Method and apparatus for the capture of intra-cellular activity
Inventors
Hope, Bruce T • Wells, Mark A • Sutton, Gregory D
Assignees
Galiana Technology Inc • Office of Technology Transfer
Publication Number
US-12268512-B2
Publication Date
2025-04-08
Expiration Date
2035-08-24
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Abstract
An intracellular monitoring device (IMD) that fits completely inside a living cell, and causes no significant impairment, to a cell's normal biological processes. The IMD monitors a cell for its level of a biological substance (e.g., calcium ion concentration) of interest. If the biological substance reaches or exceeds a threshold, the IMD transmits an electromagnetic signal, received by an antenna outside the cell. Each IMD has its electromagnetic signal encoded with a unique frequency. Detection of the frequency components, in the signals received by an antenna, permits identification of the source IMD's. A high calcium ion concentration is indicative of a strongly-activated cerebral cortex neuron. Brain tissue is relatively transparent to near infrared, making it a good frequency band, for the electromagnetic signals from neuron-monitoring IMD's. The near infrared of each IMD can be produced by quantum dots, powered by bioelectric catalysis triggered by high calcium ion concentration.
Core Innovation
The invention presents an intracellular monitoring device (IMD) that fits completely inside a living cell without causing significant impairment to the cell's normal biological processes. This IMD monitors a biological substance within the cell, such as calcium ion concentration, and transmits an electromagnetic signal encoded with a unique frequency to an external antenna when the substance reaches or exceeds a threshold level.
The IMD is small enough, with no dimension exceeding approximately 1 micrometer, to be implanted within cells, including neurons such as pyramidal neurons of the mammalian cerebral cortex. It uses quantum dots to generate near-infrared (NIR) electromagnetic radiation for transmission, as brain tissue is relatively transparent to NIR. The device is powered by bioelectrocatalysis, where certain enzymes produce electrical current in the presence of threshold concentrations of biochemical substances like calcium ions, allowing the IMD to emit NIR signals only during significant cellular activity.
The problem addressed is the existing limitation in neural activity monitoring techniques, which either capture activity over large brain regions without single-neuron resolution or capture individual neuron activity but only for a small number of neurons. There is a need for systems that can monitor the activity of thousands of individual neurons across a large cortical volume while minimally interfering with biological processes.
Claims Coverage
The claims include three independent claims introducing inventive features around a monitoring method using intracellular monitoring devices in cells, the structure and operation of these devices, and signal reception and processing.
Intracellular monitoring device structure and operation
An intracellular monitoring device located completely inside a cell with a longest dimension no more than one micrometer. The device incorporates a P-type layer, N-type layer, and a quantum dot layer between them that emits near-infrared radiation when supplied with an electric current at a threshold voltage. Metal layers face the cytoplasm and are coated with enzyme layers that activate to produce electrons upon threshold concentration of a biochemical substance (e.g., calcium ions) in the cytoplasm. These layers form the electric current and voltage powering the quantum dot layer's emission.
Use of bioelectrocatalysis for power and sensing
The enzyme layers on the metal layers activate based on the intracellular biochemical substance concentration, producing an electric current and voltage that powers the quantum dot emission, enabling the detection of strong cellular activation states like neuron action potentials.
Unique frequency encoding and external signal reception
Each IMD emits near-infrared electromagnetic radiation at a unique frequency that can be collected by an antenna outside the cell. An optical domain frequency analyzer coupled to the antenna detects the presence of specific frequencies, producing outputs representative of intracellular biochemical substance levels detected by each IMD.
Peptide coating to enable cell entry by endocytosis
A coating of peptides on the IMD surface that permits the device to induce endocytosis and completely enter cells upon contact with the cell membrane, including embodiments where the peptide is amphiphilic and digestible after entering the cell.
Multi-device monitoring and data conversion
Use of a plurality of IMDs implanted in multiple cells, each emitting frequency-coded signals collected by an external antenna, with a subsystem comprising photodetectors and digital signal processors converting frequency-specific outputs into digital pulse streams representative of cellular activity data.
Together, the inventive features enable implantation of nanoscale devices in living cells that monitor intracellular biochemical levels using bioelectrocatalysis-powered quantum dot emitters. The unique frequency encoding permits simultaneous monitoring of many cells, with external antennas and optical frequency analyzers processing signals non-invasively. Peptide coatings facilitate cell entry through endocytosis. The system supports large scale fine-grained intracellular activity monitoring with minimal biological disruption.
Stated Advantages
Enables monitoring intracellular activity at the single-cell level without significant impairment to normal biological function.
Allows monitoring of large volumes of cortical tissue with high spatial resolution, capturing individual neuron activity across thousands of cells.
Utilizes near-infrared signal transmission that experiences lower attenuation in brain tissue, facilitating external detection of intracellular signals.
Unique frequency encoding permits simultaneous identification and monitoring of many implanted devices.
Bioelectrocatalysis-based power supply enables the IMD to be powered by the cell’s biochemical environment, activating only upon threshold biochemical levels, conserving energy.
Peptide coatings enable effective cellular entry of IMDs via endocytosis.
Documented Applications
Large scale fine-grained neural monitoring to study neuronal activity across thousands of individual neurons in mammalian cerebral cortex tissue.
Development of brain-machine interfaces requiring precise monitoring of neuronal ensembles.
Cognitive neuroscience research to better understand brain functions such as memory and spatial recognition, exemplified by studies involving laboratory rats.
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