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-11627907-B2
Publication Date
2023-04-18
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 provides an intracellular monitoring device (IMD) that can be completely implanted inside a living cell without significantly impairing its normal biological functions. The IMD monitors the level of a biological substance within the cell, such as calcium ion concentration, and transmits an electromagnetic (EM) signal when the substance reaches or exceeds a threshold. Each IMD transmits a uniquely encoded frequency in the EM signal, allowing external antennas to receive and identify signals from individual IMDs.
The device is particularly suited for monitoring neurons in the cerebral cortex, where a high calcium ion concentration indicates a strongly-activated neuron. The IMD uses near-infrared (NIR) EM transmission, which passes through brain tissue with minimal attenuation. Quantum dots powered by bioelectrocatalysis triggered by high calcium concentrations generate the NIR signals. The IMD is sized to not exceed a longest dimension of approximately one micrometer, enabling it to fit within typical mammalian cell bodies, such as pyramidal neurons with diameters of about 10-20 micrometers.
Current neural activity monitoring techniques either capture the activity of large cortical regions without individual neuron resolution or monitor only a small number of adjacent neurons simultaneously. The invention addresses the need for a system capable of large-scale fine-grained (LSFG) neural monitoring, which can track the activity of hundreds of neurons within a volume of cortical tissue containing thousands of neurons, with single-cell resolution.
Claims Coverage
The claims include one independent claim detailing the system architecture and functionality of the intracellular monitoring device and its operation with an external antenna and frequency analyzer. Several dependent claims specify further features such as cell types, biological substances monitored, endocytosis-inducing coatings, and signal processing.
Miniaturized intracellular monitoring device implantation
An intracellular monitoring device located completely inside a single cell, with the longest substrate dimension no more than approximately one micrometer, ensuring minimal impairment to the cell.
Quantum dot-based near-infrared radiation emission triggered by biochemical thresholds
A quantum dot layer between P-type and N-type semiconductor layers emits near-infrared electromagnetic radiation at a specific frequency when a threshold electric current and voltage are achieved, corresponding to the activation of enzymes triggered by a biochemical substance concentration within the cell.
Bioelectrocatalysis enzyme layers producing voltage from biochemical substance concentration
First and second enzyme layers coat metal layers and produce electrons and voltage when exposed to a concentration of a biochemical substance (e.g., calcium ion) at or above a threshold, powering the quantum dot emission to indicate intracellular activity.
Unique frequency encoding for identification of individual monitoring devices
Each intracellular monitoring device emits near-infrared radiation at a unique frequency, enabling an external antenna to collect signals from multiple devices and an optical domain frequency analyzer to detect specific frequencies for source identification.
Peptide coating for endocytosis induction enabling intracellular entry
A coating of peptides on an exterior surface of the monitoring device allows the device to induce endocytosis upon contact with a cell membrane, facilitating its entry completely into the cell. The peptides can be digestible after entry.
Integrated system for signal processing into digital pulse streams
A subsystem including photodetectors and digital signal processors converts frequency-specific optical outputs from the antenna into digital pulse streams representative of the data captured by individual intracellular monitoring devices.
The claims cover a system comprising ultrasmall intracellular monitoring devices with enzyme-based bioelectrocatalysis power sources, quantum dot near-infrared emission for signaling, unique frequency encoding for individual device identification, peptide coatings to enable cellular uptake, and an external antenna with optical frequency analysis and digital signal processing to monitor intracellular biochemical activity.
Stated Advantages
Enables monitoring of intracellular activity without significant impairment to normal cellular biological processes.
Provides large scale fine-grained neural monitoring capable of tracking activity of hundreds of individual neurons within cortical tissue volumes.
Near-infrared transmission offers minimal attenuation through brain tissue, ensuring effective signal collection from implanted monitoring devices.
Utilization of unique frequency encoding allows simultaneous identification of multiple intracellular monitoring devices.
Bioelectrocatalysis provides a biochemical threshold-triggered power source, ensuring activation and signaling only when relevant intracellular conditions are met.
Documented Applications
Monitoring neural activity within cortical brain tissue to detect strongly activated neurons by measuring intracellular calcium ion concentration.
Facilitating research in neuronal ensembles and cognitive neuroscience by enabling simultaneous monitoring of large numbers of individual neurons.
Use in brain-machine interface development by providing detailed neural activity data at the single-cell level.
Application in neural activity monitoring of laboratory animals such as rats, utilizing specially designed antennas and injection methods to implant and receive signals from intracellular devices.
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