Patent Application
20240198066
The invention relates generally to devices and methods for ultrasonic delivery of an agent to an internal tissue.
The most common route of drug delivery is oral administration. Many drugs can be readily absorbed in the gastrointestinal (GI) tract, so oral administration allows them to enter the blood quickly and circulate systemically. In addition, oral administration is convenient and minimally invasive.
Nonetheless, oral administration is not suitable for all drugs. For some drugs, the acidic conditions and harsh digestive enzymes of the GI tract degrade or inactivate the active pharmaceutical ingredient (API) before it can reach its target tissue. Other therapeutic agents, such as biological therapeutics (“biologics”), which generally consist of large macromolecules, are poorly absorbed in the GI tract. Absorption may also be limited if the patient has diarrhea, which minimizes the duration of transit of the drug through the GI tract.
Ingestible ultrasonic drug delivery devices have been developed to overcome the difficulty of delivering certain drugs via the GI tract. Such devices include an ultrasound transducer, a reservoir that stores the drug, and a power source, such as a battery and drive circuitry, that drives the transducer. However, the utility of these fully self-contained devices is limited by a different set of technical obstacles. For example, the device must be small enough that it can be easily swallowed, yet large enough to accommodate the drug, transducer, drive circuitry, and battery. These factors constrain the quantity of drug that can be delivered by all-in-one ingestible ultrasonic drug delivery devices. Another consideration is that the battery can severely damage internal tissue if it makes electrical contact with the tissue. Therefore, the device must contain material to electrically insulate the battery, which further restricts the size and drug-loading capacity of the device. Consequently, these factors largely limit the therapeutic potential of drug delivery via ingestible ultrasonic devices.
The invention provides systems that may comprise an ingestible capsule that includes an ultrasound transducer, wireless power/energy, transfer/harvester (WPTH) device, a drug payload or drug reservoir and a separate power/energy transmitter that can control or power the ingestible capsule device remotely. During use, the ingestible capsule is positioned within the subject's gastrointestinal (GI) tract, while the transmitter remains external to the subject's body. The design of a system in which the ultrasound transducer is separate from the transmitter, including the power source, obviates the need to include a battery and drive circuitry in the form-factor that must be swallowed. Consequently, the system allows the ingestible capsule device to be smaller and/or have a greater drug payload than prior self-contained ingestible ultrasound devices. In addition, the two-component systems eliminate the risk associated with passage of a battery-containing device through a person's GI tract.
Certain aspects of the present disclosure may include an ingestible capsule drug delivery system for targeted or localized ultrasound-mediated drug delivery within the GI tract. In various embodiments, the ingestible capsule may comprise one or more wireless energy harvesters, antennae, impedance matching networks, rectifiers, voltage multipliers, charge controllers, energy storage devices, ultrasound transducer drivers, ultrasound transducers, drug carrier/reservoirs, and at least one drug payload containing at least one therapeutic agent. In various embodiments, the wireless energy harvester can comprise one or more components for wireless power transfer (WPT) or energy harvesting. In various embodiments, the WPT may comprise electromagnetic (EM) methods, including but not limited to, capacitive coupling, magnetic resonance, inductive coupling, inductive energy transfer, mid-field radiative/non-radiative, and radiative far-field. In various embodiments, the WPT can comprise non-EM methods, preferably acoustic or ultrasound (US) using piezoelectric structures to convert US vibration into electric energy or power. In various embodiments, one or more ingestible capsule functions may be controlled by an external power/energy transmitter, including but not limited to, energy transfer to at least one of the capsule's energy harvester, data transmission, activation of the drug carrier or reservoir, activation of the drug payload, activation of a therapeutic agent, or modification of the local external environment of the capsule within the GI tract. Activation may be in the form of capacitive, inductive coupling, inductive transfer, magnetic resonance, EM radiation, or ultrasonic energy.
Aspects of the present disclosure may include an ingestible capsule that comprises at least one inductive receiver coil configured to receive an EM wave, energy, or signal from a transmitter external to the capsule, an ultrasound transducer electrically coupled to the inductive receiver, and a reservoir configured to releasably retain a liquid comprising a therapeutic agent. The ingestible capsule does not include a power source. In certain aspects, a reservoir may be configured to releasably retain at least one non-encapsulated or encapsulated therapeutic agent.
Aspects of the present disclosure may comprise an ingestible capsule that includes one or more inductive receiver coils configured to receive an EM wave, energy, or signal from a transmitter external to the capsule; an ultrasound transducer electrically coupled to the inductive receiver; and a reservoir configured to releasably retain a liquid comprising a non-encapsulated or an encapsulated therapeutic agent. In various embodiments, electrical couplings can include one or more, antennae, tuning circuits, AC-DC voltage converters, voltage regulators, or combinations thereof. In various embodiments, said transmitter may comprise one or more antenna, coil, tuning circuit, AC-DC converter, and combinations thereof. In various embodiments, the transmitter may be worn by a person, in the proximity, or placed at a distant location. The ingestible capsule drug delivery system is preferably designed to transfer power with high efficiency and stability.
Aspects of the present invention may include ingestible capsule drug delivery systems comprising a radiofrequency (RF) transmitter containing an antenna and an ingestible capsule containing an RF energy harvester. In various embodiments, the RF energy harvester can comprise an RF receiving antenna, an impedance matching network circuit, RF-DC converter, and an energy storage device. In various embodiments, the energy storage device can provide power for an ultrasound transducer driver or load. In various embodiments, the RF receiving antenna of the capsule may comprise an isotropic or directional antenna. In various embodiments, the impedance matching network may be tuned to maximize power transfer from the receiving antenna to the rectifier circuit. In some embodiments, the RF receiving antenna may be a rectenna (rectifying antenna), rectifying incoming EM waves into DC current.
Certain aspects of the present disclosure may include an ingestible capsule drug delivery system comprising an external transmitter containing a piezoelectric ultrasonic transducer operating in conjunction with an ingestible capsule containing a piezoelectric transducer energy harvester. In various embodiments, the external transmitter can comprise a voltage source, microcontroller, one or more resistors, one or more transistors, an amplifier to drive a piezoelectric transducer or an array of piezoelectric transducers. In various embodiments, the piezoelectric transducer energy harvester can further comprise a power conditioning circuit to convert an AC output voltage into DC voltage to power an ultrasound transducer driver or load within the capsule. In various embodiments, the transmitter may contain one or more piezoelectric transducer configured to operate in one or more mode, including but not limited to, thickness vibration, radial vibration, transverse vibration, flexural, the like, or combination of. In preferred embodiments, the transmitting piezoelectric transducer may be configured to operate in the thickness vibration mode to transfer power with high efficiency and stability. In some embodiments, the external transmitter comprises a piezoelectric transducer to produce non-focused or focused ultrasound at a surface or within the ingestible capsule. In another alternative embodiment, the external transmitter comprises a piezoelectric transducer array made up of n-elements to deliver diffused or focused ultrasound to the ingestible capsule within the GI tract. In various embodiments, the ultrasound transducer may be positioned to transduce ultrasound waves in a particular direction relative to the reservoir of the ingestible capsule. The ultrasound transducer may be positioned to transduce ultrasound waves toward the reservoir. The ultrasound transducer can be positioned to transduce ultrasound waves away from the reservoir. The ultrasound transducer may be positioned to produce omnidirectional ultrasound waves through the reservoir. The reservoir can be configured to releasably retain a liquid comprising a therapeutic agent or an encapsulated therapeutic agent.
Aspects of the invention may include an ingestible capsule containing a modulator that modulates a frequency of an electromagnetic signal received by the said inductive receiver coil. The modulator may be electrically coupled to the inductive receiver coil and the transducer. The modulator may be a multiplier that increases the frequency of the electromagnetic signal received by the inductive receiver coil. The modulator may be an attenuator that decreases the frequency of the electromagnetic signal received by the inductive receiver coil. The ingestible capsule may contain a component that alters a frequency of an electromagnetic signal received by the inductive receiver coil.
The ultrasound transducer of the ingestible capsule may produce an ultrasound signal with a defined frequency or within a defined frequency range. The ultrasound transducer may produce an ultrasound signal of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz. The ultrasound transducer may produce an ultrasound signal of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz. The ultrasound transducer may produce an ultrasound signal of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
The ingestible capsule may have a defined size, length, or volume. The ingestible capsule may have the longest dimension of less than about 3.0 cm, about 2.75 cm, about 2.5 cm, about 2.25 cm, about 2.0 cm, about 1.75 cm, or about 1.5 cm. The ingestible capsule may have a transverse dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, or about 0.8 cm.
The ingestible capsule may include additional components. The ingestible capsule may include a rectifier that is electrically coupled to the inductive receiver. The ingestible capsule may include an electrode electrically coupled to the rectifier and in contact with the drug payload or reservoir.
In certain aspects the invention may provide a system that includes an inductive transmitter and an ingestible capsule that is physically separate from the transmitter. The transmitter can include a power source and a transmitter coil electrically coupled to the power source. In certain embodiments, the transmitter coil can comprise a Helmholtz coil. In some embodiments, the transmitter coil may comprise a solenoid coil. The ingestible capsule can include at least one inductive receiver coil configured to receive an electromagnetic signal or energy from the transmitter when the transmitter is not in contact with the ingestible capsule, an ultrasound transducer electrically coupled to the inductive receiver, and a reservoir configured to releasably retain a liquid comprising a therapeutic agent or an encapsulated therapeutic agent. In various embodiments, the power source may be a battery. The power source may produce a DC voltage within a defined range. The power source may produce a DC voltage of from about 1.6 VDC to about 64 VDC, from about 3.2 VDC to about 64 VDC, from about 6.4 VDC to about 32 VDC, from about 1.6 VDC to about 32 VDC, from about 3.2 VDC to about 32 VDC, from about 6.4 VDC to about 32 VDC, from about 1.6 VDC to about 16 VDC, from about 3.2 VDC to about 16 VDC, or from about 6.4 VDC to about 16 VDC.
In various aspects, the inductive transmitter may include a DC-DC converter downstream of the power source and upstream of the transmitter coil. The DC-DC converter may increase the voltage produced by the power source to a voltage within a defined range. The DC-DC converter may increase the voltage produced by the power source to from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, from about 32 VDC to about 320 VDC, from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, from about 32 VDC to about 320 VDC, from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, or from about 32 VDC to about 320 VDC. The DC-DC converter may be connected directly to the transmitter coil without intervening components. The transmitter may include one or more additional components. The transducer may include one or more voltage-controlled oscillator, a FET driver, a FET transistor, a capacitor, inductor, resistor, a user interface configured to receive input from a user, a display, and a microprocessor. The transmitter may be configured to be held in the hand of a person. The transmitter may include, or be a part of, a wearable garment. The transmitter may include, or be a part of, a square, circular, cylindrical framed structure configured to surround or expose energy to a person. The transmitter may include, or be a part of, a square, circular, cylindrical framed structure configured to enable a person to enter partially or whole within its volume. The power source may be rechargeable.
Aspects of the invention may include an ingestible capsule that may contain a modulator that modulates a frequency of an electromagnetic signal received by the inductive receiver coil, as described above or it may lack a component that alters a frequency of an electromagnetic signal received by the inductive receiver coil. In the ingestible capsule, the ultrasound transducer may produce an ultrasound signal within a defined frequency range, as described above. The ingestible capsule may have a defined size or length, as described above. The ingestible capsule may include additional components, such as any of those described above.
In some aspects, methods of the invention may include administering a therapeutic agent to a gastrointestinal tissue of a subject by orally administering to a subject an ingestible capsule that does not include a power source but does include at least one inductive receiver coil, an ultrasound transducer electrically coupled to the inductive receiver, and a reservoir comprising a liquid or a powder mixture comprising a therapeutic agent; and transmitting via a transmitter external to the subject an electromagnetic signal to the ingestible capsule to allow the ultrasound transducer to generate an ultrasound signal or ultrasound energy and thereby deliver the therapeutic agent from the reservoir into gastrointestinal tissue of the subject. The transmitter may include any of the components described above, such as a power source and a transmitter coil electrically coupled to the power source. The electromagnetic signal may be transmitted from the transmitter coil to the inductive receiver coil. The ingestible capsule may include any of the components described above, such as a rectifier electrically coupled to the inductive receiver and an electrode electrically coupled to the rectifier and in contact with the reservoir. Transmission of the electromagnetic signal may generate an electrical signal in the liquid that promotes movement of the therapeutic agent from the reservoir and into the gastrointestinal tissue. The electrical signal may be a DC signal or a DC pulse train. The electrical signal may promote movement of the therapeutic agent by iontophoresis, electrophoresis, electroporation, sonoporation, magnetosonoporation, or ultrasonic cavitation.
In certain embodiments, the external transmitter may generate a magnetic field, a magnetic flux, magnetic field gradient, or magnetic force that positions the ingestible capsule adjacent to the gastrointestinal tissue of the subject. In various embodiments, the transmitter may generate an alternating (AC) magnetic field that activate the release of the therapeutic agent from the reservoir into GI tissue. The frequency of the electromagnetic signal may be about equal to a frequency of the ultrasound signal. The frequency of the electromagnetic signal may not be equal to a frequency of the ultrasound signal. The ultrasound signal may have a defined frequency or a defined frequency range, such as any of those described above. In an alternative embodiment, the ingestible capsule comprises a magnetic component. The magnetic component may comprise a diamagnetic, paramagnetic, superparamagnetic, magnetic, or ferromagnet microparticles or nanoparticles. In various embodiments, one or more permanent magnet may be positioned about a subject to attract the ingestible capsule to a specific location of the GI tract.
In various aspects, methods of the invention can include administering a therapeutic agent to a gastrointestinal tissue of a subject by orally administering to a subject an ingestible capsule that does not include a power source but does include at least one piezoelectric transducer for harvesting ultrasonic energy, an ultrasound transducer electrically coupled to said ultrasound energy harvester, and a reservoir comprising a liquid comprising a therapeutic agent; and transmitting via a transmitter external to the subject an ultrasonic wave to the ingestible capsule to provide power for driving the ultrasound transducer to generate an ultrasound signal and thereby deliver the therapeutic agent from the reservoir into gastrointestinal tissue of the subject.
Aspects of the invention may include methods of administering a therapeutic agent to a gastrointestinal tissue of a subject by orally administering to a subject an ingestible capsule that does not include a power source but does include at least one piezoelectric transducer for harvesting ultrasonic energy, at least one inductive coil for harvesting EM energy, an ultrasound transducer electrically coupled to said ultrasound and EM energy harvesters, and a reservoir comprising a liquid comprising a therapeutic agent or an encapsulated therapeutic agent; and transmitting via a transmitter external to the subject an EM and ultrasonic waves to the ingestible capsule to provide power for driving the ultrasound transducer to generate an ultrasound signal or ultrasound energy and thereby deliver the therapeutic agent from the reservoir into gastrointestinal tissue of the subject.
In certain aspects, methods may include administering a therapeutic agent to a gastrointestinal tissue of a subject by orally administering to a subject an ingestible capsule that does not include a power source but does include at least one tethered wire providing electrical connection to an ultrasound transducer, and a reservoir comprising a liquid comprising a therapeutic agent or encapsulated therapeutic agent; and transmitting via a transmitter external to the subject electricity to the ingestible capsule to provide power for driving the ultrasound transducer to generate an ultrasound signal and thereby deliver the therapeutic agent from the reservoir into gastrointestinal tissue of the subject. In various embodiments, the transducer comprises at least one, directional, planar, spherical, hemi-spherical, or omni-directional transducer.
In some aspects, methods can comprise administering a therapeutic agent to a gastrointestinal tissue of a subject by orally administering to a subject an ingestible capsule. In various embodiments, the therapeutic agent is encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier, including but not limited to, microbubble, nanobubble, nanodroplet, nano emulsion, nanofiber, vesicle, micelle, or hydrogel sphere or coating. In various embodiments, the ingestible capsule comprises one or more payload or reservoir containing at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, or ultrasound-responsive polymeric carrier. In various embodiments, the ingestible capsule may comprise one or more reservoir or payload containing at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier. In various embodiments, the ingestible capsule can include a coating or scaffold on at least one internal or external surface, said coating or scaffold containing at least one therapeutic agent encapsulated in at least one pH, thermal, electric, magnetic, electromagnetic wave, catalytic, piezo-catalytic, or ultrasound-responsive polymeric carrier. In various embodiments, the ingestible capsule may contain an iron oxide particle-based biocompatible gel with a controlled architecture that can release its payload containing an encapsulated or non-encapsulated therapeutic agent when exposed to at least one AC magnetic field.
Aspects of the invention may include methods of administering a therapeutic agent to a gastrointestinal tissue of a subject by transporting the ingestible capsule to at least one specific location of the GI and the payload containing an encapsulated or non-encapsulated therapeutic agent is activated by an ultrasound transducer within the capsule for control-released, pulsatile, non-pulsatile, intermittent, digital, or continuous local or targeted delivery of said agent from the payload or reservoir into gastrointestinal tissue of the subject. In various embodiments, the ingestible capsule can be swallowed by a subject or person and the payload or reservoir containing an encapsulated or non-encapsulated therapeutic agent is activated by an ultrasound transducer external to the subject, exposing ultrasound energy to the capsule, capsule payload, or capsule reservoir for control-released, pulsatile, non-pulsatile, intermittent, digital, or continuous local or targeted delivery from said reservoir or payload into gastrointestinal tissue of the subject. In various embodiments, the ultrasound transducer may be a high frequency imaging transducer used to locate, manipulate, rotate, position, or transport the capsule and to transmit ultrasonic energy to at least one of: a surface of the capsule, an energy harvesting transducer, an energy producing transducer, a payload, or a reservoir within the capsule. In various embodiments, the ultrasound transducer can be a capacitive array transducer used to focus ultrasound, locate, manipulate, rotate, position, or transport the capsule, and to transmit ultrasonic energy to at least one of: a surface of the capsule, an energy harvesting transducer, an energy producing transducer, a payload, or a reservoir within the capsule. In various embodiments, the ultrasound transducer may be a capacitive array transducer used to focus ultrasound, locate, manipulate, rotate, position, or transport the capsule, and to transmit ultrasonic energy to at least one of: a surface of the capsule, an energy harvesting transducer, an energy producing transducer, a payload, or a reservoir within the capsule. In various embodiments, the ultrasound transducer can be a high frequency phased-array transducer, used to locate, manipulate, rotate, position, or transport the capsule, and to transmit ultrasonic energy to at least one of: an internal or external surface of the capsule, an energy harvesting transducer, an energy producing transducer, a payload, or a reservoir within the capsule. In various embodiments, the ultrasound transducer may be a high frequency phased-array transducer configured to first manipulate the ingestible capsule, using non-limiting energy focusing/de-focusing or frequency sweep methods, second to deliver ultrasound energy to rupture the capsule's payload or reservoir or payload containing at least one encapsulated or non-encapsulated therapeutic agent, and third to disperse the released therapeutic agent with ultrasound energy. In some embodiments, the ingestible capsule can be transported to a specific location of the GI tract and the payload or reservoir containing an encapsulated or non-encapsulated therapeutic agent may be activated by an external or internal pH, thermal, electric, magnetic, electromagnetic wave, catalytic, or piezo-catalytic source located externally to or internally in the capsule for control-released, pulsatile, non-pulsatile, intermittent, digital, or continuous local or targeted delivery from the payload or reservoir into gastrointestinal tissue of the subject.
Various embodiments of the invention can provide systems and components thereof for ultrasound-mediated drug delivery within the GI tract of a subject. The systems can comprise a transmitter that includes a power source and power emitter for transmitting EM and or non-EM energy. The power transmitter may comprise one or more capacitive, inductive, magnetic resonance, RF, or ultrasonic energy radiators. A second component may include an ingestible capsule that is physically separate from the transmitter. The ingestible capsule may be configured to harvest energy from the transmitter using a variety of components. In various embodiments, the ingestible pill can comprise at least one energy harvesting component, an ultrasound transducer, and a reservoir or payload that releasably retains a liquid or powder mixture containing an encapsulated or non-encapsulated therapeutic agent. When in use, the ingestible capsule enters the gastrointestinal (GI) tract of the subject, while the transmitter remains external to the subject's body. The energy harvesting component enables miniaturization of the capsule. Therefore the capsule is small enough to be easily ingested and yet has the capacity to hold enough drug for delivering therapeutically effective doses directly to targeted tissue.
Referring now to
The transducer 110 delivers ultrasound energy at a frequency optimal for promoting entry of the therapeutic agent 116 into the tissue of the GI tract. The ultrasound transducer 110 may produce an ultrasound signal of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz. The ultrasound transducer 110 may produce an ultrasound signal of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz. The ultrasound transducer 110 may produce an ultrasound signal of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
The design of the ingestible capsule 102 enables the transducer 110 to produce ultrasound energy at a desired power, frequency, duty cycle, or intensity. In some embodiments, the frequency of electromagnetic signal generated by the external transmitter and received by the inductive receiver 104, 106, or 108 is the same as the operating frequency of the ultrasound transducer 110. Such embodiments alleviate the need for additional circuitry within the capsule to produce an ultrasound electrical drive signal derived from a direct current (DC) power source. In other embodiments, the capsule 102 contains a component that modulates the frequency of the received electrical signal to produce the optimal transducer frequency. For example, and without limitation, a 2-diode odd-order frequency multiplier may be used to convert a 20 kHz received signal at the inductive receiver coil 104, 106, or 108 to a 60 kHz signal provided to the ultrasound drive transducer 112. Alternatively, an attenuator may be used to reduce the received frequency to achieve the desired transduction frequency. In either scenario, the modulator is placed between the inductive receiver coil 104, 106, or 108 and ultrasound transducer 112 in the electrical circuit within the capsule.
In various embodiments, the ingestible capsule 102 may have a defined size, length, or volume. For example, and without limitation, the ingestible capsule 102 may have the longest dimension of less than about 3.0 cm, about 2.75 cm, about 2.5 cm, about 2.25 cm, about 2.0 cm, about 1.75 cm, or about 1.5 cm. The ingestible capsule 102 may have a transverse dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, about 0.8 cm, about 0.7 cm, about 0.6 cm, or about 0.5 cm. The ingestible capsule 102 may have a radial dimension of less than about 1.2 cm, about 1.1 cm, about 1.0 cm, about 0.9 cm, about 0.8 cm, about 0.7 cm, about 0.6 cm, or about 0.5 cm.
Referring now to
In various embodiments, the transmitter 202 may contain a DC-DC converter 208 between the power source 204 and the transmitter coil 206. For example, the DC-DC converter 208 may be a boost-buck DC-DC converter. The DC-DC converter 208 may increase the voltage to a defined range. For example and without limitation, the DC-DC converter 208 may increase the voltage produced by the power source 204 to from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, from about 32 VDC to about 320 VDC, from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, from about 32 VDC to about 320 VDC, from about 8 VDC to about 80 VDC, from about 16 VDC to about 160 VDC, or from about 32 VDC to about 320 VDC.
In various embodiments, the transmitter 202 may contain a voltage-controlled oscillator (VCO) 210 between the DC-DC converter 208 and the transmitter coil 206. The VCO 210 may generate an alternating current (AC) waveform in a defined range. For example and without limitation, the VCO 210 may generate an alternating current (AC) waveform of from about 5 kHz to about 500 kHz, from about 10 kHz to about 500 kHz, from about 20 kHz to about 500 kHz, from about 5 kHz to about 1 MHz, from about 10 kHz to about 1 MHz, from about 20 kHz to about 1 MHz, from about 5 kHz to about 2 MHz, from about 10 kHz to about 2 MHz, or from about 20 kHz to about 2 MHz.
In various embodiments, the transmitter 202 may contain a FET driver 212 and FET transistor network 214 between the VCO 210 and the transmitter coil 206. The FET driver 212 and FET transistor network 214 may switch at the frequency of the AC waveform and generate a pulsed signal at that frequency and at a voltage level equal to the output of the DC-DC converter 202.
In various embodiments, the transmitter 202 may contain a drive capacitator 216 between the FET transistor network 214 and the transmitter coil 206 and a resistor 218 electrically connected to the transmitter coil 206. In various embodiments, the value of the drive capacitor 218 and inductive windings of the transmitter coil 206 are selected such that they resonate at the same output frequency of the VCO 210 according to:
This results in the configuration of a bandpass filter that converts the pulsed output of the FET transistor network 214 to a sinusoidal waveform with sufficiently high voltage across the inductive windings of transmitter coil 206, as predicted by
whereby I represent the network current established by the value of resistor 216 and L is the inductance of the inductive windings the transmitter coil 206. Thus, the drive capacitor 216 operates in conjunction with the inductive windings 206 in series resonance.
In various embodiments, the circuitry of the transmitter 202 may be adapted to produce a magnetic field or a magnetic field gradient that retains, position, or secure the ingestible capsule 102 of
In various embodiments, the transmitter 202 may contain components that allow the transmitter to interact with remote devices other than the ingestible capsule 102 of
In various embodiments, the transmitter 202 may contain elements that facilitate user interaction. For example, the transmitter 202 may include a user interface to receive input from a user. For example, and without limitation, the user interface may be or include a keyboard, keypad, touch screen, button, switch, knob, sensor, or the like. The transmitter 202 may include an output device that displays information to a user. For example, and without limitation, the output device may be or include a display, screen, light, or the like. The output device may display any type of information. For example, and without limitation, the output device may display information about battery charge or status of the transmitter and/or ingestible capsule.
In various embodiments, the transmitter 202 may monitor the impedance of the transmitter coil 206. A change in impedance may indicate that the transmitter 202 is in proximity to the ingestible capsule 102 of
In various embodiments, the transmitter 202 may be configured for easy use by a person. For example, the transmitter 202 may be configured to fit in the hand of a use. In some embodiments, the transmitter 202 is generally be shaped like a wand. The transmitter 202 may include a grip or other material that facilitates physical manipulation of the device. The transmitter 202 may be configured as part of a garment that may be worn by a person. For example, and without limitation, the transmitter may be integrated into a glove, vest, shirt, jacket, belt, piece of headgear, goggles, or another wearable item. In an alternative embodiment, transmitter coil 206 comprises a solenoid coil that can wrap around a subject's chest, stomach, or trunk. The transmitter 202 may be configured to connect to an external power source that recharges the internal battery 204.
Referring now to
Referring now to
Referring now to
The ingestible capsule 302 may also contain other electronic components. For example, and without limitation, the ingestible capsule 302 may contain one or more of a video cameras, components for management of the camera, and components for communications between the ingestible capsule 302 and external devices. Images obtained from a video camera may be used to identify GI ulcerations or regions of inflammation. In some embodiments, the ingestible capsule 302 contains a microprocessor with Bluetooth capability to capture video images and communicate with an external mobile device. In some embodiments, the ingestible capsule 302 contains a pH sensor and a microprocessor that manages the pH sensor and communicates local pH measurements within the GI tract to an external mobile device. Because the pH varies throughout the GI tract, pH measurements may be used to identify the anatomical location of the ingestible capsule 302 at a given point in time. Based on information obtained from video images, pH measurements, or both, the ingestible capsule may be selectively energized for ultrasound transduction and/or electrode-driven iontophoresis or electroporation at specific locations within the GI tract. Consequently, the system enables targeted delivery of therapeutic compounds to achieve the optimal therapeutic benefit.
Referring now to
Referring now to
The ingestible capsule 404 of the ultrasound-mediated drug delivery system the receives RF energy or wave transmitted by RF transmitter 402 with antenna 408. In various embodiments, antenna 408 is configured with non-limiting shape, size, and dimensions, for efficient reception of RF energy at an optimal form factor to minimize or reduce the size or volume of ingestible capsule 404. In various embodiments, antenna 408 can be miniaturized by modifying one or more basic patch shapes and embedding one or more suitable slots in the radiating patch. In various embodiments, antenna 408 comprises one or more antenna shape, including but not limited to, circular patch with slots place on the diameter, square patch with cross-shaped slot etched on its surface, slits on the perimeter of a square patch, square patch with two orthogonal pairs of regular or irregular, symmetrical or non-symmetrical slits, the like, or combination thereof. In various embodiments, antenna 408 may be fabricated using various substrates, including but not limited to, FR-4 substrate, Arlon substrates, Tarconic, TLY-5 laminate, RT/Duroid 6010 substrate, RT/Duroid 5870 substrate. In various embodiments, antenna 408 is configured with one or more slots to increase its electrical path to lengthen the surface current paths as a miniature antenna. In various embodiments, antenna 408 comprises a cylindrical or rectangular dielectric resonator antenna (DRA) for operation at high frequencies.
The RF energy received by antenna 408 of ingestible capsule 404 is fed into an impedance matching network 410 to reduce the transmission loss from the antenna to RF-DC converter 412 or rectifier. In various embodiments, matching network 410 comprises on or more reactive components, non-dissipative coil, and capacitor. In various embodiments, matching network 410 comprises a transformer, shunt inductor, or LC network. Matching network 410 for RF energy harvesting may comprise, but not limited to, L-type, π-type, and T-type matching networks. The impedance matching network 410 functions to maximize the energy or power transfer from the receiving antenna 408 to the RF-D rectifier 410 circuit and increases the RF input voltage level for the rectifier.
The ingestible capsule 404 of the ultrasound-mediated drug delivery system contains an RF-DC converter as the main block for the RF energy harvesting system. In various embodiments, RF-DC converter 412 or rectifier converts RF power captured by antenna 408 into useable DC power. In various embodiments, RF-DC converter 412 may comprises, but not limited to, a diode-base, bridge of diode, or voltage multiplier. In one embodiment, the topology for the rectifier circuit of RF-DC converter 412 is a full-wave rectifier. The full-wave rectifier converts both half-cycles (positive half-cycle and negative half-cycle) of the RF signal into a pulsating DC signal. The RF-DC converter 412 may operate in conjunction with one or more voltage multiplier.
The ingestible capsule 404 of the ultrasound-mediated drug delivery system contains a voltage multiplier. In various embodiments, voltage multiplier 414 comprises one or more cascade rectifier unit that generates an output voltage higher than the input voltage. In various embodiments, voltage multiplier 414 may comprise, but not limited to, one or more Cockcroft-Walton, Greinacher, Dickson, or Villard multiplier. In various embodiments, voltage multiplier 414 may be configured to provide a specific power input for transducer driver 416.
The ingestible capsule 404 of the ultrasound-mediated drug delivery system contains a transducer driver 416 to activate an ultrasonic transducer 418 for dispersing one or more encapsulated or non-encapsulated therapeutic agent from a payload or reservoir 420. In various embodiments, transducer driver 416 may comprise, but not limited to, a shunt-C class E-amplifier to drive transducer 418. In one embodiment, the amplifier contains a parallel inductor that can resonate at for example, 40 kHz, with the transducer, fabricated with Lead Zirconate Titanate (PZT). In various embodiments, one or more series capacitors is used to prevent DC feed-through. In various embodiments, one or more series inductor is used to improve amplifier efficiency. In various embodiments, transducer driver 416 may comprise, but not limited to one more microcontroller operating in conjunction with one or more NMOS transistors to activate the input supply voltage across the PZT transducer 418. For example, a 60 kHz, pulse width modulated with a chosen duty cycle drives the gates one or more transistors to switch a supply voltage across the activating PZT transducer to propel a therapeutic agent through one or more orifice 422.
Referring now to
In various embodiments, US transmitter 502 comprises an energy storage device, microcontroller, and power management module. US transmitter 502, preferable a portable device, operates external to the body and GI tract of a person who has ingested capsule 504. Without limitation, US transmitter 502 the may generate US energy or mechanical wave broadcast by US transmitting transducer 508 in the range of about 5 kHz to about 500 kHz, from about 10 kHz to about 500 kHz, from about 20 kHz to about 500 kHz, from about 5 kHz to about 1 MHz, from about 10 kHz to about 1 MHz, from about 20 kHz to about 1 MHz, from about 5 kHz to about 2 MHz, from about 10 kHz to about 2 MHz, from about 20 kHz to about 2 MHz, from about 2 MHz to 200 MHz, from 200M to 2 GHz, or from 2 GHz to 10 GHz. In various embodiments, US transmitting transducer 508 comprises at least one piezoelectric transducer, two or more piezoelectric transducers, or an array of piezoelectric electric transducers. In various embodiments, one or more piezoelectric transducer of US transmitting transducer 508 may be configured to produce and transmit pulsed or alternating diffuse, directional, omnidirectional, spherical, or focused ultrasound energy or wave to ingestible capsule 504. In various embodiments, US transmitting transducer 508 delivers ultrasound energy to US receiving transducer 510, reservoir 520, an external proximity of ingestible capsule 504, GI tissue, GI tract, said therapeutic that has been transported from reservoir 520, or combination thereof. In various embodiments, US transmitting transducer 508 may be configured or designed to have a large focusing gain, confined beam, operate at frequencies, or larger apertures for a given transmission depth to deliver energy to US receiving transducer 510.
The ingestible capsule 504 of the ultrasound energy powered ingestible capsule drug delivery system the receives US energy or mechanical wave transmitted by US transmitter 502 with US receiver transducer 510. In various embodiments, US receiver transducer 510 is configured or designed with non-limiting shape, size, dimensions, backing material, electrode, or air backing for efficient reception of US energy at an optimal form factor to minimize or reduce the size or volume of ingestible capsule 504. In various embodiments, US receiver transducer 510 may be configured to operate in one or more non-limiting mode, for example radial, flexural, planar, transverse, or longitudinal thickness mode. In a preferred embodiment, US receiver transducer 510 designed to simultaneously achieve small dimensions with optimal impedance for efficient energy harvesting, thus resulting in a miniature form factor or size for ingestible capsule 504. In various embodiments, US receiver transducer 510 may be constructed with millimeter dimensions or scale to minimize parasitic modes, achieve large reception acceptance angle, reduce the impact of power losses due to capsule orientation, and reduce tissue transmission losses at long depths using high operating frequencies. In various embodiments, the ultrasound energy powered ingestible capsule drug delivery system may configured for US receiver transducer 510 to operate on resonant or off-resonance, between its short and open circuit resonance or inductive band, with US transmitter 502 broadcasting with non-limiting frequencies between 0.75 to 2 MHz.
The US energy harvested by US receiver transducer 510 of ingestible capsule 404 is in the form of AC power which is the converted into DC energy via one or more power recovery network circuits. In various embodiments, the power recovery network may incorporate an impedance matching network, for example matching network 410 of
The ingestible capsule 504 of the ultrasound energy powered ingestible capsule drug delivery system contains a high frequency voltage multiplier. In various embodiments, voltage multiplier 514 comprises one or more cascade rectifier unit that generates an output voltage higher than the input voltage. In various embodiments, voltage multiplier 514 may comprise, but not limited to, one or more Cockcroft-Walton, Greinacher, Dickson, or Villard multiplier. In various embodiments, voltage multiplier 514 may be configured to provide a specific power input for drug delivery driver 418. In various embodiments, the power is stored within a power storage unit 516 such as a capacitor or supercapacitor.
Referring now to
Referring now to
An object of the present disclosure is the encapsulation of therapeutic agents with a liquid, mixture, scaffold, or responsive polymer for incorporation into a reservoir of an ingestible capsule, for example ingestible capsule 102 of
Methods of the invention can include administering a therapeutic agent to gastrointestinal tissue of a subject using the systems and devices described above. The methods can include delivering ultrasound energy to a liquid at a frequency that produces bubbles within the liquid and causes transient cavitation of the bubbles. Gentle implosion of the bubbles produces shock waves that permeabilize cells and propel the agent from the liquid into the tissue. The use of ultrasound to cause transient cavitation to deliver agents to tissue is described in, for example, Schoellhammer, C. M., Schroeder, A., Maa, R., Lauwers, G. Y., Swiston, A., Zervas, M., et al. (2015). Ultrasound-mediated gastrointestinal drug delivery. Science Translational Medicine, 7(310), 310ra168-310ra168, doi: 10.1126/scitranslmed.aaa5937; Schoellhammer, C. M & Traverso, G., Low-frequency ultrasound for drug delivery in the gastrointestinal tract. Expert Opinion on Drug Delivery, 2016, doi: 10.1517/17425247.2016.1171841; Schoellhammer C. M., et al., Ultrasound-mediated delivery of RNA to colonic mucosa of live mice, Gastroenterology, 2017, doi: 10.1053/j.gastro.2017.01.002; and U.S. Publication Nos. 2014/0228715 and 2018/0055991, the contents of each of which are incorporated herein by reference.
In methods of the invention, the ultrasound signal may have a defined frequency. The ultrasound signal may have a frequency of from about 10 kHz to about 10 MHz, from about 10 kHz to about 1 MHz, from about 10 kHz to about 100 kHz, from about 20 kHz to about 80 kHz, from about 20 kHz to about 60 kHz, or from about 30 kHz to about 50 kHz. The ultrasound signal may have a frequency of less than 100 kHz, less than 80 kHz, less than 60 kHz, or less than 50 kHz. The ultrasound signal may have a frequency of about 20 kHz, about 25 kHz, about 30 kHz, about 35 kHz, about 40 kHz, about 45 kHz, about 50 kHz, about 55 kHz, or about 60 kHz.
In methods of the invention, the ultrasound signal may have a defined intensity. For example, and without limitation, the ultrasound signal may have an intensity of from about 0.1 W/cm2 to about 10 W/cm2, from about 0.24 W/cm2 to about 1.4 W/cm2, from about 1.4 W/cm2 to about 10 W/cm2, from about 10 W/cm2 to about 100 W/cm2, from about 100 W/cm2 to about 500 W/cm2, or from about 500 W/cm2 to about 1000 W/cm2.
In some embodiments, the ultrasound energy may be delivered as a pulse, i.e., it may be delivered over a brief, finite period to minimize damage to the agent being delivered by the ultrasound energy. For example, and without limitation, the pulse may be less than 20 minutes, less than 10 minutes, less than 5 minutes, or less than 10 minutes. For example, and without limitation, the pulse may be from about 10 seconds to about 3 minutes. The pulse may be about 10 minutes, about 5 minutes, about 3 minutes, about 3 minutes, about 1 minute, about 30 seconds, about 20 seconds, or about 10 seconds.
The parameters of the ultrasound pulse, such as the frequency and/or duration, may be selected so that damage to the agent is limited to a certain fraction or percentage of the agent. For example, and without limitation, the ultrasound energy may result in breakdown of less than about 95% of the agent, less than about 90% of the agent, less than about 80% of the agent, less than about 70% of the agent, less than about 60% of the agent, less than about 50% of the agent, less than about 40% of the agent, less than about 25% of the agent, or less than about 10% of the agent.
The parameters of the ultrasound pulse, such as the frequency and/or duration, may be selected so that at least a minimum amount of the agent is transferred to the tissue. For example, and without limitation, the ultrasound energy may result in transfer of at least 1% of the agent, at least 2% of the agent, at least 5% of the agent, at least 10% of the agent, at least 20% of the agent, at least 30% of the agent, or at least 40% of the agent.
The methods may be used to deliver a therapeutic agent to a specific tissue in the GI tract. For example, the tissue may be buccal tissue, gingival tissue, labial tissue, esophageal tissue, gastric tissue, intestinal tissue, colorectal tissue, or anal tissue. The therapeutic agent may be targeted to a particular tissue in the GI tract. For example, the therapeutic agent may be targeted to the stomach, small intestine, large intestine (colon), rectum, or at a duct that enters the GI tract, such as a pancreatic duct or a common bile duct.
The methods may include administering an ingestible capsule to the subject. The ingestible capsule may be administered orally or rectally. The ingestible capsule may be administered via a duct that enters the GI tract.
The methods may include positioning the ingestible capsule within the subjects GI tract. For example, the ingestible capsule may be positioned in proximity to an affected region of the GI tract, such as an ulcer or inflamed region. The ingestible capsule may be positioned by applying a magnetic field to a portion of the subject's GI tract from a device outside the subject's body. The magnetic field may be applied using the transmitter. Alternatively, or additionally, the magnetic field may be applied from a magnetic device that is separate from the transmitter.
The therapeutic agent may be any agent that provides a therapeutic benefit. For example and without limitation, suitable agents include alpha-hydroxy formulations, ace inhibiting agents, analgesics, anesthetic agents, anthelmintics, anti-arrhythmic agents, antithrombotic agents, anti-allergic agents, anti-angiogenic agents, antibacterial agents, antibiotic agents, anticoagulant agents, anticancer agents, antidiabetic agents, anti-emetics, antifungal agents, antigens, antihypertension agents, antihypotensive agents, antiinflammatory agents, antimicotic agents, antimigraine agents, anti-obesity agents, antiparkinson agents, antirheumatic agents, antithrombins, antiviral agents, antidepressants, antiepileptics, antihistamines, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antithyroid agents, anxiolytics, asthma therapies, astringents, beta blocking agents, blood products and substitutes, bronchospamolytic agents, calcium antagonists, cardiovascular agents, cardiac glycosidic agents, carotenoids, cephalosporins, chronic bronchitis therapies, chronic obstructive pulmonary disease therapies, contraceptive agents, corticosteroids, cytostatic agents, cystic-fibrosis therapies, cardiac inotropic agents, contrast media, cough suppressants, diagnostic agents, diuretic agents, dopaminergics, elastase inhibitors, emphysema therapies, enkephalins, fibrinolytic agents, growth hormones, hemostatics, immunological agents, immunosupressants, immunotherapeutic agents, insulins, interferons, lactation inhibiting agents, lipid-lowering agents, lymphokines, muscle relaxants, neurologic agents, NSAIDS, nutraceuticals, oncology therapies, organ-transplant rejection therapies, parasympathomimetics, parathyroid calcitonin and biphosphonates, prostacyclins, prostaglandins, psycho-pharmaceutical agents, protease inhibitors, magnetic resonance diagnostic imaging agents, radio-pharmaceuticals, reproductive control hormones, respiratory distress syndrome therapies, sedative agents, sex hormones, somatostatins, steroid hormonal agents, stimulants and anoretics, sympathomimetics, thyroid agents, vasodilating agents, vitamins, and xanthines. A more complex list of chemicals and drugs that can be used as agents in embodiments of the invention is provided in the Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals Fifteenth Edition, Maryadele J O'Neil, ed., RSC Publishing, 2015, ISBN-13: 978-1849736701, ISBN-10 1849736707, the contents of which are incorporated herein by reference.
Therapeutic agents may be of any chemical form. For example, agents may be biological therapeutics, such as nucleic acids, proteins, peptides, polypeptides, antibodies, or other macromolecules. Nucleic acids include RNA, DNA, RNA/DNA hybrids, and nucleic acid derivatives that include non-naturally-occurring nucleotides, modified nucleotides, non-naturally-occurring chemical linkages, and the like. Examples of nucleic acid derivatives and modified nucleotides are described in, for example, International Publication WO 2018/118587, the contents of which are incorporated herein by reference. Nucleic acids may be polypeptide-encoding nucleic acids, such as mRNAs and cDNAs. Nucleic acids may interfere with gene expression. Examples of interfering RNAs (RNAi) include siRNAs and miRNAs. RNAi is known in the art and described in, for example, Kim and Rossi, Biotechniques. 2008 April; 44(5): 613-616, doi: 10.2144/000112792; and Wilson and Doudna, Molecular Mechanisms of RNA Interference, Annual Review of Biophysics 2013 42:1, 217-239, the contents of each of which are incorporated herein by reference. Agents may be organic molecules of non-biological origin. Such drugs are often called small-molecule drugs because they typically have a molecular weight of less than 2000 Daltons, although they may be larger. Agents may be combinations or complexes of one or more biological macromolecules and/or one or more small molecules. For example and without limitation, agents may be nucleic acid complexes, protein complexes, protein-nucleic acid complexes, and the like. Thus, the agent may exist in a multimeric or polymeric form, including homocomplexes and heterocomplexes.
An advantage of ultrasound-based delivery of therapeutic agents is the capacity to deliver large molecules, e.g., molecules having a molecular weight greater than 1000 Da. Thus, the therapeutic agent may have a minimum size. For example and without limitation, the antigen may have a molecular weight of >100 Da, >200 Da, >500 Da, >1000 Da, >2000 Da, >5000 Da, >10,000 Da, >20,000 Da, >50,000 Da, or >100,000 Da.
The therapeutic agent may be provided in a liquid that promotes delivery of the therapeutic agent using the devices or systems provided herein. For example, the liquid may facilitate ultrasound-induced cavitation, iontophoresis, sonoporation, magnetosonoporation, or electroporation. The liquid may be aqueous. The liquid may contain ions. The liquid may be an aqueous solution that contains one or more salts. The liquid may contain a buffer.
The therapeutic agent may be formulated. Formulations commonly used for delivery of biologic and small-molecule agents include drug crystals, gold particles, iron oxide particles, lipid-like particles, liposomes, micelles, microparticles, nanoparticles, polymeric particles, vesicles, viral capsids, viral particles, and complexes with other macromolecules that are not essential for the biological or biochemical function of the agent.
Alternatively, the therapeutic agent may be unformulated, i.e., it may be provided in a biologically active format that does not contain other molecules that interact with the agent solely to facilitate delivery of the agent. Thus, the agent may be provided in a non-encapsulated form or in a form that is not complexed with other molecules unrelated to the function of the agent.
The agent may be a component of a gene editing system, such as a meganuclease, zinc finger nuclease (ZFN), a transcription activator-like effector-based nuclease (TALEN), or the clustered, regularly-interspersed palindromic repeat (CRISPR) system.
Meganucleases are endodeoxyribonucleases that recognize double-stranded DNA sequences of 12-40 base pairs. They can be engineered to bind to different recognition sequences to create customized nucleases that target sequences. Meganucleases exist in archaebacterial, bacteria, phages, fungi, algae, and plants, and meganucleases from any source may be used. Engineering meganucleases to recognize specific sequences is known in the art and described in, for example, Stoddard, Barry L. (2006) “Homing endonuclease structure and function” Quarterly Reviews of Biophysics 38 (1): 49-95 doi: 10.1017/S0033583505004063, PMID 16336743; Grizot, S.; Epinat, J. C.; Thomas, S.; Duclert, A.; Rolland, S.; Paques, F.; Duchateau, P. (2009) “Generation of redesigned homing endonucleases comprising DNA-binding domains derived from two different scaffolds” Nucleic Acids Research 38 (6): 2006-18, doi: 10.1093/nar/gkp1171. PMC 2847234, PMID 20026587; Epinat, Jean-Charles; Arnould, Sylvain; Chames, Patrick; Rochaix, Pascal; Desfontaines, Dominique; Puzin, Clémence; Patin, Amélie; Zanghellini, Alexandre; Pâques, Frédéric (2003-06-01) “A novel engineered meganuclease induces homologous recombination in yeast and mammalian cells” Nucleic Acids Research 31 (11): 2952-2962; and Seligman, L. M.; Chisholm, K M; Chevalier, B S; Chadsey, M S; Edwards, S T; Savage, J H; Veillet, A L (2002) “Mutations altering the cleavage specificity of a homing endonuclease” Nucleic Acids Research 30 (17): 3870-9, doi:10.1093/nar/gkf495. PMC 137417, PMID 12202772, the contents of each of which are incorporated herein by reference.
ZFNs are artificial restriction enzymes that have a zinc finger DNA-binding domain fused to a DNA-cleavage domain. ZFNs can also be engineered to target specific DNA sequences. The design and use of ZFNs is known in the art and described in, for example, Carroll, D (2011) “Genome engineering with zinc-finger nucleases” Genetics Society of America 188 (4): 773-782, doi: 10.1534/genetics. 111.131433. PMC 3176093, PMID 21828278; Cathomen T, Joung J K (July 2008) “Zinc-finger nucleases: the next generation emerges” Mol. Ther. 16 (7): 1200-7, doi:10.1038/mt.2008.114, PMID 18545224; Miller, J. C.; Holmes, M. C.; Wang, J.; Guschin, D. Y.; Lee, Y. L.; Rupniewski, I.; Beausejour, C. M.; Waite, A. J.; Wang, N. S.; Kim, K. A.; Gregory, P. D.; Pabo, C. O.; Rebar, E. J. (2007) “An improved zinc-finger nuclease architecture for highly specific genome editing” Nature Biotechnology, 25 (7): 778-785, doi: 10.1038/nbt1319, PMID 17603475, the contents of each of which are incorporated herein by reference.
TALENs are artificial restriction enzymes that have a TAL effector DNA-binding domain fused to a DNA cleavage domain. TALENs can also be engineered to target specific DNA sequences. The design and use of TALENs is known in the art and described in, for example, Boch J (February 2011) “TALEs of genome targeting” Nature Biotechnology 29 (2): 135-6, doi:10.1038/nbt.1767. PMID 21301438; Juillerat A, Pessereau C, Dubois G, Guyot V, Maréchal A, Valton J, Daboussi F, Poirot L, Duclert A, Duchateau P (January 2015) “Optimized tuning of TALEN specificity using non-conventional RVDs” Scientific Reports, 5: 8150, doi: 10.1038/srep08150. PMC 4311247, PMID 25632877; and Mahfouz M M, Li L, Shamimuzzaman M, Wibowo A, Fang X, Zhu J K (February 2011) “De novo-engineered transcription activator-like effector (TALE) hybrid nuclease with novel DNA binding specificity creates double-strand breaks” Proceedings of the National Academy of Sciences of the United States of America, 108 (6): 2623-8, Bibcode:2011PNAS, 108.2623M, doi: 10.1073/pnas. 1019533108, PMC 3038751, PMID 21262818, the contents of each of which are incorporated herein by reference.
The CRISPR system is a prokaryotic immune system that provides acquired immunity against foreign genetic elements, such as plasmids and phages. CRISPR systems include one or more CRISPR-associated (Cas) proteins that cleave DNA at clustered, regularly-interspersed palindromic repeat (CRISPR) sequences. Cas proteins include helicase and exonuclease activities, and these activities may be on the same polypeptide or on separate polypeptides. Cas proteins are directed to CRISPR sequences by RNA molecules. A CRISPR RNA (crRNA) binds to a complementary sequence in the target DNA to be cleaved. A transactivating crRNA (tracrRNA) binds to both the Cas protein and the crRNA to draw the Cas protein to the target DNA sequence. Not all CRISPR systems require tracrRNA. In nature crRNA and tracrRNA occur on separate RNA molecules, but they also function when contained a single RNA molecule, called a single guide RNA or guide RNA (gRNA). The one or more RNAs and one or more polypeptides assemble inside the cell to form a ribonucleoprotein (RNP). CRISPR systems are described, for example, in van der Oost, et al., CRISPR-based adaptive and heritable immunity in prokaryotes, Trends in Biochemical Sciences, 34(8):401-407 (2014); Garrett, et al., Archaeal CRISPR-based immune systems: exchangeable functional modules, Trends in Microbiol. 19(11):549-556 (2011); Makarova, et al., Evolution and classification of the CRISPR-Cas systems, Nat. Rev. Microbiol. 9:467-477 (2011); and Sorek, et al., CRISPR-Mediated Adaptive Immune Systems in Bacteria and Archaea, Ann. Rev. Biochem. 82:237-266 (2013), the contents of each of which are incorporated herein by reference.
CRISPR-Cas systems have been placed in two classes. Class 1 systems use multiple Cas proteins to degrade nucleic acids, while class 2 systems use a single large Cas protein. Class 1 Cas proteins include Cas10, Cas10d, Cas3, Cas5, Cas8a, Cmr5, Cse1, Cse2, Csf1, Csm2, Csx11, Csy1, Csy2, and Csy3. Class 2 Cas proteins include C2c1, C2c2, C2c3, Cas4, Cas9, Cpf1, and Csn2.
CRISPR-Cas systems are powerful tools because they allow gene editing of specific nucleic acid sequences using a common protein enzyme. By designing a guide RNA complementary to a target sequence, a Cas protein can be directed to cleave that target sequence. In addition, although naturally-occurring Cas proteins have endonuclease activity, Cas proteins have been engineered to perform other functions. For example, endonuclease-deactivated mutants of Cas9 (dCas9) have been created, and such mutants can be directed to bind to target DNA sequences without cleaving them. dCas9 proteins can then be further engineered to bind transcriptional activators or inhibitors. As a result, guide sequences can be used to recruit such CRISPR complexes to specific genes to turn on or off transcription. Thus, these systems are called CRISPR activators (CRISPRa) or CRISPR inhibitors (CRISPRi). CRISPR systems can also be used to introduce sequence-specific epigenetic modifications of DNA, such acetylation or methylation. The use of modified CRISPR systems for purposes other than cleavage of target DNA are described, for example, in Dominguez, et al., Beyond editing: repurposing CRISPR-Cas9 for precision genome regulation and interrogation, Nat. Rev. Cell Biol. 17(1):5-15 (2016), which is incorporated herein by reference.
The agent may be any component of a CRISPR system, such as those described above. For example and without limitation, the CRISPR component may be one or more of a helicase, endonuclease, transcriptional activator, transcriptional inhibitor, DNA modifier, gRNA, crRNA, or tracrRNA. The CRISPR component contain a nucleic acid, such as RNA or DNA, a polypeptide, or a combination, such as a RNP. The CRISPR nucleic acid may encode a functional CRISPR component. For example, the nucleic acid may be a DNA or mRNA. The CRISPR nucleic acid may itself be a functional component, such as a gRNA, crRNA, or tracrRNA.
The agent may include an element that induces expression of the CRISPR component. For example, expression of the CRISPR component may be induced by an antibiotic, such as tetracycline, or other chemical. Inducible CRISPR systems have been described, for example, in Rose, et al., Rapidly inducible Cas9 and DSB-ddPCR to probe editing kinetics, Nat. Methods, 14, pages 891-896 (2017); and Cao, et al., An easy and efficient inducible CRISPR/Cas9 platform with improved specificity for multiple gene targeting, Nucleic Acids Res. 14(19): e149 (2016), the contents of which are incorporated herein by reference. The inducible element may be part of the CRISPR component, or it may be a separate component.
In certain embodiments of the invention, methods allow delivery of agents that promote wound healing. The agent may promote healing by any mechanism. For example and without limitation, the agent may facilitate one or more phases of the wound healing process; prevent infection, including bacterial or viral infection; or alleviate pain or sensitivity.
A variety of growth factors promote wound healing. For example and without limitation, growth factors that promote wound healing include CTGF/CCN2, EGF family members, FGF family members, G-CSF, GM-CSF, HGF, HGH, HIF, histatin, hyaluronan, IGF, IL-1, IL-4, IL-8, KGF, lactoferrin, lysophosphatidic acid, NGF, a PDGF, TGF-β, and VEGF. The EFG family includes 10 members: amphiregulin (AR), betacellulin (BTC), epigen, epiregulin (EPR), heparin-binding EGF-like growth factor (HB-EGF), neuregulin-1 (NRG1), neuregulin-2 (NRG2), neuregulin-3 (NRG3), neuregulin-4 (NRG4), or transforming growth factor-α (TGF-α). The FGF family includes 22 members: FGF1, FGF2 (also called basic FGF or bFGF), FGF3, FGF4, FGF5, FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF13, FGF14, FGF16, FGF17, FGF18, FGF19, FGF20, FGF21, FGF22, or FGF23. PDGF exists in three forms: PDGF AA, PDGF AB, and PDGF BB. The TGF-family includes three forms: TGF-β1, TGF-β2, and TGF-β3.
A variety of agents that prevent infection have been used to treat wounds. For example, and without limitation, the agent may be an antimicrobial, antiviral, antibiotic, antifungal, or antiseptic. Exemplary agents include silver, iodine, chlorhexidine, hydrogen peroxide, lysozyme, peroxidase, defensins, cystatins, thrombospondin, and antibodies. Nitric oxide donors, such as glyceryl trinitrate and nitrite salts, are also useful to prevent infection and promote wound healing.
The methods are useful to treat conditions of the GI tract of a subject. The condition may be any disease, disorder, or condition that affects the GI tract.
In some embodiments, the disorder is a disorder of the esophagus, including, but not limited to, esophagitis—(candidal), gastroesophageal reflux disease (gerd); laryngopharyngeal reflux (also known as extraesophageal reflux disease/eerd); rupture (Boerhaave syndrome, Mallory-Weiss syndrome); UES—(Zenker's diverticulum); LES—(Barrett's esophagus); esophageal motility disorder—(nutcracker esophagus, achalasia, diffuse esophageal spasm); esophageal stricture; and megaesophagus.
In some embodiments, the disorder is a disorder of the stomach, including but not limited to gastritis (e.g., atrophic, Menetrier's disease, gastroenteritis); peptic (i.e., gastric) ulcer (e.g., Cushing ulcer, Dieulafoy's lesion); dyspepsia; emesis; pyloric stenosis; achlorhydria; gastroparesis; gastroptosis; portal hypertensive gastropathy; gastric antral vascular ectasia; gastric dumping syndrome; and human mullular fibrillation syndrome (HMFS).
In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, enteritis (duodenitis, jejunitis, ileitis); peptic (duodenal) ulcer (curling's ulcer); malabsorption: celiac; tropical sprue; blind loop syndrome; Whipple's; short bowel syndrome; steatorrhea; milroy disease In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, both large intestine and small intestine enterocolitis (necrotizing); inflammatory bowel disease (IBD); Crohn's disease; vascular; abdominal angina; mesenteric ischemia; angiodysplasia; bowel obstruction: ileus; intussusception; volvulus; fecal impaction; constipation; and diarrhea.
In some embodiments, the disorder is a disorder of the small intestine, including but not limited to, accessory digestive glands disease; liver hepatitis (viral hepatitis, autoimmune hepatitis, alcoholic hepatitis); cirrhosis (PBC); fatty liver (Nash); vascular (hepatic veno-occlusive disease, portal hypertension, nutmeg liver); alcoholic liver disease; liver failure (hepatic encephalopathy, acute liver failure); liver abscess (pyogenic, amoebic); hepatorenal syndrome; peliosis hepatis; hemochromatosis; and Wilson's disease.
In some embodiments, the disorder is a disorder of the pancreas, including, but not limited to, pancreas pancreatitis (acute, chronic, hereditary); pancreatic pseudocyst; and exocrine pancreatic insufficiency.
In some embodiments, the disorder is a disorder of the large intestine, including but not limited to, appendicitis; colitis (pseudomembranous, ulcerative, ischemic, microscopic, collagenous, lymphocytic); functional colonic disease (IBS, intestinal pseudoobstruction/ogilvie syndrome); megacolon/toxic megacolon; diverticulitis; and diverticulosis.
In some embodiments, the disorder is a disorder of the large intestine, including but not limited to, gall bladder and bile ducts, cholecystitis; gallstones/cholecystolithiasis; cholesterolosis; Rokitansky-Aschoff sinuses; postcholecystectomy syndrome cholangitis (PSC, ascending); cholestasis/Mirizzi's syndrome; biliary fistula; haemobilia; and gallstones/cholelithiasis. In some embodiments, the disorder is a disorder of the common bile duct (including choledocholithiasis, biliary dyskinesia).
Other disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, such as systemic lupus erythematosus (SLE), rheumatoid arthritis, thyroidosis, graft versus host disease, scleroderma, diabetes mellitus, Graves' disease, Beschet's disease; inflammatory diseases, such as chronic inflammatory pathologies and vascular inflammatory pathologies, including chronic inflammatory pathologies such as sarcoidosis, chronic inflammatory bowel disease, ulcerative colitis, and Crohn's pathology and vascular inflammatory pathologies, such as, but not limited to, disseminated intravascular coagulation, atherosclerosis, giant cell arteritis and Kawasaki's pathology; malignant pathologies involving tumors or other malignancies, such as, but not limited to leukemias (acute, chronic myelocytic, chronic lymphocytic and/or myelodyspastic syndrome); lymphomas (Hodgkin's and non-Hodgkin's lymphomas, such as malignant lymphomas (Burkitt's lymphoma or Mycosis fungoides)); carcinomas (such as colon carcinoma) and metastases thereof; cancer-related angiogenesis; infantile haemangiomas; and infections, including, but not limited to, sepsis syndrome, cachexia, circulatory collapse and shock resulting from acute or chronic bacterial infection, acute and chronic parasitic and/or infectious diseases, bacterial, viral or fungal, such as a HIV, AIDS (including symptoms of cachexia, autoimmune disorders, AIDS dementia complex and infections).
Other disorders which can be treated with the methods and devices included herein include acute and chronic immune and autoimmune pathologies, inflammatory diseases, infections and malignant pathologies involving, e.g., tumors or other malignancies.
The subject suffering from the GI condition may be any type of subject, such as an animal, for example, a mammal, for example, a human.
It should be appreciated that all combinations of the concepts discussed in greater detail below (provided such concepts are not mutually inconsistent) are contemplated as being part of the inventive subject matter disclosed herein. It also should be appreciated that terminology explicitly employed herein that also may appear in any disclosure incorporated by reference should be accorded a meaning most consistent with the concepts disclosed herein.
It should be appreciated that various concepts introduced above and discussed in greater detail below may be implemented in any of numerous ways, as the disclosed concepts are not limited to any particular manner of implementation. Examples of specific implementations and applications are provided primarily for illustrative purposes. The present disclosure should in no way be limited to the exemplary implementation and techniques illustrated in the drawings and described below.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed by the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed by the invention, subject to any specifically excluded limit in a stated range. Where a stated range includes one or both endpoint limits, ranges excluding either or both of those included endpoints are also included in the scope of the invention.
As used herein, the term “includes” means includes but is not limited to, the term “including” means including but not limited to. The term “based on” means based at least in part on.
The term transducer, as used herein, may refer to a device that converts energy from one form to another.
The term Helmholtz coil, as used herein, may refer to a device for producing a region of nearly uniform magnetic field, named after the German physicist Hermann von Helmholtz. It consists of two electromagnets on the same axis.
The term load, as used herein, may refer to a device connected to a signal source, whether or not it consumes power.
The term electroporation, as used herein, may refer to a method or technique in which an electrical field is applied to cells to increase the permeability of the cell membrane, allowing chemicals, drugs, or nucleic acid to be introduced into the cell.
The term sonoporation, as used herein, may refer to the use of sound (typically ultrasonic frequencies) for modifying the permeability of the cell plasma membrane. Sonoporation employs the acoustic cavitation of microbubbles to enhance delivery of small and large molecules.
References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.
Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification, and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
The present application claims priority to and the benefit of U.S. Provisional Application Ser. No. 63/176,643, filed on Apr. 19, 2021, the content of which is incorporated herein by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/024987 | 4/15/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63176643 | Apr 2021 | US |
