WO2002026148A1 - Permeation et prelevement ameliores par irradiation - Google Patents

Permeation et prelevement ameliores par irradiation Download PDF

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Publication number
WO2002026148A1
WO2002026148A1 PCT/US2000/026218 US0026218W WO0226148A1 WO 2002026148 A1 WO2002026148 A1 WO 2002026148A1 US 0026218 W US0026218 W US 0026218W WO 0226148 A1 WO0226148 A1 WO 0226148A1
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laser
skin
energy
substance
site
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PCT/US2000/026218
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English (en)
Inventor
Kevin S. Marchitto
Stephen T. Flock
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Transmedica International, Inc.
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Priority to AU2000276114A priority Critical patent/AU2000276114A1/en
Priority to PCT/US2000/026218 priority patent/WO2002026148A1/fr
Publication of WO2002026148A1 publication Critical patent/WO2002026148A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/41—Detecting, measuring or recording for evaluating the immune or lymphatic systems
    • A61B5/411—Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
    • 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
    • A61B5/14507—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 specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—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 specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—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 specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • 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
    • A61B5/151—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
    • 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
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/20—Applying electric currents by contact electrodes continuous direct currents
    • A61N1/30—Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
    • 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, procedures facilitated primarily by laser medical equipment used in the delivery of pharmaceuticals or the removal of biomolecules, fluids or gases.
  • the traditional method for the collection of small quantities of fluids or gases from a patient utilizes mechanical perforation of the skin with a sharp device such as a metal lancet or needle. Additionally, the typical method of administering local anesthetic is through the use of a needle. These procedures have many drawbacks, two of which are the possible infection of health-care workers or the public at large with the device used to perforate the skin, and the costly 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" which is contaminated by the patient's blood and/or tissue.
  • HIN human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • hepatitis virus hepatitis virus
  • etiological agent of other diseases the contaminated sharp can pose a serious threat to others who come in contact with it.
  • HIN infection There are many documented instances of HIN infection of medical workers who were accidentally stabbed by a contaminated sharp.
  • Disposal of sharps is also a major problem. Disposal of contaminated materials poses both a logistic and a financial burden on the end user such as the medical institution. In the 1980s, numerous instances of improperly disposed biological wastes being washed up on public beaches occurred. The potential for others, such as intravenous drug users, to obtain improperly disposed needles is also problematic.
  • the current technology for applying pharmaceutical substances without the use of needles typically involves: (a) drug mixtures in creams, lotions or gels; (b) iontophoresis; (c) carriers or vehicles which are compounds that alter the chemical properties of either the stratum corneum or the pharmaceutical; (d) sonophoresis which involves altering the barrier function of stratum corneum by ultrasound; or (e) drug patches which attach to the skin to effect transdermal administration.
  • lidocaine is commonly used as a local anesthetic, especially in pediatric patients, but requires a cream to be applied for up to 60 minutes, and anesthesia is produced to a depth of only about 4 mm. The lack of penetration is a consequence of the barrier function of the stratum corneum.
  • Inherent problems with iontophoresis include the complexity of the delivery system, cost, and unknown toxicology of prolonged exposure to electrical current. Additionally, the use of carriers or vehicles involves the use of an additional compound which might alter the pharmacokinetics of the pharmaceutical of interest. Finally, most patch applications are insufficient because many drugs do not easily traverse the stratum corneum.
  • Erbium: YAG Erbium: YAG (E ⁇ YAG) laser which can be configured to emit electromagnetic energy at a wavelength (2.94 microns) which is strongly absorbed by water.
  • tissue which consists mostly of water, is irradiated with radiation at of near this wavelength, it is rapidly heated. If the intensity of the radiation is sufficient, the heating is rapid enough to cause the vaporization of tissue.
  • E ⁇ YAG lasers along, with other solid state lasers often employ a polished barrel crystal element such as a polished rod.
  • a laser built with such a polished element maximizes the laser's energy output.
  • Other lasers employ an entirely frosted element, normally with matte of about 50-55 microinch.
  • the energy output is typically separated into a central output beam surrounded by halo rays, or has an otherwise undesirable mode. Since it is extremely difficult to focus halo rays to a specific spot, the laser output may be unacceptable for specific applications.
  • Solid state lasers also typically employ two optic elements in connection with the crystal element.
  • the optic elements consist of the rear (high reflectance) mirror and the front partial reflectance mirror, also know as an output coupler.
  • the crystal element and the optic elements are rigidly mounted in order to preserve the alignment between them.
  • changes in temperature such as that caused by expansion of the crystal rod during flash lamp exposure, also cause shifts in alignment between the mirrors and the crystal.
  • the misalignment of the mirrors and the crystal element results in laser output energy loss.
  • the rigidly mounted elements require constant adjustment and maintenance.
  • thermal expansion of the crystal element during lasing can cause the crystal to break while it is rigidly -attached to a surface with different expansion characteristics.
  • the present invention primarily employs a laser to perforate or alter one or more layers of the skin of a patient in order to remove biomolecules, fluids or gases, or to administer pharmaceutical substances.
  • Alteration of a patient's skin is produced by irradiating the surface of the skin by a pulse of electromagnetic energy emitted by a laser. Such irradiation merely enhances the permeability of the stratum corneum without causing ablation (vaporization) or perforation of tissue; alternatively, it may enhance the permeation of molecules by altering such intercellular or intracellular molecules.
  • the depth and extent of alteration may be accomplished by a judicious selection of the following irradiation parameters: wavelength, energy fluence (determined by dividing the energy of the pulse by the area irradiated), pulse temporal width and irradiation spot size.
  • a pulsed laser beam may be focused to a small spot for the purpose of perforating or altering tissue.
  • the depth, width and length of the perforation or alteration can be controlled to fit the purpose for which the perforation or alteration is required.
  • continuous-wave or diode lasers may be used to duplicate the effect of a pulsed laser beam.
  • modulated lasers are controlled by Q-switching or gating the output of a continuous wave laser or fluctuating the output excitation current in a diode laser. In either case the overall effect is to achieve brief irradiation, or a series of brief irradiations, that produce the same controlled tissue permeabilizing effect as a pulsed laser.
  • This invention provides a means for perforating or altering the skin of a patient in a manner that does not result in bleeding.
  • the perforation or alteration created typically penetrates through the stratum corneum layer, or both the stratum corneum layer and the epidermis, reducing or eliminating the barrier function of the stratum corneum.
  • This will allow the administration of substances such as pharmaceuticals through the skin, or the removal of biomolecules, fluids or gases.
  • drugs can be administered continually on an out-patient basis over long periods of time, and the speed and/or efficiency of drug delivery can be enhanced for drugs which are either slow or unable to penetrate skin.
  • this method of delivery provides an alternative delivery route for drugs that would otherwise require to be injected, eliminating the pain associated with needle punctures. Furthermore, the reduced barrier properties of the stratum corneum allow the taking of measurements of various fluid constituents, such as glucose, or to conduct measurements of gases.
  • Perforation involves the complete ablation of all layers of the stratum corneum to reduce or eliminate its barrier function. Ablation may also be characterized as partial when less than all layers of the stratum corneum are ablated, leaving sufficient tissue intact to substantially maintain the barrier function.
  • perforation will mean only the complete ablation of all layers of the stratum corneum; “ablation” may mean, depending upon the context, either partial ablation or perforative ablation.
  • alteration Certain laser-induced alterations of molecules in the stratum corneum or interstitial spaces, termed herein as "alteration,” may also occur without actual ablation, and this will result in enhanced permeation of substances into or out of the body through the skin.
  • a pulse or pulses of infrared laser irradiation at a subablative energy of, for example, 60 mJ per 2 mm spot reduces or eliminates the barrier function of the stratum corneum and increases permeability without actually ablating or perforating the stratum corneum itself.
  • the technique may be used for transdermal delivery of drugs or other substances, or for obtaining samples of biomolecules, fluids or gases 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 terms “irradiation” or “alteration,” or a derivative thereof, will generally mean modification which results in enhanced transdermal permeation of substances without actual ablation.
  • the term “energized site” means the volume of tissue exposed to energy intended to enhance transdermal permeation of substances.
  • the mechanism for non-ablative alteration of the stratum corneum is not certain. It may involve changes in lipid or protein nature or function or from desiccation of the skin. Regardless, laser-induced alteration changes the permeability parameters of the skin in a manner which allows for increased passage of fluids and gases across the stratum corneum.
  • This invention avoids the use of sharps such as needles, normally needed for drug administration or sample extraction. The absence of a contaminated sharp will eliminate the risk of accidental injury and its attendant risks to the health care worker, the patient, and anyone who may come into contact with the sharp, whether by accident or by necessity. The absence of sharps also obviates the need for disposal of biologically hazardous waste. Thus, this invention provides an ecologically sound method of perforating or altering skin.
  • a typical laser can further be modified to include a container unit.
  • a container unit can be added to: (1) increase the efficiency in the collection of fluids or gases; (2) reduce the noise created when the laser beam perforates the patient's tissue; and (3) collect the ablated tissue.
  • the optional container unit is optionally evacuated to expedite the collection of the released materials such as the fluids or gases.
  • 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 container also serves to attenuate and/or absorb any stray, potentially-hazardous electromagnetic radiation.
  • the placement of the container unit in the use of this invention is unique in that it covers tissue being punctured, at the time of puncture by the laser beam, and is therefore able to collect the fluid or gas samples and/or ablated tissue as the perforation or alteration occurs.
  • a typical laser used for this invention requires no special skills to use. It can be small, light-weight 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-fo iing 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.
  • Figure 5 shows optional beam splitters for creating multiple simultaneous perforations.
  • Figure 6 shows a patch which can be used to sterilize the site of irradiation.
  • Figure 7 shows alternative patches for sterilization and/or delivery of pharmaceuticals.
  • Figure 8 shows an optional container unit for collecting fluids or gases, 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, absorbing stray electromagnetic radiation, and reducing noise resulting from the interaction between the laser and the patient's tissue.
  • Figure 11 shows an optional version of the collection container unit which is especially useful when the container unit includes a reagent for mixing with the sample.
  • 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.
  • Figure 17 shows various examples of a container unit.
  • Figure 18 shows a container unit with an additional vessel.
  • 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 (over controls) through skin irradiated at an energy of 77 mJ and 117 mJ.
  • Figure 22 shows that there is a decrease in skin electrical impedance through skin irradiated at energies as low as perhaps 10 mJ, using the fitted curve to interpolate data.
  • Figures 23-24 show, in a permeation study of tritiated water ( H 0) involving lased human skin at energies from 50 mJ (energy fluence, 1.6 J/cm 2 ) to 1250 mJ (40 J/cm 2 ), that an increase in permeation was seen in skin irradiated at low energies up to about 150 mJ (5 Rcm 2 ), whereupon the permeation is more-or-less constant.
  • Figure 25 is a chart showing permeation of lidocaine through skin in vitro.
  • Figure 26 is a chart of a study using DNA showing enhanced permeation (over controls) through skin irradiated at an energy of 150 mJ and 300 mJ.
  • Figure 27 shows that in volunteers irradiated with increasing laser energy fluence, there is a corresponding increase in transpidermal water loss.
  • the tape strip data is a positive control that proves that the measurement is indeed sensitive to increased skin water evaporation.
  • Figure 28 is a chart showing a Differential Scanning Calorimetry (DSC) scan of normally hydrated (66%) human stratum corneum (sc), and a scan of E ⁇ YAG laser irradiated sc using a sub-ablative pulse energy of 60 mJ.
  • DSC Differential Scanning Calorimetry
  • Figures 29-31 are charts showing the heat of transition ( ⁇ J), center of the transition (°C) and the full-width at half-maximum of the transition (°C) for the scans of Figure 28 as well as a scan of sc treated other ways (not shown in Figure 28).
  • Figures 32-33 are charts of Fourier Transform Infrared ("FTIR") spectra showing that absorption bands that are due to water, proteins and lipids, change when the sc is irradiated.
  • FTIR Fourier Transform Infrared
  • Figure 34 shows that Amide I and II bands, which are due to the presence of proteins shift to larger wavenumber, consistent with what happens when skin is exposed to desiccation (in the case of Amide II) or desiccation and beta-mercaptoethanol (in the case of Amide I) do.
  • Figure 35 shows that CHx vibrations may shift to a smaller wave number indicating that either the intermolecular association between adjacent lipid molecules has been disturbed and/or the environment around the lipid molecules has changed in such a way so that the vibrational behavior of the molecules changes.
  • Figure 36 shows human skin irradiated at 50 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 shows human skin that was irradiated at 80 mJ. In this case, some change in the appearance of the sc has taken place (perhaps coagulation), and yet the sc is still intact.
  • Figure 38 shows in vivo blanching assay results.
  • Figure 39-41 shows permeation of lidocaine, insulin and ⁇ -interferon through human skin in vitro.
  • Figure 42 shows the experimental arrangement to measure the electrical impedance of human skin in vivo.
  • Figure 43 shows in vivo human skin electrical impedance as a function of Er: YAG laser pulse energy; and in vivo human skin impedance as a function of days post laser irradiation and laser pulse energy.
  • Figure 44 shows in vitro human skin permeation of tritiated water as a function of prior treatment, with a solvent or denaturant.
  • Figure 45 shows enhanced lidocaine permeation through skin in vitro as a function of iontophoretic voltage.
  • Figure 46 shows cumulative lidocaine permeation through human skin in vitro as a function of time.
  • this invention provides a method of delivering at least one substance, such as a pharmaceutical, through the skin of a subject by means of administering an amount of energy to a portion of skin sufficient to enhance permeation at the energized site, at least as deep as the outermost surface of the stratum corneum without ablating the skin, and contacting said energized site with said substance.
  • the enhanced permeability following energy administration may provide for the enhanced collection of biomolecules, fluids or gases through the skin.
  • Said substances may consist of interstitial fluid, blood, blood components, cells, cellular material and mixtures thereof.
  • Said substances may include components such as glucose, electrolytes, bacteria, viruses, nucleic acids, lipids, proteins, polysaccharides, gases, foreign substances and mixtures thereof.
  • the primary embodiments described herein utilize a laser beam, specifically focused and lasing at an appropriate wavelength to create small perforations, ablations or alterations in the skin of a patient.
  • the invention may include each type of energy source, capable of transmitting energy to the skin in the amounts and manner either reducing the electrical impedance of the skin or otherwise enhancing permeation.
  • the laser beam is focused with a lens to produce an irradiated spot on the skin ranging in size from about 0.5 microns to about 5.0 cm in diameter.
  • the spot can be of any shape such as (for example) slit-shaped, with a width in the range of about 0.05 mm to 0.5 mm and a length of up to 2.5 mm.
  • Wavelength is determined by the laser material, such as E ⁇ YAG, the preferred range of wavelengths is between about 1.5 and 10 microns.
  • the preferred range of irradiation area on the skin is between about 0.1 to 10 mm in diameter.
  • Energy fluence is a function of the laser energy output, in Joules, and the area of irradiation; the preferred range is between about 0.1 to 100,000 J/cm 2 .
  • Pulse temporal width is a consequence of the pulse width produced by a bank of capacitors, the flashlamp, and the laser rod material.
  • the laser beam is focussed precisely on the skin, creating a beam diameter at the skin in the range of about 0.5 microns to 5.0 cm.
  • the width can be of any size, being determined by the anatomy of the area irradiated together with the desired permeation rate of the substance to be applied, or the biomolecules, fluids or gases to be removed.
  • the focal length of the lens can be of any length, but in one embodiment it is about 30 mm.
  • Perforation, ablation and alteration of the stratum corneum result in enhanced inbound permeation of subsequently applied substances such as pharmaceuticals, or outbound permeation of biomolecules, fluids or gases.
  • irradiative tissue-effects For example, by reducing pulse energy but holding other variables constant, it is possible to change irradiative tissue-effects.
  • a pulse energy above approximately 100 mJ causes ablation, while many pulse energies below approximately 100 mJ result in non-ablative alterations to the stratum corneum.
  • the threshold pulse energy required to enhance pharmaceutical delivery would be reduced by a factor approximately equal to the number of pulses.
  • the spot size, but holding other variables constant it is possible to change irradiative tissue-effects.
  • Irradiation of spots having diameters down to about 0.5 microns can be obtained, for example, by coupling the radiant output of the laser into a microscope objective (e.g. as available from Nikon, Inc., Melville, N. Y.). 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 objective, which is perhaps on the order of about 0.5 microns. In fact, if the beam profile is Gaussian, the size of the affected irradiated area can be less than the measured beam size and can exceed the imaging resolution of the microscope.
  • a microscope objective e.g. as available from Nikon, Inc., Melville, N. Y.
  • a 3.2 J/cm 2 energy fluence which for a half-micron spot size, would require a pulse energy of about 6 nJ.
  • This low a pulse energy is readily available from diode lasers, and can also be obtained from, for example, the E ⁇ YAG laser by attenuating the beam by an absorbing filter, such as glass.
  • these parameters can be changed to create a deeper penetration into the capillary layer.
  • the laser beam is focussed precisely on the skin, creating a beam diameter at the skin in the range of between about 0.1 mm and 1 mm, or optionally a slit-shaped beam ranging in width from between about 0.05 mm to 0.5 mm, and in length up to 2.5 mm.
  • the focal length of the lens can be of any length, but in one embodiment it is 30 mm.
  • 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. For fluid or gas collection, the location of the perforation is optimally at a site where the blood flow is high.
  • regions of the skin are on a fingertip, or the heel of a foot.
  • a region of the skin which has less contact with hard objects or with sourceis of contamination is preferred. Examples are skin on the arm, leg, abdomen or back.
  • the skin heating element is activated at this time.
  • 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 the holder 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 optical arrangement will result in an energy fluence rate that is significantly low, thus causing a negligible effect on unintentional targets.
  • a beam splitter can optionally be added to the laser.
  • the technique may be enhanced by using a laser of a wavelength that is specifically absorbed by the skin components of interest (water, lipids or protein) that strongly affect the permeation.
  • An alteration consisting of modifying the lipids in the stratum corneum may allow enhanced permeation while avoiding the higher energies which are more likely to affect the proteins and water.
  • a laser can be used to alter the skin through the outer surface, such as the stratum corneum layer, but not necessarily as deep as the capillary layer, to allow locally acting anesthetics to permeate the skin.
  • Topically applied anesthetics must penetrate the stratum corneum layer in order to be effective.
  • compounds acting as drug carriers are used to facilitate the transdermal diffusion of some drugs. These carriers sometimes alter the behavior of the drug, or are themselves toxic.
  • the intensity of the laser pump source will determine the intensity of the laser pulse, which will in turn determine the depth and extent of the resultant alteration. Therefore, various settings on the laser can be adjusted to allow penetration or modification of different thicknesses 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 which is not absorbed by the tissue, thus preventing any scattered rays from causing damage.
  • the beam-dump can 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 anesthetic creates a very small zone in which tissue is irradiated, and only an extremely small zone of thermal necrosis (if any).
  • An effective irradiation site can range from between about 0.1 mm to 10 mm in diameter, while a slit shaped site can range from between about 0.05 mm to 0.5 mm in width and up to approximately 2.5 mm in length.
  • anesthetic can then be applied to the skin of the irradiation site using means of holding the anesthetic such as by formulations including gel material, viscous material (such as lotion or cream), patch material, dressing material or combinations thereof
  • said dressing material or patch material has a lower surface having electrically conductive gel, said gel for maintaining surrounding contact with at least some of said irradiated site.
  • the substance to be delivered to the irradiation site may also be included in said gel.
  • said dressing material or patch material includes a lower surface having an electrically conductive semipermeable membrane for maintaining surrounding contact with at least some of said irradiated site.
  • the substance to be delivered to the irradiation site may also be included in ⁇ said membrane.
  • said dressing material or patch material is adapted as a conforming membrane to maintain optimal contact with an irregular terrain of said irradiated site.
  • said dressing material or patch material includes an upper layer having an outer surface and an inner surface, a lower permeable layer having an outer surface and an inner surface, said inner surface of said upper layer and said inner surface of said lower layer defining at least one enclosed intermediate chamber and dispensing means, said chamber having sufficient internal content to, upon dispensing from said chamber, exert positive outward pressure sufficient to assist the permeation of said substance.
  • the content of at least one of said chambers includes the substance to be delivered to their radiation site.
  • Said dressing material or patch material layers may define a, plurality of chambers and dispensing means, at least one of said chambers having sufficient internal content to, upon dispensing from said chamber, exert positive outward pressure sufficient to assist the permeation of the substance to be delivered to their radiation site.
  • said dressing material or patch material layers further define, in addition to said chamber, an enclosed intermediate reservoir with dispensing means, said reservoir having sufficient volume to contain said substance until dispensed.
  • the invention may include a rupturable membrane separating said chamber and said reservoir, wherein the rupturing of said membrane allows the mixing of said contents of said chamber and reservoir. Delivery of Other Substances
  • the present method can also be used to deliver a wide variety of other substances such as pharmaceuticals, in a manner similar to the above described delivery of anesthesia.
  • alterations can be made which do not penetrate as deep as the capillary layer. These alterations can be made through only the outer surfaces, such as the stratum corneum layer or both the stratum corneum layer and the epidermis:
  • an optical beam-splitter can be employed so that either single alterations or a number of alterations within a desired area can be made.
  • the pharmaceutical can then be applied to the skin of the irradiation site using means of holding the anesthetic such as by formulations including gel material, viscous material (such as lotion or cream), patch material, dressing material, or combinations thereof.
  • Said substance may eventually be delivered by essentially direct contact with interstitial fluid of the subject.
  • the present method can be used in the delivery of a variety of substances, especially pharmaceuticals.
  • Said substance may be selected from the group of in vivo diagnostic substances consisting of contrasting imaging agents, radionuclide based agents and mixtures thereof.
  • Said substance may be selected from the group of systemically active substances consisting of neuroactive agents, auto acids, anti-hypertensives, anti--- ⁇ hvthmics, hormones, chemotherapy, antiparasitic agents, chemotherapy anti-microbial agents and mixtures thereof.
  • Said substance may be selected from the group of locally active substances consisting of lidocaine, anesthetic agents, erectile dysfunction agents, metabolic inhibitors, steroidal or nonsteroidal anti-inflammatory agents, vitamins, retinoids, anticancer agents, antibodies, antibody conjugates and mixtures thereof.
  • Said substance may be selected from the group consisting of protein based pharmaceutical substances, DNA based pharmaceutical substances, RNA based pharmaceutical substances and mixtures thereof; said protein based substance may be selected from the group consisting of cytokines, hormones, cell activation factors, cellular inhibitors, proteases, protease inhibitors, clotting factors, antibodies and mixtures thereof.
  • Said DNA or RNA based substance may be selected from the group consisting of oligonucleotides, gene therapy agents, ribozymes and mixtures thereof.
  • Said substance may be selected from the group of antimicrobial chemotherapy agents consisting of anti-infectives, anitfungals, antivirals and mixtures thereof.
  • Said substance may be selected from the group of immunity generating substances consisting of vaccines, antigens, immunogen preparations and mixtures thereof.
  • Said substance may be selected from the group of permeation enhancing substances consisting of.
  • dimethyl-sulfoxide alcohol, Azone, pentae-Tthritrol dioleat, lauramide DEA, polyethyleneglycol- 10 laurate, nonoxynol-10, propylene glycol, urea, water, n-propanol, amines, amides, pyrrolidones, surfactants, fatty acids, liposomes and mixtures thereof.
  • nitroglycerin and antinauseants such as scopolamine; antibiotics such as tetracycline, streptomycin, sulfa drugs, kanamycin, neomycin, penicillin, and chloramphenicol; various hormones, such as parathyroid hormone, growth hormone, gonadotropins, insulin, ACTH, somatostatin, prolactin, placental lactogen, melanocyte stimulating hormone, thyrotropin, parathyroid hormone, calcitonin, enkephalin and angiotensin; steroid or non-steroid anti-inflammatory agents and systemic antibiotic, antiviral or antifungal agents.
  • antibiotics such as tetracycline, streptomycin, sulfa drugs, kanamycin, neomycin, penicillin, and chloramphenicol
  • various hormones such as parathyroid hormone, growth hormone, gonadotropins, insulin, ACTH, somatostatin, prolactin, placental lac
  • locally acting pharmaceuticals such as alprostadil, localized antibiotic, minoxidil, antiviral or antifungal agents or a chemotherapy or anti-cancer agent
  • pharmaceuticals such as alprostadil, localized antibiotic, minoxidil, antiviral or antifungal agents or a chemotherapy or anti-cancer agent
  • Protein or DNA based biopharmaceutical agents can also be delivered using this method.
  • Drugs may be applied by applying drug formulation directly to the irradiated skin site or by using a patch containing the drug.
  • the patch may simply take the form of a viscous gel, lotion or ointment.
  • the drug formulation may be incorporated into a laminate structure.
  • skin was lased alternatively at 2.94 micron or 2.1 micron wavelength using an E ⁇ YAG (Nenisect, Little Rock, AR) or Ho:YAG (Schwartz Electro-Optics, Orlando, FL) laser respectively. Pulse duration was 200-300 microseconds, the energy fluence delivered was between 4 and 10 J per square centimeter.
  • a local anesthetic was then applied via a simple patch consisting of a Hill Top chamber (Hill Top Research, Loveland, OH), or a self-forming patch (Dermaflex, Zila Pharmaceutical, Phoenix, AZ), or by dropping a small volume of liquid, onto the site of irradiation.
  • Anesthesia as determined by insensitivity to needle-pricking or finger pinching, was achieved after five minutes in a region that extended at least 5 to 10 mm, or more, away from the irradiation site.
  • single or multiple reservoirs containing a drug between a matrix of semipermeable membrane and laminate could be applied.
  • an unstable compound such as prostaglandin El (e.g. Caverject, Pharmacia & UpJohn, Kalamazoo, MI)
  • lyophilized drug could be stored in one reservoir while the liquid components to be mixed with the drug could be stored in a separate reservoir, both separated by a membrane that may be ruptured by crushing or other physical means, thereby allowing the components to mix freely such that they would be available for dosing.
  • This multi-reservoir concept may be further extended to include mixing of chemicals that will generate an electrical current, for the purpose of iontophoresis or electroporation.
  • a substance may be included in the drug formulation or patch and applied to the site of irradiation whereby this substance slows the healing process or reduces the rate of scab formation thereby limiting the rate of closure of the permeation site and having the effect of extending the enhanced permeability characteristics of the lased site.
  • antigens can be administered through the skin for immunization purposes.
  • the alterations are made through the outer layers of the skin, either singly or multiply, and the immunogen is provided in an appropriate formulation.
  • the immunogen can be provided in a formulation which penetrates slowly through the alterations, but at a rate faster than possible through unperforated skin.
  • This method can also be applied to the delivery of allergens for example for allergy testing. Multiple alterations can be made through the outer layer of the skin, but not penetrating to the capillary level. A variety of allergens can then be applied to the skin, as in a skin patch test.
  • 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 the collection of biomolecules, fluids or gases.
  • Such collection may be accomplished by more passive methods, such as mere diffusion followed by absorption by traditional dressings.
  • more active collection methods may utilize electrical gradients, vacuum or suction pressure, or a variety of other active transport methods.
  • the same procedure as is used in iontophoretic delivery of a particular substance may be used, except that the polarity of the electrodes used to establish the gradient are reversed.
  • the present invention includes methods of collecting at least one substance from within a subject, comprising administering an amount of energy to a portion of skin sufficient to cause alteration at the energized site, at least as deep as the outermost surface of the stratum corneum, and collecting said substance from said energized site.
  • Such capture means include medium selected from the group consisting of gel, viscous materials, activated carbon or other adsorbent material such as ceramic, activated carbon; alternatively, absorbent medium such as patch or dressing materials may offer capture means, as do collection container units or vessels.
  • 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 ablation or alteration. Therefore, various settings on the laser can be adjusted to allow penetration of different thicknesses of skin.
  • a beam-dump can be positioned in such a way as not to impede the use of the laser for ablation or alteration of extremities.
  • the beam-dump will absorb any stray electromagnetic radiation from the beam which is not absorbed by the tissue, thus preventing any scattered rays from causing damage.
  • the beam-dump can 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 drawing fluids or gases creates a very small zone in which tissue is irradiated, and only an extremely small zone of thermal necrosis.
  • a practical round hole can range from between about 0.1 mm to 1 mm in diameter, while a slit shaped hole can range from between about 0.05 mm to 0.5 mm in width and up to approximately 2.5 mm in length.
  • healing is quicker or as quick as the healing after a skin puncture with a sharp implement.
  • the fluid or gas can be collected into a suitable vessel, such as a small test tube or a capillary tube, or in a container unit placed between the laser and the tissue as described above. The process is non-contact and so neither the patient, the fluid or gas to be drawn, or the instrument creating the ablation or alteration is contaminated.
  • a collection dressing assembly utilizes a mini-vacuum created by the compression of a bulb forming the upper layer of the dressing.
  • This dressing essentially comprises an upper concave layer having an outer surface and an inner surface, said upper layer having an essentially hemibulbous concavity and sufficient elasticity to return to said concavity following departure therefrom, as when the concave bulb is compressed.
  • the dressing also has a lower permeable layer having an outer surface and an inner surface, said inner surface of said upper layer and said inner surface of said lower layer defining at least one enclosed intermediate chamber.
  • said chamber has expulsion means such as a one-way valve allowing only outflow of chamber contents upon compression of said concavity; said chamber should contain a gas (such as air) or other substance readily expelled upon compression of said concavity.
  • a partial vacuum results from the return of said upper layer to concavity, thereby exerting negative pressure upon the energized site to assist outward permeation of substance from within the subject.
  • said dressing material or patch material layers may further define, in addition to said chamber, a least one enclosed intermediate reservoir with dispensing means, said reservoir containing analytical testing materials.
  • Another version further comprises at least one rupturable membrane separating at least one of said chambers from at least one of said reservoirs; the rupturing of said membrane after compression and return of said hemibulbous concavity allows the mixing of said analytical testing materials of said reservoir with the substance collected from within the subject, to thereby perform a desired analytical test.
  • Said membrane may be ruptured by the same compression exerted upon said hemibulbous concavity, or separate compression. Other means of rupturing said membrane may be used to produce the same result.
  • such dressings may have more than one compression chamber or reservoir, and different chambers or reservoirs may contain different substances (or combinations) such as air or complimentary components that will mix with each other as part of an analytical test or to produce energy or an electrical gradient.
  • Different adjacent chambers or reservoirs may be separated by rupturable membranes so that, upon rupture, the contents of only certain ones will mix at that time.
  • the collected substances may be used for a wide variety of tests.
  • the technique of the present invention may be used to sample extracellular fluid in order to quantify glucose or the like.
  • Glucose is present in the extracellular fluid in the same concentration as (or in a known proportion to) the glucose level in blood (e.g. Lonnroth P.
  • One version of the invention includes a glucose collection chamber separated, by a rupturable membrane, from a reservoir containing glucose hydrogenase and other chemicals known in the art for analyzing glucose content.
  • the stratum corneum of a subject is altered with
  • Interstitial fluid containing glucose is collected by the dressing as it emerges from the energized site; at the desired time, the separation membrane is ruptured, and the contents of the test reservoir allowed to mix with the contents of the collection chamber. The color of the test solution will change, based on the amount of glucose collected.
  • another version of the invention includes a compressible mini-vacuum collection air chamber that, after the elastic concavity is compressed, expelling the contents, produces a vacuum as the compressed concavity returns to its concave state. This facilitates the ingress of the substance into the collection means.
  • transepidermal water loss As shown in Figure 27, with increasing laser energy fluence (J/cm 2 ), there is a corresponding increase in water loss.
  • the tape strip data is a positive control that proves that the measurement is indeed sensitive to increased skin water evaporation.
  • Two of the energy fluences used to collect the data in Figure 27 are non-ablative and therefore show that non-ablative energies allow the alteration of the barrier function of stratum corneum thereby resulting in enhanced transepidermal water loss which can provide a diagnostic sample of extracellular water.
  • the present invention can be used to employ lasers non-ablatively to reduce or eliminate the barrier properties of non-skin barriers in the human body, such as the blood-brain interface, the floor of the third ventricle in the brain, and the sclera of the eye.
  • Subablative or partially ablative levels of laser energy may be applied to the skin which do not visibly harm the epidermis, but do result in a drop in skin electrical impedance at the lasing site. This results in an increase in skin permeability to various substances. This permeation may also be further enhanced by application of an electric current across the skin, providing a heretofore unexpected synergistic effect. This approach can be used to minimize damage to the skin as a result of applying large electrical currents while optimizing permeation, an important consideration for chronic applications of drugs and other substances transdermally.
  • the practice of the present invention has been found to be effectively performed by various types of lasers; for example, the Nenisect, Inc., Er: YAG laser skin perforator, or the Schwartz: Electro-Optical Ho: YAG.
  • Any pulsed or gated continuous wave 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 non- ablative wavelength, pulse length, pulse energy, pulse number, and pulse rate.
  • a dye that absorbs said energy can be placed on, in or under the skin.
  • 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 E ⁇ 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 38 attached to
  • FIGS 1-2 are diagrammatic representations of a typical laser that can be used for this invention.
  • the laser typically draws power from a standard 110 N or 220 N line 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 from the flashlamp is located in the laser cavity 18 that has a shape such that most of the light is efficiently directed to the laser rod 20, which absorbs the light, and, upon de-excitation, subsequently lases.
  • the laser cavity mirrors of low 26 and high 24 reflectivity, positioned collinearly with the long-axis of the laser rod, serve to amplify and align the laser beam.
  • the laser cavity mirrors comprise coatings 124, 126, applied to ends of the crystal element and which have the desired reflectivity characteristics.
  • an E ⁇ YAG crystal is grown in a boule two inches in diameter and five inches long. The boule is core drilled to produce a rod in the range of between about 5 mm to 6 mm, in diameter and about 5 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 MI-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 0.01 mm diameter standard pit. For collimated laser beams, one normally would use optics with better than a 40-20 scratch-dig rating. Many coatings are available from Rocky Mountain Instruments, Colorado Springs,
  • the coating is then vacuum deposited on the ends.
  • 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%.
  • Other vacuum deposited metallic coatings with known reflectance characteristics are widely available for use with other laser wavelengths.
  • the general equation which defines the reflectivity of the mirrors in a laser cavity necessary for the threshold for population inversion is:
  • a ⁇ is the total scattering losses per pass through the cavity
  • g 21 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 which 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.
  • one diode bar may contain ten such diodes, coupled to produce at least 5 W cw output. This power corresponds to 5 J/sec. cw energy which can then be gated by Q-switching or other mechanisms to produce pulsed energy of 5 mJ/ msec. It has been shown that an ablative effect may be seen with as little as 100 mJ of energy delivered to a spot of about 1 mm diameter. Four 25 millisecond pulses or a hundred 1 millisecond pulses from a diode laser of this type will thus have an ablative effect approximately equivalent to about one 100 mJ pulse in the same time period.
  • the E ⁇ YAG lasing material is a 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 ablation or alteration of the skin.
  • Other 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 ablation or alteration of the skin.
  • a laser can effectively cut or alter tissue to create the desired ablations or alterations where tissue exhibits an absorption coefficient in the range of between about 10 to 10,000 cm "1 .
  • Examples of useful lasing elements are pulsed C0 2 lasers, Ho: YAG (holmium: YAG; 2.127 microns), En YAP, Er/C ⁇ YSGG (erbium/chromium: yttrium, scandium, gallium, garnet; 2.796 microns), Ho:YSGG (holmium: YSGG; 2.088 microns), E ⁇ GGSG (erbium: gadolinium, gallium, scandium, garnet), E ⁇ YLF (erbium: yttrium, lithium, fluoride; 2.8 microns), Tm:YAG (thulium: YAG; 2.01 microns), Ho/Nd:YA103 (holmium/neodymium: yttrium, aluminate; 2.85-2.92 microns), cobalt:MgF 2 (cobalt: magnesium fluoride; 1.75-2.5 microns), HF chemical (hydrogen fluoride; 2.6-3 microns), DF chemical
  • Solid state lasers 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 142 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 microinch is considered matte.
  • a microinch equals one millionth (0.000001) inch. This 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 microinch may be used to affect beam shape, such a finish will seriously reduce the amount of fight energy that enters the crystal rod and thus cut the laser's energy.
  • a matte area of approximately 50 microinch is present around the full circumference of an En YAG laser rod for two-thirds the length of the rod.
  • the non-matte areas of the rod are less than 10 microinch.
  • 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 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 ablated 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 ablation 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 (see 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 ablation or alteration.
  • the beam can be split by means of a beam-splitter to create multiple beams capable of ablating 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.
  • a container unit 68 is optionally fitted into the laser housing and is positioned proximal to the ablation or alteration site.
  • the container unit reduces the intensity of the sound produced when the laser beam ablates or alters the patient's tissue, increases the efficiency of fluid or gas collection, and collects the ablated tissue and other matter released by the ablation.
  • the container unit can be shaped so as to allow easy insertion into the laser housing and to provide a friction fit within the laser housing.
  • Figure 8 shows a typical container unit inserted into the laser housing and placed over the ablation site.
  • the container unit 68 comprises a main receptacle 82, including a lens 84.
  • the main receptacle collects the fluid or gas sample, the ablated tissue, and/or other matter released by the ablation.
  • the lens is placed such that the laser beam may pass through the lens to the ablation site but so that the matter released by the ablation 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 as to be capable of being inserted into the applicator to disengage a safety mechanism of the laser, 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 fluid or gas samples, ablated tissue, and/or other matter released by the ablation or alteration.
  • 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 in the range of about 1 to 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 can be 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 ablation site.
  • 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 ablation site.
  • the area defined by the lens wall of the main receptacle and the ablation or alteration site is thereby substantially enclosed during the operation of the laser.
  • 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, 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 the ablation or alteration.
  • this vessel can collect liquid or particulate matter, while the main receptacle 82 collects any ablated tissue.
  • the 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 can extend outwardly from the main receptacle's wall and into the vessel through the removable stop. Once the sample has been collected, 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 interiors of the main receptacle 82, the capillary tube 94 or other tubing, and/or the additional vessel 92 are optionally coated with anticoagulating and/or preservative chemicals. Examples of preservatives include ethylenedi- ⁇ minetetraacetic ⁇ acid (EDTA) and sodium benzoate. Examples of anticoagulating chemicals are sodium heparin and sodium citrate.
  • a typical container unit can comprise 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 ablates the tissue.
  • the interior of the main receptacle is optionally coated with anticoagulating and/or preservative chemicals.
  • the container unit can be constructed of glass or plastic. The container unit is optionally disposable.
  • the container unit may also include 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 interior of the main receptacle, the capillary tube, and/or the additional vessel may optionally be coated with anticoagulating and/or preservative chemicals.
  • the container unit can be 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 a container unit with a laser for the purpose of drawing fluids or gases or to administer pharmaceuticals.
  • 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 ablated.
  • the additional vessel 92 can be connected by tubing 94 to the receptacle.
  • the beam passes through the lens 84.
  • the container unit can be evacuated.
  • the optional vacuum in the container unit exerts a less than ambient pressure over the ablation or alteration site, thereby increasing the efficiency in fluid or gas collection.
  • the container unit is optionally coated with anticoagulating and/or preservative chemicals.
  • the container unit's end proximal to the ablation or alteration site 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 ablation site (e.g., the finger).
  • the desired ablation or alteration site is firmly pressed against the plug.
  • the plug's material is impermeable to gas transfer.
  • the plug's material is thin enough to permit ablation of the material as well as ablation of the skin by the laser.
  • the plug can be constructed of rubber.
  • the plug perforation center 74 as shown in Figure 9, 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 both the plug and the tissue adjacent to the plug.
  • the plug should be in the range of between about 10 and 500 microns thick, but at the most 1 millimeter thick.
  • the plug perforation center 74 is large enough to cover the ablation or alteration site.
  • the ablated site is a round hole with an approximate diameter ranging from 0.1-1 mm, or slit shaped with a width in the range of between about 0.05 mm to 0.5 mm and an approximate length up to 2.5 mm.
  • the plug perforation center is sufficiently large to cover ablation sites of these sizes.
  • the ablation or alteration site 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 ablation site and the container unit.
  • the ablation site on the plug is stretched when the tissue is pressed against the plug. This stretching of the plug material causes the hole created in the plug to expand beyond the size of the ablation or alteration created in the tissue. As a result, the fluid can flow unimpeded into the container unit 68.
  • the laser beam penetrates the container unit, perforates the plug perforation center 74 and ablates or alters the patient's tissue.
  • the container unit 68 can include 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 ablation site, however it is not essential because there is no need to maintain a vacuum.
  • the container unit reduces 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 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 fluid or gas.
  • reagents are sodium heparin and other reagents known in the art to be used in standard blood chemistry tests. See, for example, Garza D. et al., Phlebotomy Handbook (3d edition), Appleton and Lang Pub. Co., Norwalk, CT, 1993, which is incorporated herein by reference.
  • 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 fluid sample as it is collected.
  • FIG. 11 A preferable configuration for the container unit when it contains a reagent is shown in Figure 11.
  • 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 area is made of a infrared-transparent substance such as quartz.
  • reagents When reagents are present in the container unit prior to collection of fluid or gas, 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 labeling 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 sterile alcohol-impregnated patch of paper or other thin material can optionally be placed over the site to be ablated. This material can also prevent the blowing off of potentially infected tissue in the plume released by the ablation.
  • the material must be transparent to the laser beam. Examples of such material are a thin layer of quartz, mica, or sapphire.
  • a thin layer of plastic such as a film of polyvinyl chloride, can be placed over the skin.
  • a layer of a viscous sterile substance such as vaseline can be added to the transparent material or plastic film to increase adherence of the material or plastic to the skin and further decrease plume contamination.
  • a patch can be used to deliver allergens, local anesthetics or other pharmaceuticals as described below. Examples of such a patch are provided in Figures 6 and 7.
  • Alcohol impregnated paper 54 is surrounded by a temporary adhesive strip 58.
  • Side views of two alternative patches are shown in Figure 7, where a sterilizing alcohol, antibiotic ointment, allergen, or pharmaceutical is present in the central region of the patch 60.
  • This material is held in place by a paper or plastic layer 62, optionally with a laser-transparent material 64 such as mica, quartz or sapphire which is transparent to the laser beam at the center of the patch.
  • a laser-transparent material 64 such as mica, quartz or sapphire which is transparent to the laser beam at the center of the patch.
  • the patch can be placed on the skin using an adhesive 66.
  • a modulated laser can be used to duplicate a pulsed laser for the purpose of enhancing topical drug delivery or collection of samples. 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 using a saturable absorber. (See, for example, "The Laser Guidebook", Jeff Hecht, McGraw-Hill.NY, 1992).
  • Examples of continuous- wave lasers include C0 2 , which lases over a range between about 9 to 11 microns (e.g. Edinburgh Instruments, Edinburgh, UK), Nd:YAG, Thullium:YAG (Tm:YAG), which lases at 2.1 microns (e.g.
  • the lasing process can be modulated by modulating the 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.
  • the stratum corneum shows two important electrical features. First, it becomes polarized as an electric field is continuously applied. Second, its impedance changes with the frequency of the applied electric field. The polarization effect may operate against the electric field applied, thus reducing the magnitude of effective current across the skin. Consequently, the efficiency of iontophoresis-facilitated transdermal delivery may be reduced with the duration of treatment. To minimize this effect, the current may be applied in a pulsatile manner. When the current is switched “on,” charged molecules may be delivered iontophoretically through the skin. When the current is switched “off,” the skin is allowed to depolarize.
  • the stratum corneum typically has an impedance on the order of 10 to 5000 Kohm x cm .
  • Iontophoresis commonly utilizes a continuous current on the order of tens to hundreds of milliamperes, while electroporation may require even larger currents and voltages to drive molecules through this high resistance barrier. These currents require power sources that are driven by relatively large cumbersome power packs or batteries. These relatively high current requirements often result in burning of the skin.
  • the skin resistance at the irradiation site is reduced by several orders of magnitude.
  • much lower currents can be used to drive even large molecules across the skin.
  • This allows for low voltage iontophoresis and electroporation whereby a small current, or a pulsed current, is used to drive small and large molecules through the site of irradiation and into the tissues, thereby minimizing power and current requirements as well as the risk of skin burning.
  • One embodiment of the invention uses such electrical energy with a voltage in the range of between about 0.1 mV and 1.5 volts. In another embodiment, said electrical energy is in the range of between about 0.1 mN and 100 mN.
  • an iontophoretic drug patch may be utilized where the voltage and current requirements are multi-fold less than without alteration. Because of this, more drag may be iontophoretically permeated into the tissues than without alteration. This effect is further enhanced by placing positive and negative electrodes at independent irradiated sites. Thus, the resistance of the complete circuit is orders of magnitude lower than that where there is no irradiation, or where only one site of irradiation has been made. Experiments with laser irradiated stratum corneum show that 10-fold more drug can be pumped across the dermis using relatively minute voltages.
  • Means for delivering substances such as pharmaceuticals to or through the irradiation site may be selected from the group consisting of diffusion, thermal energy, electrical energy, mechanical displacement and combinations thereof.
  • Enhanced permeability of the stratum corneum to the permeating molecules makes passive or assisted diffusion more effective.
  • relatively small amounts of electrical or thermal energy may accomplish effective permeation. This is especially true when permeation is facilitated by an electrical gradient on the skin generated by means selected from the group consisting of electrophoresis, iontophoresis and electroporation.
  • Said delivery means may further include a source of electricity selected from the group consisting of an external electric current generator, a transportable battery, a solar powered generator, an electrochemical generator, a thermal energy generator, and a piezoelectric generator. Since such small amounts of energy are needed, body heat may be a sufficient source of thermal energy.
  • a transportable battery may also be incorporated within said dressing material or patch material.
  • Example 1 describe some methods and effects of administering energy to the skin of a subject, such as by the use of a laser, to increase the permeability of the stratum corneum for the purpose of delivering substances such as pharmaceuticals, or for drawing out biomolecules, fluids or gases. These examples are not meant to limit the scope of the invention, but are merely alternative embodiments.
  • Example 1 describe some methods and effects of administering energy to the skin of a subject, such as by the use of a laser, to increase the permeability of the stratum corneum for the purpose of delivering substances such as pharmaceuticals, or for drawing out biomolecules, fluids or gases.
  • An infrared laser radiation pulse was formed using a solid state, pulsed, multimode E ⁇ YAG laser consisting of two flat resonator mirrors, an E ⁇ 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.
  • the duration of the pulse was approximately 300 microseconds.
  • the spot size was approximately 2 mm.
  • Pulse energy used was 40, 80 or 120 mJ. Single pulses were used.
  • 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.
  • TEWL Transepidermal water loss
  • An infrared laser radiation pulse was formed using a solid state, pulsed, multimode
  • E ⁇ YAG laser consisting of two flat resonator mirrors, an E ⁇ 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, The duration of the pulse was about 300 microseconds.
  • the spot size was about 2 mm in diameter.
  • a pulse energy used was about 60 mJ.
  • a single pulse was used.
  • the volar aspect of the forearm was placed at the focal point of the laser, and the laser was discharged. After discharge of the laser, the irradiated site was treated with a
  • Example 3 Ablation threshold energy: normally hydrated (66%) stratum corneum (sc) was sandwiched between two microscope cover slides, and exposed to a single pulse of irradiation from the E ⁇ 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 was in the range of between about 90 to 120 mJ. The threshold may be different when the sc is still overlying epidermis, as in normal skin, since it takes energy to remove the sc from the epidermis, to which it is adherent.
  • DSC Differential Scanning Calorimetry
  • Figure 28 shows a DSC scan of normally hydrated (66%) human sc, and a scan of E ⁇ YAG laser irradiated sc using a subablative pulse energy of 60 mJ. Clearly there is a difference in the scans. Defining the thermal transition peaks at approximately 65°C, 80°C and 92°C (labeled as 1, 2 or 3, respectively), it was determined that the heat of transition ( ⁇ J), center of transition (°C) and the full-width at half-maximum of the transition (°C). (See Figs. 29-31).
  • FTIR spectroscopy was used to study sc treated the same way as in the DSC experiments in Example 4, except the energy used was between about 53 and 76 mJ.
  • Detailed analysis of the spectra show that absorption bands that are due to water, proteins and lipids change when the sc is irradiated. Some of these changes are consistent with changes seen during non-laser treatment of the sc (e.g. desiccation, thermal damage, or exposure to lipid solvents or protein denaturants).
  • 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 sc), shift to a larger wave number, consistent with what desiccation (in the case of Amide II) or desiccation and beta-mercaptoethanol (in the case of Amide I) do (see, for example, Figure 34).
  • the CH X vibrations due to bonds in lipids may shift to a smaller wave number indicating that either the intermolecular association between adjacent lipid molecules has been disturbed and/or the environment around the lipid molecules has changed in such a way that the vibrational behavior of the molecules changes (see, e.g., Figure 35).
  • Example 6 Histology Numerous in vivo experiments have been done on rats and humans. Usually, the skin is irradiated with the E ⁇ YAG laser with a spot having a diameter of 2 mm and particular pulse energy, and then the irradiated site is biopsied immediately or 24 hours later. Two examples of typical results are shown in Figure 36 and 37.
  • Figure 36 shows human skin irradiated at 50 mJ, which is an energy sufficient to increase the skin permeation (to lidocaine, for instance) and yet does not show any sign of stratum comeum ablation.
  • Figure 37 depicts human skin 24 hours after being irradiated at 80 mJ.
  • Example 7 Figure 22 shows that there is a decrease in skin impedance in skin spots having a diameter of 2 mm and irradiated at energies as low as 10 mJ, using the fitted curve to interpolate data. Histology studies on rat skin in vivo, however, showed no evidence of ablation at energies less than about 100 to 200 mJ. A similar histology study on human skin in vitro did not show any sign of ablation until about 140 mJ laser pulses were applied. Repeating this study showed the same result as the previous studies.
  • Example 8 The output of the E ⁇ YAG laser was passed through an aperture to define its 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. Control skin was left unirradiated.
  • a 254 mJ pulse was used, and multiple samples were irradiated.
  • a 285 mJ pulse was used, and multiple samples were irradiated.
  • insulin a 274 mJ pulse was used, and multiple samples were irradiated.
  • Diprolene beta-methasone
  • a-methasone a strong steroid that can permeate the intact stratum comeum in an amount sufficient to cause measurable skin blanching.
  • 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.
  • Example 10 The radiant output of the E ⁇ 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 comeum.
  • This site which will 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 microseconds long), with an energy of about 950 mJ, is used to irradiate a spot of skin having a diameter of 5 mm. The result is a reduction or elimination of the barrier function of the stratum comeum.
  • 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.
  • Example 11 In Vivo Skin Impedance Pilot Experiment A. Laser Ablation:
  • the 2.94 micron radiant energy output of the Nenisect E ⁇ YAG laser was passed through an iris with a 2 mm diameter.
  • the energy output of the laser was measured with a calibrated Ophir energy/power meter (Opti-Optronics, Inc., Peabody, MA).
  • Opti-Optronics, Inc. Peabody, MA
  • a single ablation on the volar aspect of the forearm of a volunteer was done.
  • Three ECG electrodes Medi-Trace, Buffalo, NY) were applied to the arm; one near the wrist as a reference site, one over the site of irradiation, and one adjacent to the site of irradiation.
  • Example 12 In Vivo Skin Impedance Human Study The arms of subjects were gently shaved with an electric razor to prevent hair follicles from interfering with the measurements and to ensure good contact from electrode to skin. The subjects were marked with a black felt marker in five diamond shaped areas on each arm. The testing period lasted for three days, taking measurements on each arm each day.
  • Example 13 In Vitro Skin Permeation.
  • Skin samples were prepared the same as was done for the in vitro impedance study (Example 11). The skin sections were cut to a size of about 0.227 cm 2 . These samples were then placed in Franz diffusion cells. The loaded Franz cells were filled with a nonsterile PBS solution on the subcutaneous surface of the skin. A micro-stirring bar was placed in the cell also. Each Franz cell was placed in a PMC Dataplate stirring digital dry block heater maintained at 37°C. A. Exposure to Methanol and Chloroform:
  • test samples were loaded with about 100 ⁇ l of a methanol/chloroform solution on the stratum corneum side of the samples, the solvent was left for a period of about 5 minutes. The solvent was then removed with a micropipetter and cotton swabs. About 100 ⁇ l of tritiated water was then placed on the stratum comeum side of the test sample and left to permeate for about 1 hour. After one hour had passed the tritiated water was removed using a micropipetter and cotton swabs. About 1 ml of the PBS from the subcutaneous side of the skin was removed with a syringe and added to about 5 ml of scintillation fluid in a scintillation vial. This was done with each sample and a control, which was made using PBS that was fresh from the bottle. Another control was made using the same procedure as above except that the skin had not had any chemical treatment before application of the tritiated water.
  • test samples were loaded with about 100 ⁇ l of a methanol/chloroform/glacial acetic acid solution on the stratum comeum side of the samples.
  • the solvent was left for a period of about 5 minutes.
  • the solvent was then removed with a micropipetter and cotton swabs.
  • About 100 ⁇ l of tritiated water was then placed on the stratum comeum side of the test sample and left to permeate for about 1 hour. After one hour had passed the tritiated water was removed using a micropipetter and cotton swabs.
  • test samples were loaded with about 100 ⁇ l of ⁇ -mercaptoethanol on the stratum comeum side of the samples.
  • the solvent was left for a period of about 5 minutes.
  • the solvent was then removed with a micropippetter and cotton swabs.
  • About 100 ⁇ l of tritiated water was then placed on the stratum corneum side of the test sample and left to permeate for about 1 hour. After one hour had passed the tritiated water was removed using a micropippetter and cotton swabs.
  • 1 ml of the PBS from the subcutaneous side of the skin was removed with a syringe and added to 5 ml of scintillation fluid in a scintillation vial. This was done with each sample and a control, which was made using PBS that was fresh from the bottle. Another control was made using the same procedure as above except that the skin had not had any chemical treatment before application of the tritiated water.
  • Skin samples were prepared the same as was done for the in vitro permeation study (Example 8). These samples were then placed in Franz diffusion cells. The samples of skin were irradiated using the same protocol as described in Example 8, lasing approximately 2 mm spots of skin using single pulses of about 175 mJ. Afterwards, 275 ⁇ l of 4% lidocaine without epinephrine, spiked with 14 C-lidocaine, was placed in the donor cells. Electrodes, consisting of silver needles (nerve conduction, electrodes) were placed in the donor and receptor chamber of the Franz cells. The voltage and current (supplied by a regulated d.c. power supply) applied to the electrodes were monitored by . two digital multimeters. The voltage (0, 50, 125, or 250 mN) was applied for about 15 minutes ( Figure 45) or for about five hours ( Figure 46) at the set voltage of 50 mN.

Abstract

L'invention concerne un procédé permettant de prélever des biomolécules par perméation à travers la peau d'un sujet. Ce procédé consiste à exciter la couche cornée conjointement à l'utilisation de différents moyens de prélèvement notamment des gels et des matériaux de pansement. L'accroissement de la perméabilité ou une impédance électrique réduite de la peau permet d'élargir la gamme de composants capables de perméation et accroît de taux de perméation et l'efficacité de cette dernière, y compris la perméation renforcée par ionophorèse. Ce procédé permet l'utilisation de moyens de prélèvement améliorés qui n'étaient pas encore disponibles jusqu'ici.
PCT/US2000/026218 2000-09-25 2000-09-25 Permeation et prelevement ameliores par irradiation WO2002026148A1 (fr)

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EP1997433A1 (fr) * 2006-03-22 2008-12-03 Panasonic Corporation Dispositif de perforation au laser et methode de perforation au laser
EP2692291A1 (fr) * 2011-03-31 2014-02-05 Isotech Co., Ltd Autopiqueur portatif àlaser comportant un dispositif à double sécurité, et embout jetable utilisé avec celui-ci

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WO1998033444A1 (fr) * 1997-01-31 1998-08-06 Transmedica International, Inc. Administration locale d'agents anesthesiques par assistance laser
US5885211A (en) * 1993-11-15 1999-03-23 Spectrix, Inc. Microporation of human skin for monitoring the concentration of an analyte
WO1999040848A1 (fr) * 1998-02-17 1999-08-19 Abbott Laboratories Dispositif de collecte et de controle de liquide interstitiel
EP0942278A2 (fr) * 1998-03-13 1999-09-15 Cygnus, Inc. Biocapteur, système d'échantillonnage iontophorétique, et procédés d'utilisation associés

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US5885211A (en) * 1993-11-15 1999-03-23 Spectrix, Inc. Microporation of human skin for monitoring the concentration of an analyte
WO1998033444A1 (fr) * 1997-01-31 1998-08-06 Transmedica International, Inc. Administration locale d'agents anesthesiques par assistance laser
WO1999040848A1 (fr) * 1998-02-17 1999-08-19 Abbott Laboratories Dispositif de collecte et de controle de liquide interstitiel
EP0942278A2 (fr) * 1998-03-13 1999-09-15 Cygnus, Inc. Biocapteur, système d'échantillonnage iontophorétique, et procédés d'utilisation associés

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1997433A1 (fr) * 2006-03-22 2008-12-03 Panasonic Corporation Dispositif de perforation au laser et methode de perforation au laser
EP1997433A4 (fr) * 2006-03-22 2012-03-14 Panasonic Corp Dispositif de perforation au laser et methode de perforation au laser
US8394085B2 (en) 2006-03-22 2013-03-12 Panasonic Corporation Laser perforation device and laser perforation method
EP2692291A1 (fr) * 2011-03-31 2014-02-05 Isotech Co., Ltd Autopiqueur portatif àlaser comportant un dispositif à double sécurité, et embout jetable utilisé avec celui-ci
EP2692291A4 (fr) * 2011-03-31 2014-09-24 Isotech Co Ltd Autopiqueur portatif àlaser comportant un dispositif à double sécurité, et embout jetable utilisé avec celui-ci
US9486165B2 (en) 2011-03-31 2016-11-08 Isotech Co., Ltd. Portable lancing device using laser and equipped with double safety device and disposable cap used therewith

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