A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy - PubMed (original) (raw)
A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy
Micah Roschelle et al. IEEE J Solid-State Circuits. 2024 Nov.
Abstract
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 microlaser 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 μ m 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.
Keywords: Biomedical implant; fluorescence imaging; immunotherapy; personalized medicine; ultrasound energy harvesting.
Figures
Fig. 1:
Concept of a fully wireless, multicolor, implantable imager for real-time monitoring of immune response.
Fig. 2:
(a) To-scale diagram of the full system. (b) Mechanical assembly.
Fig. 3:
Multicolor fluorescence imaging. (a) Each cell type is labeled with a different color fluorescent probe. (b,c) Fluorophores are excited near the absorption peak and emit light at a slightly longer wavelength. A multi-bandpass filter passes emissions while blocking the excitation light.
Fig. 4:
Measured laser diode (a) PIV curves and (b) wall-plug efficiencies.
Fig. 5:
(a) Normal incidence transmittance spectra of the multi-bandpass interference filter. (b,c) Measured transmittance through the FOP across AOIs. (d) Angular transmittance of the filter with and without the FOP measured at the excitation laser wavelengths.
Fig. 6:
(a) Piezo assembly with the air gap. (b) Measured electrical impedance of the piezo across frequency. (c) Measured harvested voltage across frequency with the piezo in open circuit condition and loaded by the chip.
Fig. 7:
(a) In black, the SNR of a pixel with the estimated photocurrent and measured dark noise (see Fig. 21(c)) across different exposure times (TEXP,i) and averaging nI images such that total imaging time TEXPini=96ms remains constant. In blue, the SNR after xi averages (orange) required to maintain 90% of the SNR at TEXPi=96ms. (b) Capacitor size vs. exposure time.
Fig. 8:
System block diagram.
Fig. 9:
PMU schematic consisting of (a) a full-wave active rectifier, (b) a cross-coupled charge pump, and (c) storage capacitors.
Fig. 10:
PTAT schematic
Fig. 11:
System timing diagram.
Fig. 12:
Schematic of watchdog circuit with error-tolerant edge detection.
Fig. 13:
Schematic of the 3-channel programmable laser driver.
Fig. 14:
(a) Active pixel architecture with correlated double sampling. (b) Pixel timing diagram.
Fig. 15:
(a) Chip micrograph. (b) Breakdown of system power consumption.
Fig. 16:
Measurement setup for wireless imaging.
Fig. 17:
Measured PMU waveforms during (a) Charge-Up and (b) Imaging and Readout. (c) Measured backscatter waveforms.
Fig. 18:
Harvested acoustic power vs. (a) transverse offset and (b) depth.
Fig. 19:
Measured bit error rate (BER) at 5cm depth in oil.
Fig. 20:
Measurements of (a) laser driver current (ILD) vs. DAC code, (b) percent change in ILD vs. driver output voltage (VLD-), and (c) PTAT voltage reference VREF0.5V variation vs. VCP.
Fig. 21:
(a) Pixel output voltage vs. incident optical power. (b) Histogram of measured dark current across pixels. (c) Measured pixel noise under dark condition for a single frame and after 8 averages.
Fig. 22:
Resolution measurements using (a) USAF target. Image of element with 125μm line width with the sensor (b) and a microscope (c). (d) Line scan of image in (a). (e) Measured contrast transfer function.
Fig. 23:
3-color imaging of fluorescent beads.
Fig. 24:
Ex vivo imaging of mouse tumors with and without immunotherapy. Imaging results for (a) the resistant tumor model (LLC) and (b) the responsive model (B16F10). (c) Metrics for quantification of cell populations. (d) Quantified results.
Update of
- A Wireless, Multicolor Fluorescence Image Sensor Implant for Real-Time Monitoring in Cancer Therapy.
Roschelle M, Rabbani R, Gweon S, Kumar R, Vercruysse A, Cho NW, Spitzer MH, Niknejad AM, Stojanović VM, Anwar M. Roschelle M, et al. ArXiv [Preprint]. 2024 Jun 27:arXiv:2406.18881v1. ArXiv. 2024. PMID: 38979489 Free PMC article. Updated. Preprint.
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