Patent Application
20160228646
This disclosure generally involves approaches for delivering particles into biological tissue and to systems and methods related to such approaches.
Particles that can be accelerated to penetrate the skin can have a very low active payload when a relatively light functional material, such as a drug, ink, cosmetics, etc., needs to be coated on dense, carrier particles such as gold. Solid particles of the functional material most efficiently carry the functional material in higher doses. However, the relatively light particle of functional material may not have enough momentum to be delivered into biological tissue at sufficient depth to reach target cells. Advanced gene therapies, such as DNA/RNA based vaccines, gene based cancer tumor therapies, and genetic pharmacology need new delivery methods to penetrate cells.
A device for delivery of particles into biological tissue includes at least one conduit and a propellant source fluidically coupled to the conduit and configured to deliver a propellant into the conduit. A particle source is configured to release elongated particles into the conduit, the elongated particles having a width, w, a length, l>w. The propellant source and the conduit are configured to propel the elongated particles in a collimated particle stream toward the biological tissue. An alignment mechanism is configured to align a longitudinal axis of the elongated particles to be substantially parallel to a direction of the particle stream in an alignment region of the conduit. The aligned elongated particles are ejected from the conduit and impact the biological tissue.
According to some implementations, the alignment mechanism comprises an aerodynamic alignment mechanism that includes a source of sheath fluid and one more ports in the conduit configured to allow entry of the sheath fluid into the conduit in one or more sheath streams adjacent to the particle stream. The one or more sheath streams are configured to align the longitudinal axis of the elongated particles along the direction of the particle stream in the alignment region.
According to some implementations the elongated particles are electrically charged and the alignment mechanism comprises an electrostatic alignment mechanism comprising one or more charged plates arranged proximate to the conduit.
In some implementations the elongated particles are magnetic and the alignment mechanism comprises a magnetic field generator that generates a magnetic field within the conduit.
The elongated particles may have various features that enhance alignment, such as at least one pointed tip and/or one or more fins. The fins can be configured to break off or fold back when the elongated particles penetrate the biological tissue.
In some implementations the elongated particles are solid particles of a functional material that interacts with the biological tissue. In some cases the elongated particles include two or more types of material such as at least a first material and a second material. The second material may be a functional material that interacts with the biological tissue and the first material may be a biologically inert material that has higher density than the second material. In some implementations, the volume of the second material in the elongated particle is greater than the volume of the first material. The elongated particles may comprise a drug, a cosmetic, a biologically nourishing material, or a marking material.
According to some embodiments, the particle delivery device includes a particle accelerator downstream from the alignment mechanism. The particle accelerator is configured to accelerate the elongated particles toward the biological tissue.
Some implementations of the particle delivery device further include an additional particle source configured to release additional particles into the particle stream. The elongated particles comprise a functional material that interacts with the biological tissue and the additional particles have a higher density than a density of the elongated particles. In some implementations, the elongated particles are electrostatically charged and the additional particles are oppositely electrostatically charged from the elongated particles. Due to their opposite charges, the elongated particles and the additional particles form particle agglomerations as the particles are transported in the particle stream.
Some embodiments involve a method for delivery of particles into biological tissue. Elongated particles having a width, w, a length, l>w, and an aspect ratio, l/w, are released into a conduit and are propelled in a collimated particle stream in the conduit. The longitudinal axis of the elongated particles are aligned to be substantially parallel to a direction of the collimated particle stream. The aligned elongated particles are ejected from the conduit toward the biological tissue. Aligning the longitudinal axis of elongated particles may comprise introducing a sheath fluid into the conduit in one or more sheath streams adjacent to the collimated particle stream. The one or more sheath streams operate to align the longitudinal axis of the elongated particles to be substantially parallel to the direction of the particle stream in an alignment region.
In some implementations the elongated particles are electrically charged and aligning the elongated particles comprises electrostatically aligning the elongated particles.
In other implementations the elongated particles are magnetic and aligning the elongated particles comprises magnetically aligning the elongated particles.
The aligned elongated particles may be accelerated toward the biological tissue using an electrostatic particle accelerator. The each of the elongated particles may comprise one or more of increased density at one end of the elongated particle and an aerodynamic drag feature.
The method may include pre or post treating the biological tissue before or after ejecting the aligned elongated particles from the conduit toward the biological tissue. The pre or post treating can comprise at least one of a laser treatment, a magnetic treatment, an electromagnetic treatment, an ultrasonic treatment and a chemical treatment.
Some embodiments involve a device for delivery of particles into biological tissue that includes at least one conduit and a propellant source fluidically coupled to the conduit and configured to deliver a propellant into the conduit. A particle source is configured to release elongated particles into the conduit, the elongated particles having a width, w, a length, l>w. The propellant source and the conduit are configured to accelerate the elongated particles in a collimated particle stream toward the biological tissue. Acceleration of the particles by the propellant aligns a longitudinal axis of the elongated particles to be substantially parallel to a direction of the particle stream. Each of the elongated particle may include at least one of a feature that provides enhanced aerodynamic drag and increased density at one end of the particle.
The figures are not necessarily to scale. Like numbers used in the figures refer to like components. However, it will be understood that the use of a number to refer to a component in a given figure is not intended to limit the component in another figure labeled with the same number.
Embodiments described herein are directed to systems and methods for delivering particles into biological tissue. According to the approaches described herein, one or more collimating conduits are disposed within a housing with a propellant, e.g., a pressurized gas, fluidically coupled to the one or more collimating conduits. The conduits include openings that allow introduction of particles into the conduit. The propellant source and the conduits are arranged so that as the particles are introduced, they are entrained by the gas from the propellant source and are propelled along the conduit in a particle flow stream.
As previously discussed, solid particles of functional material are needed to efficiently carry the functional material into tissue at higher doses. However particles of functional material may not have enough momentum to be delivered into biological tissue at sufficient depth to reach target cells. According to some implementations discussed below, particles that are heavier and/or denser than the lighter/lower density functional particles are ejected from the conduits, forming micropores in the biological tissue, at least temporarily. The heavier/denser particles may have a density greater than about 10 g/cm3, a volume greater than 0.07 μm3, and weight range of 0.5 μg to 100 mg. When penetrating the tissue, the heavier/denser particles may present an average cross sectional area substantially perpendicular to the tissue surface of greater than 0.2 μm2. The lighter/lower density second particles are ejected from the conduits, in some cases subsequently or substantially simultaneously with ejection of the heavier first particles. The heavier/denser particles may have a density more than about three times the density of the lighter/less dense particles. The lighter/less dense particles may have a density less than about 10 g/cm3 with diameter range of 50 nm to 1 mm. When penetrating the tissue, the lighter/lower density functional particles may present an average cross sectional area perpendicular to the tissue surface that is equal to or less than that of the heavier particles. For example, the average presenting cross sectional area of the lighter/lower density particles may be a fraction (¾, ½, ¼, etc.) of that of the heavier particles. In some scenarios, the heavier/denser first particles penetrate the biological tissue to create micropores that increase porosity of the biological tissues. The lighter/less dense second particles penetrate the porous biological tissue previously formed by the first particles. If the first particles follow the second particles, the second particles may be driven further into the tissue. This approach allows the lighter/lower density second particles to penetrate the skin via the micropores formed by the first particles to reach target cells.
According to some implementations, the first particles and second particles are initially collimated in the conduit by the conduit walls and may be subsequently focused in the conduit by a focusing mechanism. Particle collimation followed by focusing achieves enhanced spatial correlation between the first and second particles as they emerge from the device, which in turn leads to more effective delivery of functional material. Focusing occurs in a focus region of the conduits which may be located near the conduit outlets. The first and second particles may be focused alone or together such that the largest cross sectional diameter of the focused particle stream in the focus region is less than the largest inner cross sectional diameter of the conduit in the focus region. In some cases, the largest cross sectional diameter of the focused particle stream in the focus region is equal or greater than the presenting cross sectional diameter of the first particles, wherein the presenting cross section is the cross section of the particle that is substantially perpendicular to the direction of the flow stream.
In some implementations, the device includes a tissue-interfacing surface located at one end of the housing near the conduit outlets that provides an interface with the surface of biological tissue. The collimated and focused particle stream emerges from the outlet substantially perpendicular to the biological tissue surface and can maintain a beam diameter of less than 10 μm or equal to the presenting cross sectional diameter of the first particles over a length of about 1 cm or more between the outlet of the conduit and the tissue surface. In the unconstrained space between the conduit outlet and the tissue surface, the particle stream width may increase by less than about 10% of its width at the outlet.
According to some implementations, the particles, e.g., the first and/or second particles or other particles, are elongated particles that have a width (w) and a length (l), wherein l>w. An alignment mechanism may be used to rotationally align the elongated particles so that the major axis (also referred to as the length axis) of the particles is substantially parallel with the direction of the particle flow stream in the conduit. The particles may have a relatively high aspect ratio, e.g., l/w is in the range of 10 to 1000 and may include features, such as sharpened tips, fins, anisotropic weighting, structured surfaces and the like, that enhance alignment, tissue penetration, and surface area available for carrying a functional material. The particles emerge from the outlets of the conduits in the aligned orientation in a collimated particle stream and impinge on the tissue surface. According to some aspects, the aligned particles may also be focused into a narrower cross sectional area prior to ejection from the device.
Devices, methods, and systems are provided for producing high velocity, e.g., supersonic, particle streams of collimated, focused and/or aligned particles that maintain a beam diameter less than 50 μm, or less than or equal to about 20 μm, or equal to or greater than the presenting cross sectional diameter of the first particles, less than the larger inner diameter of conduit. In some implementations, the particle stream width increases by less than 10% over a length of about 1 cm or more in the space between the outlet of the conduit and the tissue surface. When the particles are focused in addition to being collimated, the beam diameter increase of less than 5% may be maintained over an unconstrained 1 cm length. The approaches described herein may reduce or eliminate recoil/splashing, pain, and bruising associated with other needleless injection techniques. Such devices, methods, and systems can also provide increased control and reliability of drug delivery and reduce the operational skill required to perform needleless drug injection. This, in turn, promotes more precise and accurate drug dosing.
The devices, systems, and methods described herein may be used for targeted delivery of therapeutic, diagnostic, cosmetics, or other substances into or through a variety of types of tissues or biological barriers, including suitable cells, tissues, or organs, including the skin or parts thereof, mucosal tissues, vascular tissues, lymphatic tissues, and the like. The target cells or tissues may be in animals, mammals, humans, plants, insects, or other organisms. For example, a drug or other substance may be delivered through the stratum corneum, and into underlying dermal or epidermal tissues or cells.
According to some embodiments, a particle delivery device includes a propellant source, which may be a source that contains or produces a pressurized gas. The delivery device also includes one or more collimators, each collimator comprising one or more conduits that are fluidly connected with the fluid source. Each of the conduits is configured to form a collimated particle stream comprising particles entrained in and propelled by the gas. According to some embodiments, the particle delivery device may further include a skin interfacing surface that is adapted to mate with the skin (or other tissue surface) and align the ejector with the skin such that the plurality of collimated particle streams penetrate the skin in a direction substantially perpendicular to the skin. The skin interfacing surface is disposed on a skin interfacing unit located downstream of the conduit outlet. In some embodiments, described below in connection with
The delivery device may include one or more reservoirs of functional and non-functional material, e.g., a reservoir containing a drug in solid particle or liquid form that is fluidically coupled to at least one conduit of the collimators via a port between the inlet end and the outlet end of the conduit. The port is fluidly connected (or is operable to become fluidly connected) with the reservoir, and the inlet end of each of the conduit is fluidly connected (or is operable to become fluidly connected) with the gas source.
In certain embodiments, the delivery device is configured to produce focused, collimated gas streams having a sufficient velocity to penetrate human stratum corneum. For example, the delivery device may be configured to produce collimated gas streams having a velocity of about 30 to about 1500 m/s. In certain embodiments, each of the collimated gas streams may have a diameter of about 1 μm to about 1000 μm at a distance of about 0.5 mm to 10 mm from the outlet of the collimator.
The collimated and focused particle stream emerges from the outlet substantially perpendicular to the biological tissue surface and can maintain a beam diameter of less than 10 μm or equal to the presenting cross sectional diameter of the first particles over a length of about 1 cm or more between the outlet of the conduit and the tissue surface. In the unconstrained space between the conduit outlet and the tissue surface, the particle stream width may increase by less than about 10% of its width at the outlet.
Effective collimation may be achieved by delivering a propellant into a conduit and controllably introducing or metering the particles into the conduit. The particles may then be introduced into the gas stream from one or more inlet ports. The propellant may enter the channel at a high velocity. Alternatively, the propellant may be introduced into the channel at a high pressure, and the conduit may include a constriction (e.g., de Laval or other converging/diverging type nozzle) for converting the high pressure of the propellant to high velocity. In such a case, the propellant is introduced at a port located at a proximal end of the conduit (i.e., near the converging region), and the material ports are provided near the distal end of the channel (at or further downstream of a region defined as the diverging region), allowing for introduction of material into the propellant stream. It has been demonstrated that a propellant and the material flow pattern can remain relatively collimated for a distance of up to 10 millimeters. For example, the stream does not deviate by more than about 20 percent, and preferably by not more than about 10 percent, from the width of the exit orifice for a distance of at least 4 times the exit orifice width.
In certain embodiments, the collimator may include a plurality of conduits. Each conduit has inlet and an outlet, as shown in
In some embodiments, the particle delivery device releases a particle from a particle source into the gas streams such that the particles becomes entrained in each gas stream and are transported into the skin in a direction substantially perpendicular to the skin. For example, each of the conduits may have a port that provides an opening between the inlet and outlet of the conduit, that is fluidly connected with the particle source. In certain embodiments, the port is downstream of the venturi. In some embodiments, the delivery device includes a rupturable membrane between the particle source and the collimator. For example, the rupturable membrane may seal the port until the membrane is ruptured. Rupture of the rupturable membrane may be controlled by the operator of the device.
When the particle port is placed downstream of the venturi or downstream of the location at which the high velocity stream of gas is established, the particles may be pushed into the high velocity gas stream by a pressure differential (e.g., Bernoulli's force). For example, based on Bernoulli's equation, if particles are contained in an open reservoir adjacent to a high velocity gas stream of 750 m/s, a pressure difference of about 2.2 atm is generated and pushes the particles into the gas stream.
The delivery device may include a standoff between the collimator and the skin interfacing surface such that a gap is provided between the outlets of the collimator and the skin when the skin interfacing surface is placed against the tissue. For example, the standoff may create a gap of about 0.5 to about 10 mm between the outlets of the collimator and the tissue surface. The standoff further allows the fluid stream to be diverted from the tissue and exhaust laterally from the stream. The entrained particles, having much higher momentum, continue their flight towards the tissue at substantially normal incidence.
In some embodiments, the collimator and particle source are provided in the form of a removable cartridge. The drug delivery device may include one or more cartridge receivers for receiving one or more removable cartridges. The cartridge may be inserted into the receiver for delivering particles, e.g., drug particles contained in the cartridge into a patient's skin. The cartridge, which may be depleted of drug, may thereafter be removed and replaced. In some embodiments, the drug delivery device includes a plurality of cartridge receivers for receiving multiple cartridges. In certain embodiments, each cartridge may contain an amount of a drug suitable for an individual dosage.
According to some aspects, the delivery device is configured to deliver first and second particles, wherein the first particles are heavier and/or have higher density than the second particles. The delivery device includes a collimator as discussed above and may include a focusing mechanism configured to focus the collimated particle stream to enhance the spatial correlation of the first and second particles in the particle stream. The heavier/denser first particles are used to precondition the tissue in a geometric pattern, such as a spot array, to enhance subsequent delivery via the lighter/lower density particle. For example, the heavy/denser first particles may be inert and/or decomposable by the tissue and the lighter/lower density particles may comprise a functional material such as a drug. The heavier/denser particles can be accelerated through an array of microjets to generate temporary holes in cell walls to increase permeability of cell walls to drug and/or the tissue. Lighter, lower density, solid particles can be subsequently delivered through the same array of microjets so that the lighter/lower density particles impinge the skin in the same regions which have enhanced permeability, enabling solid drugs and/or other functional agents to be delivered intracellularly and at a specified depth. The diameter of the particle beam is focused to be small enough so that there is an enhanced and high likelihood of overlap between the landing site of the preconditioning heavier/denser particle and the landing site of the lighter/lower density, functional particle.
In some embodiments, the particles delivered by the device may be elongated, high aspect ratio particles. The elongated particles may be lighter, solid particles of a functional agent, e.g., a drug, and/or may be heavier/denser inert particles, and/or may comprise a combination inert heavy/dense material and lighter functional material. The delivery device may include an alignment mechanism configured to align elongated particles in the particle stream such that their length axis is substantially parallel to the conduit axis and along the movement direction of the particle stream.
An exemplary embodiment of a particle delivery device 10 is illustrated in
As illustrated in
In the embodiment of
The ejector housing 14 in the illustrated example includes three ejector receivers for receiving the three ejectors 34. The ejectors 34 may be removable and replaceable, such that the new ejectors can be inserted into the ejector receivers once the original ejectors 34 are expended. To this end, the ejector housing 14 may comprise ejector removal devices, e.g., spring-loaded push rods, to facilitate the removal of expended ejectors from the cartridge housing 14. Although slots for three ejectors 34 are illustrated in the present embodiment, it should be noted that the device could be designed to accommodate one, two, four, or any number of ejectors 34. As shown in
The device may include a collimator for producing a plurality of discrete collimated gas streams. The term “collimated” as used herein refers to a stream of gas which may include solid particles, e.g., first and/or second particles as discussed above, or liquid entrained therein, that maintains a well-defined and substantially constant diameter over a desired, useful distance, including when unconstrained by a sidewall structure. For example, the collimator may provide a stream of gas and particles having a diameter of about 1 μm to about 1000 μm over an unconstrained distance (unconstrained by channel walls of the conduit) of about 0.5 mm to about mm. The particle delivery device may be configured and arranged to produce gas streams having a velocity of about 30 to about 1500 m/s.
The collimated and focused particle stream emerges from the outlet substantially perpendicular to the biological tissue surface and can maintain a beam diameter of less than 10 μm or equal to the presenting cross sectional diameter of the first particles over a length of about 1 cm or more between the outlet of the conduit and the tissue surface. In the unconstrained space between the conduit outlet and the tissue surface, the particle stream width may increase by less than about 10% of its width at the outlet.
The first particles and the second particles may be propelled to different velocities. For example, the first particles maybe have a higher velocity than the velocity of the second particles to retain functional material integrity of the second particles.
An exemplary ejector 34 comprising a collimator 40 is illustrated in
Particles, e.g., first or second particles as discussed above, may be provided on-board the particle delivery device from one or more particle sources. In some embodiments, the particle sources comprise one or more particle reservoirs. As previously described, a particle port may be provided between each particle source and the collimator for allowing release of the particles therethrough into the conduits of the collimator.
Release of the particles may be controlled by a rupturable membrane that seals the particle port. The rupturable membrane may be ruptured by the pressure change caused by the pressurized gas being fed through the collimator. Alternatively, the rupturable membrane may be ruptured by actuation of another element. For example, the rupturable membrane may be ruptured by electrothermal ablation, mechanical puncturing (e.g., with a scepter), heating (e.g., melting the membrane), chemical reaction, or volumetric expansion of the reservoir contents.
Other release devices may be provided to control the release of the particles from the particle reservoir. For example, an electric charge or movable cover may be used to prevent the release of the particle through the drug port until such later time that release is desired and the release device is actuated.
In some embodiments, the particles may be released from a release-activatable tape. For example, the release-activatable tape may have the particles disposed on the tape. The release-activatable tape may comprise a UV-sensitive, heat-sensitive, or electrical-sensitive material. The device may also include a controller that is adapted to actuate the release of the particles from the release-activatable tape. In some embodiments, the controller is adapted to actuate the release of the particles from the release-activatable tape after the pressurized gas has begun to pass through the collimator.
As illustrated in
As illustrated in
The delivery device may be configured to deliver various types of particles and may also deliver liquids, in the form of a stream or droplets. For example, the particles delivered may be or comprise heavier/denser particles that are configured to form micropores in the biological tissue; the particles delivered may be or comprise abrasive particles configured to abrade the biological tissue; the particles delivered may be or comprise lighter weight particles such as solid particles of functional material configured to interact with the biological tissue in some therapeutic or non-therapeutic way. The functional material may comprise drugs, cosmetics, nutritional or nourishing substances, tissue marking substances and/or any other types of particles. These categories of particles are not mutually exclusive and may overlap, for example, according to some implementations, the lighter weight particles may also be abrasive or the heavier/denser particles may include a coating of the functional material.
As used herein, the term “drug” refers to any chemical or biological material or compound suitable for administration by the methods previously known in the art and/or by the methods taught in the present disclosure, that induces a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism and preventing an undesired biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, and/or (3) either alleviating, reducing, or completely eliminating the disease from the organism. The effect may be local, such as providing for a local anesthetic effect, or it may be systemic. The drug may be a therapeutic, prophylactic, antiangiogenic agent. For example, the drug may be a vaccine. The drug may be formulated in a substantially pure form or with one or more excipients known in the art. The excipient material may be homogenously mixed with the drug or heterogenously combined with the drug. For example, the drug may be dispersed in an excipient (matrix) material known in the art, or may be included in a core or coating layer in a multi-layered structure with an excipient material. In some embodiments, the excipient material may function to control in vivo release of the drug, for example to provide timed release (e.g., controlled or sustained release) of the drug. In some embodiments, particles may include biodegradable material that is used as a sacrificial layer/coating on the functional material and potentially for protecting the active material during jetting and penetration. In some embodiments, the biodegradable material may be a constituent for controlling the release of drug content. The heavier/denser particles may comprise biodegradable and/or dissolvable particles that are absorbed by biological tissue. Where biodegradable materials are used for the heavier particles, these approaches can reduce foreign material residence in the tissue.
Some embodiments involve the use of tissue abrasive particles in addition to the heavier/denser particles and lighter/less dense particles previously discussed. The tissue abrasive particles are suitable for abrading the surface of a biological tissue after delivery from the device and impinging the biological tissue. According to some aspects the tissue abrasive particles may be made of aluminum oxide.
The heavier/denser particles may be made of a material having density greater than 10 g/cm3 and may comprise a metal such as gold, platinum or silver. The heavier/denser particles may have a shape, e.g., pointed tip, wedge shape, etc. that enhances penetrating the tissue to a predetermined depth. The heavier/denser particles are particularly effective at creating micropores in tissue.
The device may also contain and deliver nourishing or nutritional particles. The nourishing or nutritional particles may be any particles suitable for promoting or maintaining the viability of the cells of the biological tissue. Such particles may include vitamins, minerals, and other non-drug particles that contain nutrients.
The device may also contain and deliver cosmetic particles. The cosmetic particles may be any particles suitable for providing a cosmetic effect to the biological tissue when delivered to the tissue. For example, the particles may be particles that diminish the appearance of wrinkles, that provide color, such as for tattoos, or alter the coloration of the biological tissue, or that create or reduce localized swelling.
The device may also contain and deliver tissue marking particles. The tissue marking particles may be any particles suitable for marking a tissue for identification, whether such an identification may be made visually, with or without the assistance of technology (e.g., an imaging technology). For example, the particles may comprise an ink or dye or the particles may contain an agent that is visible or capable of imaging with an imaging technology, such as X-Ray, infrared (IR), magnetic resonance imaging (MRI), computed tomography (CT), or ultrasound.
In certain embodiments, the particles have a volume average diameter of about 0.1 to about 250 microns. In some embodiments, the particles have an average diameter equal to or less than ⅕ the width of the conduit or channel, and even more preferably equal to or less than 1/10 the of the width of the conduit or channel.
In some embodiments, the ejector may be configured to both collimate the particles entrained in the gas flow stream and to focus the particles. The ejector may include a focusing mechanism configured to focus the particles into a cross sectional area wherein the largest diameter of the cross sectional area is a fraction of the largest inner diameter of the conduit. In some implementations, the cross sectional area of the focused stream is less than 1/10, less than 1/100, or less than 1/1000 of the inner diameter of the conduit after focusing. In some cases, the focused, collimated stream of particles can more effectively deliver the functional material to the tissue due to spatial correlation between the first particles (heavier/denser particles) and the second particles (lighter particles of functional material). For example, the device can be configured to collimate and focus the stream of first and second particles to provide a specified spatial correlation of the particles at the impact site on the tissue. In some embodiments, the impact site of the particles has a diameter equal to or greater than the presenting cross sectional diameter of the first particles. In some embodiments, the impact site of the second particles has a diameter less than about 0.5 times the diameter of the impact site of the first particles.
When both first and second particles are ejected by the device, increased spatial correlation of these particles increases the probability that a lighter weight particle will follow a heavier weight particle into a micropore created by the heavier weight particle or that a lighter weight will be driven into the tissue by a heavier weight particle that impacts the tissue after the lighter weight particle, thereby propelling the lighter weight particle through a micropore to suitable depth in the tissue. Note that the terms “first” and “second” are used herein to identify different types of particles and are not meant to convey any particular order. The first particles may be delivered before, after, or during the time that the second particles are delivered.
The particles emerge from the outlets 86 of the conduits 82 in an aligned and focused beam substantially perpendicular to the tissue surface. The ejector includes a tissue interfacing surface 90 configured to be placed on skin or other tissue. When the tissue interfacing surface 90 is placed on the skin 92, the outlets 86 are at a distance x above the surface 92. When the particles impact the skin surface 92, they may form micropores 94 in the skin.
The inset
As illustrated in
The particles delivered by the delivery device may have a variety of two dimensional and three dimensional shapes comprising lighter, functional material, e.g., drug material, and heavier/denser material, e.g., mechanoporation material. In some implementations, portions of the particles may be the lighter material and other portions may be the heavier denser material. For example, the particles may be circular or spherical as previously shown and in general have any two dimensional or three dimensional shape. Illustrative particle shapes include a star shape with any number of points, as shown in
According to some implementations at least some of the particles delivered by the delivery device are elongated particles, e.g., having an aspect ratio greater than about 5, or in a range of about 5 to about 50, for example. The length of the elongated particles may be in the range of about 1 μm to about 1000 μm, or in a range of about 10 μm to about 100 μm. The width of the elongated particles may be in the range of about 0.25 μm to about 100 μm, or about 2 μm to about 50 μm. In some implementations, the length and/or width of the particles may be greater than 100 μm. As discussed above, a focused, collimated particle stream may be used to enable tight spatial correlation between high density mechanoporation particles and low density drug particles. The correlation should allow a drug or other functional material to diffuse into cells before the membrane has reclosed. The use of elongated particles may be employed to further facilitate correlated delivery of heavier mechanoporation particles and lighter particles of a functional material, e.g. drug particles. A high aspect ratio and alignment of particles normal to skin surface can allow sufficiently high momentum and sufficiently small cross section for adequate penetration of drug material. The high aspect ratio scales the ratio of mass to impact cross sectional area in a beneficial manner relative to spherical form factor and enhances penetration through reduced drag.
According to some implementations, the elongated particles comprise high aspect ratio solid rods of a lighter weight, functional material, e.g., drug material, as shown in
Elongated objects will align parallel to the stream lines in the conduit with maximum drag end downstream as they are accelerated by the faster moving fluid. However, because of the small drag forces in gas, the alignment time is fairly long (e.g., on the order of tens of seconds for particles in the 1 to 10 μm size range). In some configurations, even after the particles are aligned in the gas stream, small perturbations can misalign the objects again. One way to speed up the alignment and to stabilize the orientation of the particles is to add fins at one end of the elongated particles. These fins increase the drag at one end, which increases the rate of rotation into the aligned position, while stabilizing the dart against misalignments due to perturbations. As shown in
In some implementations, the elongated particles are combination particles that include a combination of materials, such as dual material, high aspect ratio structures that include a denser/heavier material in one or more regions and include a less dense, lighter weight, functional material in one or more relatively long regions of functional material.
The use of high aspect ratio particles increases the likelihood that particles are aligned such that they are substantially perpendicular to the tissue upon impact. One or both ends of the combination particle could be tapered to further enhance penetration, as illustrated by particle 1020 of
Shaping the particles can be beneficial for orientation control and stability. A few examples of shaped particles are illustrated in
For combination particles, the particle may be formed in shapes that increase the surface area of a heavier material that is available to carry the functional material. For example, an increase in surface area can be achieved by using a higher density material 1211 formed in a hollow shape, e.g., a hollow cylinder, as shown in the cross section (
As another example, the surface of the heavier/denser material can be structured to include fins (shown in
The elongated particles discussed above may be used with or without focusing, however, focusing as discussed herein is particularly useful to constrain the heavier mechanoporation particles and lighter functional particles, e.g., drug particles, more tightly to increase spatial correlation significantly. In implementations that use separate heavy and light particles, either the heavy particles, the light particles, or both may be elongated.
Some embodiments involve a particle delivery device comprising a broad area ejector, such as an ejector having a few larger conduits or a single larger conduit. In some examples, the few conduits or single conduit may have an inner diameter of about 1 cm. Such a broad area ejector may be configured to deliver aligned elongated particles, such as the particles illustrated in
As shown in inset
After the particles interact with the alignment mechanism 1395, the elongated particles 1395 are substantially aligned, e.g., the length axis of a substantial majority (greater than 75%) the particles makes an angle of less than about ±20 degrees or even ±5 degrees with respect to the flow direction 1399 as illustrated in the inset
The ejector 1380 includes a tissue interfacing surface 1390 configured to be placed on skin or other tissue 1392. When the tissue interfacing surface 1390 is placed on or near the skin 1392, the conduit outlets 1386 are at a distance x (see
As illustrated in
When charged particles 1580 are delivered, charged plates 1571, 1572, 1573 may be used as an electrostatic particle accelerator. The charged particles 1580 are first repelled by plate 1571 and are accelerated toward the oppositely charged plate 1572. After accelerating past the oppositely charged plate 1572, the positively charged particles 1580 are repelled by a plate 1573 which has the same charge as the particles, thus accelerating the particles 1580 toward the tissue surface. With charge at only one end of the high aspect ratio particles electric fields can be used to retard one end and effectively enhance the aerodynamic alignment effectiveness of the air which is moving at a higher speed than the particles.
Another configuration of an alignment mechanism 1598 is shown in
In some embodiments, a magnetic field gradient is used to focus the particles and to accelerate the magnetic particles toward the tissue The magnetic particle focusing and acceleration mechanism may be used, for example, in conjunction with the magnetic particle alignment mechanism of
In some configurations it can be helpful to remove and/or decelerate at least some of the propellant in the high speed stream of particles just before or just after the focused particle stream is unconstrained by the channel.
In some implementations, charged particles can be used to increase spatial correlation of heavier/denser particles and lighter functional particles as shown in
In some embodiments, the delivery device is capable of delivering a treatment to the tissue before and/or after delivery of the particles that enhances absorption of the functional material. For example, in some implementations, the pretreatment may involve bombarding the tissue with abrasive particles, delivering a liquid drug or other liquid to the tissue, forming micropores in and/or abrading the tissue surface using a laser, applying electromagnetic pulses to the tissue.
In some implementations, the pre/post treatment apparatus is an energy source that delivers energy to the tissue. In various implementations, the energy source may provide optical energy, high frequency electromagnetic energy, and/or ultrasonic energy, for example.
In one implementation, the pre/post treatment apparatus comprises an edge emitting semiconductor laser arranged such that the laser light generated by the laser (or array of lasers) travels through and is guided in each conduit to the tissue surface. The laser light may abrade the tissue surface before and/or after delivery of the first and/or second particles in some cases. In a higher power implementation, the laser light may have sufficient energy to produce micropores in the tissue to a depth suitable for delivering the functional substance, e.g., at a depth range of about 1 μm to about 1 mm. A lens or other focusing element may be located at the output end of the delivery device to provide for focusing the laser light into a high power spot on the skin to provide microporation.
In some implementations, the pre/post treatment apparatus may comprise a generator configured to produce magnetic pulses that enhance skin/mucosal surface permeation and provide for enhanced absorption of the functional material (dermaporation for skin delivery). For example, the generator can be configured to generate magnetic fields having a peak magnetic field of 5 mT, pulse duration of 400 μs, and duty cycle of 5% or an average magnetic field of 0.25 mT or more.
In some implementations, the pre/post treatment apparatus may comprise a generator configured to produce electrical pulses that provide electroporation for enhanced absorption of the functional material. For example, the generator can be configured to apply 50 V transdermally in 200 ms pulses or 100 V in 1 ms pulses. In some implementations, the pre/post treatment apparatus may comprise an ultrasonic generator configured to generate ultrasonic waves that increase the permeability of tissue.
Some embodiments discussed herein provide for physical tissue permeation enhancement to enable uptake of solid drug powder or other functional substances. These techniques increase cell wall permeation for subsequent payload penetration, through mechanoporation via particles. A delivery device discussed herein uses multiple conduits that can provide an array of precision spot target zones and enables multiparticle delivery schemes. In some implementations, all the conduits are used to eject particles and in other implementations fewer than all of the conduits are used to eject the particles. For example, the conduits of the delivery device may be sourced with particles or not in a gray scale manner to create patterned implantation of functional particles. Heavy/dense inert particles can be jetted into the tissue, forming transient diffusion pathways and enhancing cell wall permeability in a mechanoporation step that occurs before, simultaneous with or after delivery of the functional material to the tissue. The highly loaded, lighter mass drug particulates can be jetted to reach the target spot for internalization by cells. The approaches discussed herein may utilize micro electrical mechanical systems (MEMS) arrayed channels that provide confined jet streams and high probabilities for target overlap for the two types of particles. An in-line parallel device design confines particles to a few streamlines (to less than a few particle diameters in width) in the center of the conduit thus creating high probabilities for particles being well aligned, spatially correlated with one another. This width can be maintained when the particle stream is unconstrained by the conduit walls and reaches the tissue surface as previously discussed.
To realize drug internalization by cells, the drug should be interstitially transported to the mechanoporated regions. Since this architecture provides micro-scale spatial precision to accurately land the drug particles in <10-20 μm proximity to the mechanoporated cells, the diffusion time for interstitial transport of pDNA (<400 s; considering the interstitial diffusion coefficient, D, is ˜10−8 to 5×10−9 cm2/s) scales with the duration of the cell wall recovery times (˜9 min for pore resealing using other methods).
In some scenarios, cell wall recovery times can be very slow compared to the particle arrival frequency and therefore, the light solid particles arrival times to the target site and transport times into the cell can be faster than cell wall recovery times and thus pDNA will be able to internalize by cells. The approaches discussed herein can enable significantly higher doses and efficiencies than technologies that are restricted to low concentration coated payloads for intracellular delivery (low density solid drug particles delivered by these devices do not penetrate deep and do not enter cells). The individual delivery spots on the tissue can be smaller (e.g., less than 50 μm) and massively arrayed with low cost MEMS fabrication. In some cases plastic injection molding can be used for high volume manufacturing.
The foregoing description of various embodiments has been presented for the purposes of illustration and description and not limitation. The embodiments disclosed are not intended to be exhaustive or to limit the possible implementations to the embodiments disclosed. Many modifications and variations are possible in light of the above teaching.
