A Multi-Functional CMOS Biosensor Array With On-Chip DEP-Assisted Sensing for Rapid Low-Concentration Analyte Detection and Close-Loop Particle Manipulation With No External Electrodes.

This article presents a fully-integrated dielectrophoresis (DEP)-assisted multi-functional CMOS biosensor array chip with 4096 working electrodes (WEs), 12288 photodiodes (PDs), reference electrodes (REs), and counter electrodes (CEs), while each WE and photodiode can be reconfigured to support on-chip DEP actuation, electrochemical potentiostat, optical shadow imaging, and complex impedance sensing. The proposed CMOS biosensor is an example of an actuation-assisted label-free biosensor for the rapid sensing of low-concentration analytes. The DEP actuator of the proposed CMOS biosensor does not require any external electrode. Instead, on-chip WE pairs can be re-used for DEP actuation to simplify the sensor array design. The CMOS biosensor is implemented in a standard 130-nm BiCMOS process. Theoretical analyses and finite element method (FEM) simulations of the on-chip DEP operations are conducted as proof of concept. Biological assay measurements (DEP actuation/electrochemical potentiostat/impedance sensing) with E.coli bacteria and microbeads (optical shadow imaging) demonstrate rapid detection of low-concentration analytes and simultaneous manipulation and detection of large particles. The on-chip DEP operations draw the analytes closer to the sensor electrode surface, which overcomes the diffusion limit and accelerates low-concentration analyte sensing. Moreover, the DEP-based movement of large particles can be readily detected by on-chip photodiode arrays to achieve close-loop manipulation and sensing of particles and droplets. These show the unique advantages of the DEP-assisted multi-functional biosensor.

ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

A Multimodal and Multifunctional CMOS Cellular Interfacing Array for Digital Physiology and Pathology Featuring an Ultra Dense Pixel Array and Reconfigurable Sampling Rate.

The article presents a fully integrated multimodal and multifunctional CMOS biosensing/actuating array chip and system for multi-dimensional cellular/tissue characterization. The CMOS chip supports up to 1,568 simultaneous parallel readout channels across 21,952 individually addressable multimodal pixels with 13 µm × 13 µm 2-D pixel pitch along with 1,568 Pt reference electrodes. These features allow the CMOS array chip to perform multimodal physiological measurements on living cell/tissue samples with both high throughput and single-cell resolution. Each pixel supports three sensing and one actuating modalities, each reconfigurable for different functionalities, in the form of full array (FA) or fast scan (FS) voltage recording schemes, bright/dim optical detection, 2-/4-point impedance sensing (ZS), and biphasic current stimulation (BCS) with adjustable stimulation area for single-cell or tissue-level stimulation. Each multi-modal pixel contains an 8.84 µm × 11 µm Pt electrode, 4.16 µm × 7.2 µm photodiode (PD), and in-pixel circuits for PD measurements and pixel selection. The chip is fabricated in a standard 130nm BiCMOS process as a proof of concept. The on-chip electrodes are constructed by unique design and in-house post-CMOS fabrication processes, including a critical Al shorting of all pixels during fabrication and Al etching after fabrication that ensures a high-yield planar electrode array on CMOS with high biocompatibility and long-term measurement reliability. For demonstration, extensive biological testing is performed with human and mouse progenitor cells, in which multidimensional biophysiological data are acquired for comprehensive cellular characterization.

Effect of ß-resin of binderless coke on mechanical properties of high-density carbon blocks at high molding pressure.

High-density carbon blocks have excellent mechanical, thermal, and electrical properties. In particular, these blocks are applied in various fields while maintaining excellent physical properties even in harsh environments. In this study, binderless coke manufactured under certain conditions was used to form green bodies (GBs) under various pressure conditions of 50 to 250 MPa, and the bodies were carbonized to form a high-density carbon block (CB). Then, the effect of the ß-resin and oxygen functional groups of binderless coke on the mechanical properties of the high-density carbon block according to molding pressure was considered. When molding at a pressure of under 200 MPa, the ratio of O and C (O/C) has a greater effect, and the larger the O/C, the higher the mechanical properties. On the other hand, when molding at a high pressure of 250 MPa, the ß-resin content has a greater effect and steadily increases when the ß-resin content is low and when the mechanical properties are sufficiently reduced. In particular, in the case of CB-N7A3-250, which has the highest ß-resin content of 3.7 wt%, the density was 1.79 g/cm3, the flexural strength was 106 MPa, and the shore hardness was 99 HSD.

Preparation of Isotropic Carbon Fibers from Kerosene-Purified Coal Tar Pitch by Co-Carbonization with Pyrolysis Fuel Oil.

An inexpensive and general-purpose carbon fiber was prepared using coal tar pitch. In contrast to the solvent extraction process employing expensive solvents, a low-cost centrifugal separation method facilitated the reduction of loss due to the pitch purification and an overall yield increase. The coal tar pitch purified by centrifugation and subsequently co-carbonized with pyrolysis fuel oil improved in spinnability. Moreover, the resulting spinnable pitch had a softening point of 250 °C. The obtained carbon fibers were heat-treated at 1000 °C for 5 min, resulting in a tensile strength of approximately 1000 MPa and an average diameter of 9 µm. In this study, we present an effective method for obtaining low-cost general-purpose isotropic carbon fibers.

The Effect of Oxygen Content in Binderless Cokes for High-Density Carbon Blocks from Coal Tar Pitch.

High-density carbon blocks are much lighter than metals and have excellent mechanical properties and are one of the materials garnering attention to replace existing metal parts. In this study, a binderless coke was produced by changing the flow rates of nitrogen and air as a carrier gas during heat treatment of coal tar pitch and using this, a green body was formed at 150 MPa and carbonized to produce a high-density carbon block. We express the binderless coke produced in this way by N10A0, N7A3, N5A5, N3A7, N0A10 according to the ratio of nitrogen and air, and in the case of carbon block, we have added CB in front of it. We then considered the effect of oxygen content in the binderless cokes on the optical, chemical, and mechanical properties. It was observed that the produced binderless cokes develop into a dense mosaic structure with a small particle size as the air flow rate increased. To survey the change in oxygen content of the produced binderless coke, O1s and C1s regions were measured using X-ray photoelectric spectroscopy (XPS), and O1s/C1s was calculated. The O1s/C1s ratio steadily increased as the air flow rate increased, and in the case of N0A10, it increased about twice as much as that of N10A0 to 11.20%. ß-resin has a very large effect on the mechanical strength of the carbon block in addition to air in the pitch. And in the case of CB-N0A10, it shows the best mechanical strength with a density of 1.72 g/cm3, bending strength of 87 MPa, and shore hardness of 93 HSD.

A CMOS Multi-Modal Electrochemical and Impedance Cellular Sensing Array for Massively Paralleled Exoelectrogen Screening.

The paper presents a 256-pixel CMOS sensor array with in-pixel dual electrochemical and impedance detection modalities for rapid, multi-dimensional characterization of exoelectrogens. The CMOS IC has 16 parallel readout channels, allowing it to perform multiple measurements with a high throughput and enable the chip to handle different samples simultaneously. The chip contains a total of 2 × 256 working electrodes of size 44 µm × 52 µm, along with 16 reference electrodes of dimensions 56 µm × 399 µm and 32 counter electrodes of dimensions 399 µm × 106 µm, which together facilitate the high resolution screening of the test samples. The chip was fabricated in a standard 130nm BiCMOS process. The on-chip electrodes are subjected to additional fabrication processes, including a critical Al-etch step that ensures the excellent biocompatibility and long-term reliability of the CMOS sensor array in bio-environment. The electrochemical sensing modality is verified by detecting the electroactive analyte NaFeEDTA and the exoelectrogenic Shewanella oneidensis MR-1 bacteria, illustrating the chip's ability to quantify the generated electrochemical current and distinguish between different analyte concentrations. The impedance measurements with the HEK-293 cancer cells cultured on-chip successfully capture the cell-to-surface adhesion information between the electrodes and the cancer cells. The reported CMOS sensor array outperforms the conventional discrete setups for exoelectrogen characterization in terms of spatial resolution and speed, which demonstrates the chip's potential to radically accelerate synthetic biology engineering.

Surface oxidation of petroleum pitch to improve mesopore ratio and specific surface area of activated carbon.

In this study, surface oxidation of petroleum pitch was performed to enhance the thermal stability, specific surface area, and mesopore ratio of activated carbon. The oxygen uptake of the pitch by surface oxidation has a strong influence on the formation of the specific surface area and pore size of activated carbon. It was confirmed that the oxygen uptake from the surface to the inner side of the surface oxidized pitch was the highest at the temperature of 330 °C (IP330-AC), with a mesopore ratio of 63.35% and specific surface area of 1811 m2 g-1. The oxygen content of the surface oxidized pitch increased proportionately with the mesopore ratio in activated carbon. The specific surface area and mesopore ratio of IP330-AC were respectively 163% and 487% higher than those of petroleum-based commercial activated carbon (A-BAC), and 102% and 491% higher than those of coconut-based commercial activated carbon (P60).

Sulfonate Version of OHPAS Linker Has Two Distinct Pathways of Breakdown: Elimination Route Allows Para-Hydroxy-Protected Benzylsulfonate (PHP-BS) to Serve as an Alternative Self-Immolative Group.

Recently we have reported that the ortho-hydroxy-protected aryl sulfate (OHPAS) system can be exploited as a new self-immolative group (SIG) for phenolic payloads. We extended the system to nonphenolic payloads by simply introducing a para-hydroxy benzyl (PHB) spacer. As an additional variation of the system, we explored a benzylsulfonate version of the OHPAS system and found that it has two distinct breakdown pathways, cyclization and 1,4-elimination, the latter of which implies that para-hydroxy-protected (PHP) benzylsulfonate (BS) can also be used as an alternative SIG. The PHP-BS system was found to be stable chemically and in mouse and human plasma, having payload release rates comparable to those of the original OHPAS conjugates.

Intracellular cardiomyocytes potential recording by planar electrode array and fibroblasts co-culturing on multi-modal CMOS chip.

Intracellular action potential signals reveal enriched physiological information. Patch clamp techniques have been widely used to measure intracellular potential. Despite their high signal fidelity, they suffer from low throughput. Recently, 3D nanoelectrodes have been developed for intracellular potential recording. However, they are limited by scalability, yield, and cost, directly constraining their use in monitoring large number of cells and high throughput applications. In this paper, we demonstrate intracellular potential monitoring of cardiomyocytes using simple 2D planar electrode array in a standard CMOS process without patch clamps or post fabricated 3D nanoelectrodes. This is enabled by our unique cardiomyocytes/fibroblasts co-culturing technique and electroporation. The co-cultured fibroblasts promote tight sealing of cardiomyocytes on electrodes and enable high-fidelity intracellular potential monitoring based on 2D planar electrode. Compared to existing technologies, our platform has a unique potential to achieve an unprecedented combination of throughput, spatiotemporal resolution, and a tissue-level field-of-view for cellular electrophysiology monitoring.

Introduction of Para-Hydroxy Benzyl Spacer Greatly Expands the Utility of Ortho-Hydroxy-Protected Aryl Sulfate System: Application to Nonphenolic Payloads.

The ortho-hydroxy-protected aryl sulfate (OHPAS) linker is composed of a diaryl sulfate backbone equipped with a latent phenol moiety at the ortho position of one of the aryl units. The Ar-OH released when the ortho phenol undergoes intramolecular cyclization and displaces the second aryl unit can be viewed as a payload. We have shown in the preceding paper that the OHPAS linkers are highly stable chemically and in various plasmas, yet release payloads when exposed to suitable triggering conditions. As an extension of the OHPAS system, we employed a para-hydroxy benzyl (PHB) spacer for coupling to nonphenolic payloads; this tactic again provided a highly stable system capable of smooth release of appended payloads. The PHB modification works beautifully for tertiary amine and N-heterocycle payloads.

Aryl Sulfate is a Useful Motif for Conjugating and Releasing Phenolic Molecules: Sulfur Fluorine Exchange Click Chemistry Enables Discovery of Ortho-Hydroxy-Protected Aryl Sulfate Linker.

A new self-immolative linker motif, Ortho Hydroxy-Protected Aryl Sulfate (OHPAS), was devised, and OHPAS-containing antibody drug conjugates (ADC) were tested in vitro and in vivo. Conveniently synthesized using Sulfur Fluorine Exchange (SuFEx) chemistry, it is based structurally on diaryl sulfate, with one aryl acting as a payload and the other as a self-immolative sulfate unit having a latent phenol function at the ortho position. The chemically stable OHPAS linker was stable in plasma samples from 5 different species, yet it can release the payload molecule smoothly upon chemical or biological triggering. The payload release proceeds via intramolecular cyclization, producing a cyclic sulfate coproduct that eventually hydrolyzes to a catechol monosulfate. A set of OHPAS-containing ADCs based on Trastuzumab were prepared with a drug to antibody ratio of ∼2, and were shown to be cytotoxic in 5 different cancer cell lines in vitro and dose-dependently inhibited tumor growth in a NCI-N87 mouse xenograft model. We conclude that OHPAS conjugates will be of considerable use for delivering phenol-containing payloads to tissues targeted for medical intervention.

Mechanical and electrical properties of MCMB/Chopped carbon fiber composite with different bead size.

The carbonization and graphitization of carbon/carbon (C/C) composites prepared from mesocarbon microbeads (MCMB) and chopped carbon fiber (CCF) have been studied with a wide range of temperatures, CCF contents and MCMB sizes. Three different sizes of MCMB were prepared with coal tar pitch at three temperatures, 420, 430 and 440 °C, and identified as about 12.8, 16.0 and 20.1 µm, respectively. Each size of MCMB was mixed with CCFs at ratios of 2, 4, 6 and 8 wt. % and formed into block shape. After carbonization at 1200 °C, carbonized C/C blocks (CCBs) were graphitized at 2000, 2400 and 2800 °C. The CCB prepared with CCF content of 2 wt. % and an MCMB size of 16.0 µm exhibited the highest flexural strength of about 151 MPa. The graphitized C/C block (GCB) with CCF content of 2 wt. %, which was graphitized at 2000 °C showed the highest flexural strength of about 159 MPa.

Manufacture of high density carbon blocks by self-sintering coke produced via a two-stage heat treatment of coal tar.

High-strength and high-density carbonized carbon blocks from self-sintering coke were manufactured using coal tar and two-stage heat treatments (1st and 2nd stage treatments). First, the molecular weight distribution of the refined coal tar was controlled through a pressured heat treatment (1st stage treatment). Second, the 1st stage heat-treated coal tar (1S-CT) was treated using a delayed coking system (2nd stage treatment) to become the self-sintering coke. Finally, carbon blocks were molded from 2nd stage heat-treated coke (2S-C) and carbonized at 1200 °C for 1 h. Through rapid decomposition of the high molecular weight components in the coal tar at 360 °C in the 1st stage treatment, the molecular weight distribution of coal tar was confirmed to be controllable by the 1st stage treatment. Swelling during carbonization was observed in carbon blocks manufactured from 2S-C containing more than 15 wt% of volatile matter from 150-450 °C. The optimum conditions of the two-stage heat treatments were confirmed to be 300 °C for 3 h and 500 °C for 1 h. The highest density and flexural strength of the carbonized carbon blocks manufactured from 2S-C were 1.46 g/cm3 and 69.2 MPa, respectively.

Electrode-Electrolyte Interface Impedance Characterization of Ultra-Miniaturized Microelectrode Arrays Over Materials and Geometries for Sub-Cellular and Cellular Sensing and Stimulation.

Electrochemical interfaces with low-impedance, high biocompatibility, and long-term stability are of paramount importance for microelectrode arrays (MEAs), that are widely used in numerous cellular sensing/stimulation applications, e.g., brain interface, electroceuticals, neuroprosthetics, drug discovery, chemical screening, and fundamental biological research. It is becoming increasingly critical since sensing/actuations at sub-cellular resolution necessitate ultra-miniaturized electrodes, which exhibit exacerbated electrochemical interfaces, especially on interfacial impedance. This paper reports the first comprehensive characterization and interfacial electrochemical impedance spectroscopy (EIS) of the ultra-miniaturized electrodes for different electrode sizes ( 8×8 µm2 , 16×16 µm2 , and 32×32 µm2 ) and a wide material collection (Au, Pt, TiN, and ITO). Equivalent electrochemical interfacial circuit models with interface capacitance, charge transfer resistance, and solution resistance are obtained for all the electrode designs based on their EIS measurements. The results can potentially guide the designs of ultra-miniaturized MEAs for future bioelectronics systems.

Improving the mechanical properties of a high density carbon block from mesocarbon microbeads according to oxidative stabilization.

In this study, a high density carbon block without binder was manufactured by mesocarbon microbeads (MCMB) from coal tar pitch. To develop the high density carbon block without a binder, MCMBs were oxidized at different levels of temperature. To verify the effect of oxygen content in the carbonized carbon block (CCB), an elementary analysis (EA) and X-ray photoelectron spectroscopy (XPS) were performed. The morphological and mechanical properties of the CCBs were investigated by using scanning electron microscopy (SEM), a shore hardness test, and a flexural strength evaluation. The results revealed that the oxygen content increased with stabilization temperature and the physical properties of the CCBs were considerably improved via oxidative stabilization. Small cracks between MCMB particles were observed in the CCBs that were stabilized over 250 °C. From the results of this study, the CCB from MCMBs stabilized at 200 °C for 1 h showed optimum mechanical properties and high density.

Methanol-Tolerant Platinum-Palladium Catalyst Supported on Nitrogen-Doped Carbon Nanofiber for High Concentration Direct Methanol Fuel Cells.

Pt-Pd catalyst supported on nitrogen-doped carbon nanofiber (N-CNF) was prepared and evaluated as a cathode electrode of the direct methanol fuel cell (DMFC). The N-CNF, which was directly synthesized by the catalytic chemical vapor deposition from acetonitrile at 640 °C, was verified as having a change of electrochemical surface properties such as oxygen reduction reaction (ORR) activities and the electrochemical double layer compared with common carbon black (CB). To attain the competitive oxygen reduction reaction activity with methanol tolerance, the Pt and Pd metals were supported on the CB or the N-CNF. The physical and electrochemical characteristics of the N-CNF-supported Pt-Pd catalyst were examined and compared with catalyst supported on the CB. In addition, DMFC single cells using these catalysts as the cathode electrode were applied to obtain I-V polarization curves and constant current operating performances with high-concentration methanol as the fuel. Pt-Pd catalysts had obvious ORR activity even in the presence of methanol. The higher power density was obtained at all the methanol concentrations when it applied to the membrane electrode assembly (MEA) of the DMFC. When the N-CNF is used as the catalyst support material, a better performance with high-concentration methanol is expected.

Designing an ultrathin silica layer for highly durable carbon nanofibers as the carbon support in polymer electrolyte fuel cells.

A critical issue for maintaining long-term applications of polymer electrolyte fuel cells (PEFCs) is the development of an innovative technique for the functionalization of a carbon support that preserves their exceptional electrical conductivity and robustly enriches their durability. Here, we report for the first time how the formation of a partially coated, ultrathin, hydrophobic silica layer around the surfaces of the carbon nanofiber (CNF) helps improve the durability of the CNF without decreasing the significant electrical conductivity of the virgin CNF. The synthesis involved the adsorption of polycarbomethylsilane (PS) on the CNF's sidewalls, followed by high temperature pyrolysis of PS, resulting in a highly durable, conductive carbon support in PEFCs. The Pt nanoparticles are in direct contact with the surface of the carbon in the empty spaces between unevenly coated silica layers, which are not deposited directly onto the silica layer. The presence of a Pt nanoparticle layer that was thicker than the silica layer would be a quite advantageous circumstance that provides contact with other neighboring CNFs without having a significant adverse effect that deeply damages the electrical conductivity of the neighboring CNF composites with the silica layer. Furthermore, the ultrathin, hydrophobic silica layer around the surfaces of the CNF provides great potential to reduce the presence of water molecules in the vicinity of the carbon supports and the ˙OH radicals formed on the surface of the Pt catalyst. As a result, the CNF with a 5 wt% silica layer that we prepared has had extremely high initial performance and durability under severe carbon corrosion conditions, starting up with 974 mA cm(-2) at 0.6 V and ending up with more than 58% of the initial performance (i.e., 569 mA cm(-2) at 0.6 V) after a 1.6 V holding test for 6 h. The beginning-of-life and end-of-life performances based on the virgin CNF without the silica layer were 981 and 340 mA cm(-2) at 0.6 V, respectively. The CNF having a silica layer had long-term durability which was superior to that of the virgin CNF.

Electrocatalytic effects of carbon dissolution in Pd nanoparticles.

Highly dispersed Pd nanoparticles were prepared by borohydride reduction of Pd(acac)(2) in 1,2-propanediol at an elevated temperature. They were uniformly dispersed on carbon black without significant aggregation. X-ray diffraction showed that carbons from the Pd precursor dissolved in Pd, increasing its lattice parameter. A modified reduction process was tested to remove the carbon impurities. Carbon removal greatly enhanced catalytic activity toward the oxygen reduction reaction. It also generated an inconsistency between the electronic modifications obtained from X-ray photoelectron spectroscopy and the electrochemical method. CO displacement measurements showed that the formation of Pd-C bonds decreased the work function of the surface Pd atoms.

Preparation and Characteristics of SiOx Coated Carbon Nanotubes with High Surface Area.

An easy method to synthesize SiOx coated carbon nanotubes (SiOx-CNT) through thermal decomposition of polycarbomethylsilane adsorbed on the surface of CNTs is reported. Physical properties of SiOx-CNT samples depending on various Si contents and synthesis conditions are examined by X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), nitrogen isotherm, scanning electron microscope (SEM), and transmission electron microscope (TEM). Morphology of the SiOx-CNT appears to be perfectly identical to that of the pristine CNT. It is confirmed that SiOx is formed in a thin layer of approximately 1 nm thickness over the surface of CNTs. The specific surface area is significantly increased by the coating, because thin layer of SiOx is highly porous. The surface properties such as porosity and thickness of SiOx layers are found to be controlled by SiOx contents and heat treatment conditions. The preparation method in this study is to provide useful nano-hybrid composite materials with multi-functional surface properties.