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.

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.

Phased Array Beamforming Methods for Powering Biomedical Ultrasonic Implants.

Millimeter-scale implants using ultrasound (US) for power and communication have been proposed for a range of deep-tissue applications, including neural recording and stimulation. However, published implementations have shown high sensitivity to misalignment with the external US transducer. Ultrasonic beamforming using a phased array to these implants can improve tolerance to misalignment, reduce implant volume, and allow multiple implants to be operated simultaneously in different locations. This article details the design of a custom planar phased array US system, which is capable of steering and focusing US power within a 3-D volume. Analysis and simulation is performed to determine the choice of array element pitch, with special attention given to maximizing the power available at the implant while meeting FDA limits for diagnostic US. Time reversal (TR) is proposed as a computationally simple approach to beamforming that is robust despite scattering and inhomogeneity of the acoustic medium. This technique is demonstrated both in active drive and pulse-echo modes, and it is experimentally compared with other beamforming techniques by measuring energy transfer efficiency. Simultaneous power delivery to multiple implants is also demonstrated.

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.

Optimizing Volumetric Efficiency and Backscatter Communication in Biosensing Ultrasonic Implants.

Ultrasonic backscatter communication has gained popularity in recent years with the advent of deep-tissue sub-mm scale biosensing implants in which piezoceramic (piezo) resonators are used as acoustic antennas. Miniaturization is a key design goal for such implants to reduce tissue displacement and enable minimally invasive implantation techniques. Here, we provide a systematic design approach for the implant piezo geometry and operation frequency to minimize the overall volume of the implant. Optimal geometry of the implant piezo for backscatter communication is discussed and contrasted with that of power harvesting. A critical design aspect of an ultrasonic backscatter communication link is the response of the piezo acoustic reflection coefficient Γ with respect to the variable shunt impedance, ZE, of the implant uplink modulator. Due to the complexity of the piezo governing equations and multi-domain, electro-acoustical nature of the piezo, Γ(ZE) has often been characterized numerically and the implant uplink modulator has been designed empirically resulting in sub-optimal performance in terms of data rate and linearity. Here, we present a SPICE friendly end-to-end equivalent circuit model of the channel as a piezo-IC co-simulation tool that incorporates inherent path losses present in a typical ultrasonic backscatter channel. To provide further insight into the channel response, we present experimentally validated closed form expressions for Γ(ZE) under various boundary conditions. These expressions couple Γ to the commonly used Thevenin equivalent circuit model of the piezo, facilitating systematic design and synthesis of ultrasonic backscatter uplink modulators.

High Throughput Ultrasonic Multi-implant Readout Using a Machine-Learning Assisted CDMA Receiver.

Untethered, wireless peripheral nerve recording for prosthetic control requires multi-implant communications at high data rates. This work presents a multiple-access ultrasonic uplink data communication channel comprised of 4 free-floating implants and a single-element external transducer. Using code-division multiple access (CDMA), overall channel data rates of up to 784 kbps were measured, and a machine-learning assisted decoder improved BER by >100x. Compared with prior art, this work incorporates the largest number of implants at the highest data rate and spectral efficiency reported.