A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy.

Real-time monitoring of dynamic biological processes in the body is critical to understanding disease progression and treatment response. This data, for instance, can help address the lower than 50% response rates to cancer immunotherapy. However, current clinical imaging modalities lack the molecular contrast, resolution, and chronic usability for rapid and accurate response assessments. Here, we present a fully wireless image sensor featuring a 2.5×5 mm2 CMOS integrated circuit for multicolor fluorescence imaging deep in tissue. The sensor operates wirelessly via ultrasound (US) at 5 cm depth in oil, harvesting energy with 221 mW/cm2 incident US power density (31% of FDA limits) and backscattering data at 13 kbps with a bit error rate <10-6. In-situ fluorescence excitation is provided by micro-laser diodes controlled with a programmable on-chip driver. An optical frontend combining a multi-bandpass interference filter and a fiber optic plate provides >6 OD excitation blocking and enables three-color imaging for detecting multiple cell types. A 36×40-pixel array captures images with <125 µm resolution. We demonstrate wireless, dual-color fluorescence imaging of both effector and suppressor immune cells in ex vivo mouse tumor samples with and without immunotherapy. These results show promise for providing rapid insight into therapeutic response and resistance, guiding personalized medicine.

Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter.

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure the successful removal of all gross and microscopic diseases with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here, we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumors and nerves in ex vivo prostate tissue.

Towards A Wireless Image Sensor for Real-Time Fluorescence Microscopy in Cancer Therapy.

We present a mm-sized, ultrasonically powered lensless CMOS image sensor as a progress towards wireless fluorescence microscopy. Access to biological information within the tissue has the potential to provide insights guiding diagnosis and treatment across numerous medical conditions including cancer therapy. This information, in conjunction with current clinical imaging techniques that have limitations in obtaining images continuously and lack wireless compatibility, can improve continual detection of multicell clusters deep within tissue. The proposed platform incorporates a 2.4×4.7 mm2 integrated circuit (IC) fabricated in TSMC 0.18 µm, a micro laser diode (µLD), a single piezoceramic and off-chip storage capacitors. The IC consists of a 36×40 array of capacitive trans-impedance amplifier-based pixels, wireless power management and communication via ultrasound and a laser driver all controlled by a Finite State Machine. The piezoceramic harvests energy from the acoustic waves at a depth of 2 cm to power up the IC and transfer 11.5 kbits/frame via backscattering. During Charge-Up, the off-chip capacitor stores charge to later supply a high-power 78 mW µLD during Imaging. Proof of concept of the imaging front end is shown by imaging distributions of CD8 T-cells, an indicator of the immune response to cancer, ex vivo, in the lymph nodes of a functional immune system (BL6 mice) against colorectal cancer consistent with the results of a fluorescence microscope. The overall system performance is verified by detecting 140 µm features on a USAF resolution target with 32 ms exposure time and 389 ms ultrasound backscattering.

Multicolor fluorescence microscopy for surgical guidance using a chip-scale imager with a low-NA fiber optic plate and a multi-bandpass interference filter.

In curative-intent cancer surgery, intraoperative fluorescence imaging of both diseased and healthy tissue can help to ensure successful removal of all gross and microscopic disease with minimal damage to neighboring critical structures, such as nerves. Current fluorescence-guided surgery (FGS) systems, however, rely on bulky and rigid optics that incur performance-limiting trade-offs between sensitivity and maneuverability. Moreover, many FGS systems are incapable of multiplexed imaging. As a result, clinical FGS is currently limited to millimeter-scale detection of a single fluorescent target. Here we present a scalable, lens-less fluorescence imaging chip, VISION, capable of sensitive and multiplexed detection within a compact form factor. Central to VISION is a novel optical frontend design combining a low-numerical-aperture fiber optic plate (LNA-FOP) and a multi-bandpass interference filter, which is affixed to a custom CMOS image sensor. The LNA-FOP acts as a planar collimator to improve resolution and compensate for the angle-sensitivity of the interference filter, enabling high-resolution and multiplexed fluorescence imaging without lenses. We show VISION is capable of detecting tumor foci of less than 100 cells at near video framerates and, as proof of principle, can simultaneously visualize both tumor and nerves in ex vivo prostate tissue.

Towards A Wireless Image Sensor for Real-Time Fluorescence Microscopy in Cancer Therapy.

We present a mm-sized, ultrasonically powered lensless CMOS image sensor as a progress towards wireless fluorescence microscopy. Access to biological information within the tissue has the potential to provide insights guiding diagnosis and treatment across numerous medical conditions including cancer therapy. This information, in conjunction with current clinical imaging techniques that have limitations in obtaining images continuously and lack wireless compatibility, can improve continual detection of multicell clusters deep within tissue. The proposed platform incorporates a 2.4×4.7 mm2 integrated circuit (IC) fabricated in TSMC 0.18 µm, a micro laser diode (µLD), a single piezoceramic and off-chip storage capacitors. The IC consists of a 36×40 array of capacitive trans-impedance amplifier-based pixels, wireless power management and communication via ultrasound and a laser driver all controlled by a Finite State Machine. The piezoceramic harvests energy from the acoustic waves at a depth of 2 cm to power up the IC and transfer 11.5 kbits/frame via backscattering. During Charge-Up, the off-chip capacitor stores charge to later supply a high-power 78 mW µLD during Imaging. Proof of concept of the imaging front end is shown by imaging distributions of CD8 T-cells, an indicator of the immune response to cancer, ex vivo, in the lymph nodes of a functional immune system (BL6 mice) against colorectal cancer consistent with the results of a fluorescence microscope. The overall system performance is verified by detecting 140 µm features on a USAF resolution target with 32 ms exposure time and 389 ms ultrasound backscattering.

3D Reconstruction of cellular images from microfabricated imagers using fully-adaptive deep neural networks.

Millimeter-scale multi-cellular level imagers enable various applications, ranging from intraoperative surgical navigation to implantable sensors. However, the tradeoffs for miniaturization compromise resolution, making extracting 3D cell locations challenging-critical for tumor margin assessment and therapy monitoring. This work presents three machine-learning-based modules that extract spatial information from single image acquisitions using custom-made millimeter-scale imagers. The neural networks were trained on synthetically-generated (using Perlin noise) cell images. The first network is a convolutional neural network estimating the depth of a single layer of cells, the second is a deblurring module correcting for the point spread function (PSF). The final module extracts spatial information from a single image acquisition of a 3D specimen and reconstructs cross-sections, by providing a layered "map" of cell locations. The maximum depth error of the first module is 100 µm, with 87% test accuracy. The second module's PSF correction achieves a least-square-error of only 4%. The third module generates a binary "cell" or "no cell" per-pixel labeling with an accuracy ranging from 89% to 85%. This work demonstrates the synergy between ultra-small silicon-based imagers that enable in vivo imaging but face a trade-off in spatial resolution, and the processing power of neural networks to achieve enhancements beyond conventional linear optimization techniques.

Towards an Implantable Fluorescence Image Sensor for Real-Time Monitoring of Immune Response in Cancer Therapy.

Real-time monitoring of cellular-level changes inside the body provides key information regarding disease progression and therapy assessment for critical care including cancer therapy. Current state-of-the-art oncological imaging methods impose unnecessary latencies to detect small cell foci. Invasive methods such as biopsies, on the other hand, cause disruption if deployed on a repeated basis. Therefore, they are not practical for real-time assessments of the tumor tissue. This work presents a proof-of-concept design for an implantable fluorescence lensless image sensor to address the pervasive challenge of real-time tracking of the immune response in immunotherapy. The 2.4x4.7 mm2 integrated circuit (IC) prototype consists of a 36 by 40 pixel array, a laser driver and a power management unit harvesting power and transferring 11.5 kbits/frame through a wireless ultrasound link while implanted 2 cm deep inside the body. Compared to prior art, this is the first full-fledged wireless system implementing chip-scale fluorescence microscopy to the best of our knowledge.Clinical relevance- This prototype can be used to personalize immunotherapy for the 50% of cancer patients who do not initially respond to the therapy.