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.

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.

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.

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 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.