WO2001050970A1 - Perfectionnement de la surveillance de fluides interstitiels - Google Patents

Perfectionnement de la surveillance de fluides interstitiels Download PDF

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Publication number
WO2001050970A1
WO2001050970A1 PCT/US2000/000537 US0000537W WO0150970A1 WO 2001050970 A1 WO2001050970 A1 WO 2001050970A1 US 0000537 W US0000537 W US 0000537W WO 0150970 A1 WO0150970 A1 WO 0150970A1
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Prior art keywords
laser
skin
site
laser beam
interstitial fluid
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PCT/US2000/000537
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English (en)
Inventor
Kevin S. Marchitto
Stephen T. Flock
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Transmedica International, Inc.
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Application filed by Transmedica International, Inc. filed Critical Transmedica International, Inc.
Priority to PCT/US2000/000537 priority Critical patent/WO2001050970A1/fr
Priority to AU2000224980A priority patent/AU2000224980A1/en
Publication of WO2001050970A1 publication Critical patent/WO2001050970A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A61B18/203—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser applying laser energy to the outside of the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150015—Source of blood
    • A61B5/150022—Source of blood for capillary blood or interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150053—Details for enhanced collection of blood or interstitial fluid at the sample site, e.g. by applying compression, heat, vibration, ultrasound, suction or vacuum to tissue; for reduction of pain or discomfort; Skin piercing elements, e.g. blades, needles, lancets or canulas, with adjustable piercing speed
    • A61B5/150061—Means for enhancing collection
    • A61B5/150076—Means for enhancing collection by heating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150343—Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/151—Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15134—Bladeless capillary blood sampling devices, i.e. devices for perforating the skin in order to obtain a blood sample but not using a blade, needle, canula, or lancet, e.g. by laser perforation, suction or pressurized fluids
    • A61B5/15136—Bladeless capillary blood sampling devices, i.e. devices for perforating the skin in order to obtain a blood sample but not using a blade, needle, canula, or lancet, e.g. by laser perforation, suction or pressurized fluids by use of radiation, e.g. laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
    • A61B10/0045—Devices for taking samples of body liquids
    • A61B2010/008—Interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
    • A61B2017/00743—Type of operation; Specification of treatment sites
    • A61B2017/00747—Dermatology
    • A61B2017/00765—Decreasing the barrier function of skin tissue by radiated energy, e.g. using ultrasound, using laser for skin perforation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00452—Skin

Definitions

  • This invention is in the field of medical procedures, namely laser medical equipment used to perforate or alter tissue for monitoring analyte concentration in body fluids.
  • the traditional method of measuring blood glucose, or other analytes consists of taking a blood sample and then measuring the analyte concentration in the blood or plasma.
  • the blood- is typically collected from a patient utilizing mechanical perforation of the skin with a sharp device such as a metal lancet or needle.
  • This procedure has many drawbacks, including the possible infection of health care workers and the public by the sharp device used to perforate the skin, as well as the cost of handling and disposal of biologically hazardous waste.
  • a sharp device such as a metal lancet or needle
  • biological waste is created in the form of the "sharp" contaminated by the patient's blood and/or tissue.
  • blood-born agents such as human immunodeficiency virus (HIV) , hepatitis virus, or the etiological agent of any other diseases
  • HIV human immunodeficiency virus
  • hepatitis virus hepatitis virus
  • the contaminated sharp poses a serious threat to others that might come in contact with it.
  • many medical workers have contracted HIV as a result of accidental contact with a contaminated sharp.
  • concentrations of analytes in interstitial fluid can be measured for accurate representation of analyte concentration in the blood.
  • collecting interstitial fluid through the stratum corneum poses problems .
  • a number of different techniques are presently used, these include: (1) using a metal lancet to cut the skin, (2) chemical enhancers, (3) ultrasound, (4) tape stripping, and (5) iontophoresis.
  • Chemical enhancers pose the problem of potentially reacting with the analyte to be measured.
  • the time lapse after application to propagation of interstitial fluid is great. Tape stripping is unsatisfactory because of the pain to the patient. Iontophoresis and ultrasound, similarly have drawbacks in the collection time and the quantity of fluid removed.
  • the use of a metal lancet has the drawback of patient discomfort and the possibility of contamination.
  • the method would further obviate the need for disposal of contaminated sharps and eliminate the pain associated with sharp instruments.
  • the desired method would also, ideally, increase patient compliance for monitoring the desired analyte.
  • the method and apparatus disclosed herein achieves these and other goals .
  • Lasers have been used in recent years as a very efficient precise tool in a variety of surgical procedures. Among potentially new sources of laser radiation, the rare- earth elements are of major interest for medicine.
  • Er erbium
  • a YAG laser which can be configured to emit electromagnetic energy at a wavelength (2.94 microns), among other things, which is strongly absorbed by water.
  • tissue which consists mostly of water, is irradiated with radiation at or near this wavelength, energy is transferred to the tissue. If the intensity of the radiation is sufficient, rapid heating can result followed by vaporization of tissue can result. In addition, or alternatively, deposition of this energy can result in photomechanical disruption of tissue.
  • Er:YAG lasers Some medical uses of Er:YAG lasers have been described in the health-care disciplines of dentistry, gynecology and ophthalmology. See, e.g., Bogdasarov, B.V., et al . , "The Effect of Er:YAG Laser Radiation on Solid and Soft Tissues", Preprint 266, Institute of General Physics, Moscow, 1987; Bol'shakov, E.N. et al . , "Experimental Grounds for Er:YAG Laser Application to Dentistry", SPIE 1353:160-169, Lasers and Medicine (1989) (these and all other references cited herein are expressly incorporated by reference as if fully set forth in their entirety herein) .
  • the present invention employs a laser to perforate or alter the skin of a patient for removal and subsequent analysis of interstitial fluid. These measurements can then be used to approximate analyte concentrations in other body fluids, such as blood.
  • the care giver Prior to application, the care giver properly selects the wavelength, energy fluence (energy of the pulse divided by the area irradiated) , pulse temporal width and irradiation spot size so as to precisely perforate or alter the target tissue to a select depth and eliminate undesired damage to healthy proximal tissue..
  • interstitial fluid is allowed to propagate to the surface of the skin for collection and testing.
  • a laser emits a pulsed laser beam, focused to a small spot for the purpose of perforating or altering the target tissue.
  • the laser operator can control the depth, width and length of the perforation or alteration as needed, such as to avoid drawing blood into the interstitial fluid sample.
  • continuous-wave or diode lasers may be used to duplicate the effect of a pulsed laser beam. These lasers are modulated by gating their output, or, in the case of a diode laser, by fluctuating the laser excitation current. The overall effect is to achieve brief irradiation, or a series of brief irradiations, that produce the same tissue permeating effect as a pulsed laser.
  • perforation is used herein to indicate the ablation of the stratum corneum to reduce or eliminate its barrier function.
  • alteration of the stratum corneum is used herein to indicate a change in the stratum corneum which reduces or eliminates the barrier function of the stratum corneum and increases permeability without ablating, or by merely partially ablating, the stratum corneum itself.
  • a pulse or pulses of infrared laser radiation at a subablative energy of, e.g., 60 J using a TRANSMEDICATM International, Inc. ( "TRANSMEDICATM”) Er:YAG laser see U.S. Patent No. 5,643,252, Waner et al .
  • the technique may be used for transdermal drug delivery or for obtaining fluid samples from the body. Different wavelengths of laser radiation and energy levels less than or greater than 60 mJ may also produce the enhanced permeability effects without ablating the skin.
  • the mechanism for this alteration of the stratum corneum is not certain. It may involve changes in lipid or protein nature or function or be due to desiccation of the skin or mechanical alterations secondary for propagating pressure waves or cavitation bubbles .
  • topically applied drugs take through the stratum corneum is generally thought to be through cells and/or around them, as well as through hair follicles.
  • the impermeability of skin to topically applied drugs is dependent on tight cell to cell junctions, as well as the biomolecular makeup of the cell membranes and the intercellular milieu. Any changes to either the molecules that make up the cell membranes or intercellular milieu, or changes to the mechanical structural integrity of the stratum corneum and/or hair follicles can result in reduced barrier function.
  • the term "lyse” is used herein to indicate the breaking up of the epidermis layer covering a microblister.
  • the energy pulse used to accomplish this is between the energy required for ablation and sub-ablation.
  • one object of the present invention is to provide a means for perforating or altering the stratum corneum of a patient in a manner that does not result in bleeding.
  • the perforation or alteration created at the target tissue is accomplished by applying a laser beam that penetrates through the stratum corneum layer or both the stratum corneum layer and the epidermis, thereby reducing or eliminating the barrier function of the stratum corneum. This procedure allows for the subsequent removal of fluids, specifically interstitial fluid, through the skin.
  • Another object of this invention is to draw interstitial fluid through the perforation or alteration site (or allowing the interstitial to propagate on its own to the surface of the skin) .
  • the interstitial fluid can then be collected.
  • the skin tissue is perforated deep into the epidermis. After perforation, interstitial fluid is collected into an awaiting container.
  • the skin tissue is perforated deep into the epidermis. After perforation, interstitial fluid is collected into an awaiting container.
  • the skin tissue is perforated deep into the epidermis. After perforation, interstitial fluid is collected into an awaiting container.
  • the interstitial fluid is then allowed to propagate to surface. The fluid is then collected into a container unit for testing, or the fluid is left on the skin surface for subsequent testing.
  • a blister preferably a microblister
  • This vacuum can be created by a separate device, or the vacuum system can be part of the laser perforator container unit.
  • sub-atmospheric pressure a pressure of slightly less than 1 atmosphere
  • a microblister is formed, whereby the epidermis is separated from the dermis. Interstitial fluid collects in this pocket and the laser perforator is then used to lyse the blister. After lysing, the interstitial fluid that formed inside the blister is collected into a container.
  • pressure gradients in the tissue can be created.
  • pressure gradients are created using short rapid pulses of radiant energy on the tissue. This pressure gradient can be used to force substances, such as interstitial fluid, out of the body, or to transfer a substance into the body, through a perforation or alteration site.
  • pressure waves, plasma, and cavitation bubbles are created in or above the stratum corneum to increase the permeation of the compounds (e.g., pharmaceuticals) or fluid, gas or other biomolecule removal.
  • This method may simply overcome the barrier function of intact stratum corneum without significant alteration or may be used to increase permeation or collection in ablated or altered stratum corneum.
  • plasma can be produced by irradiating the surface of the target tissue, or material on the target tissue, with a pulse or pulses of electromagnetic energy from a laser. Prior to treatment, the care giver properly selects the wavelength, energy fluence (energy of the pulse divided by the area irradiated) , pulse temporal width and irradiation spot size to create the plasma while limiting undesired damage to healthy proximal tissue .
  • These technique for increasing the diffusion of fluids through the skin is not meant to limit the scope of this invention, but is merely an embodiment. Other techniques can be used, such as manual compression of the skin surrounding the perforation or alteration site, or the care giver can rely simply on the reduced barrier function of the perforation or alteration site for fluid to propagate to the skin surface .
  • a typical laser is modified to include a container unit.
  • a container unit can be added to: (1) increase the efficiency in the collection of fluids; (2) further testing of the collected sample, (3) apply a vacuum to the skin surface, (4) reduce the noise created when the laser beam perforates the patient's tissue; and (5) collect the ablated tissue.
  • the optional container unit is alternatively evacuated to expedite the collection of the released materials, such as the fluids, or to expedite the blistering of the tissue.
  • the container can also be used to collect only ablated tissue.
  • the noise created from the laser beam's interaction with the patient's skin may cause the patient anxiety.
  • the optional container unit reduces the noise intensity and therefore alleviates the patient's anxiety and stress.
  • the container unit also minimizes the risk of cross-contamination and guarantees the sterility of the collected sample.
  • the placement of the container unit in the use of this invention is unique in that it covers the tissue being irradiated, at the time of irradiation by the laser beam, and is therefore able to collect the fluid and/or ablated tissue as the perforation or alteration occurs.
  • An additional object of this invention is to allow the taking of measurements of various fluids constituents, such as glucose, collected through the perforation or alteration site.
  • Typical testing techniques include infrared spectrometry, enzymatic analysis, electro-chemical analysis and other means .
  • the testing can be incorporated into the laser perforator device or the testing can be completed on the fluid after the container unit has been removed from the device. Additionally, testing can be completed on the surface of the skin, at the perforation or ablation site, after the interstitial fluid has propagated through the target tissue.
  • An additional object of this invention is to administer pharmaceuticals after measurement of the interstitial fluid.
  • the appropriate drug dose can be delivered manually or automatically. Drug delivery can be triggered in combination with the monitoring of the desired analyte. For example, glucose measurements can be used to trigger the administration of insulin in diabetics.
  • a further object of this invention is to allow drugs to be administered continually on an outpatient basis over long periods of time. The speed and/or efficiency of drug delivery is thereby enhanced for drugs which were either slow or unable to penetrate skin.
  • a further object of this invention is to avoid the use of sharps. The absence of a contaminated sharp will eliminate the risk of accidental injury and its attendant risks to health care workers, patients, and others that may come into contact with the sharp . The absence of a sharp in turn obviates the need for disposal of biologically hazardous waste.
  • the present invention provides an ecologically sound method for removing body fluids or administering pharmaceuticals.
  • a typical laser used for this invention requires no special skills to use (for example, the TRANSMEDICATM Er:YAG laser) . It can be small, lightweight and can be used with regular or rechargeable batteries. The greater the laser's portability and ease of use, the greater the utility of this invention in a variety of settings, such as a hospital room, clinic, or home.
  • Safety features can be incorporated into the laser that require that no special safety eyewear be worn by the operator of the laser, the patient, or anyone else in the vicinity of the laser when it is being used.
  • Figure 1 shows a laser with its power source, high voltage pulse-forming network, flashlamp, lasing rod, mirrors, housing and focusing lens.
  • Figure 2 shows an optional spring-loaded interlock and optionally heated applicator.
  • Figure 3 shows an alternative means of exciting a laser rod using a diode laser.
  • Figure 4 shows an alternative focusing mechanism.
  • Figures 5A & 5B show optional beam splatters for creating multiple simultaneous irradiation.
  • Figure 8 shows an optional container unit for collecting fluids, ablated tissue, and/or other matter released from the site of irradiation, and for reducing noise resulting from the interaction between the laser and the patient's tissue.
  • Figure 9 shows a plug and plug perforation center.
  • Figure 10 shows an optional container unit for collecting ablated tissue and reducing noise resulting from the interaction between the laser and the patient's tissue.
  • Figure 11 shows a roll-on device for the delivery of pharmaceuticals.
  • Figure 12 shows an elastomeric mount for a solid state laser crystal element with optional mirrored surfaces applied to each end of the element.
  • Figure 13 shows an example of a crystal rod with matte finish around the full circumference of the entire rod.
  • Figure 14 shows an example of a crystal rod with matte finish around the full circumference of two-thirds of the rod.
  • Figure 15 shows an example of a crystal rod with matte stripes along its longitudinal axis.
  • Figure 16 shows a cross-section of a crystal laser rod element surrounded by a material having an index of refraction greater than the index of refraction of the rod.
  • Figures 17A - 17G show various examples of a container unit .
  • Figure 18 shows an atomizer for the delivery of pharmaceuticals .
  • Figure 19 shows examples of a container unit in use with a laser.
  • Figure 20 shows an example of a lens with a mask.
  • Figure 21 is a chart showing a study using corticosterone which showed enhanced permeation through skin irradiated at an energies of 77 mJ and 117 mJ.
  • Figure 22 shows the decrease in the impedance of skin using various laser pulse energies .
  • Figures 23-24 show in a permeation study of tritiated water ( 3 H 2 0) involving lased human skin at energies from 50 mJ (1.6 j/cm 2 ) to 1250 mJ (40 J/cm 2 ) .
  • Figure 25 shows histological sections of human skin irradiated at energies of 50 mJ and 80 mJ.
  • Figure 26 is a chart of a study using DNA showing enhanced permeation through skin irradiated at an energy of 150 mJ and 300 mJ.
  • Figure 27 shows laser pulse energy (J) versus water loss through human skin in vivo.
  • Figure 28 is a chart showing a DSC scan of normally hydrated (66%) human stratum corneum, and a scan of Er:YAG laser irradiated stratum corneum using a subablative pulse energy of 60 mJ.
  • Figures 29-31 are charts showing the heat of transition
  • Figures 32-33 are charts of FTIR spectra of control and lased stratum corneum.
  • Figure 34 shows Amide I band position (cm "1 ) as a function of stratum corneum treatment.
  • Figure 35 shows CH 2 vibration position (cm -1 ) as a function of stratum corneum treatment.
  • Figure 36 shows a histological section of rat skin that was irradiated at 80 mJ.
  • Figure 37 shows a histological section of human skin that was irradiated at 80 mJ.
  • Figure 38 shows in vivo blanching assay results.
  • Figure 39 shows an optional version of the collection container unit that is especially useful when the container unit includes a reagent for mixing with the sample.
  • Figure 40 shows permeation of insulin through human skin in vitro.
  • Figure 41 shows the creation of pressure waves in tissue converging to a focal point.
  • Figure 42 shows an example of a beam splitter suitable for making simultaneous irradiation sites.
  • Figure 43 shows one possible pattern of perforation or alteration sites using a beam splitter.
  • Figure 44 shows a pressure gradient created in the stratum corneum.
  • Figure 45 is a schematic of modulating the pulse repetition frequency of radiant energy from high (4 GHz) to low (4 MHz) .
  • Figure 46 shows a propagating pressure wave created in an absorbing material located on the skin.
  • Figure 47 shows a propagating pressure wave created at the skin surface with a transparent, or partially transparent, optic located on the skin.
  • Figure 48 shows a propagating pressure wave created in an absorbing material on the applied pharmaceutical .
  • Figure 49 shows a propagating pressure wave created in the applied pharmaceutical.
  • This invention provides a method for perforating or altering skin for the sampling and measurement of body fluids.
  • the invention utilizes a laser beam, specifically focused, and lasing at an appropriate wavelength, to create small perforations or alterations in the skin of a patient.
  • the laser beam has a wavelength between 0.2 and 10 microns. More preferably, the wavelength is between about 1.5 and 3.0 microns . Most preferably the wavelength is about 2.94 microns.
  • the laser beam is focused with a lens to produce an irradiation spot on the skin through the epidermis of the skin. In an additional embodiment, the laser beam is focused to create an irradiation spot only through the stratum corneum of the skin.
  • the caregiver may consider several factors in defining the laser beam, including wavelength, energy fluence, pulse temporal width and irradiation spot-size.
  • the energy fluence is in the range of 0.03- 100,000 J/cm 2 . More preferably, the energy fluence is in the range of 0.03 - 9 . 6 J/cm 2 .
  • the beam wavelength is dependent in part on the laser material, such as Er:YAG.
  • the pulse temporal width is a consequence of the pulse width produced by, for example, a bank of capacitors, the flashlamp, and the laser rod material.
  • the pulse width is optimally between 1 fs (femtosecond) and 1,000 ⁇ s .
  • the perforation or alteration produced by the laser need not be produced w th a single pulse from the laser.
  • the caregiver produces a perforation or alteration through the stratum corneum by using multiple laser pulses, each of which perforates or alters only a fraction of the target tissue thickness.
  • the pulse repetition rate from the laser should be such that complete perforation is produced in a time of less than 100 ms .
  • the orientation of the target tissue and the laser can be mechanically fixed so that changes in the target location do not occur during the longer irradiation time.
  • the laser beam is focussed precisely on the skin, creating a beam diameter at the skin in the range of approximately 0.5 microns - 5.0 cm.
  • the spot can be slit-shaped, with a width of about 0.05-0.5 mm and a length of up to 2.5 mm.
  • the width can be of any size, being controlled by the anatomy of the area irradiated and the desired permeation rate of the fluid to be removed or the pharmaceutical to be applied.
  • the focal length of the focusing lens can be of any length, but in one embodiment it is 30 mm.
  • the pulse energy by reducing the pulse energy while holding other variables constant, it is possible to change between ablative and non-ablative tissue-effect.
  • the TRANSMEDICATM Er:YAG laser which has a pulse length of about 300 ⁇ s , with a single pulse or radiant energy and irradiating a 2 mm spot on the skin, a pulse energy above approximately 100 mJ causes partial or complete ablation, while any pulse energy below approximately 100 mJ causes partial ablation or non-ablative alteration to the stratum corneum.
  • the threshold pulse energy required to enhance permeation of body fluids or for pharmaceutical delivery is reduced by a factor approximately equal to the number of pulses .
  • halving the spot area will result in halving the energy required to produce the same effect.
  • Irradiations down to 0.5 microns can be obtained, for example, by coupling the radiant output of the laser into the objective lens of a microscope objective. (e.g., as available from Nikon, Inc., Melville, NY) . In such a case, it is possible to focus the beam down to spots on the order of the limit of resolution of the microscope, which is perhaps on the order of about 0.5 microns.
  • the size of the affected irradiated area can be less than the measured beam size and can exceed the imaging resolution of the microscope.
  • This low a pulse energy is readily available from diode lasers, and can also be obtained from, for example, the Er:YAG laser by attenuating the beam by an absorbing filter, such as glass.
  • ablative and non-ablative tissue-effect By changing the wavelength of radiant energy while holding the other variables constant, it is possible to change between an ablative and non-ablative tissue-effect.
  • Ho:YAG holmium: YAG; 2.127 microns
  • Er:YAG erbium: YAG; 2.94 microns
  • Picosecond and femtosecond pulses produced by lasers can also be used to produce alteration or ablation in skin. This can be accomplished with modulated diode or related microchip lasers, which deliver single pulses with temporal widths in the 1 femtosecond to 1 ms range.
  • interstitial fluid is collected for subsequent measurement .
  • different perforation or alteration depths can be created.
  • the laser device perforates through the epidermis, allowing the interstitial fluid to propagate to the surface of the skin.
  • perforation or alteration through the stratum corneum is completed, allowing the interstitial fluid to propagate to the surface of the skin, albeit more slowly.
  • the laser perforator device is used in combination with sub-atmospheric pressure to obtain samples of interstitial fluid.
  • a vacuum By purposely applying a vacuum to the surface of the skin, it is possible to gently and reversibly separate the epidermis from the underlying dermis, thus creating a microblister in which interstitial fluid can collect.
  • the epidermis and dermis are interlocked by ridges and root like cytoplasmic microprocesses of basal cells that extend into the corresponding indentations of the dermis. This junction is further enforced by desmosomes which anchor the basal cells on the basal lamina, which is itself attached to the dermis by anchoring filaments and fibrils.
  • desmosomes which anchor the basal cells on the basal lamina, which is itself attached to the dermis by anchoring filaments and fibrils.
  • the hydrodynamic pressure of the plasma released by the superficial dermal blood vessels can lead to a lifting of the basal cells from the basal lamina thus leading to a (junctional) blister.
  • Such a blister can be induced by suction, mild heat, certain compounds or liquid nitrogen. See Dermatology in General Medicine, 3d ed., TB Fitzpatrick, AZ Eisen, K. Wolff, IM Freedberg, and KF Austen, McGraw-Hill :NY (1987), incorporated
  • One embodiment of the present invention is to form a microblister by using negative pressure (slightly less than 1 atmosphere) applied to a small area on the skin. Subsequent lysing of the blister with the laser device produces a pathway through which the interstitial fluid can be collected. The vacuum acts to enhance the volume of interstitial fluid.
  • the vacuum means for drawing a microblister is incorporated into the lasing device.
  • the vacuum means is performed by an alternative device and the laser is then used to lyse the formed microblister.
  • the vacuum is applied after ablation or alteration of the tissue, thereby propagating fluid through the lased site by negative pressure.
  • a pressure gradient is created at the ablated or altered site to force substances through the skin.
  • This technique can be used for the introduction of compounds including pharmaceuticals into the body or to remove fluids, gases or biomolecules from the body.
  • expansion due to heating
  • physical movement of tissue due to heating or non-thermal effects such as spallation
  • propagating pressure waves which can have frequencies in the acoustic (20 Hz to 20,000 Hz) or ultrasonic (>20,000 Hz) region of the pressure wave spectrum.
  • Flock et al. Proc SPIE Vol. 2395, pp.
  • a pressure gradient in tissue can be created, directed either into the body or out of the body, using pulsed laser radiant energy.
  • the pulse duration needs to be less than the time it takes for the created heat to diffuse out of the region of interest.
  • the effect is qualitatively equivalent to the effects of ultrasound on tissue.
  • the attenuation coefficient for sound propagation in tissue increases approximately linearly with frequency (see, for example, J. Havlice and J. Taenzer, "Medical Ultrasound Imaging: An Overview of Principles and Instrumentation", Proc. IEEE 67, 620-641, 1979), and is approximately 1 dB/cm/MHz (note that a 20 decibel (dB) intensity difference is equivalent to a factor of 10 in relative intensity) .
  • the thickness of the stratum corneum is about 25 microns and the epidermis is about 200 microns.
  • -corneum is 10 dB/(l dB/cm/MHz*0.0025cm) , or 4 GHz.
  • a transparent, or nearly transparent, optic 172 can be placed on the surface of the skin to contain the backward inertia of the propagating pressure wave or ablated stratum corneum.
  • the high-frequency propagating pressure waves can also be produced from a single laser pulse.
  • tissue absorbs a brief pulse of laser irradiation pressure waves with a spectrum of frequencies result . Some of these frequencies will propagate into lower layers in the skin, thus it may be possible to set up a reverse pressure gradient (more pressure below and less superficially) in order to enhance the diffusion of biomolecules out of the body effectively "pumping" them through the skin.
  • a continuous-wave laser can also be used to create pressure waves.
  • a continuous-wave laser beam modulated at 5-30 MHz can produce 0.01 - 5 W/cm 2 pressure intensities in tissue due to expansion and compression of sequentially heated tissue (for example, a Q-switched Er:YAG laser (40 ns pulse) at 10 mJ and focussed to a spot size of 0.05 cm, with a pulse repetition rate of 5-30 MHz, would produce in stratum corneum a stress of about 3750 bars, or 0.025 W/cm 2 ) . It takes a few hundred bars to cause transient permeability of cells. With this laser it requires about 0.01 W/cm 2 of continuous pressure wave energy to provide effective permeation of skin.
  • pressure waves are induced on the topically applied pharmaceutical.
  • the propagation of the wave towards the skin will carry some of the pharmaceutical with it (see, e.g., Figure 49).
  • pressure waves are induced on an absorbing material 170 placed over the topically applied pharmaceutical (see, e.g., Figure 48).
  • this material is a thin film of water, however, it can be created in any liquid, solid or gas located over the topically applied pharmaceutical.
  • the propagation of the wave towards the skin will carry some of the pharmaceutical with it .
  • pressure waves can be induced on an absorbing material 170 (preferably a thin film of water, however, it can be created in any liquid, solid or gas) placed over the target tissue, (see, e.g., Figure 46).
  • the propagation of the wave towards the skin will increase the permeability of the stratum corneum. Subsequent to the formation of these pressure waves, the desired pharmaceutical can be applied.
  • pressure gradients can be used to remove fluids, gases or other biomolecules from the body. This can be accomplished by focusing a beam of radiant energy down to a small volume at some point within the tissue. The resulting heating leads to pressure wave intensities (which are proportional to the degree of heating) that will be greater near the focal point of the radiant energy, and less near the surface. The consequence of this is a pressure gradient directed outwards thus enhancing the removal of fluids, gases or other biomolecules.
  • propagating pressure waves created at the surface of the skin can be focused to a point within the tissue.
  • pressure waves described can be created after perforation or alteration of the stratum corneum has taken place. Alternatively, pressure waves can be used as the sole means to increase the diffusive properties of compounds trough the skin or the removal of fluids, gases or other biomolecules . Creation of Cavitation Bubbles to Increase Stratum Corneum Permeability
  • Cavitation bubbles produced subsequent to the target tissues perforation or alteration, can be used to enhance the diffusive properties of a topically applied drug. While production of cavitation bubbles within the tissue is known (See, for example, R. Ensenaliev et al . , "Effect of Tensile Amplitude and Temporal Characteristics on Threshold of Cavitation-Driven Ablation," Proc. SPIE vol. 2681, pp 326- 333, (1996)), for the present invention, cavitation bubbles are produced in a material on or over the surface of the skin so that they propagate downwards (as they do because of conservation of momentum) and impact on the stratum corneum, thereby reducing the barrier function of the skin. The cavitation bubbles can be created in an absorbing material 170 located on or over the skin.
  • the cavitation bubbles are produced in a thin film of water placed on or over the skin, however, any liquid or solid material can be used. Subsequent to production of the cavitation bubbles a pharmaceutical is applied to the affected tissue.
  • cavitation bubbles are produced in the administered pharmaceutical subsequent to its application on the skin. Cavitation bubbles can also be produced in the stratum corneum itself before pharmaceutical application. In a further embodiment, the target tissue is not perforated or altered before the production of cavitation bubbles, the cavitation bubbles' impact on the stratum corneum being the only method used to increase stratum corneum permeability.
  • Plasma is a collection of ionized atoms and free electrons. It . takes an extremely strong electric field or extremely high temperature to ionize atoms, but at the focus of an intense pulsed laser beam (>approx. 10 8 - 10 10 W/cm 2 ) , such electric fields can result. Above this energy fluence rate, high enough temperatures can result. What one sees when plasma is formed is a transient bright white cloud
  • a loud cracking is usually heard when plasma is formed as a result of supersonic shock waves propagating out of the heated
  • a plasma can also be used to facilitate diffusion through the stratum corneum.
  • plasma is produced above the surface of the skin whereupon a portion of the plasma cloud will propagate outwards (and downwards) to the skin whereupon, ablation or tissue alteration will occur.
  • Plasma can be created in a liquid, solid or gas that is placed on or over the skin, into which the laser beam is focussed. If the plasma is created in a material with an acoustic impedance similar to tissue (say, a fluid) , then the resulting pressure waves would tend to transfer most of their energy to the skin.
  • the plasma "pressure wave" behaves similarly to propagating pressure waves. This is due to the fact that the acoustic impedance mismatch at the upper surface between air and solid/liquid material is high, and, furthermore, plasma, like ultrasonic energy propagates poorly in low- density (i.e. air) media.
  • plasma is produced within the stratum corneum layer. Because the energy fluence rate needed to produce the plasma is as high as approximately 10 8 W/cm 2 , selection of a wavelength with radiant energy that is strongly absorbed in tissue is not an important concern.
  • optical absorption of material to produce plasma is not an important consideration, although the energy fluence rate required to produce the plasma is less when the irradiated material strongly absorbs the incident radiant energy
  • the pulse power is 3333 W, and the spot size needs to be 0.0065 mm.
  • a small diode-pumped Q-switched laser can be used. Such lasers have pulse widths on the order of 10 ns, and, as such, the requisite spot size for producing plasma could be much larger.
  • a scanner made up of electro-optical or mechanical components
  • This area can be of arbitrary size and shape.
  • the path for the scan could be spiral or raster. If the laser is pulsed, or modulated, then it would be possible to do a discrete random pattern where the scanning optics/mechanics directs the beam to a site on the skin, the laser lases, and then the scanning optics/mechanics directs the beam to a different site (preferable not adjacent to the first spot so that the skin has time to cool before an adjacent spot is heated up) .
  • This scanning technique has been used before with copper-vapor lasers (in treating port-wine stains) and is in use with C0 2 lasers for the purpose of facial resurfacing.
  • the subepidermal blood vessels are targeted, while in the latter, about 100 microns of tissue is vaporized and melted with each laser pass.
  • Interstitial Fluid Testing Interstitial fluid contains concentrations of analytes that correlate with the concentration of analytes in other body fluids, such as blood. As such, the interstitial fluid analyte concentration can be tested to give an accurate measurement of analytes present in other body fluids.
  • One embodiment of the present invention is to perform testing on a number of analytes in the collected interstitial fluid sample to accurately measure levels of the analytes in other body fluids.
  • Interstitial fluid is, in many ways, filtered plasma, and has a similar constitution as plasma, except that some of the large proteins are filtered out by walls of the blood vessel.
  • components that can be assayed in serum can be assayed in interstitial fluid and such interstitial fluid ⁇ components may be directly correlated to serum components.
  • glucose in interstitial fluid is tested to monitor and treat blood sugar levels in diabetics .
  • the sample is tested for the specific analyte of interest, such as glucose.
  • testing can be done by infrared measurements, enzymatic analysis, or other testing protocols.
  • Sodium and potassium are usually detected with ion-specific electrodes which allow a particular ion to penetrate an electrode, whereupon a current proportional to the ion concentration is produced and detected (analogous to a pH meter) .
  • Proteins are detected in various ways, for example, enzyme linked immunoassay (ELISA) , gel electrophoresis, ultracentrifugation, radioimmunoassays, and fluorescence. These methodologies are discussed in N. Tietz, Textbook of Clinical Chemistry, W.B. Saunders Co., Philadelphia (1986).
  • testing examples are not meant to limit the scope of the invention, but are merely embodiments .
  • the testing is completed as part of the laser perforation or alteration process. Using infrared radiation, for example, testing can be conducted in the container unit attached to the laser device .
  • a section of the container unit, or the entire unit, is optionally constructed of a material that passes a predetermined light wavelength (e.g., for glucose, nylon, polyethylene or polyamide, which are partially transparent to infrared energy at 1040 nm, a wavelength absorbed by glucose, can be used) .
  • a predetermined light wavelength e.g., for glucose, nylon, polyethylene or polyamide, which are partially transparent to infrared energy at 1040 nm, a wavelength absorbed by glucose, can be used
  • a predetermined light wavelength e.g., for glucose, nylon, polyethylene or polyamide, which are partially transparent to infrared energy at 1040 nm, a wavelength absorbed by glucose, can be used
  • a predetermined light wavelength e.g., for glucose, nylon, polyethylene or polyamide, which are partially transparent to infrared energy at 1040 nm, a wavelength absorbed by glucose, can be used
  • a photosensitive diode, or other light detector is placed on the opposite side
  • the hydrogen peroxide is converted to water and a colored product. Because the intensity of the colored product is proportional to the amount of glucose, conventional absorbance or reflectance methods can be used to determine concentration. By calibrating the color to glucose concentration, the concentration of glucose can thereafter be visually approximated. Specific techniques for conducting this type of analysis can found in U.S.
  • Patent 5,458,140 issued to Eppstein et al . , incorporated herein by reference .
  • the testing analysis can be electronically processed and fed to a digital readout, or other suitable means, on the lasing device .
  • the interstitial fluid is removed from the container unit, or the fluid is collected in a separate device.
  • the above described testing methods can be conducted using separate equipment or by sending the sample to a testing laboratory.
  • testing is completed on the tissue using separate methods or devices.
  • the 1994 monitoring technique described by N. Ito et al is described by N. Ito et al .
  • a laser can be used to perforate or alter the skin through the outer surface, such as the stratum corneum layer, but not as deep as the capillary layer, to allow pharmaceuticals to be topically administered. Pharmaceuticals must penetrate the stratum corneum layer in order to be effective. Presently, compounds acting as drug carriers are used to facilitate the transdermal diffusion of some drugs . These carriers sometimes change the behavior of the drug, or are themselves toxic. With the other parameters set, the intensity of the laser pump source will determine the intensity of the laser pulse, which will in turn determine the depth of the resultant perforation or alteration. Therefore, various settings on the laser can be adjusted to allow perforation or alteration of different thickness' of stratum corneum.
  • a beam-dump can be positioned in such a way as not to impede the use of the laser for perforation or alteration of extremities.
  • the beam-dump will absorb any stray electromagnetic radiation from the beam that is not absorbed by the tissue, thus, preventing any scattered rays from causing damage.
  • the beam-dump can be designed so as to be easily removed for situations when the presence of the beam-dump would impede the placement of a body part on the applicator.
  • This method of delivering a pharmaceutical creates a very small zone in which tissue is irradiated, and only an extremely small zone of thermal necrosis .
  • a practical round irradiation site can range from 0.1 - 5.0 cm in diameter, while a slit shaped hole can range from approximately 0.05- 0.5 mm in width and up to approximately 2.5 mm in length, although other slit sizes and lengths can be used.
  • healing is quicker than or as quick as the healing after a skin puncture with a sharp implement .
  • pharmaceuticals can then be applied directly to the skin or in a pharmaceutically acceptable formulation such as a cream, ointment, lotion or patch.
  • the delivery zone can be enlarged by strategic location of the irradiation sites and by the use of multiple sites.
  • the present method can be used for transport of a variety of pharmaceuticals.
  • a region of skin may be anesthetized by first scanning the desired area with a pulsing laser such that each pulse is sufficient to cause perforation or alteration. This can be accomplished with modulated diode or related microchip lasers, which deliver single pulses with temporal widths in the 1 femtosecond to 1 ms range.
  • Anesthetic e.g., 10% lidocaine
  • a pharmaceutical is administered immediately after the analyte of interest has been measured.
  • a signal can be sent to a drug reservoir to deliver an appropriate amount of insulin.
  • Two embodiments of this invention incorporate an atomizer ( Figure 18) or a roll-on device ( Figure 11) .
  • the laser beam propagates through hole 162 incorporated in ball 164 of the roll-on device.
  • the roll-on device can be positioned adjacent to the path of the laser beam through the disposable applicator.
  • the roll-on device is rolled over the irradiated site, thereby administering the desired pharmaceutical.
  • the pharmaceutical is administered from a drug reservoir 166 through the use of compressed gas.
  • a cylinder 168 containing compressed gas such as, for example, carbon dioxide
  • an ink jet or mark is used for marking the site of irradiation.
  • the irradiated sites are often not easily visible to the eye, consequently the health care provider may not know exactly where to collect the fluid sample or to apply the pharmaceutical.
  • This invention further provides techniques to mark the skin so that the irradiation site is apparent.
  • an ink-jet analogous to those used in ink-jet printers
  • a circle can be marked around the irradiation site, or a series of lines all pointing inward to the irradiation site can be used.
  • a disposable safety-tip/applicator can be marked on the end (the end that touches up against the skin of the patient) with a pigment. Engaging the skin against the applicator prior to, during, or immediately after lasing results in a mark on the skin at the site of irradiation.
  • a beam-splitter or multiply pulsed laser can optionally be added to the laser or a rapidly pulsing laser, such as a diode or related microchip laser, may be used.
  • irradiated sites created simultaneously or sequentially, would result in an increased uptake of drugs as compared to a single irradiation site (i.e. an increase in uptake proportional to the total number of ablated sites) .
  • An example of a beam splitter 48 suitable for making simultaneous irradiation sites can be found in Figure 42. Any geometric pattern of spots can be produced on the skin using this technique. Because the diffusion of fluid out of the skin or drugs into skin can be approximated as symmetric, a beneficial pattern of irradiation spots (such that a uniform local concentration would result over as wide an area as possible) would be to position each spot equidistant from each other in a staggered matrix pattern ( Figure 43) .
  • multiple irradiation sites could be produced with use of a scanner.
  • oscillating mirrors which reflect the beam of laser radiant energy can operate as a scanner.
  • the laser is manipulated in such a way that a portion of the patient ' s skin is positioned at the site of the laser focus within the applicator.
  • a region of the skin which has less contact with hard objects or with sources of contamination is preferred, but not required. Examples are skin on the arm, leg, abdomen or back.
  • the skin heating element is activated at this time in order to reduce the laser energy required for altering or ablating the stratum corneum-.
  • a holder is provided with a hole coincident with the focal plane of the optical system.
  • a spring-loaded interlock 36 can be attached to the holder, so that when the patient applies a small amount of pressure to the interlock, to recess it to the focal point, a switch is closed and the laser will initiate a pulse of radiation.
  • the focal point of the beam is not in line with the end of the holder until that end is depressed.
  • the method of this invention may be enhanced by using a laser of a wavelength that is specifically absorbed by the skin components of interest (e.g., water, lipids or protein) which strongly affect the permeation of the skin tissues. Altering the lipids in stratum corneum may allow enhanced permeation while avoiding the higher energies that are necessary to affect the proteins and water.
  • skin components of interest e.g., water, lipids or protein
  • a dye is administered to the skin surface, either by application over intact stratum corneum, or by application over an Er:YAG laser treated site (so the that deep dye penetration can occur) , that absorbs such a wavelength of radiation.
  • indocyanine green is administered to the skin surface, either by application over intact stratum corneum, or by application over an Er:YAG laser treated site (so the that deep dye penetration can occur) , that absorbs such a wavelength of radiation.
  • ICG insulin glycosides
  • This dye when in stratum corneum, is expected to absorb the 810 nm radiant energy from a diode laser (e.g. a GaAlAs laser) thereby raising the temperature of the tissue, and subsequently leading to ablation or molecular changes resulting in reduced barrier function.
  • a diode laser e.g. a GaAlAs laser
  • 5- aminolevulinic acid is a precursor to porphyrins, which are molecules involved in hemoglobin production and behavior. Porphyrins are strong absorbers of light. Administration of 5-ALA stimulates production of porphyrins in cells, but is itself consumed in the process. Subsequently, there will be enhanced absorption of radiant energy in this tissue at wavelengths where porphyrins absorb (e.g., 400 mm or 630 mm) .
  • Another way to enhance the absorption of radiant energy in stratum corneum without the addition of an exogenous absorbing compound is to hydrate the stratum corneum by, for example, applying an occlusive barrier to the skin prior to laser irradiation.
  • the water produced within the body itself continues to diffuse through the stratum corneum and propagate out through pores in the. skin, but is prevented from evaporating by the occlusive barrier.
  • the moisture is available to further saturate the stratum corneum.
  • the laser irradiated site eventually heals as a result of infiltration of keratinocytes and keratin (which takes perhaps two weeks to complete) , or by the diffusion of serum up through the ablated sites which form a clot (or eschar) which effectively seals the ablated site.
  • topical delivery of drugs, or for multiple sequential administrations of topical drugs it would be beneficial to keep the ablated site open for an extended length of time.
  • the ablated or non-ablated site is kept open by keeping the area of irradiation moist and/or biochemically similar to stratum corneum. This is accomplished by minimizing contact of air with the ablated site and/or providing fluid to keep the ablated site moist.
  • a patch containing, for example, an ointment such as petroleum jelly or an ointment containing hydrocortisone
  • a hydrogel patch would also serve to provide the necessary moisture.
  • cytotoxic drugs such as cisplatin, bleomycin, doxorubicin, and methotrexate, for example, topically applied in low concentrations would locally prevent cellular infiltration and wound repair.
  • application of a vitamin C (ascorbic acid) or other known inhibitors of melanin production, following irradiation, would help to prevent additional skin coloration in the area, following treatment.
  • the skin is altered, not ablated, so that its structural and biochemical makeup allows fluid to diffuse to the skin surface and allows drugs to permeate .
  • the consequence of this embodiment is: (1) the skin after irradiation still presents a barrier, albeit reduced, to external factors such as viruses and chemical toxins; (2) less energy is required than is required to ablate the stratum corneum, thus smaller and cheaper lasers can be used; and (3) less tissue damage occurs, • thus resulting in more rapid and efficient healing.
  • the radiant energy emitted by lasers has the properties of being coherent, monochromatic, collimated and (typically) intense. Nevertheless, to enhance transdermal drug delivery or fluid, gas or biomolecule collection, the radiant energy used need not have these properties, or alternatively, can have one of all of these properties, but can be produced by a non-laser source
  • the pulsed light output of a pulsed xenon flashlamp can be filtered with an optical filter or other wavelength selection device, and a particular range of wavelengths can be selected out of the radiant energy output.
  • an optical filter or other wavelength selection device for example, the incoherent and quasi-monochromatic output of such a configuration cannot be focussed down to a small spot as can coherent radiant energy, for the aforementioned purpose that may not be important as it could be focused down to a spot with a diameter on the order of millimeters.
  • Such light sources can be used in a continuous wave mode if desirable.
  • the infrared output of incandescent lights is significantly more than their output in the visible, and so such light sources, if suitably filtered to eliminate undesirable energy that does not reduce barrier function, could be used for this purpose.
  • an intense incandescent light such as a halogen lamp
  • filter it with an optical filter or similar device, and used the continuous-wave radiant energy output to decrease the barrier function of stratum corneum without causing ablation. All of these sources of radiant energy can be used to produce pulses, or continuos-wave radiant energy.
  • the practice of the present invention has been found to be effectively performed by various types of lasers; for example, the TRANSMEDICATM Er:YAG laser skin perforator, or the Schwartz Electro-Optical Er:YAG laser.
  • Any pulsed laser producing energy that is strongly absorbed in tissue may be used in the practice of the present invention to produce the same result at a nonablative wavelength, pulse length, pulse energy, pulse number, and pulse rate.
  • lasers which produce energy that is not strongly absorbed by tissue may also be used, albeit less effectively, in the practice of this invention.
  • continuous-wave lasers may also be used in the practice of this invention.
  • Figures 1 and 2 are diagrammatic representations a typical laser that can be used for this invention.
  • a typical laser comprises a power connection which can be either a standard electrical supply 10, or optionally a rechargeable battery pack 12, optionally with a power interlock switch 14 for safety purposes; a high voltage pulse-forming network 16; a laser pump-cavity 18 containing a laser rod 20, preferably Er:YAG; a means for exciting the laser rod, preferably a flashlamp 22 supported within the laser pump-cavity; an optical resonator comprised of a high reflectance mirror 24 positioned posterior to the laser rod and an output coupling mirror 26 positioned anterior to the laser rod; a transmitting focusing lens 28 positioned beyond the output coupling mirror; optionally a second focusing cylindrical lens 27 positioned between the output coupling mirror and the transmitting focusing lens; an applicator 30 for positioning the subject skin at the focal point of the laser beam, which is optionally heated for example with a thermoelectric heater 32, attached to the laser housing 34; an interlock 36 positioned between the applicator and the power supply; and optionally a beam dump
  • the laser typically draws power from a standard 110 V or 220 V AC power supply 10 (single phase, 50 or 60 Hz) which is rectified and used to charge up a bank of capacitors included in the high voltage pulse-forming network 16.
  • a rechargeable battery pack 12 can be used instead.
  • the bank of capacitors establishes a high DC voltage across a high output flashlamp 22.
  • a power interlock 14 such as a key switch, can be provided which will prevent accidental charging of the capacitors and thus accidental laser excitation.
  • a further interlock can be added to the laser at the applicator, such as a spring- loaded interlock 36, so that discharge of the capacitors requires both interlocks to be enabled.
  • a voltage pulse can be superimposed on the already existing voltage across the flashlamp in order to cause the flashlamp to conduct, and, as a consequence, initiate the flash.
  • the light energy from the flashlamp is located in the laser cavity 18 that has a shape such that most of the light energy is efficiently directed to the laser rod 20, which absorbs the light energy, and, upon de-excitation, subsequently lases.
  • the laser cavity mirrors comprise coatings 124, 126, applied to ends of the crystal element and which have the desired reflectivity characteristics.
  • an Er.-YAG crystal is grown in a boule two inches in diameter and five inches long.
  • the boule is core drilled to produce a rod 5-6 millimeters in diameter and five inches long.
  • the ends of the crystal are ground and polished.
  • the output' end that is the end of the element from which the laser beam exits, is perpendicular to the center axis of the rod within 5 arc minutes.
  • the flatness of the output end is 1/10 a wavelength (2.9 microns) over 90% of the aperture.
  • the high reflectance end that is the end opposite the output end, comprises a two meter convex spherical radius.
  • the polished ends are polished so that there are an average of ten scratches and five digs per Military Specification Mil-0- 13830A.
  • Scratch and dig are subjective measurements that measure the visibility of large surface defects such as defined by U.S. military standards. Ratings consist of two numbers, the first being the visibility of scratches and the latter being the count of digs (small pits) . A #10 scratch appears identical to a 10 micron wide standard scratch while a #1 dig appears identical to a .01 mm diameter standard pit. For collimated laser beams, one normally would use optics with better than a 40-20 scratch-dig rating.
  • the coatings for the rear mirrored surface 124 should have a reflectivity of greater than 99%.
  • the coating for the output end surface should have a reflectance of between 93% and 95%, but other mirrored surfaces with reflectivity as low as 80% are useful.
  • Other vacuum deposited metallic coatings with known reflectance characteristics are widely available for use with other laser wavelengths .
  • R x and R 2 are the mirrors' reflectivities
  • a L is the total scattering losses per pass through the cavity
  • g 2 ⁇ is the gain coefficient which is the ratio of the stimulated emission cross section and population inversion density
  • ⁇ is the absorption of the radiation over one length of the laser cavity
  • L is the length of the laser cavity.
  • the crystal element may be non-rigidly mounted.
  • an elastomeric material O-ring 128 is in a slot in the laser head assembly housing 120 located at the high reflectance end of the crystal element .
  • a second elastomeric material O-ring 130 is in a second slot in the laser head assembly at the output end of the crystal element.
  • the O-rings contact the crystal element by concentrically receiving the element as shown.
  • elastomeric material of any shape may be used so long as it provides elastomeric support for the element (directly or indirectly) and thereby permits thermal expansion of the element.
  • the flash lamp 22 may also be non-rigidly mounted.
  • Figure 12 shows elastomeric O- rings 134, 136, each in its own slot within the laser head assembly housing.
  • the O-rings 134 and 136 concentrically receive the flash lamp.
  • the flash lamp may be supported by elastomeric material of other shapes, including shapes without openings.
  • a diode laser 42 that produces a pump-beam collinear with the long-axis of the laser crystal can be used instead of the flashlamp to excite the crystal.
  • the pump-beam of this laser is collimated with a collimating lens 44, and transmitted to the primary laser rod through the high reflectance infrared mirror 45.
  • This high reflectance mirror allows the diode pump laser beam to be transmitted, while reflecting infrared light from the primary laser.
  • the Er:YAG lasing material is the preferred material for the laser rod because the wavelength of the electromagnetic energy emitted by this laser, 2.94 microns, is very near one of the peak absorption wavelengths (approximately 3 microns) of water. Thus, this wavelength is strongly absorbed by water and tissue. The rapid heating of water and tissue causes perforation or alteration of the skin.
  • useful lasing material is any material which, when induced to lase, emits a wavelength that is strongly absorbed by tissue, such as through absorption by water, nucleic acids, proteins or lipids and consequently causes the required perforation or alteration of the skin (although strong absorption is not required) .
  • a laser can effectively cut or alter tissue to create the desired perforations or alterations where tissue exhibits an absorption coefficient of 10-10,000 cm "1 .
  • Examples of useful lasing elements are pulsed C0 2 lasers, Ho:YAG (holmium:YAG) , Er:YAP, Er/Cr:YSGG
  • Trn-.YAG (erbium: gadolinium, gallium, scandium, garnet) , Er.-YLF (erbium: yttrium, lithium, fluoride; 2.8 microns), Trn-.YAG
  • Solid state lasers including but not limited to those listed above, may employ a polished barrel crystal rod.
  • the rod surface may also contain a matte finish as shown in Figure 13.
  • both of these configurations can result in halo rays which surround the central output beam.
  • an all-matte finish although capable of diminishing halo rays relative to a polished rod, will cause a relatively large decrease in the overall laser energy output.
  • the matte finish can be present on bands of various lengths along the rod, each band extending around the entire circumference of the rod.
  • the matte finish may be present in bands along only part of the rod's circumference.
  • Figure 14 shows a laser crystal element in which the matte finish is present upon the full circumference of the element along two-thirds of its length.
  • matte stripes may be present longitudinally along the full length of the rod.
  • the longitudinal stripes may alternatively exist along only part of the length of the rod, such as in stripes of various lengths.
  • a combination of the foregoing techniques may be used to affect beam shape.
  • Other variations of patterns may also be employed in light of the beam shape desired. The specific pattern may be determined based on the starting configuration of the beam from a 100% polished element in light of the desired final beam shape and energy level.
  • a complete matte finish element may also be used as the starting reference point.
  • any surface finish of greater than 30 microinches is considered matte.
  • a microinch equals one millionth (0.000001) inch, which is a common unit of measurement employed in establishing standard roughness unit values.
  • the degree of roughness is calculated using the root-mean-square average of the distances in microinches above or below the mean reference line, by taking the square root of the mean of the sum of the squares of these distances.
  • matte surfaces of greater than 500 microinches may be used to affect beam shape, such a finish will seriously reduce the amount of light energy that enters the crystal rod, thereby reducing the laser's energy.
  • a matte area of approximately 50 microinches is present around the full circumference of an Er:YAG laser rod for two-thirds the length of the rod.
  • the non-matte areas of the rod are less than 10 microinches.
  • a baseline test of the non-matte rod can be first conducted to determine the baseline beam shape and energy of the rod.
  • the matte areas are then obtained by roughing the polished crystal laser rod, such as with a diamond hone or grit blaster.
  • the specific pattern of matte can be determined with respect to the desired beam • shape and required beam energy level. This results in a greatly reduced beam halo.
  • the rod may also be developed by core drilling a boule of crystal so that it leaves an overall matte finish and then polishing the desired areas, or by refining a partially matte, partially polished boule to achieve the desired pattern.
  • the beam shape of a crystal laser rod element may alternatively be modified as in Figure 16 by surrounding the rod 20 in a material 160 which is transparent to the exciting light but has an index of refraction greater than the rod. Such a modification can reduce the halo of the beam by increasing the escape probability of off-axis photons within the crystal. This procedure may be used in place of or in addition to the foregoing matte procedure.
  • the emitted laser beam is focused down to a millimeter or submillimeter sized spot with the use of the focusing lens 28.
  • a short focal length focusing lens be used to ensure that the energy fluence rate (W/cm 2 ) is low except at the focus of the lens where the tissue sample to be perforated or altered is positioned. Consequently, the hazard of the laser beam is minimized.
  • the beam can be focused so that it is narrower along one axis than the other in order to produce a slit-shaped perforation or alteration through the use of a cylindrical focusing lens 27.
  • This lens which focuses the beam along one axis, is placed in series with the transmitting focusing lens 28.
  • the beam can be broadened, for instance through the use of a concave diverging lens 46 ( Figure 4) prior to focusing through the focusing lens 28.
  • This broadening of the beam results in a laser beam with an even lower energy fluence rate a short distance beyond the focal point, consequently reducing the hazard level.
  • this optical arrangement reduces the optical aberrations in the laser spot at the treatment position, consequently resulting in a more precise perforation or alteration.
  • the beam can be split by means of a beam-splitter to create multiple beams capable of perforating or altering several sites simultaneously or near simultaneously.
  • Figure 5 provides two variations of useful beam splitters.
  • multiple beam splitters 48 such as partially silvered mirrors, dichroic mirrors, or beam-splitting prisms can be provided after the 'beam is focused.
  • an acousto-optic modulator 52 can be supplied with modulated high voltage to drive the modulator 52 and bend the beam. This modulator is outside the laser cavity. It functions by deflecting the laser beam sequentially and rapidly at a variety of angles to simulate the production of multiple beams.
  • the unit discharges once per 20-30 seconds. This can be increased by adding a battery and capacitor and cooling system to obtain a quicker cycle. Multiple capacitors can be strung together to get the discharge rate down to once every 5 or 10 seconds (sequentially charging the capacitor banks) . Thus, getting a higher repetition rate than with a single capacitor.
  • the TRANSMEDICATM Er:YAG laser incorporates a flashlamp, the output of which is initiated by a high-voltage pulse of electricity produced by a charged capacitor bank. Due to the high voltages required to excite the flashlamp, and because the referred to version of the laser incorporates dry cells to run (thus the charging current is much less than a wall-plug could provide) , then the capacitors take about 20 seconds to sufficiently charge. Thus, if a pulse repetition rate of 1 pulse / 20 seconds is desirable, it would be suitable to have multiple capacitor banks that charge sequentially (i.e. as one bank fires the flashlamp, another bank, which has been recharging, fires, and- so on) . Thus, the pulse repetition rate is limited only be the number of capacitor banks incorporated into the device (and is also limited by the efficiency of waste-heat removal from the laser cavity) .
  • a small heater such as a thermoelectric heater 32, is optionally positioned at the end of the laser applicator proximal to the site of perforation.
  • the heater raises the temperature of the tissue to be perforated or altered prior to laser irradiation. This increases the volume of fluid collected when the device is used for that purpose.
  • a suggested range for skin temperature is between 36 °C and 45 °C, although any temperature which causes vasodilation and the resulting increase in blood flow without altering the blood chemistry is appropriate.
  • a container unit 68 is optionally fitted' into the laser housing and is positioned proximal to the site of irradiation.
  • the container unit reduces the intensity of the sound produced when the laser beam perforates the patient's tissue, increases the efficiency of interstitial fluid collection, and collects the ablated tissue and other matter released by irradiation.
  • the container unit is shaped so as to allow easy insertion into the laser housing and to provide a friction fit within the laser housing.
  • Figure 8 shows the container unit inserted into the laser housing and placed over the site of irradiation.
  • the container unit 68 comprises a main receptacle 82, including a lens 84.
  • the main receptacle collects the interstitial fluid sample, the ablated tissue, and/or other matter released by irradiation.
  • the lens is placed such that the laser beam may pass through the lens to the site of irradiation but so that the matter released by irradiation does not splatter back onto the applicator.
  • the container unit also optionally includes a base 86, attached to the receptacle.
  • the base can optionally be formed so at to be capable of being inserted into the applicator to disengage a safety mechanism of the device, thereby allowing the laser beam to be emitted.
  • the shape and size of the container unit 68 are such as to allow placement next to or insertion into the applicator, and to allow collection of the interstitial fluid sample, ablated tissue, and/or other matter released by irradiation.
  • Examples of shapes that the main receptacle may take include cylinders, bullet shapes, cones, polygons and free form shapes.
  • the container unit has a main receptacle, with a volume of around 1-2 milliliters. However, larger and smaller receptacles will also work.
  • the lens 84 which allows the laser beam to pass through while preventing biological and other matter from splattering back onto the applicator, is at least partially transparent.
  • the lens is constructed of a laser light- transmitting material and is positioned in the pathway of the laser beam, at the end of the container unit proximal to the beam.
  • the transmitting material is quartz, but other examples of suitable infrared materials include rock salt, germanium, and polyethylene.
  • the lens may optionally include a mask of non- transmitting material 85 such that the lens may shape the portion of the beam that is transmitted to the site of irradiation.
  • the main receptacle 82 is formed by the lens and a wall 88, preferably extending essentially away from the perimeter of the lens.
  • the open end of the main receptacle or rim 90 is placed adjacent to the site of irradiation.
  • the area defined by the lens, wall of the main receptacle and the site of irradiation is thereby substantially enclosed during the operation of the laser perforator device.
  • the base 86 is the part of the container unit that can optionally be inserted into the applicator.
  • the base may comprise a cylinder, a plurality of prongs or other structure.
  • the base may optionally have threading.
  • the base when fully inserted, disengages a safety mechanism of the laser perforator device, allowing the emission of the laser beam.
  • the container unit may also include an additional vessel 92 which collects a portion of the matter released as part of irradiation.
  • this vessel can collect interstitial fluid and/or other liquid or particulate matter, while the main receptacle 82 collects the ablated tissue.
  • the interstitial fluid and/or other liquid or particulate matter may be channeled into the vessel through a capillary tube 94 or other tubing which extends from the main receptacle into the vessel .
  • the vessel is optionally detachable.
  • the main receptacle may have a hole 95 in the wall through which the capillary tube or other tubing may be securely inserted.
  • the vessel may have a removable stop 96 which sufficiently covers the open end of the vessel to prevent contamination with undesired material, but has an opening large enough for the capillary tube or other tubing to be inserted.
  • the capillary tube or other tubing will extend outwardly from the main receptacle ' s wall and into the vessel through the removable stop.
  • the stop may optionally be removed and discarded.
  • the vessel may then optionally be sealed with a cap 98 to prevent spillage.
  • the vessel is preferably bullet shaped.
  • the container unit comprises a cylindrical main receptacle 82, a cylindrical base 86, and an at least partially transparent circular lens 84 in the area between the main receptacle and base.
  • the lens may include a mask which shapes the beam that perforates the tissue .
  • the container unit is constructed of glass or plastic. The container unit is optionally disposable.
  • the container unit comprises the elements of the first embodiment and also includes an additional vessel 92 and a capillary tube 94 extending outwardly from the main receptacle's wall 88 and into the vessel through a removable stop 96.
  • the vessel may optionally have a cap 98 to seal the opening so as to prevent spillage.
  • the container unit is constructed of glass or plastic.
  • the container unit, including the capillary tube and the additional vessel, are optionally disposable.
  • Figure 19 shows examples of the use of the container unit with the laser perforator device .
  • the applicator 30 is surrounded by the housing 34.
  • the container unit is inserted in the applicator 30 and aligned so as to be capable of defeating the interlock 36.
  • the base 86 of the container unit in this embodiment is within the applicator 30, while the rim 90 of the receptacle 82 is located adjacent to the tissue to be perforated.
  • the beam passes through the lens 84.
  • the container unit is evacuated.
  • the optional vacuum in the container unit exerts a less than interstitial fluid or pressure of gases in the blood over the site of irradiation, thereby increasing the efficiency of interstitial fluid collection.
  • the container unit's end proximal to the site of irradiation is optionally sealed air-tight with a plug 70.
  • the plug is constructed of material of suitable flexibility to conform to the contours of the site of irradiation (e.g., the finger). The desired site of irradiation is firmly pressed against the plug.
  • the plug ' s material is impermeable to gas transfer .
  • the plug's material is thin enough to permit perforation of the material as well as irradiation of the skin by the laser.
  • the plug is constructed of rubber.
  • the plug perforation center 74 is preferably constructed of a thin rubber material .
  • the thickness of the plug is such that the plug can maintain the vacuum prior to perforation, and the laser can perforate the plug and irradiate the tissue adjacent to the plug.
  • the plug should be in the range of approximately 100 to 500 microns thick, but at the most 1 millimeter thick.
  • the plug perforation center 74 is large enough to cover the site of irradiation.
  • the perforated site is a round hole with an approximate diameter ranging from 0.1-1 mm, or slit shaped with an approximate width of 0.05-0.5 mm and an approximate length up to 2.5 mm.
  • the plug perforation center is sufficiently large to cover irradiation sites of these sizes.
  • the site of irradiation is firmly pressed against the rubber material.
  • an annular ring of adhesive can be placed on the rubber plug to provide an air-tight seal between the site of irradiation and the container unit.
  • the perforation site on the plug is stretched when the tissue is pressed against the plug.
  • the container unit 68 includes a hole 76 through which the laser passes.
  • the container unit optionally solely collects ablated tissue.
  • the site of irradiation is firmly pressed against the container unit .
  • the container unit can optionally include a plug proximal to the site of irradiation, however it is not essential because there is no need to maintain a vacuum in this embodiment. All embodiments of the container unit reduce the noise created from interaction between the laser beam and the patient's tissue and thus alleviate the patient's anxiety and stress.
  • the container may also be modified to hold, or receive through an opening, a pharmaceutical or other substance, which may then be delivered shortly after testing of interstitial fluid.
  • Figure 11 shows an example of a container with a built-in drug reservoir and roll-on apparatus for delivery.
  • Figure 18 shows a container with an applicator which in turn comprises an atomizer with attached high pressure gas cylinder.
  • the container unit is disposable, so that the container unit and plug can be discarded after use .
  • the main receptacle of the container unit, capillary tube and/or additional vessel can contain reagents for various tests to be performed on the collected interstitial fluid, such as the glucose oxidase test described above.
  • the reagents are positioned so that they will not be in the pathway of the laser light.
  • the reagents are preferably present in a dry form, coating the interior walls of the collection part of the container unit, and thus readily available for interaction with the interstitial fluid sample as it is collected.
  • FIG 39 A preferable configuration for the container unit when it contains a regent is shown in Figure 39.
  • the container unit has an indentation 78 at the base such that any fluid reagent present in the container unit will not fall into the line of fire of the laser beam when the container unit is held either vertically or horizontally.
  • the apex 80 of the indented are is made of an infrared-transparent substance, such as quartz, or a near transparent substance .
  • reagents are present in the container unit prior to collection of the interstitial fluid sample, it is beneficial to label the container unit in some manner as to the reagents contained inside, or as to the test to be performed on the sample using those reagents .
  • a preferred method for such labelling is through the use of color-coded plugs. For example, a blue plug might indicate the presence of reagent A, while a red plug might indicate the presence of reagents B plus C within the container unit.
  • a modulated laser can be used to duplicate a pulsed laser for the purpose of enhancing topical drug delivery, as well as enhancing the removal of fluids. This is accomplished by chopping the output of the continuous-wave laser by either modulating the laser output mechanically, optically or by other means such as a saturable absorber. (See, e.g., Jeff Hecht, The Laser Guidebook, McGraw-Hill :NY, 1992) .
  • continuous-wave lasers include C0 2 , which lases over a range between 9-11 microns (e.g.
  • the chopping of the laser output will preferably result in discrete moments of irradiation with temporal widths from a few tenths of milliseconds, down to nanoseconds or picoseconds.
  • the lasing process can be modulated by modulating the laser excitation current .
  • a modulator for a laser diode power supply can be purchased from SDL Inc., San Jose, CA.
  • the continuous-wave beam can be optically modulated using, for example, an electro-optic cell (e.g. from New Focus Inc., Santa Clara, CA) or with a scanning mirror from General Scanning, Inc., Watertown MA.
  • diode lasers The additive effect of multiple perforations or alterations may be exploited with diode lasers.
  • Laser diodes supplied by SDL Corporation (San Jose, CA) transmit a continuous beam of from 1.8 to 1.96 micron wavelength radiant energy. These diodes operate at up to 500 mW output power and may be coupled to cumulatively produce higher energies useful for stratum corneum ablation.
  • one diode bar may contain ten such diodes coupled to produce pulsed energy of 5 J per millisecond. It has been shown that an ablative effect may be seen with as little as 25 mJ of energy delivered to a 1 mm diameter spot. Five (5) millisecond pulses or (25) one millisecond pulses from a diode laser of this type will thus have an ablative effect approximately equivalent to one 25 mJ pulse in the same time period.
  • the laser comprises a flashlamp (PSC Lamps, Webster, NY) , an Er:YAG crystal (Union Carbide Crystal Products, Washagoul, WA) , optical-resonator mirrors (CVI Laser Corp., Albuquerque, NM) , an infrared transmitting lens (Esco Products Inc., Oak Ridge, NJ) , as well as numerous standard electrical components such as capacitors, resistors, inductors, transistors, diodes, silicon-controlled rectifiers, fuses and switches, which can be purchased from any electrical component supply firm, such as > Newark Electronics, Little Rock, AR.
  • Example 2 An infrared laser radiation pulse was formed using a solid state, pulsed, Er:YAG laser consisting of two flat resonator mirrors, an Er:YAG crystal as an active medium, a power supply, and a means of focusing the laser beam.
  • the wavelength of the laser beam was 2.94 microns . Single pulses were used.
  • the operating parameters were as follows: The energy per pulse was 40, 80 or 120 mJ, with the size of the beam at the focal point being 2 mm, creating an energy fluence of 1.27, 2.55 or 3.82 J/cm 2 .
  • the pulse temporal width was 300 ⁇ s, creating an energy fluence rate of 0.42, 0.85 or 1.27 x 10 4 W/cm 2 .
  • Transepidermal water loss (TEWL) measurements were taken of the volar aspect of the forearms of human volunteers. Subsequently the forearms were positioned at the focal point of the laser, and the laser was discharged. Subsequent TEWL measurements were collected from the irradiation sites, and from these the measurements of unirradiated controls were subtracted. The results (shown in Figure 27) show that at pulse energies of 40, 80 and 120 mJ, the barrier function of the stratum corneum was reduced and the resulting water loss was measured to be 131, 892 and
  • Example 3 An infrared laser radiation pulse was formed using a solid state, pulsed, Er:YAG laser consisting of two flat resonator mirrors, an Er:YAG crystal as an active medium, a power supply, and a means of focusing the laser beam.
  • the wavelength of the laser beam was 2.94 microns .
  • a single pulse was used.
  • the operating parameters were as follows :
  • the energy per pulse was 60 mJ, with the size of the beam at the focal point being 2 mm, creating an energy fluence of 1.91 J/cm 2 .
  • the pulse temporal width was 300 ⁇ s, creating an energy fluence rate of 0.64 x 10 4 W/cm 2 .
  • the volar aspect of the forearm of a volunteer was placed at the focal point of the laser, and the laser was discharged. After discharge of the laser, the ablated site was topically administered a 30% liquid lidocaine solution for two minutes. A 26G-0.5 needle was subsequently inserted into the laser ablated site with no observable pain. Additionally, after a 6 minute anesthetic treatment, a 22G-1 needle was fully inserted into the laser ablated site with no observable pain. The volunteer experienced no irritation and did not require medical treatment.
  • Ablation threshold energy Normally hydrated (66%) stratum corneum was sandwiched between two microscope cover slides, and exposed to a single pulse of irradiation from the Er:YAG laser. Evidence of ablation was determined by holding the sample up to a light and seeing whether any stratum corneum was left at the irradiated site. From this experiment, it was determined that the irradiation threshold energy (for a 2 mm irradiation spot) was approximately 90- 120 mJ. The threshold will likely be higher when the stratum corneum is still overlying epidermis, as in normal skin, since it takes energy to remove the stratum corneum from the epidermis, to which it is adherent.
  • Example 5 Differential Scanning Calori etry (DSQ: Figure 28 shows a DSC scan of normally hydrated (66k) human stratum corneum, and a scan of stratum corneum irradiated with the Er:YAG laser using a subablative pulse energy of 60 mJ. Defining the thermal transition peaks at approximately 65, 80 and 92°C, we determined the heat of transition ( ⁇ J) , center of the transition (°C) and the full-width at half-maximum of the transition (°C) ( Figures 29-31).
  • results shown are on normal 66% hydrated stratum corneum, dehydrated 33% stratum corneum, steam heated stratum corneum, Er:YAG laser irradiated stratum corneum, or stratum corneum that was immersed in c loroform-methanol (a lipid solvent) , or beta- mercaptoethanol (a protein denaturant) .
  • the effect of laser irradiation on stratum corneum is consistent (depending on which transition you look at, 1, 2 or 3) with changes seen due to thermal damage (i.e. heated with steam), and de- lipidization.
  • FTIR spectroscopy was used to study stratum corneum treated the same way as in the above DSC experiments, except the energy used was between 53 and 76 J.
  • the spectra show that absorption bands that are due to water, proteins and lipids change when the stratum corneum is irradiated. Some of these changes are consistent with changes seen during non-laser treatment of the stratum corneum (e.g. desiccation, thermal damage, lipid solubilization, or protein denaturation) .
  • the Amide I and II bands which are due to the presence of proteins (most likely keratin, which makes up the bulk of protein in stratum corneum) shift to a larger wavenumber, consistent with the effect of desiccation alone (in the case of Amide II) or desiccation and beta-mercaptoethanol treatment (in the case of Amide I) (see, e.g., Figure 34).
  • the CH 2 vibrations due to bonds in lipids
  • FIG. 36 shows rat skin irradiated at 80 mJ, which is an energy sufficient to make the skin permeable (to lidocaine, for instance) and yet does not show any sign of stratum corneum ablation.
  • Figure 37 depicts human skin 24 hours after being irradiated at 80 mJ.
  • Pieces of human skin were placed in diffusion cells and irradiated with a single pulse of radiant energy produced by an Er:YAG laser. The spot size was 2 mm and the energy of the pulse was measured with a calibrated energy meter. After irradiation, the diffusion cells were placed in a 37 degrees Celsius heating block. Phosphate buffered saline was added to the receptor chamber below the skin and a small stir bar was inserted in the receptor chamber to keep the fluid continually mixed. Control skin was left unirradiated. Small volumes of radiolabelled compounds
  • Example 11 The output of the Er:YAG laser was passed through an aperture to define it's diameter as 2 mm.
  • Human skin purchased from a skin bank, was positioned in Franz diffusion cells. The receptor chamber of the cell was filled with 0.9% buffered saline. A single pulse, of measured energy, was used to irradiate the skin in separate diffusion cells. Control skin was left unirradiated. In the case of insulin, a 274 mJ pulse was used, and multiple samples were irradiated. After irradiation, a stirring magnet was place in the receptor chamber of the diffusion cells and the cells were placed in a heating block held at 37 °C.
  • the radiolabelled insulin was diluted in buffered saline, and 100 ⁇ L of the resulting solutions was placed in the donor chamber of separate diffusion cells. The donor was left on the skin for the duration of the experiment.
  • samples were taken from the receptor chamber and the amount of drug present was assayed with either a gamma-counter, or a liquid scintillation counter.
  • a graph of the resulting data is shown in Figure 40. From this, and similar data, the permeability constant (K p ) for insulin was derived to be 11.3 ⁇ 0.93 (x 10 "3 cm/hr) .
  • Diprolene ⁇ -methasone
  • ⁇ -methasone Diprolene
  • An occlusive patch consisting of simple plastic wrap, was fixed with gauze and dermatological tape over all sites on both arms and left in place for two hours, after which the administered steroids were gently removed with cotton swabs. Colorimeter measurements were then taken over every unirradiated and irradiated spot at 2, 4, 8, 10, 12 and 26 hours post- irradiation, these results are shown in Figure 38. Finally, the skin was clinically assessed for evidence of irritation at the 26 hour evaluation.
  • the radiant output of the Er:YAG laser is focussed and collimated with optics to produce a spot size at the surface of the skin of, for example, 5 mm.
  • the skin of the patient being the site of, or close to the site of, disease, is visually examined for anything that might affect the pharmacokinetics of the soon to be administered drug (e.g., significant erythema or a wide-spread loss of the integrity of the stratum corneum) .
  • This site which is to be the site of irradiation, is gently cleansed to remove all debris and any extraneous compounds such as perfume or a buildup of body oils.
  • a disposable tip attached to the laser pressed up to the skin prior to irradiation is used to contain any ablated biological debris, as well as to contain any errant radiant energy produced by the laser.
  • a single laser pulse (approximately 350 ⁇ s long) , with an energy of 950 mJ, is used to irradiate the spot. The result is a reduction or elimination of the barrier function of the stratum corneum.
  • an amount of pharmaceutical, hydrocortisone for example is spread over the irradiation site.
  • the pharmaceutical may be in the form of an ointment so that it remains on the site of irradiation.
  • an occlusive patch is placed over the drug in order to keep it in place over the irradiation site.

Abstract

La présente invention concerne un perfectionnement apporté à un procédé de mesure d'analysats dans des fluides anatomiques sans utiliser d'aiguille. A cet effet, on expose la peau du patient au rayonnement électromagnétique impulsionnel focalisé d'un laser. En choisissant correctement la longueur d'ondes, la fluence, la largeur temporelle, et la taille de la fenêtre exposée, le rayonnement pénètre à une profondeur déterminée avec précision sans provoquer de lésions aux parties saines de la peau. Après l'exposition au rayonnement, on recueille le fluide interstitiel dans un récipient ou on le laisse sur la peau. Il ne reste plus qu'à rechercher dans le fluide interstitiel l'analysat considéré de façon à obtenir une teneur approchée de l'analysat dans d'autres fluides anatomiques. Une autre procédure consiste à lyser l'épiderme couvrant cloques ainsi provoquées, puis à recueillir et analyser le fluide interstitiel.
PCT/US2000/000537 2000-01-10 2000-01-10 Perfectionnement de la surveillance de fluides interstitiels WO2001050970A1 (fr)

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AU2000224980A AU2000224980A1 (en) 2000-01-10 2000-01-10 Improved interstitial fluid monitoring

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014204646A1 (fr) * 2013-06-19 2014-12-24 Zoll Medical Corporation Analyse de la coloration de la peau

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Publication number Priority date Publication date Assignee Title
US5165418A (en) * 1992-03-02 1992-11-24 Tankovich Nikola I Blood sampling device and method using a laser
US5458140A (en) 1993-11-15 1995-10-17 Non-Invasive Monitoring Company (Nimco) Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers
US5582184A (en) 1993-10-13 1996-12-10 Integ Incorporated Interstitial fluid collection and constituent measurement
US5586981A (en) 1994-08-25 1996-12-24 Xin-Hua Hu Treatment of cutaneous vascular and pigmented lesions
US5643252A (en) 1992-10-28 1997-07-01 Venisect, Inc. Laser perforator
WO1998042267A1 (fr) * 1997-03-25 1998-10-01 Abbott Laboratories Ablation de la couche cornee au moyen d'une source de lumiere

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5165418A (en) * 1992-03-02 1992-11-24 Tankovich Nikola I Blood sampling device and method using a laser
US5165418B1 (en) * 1992-03-02 1999-12-14 Nikola I Tankovich Blood sampling device and method using a laser
US5643252A (en) 1992-10-28 1997-07-01 Venisect, Inc. Laser perforator
US5582184A (en) 1993-10-13 1996-12-10 Integ Incorporated Interstitial fluid collection and constituent measurement
US5458140A (en) 1993-11-15 1995-10-17 Non-Invasive Monitoring Company (Nimco) Enhancement of transdermal monitoring applications with ultrasound and chemical enhancers
US5586981A (en) 1994-08-25 1996-12-24 Xin-Hua Hu Treatment of cutaneous vascular and pigmented lesions
WO1998042267A1 (fr) * 1997-03-25 1998-10-01 Abbott Laboratories Ablation de la couche cornee au moyen d'une source de lumiere

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014204646A1 (fr) * 2013-06-19 2014-12-24 Zoll Medical Corporation Analyse de la coloration de la peau
US10799149B2 (en) 2013-06-19 2020-10-13 Zoll Medical Corporation Analysis of skin coloration

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