairly good and the result was nearly identical to the strain gauge. A neuron, which is a biomimetic long continuous NCSS, was also developed, and its vibration response was investigated for structural damage detection of a composite cantilever. The vibration response for damage detection was measured by tracking the first natural frequency, which demonstrated good result that matched the finite element (FE) analysis.

Discovery of a Novel 2,6-Disubstituted Glucosamine Series of Potent and Selective Hexokinase 2 Inhibitors.

A novel series of potent and selective hexokinase 2 (HK2) inhibitors, 2,6-disubstituted glucosamines, has been identified based on HTS hits, exemplified by compound 1. Inhibitor-bound crystal structures revealed that the HK2 enzyme could adopt an "induced-fit" conformation. The SAR study led to the identification of potent HK2 inhibitors, such as compound 34 with greater than 100-fold selectivity over HK1. Compound 25 inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line via (13)CNMR measurement of [3-(13)C]lactate produced from [1,6-(13)C2]glucose added to the cell culture.

Polymer Coating of Carbon Nanotube Fibers for Electric Microcables.

Carbon nanotubes (CNTs) are considered the most promising candidates to replace Cu and Al in a large number of electrical, mechanical and thermal applications. Although most CNT industrial applications require macro and micro size CNT fiber assemblies, several techniques to make conducting CNT fibers, threads, yarns and ropes have been reported to this day, and improvement of their electrical and mechanical conductivity continues. Some electrical applications of these CNT conducting fibers require an insulating layer for electrical insulation and protection against mechanical tearing. Ideally, a flexible insulator such as hydrogenated nitrile butadiene rubber (HNBR) on the CNT fiber can allow fabrication of CNT coils that can be assembled into lightweight, corrosion resistant electrical motors and transformers. HNBR is a largely used commercial polymer that unlike other cable-coating polymers such as polyvinyl chloride (PVC), it provides unique continuous and uniform coating on the CNT fibers. The polymer coated/insulated CNT fibers have a 26.54 µm average diameter-which is approximately four times the diameter of a red blood cell-is produced by a simple dip-coating process. Our results confirm that HNBR in solution creates a few microns uniform insulation and mechanical protection over a CNT fiber that is used as the electrically conducting core.

Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors.

A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.

Rational Design, Synthesis, and SAR of a Novel Thiazolopyrimidinone Series of Selective PI3K-beta Inhibitors.

A novel thiazolopyrimidinone series of PI3K-beta selective inhibitors has been identified. This chemotype has provided an excellent tool compound, 18, that showed potent growth inhibition in the PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage-independent conditions, and it also demonstrated pharmacodynamic effects and efficacy in a PTEN-deficient prostate cancer PC-3 xenograft mouse model.

The characterization of a novel V1b antagonist lead series.

The SAR around a V1b antagonist HTS hit 3 was explored to produce a series of thiazole sulfonamides as a lead series with selectivity over the related V1 and oxytocin receptors.

Self-aligned nanogaps on multilayer electrodes for fluidic and magnetic assembly of carbon nanotubes.

A self-aligned nanogap between multiple metal layers has been developed using a new controlled undercut and metallization technique (CUMT), and practically applied for self-assembly of individual carbon nanotubes (CNTs) over the developed nanogap. This new method allows conventional optical lithography to fabricate nanogap electrodes and self-aligned patterns with nanoscale precision. The self-aligned nickel (Ni) pattern on the nanogap electrode works as an assembly spot where the residual iron (Fe) catalyst at the end of the CNT is magnetically captured. The captured CNT is forced to be aligned parallel to the flow direction by fluidic shear force. The combined forces of magnetic attraction and fluidic alignment provide massive self-assembly of CNTs at target positions. Both multiwalled nanotubes (MWNTs) and single walled nanotubes (SWNTs) were successfully assembled over the nanogap electrodes, and their electrical characteristics were fully characterized. The CNTs self-assembled on the developed electrodes with a nanogap and showed a very reliable and reproducible current-voltage (I-V) characteristic. The method developed in this work can envisage the mass fabrication of individual CNT-assembled devices which can be applied to nanoelectronic devices or nanobiosensors.

Development of an electrode cell impedance method to measure osteoblast cell activity in magnesium-conditioned media.

Magnesium (Mg) as a biodegradable metal has potential advantages as an implant material. This paper studies the effect of magnesium ions on osteoblast (U2-OS) behavior since magnesium implants mainly dissolve as divalent magnesium ions (Mg(2+)). A real-time monitoring technique based on electric cell-substrate impedance sensing (ECIS) was used for measuring cell proliferation, migration, adhesion, and cytotoxicity in magnesium-conditioned media. The impedance results show that U2-OS proliferation and adhesion were inhibited in not only a magnesium-free medium but also in a medium with a high concentration of magnesium. The impedance method produced more sensitive results than the output of an MTT assay. Other standard bioanalytical tests were conducted for comparison with the ECIS method. Immunochemistry was carried out to study cell adhesion in magnesium-conditioned media by staining using F-actin and alpha-tubulin and correlated cell density on the electrode with impedance. Bone tissue formation was studied using von Kossa staining and indicated the mineralization level of cells in magnesium-conditioned media decreased with the increase of magnesium ion concentration. Real-time PCR provided gene expression indicators of cell growth, apoptosis, inflammation, and migration. Compared to the bioanalytical methods of immunochemistry and MTT assays, which need preparation time and post-washing step, ECIS was able to measure cell activity in real time without any cell culture modification. In summary, ECIS might be an effective way to study biodegradable magnesium implants.

Carbon nanotube composites multi-sensing characteristics based on electrical impedance properties.

CNT composites demonstrate sensory materials properties such as piezoresistivity, chemical and bio selectivity and they can detect structural deterioration, chemical contamination and bio signal by means of their impedance measurement (resistance and capacitance). In this study, electrical impedance characteristics of CNT composite electrodes are studied to simultaneously detect mechanical and chemical symptoms in engineering applications. We measured variations of electrical resistance and capacitance values of CNT composite electrodes under static load for mechanical sensing behavior and under the change of buffer solution amount for chemical sensing behavior. At the mechanical sensing behavior test, the resistance values changed quite linearly under bending and compression loads while the capacitance value varied within small range with invalid relationship to the loads. At the chemical sensing behavior investigation, the electrode's capacitance showed drastic change while the resistance value only changed within few percent range. The independently changing pattern of electrical impedance parameters according to mechanical strain and chemical effect can provide new opportunities to design a novel multifunctional sensor that can simultaneously monitor mechanical and chemical behaviors of a target system.

The precise self-assembly of individual carbon nanotubes using magnetic capturing and fluidic alignment.

A new method for the self-assembly of a carbon nanotube (CNT) using magnetic capturing and fluidic alignment has been developed and characterized in this work. In this new method, the residual iron (Fe) catalyst positioned at one end of the CNT was utilized as a self-assembly driver to attract and position the CNT, while the assembled CNT was aligned by the shear force induced from the fluid flow through the assembly channel. The self-assembly procedures were successfully developed and the electrical properties of the assembled multi-walled carbon nanotube (MWNT) and single-walled carbon nanotube (SWNT) were fully characterized. The new assembly method developed in this work shows its feasibility for the precise self-assembly of parallel CNTs for electronic devices and nanobiosensors.

Triazinediones as prokineticin 1 receptor antagonists. Part 1: SAR, synthesis and biological evaluation.

A series of guanidine triazinediones were identified as potent PK1 receptor antagonists. A compound in this series inhibited the PK1 invoked prosecretory response in rat ileum tissue.

Tiny medicine: nanomaterial-based biosensors.

Tiny medicine refers to the development of small easy to use devices that can help in the early diagnosis and treatment of disease. Early diagnosis is the key to successfully treating many diseases. Nanomaterial-based biosensors utilize the unique properties of biological and physical nanomaterials to recognize a target molecule and effect transduction of an electronic signal. In general, the advantages of nanomaterial-based biosensors are fast response, small size, high sensitivity, and portability compared to existing large electrodes and sensors. Systems integration is the core technology that enables tiny medicine. Integration of nanomaterials, microfluidics, automatic samplers, and transduction devices on a single chip provides many advantages for point of care devices such as biosensors. Biosensors are also being used as new analytical tools to study medicine. Thus this paper reviews how nanomaterials can be used to build biosensors and how these biosensors can help now and in the future to detect disease and monitor therapies.

A label-free electronic biosensor for detection of bone turnover markers.

This paper describes the development of a biosensor based on label-free immunosensing for the detection of the C-terminal telopeptide bone turnover marker from type-1 collagen. A self-assembled monolayer (SAM) of dithiodipropionic acid was deposited on a gold electrode. Then streptavidin and biotinylated anti-human C-terminal telopeptide antibody were successively conjugated on the self-assembled monolayer. Electrochemical impedance measurements were made to characterize each step of the SAM/streptavidin/biotinylated antibody binding. Subsequently, electrochemical impedance was measured with different concentrations of C-teminal telopeptide. A detection limit of 50 ng/mL and a dynamic range up to 3 µg/mL were achieved. To our knowledge, this is the first attempt to develop a label-free immunosensor based on electrochemical impedance with DC bias for detection of bone-related degradation and rebuilding products. The electronic biosensor might eventually be used for quantitative point-of-care screening of bone health. It is hoped that analysis of bone turnover markers can indicate the beginning of bone diseases such as osteoarthritis and osteoporosis so that treatment might start early when it is most effective.

The bulk piezoresistive characteristics of carbon nanotube composites for strain sensing of structures.

The bulk piezoresistivity of carbon nanotube (CNT) in polymer matrix was discussed to develop a strain sensor for engineering applications. The polymer improves interfacial bonding between the nanotubes and the CNT composite and that enhances the strain transfer, repeatability, and linearity of the sensor. The largest contribution of piezoresistivity of the sensor may come from slippage of overlaying or bundled nanotubes in the matrix, from a macroscopic point of view. Nano interfaces of CNTs in a matrix polymer also contribute to the linear strain response compared to other micro size carbon filler. The strain sensor had a low bandwidth and adequate strain sensitivity. The nanocomposite strain sensor is particularly useful for detecting large strains which can monitor strain and stress on a structure with simple electric circuit for strain monitoring of structures.

A carbon nanotube needle biosensor.

A carbon nanotube needle biosensor was developed to provide fast, cost effective and highly sensitive electrochemical detection of biomolecules. The sensor was fabricated based on an array of aligned multi-wall carbon nanotubes synthesized by chemical vapor deposition. A bundle of nanotubes in the array was welded onto the tip of a tungsten needle under a microscope. The needle was then encased in glass and a polymer coating leaving only the tip of the needle exposed. Cyclic voltammetry was performed to examine the redox behavior of the nanotube needle. The cyclic voltammetry results showed a steady-state response attributable to radial diffusion with a high steady-state current density. An amperometric sensor was then developed for glucose detection by physically attaching glucose oxidase on the nanotube needle. The amperometric response of these nanotube needles showed a high sensitivity with a low detection limit. It is expected that the nanotube needle can be sharpened to increase the sensitivity to the point where the current is almost too small to measure. The simple manufacturing method should allow commodity level production of highly sensitive electronic biosensors.

Carbon nanotubes grown on stainless steel to form plate and probe electrodes for chemical/biological sensing.

This paper describes the fabrication and evaluation of carbon nanotube (CNT) electrodes grown on stainless steel (SS) plate and wire for electrochemical sensor applications. Multi-wall carbon nanotubes with different diameters were grown on the SS plate and wire by chemical vapor deposition from an ethylene precursor. The SS provides a good electrical and mechanical connection to the CNT, and the SS is a tough substrate. The SS part of the electrode was electrically insulated from the analyte so that only the CNT were active in sensing. Cyclic voltammetry for the reduction of 6 mM K3Fe(CN)6 in a 1.0 M KNO3 supporting electrolyte was performed to examine the redox behavior of the CNT-SS electrode. The cyclic voltammograms showed sigmoidal-like shapes, indicating that mass transport around the electrodes is dominated by radial diffusion. Based on the cyclic voltammograms, the effective area of the CNT-SS electrodes and the number of individual CNTs were estimated. These results indicate that the CNT-SS plate and wire electrodes are good candidates to develop practical in vivo biosensors.

Electrochemical impedance measurement of prostate cancer cells using carbon nanotube array electrodes in a microfluidic channel.

Highly aligned multi-wall carbon nanotubes were synthesized in the shape of towers and embedded into fluidic channels as electrodes for impedance measurement of LNCaP human prostate cancer cells. Tower electrodes up to 8 mm high were grown and easily peeled off a silicon substrate. The nanotube electrodes were then successfully soldered onto patterned printed circuit boards and cast into epoxy under pressure. After polishing the top of the tower electrodes, RF plasma was used to enhance the electrocatalytic effect by removing excess epoxy and activating the open end of the nanotubes. Electrodeposition of Au particles on the plasma-treated tower electrodes was done at a controlled density. Finally, the nanotube electrodes were embedded into a polydimethylsiloxane (PDMS) channel and electrochemical impedance spectroscopy was carried out with different conditions. Preliminary electrochemical impedance spectroscopy results using deionized water, buffer solution, and LNCaP prostate cancer cells showed that nanotube electrodes can distinguish the different solutions and could be used in future cell-based biosensor development.

Growth mechanism of long aligned multiwall carbon nanotube arrays by water-assisted chemical vapor deposition.

Highly aligned arrays of multiwalled carbon nanotube (MWCNT) on layered Si substrates have been synthesized by chemical vapor deposition (CVD). The effect of the substrate design and the process parameters on the growth mechanism were studied. Adding water vapor to the reaction gas mixture of hydrogen and ethylene enhanced the growth which led to synthesis of longer CNT arrays with high density. Environmental scanning electron microscopy (ESEM), energy-dispersive spectroscopy (EDS), and atomic force microscopy (AFM) were used to analyze the CNT morphology and composition. Quadrupole mass spectroscopy (QMS) provided in-situ information on the gas spices within the reaction zone. On the basis of results, we verified the top growth mechanism and evaluated the reason of decline and stoppage of the CNT growth after extended period of deposition. Multilayered Si substrates with a top film of Al2O3, having appropriate roughness, provide favorable conditions to form catalyst islands with uniform distribution and size. Using water-assisted CVD process and optimized substrate design, our group succeeded to grow vertically aligned, patterned MWCNT up to 4-mm long. The arrays were of high purity and weak adhesion which allowed to be peeled off easily from the substrate.