Multi-color flow cytometer with PIC-based structured illumination.

We demonstrate a flow cytometer in which structured light illumination is used to attribute fluorescent and scattering signals to their excitation wavelength. A suitable multi-color light source emitting structured illumination patterns at 405, 488, 561 and 640 nm is developed based on a silicon nitride photonic integrated circuit and cytometry experiments are conducted with calibration beads. Performance metrics of the novel cytometer are compared with those of a mature, commercial device. While the experimental device still features a slightly higher sensitivity floor than the commercial one, all but the most weakly stained beads can be categorized. These promising results validate the feasibility of the proposed concept.

Curriculum learning for human compositional generalization.

Generalization (or transfer) is the ability to repurpose knowledge in novel settings. It is often asserted that generalization is an important ingredient of human intelligence, but its extent, nature, and determinants have proved controversial. Here, we examine this ability with a paradigm that formalizes the transfer learning problem as one of recomposing existing functions to solve unseen problems. We find that people can generalize compositionally in ways that are elusive for standard neural networks and that human generalization benefits from training regimes in which items are axis aligned and temporally correlated. We describe a neural network model based around a Hebbian gating process that can capture how human generalization benefits from different training curricula. We additionally find that adult humans tend to learn composable functions asynchronously, exhibiting discontinuities in learning that resemble those seen in child development.

Focused ultrasound neuromodulation on a multiwell MEA.

BACKGROUND: Microelectrode arrays (MEA) enable the measurement and stimulation of the electrical activity of cultured cells. The integration of other neuromodulation methods will significantly enhance the application range of MEAs to study their effects on neurons. A neuromodulation method that is recently gaining more attention is focused ultrasound neuromodulation (FUS), which has the potential to treat neurological disorders reversibly and precisely. METHODS: In this work, we present the integration of a focused ultrasound delivery system with a multiwell MEA plate. RESULTS: The ultrasound delivery system was characterised by ultrasound pressure measurements, and the integration with the MEA plate was modelled with finite-element simulations of acoustic field parameters. The results of the simulations were validated with experimental visualisation of the ultrasound field with Schlieren imaging. In addition, the system was tested on a murine primary hippocampal neuron culture, showing that ultrasound can influence the activity of the neurons. CONCLUSIONS: Our system was demonstrated to be suitable for studying the effect of focused ultrasound on neuronal cultures. The system allows reproducible experiments across the wells due to its robustness and simplicity of operation.

A Microfluidic Cancer-on-Chip Platform Predicts Drug Response Using Organotypic Tumor Slice Culture.

Optimal treatment of cancer requires diagnostic methods to facilitate therapy choice and prevent ineffective treatments. Direct assessment of therapy response in viable tumor specimens could fill this diagnostic gap. Therefore, we designed a microfluidic platform for assessment of patient treatment response using tumor tissue slices under precisely controlled growth conditions. The optimized Cancer-on-Chip (CoC) platform maintained viability and sustained proliferation of breast and prostate tumor slices for 7 days. No major changes in tissue morphology or gene expression patterns were observed within this time frame, suggesting that the CoC system provides a reliable and effective way to probe intrinsic chemotherapeutic sensitivity of tumors. The customized CoC platform accurately predicted cisplatin and apalutamide treatment response in breast and prostate tumor xenograft models, respectively. The culture period for breast cancer could be extended up to 14 days without major changes in tissue morphology and viability. These culture characteristics enable assessment of treatment outcomes and open possibilities for detailed mechanistic studies. SIGNIFICANCE: The Cancer-on-Chip platform with a 6-well plate design incorporating silicon-based microfluidics can enable optimal patient-specific treatment strategies through parallel culture of multiple tumor slices and diagnostic assays using primary tumor material.

Cavity-BOX SOI: Advanced Silicon Substrate with Pre-Patterned BOX for Monolithic MEMS Fabrication.

Several Silicon on Insulator (SOI) wafer manufacturers are now offering products with customer-defined cavities etched in the handle wafer, which significantly simplifies the fabrication of MEMS devices such as pressure sensors. This paper presents a novel cavity buried oxide (BOX) SOI substrate (cavity-BOX) that contains a patterned BOX layer. The patterned BOX can form a buried microchannels network, or serve as a stop layer and a buried hard-etch mask, to accurately pattern the device layer while etching it from the backside of the wafer using the cleanroom microfabrication compatible tools and methods. The use of the cavity-BOX as a buried hard-etch mask is demonstrated by applying it for the fabrication of a deep brain stimulation (DBS) demonstrator. The demonstrator consists of a large flexible area and precisely defined 80 µm-thick silicon islands wrapped into a 1.4 mm diameter cylinder. With cavity-BOX, the process of thinning and separating the silicon islands was largely simplified and became more robust. This test case illustrates how cavity-BOX wafers can advance the fabrication of various MEMS devices, especially those with complex geometry and added functionality, by enabling more design freedom and easing the optimization of the fabrication process.

PDMS-Parylene Adhesion Improvement via Ceramic Interlayers to Strengthen the Encapsulation of Active Neural Implants.

Parylene-C has been used as a substrate and encapsulation material for many implantable medical devices. However, to ensure the flexibility required in some applications, minimize tissue reaction, and protect parylene from degradation in vivo an additional outmost layer of polydimethylsiloxane (PDMS) is desired. In such a scenario, the adhesion of PDMS to parylene is of critical importance to prevent early failure caused by delamination in the harsh environment of the human body. Towards this goal, we propose a method based on creating chemical covalent bonds using intermediate ceramic layers as adhesion promoters between PDMS and parylene.To evaluate our concept, we prepared three different sets of samples with PDMS on parylene without and with oxygen plasma treatment (the most commonly employed method to increase adhesion), and samples with our proposed ceramic intermediate layers of silicon carbide (SiC) and silicon dioxide (SiO2). The samples were soaked in phosphate-buffered saline (PBS) solution at room temperature and were inspected under an optical microscope. To investigate the adhesion property, cross-cut tape tests and peel tests were performed. The results showed a significant improvement of the adhesion and in-soak long-term performance of our proposed encapsulation stack compared with PDMS on parylene and PDMS on plasma-treated parylene. We aim to use the proposed solution to package bare silicon chips on active implants.

Metal and Polymeric Strain Gauges for Si-Based, Monolithically Fabricated Organs-on-Chips.

Organ-on-chip (OOC) is becoming the alternative tool to conventional in vitro screening. Heart-on-chip devices including microstructures for mechanical and electrical stimulation have been demonstrated to be advantageous to study structural organization and maturation of heart cells. This paper presents the development of metal and polymeric strain gauges for in situ monitoring of mechanical strain in the Cytostretch platform for heart-on-chip application. Specifically, the optimization of the fabrication process of metal titanium (Ti) strain gauges and the investigation on an alternative material to improve the robustness and performance of the devices are presented. The transduction behavior and functionality of the devices are successfully proven using a custom-made set-up. The devices showed resistance changes for the pressure range (0-3 kPa) used to stretch the membranes on which heart cells can be cultured. Relative resistance changes of approximately 0.008% and 1.2% for titanium and polymeric strain gauges are respectively reported for membrane deformations up to 5%. The results demonstrate that both conventional IC metals and polymeric materials can be implemented for sensing mechanical strain using robust microfabricated organ-on-chip devices.

Effect of Signals on the Encapsulation Performance of Parylene Coated Platinum Tracks for Active Medical Implants.

Platinum is widely used as the electrode material for implantable devices. Owing to its high biostability and corrosion resistivity, platinum could also be used as the main metallization for tracks in active implants. Towards this goal, in this work we investigate the stability of parylene-coated Pt tracks using passive and active tests. The test samples in this study are Pt-on-SiO2 interdigitated comb structures. During testing all samples were immersed in saline for 150 days; for passive testing, the samples were left unbiased, whilst for active testing, samples were exposed to two different stress signals: a 5 V DC and a 5 Vp 500 pulses per second biphasic signal. All samples were monitored over time using impedance spectroscopy combined with optical inspection. After the first two weeks of immersion, delamination spots were observed on the Pt tracks for both passive and actively tested samples. Despite the delamination spots, the unbiased samples maintained high impedances until the end of the study. For the actively stressed samples, two different failure mechanisms were observed which were signal related. DC stressed samples showed severe parylene cracking mainly due to the electrolysis of the condensed water. Biphasically stressed samples showed gradual Pt dissolution and migration. These results contribute to a better understanding of the failure mechanisms of Pt tracks in active implants and suggest that new testing paradigms may be necessary to fully assess the long-term reliability of these devices.

A Platform for Mechano(-Electrical) Characterization of Free-Standing Micron-Sized Structures and Interconnects.

A device for studying the mechanical and electrical behavior of free-standing micro-fabricated metal structures, subjected to a very large deformation, is presented in this paper. The free-standing structures are intended to serve as interconnects in high-density, highly stretchable electronic circuits. For an easy, damage-free handling and mounting of these free-standing structures, the device is designed to be fabricated as a single chip/unit that is separated into two independently movable parts after it is fixed in the tensile test stage. Furthermore, the fabrication method allows for test structures of different geometries to be easily fabricated on the same substrate. The utility of the device has been demonstrated by stretching the free-standing interconnect structures in excess of 1000% while simultaneously measuring their electrical resistance. Important design considerations and encountered processing challenges and their solutions are discussed in this paper.

Comparing continual task learning in minds and machines.

Humans can learn to perform multiple tasks in succession over the lifespan ("continual" learning), whereas current machine learning systems fail. Here, we investigated the cognitive mechanisms that permit successful continual learning in humans and harnessed our behavioral findings for neural network design. Humans categorized naturalistic images of trees according to one of two orthogonal task rules that were learned by trial and error. Training regimes that focused on individual rules for prolonged periods (blocked training) improved human performance on a later test involving randomly interleaved rules, compared with control regimes that trained in an interleaved fashion. Analysis of human error patterns suggested that blocked training encouraged humans to form "factorized" representation that optimally segregated the tasks, especially for those individuals with a strong prior bias to represent the stimulus space in a well-structured way. By contrast, standard supervised deep neural networks trained on the same tasks suffered catastrophic forgetting under blocked training, due to representational interference in the deeper layers. However, augmenting deep networks with an unsupervised generative model that allowed it to first learn a good embedding of the stimulus space (similar to that observed in humans) reduced catastrophic forgetting under blocked training. Building artificial agents that first learn a model of the world may be one promising route to solving continual task performance in artificial intelligence research.

Ultra-Stretchable Interconnects for High-Density Stretchable Electronics.

The exciting field of stretchable electronics (SE) promises numerous novel applications, particularly in-body and medical diagnostics devices. However, future advanced SE miniature devices will require high-density, extremely stretchable interconnects with micron-scale footprints, which calls for proven standardized (complementary metal-oxide semiconductor (CMOS)-type) process recipes using bulk integrated circuit (IC) microfabrication tools and fine-pitch photolithography patterning. Here, we address this combined challenge of microfabrication with extreme stretchability for high-density SE devices by introducing CMOS-enabled, free-standing, miniaturized interconnect structures that fully exploit their 3D kinematic freedom through an interplay of buckling, torsion, and bending to maximize stretchability. Integration with standard CMOS-type batch processing is assured by utilizing the Flex-to-Rigid (F2R) post-processing technology to make the back-end-of-line interconnect structures free-standing, thus enabling the routine microfabrication of highly-stretchable interconnects. The performance and reproducibility of these free-standing structures is promising: an elastic stretch beyond 2000% and ultimate (plastic) stretch beyond 3000%, with <0.3% resistance change, and >10 million cycles at 1000% stretch with <1% resistance change. This generic technology provides a new route to exciting highly-stretchable miniature devices.

Cytostretch, an Organ-on-Chip Platform.

Organ-on-Chips (OOCs) are micro-fabricated devices which are used to culture cells in order to mimic functional units of human organs. The devices are designed to simulate the physiological environment of tissues in vivo. Cells in some types of OOCs can be stimulated in situ by electrical and/or mechanical actuators. These actuations can mimic physiological conditions in real tissue and may include fluid or air flow, or cyclic stretch and strain as they occur in the lung and heart. These conditions similarly affect cultured cells and may influence their ability to respond appropriately to physiological or pathological stimuli. To date, most focus has been on devices specifically designed to culture just one functional unit of a specific organ: lung alveoli, kidney nephrons or blood vessels, for example. In contrast, the modular Cytostretch membrane platform described here allows OOCs to be customized to different OOC applications. The platform utilizes silicon-based micro-fabrication techniques that allow low-cost, high-volume manufacturing. We describe the platform concept and its modules developed to date. Membrane variants include membranes with (i) through-membrane pores that allow biological signaling molecules to pass between two different tissue compartments; (ii) a stretchable micro-electrode array for electrical monitoring and stimulation; (iii) micro-patterning to promote cell alignment; and (iv) strain gauges to measure changes in substrate stress. This paper presents the fabrication and the proof of functionality for each module of the Cytostretch membrane. The assessment of each additional module demonstrate that a wide range of OOCs can be achieved.

Stress-optic modulator in TriPleX platform using a ezoelectric lead zirconate titanate (PZT) thin film.

We will demonstrate a stress-optic phase modulator in the passive SiN-based TriPleX platform using a layer of piezoelectric material. Regarding the stress-optic effect, the piezoelectric layer deposited on top of an optical waveguide is employed to control the phase of propagating light in the structure by applying an electrical field across the layer. In this work, it is demonstrated that the stress-optic effect lowers the power consumption by a factor of one million for quasi-DC operation and increases the modulation speed by three orders of magnitude, compared to currently used thermo-optic modulation in the TriPleX platform.

Fluorescence monitoring of microchip capillary electrophoresis separation with monolithically integrated waveguides.

Using femtosecond laser writing, optical waveguides were monolithically integrated into a commercial microfluidic lab-on-a-chip device, with the waveguides intersecting a microfluidic channel. Continuous-wave laser excitation through these optical waveguides confines the excitation window to a width of 12 microm, enabling high-resolution monitoring of the passage of different types of fluorescent analytes when migrating and being separated in the microfluidic channel by microchip capillary electrophoresis. Furthermore, we demonstrate on-chip-integrated waveguide excitation and detection of a biologically relevant species, fluorescently labeled DNA molecules, during microchip capillary electrophoresis. Well-controlled plug formation as required for on-chip integrated capillary electrophoresis separation of DNA molecules, and the combination of waveguide excitation and a low limit of detection, will enable monitoring of extremely small quantities with high spatial resolution.