Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
2001-06-07
2004-03-16
Casler, Brian L. (Department: 3763)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C604S068000, C604S022000, C128S898000
Reexamination Certificate
active
06706032
ABSTRACT:
BACKGROUND OF THE INVENTION
Transdermal drug delivery, as the term is used generally, refers to permeation of the stratum corneum, the tough outer barrier of the skin, by a pharmaceutically active molecule. The stratum corneum, the thin (approximately 20 &mgr;m) outer layer of the epidermis, is dead tissue containing both multilamellar lipid barriers, and tough protein-based structures.
The epidermis, directly beneath the stratum corneum, also behaves as a lipid barrier. The dermis, directly beneath the epidermis, is permeable to many types of solutes. In the administration of a drug by topical application to skin, lipid-soluble drug molecules dissolve into and diffuse through the skin's multilamellar lipid bilayer membranes along a concentration gradient by virtue of the drug molecules' solubility in the lipid bilayer. Transdermal drug delivery may be targeted to a tissue directly beneath the skin, or to capillaries for systemic distribution within the body by the circulation of blood.
The term “transdermal drug delivery” usually excludes hypodermic injection, long term needle placement for infusion pumps, and other needles which penetrate the skin's stratum corneum. Thus, transdermal drug delivery is generally regarded as minimally invasive. However, the low rate of transport of therapeutic molecules through the stratum corneum remains a common clinical problem.
Transdermal delivery of only a limited number of lipophilic drugs is commercially available. Existing methods include, for example, the use of wearable “patches,” a passive transdermal drug delivery method that tends to be slow, and difficult to control.
Another method includes the use of a “gene gun,” to accelerate 20 to 70 &mgr;m diameter drug particles, or smaller DNA-coated gold particles, to supersonic velocities, such that the particles pass through the stratum corneum into the epidermis or dermis. A single particle, 20 &mgr;m to 70 &mgr;m, in diameter, such as used in the gene gun, when fired at the stratum corneum at supersonic speeds, ruptures and tears through the tissues of the stratum corneum, epidermis and dermis, stopping and remaining at some depth which is determined by the initial velocity and mass of the particle. The resulting path through the above-mentioned tissues may be in the range of 1 &mgr;m to perhaps 30 &mgr;m because the tissues are elastic to various degrees, depending on the individual. The semi-static analogue is to pierce a rubber sheet with a common pin, 750 &mgr;m in diameter. When pulled out of the rubber sheet, the resultant opening size is less than 1 &mgr;m, or perhaps not open at all. This is because the pin has torn the rubber sheet and pushed it aside, due to the rubber sheet's elasticity (ability to get out of the way), as the pin is forced through. As in the analogue, because of the elasticity of skin, use of the gene gun does not form microconduits in the skin because the tissue is only temporarily pushed aside as a particle is forced through the skin.
Examples of transdermal drug delivery methods presently being investigated include the use of ultrasound (sonophoresis) to cause cavitation in the stratum corneum; laser ablation of a small region of the stratum corneum, thereby providing access to the epidermis; the use of microneedles to create openings in the stratum corneum; the use of electrical methods, including low voltage iontophoresis, wherein transport is believed to occur through pre-existing aqueous pathways; and the use of high voltage pulses to cause electroporation of the skin. There are disadvantages associated with each of these methods. For example, often the rate of transport of molecules tends to diminish rapidly with increasing molecular size. Other disadvantages include pain and discomfort, skin irritation, the high cost and the large size of equipment required, and the potential for breaking off needles, which might remain imbedded in the skin.
Also, a common problem encountered in using established techniques such as subcutaneous and intradermal injection to deliver vaccines, is the inaccurate placement of the immunizing material with respect to the epidermal and dermal antigen-presenting cells, or with respect to keratinocytes. There is also a long-standing need for an effective method to deliver therapeutic agents to treat a fungal infection of the tissue underlying nail tissue of fingers and toes.
An existing problem with currently used methods of making biopotential measurements and other electrical measurements at the surface of the skin of a living organism is that the measurements are often degraded by motion and by other potentials that are associated with the skin. Techniques such as microscission or stripping of the stratum corneum of the skin can significantly improve the quality of such electrical measurements. However, mechanical alteration of the skin is highly undesirable, because it is difficult to control the degree of alteration; mechanical alteration can cause pain and discomfort, and can lead to infection. Therefore, there is a need for improved methods of making biopotential measurements at the surface of the skin.
The present invention satisfies these needs by providing, for example, an improved method of delivery of therapeutic agents to a tissue; an improved method of transdermal delivery of therapeutic agents; an improved method for delivering therapeutic agents to tissue underlying nail tissue; an improved method for obtaining samples of interstitial fluid or blood for sensing of analytes within the extracted fluid, including the measurement of analytes while within the microconduit; and an improved method of making biopotential measurements.
SUMMARY OF THE INVENTION
The present invention relates to methods and devices for forming microconduits in a tissue. The invention, inter alia includes the following, alone or in combination. In one embodiment, a method for forming at least one microconduit in tissue includes the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; and scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit.
In another embodiment, a method for forming at least one opening in the stratum corneum of skin includes: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of the skin surface upon impingement of the microparticles on the skin surface; directing the microparticles towards the region of skin surface, thereby causing the microparticles to penetrate the skin; scissioning the skin with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit.
The invention also relates to a method of delivery of a therapeutic molecule or ion to tissue, the method including the steps of: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of tissue surface upon impingement of the microparticles on the tissue surface; directing the microparticles towards the region of tissue surface, thereby causing the microparticles to penetrate the tissue; scissioning the tissue with the impinging microparticles, thereby forming a plurality of free microtissue particles, and thereby forming a microconduit; and administering at least one therapeutic molecule or ion by directing the therapeutic molecule or ion into at least one microconduit, thereby delivering a therapeutic molecule or ion to tissue.
In another embodiment, a method of extracting an analyte from a tissue includes: accelerating a plurality of microparticles to a velocity that causes the microparticles to penetrate a region of a tissue surface upon impingement of the microparticles on the tissue surface; dire
Anderson R. Rox
Gift Elizabeth A.
Gonzalez Salvador
Gowrishankar T. R.
Herndon Terry O
Casler Brian L.
Massachusetts Institute of Technology
Maynard Jennifer
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