High-density integration of ultrabright OLEDs on a miniaturized needle-shaped CMOS backplane

This work was supported in part by the Defense Advanced Research Projects Agency (DARPA) under Contract N6600117C4012, by the National Institutes of Health under Grant U01NS090596, and by the Leverhulme Trust (RPG-2017-231). C.K.M. acknowledges funding from the European Commission through a Marie Skłodowska Curie individual fellowship (101029807). M.C.G. acknowledges funding from the Alexander von Humboldt Stiftung (Humboldt-Professorship). We thank Aaron Naden for the FIB/STEM measurements (Engineering and Physical Sciences Research Council under grant numbers EP/L017008/1, EP/R023751/1 and EP/T019298/1).Direct deposition of organic light-emitting diodes (OLEDs) on silicon-based complementary metal–oxide–semiconductor (CMOS) chips has enabled self-emissive microdisplays with high resolution and fill-factor. Emerging applications of OLEDs in augmented and virtual reality (AR/VR) displays and in biomedical applications, e.g., as brain implants for cell-specific light delivery in optogenetics, require light intensities orders of magnitude above those found in traditional displays. Further requirements often include a microscopic device footprint, a specific shape and ultrastable passivation, e.g., to ensure biocompatibility and minimal invasiveness of OLED-based implants. In this work, up to 1024 ultrabright, microscopic OLEDs are deposited directly on needle-shaped CMOS chips. Transmission electron microscopy and energy-dispersive X-ray spectroscopy are performed on the foundry-provided aluminum contact pads of the CMOS chips to guide a systematic optimization of the contacts. Plasma treatment and implementation of silver interlayers lead to ohmic contact conditions and thus facilitate direct vacuum deposition of orange- and blue-emitting OLED stacks leading to micrometer-sized pixels on the chips. The electronics in each needle allow each pixel to switch individually. The OLED pixels generate a mean optical power density of 0.25 mW mm−2, corresponding to >40 000 cd m−2, well above the requirement for daylight AR applications and optogenetic single-unit activation in the brain.Publisher PDFPeer reviewe

Optogenetic stimulation probes with single-neuron resolution based on organic LEDs monolithically integrated on CMOS

Funding: This work was supported in part by the Defense Advanced Research Projects Agency (DARPA) under contract N6600117C4012, by the National Institutes of Health under grant U01NS090596, by the Leverhulme Trust (RPG-2017-231) and by the Alexander von Humboldt Stiftung (Humboldt-Professorship to M.C.G.). This work was performed in part at the Columbia Nano Initiative cleanroom facility, at the CUNY Advanced Science Research Center Nanofabrication Facility, and at the Singh Center for Nanotechnology, part of the National Nanotechnology Coordinated Infrastructure Program, which is supported by the National Science Foundation grant NNCI-2025608. C.-K.M. acknowledges funding from the European Commission through a Marie-Skłodowska Curie Individual Fellowship (101029807).The use of optogenetic stimulation to evoke neuronal activity in targeted neural populations—enabled by opsins with fast kinetics, high sensitivity and cell-type and subcellular specificity—is a powerful tool in neuroscience. However, to interface with the opsins, deep-brain light delivery systems are required that match the scale of the spatial and temporal control offered by the molecular actuators. Here we show that organic light-emitting diodes can be combined with complementary metal–oxide–semiconductor technology to create bright, actively multiplexed emissive elements. We create implantable shanks in which 1,024 individually addressable organic light-emitting diode pixels with a 24.5 µm pitch are integrated with active complementary metal–oxide–semiconductor drive and control circuitry. This integration is enabled by controlled electrode conditioning, monolithic deposition of the organic light-emitting diodes and optimized thin-film encapsulation. The resulting probes can be used to access brain regions as deep as 5 mm and selectively activate individual neurons with millisecond-level precision in mice.Publisher PDFPeer reviewe

Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes

BACKGROUND: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. METHODS: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. RESULTS: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2–11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). CONCLUSIONS: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/N

A 512-Pixel 3kHz-Frame-Rate Dual-Shank Lensless Filterless Single-Photon-Avalanche-Diode CMOS Neural Imaging Probe

Optical functional neural imaging has revolutionized neuroscience with optical reporters that enable single-cell-resolved monitoring of neuronal activity in vivo. State-of-the-art microscopy methods, however, are fundamentally limited in imaging depth by absorption and scattering in tissue even with the use of the most sophisticated two-photon microscopy techniques [1]. To overcome this imaging depth problem, we develop a lens-less, optical-filter-less, shank-based image sensor array that can be inserted into the brain, allowing cellular-resolution recording at arbitrary depths with excitation provided by an external laser light source (Fig. 11.5.1). Lens-less imaging is achieved generally by giving each pixel a spatial sensitivity function, which can be introduced by near-field or far-field, phase or amplitude masking. Since probe thickness must be less than 70μm to limit tissue damage and far-field masks are characterized by distances on the order of 200μm between the mask and the detector [2], we employ a near-field amplitude mask formed by Talbot gratings in the back-end metal of the CMOS process, which gives each pixel a diffraction-grating-induced angle-sensitivity [3]. Filter-less fluorescence imaging is achieved with time-gated operation in which the excitation light source is pulsed and pixel-level time-gated circuitry collects photons only after the excitation source has been removed

A 512-Pixel 3kHz-Frame-Rate Dual-Shank Lensless Filterless Single-Photon-Avalanche-Diode CMOS Neural Imaging Probe

Optical functional neural imaging has revolutionized neuroscience with optical reporters that enable single-cell-resolved monitoring of neuronal activity in vivo. State-of-the-art microscopy methods, however, are fundamentally limited in imaging depth by absorption and scattering in tissue even with the use of the most sophisticated two-photon microscopy techniques [1]. To overcome this imaging depth problem, we develop a lens-less, optical-filter-less, shank-based image sensor array that can be inserted into the brain, allowing cellular-resolution recording at arbitrary depths with excitation provided by an external laser light source (Fig. 11.5.1). Lens-less imaging is achieved generally by giving each pixel a spatial sensitivity function, which can be introduced by near-field or far-field, phase or amplitude masking. Since probe thickness must be less than 70μm to limit tissue damage and far-field masks are characterized by distances on the order of 200μm between the mask and the detector [2], we employ a near-field amplitude mask formed by Talbot gratings in the back-end metal of the CMOS process, which gives each pixel a diffraction-grating-induced angle-sensitivity [3]. Filter-less fluorescence imaging is achieved with time-gated operation in which the excitation light source is pulsed and pixel-level time-gated circuitry collects photons only after the excitation source has been removed

A 512-Pixel, 51-kHz-Frame-Rate, Dual-Shank, Lens-Less, Filter-Less Single-Photon Avalanche Diode CMOS Neural Imaging Probe

We present an implantable single-photon shank-based imager, monolithically integrated onto a single CMOS IC. The imager comprises of 512 single-photon avalanche diodes distributed along two shanks, with a 6-bit depth in-pixel memory and an on-chip digital-to-time converter. To scale down the system to a minimally invasive form factor, we substitute optical filtering and focusing elements with a time-gated, angle-sensitive detection system. The imager computationally reconstructs the position of fluorescent sources within a 3-D volume of 3.4 mm × 600 μm× 400 μm

Fully Integrated Time-Gated 3D Fluorescence Imager for Deep Neural Imaging

This paper presents a device for time-gated fluorescence imaging in the deep brain, consisting of two on-chip laser diodes and 512 single-photon avalanche diodes (SPADs). The edge-emitting laser diodes deliver fluorescence excitation above the SPAD array, parallel to the imager. In the time domain, laser diode illumination is pulsed and the SPAD is time-gated, allowing a fluorescence excitation rejection up to O.D. 3 at 1 ns of time-gate delay. Each SPAD pixel is masked with Talbot gratings to enable the mapping of 2D array photon counts into a 3D image. The 3D image achieves a resolution of 40, 35, and 73 μm in the x, y, and z directions, respectively, in a noiseless environment, with a maximum frame rate of 50 kilo-frames-per-second. We present measurement results of the spatial and temporal profiles of the dual-pulsed laser diode illumination and of the photon detection characteristics of the SPAD array. Finally, we show the imager's ability to resolve a glass micropipette filled with red fluorescent microspheres. The system's 420 μm-wide cross section allows it to be inserted at arbitrary depths of the brain while achieving a field of view four times larger than fiber endoscopes of equal diameter

Fully Integrated Time-Gated 3D Fluorescence Imager for Deep Neural Imaging

This paper presents a device for time-gated fluorescence imaging in the deep brain, consisting of two on-chip laser diodes and 512 single-photon avalanche diodes (SPADs). The edge-emitting laser diodes deliver fluorescence excitation above the SPAD array, parallel to the imager. In the time domain, laser diode illumination is pulsed and the SPAD is time-gated, allowing a fluorescence excitation rejection up to O.D. 3 at 1 ns of time-gate delay. Each SPAD pixel is masked with Talbot gratings to enable the mapping of 2D array photon counts into a 3D image. The 3D image achieves a resolution of 40, 35, and 73 μm in the x, y, and z directions, respectively, in a noiseless environment, with a maximum frame rate of 50 kilo-frames-per-second. We present measurement results of the spatial and temporal profiles of the dual-pulsed laser diode illumination and of the photon detection characteristics of the SPAD array. Finally, we show the imager's ability to resolve a glass micropipette filled with red fluorescent microspheres. The system's 420 μm-wide cross section allows it to be inserted at arbitrary depths of the brain while achieving a field of view four times larger than fiber endoscopes of equal diameter