A Dual-Mode Multifunctional Pulsed Radio-Frequency Stimulator for Trigeminal Neuralgia Relief and its Animal Model.

This work proposed a programmable pulsed radio-frequency (PRF) stimulator for trigeminal neuralgia (TN) relief on demand. The implantable stimulator is a miniaturized micro-system which integrates a wireless interface circuit, a sensor interface circuit, a PRF pattern generation circuit and a logic controller. The multifunctional stimulator capable of delivering current/voltage stimulation provides the choice of the biphasic sinusoidal, square and patterned waveform for PRF treatment researches. The external handheld device can wirelessly transmit the parameters of frequency, amplitude, pulse duration and repetition rate of the pulse train to the implanted stimulator. While stimulating, the temperature sensor can monitor the operating temperature. The feedback signal is transmitted in medical implanted communication system (MICS). The micro-system is fabricated in a 0.35 µm CMOS process with a chip size of 3.1 × 2.7 mm2. The fabricated chip was mounted on a 2.6 × 2.1 cm2 test board for studying the in vivo efficacy of pain relief by PRF. Animal studies of PRF stimulation and commonly-used medication for trigeminal neuralgia are also demonstrated and the presented results prove that PRF stimulation has greater effectiveness on trigeminal neuralgia relief comparing to the medication. The effectiveness period lasts at least 14 days. The results of neural recording show that the PRF stimulation of trigeminal ganglion (TG) attenuated neuron activities without being severely damaged. Pathology also revealed no lesion found on the stimulated area.

CD28 engagement inhibits CD73-mediated regulatory activity of CD8+ T cells.

CD28 is required for T cell activation as well as the generation of CD4+Foxp3+ Treg. It is unclear, however, how CD28 costimulation affects the development of CD8+ T cell suppressive function. Here, by use of Hepa1.6.gp33 in vitro killing assay and B16.gp33 tumor mouse model we demonstrate that CD28 engagement during TCR ligation prevents CD8+ T cells from becoming suppressive. Interestingly, our results showed that ectonucleotidase CD73 expression on CD8+ T cells is upregulated in the absence of CD28 costimulation. In both murine and human tumor-bearing hosts, CD73 is upregulated on CD28-CD8+ T cells that infiltrate the solid tumor. UPLC-MS/MS analysis revealed that CD8+ T cells activation without CD28 costimulation produces elevated levels of adenosine and that CD73 mediates its production. Adenosine receptor antagonists block CD73-mediated suppression. Our data support the notion that CD28 costimulation inhibits CD73 upregulation and thereby prevents CD8+ T cells from becoming suppressive. This study uncovers a previously unidentified role for CD28 costimulation in CD8+ T cell activation and suggests that the CD28 costimulatory pathway can be a potential target for cancer immunotherapy.

Probe-antenna and multifunctional switch for biomedical neural implants.

A probe-antenna and a multifunctional single-pole-four-throw switch are proposed for biomedical neural implants. The multifunctional switch is fabricated in TSMC 90-nm CMOS process and occupies the core area of 297 × 248 µm2. Operating in transmitter/receiver mode, the switch achieves the insertion loss of 4.5/4.8 dB, return loss of 16.7/15.4 dB, isolation of 19.2/20.3 dB and P1dB of 4/5 dBm at 60 GHz. Based on the dipole antenna, the antenna with probe function is designed and fabricated on the Roger 4003C two-layer printed circuit board. This probe-antenna achieves the input matching over 59.35-65 GHz. According to the simulation, it achieves the radiation efficiency of 69.8/34.4% and gain of 3.88/5.47 dBi without/with a drop of deionized water on the feed. The probe/electrode function is verified by performing impedance measurement on the deionized water, phosphate buffered saline (PBS) solution, and solution with conductivity of 1413 µS/cm.

Chopper-Stabilized Instrumentation Amplifier with Automatic Frequency Tuning Loop.

A variable-gain chopper-stabilized instrumentation amplifier (chopper IA), which employs a low pass filter (LPF) to attenuate the up-converted noise at the chopping frequency, is presented. The circuit is designed and fabricated with Taiwan Semiconductor Manufacturing Company (TSMC) (Hsinchu, Taiwan) 0.18 µm complementary metal-oxide-semiconductor (CMOS) technology. Consuming 1.1 mW from a 1.2 V supply voltage, the chopper IA achieves a variable gain of 20.7⁻48.5 dB, with a minimum bandwidth of 6.7 kHz and a common-mode rejection ratio (CMRR) of 95 dB below 10 kHz. By using the chopper technique, the input-referred noise of the chopper IA can be reduced to 0.28 µVrms (0~96 kHz), with a chopping frequency of 83.3 kHz. An automatic frequency tuning loop (ATL) is employed to adjust the corner frequency of the LPF dynamically so that the frequency ratio between the chopping frequency and the LPF corner frequency is 8.3, ensuring a noise reduction of 36.7 dB.

Polysaccharides PS-G and protein LZ-8 from Reishi (Ganoderma lucidum) exhibit diverse functions in regulating murine macrophages and T lymphocytes.

Bioactive components in Ganoderma lucidum mainly include polysaccharides (PS-G) and immunomodulatory protein Ling Zhi-8 (LZ-8). These components may have diverse regulatory functions in the immune system. However, the PS-G preparations from different procedures still contained partial LZ-8 residue, indicating that the specific target and regulating function of PS-G and LZ-8 were not fully understood. In the present study, PS-G was subjected to 15% TCA for removing proteins and the LZ-8 detection using anti-LZ-8 monoclonal antibodies showed a remarkable 89.7% protein reduction of the deproteinized PS-G (dpPS-G). The Saccharomyces cerevisiae which expressed recombinant LZ-8 protein (rLZ-8) without glycosylation was generated and then compared with dpPS-G in the induction toward murine primary macrophage and T lymphocytic cells. The peritoneal macrophages from TLR4-deficient and wild type mice revealed that TLR4 was a putative receptor of dpPS-G, mediating the TNF-alpha, IL-1beta and IL-12p70 cytokine production and CD86, MHC II expression on macrophages, while rLZ-8 enhanced the production of IL-1beta, IL-12p70, CD86, and MHC II expression by another obscure route. rLZ-8-treated macrophages enhanced the release of IFN-gamma and IL-2 by murine CD4(+) and CD8(+) T cells, whereas dpPS-G treatment did not enhance the release of IFN-gamma and IL-2. Furthermore, although the direct rLZ-8-treatment conduced dramatic CD154, CD44 expression on CD3(+) T cells and increased IL-2, IFN-gamma secretion on CD4(+) and CD8(+) T cells, the dpPS-G was incapable of priming CD3(+), CD4(+) or CD8(+) T cells unitarily. Taken together, these results demonstrated that LZ-8 could activate murine macrophages and T lymphocytes but PS-G was merely the activator for macrophages, suggesting their diverse roles in activating the innate and adaptive immunity.

A wireless bio-MEMS sensor for C-reactive protein detection based on nanomechanics.

A quick wireless label-free detection of disease-related C-reactive proteins (CRPs) using a 200-microm-long microelectromechanical systems (MEMS) microcantilever housed in a 7 x 7 mm(2) reaction chamber with a safe reusable feature is reported. The assay time ranges from about 30 min to 3 h, depending on accuracy. The deflection of the microcantilever due to specific CRP-antiCRP binding is detected using a position-sensitive detector. The converted bio-signal is transmitted by a custom designed wireless amplitude-shift-keying (ASK) transceiver IC fabricated in a 0.18 microm CMOS process. CRP concentrations from 1 microg/mL to 500 microg/mL can be detected. A 0.2-Hz 1-V ac signal instead of traditional bases/acids is applied to the bio-MEMS sensor to unbind the CRP from the microcantilever for reusability.

An implantable multifunctional needle type biosensor with integrated RF capability.

We report the development of an implantable multifunctional (glucose and cholesterol) needle type biosensor with integrated RF wireless circuitry for continuous in vivo monitoring of metabolites during short term stays in emergency room or intensive care unit. Silicon-based MEMS technologies are used for the fabrication of micro needle sensors. The whole device is covered by a biocompatible Parylene layer with opening structure at the active areas of electrodes. Electropolymerization of active biomolecules and conducting polymer provides in situ nanoscale physical entrapments of various oxidoreductases (Glucose oxidase and cholesterol oxidase) and functions as a viable matrix for the construction of micro amperometric biosensors. Hybrid CMOS fabrication processes are used to accomplish the 433 MHz ASK RF transmitter and receiver (0.18μm CMOS 1P6M process) and the data converter (0.35μm CMOS 2P4M process). We will present and discuss the detail design and the integrated system performance in this paper.