CA2464673C - Impedance sensor - Google Patents

Impedance sensor Download PDF

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Publication number
CA2464673C
CA2464673C CA2464673A CA2464673A CA2464673C CA 2464673 C CA2464673 C CA 2464673C CA 2464673 A CA2464673 A CA 2464673A CA 2464673 A CA2464673 A CA 2464673A CA 2464673 C CA2464673 C CA 2464673C
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CA
Canada
Prior art keywords
impedance
needles
skin
microneedles
target area
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CA2464673A
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French (fr)
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CA2464673A1 (en
Inventor
Aimee B. Angel
Ian W. Hunter
Laura L. Proctor
James Tangorra
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Massachusetts Institute of Technology
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Massachusetts Institute of Technology
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/145Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons
    • A61M5/155Pressure infusion, e.g. using pumps using pressurised reservoirs, e.g. pressurised by means of pistons pressurised by gas introduced into the reservoir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/168Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
    • A61M5/172Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic
    • A61M5/1723Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body electrical or electronic using feedback of body parameters, e.g. blood-sugar, pressure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/46Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for controlling depth of insertion
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M2005/1401Functional features
    • A61M2005/1405Patient controlled analgesia [PCA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M2005/14204Pressure infusion, e.g. using pumps with gas-producing electrochemical cell
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M5/14248Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type
    • A61M2005/14252Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body of the skin patch type with needle insertion means
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • A61M2005/14268Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body with a reusable and a disposable component
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/158Needles for infusions; Accessories therefor, e.g. for inserting infusion needles, or for holding them on the body
    • A61M2005/1581Right-angle needle-type devices
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M2037/0007Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023Drug applicators using microneedles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0038Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a channel at the side surface
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/02General characteristics of the apparatus characterised by a particular materials
    • A61M2205/0266Shape memory materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/50General characteristics of the apparatus with microprocessors or computers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/82Internal energy supply devices
    • A61M2205/8206Internal energy supply devices battery-operated
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2230/00Measuring parameters of the user
    • A61M2230/65Impedance, e.g. conductivity, capacity
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A61M5/142Pressure infusion, e.g. using pumps
    • A61M5/14244Pressure infusion, e.g. using pumps adapted to be carried by the patient, e.g. portable on the body
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/42Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests having means for desensitising skin, for protruding skin to facilitate piercing, or for locating point where body is to be pierced
    • A61M5/425Protruding skin to facilitate piercing, e.g. vacuum cylinders, vein immobilising means

Abstract

A transdermal transport device includes a reservoir for holding a formulation of an active principle, a needle (14) with a bore through which the formulation is transported between the reservoir and a target area of a biological body, and an impedance sensor(32). The impedance sensor has an electrode positioned to measure the impedance of a portion of the target area between the needle and the electrode to indicate the depth of penetration of the needle into the target area.

Description

IMPEDANCE SENSOR

BACKGROUND
Delivery of drugs to a patient is performed in a number of ways. For example, intravenous delivery is by injection directly into a blood vessel;

intraperitoneal delivery is by injection into the peritoneum; subcutaneous delivery is under the skin; intramuscular is into a muscle; and orally is through the mouth. One of the easiest methods for drug delivery, and for collection of body fluids, is through the skin.

Skin is the outermost protective layer of the body. It is composed of the epidermis, including the stratum cornetun, the stratum granulosum, the stratum spinosum, and the stratum basale, and the dermis, containing, among other things, the capillary layer. The stratum corneum is a tough, scaly layer made of dead cell tissue. It extends around 10-20 microns from the skin surface and has no blood supply. Because of the density of this layer of cells, moving compounds across the skin, either into or out of the body, can be very difficult.

The current technology for delivering local pharmaceuticals through the skin includes both methods that use needles or other skin piercing devices and methods that do not use such devices. Those methods that do not use needles typically involve: (a) topical applications, (b) iontophoresis, (c) electroporation, (d) laser perforation or alteration, (e) carriers or vehicles, which are compounds that modify the chemical properties of either the stratum corneum and/or the pharmaceutical, (f) physical pretreatment of the skin, such as abrasion of the stratum comeum (e.g.
repeatedly applying and removing adhesive tape), and (g) sonophoresis, which involves modifying the barrier function of stratum corneum by ultrasound.

Topical applications, such as a patch, or direct application of a pharmaceutical to the skin, depend on diffusion or absorption through the skin.
These methods of transdermal transport are not widely useful because of the limited permeability of the stratum corneum. Although techniques such as those listed above have been developed to enhance the effectiveness of topical applications, topical applications still cannot provide optimum transdermal transport.
On the other hand, invasive procedures, such as use of needles or lances, effectively overcome the barrier function of the stratum corneum. However, these methods suffer from several major disadvantages: pain, local skin damage, bleeding, and risk of infection at the injection site, and creation of contaminated needles or lances that must be disposed of. These methods also usually require a trained administrator and are not suitable for repeated, long-term, or controlled use.
Additionally, drug delivery through the skin has been relatively imprecise in both location and dosage of the pharmaceutical. Some of the problems include movement of the patient during administration, delivery of incomplete dosages, difficulties in administering more than one pharmaceutical at the same time, and difficulties in delivering a pharmaceutical to the appropriate part of the skin. Drugs have traditionally been diluted to enable handling of the proper dosages. This dilution step can cause storage as well as delivery problems. Thus, it would be advantageous to be able to use small, precise volumes of pharmaceuticals for quick, as well as long-term, delivery through the skin.
SUMMARY
The present invention implements an effective, multi-application impedance sensor to detect the penetration depth into a biological body. For instance, the sensor can be used in combination with a microneendle transport system, which provides painless, precision insertion and controlled, programmable transport of a formulation, such as a drug, at commercially viable costs.
In one embodiment, a transdermal transport device includes a reservoir for holding a formulation of an active principle, a needle with a bore through which the formulation is transported between the reservoir and a target area of a biological body, and an impedance sensor. The impedance sensor has an electrode positioned to measure the impedance of a portion of the target area between the needle and the electrode to indicate the depth of penetration of the needle into the target area.

In certain embodiments, the device includes one or more additional needles.
One of these additional needles can be the electrode. In some embodiments, the measured impedance after the needle penetrates the skin is an order of magnitude less than the measured impedance before the needle penetrates the skin. And in particular embodiments, the impedance drops by over three orders of magnitude when the needle has penetrated to the proper depth.

In another embodiment, a device to measure the penetration into a biological body includes an impedance sensor with an electrode positioned to measure the impedance of a portion of a target area of a biological body between the electrode, and a ground to indicate the depth of penetration of the electrode into the target area.
The electrode can be a medical instrument, such as, for example, a needle or a scalpel.

In yet another embodiment, a transdermal transport device includes a reservoir for holding a formulation of an active principle, at least two needles, with each needle having a'bore through which the formulation is transported between the reservoir and a target area of a biological body, and an impedance sensor. The impedance sensor measures the impedance of a portion of the target area between two of the at least two needles when the two needles have penetrated into the target area to indicate the depth of penetration of the needles into the target area.
Other embodiments are directed to methods of using the aforementioned impedance sensor with various types of devices.

Some embodiments of the invention may have one or more of the following advantages. Particularly in regards to ease of use, the automated/mechanical system of the microneedle device reduces the error and uncertainty usually introduced by manual application. Very little (if any) pain, local damage, bleeding, or risk of infection is caused by the microneedles. The device provides for controllable and precise drug delivery to a location below the outer surface of the skin of the patient.
That is, any desirable delivery profile can be set, for example, constant or intermittent, for delivery to a desired location. The device can provide on-demand delivery, for example, by pushing a button, when a patient desires some sort of pain control. Since a precise amount of volume of drug can be delivered, there is a low volume of wasted drug.

The device provides reduced pain as compared to traditional hypodermic injections, with minimal air injected under the skin. A user of the device is able to verify drug, dosing, expiration, etc. with, for example, a computer server via the internet. The impedance testing provides a convenient way of determining the depth of penetration of the needles. The device is inexpensive and easy to use, and, hence, increases patient compliance.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

FIG. 1 is a side schematic view of an applicator with a transdermal transport device in accordance with the invention.

FIG. 2A is a cross-sectional view of the transdermal transport device shown in FIG. 1.

FIG. 2B is a top view of the transdermal transport device shown in FIG. 1.
FIG. 2C is a bottom view of the transdermal transport device shown in FIG.
1.

FIG. 2D is a close-up view of a suction port shown in FIG. 2C illustrating a microneedle in retracted and protracted states.
FIG. 3 is a close-up view of a tip of a microneedle of the transdermal transport device shown in FIG. 1 shown penetrating the skin of a patient and dispensing a drug into the patient.

FIG. 4 is a close-up view of the tip of a microneedle of the transdermal transport device shown in FIG. 1.

FIG. 5 is a side view of an alternative embodiment of a microneedle in accordance with the invention.

FIG. 6A is a graph of the insertion force of a microneedle versus the penetration depth of the microneedle.

FIG. 6B-6I is a sequence of graphs of the insertion force of a microneedle versus the penetration depth of the microneedle for different diameter needles.

FIG. 7A is a view of an actuator of the transdermal transport device shown in FIG. 2A.

FIG. 7B is a graph of the voltage requirements of the actuator shown in FIG.
7A with stainless steel electrodes.

FIG. 7C is a graph of the voltage requirements of the actuator shown in FIG.
7A with Nichrome electrodes.

FIG. 8A is schematic of a circuit formed with electrodes of an impedance sensor of the transdermal transport device shown in FIG. 1 and the skin of a patient.
FIG. 8B is a schematic diagram of a circuit used for the impedance sensor in accordance with the invention.

FIG. 9A is a graph of the magnitude of the impedance measured by the impedance sensor of FIG. 8A versus frequency.

FIG. 9B is a graph of the impedance versus the penetration depth.
FIG. 10 is a cross-sectional view of an alternative embodiment of the transdermal transport device.

FIG. 11 is a cross-sectional view of yet another alternative embodiment of the transdermal transport device.

DETAILED DESCRIPTION OF THE INVENTION

A description of preferred embodiments of the invention follows.
Referring to FIG. 1, there is shown a transdermal transport device 10 mounted to a coupling 11 of an applicator 12 which is used to attach the transport device 10 to the skin of a biological body, such as a human patient.
Furthermore, the applicator 12 activates the device 10 to initiate the transport process before being disengaged from the device.

The device 10 includes an array of microneedles 14 for piercing the outer layers of skin of the patient and for delivering a formulation of an active principle such as pharmaceuticals through the skin to provide accurate delivery of the pharmaceuticals to the patient. Moreover, because of the shape and size of the needles and the minimal depth of penetration of the needles, contact between the needles and the nerve endings beneath the outer layer of the skin is minimized so that pain is reduced or absent in the patient. The pharmaceutical may be a liquid formulation, or it may be one or more non-liquid drugs that are reconstituted just before delivery.

The applicator 12 is powered by a set of batteries 16 and controlled by an embedded processor 18 positioned within a housing 20 which holds various other internal components of the applicator. A display 22, such as an LCD, mounted on top of the housing 20 communicates to a user the operating parameters of the transport device 10 and the applicator 12. The applicator 12 is able to communicate with a mother unit such as a PC and/or through the internet with a communication card 24. In some embodiments, the communication card is an ethernet card.
Additionally or alternatively, the communication card can be a Bluetooth card which provides wireless communication capabilities.

The transport device 10 is mounted to the applicator 12 with an electromagnet 26. To disengage the transport device 10 from the applicator, voltage to the electromagnet is simply turned off to break the magnetic coupling between the top of the transport device 10 and the electromagnet 26. The applicator 12 also includes a vacuum pump 28 which draws a vacuum through a suction port 41 (FIG.
2A) to create a suction between suction ports 60 (FIG. 2A) of the transport device 10 and the skin of the patient to attach the device 10 to the skin. The microneedles 14 are bent at about a 90 angle about 1/3 of the distance from the tip 62 to the other end 64 (FIG. 2A) of each microneedle. Accordingly, as a rotary actuator 30, such as a stepper motor, shape memory alloy, contractile polymer, rotary solenoid, or any other suitable rotary actuator, rotates the transport device 10 and thus moves the mirconeedles 14, they penetrate laterally into the skin since the suction produced by the vacuum pump 28 also draws the skin into the suction ports 60 above a plane defined by the tip portions 62 of the microneedles. An impedance sensor 32 is used to indicate when the microneedles have sufficiently penetrated into the skin.
A
piezoelectric or a speaker 34 is also used to provide audible, perhaps verbal, indications to the user. The operation of the transport device 10 and applicator 12 will be described below in greater detail.
Referring now to FIGs. 2A and 2B, in addition to a base portion 36 which holds the microneedles 14, the transport device 10 includes a control unit 38 and a drug vial 40. The control unit 38 is provided with electrical connections 42 which facilitate communication between the device 10 and the applicator 12, control electronics 43, and various sensors 44 that measure, for example, impedance, pressure, temperature, injection flow rate, as well as other sensors. Any of these sensors can also be located in the applicator 12, such as a pressure sensor 37. The control unit 38 also includes a power source 45 such as a supercapacitor and batteries which provide power to the device 10.
The drug vial 40 includes a drug chamber or reservoir 46 defined by a flexible membrane 48 and a rigid top section 50. Located above the drug vial 40 in the control unit 38 is an actuator 52. The actuator 52 is provided with a rigid base 54 that is joined to a cap 56 with a flexible bellow 58, or any other suitable expanding material, defining a chamber 59. As illustrated in FIGs. 2C and 2D, the suction ports 60 are located at the bottom of the base portion 36 to provide access for the tips 62 of the microneedles 14 to the skin.
In use, the applicator 12 is turned on by the user, such as a medical clinician, to activate the electromagnet 26 to attach the device 10 to the applicator 12.
The user then delivers the device 10 to the skin. Next, the vacuum pump 28 creates a vacuum seal through the vacuum ports 60 with the skin to hold the device 10 in place, and also to make the skin more accessible to the microneedles 14 as discussed above.
Referring to FIG. 3, the vacuum pump 28 draws a suction, indicated by the arrows A, in the ports 60 to bring the skin up to the necessary height in the ports.

The rotary actuator 30 then rotates and hence moves the microneedles 14 towards the skin in a direction at or about right angles to the direction of movement of the skin as it is sucked into the openings 60. Once the microneedles 14 contact the skin, they continue to move in the same direction approximately 50 m to several mm into the skin, thereby penetrating the sidewall of the raised skin as illustrated in FIG. 4.

In one embodiment, the penetration depth is approximately 200 m. The extent of movement in this direction is dictated by the depth of the stratum corneuin at the site where the microneedles 14 penetrate the skin. As stratum corneum depth varies, the applicator 12 uses the impedance sensor 32 to determine when the stratum corneum has been transversed. The impedance sensor 32 measures impedance of electric current flow between two of the microneedles 14. Impedance is high in the stratum corneum, and drops dramatically in the portion of the dermis just below the stratum corneum (see, e.g., FIG. 9B which shows a drop of approximately three orders of magnitude). The sensor 32 reads the change in impedance as the microneedles 14 penetrate into the skin, and movement is stopped when the impedance drops by an order of magnitude. Additionally or alternatively, there can be a hard mechanical stop, for example, the top of the ports 60, that prevents the microneedles from penetrating too deeply.
At this point, the vacuum pump 28 and the electromagnet 26 are de-activated to disengage the device 10 from the applicator 12. The vacuum seal between the device 10 and the skin is no longer needed to secure the device to the skin since the device 10 is now attached to the skin with the microneedles 14.

The control unit 38 of the device 10 then activates the actuator 52 which operates in the illustrated embodiment by an electrolytic process to cause the volume within the chamber 59 to increase and hence forcing the cap 56 against the rigid top section 50 of the drug vial 40, thereby pushing the drug vial 40 downwards.
Consequently, the flexible membrane 48 is pushed against a bowed section 68 of a base plate 39, while the ends 64 of the microneedles 14 pierce through the membrane 48 and into the reservoir 46. Compression of the membrane 48 into the reservoir 46 expels the pharmaceutical through hollow pathways or bores of the microneedles into the skin. Thus, the device is able to deliver a pharmaceutical to a precise location just below the stratum corneum of the skin, as indicated by the letter B in FIG. 3.
Once the correct dose of the phanmaceutical is delivered, the device 10 is re-attached to the applicator 12 and the rotary actuator 30 moves the microneedles out of the skin to disengage the device 10 from the patient. Typically, the base portion 36 and the drug vial 40 are discarded, while the control unit 38 is re-used.
The device 10 is used to deliver precise amounts of drugs as needed by a patient.
Information relating to the patient can be relayed through an associated computer to the device 10 and the applicator 12 via the communication card 24.
The same device 10 can be used for collecting fluid, such as interstitial fluid, from the dermis. For collection to occur, the reservoir 46 must first be compressed.
This is accomplished by moving the drug vial 40 downward with the actuator 50 such that the membrane 48 of the reservoir 46 is compressed to expel any air in the reservoir 46. Upon penetration of the microneedles into the skin, the expansion chamber 59 of the actuator 52 is contracted to allow the drug vial 40 to rise which creates a vacuum inside the reservoir 46 to draw fluid through the microneedles into the reservoir 46.

Thus, the actuator 52 acts as a pump which facilitates pumping a drug through the microneedles into the skin or collecting a sample from the patient. The actuator 52 can be used to create a vacuum within the reservoir 46 before the device 10 is placed against the skin. In sum, the actuator 52 provides controlled, programmable transport to and from the target site.

The various features of the transport device 10 and the applicator 12 will now be described in greater detail.

In the present application, the term "microneedle" is intended to be construed as singular or plural, unless specifically modified by a term indicating the number of microneedles. Microneedles disclosed herein may be porous or non-porous, uniform or of varying diameters or cross-sectional geometries, or some combination thereof.
Hollow microneedles with uniform diameter are sometimes referred to as microtubes. As used herein, the term "microneedle" refers to both microtubes and any other kind of microneedle as described previously. Additionally, microneedles may also have openings at either or both ends, as well as, on the side-walls at various and/or multiple positions along the length, or any combination thereof.
Further, either or both ends of the microneedle maybe flat, tapered to a point, rounded, or beveled from one or more sides, as described below.
As shown in FIG. 4, the tip 62 has an opening 71 and is cut at an angle, a, of approximately 10 to 60 , to provide a slanted surface 66a. This surface 66a and/or the outer surface 66b can be beveled. The illustrated embodiment has four microneedles 14, but there can be ten microneedles or more. The microneedles are metal welded or soldered to the base plate 39, made from, for example, stainless steel, of the base portion 36, and the bellows 58 is formed of a polymer and is ultrasonic welded to the base 54 and the cap 56 of the actuator 52, or the bellow can be permanently attached to either the control unit 38 or the drug vial 40.
Alternatively, these parts may be fitted together via a thermal seal or any other suitable technique for forming a fluid-tight seal. Note that the device 10 is in use or not, the microneedles 14 are always contained within the base portion 36 and never extend outside of the suction ports 60 beyond the bottom of the base portion 36.
This minimizes or eliminates contamination of the microneedles and accidental contact between the needles and a patient or medical clinician.
The beveled surfaces 66a and/or 66b of the tip 62 has many advantages. It reduces the trauma to the skin; it further reduces any pain felt by the subject; it prevents coring of the tissue into the microneedle; and it decreases the amount of force required for penetration into the skin. Particularly, in regards to coring, sharp tipped microneedles having a small inner diameter are less likely to accumulate tissue within the hollow opening, thereby avoiding transport blockage. In the above embodiment, both ends of each microneedle 14 are sharpened: one end for insertion into the skin, and the other end for insertion through membrane 48 into the reservoir 46.
In certain embodiments, as illustrated in FIG. 5, the microneedles 14 can have holes 73 on the side-walls at various and/or multiple positions along the length through which fluid can be transmitted, combined with the openings 71 (FIG. 4) or with solid tips 75. There can be from one to 20 or more holes 73. The spacing between the holes is approximately in the range of 100 pm to 2 mm.

The microneedles 14 may be manufactured from a variety of materials and by a variety of methods. Representative materials include metals, ceramics, semiconductors, organics, biodegradable and non-biodegradable polymers, glass, quartz, and various composites. Representative methods include micro-fabrication techniques. In the above illustrated embodiment, the microneedles 14 are made of medical grade stainless steel, such as 304 stainless steel. Stainless steel microneedles are advantageous because they are durable, semi-flexible, and have the mechanical strength to endure insertion into the stratum corneum. They can be cut from readily available, relatively inexpensive commercial stock via a chemical saw, or any suitable technique, to the desired dimensions, and ground to the desired tip geometry.

The microneedles 14 have an inner diameter of about 10 m to 100 m, an outer diameter of 30 m to 250 m, and a length of approximately 5 mm to 10 mm.
In the above illustrated embodiment, each of the microneedles has an inner diameter of 54 m, and an outer diameter of 108 [tin. Other embodiments use microneedles with an inner diameter of about 100 m and outer diameter of about 175 m.

The microneedles 14 can also be coated on the outside, the inside, or both.
Coatings can cover part or all of either or both surfaces. Coatings can be selected from, but are not limited to, the group consisting of lubricants, chemical or biological reaction elements, and preservatives.

The microneedles may be made of one or more rows of microneedles of uniform or varying dimensions and geometries, with uniform or varying spacing, at uniform or varying projection angles, and any combination thereof. In the embodiment above, the set of microneedles form a circular array of four microneedles. The array has a radius of approximately 5 mm to 20 mm. In the illustrated embodiment, the radius is about 12 mm. In another embodiment, the set may include more than one circular array of microneedles. In yet another embodiment, the microneedles are arranged in an X by Y array, where X may or may not equal Y.

Additionally, as described above, the microneedle is bent, at approximately a 90 angle. As shown in FIG. 3, the bend of around 90 is positioned such that the segment from the bend to the tip 62 of the microneedle is long enough to penetrate through the stratum corneum. However, the angle, curvature, and location of the bend in the microneedle; as well as the orientation of the microneedle with respect to the device 10, can vary. For example, the bend angle may be 90 or more or less, but typically less than 180 .

In the bent microneedle embodiment, the bevel side 66a faces away from the bend and towards the skin surface, prior to insertion of the microneedle into the skin, and continues to face away from the rest of the device once it is inserted.
Penetration occurs at "acute-angle insertion" of the microneedle. The angle of insertion, p, (FIG. 3) is the angle formed by the skin surface and the microneedle 14, with the vertex of the angle at the point of contact between the microneedle and the skin surface. Acute-angle insertion reduces the associated pain relative to 90 insertion. The microneedle, with varying bend angle, can be oriented for an insertion angle from 0 to 90 . Where the microneedle is close to or perpendicular to the skin at the entry site, a clear pathway for the substance to exit the skin is created upon withdrawal of the microneedle, resulting in leakage. Delivery of a complete dose of a substance under the stratum corneuin is improved by the low acute angle insertion, especially when coupled with the downward facing beveled tip. The substance will more readily move down through the dermis. Moreover, with a low acute angle insertion, one has better control of the needle insertion depth.
Referring to FIG. 6A, there is shown a plot of insertion force of a needle versus penetration depth, illustrating the skin and needle behavior as described by the various labels. After the needle touches the skin, the skin is deformed until a first point of puncture, after which the needle slips. Subsequently, the needle deforms the second layer of skin until a second point of puncture, after which the needle slips again. Then the skin slides up the shaft of the needle. As the needle is pulled out, the skin is also deformed, as shown in the bottom portion of the graph.

Turning now to FIG. 6B-6I, a sequence of graphs illustrate the insertion force [N] versus penetration depths [mm] profiles for 100 m (top graphs, FIGs. 6B-6E) and 570 m (bottom graphs, FIGs. 6F-6I) needles that are at an angle of 15 to with respect to the surface of the skin and for needle insertion velocities of 0.1 and 1.0 mm/s. As is evident from the figures, the smaller needles have significantly smaller penetration forces. The figures also show that the velocity of needle insertion does not significantly affect the penetration forces. Finally, the figures show that needles inserted at smaller angles (for example, 15 ) to the surface of the skin require smaller penetration forces. The peak insertion force for a 100 m needle into the skin at a 90 angle at a velocity of 1 mm/s is approximately 250 mN
(FIG. 6E), while the peak insertion force for a 100 m needle into the skin at a 15 angle at a velocity of 1 mm/s is approximately 175 mN (FIG. 6C).
Thus, the microneedles 14 need not be parallel to the skin. They can be angled downward, for example, to facilitate penetration into the skin. The base 36 can be pushed against the skin so that portions of the skin will rise within access ports similar to the suction ports 60.
The rigid top section 50 of the reservoir 46 is made from stainless steel, glass, such as Type I or Type II high purity glass, or polymer, and the flexible membrane 48 is approximately 20 m to 300 m, preferably 100 m, thick, and is made from a deformable elastopolymer such as silicone rubber or any other suitable flexible material. The reservoir 46 is typically filled with one or more pharmaceuticals for delivery to the patient, and then sealed.
In the embodiment shown in FIGs. 2A and 2B, the reservoir 46 is a single-chambered, hollow container with one rigid top section 50, and one deformable membrane 48. The reservoir 46 has a maximum fill thickness of approximately one to 5 mm, preferably about 2 mm, and a volume capacity approximately in the range of 100 l to 5 ml In the device 10, the microneedles 14 are in contact with the pharmaceutical in the reservoir 46 when the ends 64 of the microneedles are inserted into the reservoir. There can be a semi-permeable membrane, filter, or valve placed between the reservoir 46 and the openings at the ends 64 of the microneedles. The membrane or filter can serve to purify the substance, or remove a selected material from the substance entering or leaving the reservoir. A membrane or filter can also contain a binding partner to the selected material, thereby capturing or trapping that material during the transport. The binding partner can be specific or nonspecific. A
valve is useful in preventing leakage as well as in precisely releasing a set amount of substance. The valve is also useful to prevent backflow of a collected fluid through the iicroneedles. In some embodiments, a microvalve is opened in each microneedle 14 to allow movement of fluid for delivery or collection. For example, the microvalve could be embedded in the microneedles 14 or be part of the reservoir 46. Alternatively, a non-permeable membrane, covering for example the end of the microneedle opening into the reservoir, can be breached to allow the fluid movement.
Rather than being a hollow chamber, in some embodiments the reservoir 46 can be a porous matrix, single or multi-chambered, or any combination thereof.
The reservoir 46 can contain one or more chambers. Each chamber can be the same or may differ from any or all of the others. For example, a reservoir 46 can have one chamber that contains a reagent and into which fluid is drawn through the microneedles. A reaction might then occur in this first chamber, the results of which might trigger manual or automatic release of a substance from the second chamber through the microneedles into the skin.
The reservoir 46 is easily loaded with a substance to be delivered. Loading can occur before or after association of the reservoir 46 with the microneedles 14.
As mentioned earlier, the formulation can be one or more non-liquid drugs (for example, that have been dehydrated) that may be preloaded into the reservoir and then reconstituted before delivery. In some embodiments, the inside of the reservoir 46 is coated with a material prior to assembly of the reservoir. The coating can have one or more purposes, including, but not limited to, aiding flow so that the substance exiting or entering the reservoir moves smoothly and/or does not leave behind droplets, serving as a reactant used for detecting the presence or absence of a particular material in the fluid, and/or serving as a preservative.

When the transport device 10 is used to deliver drugs, the reservoir 46 stores one or more drugs in one or more chambers to be delivered to the target site.
The reservoir 46 can be filled with the desired drug through an opening situated opposite the placement of the microneedles 14. Alternatively, the desired drug can be drawn up into the reservoir 46 through the iicroneedles or the desired drug can be placed within the reservoir 46 when it is sealed.
When the transport device 10 is used to obtain samples from the patient, the reservoir 46 stores, in one or more chambers, one or more biological samples drawn from the patient. The device can include one or more elements directed at securing the sample within the reservoir during removal of the device from the skin.
These elements might include valves, flaps and the like.

Although in the embodiment illustrated in FIGs. 1 and 2 a vacuum seal is initially used to secure the device 10 to the skin, alternative mechanisms for securing the device 10 on the skin are available that include, but are not limited to, one or more straps, tape; glue, and/or bandages. The outer casings of the control unit 38, the drug vial 40, and the base portion 36 can be made of any stiff material, such as, but not limited to, stainless steel and other hard metals, plastics, woven or matted stiffened fibers, cardboard, and wood.
The actuator 52 disclosed herein facilitates pumping a drug through the microneedles into the skin or removing a sample from the patient. The actuator can be used to create a vacuum within the reservoir 46 before the device 10 it is placed against the skin. The actuator 52 provides controlled, programmable transport to and from the target site.
In the illustrated embodiment, the actuator 52 operates by an electrochemical reaction, in particular electrolysis of water (H20) that converts water into hydrogen (H2) and oxygen(02)gas. There are two electrochemical reactions taking place:
oxidation is occurring at the anode according to the reaction 2H20(1) -02(g)+ 4 H+ (aqj+ 4e and reduction is occurring at the cathode according to the reaction 21120(1) + 2e -H2(9)+ OH-To keep the numbers of electrons balance, the cathode reaction must take place twice as much as the anode reaction. Thus, if the cathode reaction is multiplied by two and the two reactions are added together, the total reaction becomes 61120(1) + 4e -2H2(9)+02(9)+ 4 H+ (aq) + 40H-(aq) + 4e The H+ and OH- form H2O and cancel species that appear on both side of the equation. The overall net reaction therefore becomes 6H20(1) -2H2(g)+ 02(g) Hence, three molecules (102,2 H2) are produced per 4 electrons. That is, the number of moles of gas created by electrochemical decomposition of water as described by the following equation is nge = nge/(e NA) = 7.784 x 10-6 mol/C

where nge is the number of molecules of gas produced per electron put into the system, 3/4, e is the charge of one electron, and NA is Avogadro's number.
This conversion results in a large volume change of over, for example, three orders of magnitude, which is harnessed to expel the drug from the reservoir 46. When the conversion of water to hydrogen and oxygen occurs, the expansion compresses the flexible membrane 48, expelling the drug and any carriers or other compounds or solvents out of the reservoir 46 through the microneedles 14.

Referring in particular to FIG. 7A, there is shown the actuator 52 by itself for illustrative purposes. The chamber 59 contains, for example, 1 l to 10 ml, preferably ,l l to 1 ml, of water with 1 M of Na2SO4 or NaOH. To initiate the electrolytic process, a current, I, is applied to two electrodes 72 positioned within the chamber 59 of the actuator 52. Each electrode 72 can be solid or a mesh. The mesh configuration provides a larger surface area to initiate the decomposition process.
The electrodes can be made of stainless steel, platinum, or platinum/iridium gauze, such as Alfa Aesar #40934, or any other suitable material.
Referring to the graph depicted in FIG. 7B, there is shown a representative voltage to current relationship for the actuator or pump 52 with two 3 mm x 12 mm x 50 m thick stainless steel electrodes. FIG. 7C shows the voltage to current relationship for the actuator 52 with two 40 min long Nichrome electrodes.
Both FIGs. 7B and 7C show that no current is drawn, and therefore no gas is created, until the voltage reaches approximately 1.7 V. At this point, the current drawn by the pump begins to increase almost linearly until the current reaches approximately 115 mA, where it reaches steady state. The current versus voltage slopes for the linear region are different based on the electrode materials and configuration. For the pump 52 with stainless steel electrodes (FIG. 7B), the pump reaches steady current consumption at approximately 3. 8 V, while the pump with Nichrome electrodes (FIG. 7C) reaches steady current consumption at approximately 2.5 V.
Furthermore, at an operating current of about 10 mA, the operating voltage is about 2.5 V
and 1.79V for the stainless steel electrodes, and the Nichrome electrodes, respectively.

The electrolytic process can be easily stopped and if desired initiated again, and this process can be repeated to precisely control the expansion rate of the chamber and hence the drug delivery rate of the device 10.
The actuator 52 can be a micro-electric motor, such as, for example, Lorentz force or electrostatic motors, or operate by chemical or electrochemical reactions, contractile polymers, shape memory alloys, or any other suitable mechanism to facilitate the transport of the pharmaceutical. Alternatively or additionally, the actuator can include mechanical or organic members, such as micro-valves or permeable membranes, respectively, to further control transport rates. The actuator 52 can also be any other suitable micro-mechanism, such as motors, levers, pistons, solenoids, magnetic actuators, and the like, for controlling the motion of the flexible membrane 48 of the drug vial 40 to provide precise and controlled delivery of compounds and/or collection of body fluids.
In certain embodiments, the actuator 52 operates as a vapor generator.
Liquid water, for example, contained in the chamber 59 of the actuator 52 is heated with an on-board heater which causes the liquid to change to steam resulting in a significant increase in volume. In such embodiments, the volume of the liquid water is about 500 nl to 5 l. The temperature of vaporization of water is 100 C, and at that temperature the latent heat of vaporization is 2.25 kJ/kg. Thus for 1 l of liquid water, the steam volume becomes approximately 1.706 ml.
Alternatively, the top section 50 of the reservoir 46 can be formed from a conducting polymer, such as polypyrrol, which contracts (usually in one direction) under the application of a low voltage current. The conducting polymers act like human muscle, that is, they contract lengthwise. The force produced per area of these polymers is about 1 to 10 Mpa, which is about a factor of 10 greater than that of human muscles. The change in length of these polymers is about 2%.
Contraction of the conducting polymer forces the drug and any carriers or other compounds or solvents out of the reservoir 46.
When the device is used to collect samples, the actuator 52 functions as a reversible actuator to facilitate transport from the target area to the reservoir 46. For example, in the conducting polymer pump system, initial application of a low voltage current compresses the top section 50, emptying the reservoir 46.
While the reservoir is in its contracted state, the device 10 is applied to the target site. The voltage is then disrupted to allow the polymer to expand to its natural state.
Expansion of the reservoir 46 creates a vacuum inside the reservoir, which causes fluid to be drawn into the reservoir.
Another embodiment of the actuator 52 is a shape memory alloy or contractile polymer wrapped around a circle. The actuator forms a twist that is guided along a thread so that there is a linear (vertical) motion which places a force on the drug vial 40, thereby expelling the drug from the reservoir 46. The actuator is returned to its initial retracted state by one of many available means that includes but is not limited to shape memory alloys, springs, and super-elastic metal.
Recall, the vacuum pump 28 of the applicator 12 creates a suction to draw the skin in one direction into the openings 60 of the transport device 10, and the rotary actuator 30 provides an orthogonal direction of motion of the microneedles 14 to facilitate acute-angle insertion into the skin with the bent microneedles 14.

In other embodiments, these orthogonal motions may be accomplished by use of one or more actuators. For example, an actuator can be used to move the microneedles in a direction perpendicular to the skin surface so that the bent portion of the microneedle are parallel to and come into contact with the skin, with the microneedle tip opening facing the skin. The actuator continues to move the microneedles in the perpendicular direction, causing them to depress the skin under the microneedle, and resulting in the neighboring skin being above the level of the microneedle tips. The rotary actuator 30 then moves the microneedles 14 forward in the direction of the microneedle tip 62, parallel to the skin surface. The microneedle tips 62 contact the surface of the skin at the side of the depression formed by the initial perpendicular motion of the microneedle. The rotary actuator 30 continues to move the microneedles in the parallel direction causing the microneedles to penetrate the stratum corneum. When the microneedle tip 62 has reached the target site, the rotary actuator stops the motion. One or more actuators can be involved in each motion. Again, a stop signal can be generated using the impedance sensor system 32, discussed in detail below. Alternatively, there can be a hard mechanical stop or the insertion motion can be stopped after a defined distance of penetration, or a defined period of time of insertion. Removal of the microneedles 14 is accomplished in basically the reverse order.
Any of the foregoing embodiments, as well as any other applicable to the situation, could be synchronized with the impedance sensor 32, discussed in detail below, so that the drop in impedance, upon penetration through the stratum corneum, triggers the pumping action of the actuator 52, such as the electrolytic, chemical reaction, polymer contraction actuators, or an electric motor or any other actuators used in the device 10.
In certain embodiments, the device 10 is provided with contoured, drilled tunnels or guide sleeves through which the microneedles 14 are guided into the skin.
For safety and other reasons, the microneedles 14 can have caps or holsters covering the tips 62, as discussed previously, requiring additional movement of the device 10 as a first step to uncap the microneedles 14. The caps can be fastened to a moveable part within the device 10, and this part is moved by an actuator away from the microneedle tips to uncap the stationary microneedles 14. In another embodiment, the caps may be a free-standing structure that is manually removable prior to application, or the microneedles may penetrate through the protective caps prior to application.
In some embodiments, the transport device 10 and/or the applicator 12 is combined with an oscillator system, made from, for example, a piezoelectric crystal, to assist the insertion of the microneedles 14. The oscillator system can be an independent system, integrated with the actuators, or some combination thereof.
Preferably, the microneedles are vibrated at 10 kHz in the direction of the penetration motion. A potential advantage of using such an oscillator system is that less force may be required to penetrate the skin.
As discussed above, the device 10 includes electrical sensors, such as the impedance sensor 32 which detects penetration of the stratum corneum. That is, the sensor 32 signals when the desired insertion of the microneedles 12 have been achieved. The determination of the location of the microneedle tip(s) within or through the stratum corneum allows for delivery of a complete, predetermined dose to the patient at a location amenable for absorption by the patient's body.
This is accomplished by measuring impedance of the tissue as the microneedles proceed through it. As the stratum corneuin creates a high level of impedance, and the tissue beyond the stratum corneum only provides a relatively low level of impedance, impedance is monitored to determine when the microneedles have passed through the stratum comeum. At that point insertion may be stopped so as to avoid penetrating the skin layer containing nerves and capillaries.
In particular, as illustrated in FIG. 8A, a low voltage circuit is formed with two of the microneedles 14 acting as electrodes. Because the dry stratum comeum of the epidermis 90 acts as a capacitive barrier while the sub-epidermal layers 92 are well conducting, the impedance of the circuit drops as the microneedles pierce through the stratum corneum 90. The change in impedance is by one or more orders of magnitude and reliably indicates when the microneedles have pierced through the stratum corneum 90. Furthermore, at less than 1 Volt, the voltage stimulus is not felt by the subject. Note that the microneedles 14 are electrically isolated from the base. An illustrative embodiment of a circuit diagram of the circuit used here is shown in FIG. 8B, where the Zload represents the unknown impedance.
As an example, impedance measurements of pig skin is illustrated in FIG.
9A. The top portion 94 of the graph illustrates the measured impedance of pig skin over a frequency range before a microneedle penetrates the stratum corneum and the bottom portion 96 represents the measured impedance after the microneedle has penetrated the stratum corneum. As can be seen, the difference between the two portions 94 and 96 of the graph can be over three orders of magnitude. Turning also to FIG. 9B, there is shown a plot of impedance versus the perpendicular depth into the skin, which clearly illustrate that the penetration into the skin produces smaller impedances.

Rather than sweeping over a frequency range, the input signal of the impedance sensor 32 can be set at one frequency. The input signal can be a square wave generated by an embedded processor such as a TI-MSP430F149IPM, produced by Texas Instruments of Dallas, Texas. Certain characteristics of this chip are that it draws 35 A when active, and less than 1 A in low power mode, and has a 64 pin PQFP package, a 1.8 to 3.6 V power supply, 8 analog to digital converters, 60 kbytes of flash memory, 2 kbytes of RAM, 2 16-bit timers, and an on-chip comparator.
Alternatively, a processor such as a TI-MSP43OF1 l OIPW can be used. This chip draws 35 A when active, and less than 1 A in low power mode, and includes a pin TSSOP, 1.8 to 3.6 V power supply, 1 kbyte of flash memory, 128 bytes of RAM, and a 16-bit timer. Regardless which processor is used, the output signal can be pulse width modulated, and the impedance sensor 32 can be provided with a log transformer to compress the output signal to within the range of the analog to digital converter of the processor.

As mentioned earlier, in certain embodiments, a glucose sensor is associated with the transport device 10. In these embodiments, fluid is withdrawn from the patient through the microneedles 14 into one of a multiplicity of reservoir chambers.
The glucose sensor is at least partially in one of the chambers, where it can detect the concentration of glucose in the fluid. Information from the glucose sensor is read and interpreted by the operator of the device 10, for example, with the use of the display 22 of the applicator 12, who can then activate another chamber of the reservoir to deliver the appropriate amount of insulin to bring the glucose concentration to an appropriate level. Alternatively, the procedure can be automated so that the glucose sensor reads the glucose concentration in the fluid, and, based on that concentration, sends a signal, such as an electronic signal, to the other chamber, "telling" that chamber whether or not to deliver insulin through a set of microneedles, and how much insulin to deliver.

In any of the above describe embodiments, one or more controllers such as a programmable microprocessor located in the transport device 10 and/or the applicator 12 can control and coordinate the actuators, pumps, sensors, and oscillators. For example, the controller can instruct the actuator 52 to pump a specified amount of drug into a patient at a specified time. The specified amount may be the full amount contained in the reservoir 46 or a partial amount.
Thus, the device is able to inject a partial or full amount of drug incrementally over a desired time period. One controller may control the operation of the applicator 12, while another controller controls the operation of the device 10. Alternatively, a single controller may control the operations of the applicator 12 and the device 10.
In any case, the applicator 12 and/or the device 10 can communicate with each other or with a central processor, for instance, using wireless communications capabilities provided with either or both the applicator 12 and the device 10.

The transdermal transport device 10 is not limited to the embodiments described above. For example, other embodiments of the transdermal transport device 10 are shown in FIGs. 10 and 11, where like reference numerals identify like features.

In the device 10 of FIG. 10, the microneedles 14 are again bent at about a 90 angle. They are oriented so that there is a section that is parallel to the surface of the skin S and a section that is perpendicular to the base 36 of the device 10.
The microneedles 14 are soldered or attached in any suitable manner to a needle plate 100 that is able to turn, but not able to translate. In this embodiment, the microneedles 41 are not inserted into the drug vial 40 until just before delivery. The pump assembly or actuator 52 is pinned in place by three pins that slide in angled slots 101 as the inner portion of the device 10 is turned. For extra guidance and stability, the actuator 52 also rides on pins 102 in slots that are cut into the actuator 52.

The device 10 is first brought to the skin S by the applicator 12 (FIG. 1).
The electromagnet 26 in the applicator 12 turns the inside portion of the device 10, which causes the actuator 52 to translate down onto the ends 64 of the microneedles 14 as the needles are turned into the skin S while suction is being applied through the ports 14 to draw the skin S into the suction ports 60. Thus, the back ends 64 of the microneedles penetrate the vial 40 as the front ends penetrate the skin.

Alternatively, the back ends 64 of the microneedles can already be in the vial 40, while the front ends are provided with caps through which the needles penetrate, or are removed before inserting the needles into the skin. The drug in the reservoir 46 is then pumped through the microneedles 14 as the actuator 52 is activated.
The depth of insertion is controlled by hard stops 104 on the base plate 36.
The skin S is sucked into the suction ports 60 by vacuum up to these hard stops 104.
Since the microneedles 14 soldered into place at a specific depth, and the hard stops can be set to a desired distance from the plane of the needles, the depth of insertion can therefore be controlled.
The actuator 52 is mounted on top of the vial 40, with the flexible membrane 48 positioned between the two. The electrodes 72 are mounted inside the actuator 52, and the leads come out directly into a circuit board 106, which is mounted just above the top of the actuator 52. On the underside of the circuit board 106 are mounted the electronic components 43, and on the top side is mounted the battery or power source 45. The applicator 12 magnetically attaches to the battery 45 to hold and rotate the device 10, while electrical connection is made between the applicator 12 and the device 10 through the copper ring 42.
The device 10 of FIG. 10 has a height of about 15 mm, while the device 10 of FIG. 11 has a lower profile with a height of about 7 mm. In FIG. 11, the rnicroneedles 14 are mounted such that they always remain in the same plane of rotation. This helps reduce the overall height of the device 10, since open space between the ends 64 of the microneedles 14 and the drug vial 40 is not necessary.
The microneedles 14 can either be permanently affixed as part of the drug vial 40, or as a separate ring. If the microneedles 14 are mounted on a separate ring, the actuator 52 is rotated onto the back end 64 of the microneedles 14 before delivery.
Then, the entire actuator/microneedle assembly is rotated into the skin S.
The depth of insertion is controlled by the space 200 between the base 36 and the component 202 that couples the microneedles 14 to the vial 40. This component 202 could either be some sort of fluidic circuit or simply a ring that holds the microneedles 14 in place for insertion into the vial 40, or the microneedles may be part of the vial 40. Vacuum suction would still be used to draw the skin into the ports 60 before insertion of the microneedles 14.
The actuator 52 is mounted as a ring around the vial 40. The top portion 204 of the actuator 52 is still above the vial 40, and the flexible membrane 48 is located between the top portion 204 and the vial 40. However, most of the actuator 52 is placed round the outside of the vial 40. This helps reduce the overall height of the device 10. The electrodes can be mounted as ring electrodes directly from the circuit board 106, which can also function as the top of the actuator 52. The battery 45 and the elcctronic components 43 are all mounted on the top of the circuit board 106.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.
For example, the actuator or pump arrangements, such as the electrolytic actuator, can be used in other types of transdermal transport devices, as well, such as the devices described in the U.S. Application No. 10/238,844, filed September 9, 2002, by Angel and Hunter, which issued as U.S. Patent No. 7,429,258.

Claims (13)

CLAIMS:
1. A transdermal transport device, comprising:
a reservoir for holding a formulation of an active principle;
at least two needles including a first needle and a second needle, each needle having a bore through which the formulation is transported between the reservoir and a target area of a biological body;
an impedance sensor which measures electrical impedance of a portion of the target area between the first and the second needles, the impedance changing as the needles penetrate through the target area and being indicative of the depth of penetration of the needles into the target area; and an automated control unit responding to the measured impedance that monitors the changing impedance through the target area and stops the penetration of the needles into the target area when a desired impedance change has been achieved.
2. The transdermal transport device of claim 1, wherein the measured impedance after the needles penetrate the skin is an order of magnitude less than the measured impedance before the needles penetrate the skin.
3. The transdermal transport device of claim 2, wherein the impedance drops by over three orders of magnitude when the needles have penetrated to the proper depth.
4. The transdermal transport device of claim 1, wherein the needles are microneedles.
5. Use of the device of any one of claims 1 to 4 to measure penetration into a biological body, wherein impedance of a portion of a target area of penetration of the body is measured between the at least two needles to determine when the needles have penetrated to a desired depth into the target area.
6. The use of claim 5, wherein a range of frequencies are swept over for measuring impedance.
7. The use of claim 5 or 6, wherein measuring impedance includes providing a single frequency as an input.
8. The use of any one of claims 5 to 7, wherein the desired depth is indicated by a measured impedance that is an order of magnitude less than the measured impedance before the needle penetrates to the desired depth.
9. The use of any one of claims 5 to 8, wherein measuring impedance includes using a square wave as an input signal.
10. The use of any one of claims 5 to 9, wherein measuring impedance includes pulse width modulating an output signal.
11. The use of any one of claims 5 to 10, wherein an output voltage is compressed with a log transformer.
12. Use of the device of any one of claims 1 to 4 for measuring penetration into a biological body, wherein a target area of the body is penetrated with said at least two needles, each needle having a bore; and the impedance of a portion of the target area between the two of the at least two needles is measured to determine when the needles have penetrated to a desired depth into the target area.
13. Use of the transdermal transport device of any one of claims 1 to 4 for measuring penetration into a biological body.
CA2464673A 2001-10-26 2002-10-22 Impedance sensor Expired - Fee Related CA2464673C (en)

Applications Claiming Priority (5)

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US33842501P 2001-10-26 2001-10-26
US60/338,425 2001-10-26
US39948902P 2002-07-29 2002-07-29
US60/399,489 2002-07-29
PCT/US2002/033823 WO2003037405A1 (en) 2001-10-26 2002-10-22 Impedance sensor

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CA2464673C true CA2464673C (en) 2011-04-26

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CA2464483A Expired - Fee Related CA2464483C (en) 2001-10-26 2002-10-18 Microneedle transport device
CA2464485A Expired - Fee Related CA2464485C (en) 2001-10-26 2002-10-21 Microneedle transdermal transport device
CA2464670A Expired - Fee Related CA2464670C (en) 2001-10-26 2002-10-22 Transdermal transport device with suction
CA002464487A Abandoned CA2464487A1 (en) 2001-10-26 2002-10-22 Transdermal transport device with an electrolytic actuator
CA2464673A Expired - Fee Related CA2464673C (en) 2001-10-26 2002-10-22 Impedance sensor

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CA2464483A Expired - Fee Related CA2464483C (en) 2001-10-26 2002-10-18 Microneedle transport device
CA2464485A Expired - Fee Related CA2464485C (en) 2001-10-26 2002-10-21 Microneedle transdermal transport device
CA2464670A Expired - Fee Related CA2464670C (en) 2001-10-26 2002-10-22 Transdermal transport device with suction
CA002464487A Abandoned CA2464487A1 (en) 2001-10-26 2002-10-22 Transdermal transport device with an electrolytic actuator

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Families Citing this family (389)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6471635B1 (en) 2000-02-10 2002-10-29 Obtech Medical Ag Anal incontinence disease treatment with controlled wireless energy supply
US6464628B1 (en) 1999-08-12 2002-10-15 Obtech Medical Ag Mechanical anal incontinence
US6461292B1 (en) 1999-08-12 2002-10-08 Obtech Medical Ag Anal incontinence treatment with wireless energy supply
US6482145B1 (en) 2000-02-14 2002-11-19 Obtech Medical Ag Hydraulic anal incontinence treatment
ATE304336T1 (en) 2000-02-10 2005-09-15 Potencia Medical Ag CONTROLLED URINARY INCONTINENCE TREATMENT
DE60113965T2 (en) 2000-02-10 2006-07-06 Potencia Medical Ag TREATMENT OF HARNINE CONTINENCE WITH WIRELESS ENERGY SUPPLY
ATE295136T1 (en) 2000-02-10 2005-05-15 Potencia Medical Ag MECHANICAL DEVICE FOR TREATING IMPOTENCY
ATE380006T1 (en) 2000-02-11 2007-12-15 Potencia Medical Ag CONTROLLED IMPOTENCY TREATMENT
EP1253886B1 (en) 2000-02-11 2008-12-10 Potentica AG Impotence treatment apparatus with energy transforming means
CN1196451C (en) 2000-02-14 2005-04-13 波滕西亚医疗公司 Male impotence prosthesis apparatus with wireless energy supply
US20030100929A1 (en) 2000-02-14 2003-05-29 Peter Forsell Controlled penile prosthesis
US7442165B2 (en) 2000-02-14 2008-10-28 Obtech Medical Ag Penile prosthesis
US7419481B2 (en) * 2000-10-13 2008-09-02 Alza Corporation Apparatus and method for piercing skin with microprotrusions
US8641644B2 (en) 2000-11-21 2014-02-04 Sanofi-Aventis Deutschland Gmbh Blood testing apparatus having a rotatable cartridge with multiple lancing elements and testing means
EP1227094B1 (en) * 2001-01-30 2005-12-14 Nissan Chemical Industries Ltd. Isocyanurate compound and method for producing the same
US9226699B2 (en) 2002-04-19 2016-01-05 Sanofi-Aventis Deutschland Gmbh Body fluid sampling module with a continuous compression tissue interface surface
US7041068B2 (en) * 2001-06-12 2006-05-09 Pelikan Technologies, Inc. Sampling module device and method
US9427532B2 (en) 2001-06-12 2016-08-30 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US9795747B2 (en) 2010-06-02 2017-10-24 Sanofi-Aventis Deutschland Gmbh Methods and apparatus for lancet actuation
US6966880B2 (en) * 2001-10-16 2005-11-22 Agilent Technologies, Inc. Universal diagnostic platform
US7429258B2 (en) * 2001-10-26 2008-09-30 Massachusetts Institute Of Technology Microneedle transport device
US6908453B2 (en) * 2002-01-15 2005-06-21 3M Innovative Properties Company Microneedle devices and methods of manufacture
US7858112B2 (en) * 2002-02-28 2010-12-28 Lintec Corporation Percutaneous absorption system and percutaneous absorption method
US7115108B2 (en) * 2002-04-02 2006-10-03 Becton, Dickinson And Company Method and device for intradermally delivering a substance
US6912417B1 (en) 2002-04-05 2005-06-28 Ichor Medical Systmes, Inc. Method and apparatus for delivery of therapeutic agents
US8784335B2 (en) * 2002-04-19 2014-07-22 Sanofi-Aventis Deutschland Gmbh Body fluid sampling device with a capacitive sensor
US8702624B2 (en) 2006-09-29 2014-04-22 Sanofi-Aventis Deutschland Gmbh Analyte measurement device with a single shot actuator
US9314194B2 (en) 2002-04-19 2016-04-19 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US9248267B2 (en) 2002-04-19 2016-02-02 Sanofi-Aventis Deustchland Gmbh Tissue penetration device
US9795334B2 (en) 2002-04-19 2017-10-24 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US8579831B2 (en) 2002-04-19 2013-11-12 Sanofi-Aventis Deutschland Gmbh Method and apparatus for penetrating tissue
US7198606B2 (en) 2002-04-19 2007-04-03 Pelikan Technologies, Inc. Method and apparatus for a multi-use body fluid sampling device with analyte sensing
US20040039289A1 (en) * 2002-04-30 2004-02-26 Christensen Lars Hofmann Needle insertion sensor
JP4764626B2 (en) * 2002-05-06 2011-09-07 ベクトン・ディキンソン・アンド・カンパニー Method and device for controlling the pharmacokinetics of a drug
EP1389476A1 (en) * 2002-08-14 2004-02-18 Precimedix S.A. Programming device for a pump for injecting medicaments
US20040082934A1 (en) * 2002-08-30 2004-04-29 Pettis Ronald J. Method of controlling pharmacokinetics of immunomodulatory compounds
US20120296233A9 (en) * 2002-09-05 2012-11-22 Freeman Dominique M Methods and apparatus for an analyte detecting device
EP1534365A2 (en) 2002-09-06 2005-06-01 Massachusetts Institute Of Technology Needless drug injection device
US8574895B2 (en) 2002-12-30 2013-11-05 Sanofi-Aventis Deutschland Gmbh Method and apparatus using optical techniques to measure analyte levels
JP2006520251A (en) * 2003-03-06 2006-09-07 ライフスキャン・インコーポレイテッド System and method for piercing skin tissue
WO2006001797A1 (en) 2004-06-14 2006-01-05 Pelikan Technologies, Inc. Low pain penetrating
EP1644004A4 (en) 2003-06-20 2010-10-06 Ronald Aung-Din Tropical therapy for the treatment of migraines, muscle sprains, muscle spasm, spasticity and related conditions
TW200514596A (en) * 2003-08-04 2005-05-01 Alza Corp Method and device for enhancing transdermal agent flux
EP1671096A4 (en) 2003-09-29 2009-09-16 Pelikan Technologies Inc Method and apparatus for an improved sample capture device
EP1680014A4 (en) 2003-10-14 2009-01-21 Pelikan Technologies Inc Method and apparatus for a variable user interface
EP1527792A1 (en) 2003-10-27 2005-05-04 Novo Nordisk A/S Medical injection device mountable to the skin
ES2377647T3 (en) * 2003-10-31 2012-03-29 Alza Corporation Self-acting applicator for microprojection ordering
US7361182B2 (en) 2003-12-19 2008-04-22 Lightnix, Inc. Medical lancet
CA2554232C (en) * 2003-12-22 2013-07-09 Paul Hadvary Dermallly affixed sensor device
EP1706171A1 (en) * 2003-12-29 2006-10-04 3M Innovative Properties Company Medical devices and kits including same
WO2005065414A2 (en) 2003-12-31 2005-07-21 Pelikan Technologies, Inc. Method and apparatus for improving fluidic flow and sample capture
SI1729848T1 (en) 2004-03-08 2015-08-31 Ichor Medical Systems Inc. Improved apparatus for electrically mediated delivery of therapeutic agents
EP3108925B1 (en) * 2004-04-12 2019-09-04 Allergan, Inc. Multi-site injection system
US20050288566A1 (en) * 2004-04-30 2005-12-29 Levendusky Joseph A Apparatus with partially insulated needle for measuring tissue impedance
US8828203B2 (en) 2004-05-20 2014-09-09 Sanofi-Aventis Deutschland Gmbh Printable hydrogels for biosensors
US9775553B2 (en) * 2004-06-03 2017-10-03 Sanofi-Aventis Deutschland Gmbh Method and apparatus for a fluid sampling device
WO2005120365A1 (en) * 2004-06-03 2005-12-22 Pelikan Technologies, Inc. Method and apparatus for a fluid sampling device
US7872396B2 (en) * 2004-06-14 2011-01-18 Massachusetts Institute Of Technology Electrochemical actuator
CA2570092A1 (en) 2004-06-14 2005-12-29 Massachusetts Institute Of Technology Electrochemical methods, devices, and structures
US8247946B2 (en) * 2004-06-14 2012-08-21 Massachusetts Institute Of Technology Electrochemical actuator
US7556650B2 (en) 2004-06-29 2009-07-07 Spine Wave, Inc. Methods for injecting a curable biomaterial into an intervertebral space
US20060030811A1 (en) * 2004-08-03 2006-02-09 Wong Patrick S Method and device for enhancing transdermal agent flux
WO2006016364A2 (en) * 2004-08-10 2006-02-16 Hellman De Picciotto, Tania Drug delivery devices
ES2463818T3 (en) 2004-08-16 2014-05-29 Functional Microstructures Limited Device to be applied to a biological barrier
WO2006031856A2 (en) 2004-09-13 2006-03-23 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery
US8252321B2 (en) 2004-09-13 2012-08-28 Chrono Therapeutics, Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US8057842B2 (en) 2004-11-18 2011-11-15 3M Innovative Properties Company Method of contact coating a microneedle array
WO2006055799A1 (en) * 2004-11-18 2006-05-26 3M Innovative Properties Company Masking method for coating a microneedle array
KR20130026511A (en) * 2004-11-18 2013-03-13 쓰리엠 이노베이티브 프로퍼티즈 컴파니 Low-profile microneedle array applicator
WO2006055802A1 (en) 2004-11-18 2006-05-26 3M Innovative Properties Company Microneedle array applicator and retainer
EP2388078B1 (en) 2004-11-18 2013-03-20 3M Innovative Properties Co. Method of contact coating a microneedle array
US20080009800A1 (en) * 2004-12-02 2008-01-10 Nickel Janice H Transdermal drug delivery device
CN100367906C (en) * 2004-12-08 2008-02-13 圣美迪诺医疗科技(湖州)有限公司 Endermic implantating biological sensors
US7850645B2 (en) 2005-02-11 2010-12-14 Boston Scientific Scimed, Inc. Internal medical devices for delivery of therapeutic agent in conjunction with a source of electrical power
US7833189B2 (en) * 2005-02-11 2010-11-16 Massachusetts Institute Of Technology Controlled needle-free transport
EP1709989A1 (en) * 2005-04-04 2006-10-11 Christoph Burckhardt AG Tattoo machine
JP5301985B2 (en) * 2005-04-07 2013-09-25 スリーエム イノベイティブ プロパティズ カンパニー System and method for tool feedback sensing
EP1709906A1 (en) * 2005-04-07 2006-10-11 F. Hoffmann-La Roche Ag Method and device for blood sampling
WO2006108809A1 (en) 2005-04-13 2006-10-19 Novo Nordisk A/S Medical skin mountable device and system
US8372040B2 (en) 2005-05-24 2013-02-12 Chrono Therapeutics, Inc. Portable drug delivery device including a detachable and replaceable administration or dosing element
EP2921169A1 (en) * 2005-05-24 2015-09-23 Chrono Therapeutics, Inc. Portable drug delivery device including a detachable and replaceable administration or dosing element
WO2006128034A1 (en) * 2005-05-25 2006-11-30 Georgia Tech Research Corporation Microneedles and methods for microinfusion
WO2006126653A1 (en) * 2005-05-27 2006-11-30 Olympus Corporation Device for introduction into subject
US8505544B2 (en) * 2005-05-31 2013-08-13 The Board Of Trustees Of The Leland Stanford Junior University Optically-implemented microsurgery system and approach
US9457147B2 (en) 2005-06-16 2016-10-04 Novo Nordisk A/S Method and apparatus for assisting patients in self-administration of medication
WO2007002523A2 (en) * 2005-06-24 2007-01-04 3M Innovative Properties Company Collapsible patch with microneedle array
CA2613111C (en) 2005-06-27 2015-05-26 3M Innovative Properties Company Microneedle array applicator device and method of array application
US9162037B2 (en) 2005-07-06 2015-10-20 Vascular Pathways, Inc. Intravenous catheter insertion device and method of use
IL175460A (en) 2006-05-07 2011-05-31 Doron Aurbach Drug delivery device
US9687186B2 (en) 2005-07-21 2017-06-27 Steadymed Ltd. Drug delivery device
US9011473B2 (en) 2005-09-07 2015-04-21 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US9358033B2 (en) 2005-09-07 2016-06-07 Ulthera, Inc. Fluid-jet dissection system and method for reducing the appearance of cellulite
US8518069B2 (en) 2005-09-07 2013-08-27 Cabochon Aesthetics, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US10548659B2 (en) 2006-01-17 2020-02-04 Ulthera, Inc. High pressure pre-burst for improved fluid delivery
US9486274B2 (en) 2005-09-07 2016-11-08 Ulthera, Inc. Dissection handpiece and method for reducing the appearance of cellulite
US20070066934A1 (en) * 2005-09-19 2007-03-22 Transport Pharmaceuticals, Inc. Electrokinetic delivery system and methods therefor
US20070185432A1 (en) * 2005-09-19 2007-08-09 Transport Pharmaceuticals, Inc. Electrokinetic system and method for delivering methotrexate
JP4935286B2 (en) * 2005-10-12 2012-05-23 パナソニック株式会社 Blood sensor
EP1940489A1 (en) 2005-10-17 2008-07-09 Novo Nordisk A/S Vented drug reservoir unit
CN101351240B (en) * 2005-11-02 2011-12-07 英杰克蒂卡股份公司 Implantable infusion device with advanceable and retractable needle
US7885793B2 (en) 2007-05-22 2011-02-08 International Business Machines Corporation Method and system for developing a conceptual model to facilitate generating a business-aligned information technology solution
US9248317B2 (en) 2005-12-02 2016-02-02 Ulthera, Inc. Devices and methods for selectively lysing cells
US9636035B2 (en) * 2005-12-14 2017-05-02 Scibase Ab Medical apparatus for determination of biological conditions using impedance measurements
JP4402648B2 (en) * 2005-12-16 2010-01-20 オリンパス株式会社 Intra-subject introduction device
US7736310B2 (en) 2006-01-30 2010-06-15 Abbott Diabetes Care Inc. On-body medical device securement
EP1815790A1 (en) * 2006-02-04 2007-08-08 Roche Diagnostics GmbH Lancet device with impedance measuring unit
EP3165247B1 (en) 2006-02-09 2020-10-28 DEKA Products Limited Partnership Pumping fluid delivery systems and methods using force application assembley
US11318249B2 (en) 2006-02-09 2022-05-03 Deka Products Limited Partnership Infusion pump assembly
US8419708B2 (en) 2006-02-10 2013-04-16 Hisamitsu Pharmaceuticals Co., Inc. Transdermal drug administration apparatus having microneedles
US20070202186A1 (en) 2006-02-22 2007-08-30 Iscience Interventional Corporation Apparatus and formulations for suprachoroidal drug delivery
US7981034B2 (en) 2006-02-28 2011-07-19 Abbott Diabetes Care Inc. Smart messages and alerts for an infusion delivery and management system
DE602007012417D1 (en) 2006-03-14 2011-03-24 Univ Southern California Mems device for drug release
WO2007124411A1 (en) * 2006-04-20 2007-11-01 3M Innovative Properties Company Device for applying a microneedle array
US7918814B2 (en) * 2006-05-02 2011-04-05 Georgia Tech Research Corporation Method for drug delivery to ocular tissue using microneedle
US8197435B2 (en) 2006-05-02 2012-06-12 Emory University Methods and devices for drug delivery to ocular tissue using microneedle
US7621895B2 (en) * 2006-05-17 2009-11-24 Abbott Cardiovascular Systems Inc. Needle array devices and methods
US20070276318A1 (en) * 2006-05-26 2007-11-29 Mit, Llp Iontosonic-microneedle applicator apparatus and methods
US20090171269A1 (en) * 2006-06-29 2009-07-02 Abbott Diabetes Care, Inc. Infusion Device and Methods Therefor
US9119582B2 (en) 2006-06-30 2015-09-01 Abbott Diabetes Care, Inc. Integrated analyte sensor and infusion device and methods therefor
US20090326441A1 (en) * 2006-08-01 2009-12-31 Agency For Science ,Technology And Research Ultrasonic Enhanced Microneedles
US8932216B2 (en) 2006-08-07 2015-01-13 Abbott Diabetes Care Inc. Method and system for providing data management in integrated analyte monitoring and infusion system
US8206296B2 (en) 2006-08-07 2012-06-26 Abbott Diabetes Care Inc. Method and system for providing integrated analyte monitoring and infusion system therapy management
WO2008027011A1 (en) * 2006-08-28 2008-03-06 Agency For Science, Technology And Research Microneedles and methods for fabricating microneedles
US20080058703A1 (en) * 2006-08-29 2008-03-06 Subramony Janardhanan A Drug electrotransport with hydration measurement of hydratable reservoir
WO2008036043A1 (en) * 2006-09-18 2008-03-27 Agency For Science, Technology And Research Needle structures and methods for fabricating needle structures
CN101595251B (en) 2006-10-05 2014-06-11 技术研究及发展基金有限公司 Microtubes and methods of producing same
DK2084802T3 (en) * 2006-10-25 2019-05-13 Hoffmann La Roche Uninterruptible power supply for medical device
US20080117416A1 (en) * 2006-10-27 2008-05-22 Hunter Ian W Use of coherent raman techniques for medical diagnostic and therapeutic purposes, and calibration techniques for same
US10525246B2 (en) * 2006-12-22 2020-01-07 Nanomed Skincare, Inc. Microdevice and method for transdermal delivery and sampling of active substances
US8845530B2 (en) * 2007-01-02 2014-09-30 Isense Corporation Resposable biosensor assembly and method of sensing
FR2912919B1 (en) * 2007-02-22 2009-05-01 Bernard Perriere MINIATURIZED INJECTION DEVICE FOR MEDICAL USE
US20080249469A1 (en) * 2007-03-22 2008-10-09 Ponnambalam Selvaganapathy Method and apparatus for active control of drug delivery using electro-osmotic flow control
AU2008241470B2 (en) 2007-04-16 2013-11-07 Corium Pharma Solutions, Inc. Solvent-cast microneedle arrays containing active
GB2448493B (en) * 2007-04-16 2009-10-14 Dewan Fazlul Hoque Chowdhury Microneedle transdermal delivery device
EP2272432B1 (en) 2007-05-07 2012-03-14 Vascular Pathways Inc. Intravenous catheter insertion and blood sample devices
US20090069830A1 (en) * 2007-06-07 2009-03-12 Piezo Resonance Innovations, Inc. Eye surgical tool
SI2158908T1 (en) * 2007-06-21 2013-07-31 Fujimoto Co., Ltd. Composition for transdermal administration
US8641618B2 (en) 2007-06-27 2014-02-04 Abbott Diabetes Care Inc. Method and structure for securing a monitoring device element
US8085151B2 (en) 2007-06-28 2011-12-27 Abbott Diabetes Care Inc. Signal converting cradle for medical condition monitoring and management system
US8160900B2 (en) 2007-06-29 2012-04-17 Abbott Diabetes Care Inc. Analyte monitoring and management device and method to analyze the frequency of user interaction with the device
US9987468B2 (en) 2007-06-29 2018-06-05 Actuated Medical, Inc. Reduced force device for intravascular access and guidewire placement
WO2009006291A1 (en) * 2007-06-29 2009-01-08 Piezo Resonance Innovations, Inc. Medical tool for reduced penetration force
US8328738B2 (en) 2007-06-29 2012-12-11 Actuated Medical, Inc. Medical tool for reduced penetration force with feedback means
US10219832B2 (en) 2007-06-29 2019-03-05 Actuated Medical, Inc. Device and method for less forceful tissue puncture
JP2010534530A (en) * 2007-07-26 2010-11-11 エントラ ファーマシューティカルズ,インコーポレイテッド System and method for delivering drugs
WO2009023798A2 (en) * 2007-08-14 2009-02-19 Fred Hutchinson Cancer Research Center Needle array assembly and method for delivering therapeutic agents
WO2009029044A1 (en) * 2007-08-24 2009-03-05 Agency For Science, Technology And Research A system and method for detecting skin penetration
WO2009029572A1 (en) * 2007-08-24 2009-03-05 Deka Products Limited Partnership Microneedle systems and apparatus
US9096845B2 (en) * 2007-08-29 2015-08-04 Technion Research & Development Foundation Limited Encapsulation of bacteria and viruses in electrospun fibers
US20090088682A1 (en) * 2007-09-28 2009-04-02 Seattle Medical Technologies Wearable infusion device
US8439940B2 (en) 2010-12-22 2013-05-14 Cabochon Aesthetics, Inc. Dissection handpiece with aspiration means for reducing the appearance of cellulite
WO2010042045A1 (en) 2008-10-10 2010-04-15 Milux Holding S.A. A system, an apparatus, and a method for treating a sexual dysfunctional female patient
CN103961792B (en) * 2007-12-17 2016-09-21 新世界药品有限公司 Intra-dermal delivery, diagnosis and the communication system integrated
ES2425769T5 (en) 2007-12-20 2017-07-28 University Of Southern California Apparatus for the administration of therapeutic agents
US11357910B2 (en) 2007-12-31 2022-06-14 Deka Products Limited Partnership Pump assembly with switch
CN104874047B (en) 2007-12-31 2019-05-28 德卡产品有限公司 It is transfused pump assembly
FI20075978A0 (en) * 2007-12-31 2007-12-31 Katja Paassilta Arrangement and method
US8414563B2 (en) 2007-12-31 2013-04-09 Deka Products Limited Partnership Pump assembly with switch
US8986253B2 (en) 2008-01-25 2015-03-24 Tandem Diabetes Care, Inc. Two chamber pumps and related methods
EP3964243A1 (en) * 2008-01-28 2022-03-09 Implantica Patent Ltd Blood clot removal device, system, and method
HUE054386T2 (en) 2008-01-29 2021-09-28 Implantica Patent Ltd Apparatus for treating obesity
ES2483465T3 (en) * 2008-02-21 2014-08-06 Technion Research And Development Foundation, Ltd. Use of electro-spinning microtubes to deliver a drug
WO2009108836A1 (en) * 2008-02-29 2009-09-03 Path Scientific, Llc Unitized painfree blood glucose measuring device
JP2009222474A (en) * 2008-03-14 2009-10-01 Panasonic Corp Micro-liquid transfer apparatus and micro-mliquid transfer method
US9849238B2 (en) 2008-05-08 2017-12-26 Minipumps, Llc Drug-delivery pump with intelligent control
ES2534865T3 (en) 2008-05-08 2015-04-29 Minipumps, Llc Drug delivery pumps
CN102202719B (en) 2008-05-08 2014-11-26 迷你泵有限责任公司 Implantable pums and cannulas therefor
JP5584202B2 (en) 2008-05-21 2014-09-03 セラジェクト, インコーポレイテッド Method for manufacturing solid solution punch patch and use thereof
US8924159B2 (en) 2008-05-30 2014-12-30 Abbott Diabetes Care Inc. Method and apparatus for providing glycemic control
US8591410B2 (en) 2008-05-30 2013-11-26 Abbott Diabetes Care Inc. Method and apparatus for providing glycemic control
CA2729346A1 (en) 2008-06-30 2010-01-14 Afgin Pharma, Llc Topical regional neuro-affective therapy
JP4482617B2 (en) * 2008-07-08 2010-06-16 パナソニック株式会社 Fluid transfer device using conductive polymer
US8868176B2 (en) * 2008-07-22 2014-10-21 New York University Microelectrode-equipped subdural therapeutic agent delivery strip
EP2328636B1 (en) * 2008-08-28 2013-06-12 Medingo Ltd. Device for enhanced subcutaneous insulin absorption
US8408421B2 (en) 2008-09-16 2013-04-02 Tandem Diabetes Care, Inc. Flow regulating stopcocks and related methods
WO2010033878A2 (en) 2008-09-19 2010-03-25 David Brown Solute concentration measurement device and related methods
WO2010042058A1 (en) 2008-10-10 2010-04-15 Milux Holding S.A. An improved artificial valve
EP2349170B1 (en) 2008-10-10 2023-09-27 Implantica Patent Ltd. Apparatus for the treatment of female sexual dysfunction
CA3004075C (en) 2008-10-10 2020-06-02 Medicaltree Patent Ltd. Heart help device, system, and method
EP2349078A4 (en) 2008-10-10 2018-02-07 Kirk Promotion LTD. Fastening means for implantable medcial control assembly
EP3708136A1 (en) 2008-10-10 2020-09-16 MedicalTree Patent Ltd. Heart help device, system, and method
EP2349448A1 (en) * 2008-11-04 2011-08-03 Janisys Limited A transfer device for transferring a substance between the device and a subject
US20110301628A1 (en) * 2008-12-05 2011-12-08 Yossi Gross Techniques for use with a nail penetration device
WO2010070628A1 (en) * 2008-12-19 2010-06-24 Janisys Limited A fluid transfer device and an active substance cartridge for the fluid transfer device, and a method for controlling the pressure at which an active substance is delivered to a subject from a fluid transfer device
US20100187132A1 (en) * 2008-12-29 2010-07-29 Don Alden Determination of the real electrochemical surface areas of screen printed electrodes
US9375169B2 (en) 2009-01-30 2016-06-28 Sanofi-Aventis Deutschland Gmbh Cam drive for managing disposable penetrating member actions with a single motor and motor and control system
JP6126783B2 (en) * 2009-03-02 2017-05-10 セブンス センス バイオシステムズ,インコーポレーテッド Device for analysis of a medium drawn from and / or under the skin of a subject
WO2012018486A2 (en) 2010-07-26 2012-02-09 Seventh Sense Biosystems, Inc. Rapid delivery and/or receiving of fluids
US9041541B2 (en) 2010-01-28 2015-05-26 Seventh Sense Biosystems, Inc. Monitoring or feedback systems and methods
US9033898B2 (en) 2010-06-23 2015-05-19 Seventh Sense Biosystems, Inc. Sampling devices and methods involving relatively little pain
US8781576B2 (en) * 2009-03-17 2014-07-15 Cardiothrive, Inc. Device and method for reducing patient transthoracic impedance for the purpose of delivering a therapeutic current
WO2010107707A2 (en) 2009-03-17 2010-09-23 Savage Walter T External defibrillator
DE102009002019A1 (en) 2009-03-31 2010-10-07 Robert Bosch Gmbh Applicator for the treatment of skin
US20120130207A1 (en) * 2009-04-29 2012-05-24 Janisys Limited micro-needle device and apparatus and a method for applying a micro-needle element to a site on the skin of a subject
EP2425209A4 (en) 2009-04-29 2013-01-09 Abbott Diabetes Care Inc Method and system for providing real time analyte sensor calibration with retrospective backfill
WO2010145908A1 (en) * 2009-05-20 2010-12-23 Sanofi-Aventis Deutschland Gmbh Drug delivery device
US10952836B2 (en) 2009-07-17 2021-03-23 Peter Forsell Vaginal operation method for the treatment of urinary incontinence in women
US9949812B2 (en) 2009-07-17 2018-04-24 Peter Forsell Vaginal operation method for the treatment of anal incontinence in women
US8641671B2 (en) 2009-07-30 2014-02-04 Tandem Diabetes Care, Inc. Infusion pump system with disposable cartridge having pressure venting and pressure feedback
WO2011014514A1 (en) 2009-07-31 2011-02-03 3M Innovative Properties Company Hollow microneedle arrays
US9358064B2 (en) 2009-08-07 2016-06-07 Ulthera, Inc. Handpiece and methods for performing subcutaneous surgery
US11096708B2 (en) 2009-08-07 2021-08-24 Ulthera, Inc. Devices and methods for performing subcutaneous surgery
CN102576385B (en) 2009-08-18 2016-02-24 迷你泵有限责任公司 There is the electrolytic drug discharge pump of adaptive control
US8758271B2 (en) 2009-09-01 2014-06-24 Massachusetts Institute Of Technology Nonlinear system identification techniques and devices for discovering dynamic and static tissue properties
US20110060202A1 (en) * 2009-09-08 2011-03-10 Seth Adrian Miller Dehydration detector using micro-needles
CA2772271A1 (en) * 2009-09-10 2011-03-17 Sanofi-Aventis Deutschland Gmbh Medicament container
US8834423B2 (en) 2009-10-23 2014-09-16 University of Pittsburgh—of the Commonwealth System of Higher Education Dissolvable microneedle arrays for transdermal delivery to human skin
WO2011053796A2 (en) * 2009-10-30 2011-05-05 Seventh Sense Biosystems, Inc. Systems and methods for treating, sanitizing, and/or shielding the skin or devices applied to the skin
US8685038B2 (en) 2009-12-07 2014-04-01 Incube Labs, Llc Iontophoretic apparatus and method for marking of the skin
US9333060B2 (en) 2009-12-15 2016-05-10 Massachusetts Institute Of Technology Plaque removal and differentiation of tooth and gum
US20110172637A1 (en) * 2010-01-08 2011-07-14 Ratio, Inc. Drug delivery device including tissue support structure
EP3243435A1 (en) * 2010-01-13 2017-11-15 Seventh Sense Biosystems, Inc. Sampling device interfaces
EP2523603A2 (en) * 2010-01-13 2012-11-21 Seventh Sense Biosystems, Inc. Sampling device interfaces
JP5806236B2 (en) * 2010-01-13 2015-11-10 セブンス センス バイオシステムズ,インコーポレーテッド Rapid delivery and / or collection of fluids
US8366667B2 (en) * 2010-02-11 2013-02-05 Baxter International Inc. Flow pulsatility dampening devices
US8965476B2 (en) 2010-04-16 2015-02-24 Sanofi-Aventis Deutschland Gmbh Tissue penetration device
US8285328B2 (en) 2010-04-20 2012-10-09 Minipumps, Llc Remote-controlled drug pump devices
AU2011246882B2 (en) 2010-04-28 2016-02-25 Sorrento Therapeutics, Inc. Nanopatterned medical device with enhanced cellular interaction
MX2012012567A (en) 2010-04-28 2012-11-21 Kimberly Clark Co Method for increasing permeability of an epithelial barrier.
KR101799612B1 (en) 2010-04-28 2017-11-20 킴벌리-클라크 월드와이드, 인크. Device for delivery of rheumatoid arthritis medication
US9522262B2 (en) 2010-04-28 2016-12-20 Kimberly-Clark Worldwide, Inc. Medical devices for delivery of siRNA
US9629979B2 (en) * 2010-04-28 2017-04-25 Sanovas, Inc. Pressure/Vacuum actuated catheter drug delivery probe
US9687641B2 (en) 2010-05-04 2017-06-27 Corium International, Inc. Method and device for transdermal delivery of parathyroid hormone using a microprojection array
WO2011140359A2 (en) * 2010-05-05 2011-11-10 Springleaf Therapeutics, Inc. Systems and methods for delivering a therapeutic agent
US10384039B2 (en) 2010-05-14 2019-08-20 C. R. Bard, Inc. Catheter insertion device including top-mounted advancement components
US8932258B2 (en) 2010-05-14 2015-01-13 C. R. Bard, Inc. Catheter placement device and method
US9950139B2 (en) 2010-05-14 2018-04-24 C. R. Bard, Inc. Catheter placement device including guidewire and catheter control elements
US9872971B2 (en) 2010-05-14 2018-01-23 C. R. Bard, Inc. Guidewire extension system for a catheter placement device
WO2011156095A2 (en) 2010-06-10 2011-12-15 The Regents Of The University Of California Textile-based printable electrodes for electrochemical sensing
US9227021B2 (en) 2010-06-29 2016-01-05 Genesis Biosystems, Inc. Microneedle roller (MNR) infusion system
WO2012009613A1 (en) 2010-07-16 2012-01-19 Seventh Sense Biosystems, Inc. Low-pressure environment for fluid transfer devices
US9055925B2 (en) 2010-07-27 2015-06-16 Carefusion 303, Inc. System and method for reducing false alarms associated with vital-signs monitoring
US9357929B2 (en) 2010-07-27 2016-06-07 Carefusion 303, Inc. System and method for monitoring body temperature of a person
US9615792B2 (en) 2010-07-27 2017-04-11 Carefusion 303, Inc. System and method for conserving battery power in a patient monitoring system
US9017255B2 (en) 2010-07-27 2015-04-28 Carefusion 303, Inc. System and method for saving battery power in a patient monitoring system
US8814792B2 (en) 2010-07-27 2014-08-26 Carefusion 303, Inc. System and method for storing and forwarding data from a vital-signs monitor
US9585620B2 (en) 2010-07-27 2017-03-07 Carefusion 303, Inc. Vital-signs patch having a flexible attachment to electrodes
US9420952B2 (en) 2010-07-27 2016-08-23 Carefusion 303, Inc. Temperature probe suitable for axillary reading
DE102010038733A1 (en) 2010-07-30 2012-02-02 Robert Bosch Gmbh Modular microneedle transport device
US20120039809A1 (en) 2010-08-13 2012-02-16 Seventh Sense Biosystems, Inc. Systems and techniques for monitoring subjects
US9173994B2 (en) * 2010-08-20 2015-11-03 Purdue Research Foundation Touch-actuated micropump for transdermal drug delivery and method of use
KR20140039132A (en) 2010-09-27 2014-04-01 스테디메드 리미티드 Size-efficient drug-delivery device
CN107096101A (en) 2010-10-07 2017-08-29 麻省理工学院 Use the injecting method of servo-controlled needleless injector
WO2012048268A2 (en) 2010-10-07 2012-04-12 Massachusetts Instiute Of Technology Delivery of a solid body and/or a fluid using a linear lorentz-force actuated needle-free jet injection system
EP3520749A1 (en) 2010-10-15 2019-08-07 Clearside Biomedical, Inc. Device for ocular access
WO2012058192A1 (en) * 2010-10-26 2012-05-03 7944942 Canada Inc. Automatic medication injection device
US9017289B2 (en) 2010-11-03 2015-04-28 Covidien Lp Transdermal fluid delivery device
EP2637562B1 (en) 2010-11-09 2016-01-27 Seventh Sense Biosystems, Inc. Systems and interfaces for blood sampling
WO2012083174A2 (en) 2010-12-17 2012-06-21 Massachusetts Institute Of Technology Electrochemical actuators
US8690833B2 (en) 2011-01-31 2014-04-08 Vascular Pathways, Inc. Intravenous catheter and insertion device with reduced blood spatter
EP2673025A4 (en) * 2011-02-09 2018-02-28 Becton, Dickinson and Company Improvements in infusion systems
ES2750035T3 (en) 2011-02-25 2020-03-24 Bard Inc C R Medical component insertion device including a retractable needle
US8696637B2 (en) 2011-02-28 2014-04-15 Kimberly-Clark Worldwide Transdermal patch containing microneedles
US10136845B2 (en) 2011-02-28 2018-11-27 Abbott Diabetes Care Inc. Devices, systems, and methods associated with analyte monitoring devices and devices incorporating the same
EP2691101A2 (en) 2011-03-31 2014-02-05 Moderna Therapeutics, Inc. Delivery and formulation of engineered nucleic acids
WO2012139593A2 (en) * 2011-04-15 2012-10-18 Rigshospitalet Copenhagen University Hospital System and method for injecting a substance into a human body
JP2014515665A (en) * 2011-04-19 2014-07-03 インビジダーム, エルエルシー Method for producing a substance with a supersaturated gas, transdermal delivery device and use thereof
BR112013027010A2 (en) * 2011-04-19 2016-12-27 Invisiderm Llc method of producing substances with supersaturated gas, device for their transdermal delivery, and their uses
CN103874461B (en) 2011-04-29 2017-05-10 第七感生物系统有限公司 Devices for collection and/or manipulation of blood spots or other bodily fluids
BR112013027351B1 (en) * 2011-04-29 2022-03-03 Seventh Sense Biosystems, Inc Device for receiving fluid from an individual
EP3106092A3 (en) 2011-04-29 2017-03-08 Seventh Sense Biosystems, Inc. Systems and methods for collecting fluid from a subject
US20130158468A1 (en) 2011-12-19 2013-06-20 Seventh Sense Biosystems, Inc. Delivering and/or receiving material with respect to a subject surface
USD903101S1 (en) 2011-05-13 2020-11-24 C. R. Bard, Inc. Catheter
US8636696B2 (en) * 2011-06-10 2014-01-28 Kimberly-Clark Worldwide, Inc. Transdermal device containing microneedles
WO2013006643A1 (en) 2011-07-06 2013-01-10 The Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
WO2013058879A2 (en) 2011-09-02 2013-04-25 The Regents Of The University Of California Microneedle arrays for biosensing and drug delivery
BR112014009712A2 (en) 2011-10-27 2017-04-18 Kimberly Clark Co implantable devices for the administration of bioactive agents
US20170246439A9 (en) 2011-10-27 2017-08-31 Kimberly-Clark Worldwide, Inc. Increased Bioavailability of Transdermally Delivered Agents
KR102265775B1 (en) 2011-10-27 2021-06-16 소렌토 쎄라퓨틱스, 인코포레이티드 Transdermal delivery of high viscosity bioactive agents
JP2014534864A (en) 2011-10-28 2014-12-25 プレサージュ バイオサイエンシズ,インコーポレイテッド Drug delivery method
US9317656B2 (en) 2011-11-23 2016-04-19 Abbott Diabetes Care Inc. Compatibility mechanisms for devices in a continuous analyte monitoring system and methods thereof
CA3018046A1 (en) 2011-12-16 2013-06-20 Moderna Therapeutics, Inc. Modified nucleoside, nucleotide, and nucleic acid compositions
DE102011089723A1 (en) * 2011-12-23 2013-06-27 Robert Bosch Gmbh Microneedle array applicator and method of applying a microneedle array
US10130800B2 (en) 2012-01-27 2018-11-20 Invisiderm, Llc Method of producing substances with supersaturated gas, transdermal delivery device thereof, and uses thereof
ES2741348T3 (en) 2012-03-13 2020-02-10 Becton Dickinson France Injection device having a miniaturized drug delivery portion
WO2013136327A1 (en) 2012-03-15 2013-09-19 Steadymed Ltd. Enhanced infusion-site pain-reduction for drug-delivery devices
EP2827923B1 (en) 2012-03-19 2018-12-26 Steadymed Ltd. Fluid-connection mechanism for patch-pumps
KR20130114996A (en) * 2012-04-10 2013-10-21 삼성디스플레이 주식회사 Display apparatus and fabricating method thereof
AU2013256348B2 (en) 2012-05-01 2017-06-15 Carnegie Mellon University Tip-loaded microneedle arrays for transdermal insertion
US9180242B2 (en) 2012-05-17 2015-11-10 Tandem Diabetes Care, Inc. Methods and devices for multiple fluid transfer
US9555186B2 (en) 2012-06-05 2017-01-31 Tandem Diabetes Care, Inc. Infusion pump system with disposable cartridge having pressure venting and pressure feedback
KR102370581B1 (en) * 2012-07-06 2022-03-03 더 제너럴 하스피탈 코포레이션 Method and apparatus for dermatological treatment
US9782538B2 (en) 2012-09-27 2017-10-10 Becton, Dickinson And Company Angled inserter for drug infusion
CN110893188A (en) 2012-11-08 2020-03-20 克莱尔塞德生物医学股份有限公司 Methods and devices for treating ocular diseases in human subjects
RS63237B1 (en) 2012-11-26 2022-06-30 Modernatx Inc Terminally modified rna
WO2014100750A1 (en) 2012-12-21 2014-06-26 Corium International, Inc. Microarray for delivery of therapeutic agent and methods of use
AU2013374345A1 (en) 2013-01-17 2015-08-06 Moderna Therapeutics, Inc. Signal-sensor polynucleotides for the alteration of cellular phenotypes
US10105487B2 (en) 2013-01-24 2018-10-23 Chrono Therapeutics Inc. Optimized bio-synchronous bioactive agent delivery system
US9522254B2 (en) 2013-01-30 2016-12-20 Vascular Pathways, Inc. Systems and methods for venipuncture and catheter placement
EP2961471B1 (en) * 2013-02-28 2023-10-25 Sorrento Therapeutics, Inc. Transdermal drug delivery device
CA2903748C (en) 2013-03-12 2021-11-02 Corium International, Inc. Microprojection applicators
US20160024181A1 (en) 2013-03-13 2016-01-28 Moderna Therapeutics, Inc. Long-lived polynucleotide molecules
JP6098250B2 (en) * 2013-03-14 2017-03-22 セイコーエプソン株式会社 Liquid transport device
US10080839B2 (en) 2013-03-14 2018-09-25 Becton, Dickinson And Company Angled inserter for drug infusion
US9173998B2 (en) 2013-03-14 2015-11-03 Tandem Diabetes Care, Inc. System and method for detecting occlusions in an infusion pump
US9821113B2 (en) 2013-03-15 2017-11-21 Becton, Dickinson And Company Automatic angled infusion set assembly
MX2015012933A (en) 2013-03-15 2016-09-19 Corium Int Inc Microarray for delivery of therapeutic agent and methods of use.
US10195409B2 (en) * 2013-03-15 2019-02-05 Corium International, Inc. Multiple impact microprojection applicators and methods of use
US9603995B2 (en) 2013-03-15 2017-03-28 Tandem Diabetes Care. Inc. Device and method for setting therapeutic parameters for an infusion device
AU2014237279B2 (en) 2013-03-15 2018-11-22 Corium Pharma Solutions, Inc. Microarray with polymer-free microstructures, methods of making, and methods of use
WO2014143770A1 (en) * 2013-03-15 2014-09-18 Amgen Inc. Body contour adaptable autoinjector device
CN116327482A (en) 2013-05-03 2023-06-27 科尼尔赛德生物医学公司 Apparatus and method for ocular injection
US20140350516A1 (en) 2013-05-23 2014-11-27 Allergan, Inc. Mechanical syringe accessory
US20140350518A1 (en) 2013-05-23 2014-11-27 Allergan, Inc. Syringe extrusion accessory
EP3003454B1 (en) 2013-06-03 2020-01-08 Clearside Biomedical, Inc. Apparatus for drug delivery using multiple reservoirs
US9833630B2 (en) 2013-06-14 2017-12-05 Cardiothrive, Inc. Biphasic or multiphasic pulse waveform and method
US9907970B2 (en) 2013-06-14 2018-03-06 Cardiothrive, Inc. Therapeutic system and method using biphasic or multiphasic pulse waveform
US10149973B2 (en) 2013-06-14 2018-12-11 Cardiothrive, Inc. Multipart non-uniform patient contact interface and method of use
US9616243B2 (en) 2013-06-14 2017-04-11 Cardiothrive, Inc. Dynamically adjustable multiphasic defibrillator pulse system and method
US9656094B2 (en) 2013-06-14 2017-05-23 Cardiothrive, Inc. Biphasic or multiphasic pulse generator and method
US10279189B2 (en) 2013-06-14 2019-05-07 Cardiothrive, Inc. Wearable multiphasic cardioverter defibrillator system and method
CN105324147B (en) * 2013-06-18 2018-03-02 久光制药株式会社 Applicator
EP3011993B1 (en) 2013-06-19 2019-10-02 Hisamitsu Pharmaceutical Co., Inc. Applicator
US20150027241A1 (en) * 2013-07-23 2015-01-29 Diba Industries, Inc. Piercing probes with offset conical piercing tip and fluid-sampling systems comprising the piercing probes
WO2015059699A2 (en) 2013-10-23 2015-04-30 Valtech Cardio, Ltd. Anchor magazine
JP2017500865A (en) 2013-12-19 2017-01-12 ノバルティス アーゲー Compositions and formulations of leptin mRNA
WO2015119906A1 (en) 2014-02-05 2015-08-13 Amgen Inc. Drug delivery system with electromagnetic field generator
GB201403773D0 (en) * 2014-03-04 2014-04-16 Univ Cardiff Microneedle based cell delivery
US10279106B1 (en) 2014-05-08 2019-05-07 Tandem Diabetes Care, Inc. Insulin patch pump
US10029048B2 (en) 2014-05-13 2018-07-24 Allergan, Inc. High force injection devices
JP6817074B2 (en) 2014-06-03 2021-01-20 アムジエン・インコーポレーテツド Controllable drug delivery system and usage
MX2016017028A (en) 2014-06-20 2017-08-07 Clearside Biomedical Inc Variable diameter cannula and methods for controlling insertion depth for medicament delivery.
US10321858B2 (en) 2014-08-18 2019-06-18 Proteadx, Inc. Apparatus and methods for transdermal sensing of analytes in interstitial fluid and associated data transmission systems
EP3188714A1 (en) 2014-09-04 2017-07-12 Corium International, Inc. Microstructure array, methods of making, and methods of use
US10232146B2 (en) 2014-09-05 2019-03-19 C. R. Bard, Inc. Catheter insertion device including retractable needle
EP3193973A1 (en) * 2014-09-15 2017-07-26 Sanofi Medicament delivery device with rotatable housing on a base
DE102014219719B4 (en) * 2014-09-29 2018-05-03 Ipr Intelligente Peripherien Für Roboter Gmbh needle grippers
US10226585B2 (en) 2014-10-01 2019-03-12 Allergan, Inc. Devices for injection and dosing
USD750223S1 (en) 2014-10-14 2016-02-23 Clearside Biomedical, Inc. Medical injector for ocular injection
DK3207871T3 (en) * 2014-10-27 2021-10-11 Glutalor Medical Inc DYNAMIC BLOOD GLUCOSE DATA ACQUIRING DEVICE AND HOST
EP3233159B1 (en) 2014-12-19 2020-03-04 Amgen Inc. Drug delivery device with live button or user interface field
EP3233163B1 (en) 2014-12-19 2021-10-13 Amgen Inc. Drug delivery device with proximity sensor
EP3238352A4 (en) 2014-12-23 2018-08-22 Axell Wireless Ltd. Harmonizing noise aggregation and noise management in distributed antenna system
EP3045185A1 (en) * 2015-01-16 2016-07-20 Sanofi-Aventis Deutschland GmbH Connector for a container filled with a liquid medicament
WO2016123406A1 (en) 2015-01-28 2016-08-04 Chrono Therapeutics Inc. Drug delivery methods and systems
JP6484345B2 (en) * 2015-02-17 2019-03-20 アムジエン・インコーポレーテツド Drug delivery device with fixation and / or return assisted by vacuum
BR112017019272A2 (en) 2015-03-10 2018-05-02 Allergan Pharmaceuticals Holdings Ireland Unlimited Company multiple needle injector
WO2016145373A1 (en) 2015-03-12 2016-09-15 Chrono Therapeutics Inc. Craving input and support system
US10441768B2 (en) 2015-03-18 2019-10-15 University of Pittsburgh—of the Commonwealth System of Higher Education Bioactive components conjugated to substrates of microneedle arrays
USD903100S1 (en) 2015-05-01 2020-11-24 C. R. Bard, Inc. Catheter placement device
JP6784352B2 (en) * 2015-05-11 2020-11-11 国立大学法人 東京医科歯科大学 Insulin delivery device
CN116672577A (en) 2015-05-15 2023-09-01 C·R·巴德股份有限公司 Catheter placement device including an extendable needle safety member
US10463847B2 (en) 2015-06-11 2019-11-05 Steadymed Ltd. Infusion set
WO2017004067A1 (en) 2015-06-29 2017-01-05 Corium International, Inc. Microarray for delivery of therapeutic agent, methods of use, and methods of making
US10940292B2 (en) 2015-07-08 2021-03-09 Actuated Medical, Inc. Reduced force device for intravascular access and guidewire placement
US11793543B2 (en) 2015-09-18 2023-10-24 Obvius Robotics, Inc. Device and method for automated insertion of penetrating member
WO2017066768A1 (en) 2015-10-16 2017-04-20 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Mullti-component biio-active drug delivery and controlled release to the skin by microneedle array devices
WO2017120322A1 (en) 2016-01-05 2017-07-13 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Skin microenvironment targeted delivery for promoting immune and other responses
EP3413851B1 (en) 2016-02-10 2023-09-27 Clearside Biomedical, Inc. Packaging
US10980992B2 (en) * 2016-02-19 2021-04-20 North Carolina State University Methods and compositions related to physiologically responsive microneedle delivery systems
KR102424007B1 (en) 2016-03-28 2022-07-26 아이커 메디칼 시스템스 인코포레이티드 Methods and devices for delivering therapeutics
JP2019510589A (en) 2016-04-08 2019-04-18 アラーガン、インコーポレイテッドAllergan,Incorporated Suction and injection device
CA3062845A1 (en) 2016-05-02 2017-11-09 Clearside Biomedical, Inc. Systems and methods for ocular drug delivery
NL2016807B1 (en) * 2016-05-20 2017-11-27 Uprax System and method for applying microneedles
EP3458141A1 (en) * 2016-05-20 2019-03-27 Uprax Microsolutions B.V. System and method for applying microneedles
US10220195B2 (en) * 2016-06-08 2019-03-05 Eclipse Medcorp, Llc Radio frequency needling device for use with disposable needle cartridges
IL264764B2 (en) 2016-08-12 2024-02-01 Clearside Biomedical Inc Devices and methods for adjusting the insertion depth of a needle for medicament delivery
AU2017322745B2 (en) 2016-09-12 2021-09-23 C. R. Bard, Inc. Blood control for a catheter insertion device
US11241563B2 (en) 2016-12-22 2022-02-08 Johnson & Johnson Consumer Inc. Microneedle arrays and methods for making and using
EP3338832A1 (en) * 2016-12-23 2018-06-27 Sanofi-Aventis Deutschland GmbH Medicament delivery device
EP3565617A1 (en) 2017-01-06 2019-11-13 Chrono Therapeutics Inc. Transdermal drug delivery devices and methods
AU2017401073B2 (en) 2017-03-01 2022-06-02 C. R. Bard, Inc. Catheter insertion device
USD867582S1 (en) 2017-03-24 2019-11-19 Allergan, Inc. Syringe device
CN109833562A (en) * 2017-11-27 2019-06-04 苏州纳通生物纳米技术有限公司 A kind of disposable self-destructing vibration head assembly and the rush infiltration instrument using the component
US10828500B2 (en) 2017-12-22 2020-11-10 Cardiothrive, Inc. External defibrillator
IL275855B2 (en) * 2018-01-07 2023-11-01 Avraham Amir High-load microneedles and compositions for skin augmentation
EP3762084A4 (en) 2018-03-07 2021-09-29 Bard Access Systems, Inc. Guidewire advancement and blood flashback systems for a medical device insertion system
US11090506B2 (en) * 2018-05-15 2021-08-17 Omm Imports, Inc. Disposable product cap and assembly having a manually usable thermo-optical device for skin care
CA3101966A1 (en) 2018-05-29 2019-12-05 Morningside Venture Investments Limited Drug delivery methods and systems
EP3813809A1 (en) 2018-06-29 2021-05-05 Johnson & Johnson Consumer Inc. Three-dimensional microfluidics devices for the delivery of actives
USD921884S1 (en) 2018-07-27 2021-06-08 Bard Access Systems, Inc. Catheter insertion device
FR3084578B1 (en) * 2018-08-03 2024-01-12 Pkvitality MANAGEMENT OF MICRONEEDLE INVESTMENT
CA3208266A1 (en) 2019-02-22 2020-08-27 Deka Products Limited Partnership Infusion set and inserter assembly systems and methods
WO2020188484A1 (en) * 2019-03-19 2020-09-24 King Abdullah University Of Science And Technology Miniaturized delivery system and method
US11590332B2 (en) * 2019-04-17 2023-02-28 Path Scientific, Llc Precision microneedling device and methods of use
GB201908043D0 (en) * 2019-06-05 2019-07-17 Lekkos Vasileios Transdermal patch for therapeutic uses
KR102279603B1 (en) * 2019-06-11 2021-07-20 (주)비올 Needle assembly, skin stimulator including the same, and manufacturing method thereof
WO2021009559A1 (en) * 2019-07-12 2021-01-21 Qulab Medical Ltd. Electrochemical fet sensor
WO2021020730A2 (en) * 2019-07-26 2021-02-04 주식회사 림사이언스 Apparatus for applying pressure to medical needle
WO2021034862A1 (en) 2019-08-19 2021-02-25 Becton, Dickinson And Company Midline catheter placement device
WO2021087249A1 (en) * 2019-10-30 2021-05-06 Thermalin, Inc. Agent delivery systems, devices, and methods
GB2608290B (en) 2020-07-29 2023-07-26 Biolinq Incorporated Continuous analyte monitoring system with microneedle array
CN112370653B (en) * 2020-11-12 2022-08-30 深圳市圣通生物科技有限公司 Spray disinfection type nanometer microneedle mesoderm leading-in beauty instrument
US20220273352A1 (en) * 2021-03-01 2022-09-01 Bluexthermal, Inc. Device and method for thermal modulation of tissue
US11452474B1 (en) 2021-04-14 2022-09-27 Satio, Inc. Dual lever dermal patch system
JP7341583B6 (en) 2021-05-08 2023-09-29 バイオリンク インコーポレイテッド Fault detection for microneedle array-based continuous analyte monitoring devices
US11877848B2 (en) 2021-11-08 2024-01-23 Satio, Inc. Dermal patch for collecting a physiological sample
US11510602B1 (en) 2021-11-08 2022-11-29 Satio, Inc. Dermal patch for collecting a physiological sample
EP4295873A1 (en) * 2022-06-21 2023-12-27 National University of Ireland Galway An infusion catheter system

Family Cites Families (144)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US447225A (en) * 1891-02-24 Machine for attaching stays to the corners of boxes
US3537A (en) 1844-04-13 X g gupping instrument
US3659A (en) * 1844-07-11 Machine for hulling and pearling rice
US1934043A (en) * 1929-05-17 1933-11-07 Standard Oil Dev Co Process of improvement of lubricating oils
DE596981C (en) 1931-10-30 1934-05-12 Mario Demarchi Dr Injection syringe
FR757501A (en) 1932-09-23 1933-12-28 Automatic device for handling injection syringes
US2088780A (en) 1936-10-09 1937-08-03 Sigurd E Follese Massage device
US2763935A (en) 1954-06-11 1956-09-25 Purdne Res Foundation Determining depth of layers of fat and of muscle on an animal body
US2945496A (en) 1958-08-18 1960-07-19 Fosdal Alfred Dental instrument for immobilizing tissue
DE1115722B (en) 1960-04-30 1961-10-26 Hoechst Ag Metal anode for the electrolytic separation of chlorine
GB1128329A (en) 1964-12-23 1968-09-25 Nat Res Dev Electrodes for making electrical contact to the living body of a mammal
US3568735A (en) * 1968-06-26 1971-03-09 Cooke Eng Co Laboratory microtitration dispensing apparatus
US3568732A (en) 1969-02-28 1971-03-09 Kelly James A Jun Splice straightener for aerial conductors
US3659600A (en) 1970-02-24 1972-05-02 Estin Hans H Magnetically operated capsule for administering drugs
US3727614A (en) 1971-05-13 1973-04-17 Merck & Co Inc Multiple dosage inoculator
US3964482A (en) 1971-05-17 1976-06-22 Alza Corporation Drug delivery device
US3738493A (en) 1971-09-24 1973-06-12 Analytical Instr Spec Apparatus for simultaneous application of samples to thin layer chromatography plates
BE795384A (en) 1972-02-14 1973-08-13 Ici Ltd DRESSINGS
CH557178A (en) 1972-08-10 1974-12-31 Siemens Ag DEVICE FOR DISPENSING DRUGS.
US3923060A (en) 1974-04-23 1975-12-02 Jr Everett H Ellinwood Apparatus and method for implanted self-powered medication dispensing having timing and evaluator means
US4140109A (en) 1977-10-17 1979-02-20 Savic Michael I Impedance-based method and apparatus for monitoring cryodestruction in controlled cryosurgery
FR2460343A1 (en) 1979-06-29 1981-01-23 Solvay CATHODE FOR THE ELECTROLYTIC PRODUCTION OF HYDROGEN
JPS5683360A (en) * 1979-12-10 1981-07-07 Olympus Optical Co Pneumoperitoneum needle
US4447225A (en) 1982-03-22 1984-05-08 Taff Barry E Multidose jet injector
US4619652A (en) 1982-12-23 1986-10-28 Alza Corporation Dosage form for use in a body mounted pump
US4505710A (en) 1983-05-13 1985-03-19 Collins Earl R Implantable fluid dispensing system
DE3502913C1 (en) 1985-01-29 1986-07-03 Günter Prof. Dr.rer.nat. 5100 Aachen Rau Sensor for non-invasive detection of electrophysiological values
US4777599A (en) 1985-02-26 1988-10-11 Gillette Company Viscoelastometry of skin using shear wave propagation
FR2594341B1 (en) * 1986-02-14 1990-08-10 Charton Jean Pierre INJECTOR APPARATUS FOR THE PRACTICE OF MESOTHERAPY
AT384737B (en) 1986-04-04 1987-12-28 Thoma Dipl Ing Dr Techn Herwig DEVICE FOR CONTINUOUSLY DELIVERING LIQUID MEDICINAL PRODUCTS
AU7847487A (en) * 1986-09-18 1988-02-04 Selfridge, A.R. Cannulation of blood vessels
US4886499A (en) 1986-12-18 1989-12-12 Hoffmann-La Roche Inc. Portable injection appliance
US4808156A (en) 1987-03-09 1989-02-28 Dean Consuelo M Cannular instrument and method for inserting a cannular instrument into a vein
US6056716A (en) 1987-06-08 2000-05-02 D'antonio Consultants International Inc. Hypodermic fluid dispenser
DD262803A1 (en) 1987-08-05 1988-12-14 Transform Roentgen Matern Veb INJECTION DEVICE
US5312486A (en) 1987-12-24 1994-05-17 Frank Meyer Water-containing, hardenable foam compositions with inorganic components and process for their preparation
US4989614A (en) 1988-02-23 1991-02-05 Vance Products Incorporated Fine-needle aspiration cell sampling methods
CA2008262A1 (en) * 1989-01-30 1990-07-30 John A. Gilly Clinical applicator
US5062834A (en) 1989-02-24 1991-11-05 Product Development (S.G.Z.) Ltd Device for dispensing a liquid particularly useful for delivering medicaments at a predetermined rate
US5425706A (en) 1989-02-24 1995-06-20 S. I. Scientific Innovations Ltd. Dispensing device particularly useful for dispensing nutritional liquids
JPH0648975B2 (en) 1989-10-02 1994-06-29 俊郎 樋口 Micro injection device and injection control method thereof
US5262128A (en) 1989-10-23 1993-11-16 The United States Of America As Represented By The Department Of Health And Human Services Array-type multiple cell injector
EP0429842B1 (en) 1989-10-27 1996-08-28 Korea Research Institute Of Chemical Technology Device for the transdermal administration of protein or peptide drug
US6090790A (en) 1989-12-14 2000-07-18 Eriksson; Elof Gene delivery by microneedle injection
US5697901A (en) 1989-12-14 1997-12-16 Elof Eriksson Gene delivery by microneedle injection
US5092901A (en) 1990-06-06 1992-03-03 The Royal Institution For The Advancement Of Learning (Mcgill University) Shape memory alloy fibers having rapid twitch response
US5527288A (en) 1990-12-13 1996-06-18 Elan Medical Technologies Limited Intradermal drug delivery device and method for intradermal delivery of drugs
US5279544A (en) * 1990-12-13 1994-01-18 Sil Medics Ltd. Transdermal or interdermal drug delivery devices
US5156591A (en) 1990-12-13 1992-10-20 S. I. Scientific Innovations Ltd. Skin electrode construction and transdermal drug delivery device utilizing same
TW279133B (en) 1990-12-13 1996-06-21 Elan Med Tech
US5279547A (en) 1991-01-03 1994-01-18 Alcon Surgical Inc. Computer controlled smart phacoemulsification method and apparatus
SE9101022D0 (en) * 1991-01-09 1991-04-08 Paal Svedman MEDICAL SUSPENSION DEVICE
US5312456A (en) 1991-01-31 1994-05-17 Carnegie Mellon University Micromechanical barb and method for making the same
WO1993009842A1 (en) 1991-11-13 1993-05-27 Elan Corporation, Plc Drug delivery device
US6048337A (en) 1992-01-07 2000-04-11 Principal Ab Transdermal perfusion of fluids
JP2547520B2 (en) 1992-01-21 1996-10-23 ヴァリーラブ・インコーポレーテッド Electrosurgical controller for trocar
US5252023A (en) * 1992-02-10 1993-10-12 Kelly Kevin M Lifting apparatus
JP2572823Y2 (en) 1992-02-13 1998-05-25 株式会社アドバンス Simple blood sampler
WO1993020784A1 (en) 1992-04-10 1993-10-28 State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University A microneedle for injection of ocular blood vessels
US5478328A (en) 1992-05-22 1995-12-26 Silverman; David G. Methods of minimizing disease transmission by used hypodermic needles, and hypodermic needles adapted for carrying out the method
JPH0698920A (en) * 1992-09-21 1994-04-12 Hayashi Shigetada Acupuncture precise measuring instrument
US5354273A (en) 1992-12-14 1994-10-11 Mallinckrodt Medical, Inc. Delivery apparatus with pressure controlled delivery
US5478323A (en) * 1993-04-02 1995-12-26 Eli Lilly And Company Manifold for injection apparatus
IE68890B1 (en) 1993-04-08 1996-07-24 Elan Med Tech Intradermal delivery device
US5335668A (en) * 1993-04-30 1994-08-09 Medical Scientific, Inc. Diagnostic impedance measuring system for an insufflation needle
JP3494183B2 (en) * 1993-08-10 2004-02-03 株式会社アドバンス Simple blood collection device
CA2171563A1 (en) 1993-09-14 1995-03-23 Eric Le Cheminant Injection device
US5389222A (en) 1993-09-21 1995-02-14 The United States Of America As Represented By The United States Department Of Energy Spring-loaded polymeric gel actuators
US5599346A (en) 1993-11-08 1997-02-04 Zomed International, Inc. RF treatment system
US5997501A (en) 1993-11-18 1999-12-07 Elan Corporation, Plc Intradermal drug delivery device
CA2149943C (en) 1994-05-23 1999-07-13 Kwang Kyun Jang Skin perforating device for transdermal medication
CA2149836C (en) 1994-05-23 1999-07-06 Sang Bae Choi Perforating device for dermal administration
US5591139A (en) 1994-06-06 1997-01-07 The Regents Of The University Of California IC-processed microneedles
DE4420232A1 (en) 1994-06-07 1995-12-14 Robert Waltereit Penetration depth checking device for hollow needle or probe inserted in human or animal patient
US5649423A (en) 1994-06-07 1997-07-22 Sandia Corporation Micromechanism linear actuator with capillary force sealing
US5478315A (en) 1994-08-08 1995-12-26 Brothers Family Investments, L.C. Local anesthetic injection system
US5432098A (en) 1994-10-31 1995-07-11 Dynatech Precision Sampling Corporation Apparatus, and process, for automatically sampling solids and semi-solids materials for analysis
IE72524B1 (en) * 1994-11-04 1997-04-23 Elan Med Tech Analyte-controlled liquid delivery device and analyte monitor
GB9508606D0 (en) 1995-04-27 1995-06-14 Svedman Paul Suction blister sampling
WO1996037256A1 (en) 1995-05-22 1996-11-28 Silicon Microdevices, Inc. Micromechanical patch for enhancing the delivery of compounds through the skin
WO1996037155A1 (en) 1995-05-22 1996-11-28 Silicon Microdevices, Inc. Micromechanical device and method for enhancing delivery of compounds through the skin
US5827216A (en) * 1995-06-07 1998-10-27 Cormedics Corp. Method and apparatus for accessing the pericardial space
ZA9610374B (en) * 1995-12-11 1997-06-23 Elan Med Tech Cartridge-based drug delivery device
JPH09192218A (en) * 1996-01-16 1997-07-29 Hitachi Ltd Blood-sugar level control system
JPH09239031A (en) * 1996-03-09 1997-09-16 Honda Electron Co Ltd Injector mounting ultrasonic vibrator transducer
US5843016A (en) 1996-03-18 1998-12-01 Physion S.R.L. Electromotive drug administration for treatment of acute urinary outflow obstruction
US6117155A (en) 1996-05-01 2000-09-12 Lee; Young H. Coated needle for use with an intramuscular stimulation treatment device
US5785688A (en) 1996-05-07 1998-07-28 Ceramatec, Inc. Fluid delivery apparatus and method
US5954668A (en) 1996-06-14 1999-09-21 Medrad, Inc. Extravasation detector using microwave radiometry
ES2195151T3 (en) 1996-06-18 2003-12-01 Alza Corp IMPROVEMENT OR SAMPLING DEVICE FOR TRANSDERMAL AGENTS.
ATE241405T1 (en) 1996-07-03 2003-06-15 Altea Therapeutics Corp MULTIPLE MECHANICAL MICROPERFORATION OF SKIN OR MUCOUS MEASURES
JPH1043296A (en) * 1996-08-05 1998-02-17 Terumo Corp Chemical injecting apparatus
WO1998011937A1 (en) 1996-09-17 1998-03-26 Deka Products Limited Partnership System for delivery of drugs by transport
US6071249A (en) 1996-12-06 2000-06-06 Abbott Laboratories Method and apparatus for obtaining blood for diagnostic tests
SE9604564D0 (en) 1996-12-12 1996-12-12 Paal Svedman Method and apparatus for conducting electrical currents
US6246904B1 (en) 1996-12-17 2001-06-12 Alza Corporation Electrotransport drug delivery reservoirs containing inert fillers
US5928194A (en) 1997-04-07 1999-07-27 Maget; Henri J. R. Self-contained liquid microdispenser
US5928207A (en) 1997-06-30 1999-07-27 The Regents Of The University Of California Microneedle with isotropically etched tip, and method of fabricating such a device
US5972013A (en) 1997-09-19 1999-10-26 Comedicus Incorporated Direct pericardial access device with deflecting mechanism and method
JPH11137684A (en) * 1997-11-12 1999-05-25 Hiroshi Oya Indolent and safe syringe
DE69727985T2 (en) * 1997-11-26 2005-01-20 E-Z-Em, Inc. EXTRAVASATIONSERKENNUNGSVORRICHTUNG
US6918901B1 (en) * 1997-12-10 2005-07-19 Felix Theeuwes Device and method for enhancing transdermal agent flux
DK1037686T3 (en) 1997-12-11 2006-01-02 Alza Corp Apparatus for enhancing transdermal flow of agents
ATE221400T1 (en) 1997-12-11 2002-08-15 Alza Corp DEVICE FOR INCREASE THE TRANSDERMAL FLOW OF ACTIVE INGREDIENTS
US6126629A (en) 1997-12-18 2000-10-03 Bausch & Lomb Surgical, Inc. Multiple port phaco needle
US6154673A (en) * 1997-12-30 2000-11-28 Agilent Technologies, Inc. Multilingual defibrillator
US6048204A (en) * 1998-02-03 2000-04-11 Lifecore Biomedical, Inc. Self tapping screw type dental implant
US5957895A (en) 1998-02-20 1999-09-28 Becton Dickinson And Company Low-profile automatic injection device with self-emptying reservoir
US6391005B1 (en) * 1998-03-30 2002-05-21 Agilent Technologies, Inc. Apparatus and method for penetration with shaft having a sensor for sensing penetration depth
US5971998A (en) 1998-03-31 1999-10-26 Donald G. Russell Support device and method for controlling breast thickness during stereotactic guided needle biopsy
PT1077636E (en) 1998-05-13 2004-06-30 Cygnus Therapeutic Systems SIGNAL PROCESSING FOR PHYSIOLOGICAL ANALYZES MEDICATION
ATE245937T1 (en) 1998-05-13 2003-08-15 Cygnus Therapeutic Systems MONITORING PHYSIOLOGICAL ANALYTES
CA2334174A1 (en) 1998-06-04 1999-12-09 Izrail Tsals Gas driven drug delivery device
CA2330207C (en) 1998-06-10 2005-08-30 Georgia Tech Research Corporation Microneedle devices and methods of manufacture and use thereof
US6678556B1 (en) 1998-07-13 2004-01-13 Genetronics, Inc. Electrical field therapy with reduced histopathological change in muscle
GB9815820D0 (en) 1998-07-22 1998-09-16 Secr Defence Improvements relating to micro-machining
GB9815819D0 (en) 1998-07-22 1998-09-16 Secr Defence Transferring materials into cells and a microneedle array
WO2000006227A1 (en) 1998-07-27 2000-02-10 Medi-Ject Corporation Loading mechanism for medical injector assembly
EP1113832A4 (en) 1998-09-18 2002-04-17 Univ Utah Res Found Surface micromachined microneedles
DE19843733A1 (en) * 1998-09-24 2000-03-30 Voith Sulzer Papiertech Patent Wiper blade assembly coating paper or card bands with optionally-viscous liquid, employs system of leaf spring tensioning which forms ductor chamber and is readily replaced and adjusted
US6148232A (en) 1998-11-09 2000-11-14 Elecsys Ltd. Transdermal drug delivery and analyte extraction
US6317630B1 (en) 1999-01-29 2001-11-13 Yossi Gross Drug delivery device
US6132449A (en) 1999-03-08 2000-10-17 Agilent Technologies, Inc. Extraction and transportation of blood for analysis
US6319230B1 (en) 1999-05-07 2001-11-20 Scimed Life Systems, Inc. Lateral needle injection apparatus and method
US6743211B1 (en) * 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
US6611707B1 (en) 1999-06-04 2003-08-26 Georgia Tech Research Corporation Microneedle drug delivery device
CA2376128C (en) 1999-06-04 2009-01-06 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
US6256533B1 (en) 1999-06-09 2001-07-03 The Procter & Gamble Company Apparatus and method for using an intracutaneous microneedle array
US6379324B1 (en) 1999-06-09 2002-04-30 The Procter & Gamble Company Intracutaneous microneedle array apparatus
AU5625200A (en) * 1999-06-18 2001-01-09 University Of Virginia Patent Foundation An apparatus for fluid transport and related method thereof
US6408204B1 (en) 1999-07-28 2002-06-18 Medrad, Inc. Apparatuses and methods for extravasation detection
JP2003513765A (en) * 1999-11-15 2003-04-15 ベルクロ インダストリーズ ビー ヴィッ Skin mounting member
AU2088301A (en) * 1999-12-16 2001-06-25 Alza Corporation Device for enhancing transdermal flux of sampled agents
US7003336B2 (en) * 2000-02-10 2006-02-21 Medtronic Minimed, Inc. Analyte sensor method of making the same
US6572740B2 (en) 2000-04-13 2003-06-03 Elan Pharma International Limited Electrolytic cell
US6565532B1 (en) 2000-07-12 2003-05-20 The Procter & Gamble Company Microneedle apparatus used for marking skin and for dispensing semi-permanent subcutaneous makeup
US6440096B1 (en) * 2000-07-14 2002-08-27 Becton, Dickinson And Co. Microdevice and method of manufacturing a microdevice
JP2002028247A (en) * 2000-07-18 2002-01-29 Japan Science & Technology Corp Method and instrument for sensing venous pricking by puncture needle
EP2554196B1 (en) 2000-11-30 2018-10-17 Valeritas, Inc. Fluid delivery and measurement systems
EP1395320B1 (en) 2001-06-11 2006-06-28 Glaxo Group Limited Medicament dispenser
US6835193B2 (en) 2001-07-10 2004-12-28 Myocardial Therapeutics, Inc. Methods for controlled depth injections into interior body cavities
US7429258B2 (en) * 2001-10-26 2008-09-30 Massachusetts Institute Of Technology Microneedle transport device
AU2002360712A1 (en) * 2001-12-21 2003-07-30 The Trustees Of Columbia University In The City Of New York C3 exoenzyme-coated stents and uses thereof for treating and preventing restenosis
EP1403519A1 (en) * 2002-09-27 2004-03-31 Novo Nordisk A/S Membrane pump with stretchable pump membrane

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