Reactive oxygen species and nitric oxide scavenging nanoparticles alleviating rheumatoid arthritis through adjusting the seeds and growing soils.

Normalizing inflamed soils including reactive oxygen species (ROS), nitric oxide (NO), cell-free DNA, and regulating inflammation-related seeds such as macrophages, neutrophils, fibroblasts, represent a promising strategy to maintain synovial tissue homeostasis for rheumatoid arthritis (RA) treatment. Herein, ROS scavenging amphiphilic block copolymer PEGylated bilirubin and NO-scavenging PEGylated o-phenylenediamine were fabricated to self-assemble into a dually responsive nanoparticle loaded with JAK inhibitor notopterol (Not@BR/oPDA-PEG, NBOP NPs). The simultaneous ROS and NO depletion combined with JAK-STAT pathway inhibition could not only promote M2 polarization to reduce further ROS and NO generation, but also decrease cytokines and chemokines to prevent immune cell recruitment. Specifically, NBOP NPs responded to high level ROS and NO, and disintegrated to release notopterol in inflamed joints as the hydrophobic heads BR and oPDA were transformed into hydrophilic ones. The released notopterol could inhibit the JAK-STAT pathway of inflammatory cells to reduce the secretion of pro-inflammatory cytokines and chemokines. This strategy represented an effective way to regulate RA soils and seeds through breaking the positive feedback loop of inflammation aggravation, achieving an excellent anti-RA efficacy in a collagen-induced arthritis rat model. Taken together, our work offered a reference to adjust RA soils and seeds for enhanced RA treatment.

Sub-5-Minute Ultrafast PCR using Digital Microfluidics.

The development of a rapid and reliable polymerase chain reaction (PCR) method for point-of-care (POC) diagnosis is crucial for the timely identification of pathogens. Microfluidics, which involves the manipulation of small volumes of fluidic samples, has been shown to be an ideal approach for POC analysis. Among the various microfluidic platforms available, digital microfluidics (DMF) offers high degree of configurability in manipulating µL/nL-scale liquid and achieving automation. However, the successful implementation of ultrafast PCR on DMF platforms presents challenges due to inherent system instability. In this study, we developed a robust and ultrafast PCR in 3.7-5 min with a detection sensitivity comparable to conventional PCR. Specifically, the implementation of the pincer heating scheme homogenises the temperature within a drop. The utilization of a µm-scale porous hydrophobic membrane suppresses the formation of bubbles under high temperatures. The design of a groove around the high-temperature zone effectively mitigates the temperature interference. The integration of a soluble sensor into the droplets provides an accurate and instant in-drop temperature sensing. We envision that the fast, robust, sensitive, and automatic DMF system will empower the POC testing for infectious diseases.

Ni-doped Bi2O2CO3 nanosheet with H+/Zn2+ co-insertion for "rocking chair" zinc-ion battery.

Developing insertion-type anode is key to advancing "rocking chair" zinc-ion batteries, though there are few reported insertion-type anodes. Herein, the Bi2O2CO3 is a high-potential anode, with a special layered structure. A one-step hydrothermal method was used to prepare Ni-doped Bi2O2CO3 nanosheet, and also a free-standing electrode consisting of Ni-Bi2O2CO3 and CNTs was designed. Both cross-linked CNTs conductive networks and Ni doping improve charge transfer. Ex situ tests (XRD, XPS, TEM, etc.) reveal the H+/Zn2+ co-insertion mechanism of Bi2O2CO3 and that Ni doping improves its electrochemical reversibility and structural stability. Therefore, this optimized electrode offers a high specific capacity of 159 mAh g-1 at 100 mA g-1, a suitable average discharge voltage of ≈0.400 V, and a long-term cycling stability of 2200 cycles at 700 mA g-1. Besides, the Ni-Bi2O2CO3//MnO2 "rocking chair" zinc-ion battery (based on the total mass of cathode and anode) delivers a high capacity of ≈100 mAh g-1 at 50.0 mA g-1. This work provides a reference for designing high-performance anode in zinc-ion batteries.

Functionalized PAMAM constructed nanosystems for biomacromolecule delivery.

Polyamidoamines (PAMAMs) are a class of dendrimer with monodispersity and controlled topology, which can deliver biologically active macromolecules (e.g., genes and proteins) to specific regions with high efficiency and minimum side effects. In detail, PAMAMs can be functionalized easily by core modification or surface amendment to encapsulate a wide range of biomacromolecules. Besides, self-assembled, cross-linked and hybrid PAMAMs with customized therapeutic purposes are developed as delivery vehicles, which makes PAMAMs promising for biomacromolecule therapy. In this review, we comprehensively summarize the application of PAMAMs in biomacromolecule delivery from the synthesis of functionalized PAMAM carriers to the development of PAMAM-based drug delivery systems. The underlying strategies for PAMAM functionalization and assembly are first systematically discussed, and then the current applications of PAMAMs for biomacromolecule delivery are reviewed. Finally, a brief perspective on the further applications of PAMAMs concludes, aiming to provide insights into developing PAMAM-based biomacromolecule delivery systems.

A multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced chemodynamic therapy.

Chemodynamic therapy (CDT) eradicates tumors by intratumoral catalytic chemical reaction and subsequently disrupts redox homeostasis, which shows tumor specific reactive oxygen species (ROS)-mediated therapy. However, insufficient ROS generation and high levels of glutathione (GSH) in cancer cells have limited the therapeutic efficacy of CDT. Herein, we constructed a multifunctional oxidative stress nanoamplifier with ROS amplification and GSH exhaustion for enhanced CDT. Such a sandwich-like nanoamplifier comprised layer-by-layer artesunate (AS) and calcium carbonate coatings on the surface of manganese dioxide (MnO2) nanoparticles. The nanoamplifier was disassembled under an acidic environment once accumulated into tumor sites, and subsequently released AS to replenish the intratumoral peroxide pool for ROS amplification. Besides being an AS carrier, MnO2 exhausted GSH to yield Mn2+ ions that catalyzed the overexpression of H2O2 in the tumor, further intensifying the oxidative stress and facilitating cancer cell death. Taken together, our findings not only provide a paradigm for fabricating intratumoral catalytic nanomaterials, but also present a new ROS enhancement strategy to improve anti-tumor efficacy. Our multifunctional oxidative stress nanoamplifier might broaden the future of CDT.

One-shot high-resolution melting curve analysis for KRAS point-mutation discrimination on a digital microfluidics platform.

Single-nucleotide polymorphism (SNP) plays a critical role in personalized medicine, forensics, pharmacogenetics, and disease diagnostics. Among different existing SNP genotyping techniques, melting curve analysis (MCA) becomes increasingly popular due to its high accuracy and straightforward procedures in extracting the melting temperature (Tm). Yet, its study on existing digital microfluidic (DMF) platforms has intrinsic limitations due to the temperature inhomogeneity within a thickened droplet during the on-chip rapid heating process. Although the utilization of an on-chip thermostat can regulate and monitor the dynamic melting process in real time, the limited Tm accuracy resulting from the insufficient system response time to accommodate the fast-melting evolution still poses a great challenge for precise MCA with high throughput. This work proposes a one-shot MCA on a DMF platform. The tailoring of a functional substrate with hierarchical micro/nano structure enables high-resolution patterning of pL-scale droplets. Specifically, the hydrothermal and photocatalysis treatment allows the functional substrate to exhibit a superwettability contrast of >170°, facilitating passive isolation of the pL-scale DNA sample into highly-resolved pL droplets above the 200 µm superhydrophilic patterns. This high-resolution MCA technique can successfully discriminate KRAS gene targets with single-nucleotide mutations in 3 seconds. The high accuracy and consistency in the acquired Tm when compared with off-chip results demonstrate its opportunities for near-patient diagnostics, precision medicines, genetic counseling, and prevention strategies on DMF platforms.

Self-Powered Implantable Medical Devices: Photovoltaic Energy Harvesting Review.

Implantable technologies are becoming more widespread for biomedical applications that include physical identification, health diagnosis, monitoring, recording, and treatment of human physiological traits. However, energy harvesting and power generation beneath the human tissue are still a major challenge. In this regard, self-powered implantable devices that scavenge energy from the human body are attractive for long-term monitoring of human physiological traits. Thanks to advancements in material science and nanotechnology, energy harvesting techniques that rely on piezoelectricity, thermoelectricity, biofuel, and radio frequency power transfer are emerging. However, all these techniques suffer from limitations that include low power output, bulky size, or low efficiency. Photovoltaic (PV) energy conversion is one of the most promising candidates for implantable applications due to their higher-power conversion efficiencies and small footprint. Herein, the latest implantable energy harvesting technologies are surveyed. A comparison between the different state-of-the-art power harvesting methods is also provided. Finally, recommendations are provided regarding the feasibility of PV cells as an in vivo energy harvester, with an emphasis on skin penetration, fabrication, encapsulation, durability, biocompatibility, and power management.

Suppression of coffee-ring effect via periodic oscillation of substrate for ultra-sensitive enrichment towards surface-enhanced Raman scattering.

Surface-enhanced Raman scattering (SERS) has attracted extensive interest due to excellent molecule recognition and sensitive concentration detection. Nevertheless, the coffee ring effect (CR) during the analyte evaporation always causes an uneven distribution of the assembled hot-spots, and hence the unreliable SERS signal is produced. In this study, for the first time, we present a suppressed coffee ring (SCR) system via a combination of a magnetically functionalized membrane and reciprocating magnetic field to dynamically suppress the CR for highly reliable and ultra-sensitive SERS detection. The enrichment mechanism of the nanoparticles and the analyte molecules within the sessile droplet based on the proposed system was studied. We experimentally observed that the driving frequency could well affect the final pattern, and typically a higher driving frequency facilitated a smaller coverage area with better enrichment performance. With the use of R6G molecule and (100 nm) gold nanoparticles, we examined the uniformity and SERS of the assembled 'hot-spots' in the SCR system. The results indicate that the uniformity can be greatly improved via SCR in comparison of ring stain, with the RSD of a Raman signal as low as 7.1% even at a low concentration of 10-12 mol L-1. Such system also enables the further enhancement in the SERS signal, with the detection limit down to 10-16 mol L-1, the enhancement factor magnitude up to 1013, and the linear relationship between the SERS intensity and the analyte concentrations within the range of 10-6-10-12 and 10-12-10-16 mol L-1, respectively. The applicability of the SCR-based SERS detection for diverse analytes was also proved with a similar but further enhanced signal of MB and 4-ATP. We believe that the excellent SCR-based SERS performance via the proposed system has great potentials for ultra-sensitive detection and/or precise quantitative analysis in various research fields and applications.

A Single-Chip Solar Energy Harvesting IC Using Integrated Photodiodes for Biomedical Implant Applications.

In this paper, an ultra-compact single-chip solar energy harvesting IC using on-chip solar cell for biomedical implant applications is presented. By employing an on-chip charge pump with parallel connected photodiodes, a 3.5 × efficiency improvement can be achieved when compared with the conventional stacked photodiode approach to boost the harvested voltage while preserving a single-chip solution. A photodiode-assisted dual startup circuit (PDSC) is also proposed to improve the area efficiency and increase the startup speed by 77%. By employing an auxiliary charge pump (AQP) using zero threshold voltage (ZVT) devices in parallel with the main charge pump, a low startup voltage of 0.25 V is obtained while minimizing the reversion loss. A 4 Vin gate drive voltage is utilized to reduce the conduction loss. Systematic charge pump and solar cell area optimization is also introduced to improve the energy harvesting efficiency. The proposed system is implemented in a standard 0.18- [Formula: see text] CMOS technology and occupies an active area of 1.54 [Formula: see text]. Measurement results show that the on-chip charge pump can achieve a maximum efficiency of 67%. With an incident power of 1.22 [Formula: see text] from a halogen light source, the proposed energy harvesting IC can deliver an output power of 1.65 [Formula: see text] at 64% charge pump efficiency. The chip prototype is also verified using in-vitro experiment.

CMOS biosensors for in vitro diagnosis - transducing mechanisms and applications.

Complementary metal oxide semiconductor (CMOS) technology enables low-cost and large-scale integration of transistors and physical sensing materials on tiny chips (e.g., <1 cm2), seamlessly combining the two key functions of biosensors: transducing and signal processing. Recent CMOS biosensors unified different transducing mechanisms (impedance, fluorescence, and nuclear spin) and readout electronics have demonstrated competitive sensitivity for in vitro diagnosis, such as detection of DNA (down to 10 aM), protein (down to 10 fM), or bacteria/cells (single cell). Herein, we detail the recent advances in CMOS biosensors, centering on their key principles, requisites, and applications. Together, these may contribute to the advancement of our healthcare system, which should be decentralized by broadly utilizing point-of-care diagnostic tools.

Low-Power CMOS Laser Doppler Imaging Using Non-CDS Pixel Readout and 13.6-bit SAR ADC.

Laser Doppler imaging (LDI) measures particle flows such as blood perfusion by sensing their Doppler shift. This paper is the first of its kind in analyzing the effect of circuit noise on LDI precision which is distinctively different from conventional imaging. Based on this result, it presents a non-correlated-double-sampling (non-CDS) pixel readout scheme along with a high-resolution successive-approximation-register (SAR) analog-to-digital-converter (ADC) with 13.6b effective resolution (ER). Measurement results from the prototype chip in 0.18 µm technology confirm the theoretical analysis and show that the two techniques improve LDI sensing precision by 6.9 dB and 4.4 dB (compared to a 10b ADC) respectively without analog pre-amplification. The sensor's ADC occupies 518 µm×84 µm and is suitable for fast column parallel readout. Its differential non-linearity (DNL), integral non-linearity (INL), and input referred noise are +3.0/-2.8 LSB, +24/-17 LSB, and 110 µVrms respectively, leading to a Figure-of-Merit (FoM) of 23 fJ/state which makes it one of the most energy efficient image sensor ADCs and an order of magnitude better than the best reported LDI system using commercial high-speed image sensors.

A palm-size µNMR relaxometer using a digital microfluidic device and a semiconductor transceiver for chemical/biological diagnosis.

Herein, we describe a micro-nuclear magnetic resonance (µNMR) relaxometer miniaturized to palm-size and electronically automated for multi-step and multi-sample chemical/biological diagnosis. The co-integration of microfluidic and microelectronic technologies enables an association between the droplet managements and µNMR assays inside a portable sub-Tesla magnet (1.2 kg, 0.46 Tesla). Targets in unprocessed biological samples, captured by specific probe-decorated magnetic nanoparticles (NPs), can be sequentially quantified by their spin-spin relaxation time (T2) via multiplexed µNMR screening. Distinct droplet samples are operated by a digital microfluidic device that electronically manages the electrowetting-on-dielectric effects over an electrode array. Each electrode (3.5 × 3.5 mm(2)) is scanned with capacitive sensing to locate the distinct droplet samples in real time. A cross-domain-optimized butterfly-coil-input semiconductor transceiver transduces between magnetic and electrical signals to/from a sub-10 µL droplet sample for high-sensitivity µNMR screening. A temperature logger senses the ambient temperature (0 to 40 °C) and a backend processor calibrates the working frequency for the transmitter to precisely excite the protons. In our experiments, the µNMR relaxometer quantifies avidin using biotinylated Iron NPs (Φ: 30 nm, [Fe]: 0.5 mM) with a sensitivity of 0.2 µM. Auto-handling and identification of two targets (avidin and water) are demonstrated and completed within 2.2 min. This µNMR relaxometer holds promise for combinatorial chemical/biological diagnostic protocols using closed-loop electronic automation.

NMR-DMF: a modular nuclear magnetic resonance-digital microfluidics system for biological assays.

We present a modular nuclear magnetic resonance-digital microfluidics (NMR-DMF) system as a portable diagnostic platform for miniaturized biological assays. With increasing number of combinations between designed probes and a specific target, NMR has become an accurate and rapid assay tool, which is capable of detecting particular kinds of proteins, DNAs, bacteria and cells with a customized probe quantitatively. Traditional sample operation (e.g., manipulation and mixing) relied heavily on human efforts. We herein propose a modular NMR-DMF system to allow the electronic automation of multi-step reaction-screening protocols. A figure-8 shaped coil is proposed to enlarge the usable inner space of a portable magnet by 4.16 times, generating a radio frequency (RF) excitation field in the planar direction. By electronically managing the electro-wetting-on-dielectric (EWOD) effects over an electrode array, preloaded droplets with the inclusion of biological constituents and targets can be programmed to mix and be guided to the detection site (3.5 × 3.5 mm(2)) for high-sensitivity NMR screening (static B field: 0.46 T, RF field: 1.43 mT per ampere), with the result (voltage signal) displayed in real-time. To show the system's utility, automated real-time identification of 100 pM of avidin in a 14 µL droplet was achieved. The system shows promise as a robust and portable diagnostic device for a wide variety of biological analyses and screening applications.

15-nW Biopotential LPFs in 0.35- µm CMOS using subthreshold-source-follower Biquads with and without gain compensation.

Most biopotential readout front-ends rely on the g m- C lowpass filter (LPF) for forefront signal conditioning. A small g m realizes a large time constant ( τ = C / g m) suitable for ultra-low-cutoff filtering, saving both power and area. Yet, the noise and linearity can be compromised, given that each g m cell can involve one or several noisy and nonlinear V- I conversions originated from the active devices. This paper proposes the subthreshold-source-follower (SSF) Biquad as a prospective alternative. It features: 1) a very small number of active devices reducing the noise and nonlinearity footsteps; 2) No explicit feedback in differential implementation, and 3) extension of filter order by cascading. This paper presents an in-depth treatment of SSF Biquad in the nW-power regime, analyzing its power and area tradeoffs with gain, linearity and noise. A gain-compensation (GC) scheme addressing the gain-loss problem of NMOS-based SSF Biquad due to the body effect is also proposed. Two 100-Hz 4th-order Butterworth LPFs using the SSF Biquads with and without GC were fabricated in 0.35- µm CMOS. Measurement results show that the non-GC (GC) LPF can achieve a DC gain of -3.7 dB (0 dB), an input-referred noise of 36 µV rms (29 µV rms ), a HD3@60 Hz of -55.2 dB ( - 60.7 dB) and a die size of 0.11 mm² (0.08 mm²). Both LPFs draw 15 nW at 3 V. The achieved figure-of-merits (FoMs) are favorably comparable with the state-of-the-art.

Sub-threshold standard cell library design for ultra-low power biomedical applications.

Portable/Implantable biomedical applications usually exhibit stringent power budgets for prolonging battery life time, but loose operating frequency requirements due to small bio-signal bandwidths, typically below a few kHz. The use of sub-threshold digital circuits is ideal in such scenario to achieve optimized power/speed tradeoffs. This paper discusses the design of a sub-threshold standard cell library using a standard 0.18-µm CMOS technology. A complete library of 56 standard cells is designed and the methodology is ensured through schematic design, transistor width scaling and layout design, as well as timing, power and functionality characterization. Performance comparison between our sub-threshold standard cell library and a commercial standard cell library using a 5-stage ring oscillator and an ECG designated FIR filter is performed. Simulation results show that our library achieves a total power saving of 95.62% and a leakage power reduction of 97.54% when compared with the same design implemented by the commercial standard cell library (SCL).