Biologics are antibodies produced by genetically engineered cells and are widely used in therapeutic applications. Examples include pembrolizumab (Keytruda) and atezolizumab (Tecentriq), both employed in cancer immunotherapy as checkpoint inhibitors to restore T- cell immune responses against tumor cells. These biologics are produced by engineered cells in bioreactors in a process that is highly sensitive to the bioreactor environment, making it essential to integrate process analytical technologies (PAT) for closed-loop, real-time adjustments. Recent trends have focused on leveraging integrated circuit (IC) solutions for system miniaturization and enhanced functionality, for example enabling a single IC that monitors O2, pH, oxidation-reduction potential (ORP), temperature, and glucose levels. However, no current technology can directly and continuously quantify the concentration and quality of the produced biologics in real-time within the bioreactor. Such critical measurements still rely on off-line methods such as immunoassays and mass spectrometry, which are time-consuming and not suitable for real- time process control.       UC Berkeley researchers have developed a microsystem for real-time, in-vivo monitoring of antibody therapeutics using structure-switching aptamers by employing an integrator-based readout front-end. This approach effectively addresses the challenge of a 100× reduction in signal levels compared to the measurement of small-molecule drugs in prior works. The microsystem is also uniquely suited to the emerging paradigm of “living pharmacies.” In living pharmacies, drug-producing cells will be hosted on implantable devices, and real-time monitoring of drug production/diffusion rates based on an individual’s pharmokinetics will be crucial.

      Integrating microelectronics with microfluidics, especially those implemented in silicon-based CMOS technology, has driven the next generation of in vitro diagnostics. CMOS/microfluidics platforms offer (1) close interfaces between electronics and biological samples, and (2) tight integration of readout circuits with multi-channel microfluidics, both of which are crucial factors in achieving enhanced sensitivity and detection throughput. Conventionally bulky benchtop instruments are now being transformed into millimeter-sized form factors at low cost, making the deployment for Point-of-Care (PoC) applications feasible. However, conventional CMOS/microfluidics integration suffers from significant misalignment between the microfluidics and the sensing transducers on the chip, especially when the transducer sizes are reduced or the microfluidic channel width shrinks, due to limitations of current fabrication methods.       UC Berkeley researchers have developed a novel methodology for fabricating microfluidics platforms closely embedded within a silicon chip implemented in CMOS technology. The process utilizes a one-step approach to create fluidic channels directly within the CMOS technology and avoids the previously cited misalignment. Three types of structures are presented in a TSMC 180-nm CMOS chip: (1) passive microfluidics in the form of a micro-mixer and a 1:64 splitter, (2) fluidic channels with embedded ion-sensitive field-effect transistors (ISFETs) and Hall sensors, and (3) integrated on-chip impedance-sensing readout circuits including voltage drivers and a fully differential transimpedance amplifier (TIA). Sensors and transistors are functional pre- and post-etching with minimal changes in performance. Tight integration of fluidics and electronics is achieved, paving the way for future small-size, high-throughput lab-on-chip (LOC) devices.

      Current clinical practice for detecting low-concentration molecular biomarkers requires sending samples to centralized labs, leading to high costs and delays. Successful point-of-care (POC) diagnostic technology exist, such as the paper-based lateral-flow assay (LFA) used for pregnancy tests and SARS-CoV-2 rapid antigen tests, or miniaturized instruments such as the Abbot i-Stat Alinity. However, the former provides binary results or limited quantitative accuracy, and the latter is too expensive for in-home deployment. A promising approach for POC diagnostics, offering tailored circuit optimization, multiplexed detection, and significant cost and size reductions, is millimeter-sized CMOS integrated circuits coupled with microfluidics. Recent demonstrations include protein, DNA/RNA, and cell detection. The current complexity of system packaging (e.g., wire/flip-chip bonding) makes integrating microfluidics with more sophisticated functions challenging, and often-required syringe pumps and tubing are operationally unfriendly, limiting current approaches.       UC Berkeley researchers have developed a fully integrated, multi-mode POC device that requires single-step assembly and operates autonomously. Drawing inspiration from RFID technology and implantables, they have introduced inductively-coupled wireless powering and communication functionality into a CMOS bio-analyzer. With the chip being fully wireless, the die can be easily integrated into a substrate carrier, achieving a completely flat surface that allows for seamless bonding with the microfluidic module. In the final product, the device will be sealed in a pouch inside a vacuum desiccator. The user tears the pouch, adds a drop of sample, and the system automatically begins operation. The operation window can last up to 40 minutes, making the process insensitive to time delays. The present CMOS bio-analyzer integrates pH-sensing and amperometric readout circuits for both proton-based and redox-based immunoassays.

      Molecular dynamics (MD) is a computational materials science modality widely used in academic and industrial settings for materials discovery and more. A critical aspect of modern MD calculations are machine learning interatomic potentials (MLIPs), which learn from reference quantum mechanical calculations and predict the energy and forces of atomic configurations quickly. MLIPs allow for more accurate and comprehensive exploration of material/molecular properties at-scale. However, state-of-the-art MLIP methods mostly use a short-range approximation, which may be sufficient for describing properties of homogeneous bulk systems but fail for liquid-vapor interfaces, dielectric response, dilute ionic solutions with Debye-Huckel screening, and interactions between gas phase molecules. Short-range MLIPs neglect all long-range interactions, such as Coulomb and dispersion interactions.      To address the current shortcoming, UC Berkeley researchers have developed a straightforward and efficient algorithm to account for long-range interactions in MLIPs. The algorithm can predict system properties including those with charged, polar or apolar molecular dimers, bulk water, and water-vapor interfaces. In these cases standard short-range MLIPs lead to unphysical predictions, even when utilizing message passing algorithms. The present method eliminates artifacts while only about doubling the computational cost. Furthermore, it can be incorporated into most existing MLIP architectures, including potentials based on local atomic environments such as HDNPP, Gaussian Approximation Potentials (GAP), Moment Tensor Potentials (MTPs), atomic cluster expansion (ACE), and MPNN (e.g., NequIP, MACE).

      Image quality and sample structure information from an optical microscope is in large part determined by optical aberrations. Optical aberrations originating from the microscope optics themselves or the sample can degrade the imaging performance of the system. Given the difficulty to find and correct all sources of aberration, a collection of methods termed adaptive optics is used to measure and correct optical aberrations in other ways, to recover imaging performance. However, state-of-the-art adaptive optics systems typically comprise complex hardware and software integration, which has impeded their wide adoption in microscopy. UC Berkeley researchers recently demonstrated how self-supervised machine learning (ML)-based adaptive optics can accurately estimate optical aberrations from a single 3D fluorescence image stack, without requiring external datasets for training. While demonstrated for widefield fluorescence microscopy, many optical microscopy modalities present unique challenges.       In the present technology, UC Berkeley researchers have developed a novel self-supervised ML-based adaptive optics system for two-photon fluorescence microscopy, which should also be extensible to confocal and other modalities. The system can effectively image tissues and samples for cell biology applications. Importantly, the method can address common errors in optical conjugation/alignment in commercial microscopy systems that have yet to be systematically addressed. It can also integrate advanced computational techniques to recover sample structure.

      The demand for miniaturized power electronics with increased efficiency and performance motivates the exploration of piezoelectric structures as alternative passive components; piezoelectric components store energy in mechanical compliance and inertia with extremely high quality factors and energy densities significantly greater than those of magnetics at small scales. Recent magnetic-less dc-dc converter designs based on single-port piezoelectric resonators (PRs) have demonstrated power stage efficiencies of 99% and PR power handling densities of up to 5.7 kW/cm3. While marking tremendous milestones, such performance has only been achieved in non-isolated dc-dc converters with mild (2:1) voltage conversion ratios, confining the utility of piezoelectric-based power conversion to a narrow subset of applications.       Piezoelectrics may be expanded to a broader set of applications through use of multi-port piezoelectric transformers (PTs), which offer the same advantages as PRs but with the added potential for galvanic isolation and inherent voltage transformation. The present invention overcomes standing performance shortcomings in isolated magnetic-less PT-based dc-dc converters, providing a framework for high-efficiency piezoelectric transformer (PT) designs (wherein isolated PTs serve as the primary passive components in isolated dc-dc converters). One of the proposed PT designs is validated in a dc-dc power converter prototype and demonstrates a peak efficiency of 97.5%. The measured performance represents a 17x reduction in loss ratio compared to previous isolated magnetic-less PT-based dc-dc converter designs, and expands the value of piezoelectrics to applications requiring isolation.

Glaucoma is a leading blinding disease affecting at least 60 million people worldwide. A major risk factor for glaucoma is high intraocular pressure (IOP), which can damage the optic nerve and cause permanent blindness without treatment.  UC researchers have found that Schlemm’s canal (SC) is a critical structure involved in aqueous humor drainage and IOP regulation and have found certain receptors that are expressed on SC.  The researchers are working to develop several molecules that can be targeted or modulated to regulate SC function to treat glaucoma.  

In magnetic resonance imaging (MRI) scanners, the detection of nuclear magnetic resonance (NMR) signals is achieved using radiofrequency, or RF, coils. RF coils are often equivalently called “resonance coils” due to their circuitry being engineered for resonance at a single frequency being received, for low-noise voltage gain and performance. However, such coils are therefore limited to a small bandwidth around the center frequency, restricting MRI systems from imaging more than one type of nucleus at a time (typically just hydrogen-1, or H1), at one magnetic field strength.To overcome the inherent restriction without sacrificing performance, UC Berkeley researchers have developed an MRI coil that can perform low-noise voltage gain at arbitrary relevant frequencies. These frequencies can be programmably chosen and can include magnetic resonance signals from any of various nuclei (e.g., 1H, 13C, 23Na, 31P, etc.), at any magnetic field strength (e.g., 50 mT, 1.5T, 3T, etc.). The multi-frequency resonance can be performed in a single system. The invention has further advantages in terms of resilience due to its decoupled response relative to other coils and system elements.