Intracellular detection and communication of a wireless chip in cell

Abstract

The rapid growth and development of technology has had significant implications for healthcare, personalized medicine, and our understanding of biology. In this work, we leverage the miniaturization of electronics to realize the first demonstration of wireless detection and communication of an electronic device inside a cell. This is a significant forward step towards a vision of non-invasive, intracellular wireless platforms for single-cell analyses. We demonstrate that a 25 [Formula: see text]m wireless radio frequency identification (RFID) device can not only be taken up by a mammalian cell but can also be detected and specifically identified externally while located intracellularly. The S-parameters and power delivery efficiency of the electronic communication system is quantified before and after immersion in a biological environment; the results show distinct electrical responses for different RFID tags, allowing for classification of cells by examining the electrical output noninvasively. This versatile platform can be adapted for realization of a broad modality of sensors and actuators. This work precedes and facilitates the development of long-term intracellular real-time measurement systems for personalized medicine and furthering our understanding of intrinsic biological behaviors. It helps provide an advanced technique to better assess the long-term evolution of cellular physiology as a result of drug and disease stimuli in a way that is not feasible using current methods.

Figure 1

Cell containing intracellular RFID aligned within transceiver antenna loops for RFID detection and identification. The transceiver antennas are connected to a transmission line and probe pads used for electrical measurements. The insert shows an optical image of the RFID in a cell taken with a Keyence VK-X Series 3D Laser Scanning Confocal Microscope.

Figure 2

Hardware components of the intracellular detection system. (a) Transceiver structures are fabricated on an integrated circuit. Each chip includes a standalone transceiver and three transceivers with concentric, integrated RFIDs. Each transceiver loop is connected to a 300 $\mathrm{\mu }$m transmission line and probe pads. (b) Schematic cross section of RFIDs fabricated in the Stanford Nanofabrication Facility (SNF). (c) Top view of a loose RFID device. The device consists of an antenna (white outer ring) and a capacitor (square feature situated inside the ring), whose size and value can be modified during fabrication to generate different RFID batches with different electrical characteristics. (d) Using Kapton film as a carrier, individual RFIDs can be placed within the footprint of the transceiver antenna to be detected and identified. The probe pads must be uncovered to perform electrical measurements.

Figure 3

RFID internalization process procedure. (a) Drop an aliquot of the RFID solution into a cell well. (b) Once the isopropyl alcohol evaporates, the RFIDs remain at the well bottom. (c) Dispense a suspension of cells on top of the RFIDs. (d) After 24 h, many RFIDs are internalized inside the cells. In this microscope image of cultured cells, the arrows point to the RFIDs. (e) Dissociate the cells and RFID culture with Trypsin, as described in the methods section. (f) The result is a suspension of cells and cells with implanted RFIDs.

Figure 4

Cell and RFID alignment onto a transceiver. (a) Using the flip chip bonder, flip a Kapton film with a RFID in a cell onto the transceiver structure on the integrated circuit chip. (b) RFID is aligned in the transceiver loop, and probe pads are uncovered for electrical measurements. (c) Cross section schematic shows that the Kapton film pins the cell and intracellular RFID within the transceiver detection zone.

Figure 5

(a–c) Electrical response of the standalone transceiver (green) and the three different classes of RFIDs (80%C, 100%C, and 120%C) stored in isopropyl alcohol (blue) and 24 h after completing the uptake process (red). (d) A direct comparison of the electrical responses of the three batches of intracellular RFIDs 24 h after completing the uptake process. The different devices show different electrical signatures with different resonant frequencies. (e) Mean and standard deviation of the resonant frequency of a sample of 5 devices for each capacitor value RFID. (f) Given a mixed batch of RFIDs with all three types of devices, individual RFIDs can be categorized according to the correlation match between the $S_{11}$ response and the expected RFID $S_{11}$ responses. The x-axis designates individual RFID measurements and the y-axis represents the correlation coefficient calculated from the measurements. Note that high correlation (circled) indicates the measured RFID’s most probable capacitance and corresponding design, enabling us to identify individual RFID tags.