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  1. Abstract

    Mesoscopic calcium imaging enables studies of cell-type specific neural activity over large areas. A growing body of literature suggests that neural activity can be different when animals are free to move compared to when they are restrained. Unfortunately, existing systems for imaging calcium dynamics over large areas in non-human primates (NHPs) are table-top devices that require restraint of the animal’s head. Here, we demonstrate an imaging device capable of imaging mesoscale calcium activity in a head-unrestrained male non-human primate. We successfully miniaturize our system by replacing lenses with an optical mask and computational algorithms. The resulting lensless microscope can fit comfortably on an NHP, allowing its head to move freely while imaging. We are able to measure orientation columns maps over a 20 mm2field-of-view in a head-unrestrained macaque. Our work establishes mesoscopic imaging using a lensless microscope as a powerful approach for studying neural activity under more naturalistic conditions.

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  2. Abstract

    Histopathology plays a critical role in the diagnosis and surgical management of cancer. However, access to histopathology services, especially frozen section pathology during surgery, is limited in resource-constrained settings because preparing slides from resected tissue is time-consuming, labor-intensive, and requires expensive infrastructure. Here, we report a deep-learning-enabled microscope, named DeepDOF-SE, to rapidly scan intact tissue at cellular resolution without the need for physical sectioning. Three key features jointly make DeepDOF-SE practical. First, tissue specimens are stained directly with inexpensive vital fluorescent dyes and optically sectioned with ultra-violet excitation that localizes fluorescent emission to a thin surface layer. Second, a deep-learning algorithm extends the depth-of-field, allowing rapid acquisition of in-focus images from large areas of tissue even when the tissue surface is highly irregular. Finally, a semi-supervised generative adversarial network virtually stains DeepDOF-SE fluorescence images with hematoxylin-and-eosin appearance, facilitating image interpretation by pathologists without significant additional training. We developed the DeepDOF-SE platform using a data-driven approach and validated its performance by imaging surgical resections of suspected oral tumors. Our results show that DeepDOF-SE provides histological information of diagnostic importance, offering a rapid and affordable slide-free histology platform for intraoperative tumor margin assessment and in low-resource settings.

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  3. Traditional miniaturized fluorescence microscopes are critical tools for modern biology. Invariably, they struggle to simultaneously image with a high spatial resolution and a large field of view (FOV). Lensless microscopes offer a solution to this limitation. However, real-time visualization of samples is not possible with lensless imaging, as image reconstruction can take minutes to complete. This poses a challenge for usability, as real-time visualization is a crucial feature that assists users in identifying and locating the imaging target. The issue is particularly pronounced in lensless microscopes that operate at close imaging distances. Imaging at close distances requires shift-varying deconvolution to account for the variation of the point spread function (PSF) across the FOV. Here, we present a lensless microscope that achieves real-time image reconstruction by eliminating the use of an iterative reconstruction algorithm. The neural network-based reconstruction method we show here, achieves more than 10000 times increase in reconstruction speed compared to iterative reconstruction. The increased reconstruction speed allows us to visualize the results of our lensless microscope at more than 25 frames per second (fps), while achieving better than 7 µm resolution over a FOV of 10 mm2. This ability to reconstruct and visualize samples in real-time empowers a more user-friendly interaction with lensless microscopes. The users are able to use these microscopes much like they currently do with conventional microscopes.

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  4. This paper presents the design, implementation, and experimental evaluation of a wireless biomedical implant platform exploiting the magnetoelectric effect for wireless power and bi-directional communication. As an emerging wireless power transfer method, magnetoelectric is promising for mm-scaled bio-implants because of its superior misalignment sensitivity, high efficiency, and low tissue absorption compared to other modalities [46, 59, 60]. Utilizing the same physical mechanism for power and communication is critical for implant miniaturization, but low-power magnetoelectric uplink communication has not been achieved yet. For the first time, we design and demonstrate near-zero power magnetoelectric backscatter from the mm-sized implants by exploiting the converse magnetostriction effects. The system for demonstration consists of an 8.2-mm3 wireless implantable device and a custom portable transceiver. The implant's ASIC interfacing with the magnetoelectric transducer encodes uplink data by changing the transducer's load, resulting in resonance frequency changes for frequency-shift-keying modulation. The magnetoelectrically backscattered signal is sensed and demodulated through frequency-to-digital conversion by the external transceiver. With design optimizations in data modulation and recovery, the proposed system archives > 1-kbps data rate at the 335-kHz carrier frequency, with a communication distance greater than 2 cm and a bit error rate less than 1E-3. Further, we validate the proposed system for wireless stimulation and sensing, and conducted ex-vivo tests through a 1.5-cm porcine tissue. The proposed magnetoelectric backscatter approach provides a path towards miniaturized wireless bio-implants for advanced biomedical applications like closed-loop neuromodulation. 
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  5. Lensless imaging provides opportunities to design imaging systems free from the constraints imposed by traditional camera architectures. Due to advances in imaging hardware, fabrication techniques, and new algorithms, researchers have recently developed lensless imaging systems that are extremely compact and lightweight or able to image higher-dimensional quantities. Here we review these recent advances and describe the design principles and their effects that one should consider when developing and using lensless imaging systems.

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  6. Abstract The simple and compact optics of lensless microscopes and the associated computational algorithms allow for large fields of view and the refocusing of the captured images. However, existing lensless techniques cannot accurately reconstruct the typical low-contrast images of optically dense biological tissue. Here we show that lensless imaging of tissue in vivo can be achieved via an optical phase mask designed to create a point spread function consisting of high-contrast contours with a broad spectrum of spatial frequencies. We built a prototype lensless microscope incorporating the ‘contour’ phase mask and used it to image calcium dynamics in the cortex of live mice (over a field of view of about 16 mm 2 ) and in freely moving Hydra vulgaris , as well as microvasculature in the oral mucosa of volunteers. The low cost, small form factor and computational refocusing capability of in vivo lensless microscopy may open it up to clinical uses, especially for imaging difficult-to-reach areas of the body. 
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