HK1027273A - Laser assisted topical anesthetic permeation - Google Patents

Description

Laser assisted local anesthetic infiltration

This application is a pending partial continuation of U.S. patent No. 08/792,335 applied on 31/1/1997, U.S. patent No. 08/792,335 is itself a partial continuation of U.S. patent No. 5,643,252 applied on 24/9/1993, and U.S. patent No. 5,643,252 is a partial continuation of U.S. patent No. 07/968,862 applied on 28/10/1992, all of which are incorporated herein by reference.

The present invention is in the field of medical procedures, namely laser medical devices for delivering anesthetic or pharmaceutical agents to a patient, or removing fluids, gases or other biomolecules from a patient.

The traditional method of collecting small amounts of fluids, gases or other biomolecules from a patient is to mechanically perforate the skin with a sharp instrument such as a metal knife or needle. In addition, the traditional method of using anesthetics or other drugs is through the use of needles.

This step has a number of disadvantages, including possible infections of the health care workers and general public caused by sharp instruments used to perforate the skin, and the expense of handling and disposing of biohazardous waste.

When the skin is pierced by a sharp device, such as a metal knife or needle, biological waste in the form of "visible" contamination is produced by the patient's blood and/or tissue. If a patient is infected with a pathogen derived from blood, such as Human Immunodeficiency Virus (HIV), hepatitis b virus, or any other pathogen, the contaminated sharps pose a serious threat to other persons who may come into contact with it. For example, many healthcare workers become infected with HIV due to accidental contact with contaminated sharps.

Disposal of the contaminated sharp after use places a logistical and financial burden on the end user. These fees are taxed as a social consequence of improper handling. For example, the improper disposal of biological waste in public beach flushes in many occasions in the eighties of the twentieth century. Improper handling also allows other people, such as intravenous drug users, to gain access to contaminated needles and get an infection.

Conventional methods of using needles to administer anesthetic or drugs and to withdraw fluids, gases, or other biomolecules also have a disadvantage. The stinging of sharp instruments is a delicate and damaging step, especially for pediatric patients, which can cause significant stress and anxiety in the patient. Moreover, for the extraction of fluids, gases or other biomolecules, it is often necessary to repeat the piercing step a number of times before a sufficient sample is obtained.

The prior art for local anesthesia without the use of needles generally includes (a) topical lidocaine (lidocaine) mixtures, (b) iontophoresis, (c) carriers or excipients made of compounds that improve the stratum corneum or the chemical properties of the drug, and (d) sonophoresis (sonophoresis) which involves altering the barrier function of the stratum corneum with ultrasound. A lidocaine-containing ointment is commonly used, especially for pediatric patients, but this takes up to 60 minutes, resulting in anesthesia depths of only about 4 mm. Lidocaine lacks permeability due to the barrier function of the epidermal layer. Inherent problems with iontophoresis include the complexity, expense, and unknown toxicity of the delivery system over long-term exposure to electrical current. In addition, the use of carriers and excipients involves additional compounds that may alter the pharmacokinetics or be unpleasant for the drug of interest.

Thus, there is a need for a technique that does not require a sharp instrument in order to remove fluids, gases or other biomolecules or administer anesthetics or other drugs. The techniques and apparatus disclosed herein address this need by avoiding the handling of contaminated instruments, thereby reducing the risk of infection.

In recent years, lasers have been used as highly efficient and accurate tools for use in some surgical procedures. Among the potential new materials available for laser radiation, the most medically attractive ones are rare earth elements. One of the most promising of these rare earth elements is YAG (yttrium, aluminum, garnet) crystals doped with erbium (Er) ions. With this crystal, it is possible to establish an erbium: YAG (Er-ARG) laser, set to emit electromagnetic energy at a wavelength (2.94 microns) that is strongly absorbed by water and other objects. When tissue consisting essentially of water is irradiated at or near this wavelength, energy is transferred into the tissue. If the radiation intensity is sufficient, rapid heating is induced and the tissue then evaporates. In addition, this deposition of energy can cause optomechanical destruction of the tissue. Some medical Er are described in the health care protocols of dentistry, gynecology and ophthalmology: YAG laser, see, e.g., bogdasov, b.v., etc., "Er: YAG laser irradiation on solid and soft tissue ", preprint 266 p, general physical institute, mosco, 1987; BOL' shakov, e.n. et al, "Er: experimental basis for YAG in dentistry applications ", SPIE 1353: 160-169, laser and medicine (1989) (these and all other references cited herein are incorporated herein as if fully set forth herein).

The present invention employs a laser to perforate or otherwise modify the skin of a patient to remove fluids, gases or other biomolecules or to administer anesthetics or other drugs. By irradiating the surface of the target tissue with pulses of electromagnetic energy of the laser. Prior to treatment, the caregiver appropriately selects the wavelength, energy flux (pulse energy divided by irradiation area), pulse temporal width, and irradiation spot size to precisely perforate or alter the target tissue to a selected depth, avoiding undesirable damage to healthy adjacent tissue.

According to an embodiment of the present invention, a laser emits a pulsed laser beam focused at a small spot for perforating or altering target tissue. By adjusting the output of the laser, the laser operator can control the depth, width and length of the perforation or change as desired.

In another embodiment, a pulsed laser may be achieved using a continuous wave or diode laser. The lasers are regulated by gating their output or, in the case of diode lasers, by varying the laser firing current at the diode laser. The overall effect is to achieve a brief irradiation, or a series of brief irradiations, which produces the same tissue penetration effect as a pulsed laser. The term "modulated laser" as used herein refers to such a replicated pulsed laser beam.

The term "perforation" as used herein refers to the ablation of the stratum corneum, thereby reducing or removing its barrier function. The term "alteration" of the stratum corneum as used herein refers to a change in the stratum corneum which weakens or removes the barrier function of the stratum corneum and increases permeability without ablating or ablating only a very small portion of the stratum corneum itself. Pulses or pulse beams of infrared laser radiation at near ablative energies, e.g., 60mJ (using TRANSMEDIA)^TMInternational Inc. of radiation energy is 2.94 microns in wavelength, 200 mus (microseconds) pulsed, 2mm spot size ("TRANSMEDIA)^TM") Er: YAG laser) will alter the stratum corneum. This technique can be used for transdermal drug delivery or for taking samples, fluids, gases or other biomolecules from the body. Laser irradiation at different wavelengths or energy levels below or above 60mJ may also produce enhanced permeability effects without ablating the skin.

The mechanism of this change of the stratum corneum is not certain. It may include changes in lipid or protein properties or functions, or mechanical changes due to dryness of the skin or secondary to propagating pressure waves or cavitation bubbles. It is generally believed that the route taken by topically applied drugs through the stratum corneum is through the cells and/or around them, as well as through the hair follicles. The impermeability of the skin to topically applied drugs depends on the tight cell-to-cell junctions, as well as the biomolecular composition of the cell membrane and the intracellular environment. Any alteration of the molecules that make up the cell membrane or intracellular environment, or of the mechanical structural integrity of the stratum corneum or hair follicles, leads to a reduction in barrier function. It is believed that with Er: YAG laser irradiation of the skin causes a measurable change in thermal properties, as evidenced by Differential Scanning Calorimeter (DSC) patterns and Fourier Transform Infrared (FTIR) patterns of the stratum corneum. Changes in DSC and FTIR spectra are the result of changes in the structure of molecules or macromolecules, or the environment surrounding these molecules or structures. Without wishing to be bound by any particular theory, we can temporarily attribute these observations to changes in lipids, water and proteins in the stratum corneum caused by irradiating the molecules with electromagnetic radiation, both by directly altering the molecules and by generating heat and pressure waves that can also alter the molecules.

Both perforation and alteration can alter the skin's permeability parameters in a manner that results in increased access of drugs and the passage of fluids, gases or other biomolecules through the stratum corneum.

It is therefore an object of the present invention to provide a method of perforating or altering the stratum corneum of a patient without causing bleeding. For example, the perforation or alteration created in the target tissue is accomplished by the application of a laser beam that passes through the stratum corneum or the stratum corneum and dermis, thereby reducing or eliminating the barrier effect of the stratum corneum. This step allows for transdermal administration of anesthetics or other drugs as well as removal of fluids, gases, or other biomolecules. Moreover, this step allows for long term continuous administration of the drug to an outpatient. The rate and/or efficiency of drug delivery is thus improved for drugs that are slower or impermeable to penetrate the skin.

It is another object of the present invention to provide an alternative method of administering drugs that would otherwise require the use of other methods, such as oral administration or injection, thereby increasing patient compliance and reducing patient anxiety.

It is a further object of the invention to allow the determination of a variety of fluid components, such as glucose, or the determination of gases.

It is also an object of the present invention to avoid the use of sharp edges. The elimination of a contaminated sharp eliminates the risk of accidental injury and the risk it carries to health care workers, patients, and others who may come into contact with the sharp. The elimination of sharp edges also avoids the need to dispose of biohazardous waste. Thus, the present invention provides an ecologically sound method of using anesthetics and other drugs and removing fluids, gases, or other biomolecules.

In another embodiment a conventional laser is adapted to include a container means. The addition of this container means enables: (1) increasing the efficiency of collection of fluids, gases or other biomolecules; (2) reducing noise generated when the laser beam penetrates patient tissue; and (3) collecting the ablated tissue. The optional containment means is often emptied to speed up the collection of released substances such as fluids, gases or other biomolecules. The container can also be used to collect only ablated tissue. The noise generated by the interaction of the laser light with the patient's skin may cause anxiety in the patient. The optional containment means reduces noise intensity and relieves anxiety and stress on the patient. The containment device also minimizes the risk of cross-contamination and ensures sterility of the collected sample. The placement of the containment device is very unique in the use of the present invention in that it covers the tissue to be irradiated when irradiated with a laser beam, thus enabling the collection of fluid, gas or other biomolecular samples and/or ablated tissue as perforation or alteration occurs. The container may be adapted to contain a substance, such as a drug, which may be used before, during and after irradiation.

Conventional lasers used in the present invention do not require special skills to use. It can be small, lightweight and can use conventional batteries or rechargeable batteries. The easier the laser is to carry and use, the greater the utility of the invention in a variety of environments, such as a hospital room, clinic, or home.

Safety features can be incorporated into the laser that do not require special safety glasses to be worn by the laser operator, patient, or anyone in the vicinity of the laser when in use.

The present invention may be better understood, and its advantages more readily appreciated by those skilled in the art by reference to the accompanying drawings. Wherein:

fig. 1 shows a laser with its power supply, high voltage pulse forming network, flash lamp, laser bar, mirror, housing and focusing lens.

Figure 2 shows an alternative spring-loaded interlock and an alternative heating applicator.

Fig. 3 shows an alternative method of exciting a laser bar using a diode laser.

Fig. 4 shows another focusing mechanism.

Figures 5A and 5B illustrate alternative beam splitters used to create multiple simultaneous perforations.

Figure 6 shows a small block used to sterilize the irradiation site.

Fig. 7A and 7B illustrate another patch used to sterilize and/or deliver drugs, and/or collect fluids, gases, or other biomolecules.

Figure 8 illustrates an alternative containment device for collecting fluids, gases or other biomolecules, ablating tissue and/or other matter released from the irradiation device site, and reducing noise caused by the interaction of the laser light with the patient's tissue.

Fig. 9 shows a plug and a plug penetration center.

Figure 10 illustrates an alternative containment device for collecting ablated tissue and/or other material released from the site of the irradiation device and reducing noise caused by the interaction of the laser light with the patient's tissue.

Figure 11 shows a roll-on device for delivering anesthetic and drug.

Fig. 12 shows a support for a solid state laser crystal element with an optional coated surface at each end of the solid state laser crystal element.

FIG. 13 shows an example of a crystal rod having a matte coating around the entire periphery of the crystal rod.

FIG. 14 shows an example of a crystal rod having a matte coating around two thirds of the entire circumference of the crystal rod.

FIG. 15 shows an example of a crystal rod with a layer of non-smooth striations along the longitudinal direction of the crystal rod.

FIG. 16 shows a cross-sectional view of a crystal laser rod element surrounded by a material having a refractive index greater than that of the rod.

Fig. 17A-17G illustrate various examples of containment devices.

Figure 18 shows a nebulizer for delivering anesthetic and drug.

Figure 19 shows an example of a containment device for use with a laser.

Fig. 20 shows an example of a lens with a mask.

FIG. 21 is a graph showing a study of the enhanced permeability (higher than control) exhibited by corticosterone at 77mJ and 117 mJ.

FIG. 22 illustrates the reduction in skin impedance of a living subject using multiple laser pulses.

FIGS. 23-24 show tritium water: (³H₂O) at an energy of from 50mJ (1.6J/cm)²) To 1250mJ (40J/cm)²) Lower partPermeation studies of human skin irradiated with laser light.

FIG. 25 shows a tissue slice of human skin illuminated at 150 to 300 mJ.

FIG. 26 is a graph showing that enhanced permeability was exhibited upon irradiation of DNA at 150mJ and 300 mJ.

Fig. 27 shows the loss of laser pulse energy (J) relative to water that has penetrated human skin in vivo.

Fig. 28 is a DSC scan showing normal hydrated (66%) human stratum corneum and Er: scanning pattern of YAG laser

FIGS. 29-31 are graphs showing the full length at half maximum of the three peak thermal transitions (. mu.J), centers of transformation (. degree.C.) and transformations (. degree.C.) of DSC profiles of stratum corneum treated with different methods.

FIGS. 32-33 are graphs of FTIR spectra of control and laser stratum corneum.

FIG. 34 shows the position (cm) of amino compound I band (Amide I band) as one effect of stratum corneum treatment^-1)。

FIG. 35 shows CH as a function of stratum corneum treatment₂Vibration position (cm)^-1)。

FIG. 36 shows a histological section of the skin of a mouse irradiated at 80 mJ.

FIG. 37 shows a tissue slice of human skin illuminated at 80 mJ.

Figure 38 shows the results of the in vitro bleaching test.

Figures 39-41 show the permeation of interferon-gamma, insulin, and lidocaine through human skin in vitro.

Fig. 42 shows an example of a beam splitter suitable for simultaneously irradiating a plurality of portions.

FIG. 43 is a schematic showing one possible perforation or change of location using a beamsplitter.

The present invention provides a method of perforating or altering the skin for sampling fluids, gases or other biomolecules or for administering anesthetics or other drugs. The present invention utilizes a laser beam that is specifically focused and irradiated at a suitable wavelength to create a small puncture or change in the patient's skin. In a preferred embodiment, the laser beam has a wavelength of between about 0.2 and 10 microns. Preferably, the wavelength is between about 1.5 and 3.0 microns. More preferably, the wavelength is about 2.94 microns. In one embodiment, the laser beam is focused with a lens to produce an irradiated spot on the skin, the irradiated spot having a size of about 0.5 microns to 5.0 centimeters in diameter. Optionally, the dots may be slit-shaped, about 0.05 to 0.5mm wide and up to 2.5mm long.

The caregiver may consider several factors that define the laser beam, including wavelength, energy flux, pulse temporal width, and irradiation spot size. In a preferred embodiment, the energy flux is at 0.03' C100,000J/cm². More preferably, the energy flux is between 0.03 and 9.6J/cm². The wavelength of the laser beam depends in part on the laser material, e.g., Er: YAG. The pulse temporal width is a result of the pulse width produced by, for example, a set of capacitors, flash lamps, and laser bar materials. The pulse width is preferably 1fs (femtosecond) to 1000. mu.s.

According to the method of the present invention, the penetration or modification of the laser generation does not require a single pulse generation of the laser. In a preferred embodiment, the caregiver creates perforations or changes in the stratum corneum by using multiple laser pulses, each perforating or changing only a small portion of the targeted tissue thickness.

To achieve this, the energy required to perforate or alter the stratum corneum with multiple pulses can be roughly estimated by dividing the energy of a single pulse by the number of pulses required. For example, if a point of a particular size requires 1J of energy to produce a perforation or change across the stratum corneum, a qualitatively similar perforation or change can be produced using 10 pulses of 1/10 with each pulse having that energy. Because the patient is required to not move the target tissue during irradiation (human response time is about 100ms), the heat generated at each pulse cannot spread significantly, and in a preferred embodiment the pulse repetition rate of the laser should produce complete perforation in less than 100 ms. Alternatively, the orientation of the target tissue and the laser can be mechanically selected so that the location of the target tissue cannot be changed during prolonged irradiation.

In order to penetrate the skin in a manner that does not cause bleeding, the skin is perforated or altered from the outer surface of the skin, such as the stratum corneum, but not deep into the capillary layers. The laser beam is precisely positioned on the skin, producing a beam on the skin having a diameter of 0.5 microns to 5.0 cm. The width can be any dimension, controlled by the anatomical area to be irradiated and the desired permeation rate of the drug used, or fluid, gas or other biomolecule to be removed. The focal length of the focusing lens can be any length, but in one embodiment it is 30 cm.

By varying the wavelength, pulse length, energy fluence (being the laser energy output (joules)) and beam size (cm) at the focus²) The effect of (b), and the size of the point of irradiation, it is possible to vary the effect on the skin between ablation (perforation) and non-ablation or partial ablation (modification). Both ablation and non-ablation of the stratum corneum result in increased penetration of subsequently applied drugs, or removal of fluids, gases, or other biomolecules.

For example, by reducing the pulse energy while keeping other parameters constant, it is possible to vary the effect of ablation between that of ablated and non-ablated tissue. Using TRANSMEDIA with a pulse length of about 300 mus^TMEr: YAG lasers, irradiate at a 2mm point of the skin with a single pulse or irradiation energy, the pulse energy being greater than about 100mJ to cause partial or complete ablation, while any pulse energy below about 100mJ causes partial or no ablation of the stratum corneum. Optionally, by using multiple pulses, the threshold pulse energy required to enhance drug delivery is reduced by a factor approximately equal to the number of pulses.

Alternatively, by reducing the size of the dots while maintainingKeeping other parameters constant, it is also possible to vary the effect of ablation between that of ablated and non-ablated tissue. For example, halving the spot area will result in halving the energy that produces the same effect. For example, illumination below 0.5 microns can be obtained by coupling the illumination output of the laser to the objective of a microscope (e.g., available from Nikon corporation, Melville, new york). In this case it is possible to focus the beam down to a point at the resolution limit of the microscope, which may be on the order of 0.5 microns. In fact, if the beam pattern is gaussian, the size of the illuminated area affected can be smaller than the measured beam size and can exceed the imaging accuracy of the microscope. For the non-removed type of altered tissue at this time, 3.2J/cm was used²The energy flux of (a) would be suitable, and for a half micron spot size, a pulse energy of about 5nJ would be required. This low pulse energy is easily achieved from diodes, and can also be measured from e.g. Er: YAG lasers attenuate the beam by using an absorptive filter such as glass.

Optionally, varying the wavelength of the illumination energy while maintaining other parameters constant, it is possible to vary the ablation effect between the effects of ablated and non-ablated tissue. For example, using Ho: YAG; (holmium: 2.127 μm) in place of Er: YAG (erbium: 2.94 microns) laser, will result in less energy being absorbed by the tissue, resulting in weaker perforations or alterations.

Picosecond and femtosecond pulses generated by a laser can also be used to create changes and ablation on the skin. This can be done with a tuned diode laser or related microchip laser that will deliver a single pulse in the range of 1 femtosecond to 1 microsecond. (see D.Stern et al, "ablation of the cornea at 532 and 625nm by nanosecond, picosecond, and femtosecond lasers", Vol.107, 587 & 592 (1989), incorporated herein by reference, which discloses the use of pulses having a length of less than 1 femtosecond).

According to one embodiment of the invention, the anesthetic or drug may be administered immediately after the laser irradiation. Two embodiments of the present invention incorporate either a sprayer (fig. 18) or a roll-on device (fig. 11). In the case of a frothing device, the laser beam passes through an aperture 162 that engages a ball 164 of the frothing device. Alternatively, the roll-foaming device may be positioned adjacent to the path of the laser beam through the single-use applicator. After irradiation, the roll-foaming device is rolled across the irradiation site to administer the desired anesthetic or drug. In the case of a nebulizer device, the anesthetic is administered from the drug reservoir 166 by use of compressed gas. After irradiation, the cylinder 168 containing a compressed gas (e.g., carbon dioxide) is triggered to inject a prescribed amount of anesthetic or drug at the irradiation site.

Alternatively, positive pressure is applied to the drug reservoir to push the drug towards the skin, or negative pressure is used at the collection reservoir to promote diffusion of the analyte out of the skin. The atmospheric pressure of the environment is 760mmHg, or one atmosphere. Because of the hydrostatic pressure in an upright individual, the differential pressure at the reference value measured horizontally at the head versus the neck may be 10mmHg, with the head being 90mmHg higher than the foot. The height of the arm is 8-35 mmHg. It is also noted that there is a dynamic pressure of 80-120mmHg in the circulatory system (in normal healthy individuals) due to the beating heart. Thus, a positive pressure of greater than about (760mm +35mm) is suitable in order to allow the drug to penetrate the skin (e.g., the skin at the arm). Pressures slightly greater than one atmosphere are suitable to enhance drug penetration, while dynamic pressures due to blood flow are not able to penetrate into the blood flow. A slightly higher pressure favors diffusion to the blood. However, prolonged periods of time much greater than about 5 atmospheres do produce side effects.

In another embodiment of the invention, an ink jet or marker is used to mark the irradiation site. The site of irradiation is not always readily visible to the naked eye, and thus the healthcare worker may not be able to know precisely where to administer the anesthetic or drug after irradiation. The present invention also provides a technique for marking the skin so that the irradiated site is apparent. For example, before, during, or immediately after laser irradiation, marking with ink nozzles (similar to an ink jet printer) is performed. In addition, a circle may be drawn along the ablation site, or a series of lines may be used that are all directed at the ablation site. Alternatively, the end of the disposable safety applicator tip/applicator (the end that touches the patient's skin) is marked with a dye. The applicator is brought into contact with the skin before, during or immediately after laser irradiation, thereby marking the skin irradiation site.

For certain purposes, it is advantageous to have the skin produce multiple perforations or alterations simultaneously or in rapid sequence. To accomplish this, a beam splitter, or fast pulsed laser such as a diode or related microchip laser, may optionally be added to the laser. Multiple irradiation sites, either simultaneously or sequentially, will result in enhanced absorption of the drug compared to a single irradiation site (i.e., increased uptake proportional to the total number of ablation sites). An example of a site beam splitter 48 suitable for simultaneous illumination for use with a laser is shown in fig. 42. Any geometric pattern of dots can be created on the skin using this technique. Since the diffusion of the topically applied drug into the skin is nearly symmetrical, an advantageous pattern of irradiation spots for local drug delivery would be (thus producing a uniform concentration over as large an area as possible) located at every point in the staggered matrix pattern that is equidistant from each other.

Alternatively, multiple illumination locations, or illumination areas of any size or shape, can be created using the scanner. For example, an oscillating mirror that reflects the laser irradiation energy beam may be operated as a scanner.

For anesthetic or drug delivery and removal of fluids, gases, or other biomolecules with the use of laser devices, the laser is operated in a manner such that a portion of the patient's skin is positioned within the applicator at the location where the laser is focused. Anesthetic or drug delivery to the perforation or change, and removal of fluids, gases, or other biomolecules is preferred, but not required, to areas of the skin that are less associated with hard objects or sources of contamination. Such as the skin in the arms, legs, abdomen or back. Optionally, the skin heating element is triggered at this point to reduce the laser energy required to alter or ablate the stratum corneum.

It is desirable to provide a holder having an aperture that coincides with the focal plane of the optical system. Optionally, as shown in FIG. 2, a spring loaded interlock 36 is attached to the cradle such that when the patient applies a small amount of pressure to the interlock, it is recessed into focus, the switch is closed and the laser fires an irradiation pulse. In this device, the focal point of the beam is in line with the end of the stent only when the end is depressed. In the unlikely event that the laser accidentally lases before the laser applicator tip is properly positioned, the energy flux that the optical component will produce is very low and thus has negligible effect on unintended targets.

The efficacy of the method of the invention can be enhanced by using a laser having a wavelength that is specifically absorbed by a skin component of interest (e.g., water, lipids, or proteins) that can strongly affect the permeability of the skin. However, it is not necessary to select a laser that emits a wavelength that is strongly absorbing. Altering the lipids of the stratum corneum may allow for enhanced penetration while avoiding the higher energy necessary to affect proteins and water.

Use of a different Er: YAG is advantageous for stratum corneum ablation or alteration. For example, diode lasers emit relatively low-energy radiation at a wavelength of 810nm (0.8 microns), but radiation of this wavelength is only poorly absorbed by tissue. In another embodiment of the invention, a dye is applied to the skin surface that absorbs this radiation wavelength, either on the intact stratum corneum or in an Er: YAG laser treatment (which can produce deep dye penetration). For example, indocyanine green (ICG), a harmless dye used in endoplasmic reticulum vasculology and liver clearance studies, has a maximum absorption at 810nm when in plasma (Stephen Flock and StevenJacqes, "thermal injury of blood vessels in the mouse skin valve compartment using indocyanine green and pulsed alexandrite lasers: feasibility studies", laser medical science, 8, 185-. This dye, when in the stratum corneum, is expected to absorb the 810nm radiant energy of diode (e.g., GaAlAs laser) laser light, thereby raising the temperature of the tissue, subsequently causing ablation and molecular changes, resulting in a diminished barrier function.

Alternatively, it is possible to chemically alter the optical properties of the skin to enhance subsequent absorption of laser radiation, while virtually no chemicals are present at the time of laser radiation. For example, 5-aminolevulinic acid (5-ALA) is a precursor to porphyrins, a molecule involved in hemoglobin production and activity. Porphyrins are strong absorbers of light. Administration of 5-ALA stimulates the production of porphyrins in the cell, but in the process he consumes himself. Subsequently, the energy absorption is enhanced by irradiation at the absorbed wavelength (e.g., 400nm or 630nm) in this tissue porphyrin.

Another method of enhancing the stratum corneum's absorption of irradiation energy without the addition of exogenous absorbing compounds is to hydrate the stratum corneum by applying a occlusive barrier to the skin prior to laser irradiation. In this case, the water produced in vivo continues to diffuse into the stratum corneum and through the pores in the skin, but evaporation is avoided due to the closed barrier. Thus, the stratum corneum can be further saturated with moisture. Because Er: the irradiation energy emitted by YAG is strongly absorbed by water and this step will increase the absorption coefficient of the stratum corneum and therefore less energy is required to cause the changes or ablations required to enhance the local drug delivery at the stratum corneum.

In addition, the laser ablation site eventually heals by infiltration of keratinocytes and keratin, which effectively heal the ablation site (about two weeks complete), or by diffusion of serum into the ablation site to form clots (eschar), which effectively heal the ablation site. For long-term local delivery of drugs, or multiple-step application of topical drugs, it is advantageous to keep the ablation site open for a long period of time.

Thus, in another embodiment of the invention, the ablation or non-ablation site is left open by keeping the irradiation site moist. This is accomplished by minimizing air contact with the ablation site and/or providing fluids to keep the ablation site moist and/or biochemical like the stratum corneum. Applying a patch (containing, for example, an ointment such as petrolatum or hydrocortisone-containing petrolatum) to the site helps keep it open. The hydrogel patch can be used to provide the necessary moisture. In addition, cytotoxic drugs such as cisplatin, bleomycin, doxorubicin and methotrexate, for example, when used topically at low concentrations will prevent local cell and wound repair. Furthermore, the use of vitamin C (ascorbic acid) or other melanin production inhibitors after irradiation will help prevent additional skin coloration after treatment.

Continuous wave (Cw) laser scanning

Under machine or microprocessor control, it is possible to scan a laser beam (continuous wave or pulsed wave) over the target tissue to minimize or eliminate thermal damage to the epidermis or adjacent tissue at the anatomical site.

For example, a scanner (made of electro-optical or mechanical components) can be made to move the laser continuously over a user-defined area. This area may be of any size or shape. The scanning path may be helical or raster. If the laser is pulsed or modulated, it is possible to have a discrete random pattern in which the scanning optics mechanically direct the beam to a region of the skin, the laser emits the laser light, and then the scanning optics mechanically direct the beam to a different region (preferably not near the first point so that the skin has time to cool before the adjacent skin site is heated).

This scanning technique has been used previously with copper vapor lasers (for treating port-deep erythema) and with CO2 lasers for resurfacing. The former targets subcutaneous blood vessels, while in the latter, tissue of about 100 microns is vaporized and melted along each laser pass.

Delivery of anesthetic agents

A laser may be used to perforate or otherwise alter the skin along an external surface, such as the stratum corneum, but not deep enough to reach the capillary layers so that a local anesthetic is topically applied. Locally applied anesthetics must pass through the stratum corneum to be effective. Currently, compounds used as drug carriers are used to aid transdermal diffusion of some drugs. These carriers sometimes change the state of the drug or are toxic themselves.

The size of the laser excitation source determines, among other parameter settings, the intensity of the laser pulse, which in turn determines the depth of the resulting perforation or change. Thus, the various settings of the laser can be adjusted to allow different depths of perforation and alteration of the stratum corneum.

Optionally, the beam dump should be positioned in such a way that does not interfere with the laser's perforation and alteration of the tip. The beam dump will absorb all of the discrete electromagnetic radiation emanating from the beam that cannot be absorbed by the tissue, thus avoiding any stray light causing damage. The beam dump may be designed or easily removed in the event that the beam dump prevents the body part from being placed on the applicator.

This method of delivering anesthetic produces very small areas of tissue being irradiated and thermal necrosis in the very small areas. A feasible circular irradiation spot diameter may be from 0.1 to 5.0cm, while a slit-type aperture may be from 0.05 to 0.5mm wide and up to approximately 2.5mm long, although slits of other sizes and lengths may be used. Thus, healing is faster or as fast as compared to piercing the skin with a sharp instrument. The anesthetic or pharmaceutically acceptable formulation such as a cream, ointment, lotion, or spot can be applied directly to the skin after irradiation.

In addition, the delivery area can be enlarged by strategic positioning of the irradiation spot and the use of multiple sites. For example, an area of skin may be anesthetized with a pulsed laser through the area desired for the first scan, with each pulse sufficient to cause perforation or alteration. This can be done by modulated diode or related chip lasers that deliver a single pulse with an instantaneous width of 1 femtosecond to 1 millisecond. (see D.Stern et al, "ablation of the cornea at 532 and 625nm by nanosecond, picosecond, and femtosecond lasers", Vol.107, 587 & 592 (1989), which is incorporated herein by reference, discloses the use of pulses down to 1 femtosecond in length). An anesthetic (e.g., 10% lidocaine) is then applied to the treated area to complete anesthesia of the area.

The method can be used to deliver a variety of anesthetics. These anesthetics vary in their systemic and local toxicity, the degree of anesthesia produced, the time at which anesthesia begins, the length of the anesthetic episode, biological interference and side effects. Can be found in "preoperative anesthesia and postoperative considerations at laser resurfacing" of Fitzpatrick r.e., Williams b.goldman m.p., semin.cutan.med.surg.15 (3): 170-6, 1996, to find an example of local anesthesia with laser resurfacing of facial skin. The partial list consists of: cocaine, procaine, mepivacaine, etidocaine, ropivacaine (ropivacaine), bupivacaine, lidocaine, tetracaine, procainamide, perocaine, MEGX (desethyllidocaine), and PPX (mepivacaine dicarbanile). References to local anesthesia can be found in Rudolph de Jong, "local anesthesia," Mosby-Year, St.Louis, 1994.

Delivery of drugs

The present invention can also be used to deliver drugs in a manner similar to that described above for delivery of anesthetics. By varying the power level, and/or the spot size of the laser beam, the capillary layer can be perforated or otherwise made less deep. These perforations or alterations can only penetrate through the outer surface, e.g., the stratum corneum or stratum corneum and epidermis. Optionally, an optical beam splitter or multi-pulse laser may be used to make a single or multiple perforations at the desired location. After perforation or modification, the medicament can be applied directly to the skin or in a pharmaceutically acceptable formulation such as a cream, ointment, lotion or patch.

The method can be used for the delivery of a variety of systemically acting drugs. Such as nitroglycerin and antiemetics such as scopolamine; antibiotics such as tetracycline, streptomycin, sulfonamides, 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; steroidal or non-steroidal anti-inflammatory agents and systemic antibiotics, antivirals or antifungals.

Delivery of locally acting drugs

Laser-assisted perforation or alteration provides a unique site for local absorption of the drug to the desired site. Thus, high local concentrations of the drug can be achieved, which are effected in the area near the point of application by means of limited dilution near the point of application. This embodiment of the invention provides a method for treating local pain or infection, or applying drugs directly to small specific areas, thus avoiding the high potential systemic toxic dose by oral or intravenous injection. Topically applied drugs such as alprostadil (e.g., carveject by Pharmacia & Upjohn), various antibiotics, antiviral or antifungal agents, or chemotherapy or anticancer agents can be delivered to the treatment area adjacent to the delivery site using this method. Biopharmaceutical based proteins or DNA can also be delivered in this way.

Immunization

Like drug delivery, antigens derived from viruses, bacteria or other agents that stimulate an immune response can be administered through the skin for immunization purposes. The perforations or alterations are made through the outer layers of the skin, either individually or in multiple, and the immunogen is provided in a suitable immunogen dosage form. For boosting immunity, which is delivered over a period of time to increase the immune response, the immunogen may be provided in a dosage form that passes slowly through the perforations or alterations, but at a faster rate than through non-perforated or unaltered skin.

This approach provides a new method of immunization for clinicians, solving some of the problems encountered with other routes of use (e.g., many vaccine formulations are not very effective via the oral or intravenous routes). Moreover, the skin is often the first line of defense for invading microorganisms, and consists of immunoglobulin a (iga) antibodies in the immunoreactive parts of the skin, like the mucous membranes. Scientists have long sought ways to induce mucosal immunity using a variety of vaccine formulations. Unfortunately, they have met with limited success because, in order to produce an IgA response, it is necessary to deliver vaccine formulations to the mucosa of the intestine or sinuses, where access is difficult with standard formulations. Through intradermal immunization, a unique population of antibodies, including IgA, can be generated, which is a key component of mucosal immunity. This laser assisted intradermal antigen presentation method can thus be used to generate an antibody to IgA that invades the organism.

Allergen delivery

Traditional allergy testing requires an allergy specialist to make multiple pricks on a patient's skin and apply a specific immune source to determine intradermal hypersensitivity. The method of the invention can be used to deliver immunogens for allergy assays with reproducible results. Multiple perforations or alterations can pass through the outer layer of the skin without piercing the capillary level. This allows a variety of immunity sources to be applied to the skin for skin spot detection. One benefit of this approach is that the degree of reduction in stratum corneum barrier function (i.e., laser irradiation) is more consistent than with a sharp needle prick.

Delivery of penetration enhancers

Certain compounds may be used to enhance penetration of a substance beneath the perforated or ablated stratum corneum. These enhancers include DMSO, alcohols, and salts. Other compounds specifically aid penetration based on specific effects, such as by increasing ablation or by enhancing capillary flow through inhibition of inflammation (i.e., salicylic acid). The methods of the present invention can be used to deliver these penetration enhancers. Multiple or single perforations or alterations can be made through the outer layers of the skin without piercing the capillary levels. In turn, a variety of permeation enhancers can be applied to the irradiation site, for example, at a skin spot.

Delivery of anti-inflammatory agents

Analgesics and other non-steroidal anti-inflammatory agents, as well as steroidal anti-inflammatory agents, may be caused to permeate through the perforated or altered stratum corneum to locally affect tissue in the vicinity of the irradiation site. For example, an anti-inflammatory agent such as Indocin (Merck & Co.), a non-steroidal drug, is an effective agent for the treatment of rheumatoid arthritis when taken orally, but sometimes suffers from a gastrointestinal debilitating effect. These dangerous complications can be avoided by administering the agent at the laser-assisted perforation or change site. Furthermore, high local drug concentrations are more likely to be achieved at the site of irradiation than systemic concentrations that occur upon oral administration.

Sucking fluids, gases, or other biomolecules

A laser may be used to perforate or alter the outer surface layers of the skin, such as the stratum corneum, but not as deep as the capillary layers, to enable the collection of fluids, gases, or other biomolecules. Fluids, gases or other biomolecules can be used for a wide variety of assays. The size of the laser pump source will determine, among other parameter settings, the intensity of the laser pulse, which in turn determines the resulting perforation and the varying depth. Thus, a variety of preset values can be adjusted on the laser to perforate skin of different thicknesses.

Optionally, the beam dump is positioned in a manner that does not impede the use of the laser to perforate or alter the limb, and will absorb all of the discrete electromagnetic radiation emitted from the beam that is not absorbed by the tissue, thereby avoiding any stray light causing damage. The beam dump may be designed to be easily removed in the event that the beam dump interferes with the placement of the body part on the applicator.

This method of extracting fluid, gas or other biomolecules creates very small areas on the tissue being irradiated and thermal necrosis in the very small areas. For example, a practically circular irradiation spot may have a diameter of from 0.1 to 1mm, while a slit-shaped aperture may have a width of from 0.05 to 0.5mm and a length of up to approximately 2.5 mm. Thus, healing is faster or as fast as compared to piercing the skin with a sharp instrument.

The fluid, gas or other biomolecules may be collected in a suitable container, such as a cuvette or capillary, or a container unit placed between the laser and the tissue as described above. This step does not require contact. Thus, neither the patient, the fluid, gas or other biomolecules to be aspirated, nor the instruments that create the perforations or changes are contaminated.

The techniques of the present invention may be used to sample extracellular fluids for the quantification of glucose and the like. Glucose is present extracellularly at the same concentration (or in a known proportion) as in blood vessels (e.g., lonnroth p. strandberg l. determination of "internal reference technique" for in situ microdialysis tubes, ActaPhysiological Scandinavica, 153 (4): 37580, april 1995).

Perforation or alteration of the stratum corneum causes a local increase in transepidermal water loss (referred to as transepidermal water loss, or TEWL). As shown in FIG. 27, the fluence (J/cm) of the laser light is varied²) The loss of water increases accordingly. The tape strip test result is a positive control, demonstrating that this measurement method is indeed sensitive to an increase in skin water evaporation.

Two energies used in FIG. 27, 40mJ and 80mJ (1.27 and 2.55J/cm)²) Is non-ablative, thus it is shown that non-ablative energy causes a change in the barrier function of the stratum corneum, resulting in an increase in transepidermal water loss, which provides a diagnostic sample of extracellular fluid.

In addition to glucose, other compounds and pathological agents can also be detected in the extracellular fluid. For example, the presence of HIV extracellularly can be determined according to the method. The benefit of obtaining samples for HIV analysis is evident without the use of a sharp instrument and without blood withdrawal, thus preventing infection of healthcare workers. In addition, the present invention can be used to reduce or eliminate the barrier properties of non-skin-like barriers in humans using non-ablative lasers, such as membranes at the blood-brain interface, membranes located in the third compartment of the brain and the hypothalamus, the sclera of the eye, or other mucosal tissue, such as membranes in the oral cavity.

Change without ablation

There are many advantages to changing the technique without ablating the corneal membrane. In a preferred embodiment, the skin is altered, but not ablated, so that its structural and biochemical composition allows penetration of the drug. The result of this embodiment is: (1) the barrier function of the skin is reduced after irradiation, but the skin still presents a barrier to viruses and chemical toxins; (2) less energy is required to ablate the stratum corneum, thus enabling the use of smaller and less expensive lasers; and (3) less tissue damage occurs, thus resulting in faster and effective healing.

Irradiation energy to laser irradiation energy

The radiation emitted by the laser can have coherent, monochromatic, parallel and (generally) intense characteristics. However, to enhance transdermal drug delivery or collection of fluids/gases or biomolecules, the illumination energy used need not have these properties, or have one of all of these properties, but can also be generated by a non-laser light source.

For example, the pulsed light output of a pulsed xenon flash lamp can be filtered with an optical filter or other wavelength selective device to select a range of wavelengths from the illumination energy output. The incoherent and near monochromatic output of this configuration cannot be focused down to a small spot as coherent illumination energy, since this is unimportant for the purposes described above, since it can be focused down to a spot on the order of a millimeter. The light source may be used in a continuous wave mode if desired.

Incandescent infrared output is significantly greater than visible output, and this can be used for this purpose if the source is properly filtered to remove unwanted energy that does not degrade the barrier function. In another embodiment of the invention, it is possible to filter it with an optical filter or similar device using intense incandescent light (e.g., halogen lamp), using continuous wave irradiation energy output to reduce the barrier function of the stratum corneum without causing ablation. All of these sources of illumination energy can be used to generate pulsed or continuous wave illumination energy.

Laser device

It has been found that the practice of the invention can be effectively performed by a variety of lasers; for example, TRANSMEDIA^TMEr: YAG laser perforator, or Schwartz electro-optical Er-YAG laser. Preferably, any pulsed laser that produces energy that is strongly absorbed in tissue can be used in the practice of the present invention, producing the same results at non-ablative wavelengths, pulse lengths, pulse energies, pulse numbers, and pulse rates. However, lasers that produce energy that is not strongly absorbed by tissue may also be used in the practice of the present invention, but only inefficiently. In addition, as described herein, continuous wave lasers may also be used in the practice of the present invention。

Fig. 1 and 2 are diagrams showing a general laser that can be used in the present invention. As shown in fig. 1 and 2, a typical laser contains power circuitry, which may be a standard power supply 10 or an optional rechargeable battery pack 12, an optional power interlock switch 14 for safety purposes; the high-voltage pulse forms a web 16; laser-containing bar 20, preferably Er: YAG, laser pump cavity 18; a device for exciting the laser bar, preferably a flash lamp 22 supported in the laser pump cavity; an optical resonator consisting of a high reflector 24 at the rear of the laser rod and an output coupling mirror 26 at the front of the laser rod; a propagation focusing lens 28 located behind the output coupler; an optional second focusing cylindrical lens 27 between the output coupling lens and the propagation focusing lens; an applicator 30 for positioning the patient's skin in the focal plane of the laser beam, the applicator 30 optionally being heated, for example by an electric heater 32, attached to a laser housing 34; an interlock 36 between the applicator and the power source; and optionally a laser ablation 38 attached to the applicator with a fingertip access port 40.

Typically, the laser derives energy from a standard 110V or 220V ac power supply 10 (single phase, 50 or 60Hz) which is rectified and used to charge a bank of capacitors comprising the high voltage pulse forming network 16. Optionally, the battery 12 is recharged. The capacitor bank establishes a high dc voltage across the high output flash lamp 22. A power interlock 14, such as a push button switch, is optionally provided, which will prevent accidental charging of the capacitor and thus accidental laser firing. An interlock, such as spring loaded interlock 36, may also be added to the laser at the applicator, thus requiring two interlock capacitors to discharge.

When the switch is pressed, a pulse voltage is superimposed on the already existing voltage by the flash lamp in order to energize the flash lamp, resulting in causing the flash lamp to perform an ignition flash. The applicator of light energy from the flash lamp is located in a laser cavity 18 which is shaped so that most of the light energy is effectively directed to a laser rod 20 which absorbs the light energy and deactivates its consequent lasing. The low reflectivity 26 and high reflectivity 28 laser cavity mirrors, which are aligned with the long axis of the laser rod, are suitable for amplifying and modulating the laser beam.

Optionally, the laser cavity mirror as shown in FIG. 12 contains cladding layers 124, 126 that are applied to the ends of the crystal element and have the desired reflectivity characteristics. In a preferred embodiment, Er: YAG crystals are grown in pear-type synthetic gemstones that are two inches in diameter and five inches long. The pear-shaped synthetic stone was drilled through a central hole to produce a rod 5-6 mm in diameter and 5 inches long. The ends of the crystals are ground and polished. The output end, i.e. the end where the laser beam exits the element, is perpendicular to the central axis of the rod within 5 arc minutes. The planarity of the output is 1/10 wavelengths (2.9 microns) over 90% of the holes. The highly reflective end, i.e. the end opposite the output end, contains a convex sphere with a radius of two meters. The polished end was polished so there were an average of ten scratches and five pits per military specification Mil-013830A. Scratches and gouges as specified by U.S. military standards are a subjective measure of the visibility of defects in large surfaces. The rating consists of two numbers, the first being the visibility of scratches and the latter being the number of pits (small depressions). A #10 scratch looks like a 10 micron wide standard scratch, while a #1 pit looks like a 0.01mm diameter standard pit. To collimate the laser beam, optics of a better than 40-20 scratch-pit rating are typically used.

Many plating materials are available from Rocky Mountain Instruments, Colorado Springs, Colorado. A top coating is then vacuum deposited on the ends. The reflectivity of the rear reflective surface 124 should be greater than 99% for a wavelength of 2.9 microns. Conversely, the output end surface should have a coating reflectivity of between 93% and 95%, but other reflective surfaces having a reflectivity as low as 80% are useful. Other vacuum deposited metal coatings having known reflective properties are commonly available for use with other laser wavelengths.

The general equation defining the reflectivity of the mirror necessary for the inversion limit of the population of particles in the laser cavity is:

R₁R₂(1-a_L)²exp((g₂₁-α)2L)＝1

wherein R is₁And R₂Is the reflectivity of the mirror, a_LIs the total scattering loss, g, of each pass through the cavity₂₁Is the gain factor, i.e. the ratio of the excitation light cross section to the particle population inversion intensity, α is the absorption of the illumination over the length of the laser cavity, and L is the length of the laser cavity. Using the above equation, a coating having a suitable spectral reflectance can be selected from the following references. Drisscoll and w. vaughan, "handbook of optics", chapter 8, McGraw-Hill eds: new york (1978); bases et al, "optics handbook", chapter 35, McGraw Hill eds: new york (1995).

Optionally, as also shown in fig. 12, the crystal element may be non-rigidly mounted. In fig. 12 there is an O-ring 130 of elastomer material in a slit in the laser end fitting cap 120 located at the highly reflective end of the crystal element. The O-rings connect the crystal elements by concentrically receiving the elements as shown. However, any shape of elastomeric material may be used so long as it provides elastomeric support to the element (directly or indirectly) to allow for thermal expansion of the element. Optionally, the flash 22 may also be non-rigidly mounted. Fig. 12 shows elastomeric O-rings 134, 136 in the laser end fitting housing, each in its own slit. However, the flash may be supported by other shapes of elastomeric material, including shapes without openings.

Optionally, as shown in FIG. 3, a pump beam diode laser 42, which produces alignment with the long axis of the laser crystal, may be used instead of a flash lamp to excite the crystal. The pump beam of this laser is collimated by a collimating mirror 44 and transmitted to the starting laser rod by a highly reflective infrared mirror 45. The high reflectivity mirror allows the diode pump laser beam to propagate while reflecting the infrared light from the original laser.

Er: YAG lasing material is the preferred material for the laser bar because the wavelength of the electromagnetic energy emitted from this laser, 2.94 microns, is very close to the peak absorption wavelength of water (nearly 3 microns). Thus, this wavelength is strongly absorbed by water and tissues. Rapid heating of water and tissue causes skin perforation or changes.

Other useful lasing materials are any materials that, when stimulated to emit laser light, emit wavelengths that are strongly absorbed by tissue, such as water, nucleic acids, proteins or lipids, and subsequently cause (although not necessarily strongly absorbed) perforation or alteration of the skin. The laser energy effective to ablate or alter exhibits an absorption coefficient of 10-10,000cm^-1The tissue of (1). Lasing elements, e.g. pulsed CO₂Laser, Ho: YAG (holmium: YAG), Er: YAP, Er/Cr: YSGG (erbium/chromium: yttrium, scandium, gallium, garnet; 2.796 microns), Ho: YSGG (holmium: YSGG; 2.088 micrometers), Er: GGSG (erbium/yttrium, scandium, gallium, garnet), Er: YLF (erbium: yttrium, lithium, fluoride; 2.8 microns), Tm: YAG (thulium: YAG; 2.01 microns), Ho: YAG (holmium: YAG; 2.127 micrometers), Ho/Nd: YAlO₃(holmium/neodymium: yttrium, aluminate, 2.85-2.92 microns), cobalt: MgF₂(cobalt: magnesium fluoride; 1.75-2.5 microns), HF reagent (hydrogen fluoride; 2.6-3 microns), DF reagent (deuterium fluoride; 3.6-4 microns), carbon monoxide (5-6 microns), low UV laser, and Nd increased to three times the frequency: YAG (neodymium: YAG, in which the laser beam passes through a crystal that triples the frequency).

Some laser materials additionally have the benefit of being small in size with current technology, allowing the laser to be small and portable. For example, in addition to Er: YAG outside, Ho: YAG lasers can also provide these advantages.

Solid state lasers, including but not limited to those listed above, may use polished barreled crystal rods. The rod surface may also contain a matte finish as shown in fig. 13. However, these two configurations cause a halo around the central output beam. Moreover, while a matte finish can reduce the halo line relative to the polishing rod, this can result in a relatively large drop in the total laser energy output. To reduce the halo and affect the beam pattern in another way, a matte finish may be provided along the bands of the rod, each band extending around the entire circumference of the rod. Alternatively, a bar matte finish may be provided on only a portion of the outer circumference of the bar. Fig. 14 shows a laser crystal element in which a matte finish is provided along two thirds of the length of the entire periphery of the element. Alternatively, as shown in fig. 15, a matte finish is provided along the longitudinal direction of the entire rod of the element. The longitudinal stripes may alternate along the length of the rod portion, for example in stripes of various lengths. The shape of the beam may be affected using a combination of the foregoing techniques. Other pattern variations may be used in the desired beam shape. The particular pattern may be determined based on the starting configuration of the beam emanating from the 100% polishing element, according to the desired final beam shape and energy level. A fully matte finished element may also be used as a reference point for initiation.

Any surface finish greater than 30 microns is considered matte in order to control the shape of the beam. One micro-inch is equal to one-hundredth of an inch (0.000001), a common unit of measure used to establish a standard coarse unit value. Roughness is calculated by squaring the average of the sum of the squares of these distances using the square root average of microinches above or below the average reference line distance. While a rough surface greater than 500 microinches may be used to affect the beam shape, such a finish greatly reduces the amount of light energy entering the crystal rod, thereby reducing the laser energy.

To remove the halo of the beam, Er: two thirds of the full length of the YAG laser bar provides a matte area of about 50 microinches. The smooth area of the rod is less than 10 micro-inches. A baseline check of the non-smooth rod may be first performed to determine the shape of the baseline beam and the energy of the rod. The matte area is then obtained by rough polishing the crystal laser bar, for example with a diamond grinder or grit blaster. The particular pattern of non-smoothness is determined by the desired beam shape and the desired beam energy level. This results in a greatly reduced halo of the beam. The rod may also be made by center drilling a pear-type synthetic stone crystal to leave a rough finish and then polishing the desired area, or by refining a partially rough, partially polished pear-type synthetic stone to achieve the desired pattern.

The beam shape of the crystal laser rod element can be chosen to be modified as shown in figure 16 by the rods 20 surrounding a material 160 that is transparent to the excitation light but has a larger index of reflection than the rods. This modification can reduce the halo of the beam by increasing the probability of photons within the crystal that are off-axis to escape. This step may also be used instead of or in addition to the previous matte step.

The laser beam emitted by the focusing lens 28 is focused to a spot of millimeter or sub-millimeter size. Considering the safety of the laser, a short focal length focusing lens will be used to ensure the energy flux rate (W/cm)²) The tissue sample to be perforated or modified is positioned at the focal point, lower than at the focal point of the lens. Thus, the hazard of the laser beam is minimized.

To create a slit-shaped perforation or alteration by using a cylindrical focusing lens group 27, the laser is focused in such a way that it is narrower in one axis than in the other. This lens group, converging the light beam in one axial direction, is placed in series with the transmission focusing lens 28. When the perforation or modification is slit-shaped, the discomfort or pain to the patient resulting from the perforation or modification is significantly reduced.

Optionally, the beam may be widened, for example using a concave diverging lens 46 (FIG. 4) before being focused by the focusing lens 28. This widened laser beam results in a lower energy flux for a shorter distance of the laser beam at the focal point, thus reducing the hazard level. Furthermore, this optical arrangement reduces optical aberrations at the laser spot at the treatment location, resulting in more accurate perforation or alteration.

Optionally, the laser beams can be split by means of beam splitters to produce multiple beams that are simultaneously or nearly simultaneously perforated or modified. Figure 5 provides two forms of useful spectroscopes. In one form a multi-dichroic mirror such as a partially silvered mirror, dichroic mirror, or a dichroic prism may be provided after the beam is focused. Alternatively, an acousto-optic modulator 52 may be provided, with the modulator 52 being driven with a modulated high voltage and bending the beam. This regulator is outside the laser cavity. So that it rapidly functions to deflect the laser beam at various angles to stimulate the generation of multiple laser beams.

Portability

Currently, a portable TRANSMEDICA is used^TMEr: YAG laser, and the device discharges every 20-30 seconds. This can be improved by adding batteries and capacitors and cooling systems to achieve faster cycle times. Multiple capacitors can be arranged together to reduce the discharge rate to once every 5 or 10 seconds (sequentially charging the capacitor banks). Thus, a higher cycling rate is achieved than with a single capacitor.

TRASMEDIA^TMEr: YAG lasers incorporate a flash lamp whose output is excited by electrical high voltage pulses generated by a bank of charged capacitors. Since high voltage is required to fire the flash lamp and since the laser type involved is to work in conjunction with a dry cell (and thus the charging current is less than that provided by a wall plug), the capacitor takes 20 seconds to fully charge. Thus, if a pulse cycle frequency of 1 pulse/20 seconds is desired, it would be appropriate to use multiple capacitor banks that can be charged sequentially (i.e., when one capacitor bank starts the flash, another capacitor bank is recharged, started, and so on). Thus, the cycle frequency of the pulses is limited only by the number of capacitor banks used in the device (and also by the rate of waste heat removal from the laser cavity).

A small heater, such as a thermo-electric heater 32, may optionally be located at the end of the laser applicator closest to the perforations. The heater raises the temperature at the pre-perforated or altered tissue prior to laser irradiation. When the present device is used for this purpose, this increases the volume of liquid collected. Although any temperature that causes vasodilatation and results in accelerated blood flow, but does not alter blood chemistry, is suitable, it is recommended that skin temperature be in the range of 36EC-45 EC.

Container device

The containment device 68 may optionally be mounted within the laser enclosure proximate to the perforations or changes. The containment device can reduce the intensity of sound generated when the laser beam penetrates or alters the tissue of the patient, improve the collection efficiency of fluids, gases or other biomolecules, and collect ablated tissue and other material released by the perforations. The container means is shaped to facilitate easy insertion into the laser housing and to provide a friction fit within the laser housing. Fig. 8 shows a typical container device inserted into a laser housing and placed over a perforation site.

The containment device 68 includes a primary receptacle 82 that includes a lens 84. The primary receptor collects fluid, gas or other biomolecule samples, ablated tissue, and/or other material released by the perforations. The lens is positioned so that the laser beam can pass through the lens to the perforation locations, but the material released by the perforations does not splash back onto the applicator. The containment device may optionally include a base 86 attached to the receptacle. The base may be selectively shaped to allow insertion of the applicator to interrupt the safety of the laser, thereby allowing the firing of the laser beam.

As shown in FIG. 17, the containment device 68 is shaped and dimensioned for placement alongside or insertion into an applicator and may collect fluid, gas or other biomolecule samples, ablated tissue, and/or other matter released as a result of perforation or alteration. Examples of shapes that the primary receptacle may take include cylindrical, bullet-shaped, conical, polyhedral or any shape. Preferably the container means comprises a primary receptacle having a volume of about 1-2 ml. However, larger and smaller receptacles may also function properly.

The lens 84, which is at least partially transparent, allows the laser beam to pass through while preventing biological or other matter from being splashed back onto the applicator. The material constituting the lens is capable of propagating the wavelength of the laser used. The lens is located in the path traversed by the laser beam at the end of the container means closest to the laser beam. The transmitting substance may be quartz, but examples of other suitable infrared transmitting substances include rock salt, germanium, glass, crystalline sapphire, polyvinyl chloride, and polyethylene. However, these substances should not contain impurities that would absorb the energy of the laser beam. As shown in fig. 20, the lens may optionally include a mask of a non-transmissive substance 85 so that the lens shapes the portion of the beam delivered to the perforation site.

The primary receptacle 82 is formed by the lens and the wall 88, preferably extending outwardly substantially away from the periphery of the lens. The open end or edge 90 of the primary receptacle is adjacent to the perforation or alteration site. The area determined by the lens, the wall of the main receptacle and the perforation and the point of change is therefore essentially closed during operation of the laser.

The base 86 is part of a container device, optionally insertable into an applicator. The base may comprise a cylinder, a multi-element stent, or other structure. The base may optionally include threading. When the base is fully inserted, the safety device of the laser may optionally be switched off, allowing the emission of the laser beam.

Exemplary containment devices may include a cylindrical main receptacle 82, a cylindrical base 86 and an at least partially transparent circular lens 84 positioned between the bases of the main receptacle. The lens may optionally include a mask that shapes the beam of perforated tissue. The interior of the primary receptacle may optionally be coated with an anticoagulant and/or a preservative compound. The containment device may be constructed of glass or plastic. The container device is optionally disposable.

Fig. 19 shows an example of using a laser with a container equipped to aspirate fluids, gases or other biomolecules or to administer drugs. In this embodiment, the applicator 30 is surrounded by a cover 34. The container apparatus is inserted into the applicator 30 and aligned so that the action of the interlock 36 can be eliminated. In this embodiment, the base 86 of the container device is positioned within the applicator 30, while the rim 90 of the receptacle 82 is adjacent to the pre-perforated tissue.

Further, the containment device may be vacuum. The optional vacuum within the containment device is less effective at the puncture or change site than the gas pressure in the interstitial fluid or blood, thus improving the efficiency of fluid, gas, or other biomolecule collection. The container device may optionally be coated with an anticoagulant and/or a preservative compound. The end of the container means may be sealed with a plug 70. The stopper is made of a material having suitable elasticity and conforming to the contour of the puncture site (e.g., a finger). The desired puncture or change site is firmly held down with a plug. The material of the plug is preferably impermeable to gases. Furthermore, the material of the plug is so thin that the laser light can penetrate the substance and penetrate the skin. The plug may be constructed of, for example, rubber.

As shown in fig. 9, the plug piercing center 74 is preferably constructed of a thin rubber material. The plug is of a thickness such that the plug is held in a vacuum prior to piercing and the laser penetrates the plug and tissue adjacent the plug when Er: at YAG laser, the plug can have a thickness of about 100 and 500 microns.

The plug puncture center 74 is large enough to cover the puncture or change site. The perforation sites may optionally be circular holes having a diameter in the range of about 0.1-1mm, or slits having a width of about 0.05-0.5mm and a length of about 2.5 mm. Thus, the center of the plug perforation is large enough to cover these size perforation sites.

As shown in FIG. 10, containment device 68 may include an aperture 76 through which the laser passes. In this embodiment, the containment device optionally collects only ablated tissue. In other embodiments, the irradiation site is firmly held down by the containment device. The container means may optionally include a stopper proximal to the perforation site, however, this is not necessary since it is not necessary to maintain a vacuum. The containment device reduces noise generated by interaction between the laser beam and the patient's tissue and thereby reduces anxiety and stress on the patient.

The container may also be adapted to contain or receive through the opening a drug or other substance which is subsequently released either simultaneously with or shortly after irradiation. Figure 11 shows an embodiment with a container and built-in drug reservoir and a roll-on device for delivery. Figure 18 shows a container and applicator further comprising a sprayer connected to a high pressure cylinder.

The container means may alternatively be disposable such that the container means and the stopper may be thrown away after use.

To disinfect the skin prior to perforation or alteration, a sheet of sterile ethanol soaked paper or other thin material may optionally be placed at the site of the pre-perforation. Such a material also prevents potentially contaminated material from being blown away from the smoke plume released by the perforations. The material must have a low total absorption characteristic for the wavelength of the laser beam. Examples of such materials include, but are not limited to, thin layer glass, quartz, mica, or sapphire. In other words, a thin layer of plastic, such as polyvinyl chloride or polyethylene film, can be placed on the skin. Although the laser beam can penetrate the skin, the plastic prevents most of the plume from flying away and thus reduces the risk of any possible contamination due to infected tissue. In other words, a layer of viscous sterile substance, such as petrolatum, may be added to the transparent material or plastic film to increase the adherence of the transparent substance or plastic film to the skin and further reduce smoke plume contamination. In addition such tablets may be used to deliver allergens, local anesthetics, or other drugs as described below.

An embodiment of such a patch is given in fig. 6 and 7. In fig. 6, the alcohol soaked paper sheet 54 is surrounded by a temporary adhesive tape 58. The test pattern for either of the two patches is shown in fig. 7, in which sterile ethanol, antibiotic ointment, allergen or drug is present in the central region of the patch 60. This substance is retained in this position by a paper or plastic film 62, optionally together with a laser transparent material 64. Examples of such materials include, but are not limited to, mica, quartz or sapphire, which are transparent to the laser beam and are centrally located in the patch. However, such materials need not be completely transparent. The patch may be placed on the skin with adhesive 66.

Modulated laser

In addition to the pulsed laser described above, the modulated laser may also be used to replicate the pulsed laser to enhance delivery of surface drugs while enhancing the removal of fluids, gases, or other biomolecules. This can be achieved by mechanically modulating or alternatively turning off the output of the continuous wave laser by other means such as a saturable absorber (see, e.g., Jeff Hecht, "laser guide," McGraw-Hill: NY, 1992). Examples of continuous wave lasers include CO₂The range of the emitted laser is 9-11 microns (e.g., Edinburgh Instruments, Edinburgh, UK), neodymium: YAG, thulium: YAG (Tm: YAG) which emits 2.1 micron laser light (e.g., CLR Photonics inc., Boulder CO), and semiconductor (diode) lasers emit laser light in the range of 1.0-2.0 microns (SDL inc., San Jose, CA).

Turning off the laser output (e.g., with a mechanical chopper of Stanford Research Instruments inc., SunnyvaleCA) better results in discrete periods of illumination from tenths of milliseconds to nanoseconds or picosecond short intervals. In other words, in the case of a diode laser, the lasing process can be modulated with the excitation current of the modulated laser. Modulators of laser diode power are commercially available from SDL inc. In other words, the continuous beam may be modulated using, for example, a photovoltaic cell (e.g., available from New Focus nc., Santa Clara, Calif.) or a scanning mirror from general scanning, Inc., Watertown MA.

The additive effect of multiple perforations can be exploited using a diode laser. The laser diode supplied by SDL Corporation (San Jose, CA) emits a continuous beam of 1.8-1.96 micron wavelength illumination energy. These diodes operate at an output power equivalent to 500mW and can combine to cumulatively generate higher energy for stratum corneum ablation. For example, a diode bar may contain ten such diodes combined to produce a pulse energy of 5 mJ/ms. It has been demonstrated that ablation effects can be seen with only 25mJ of energy delivered to a 1mm diameter spot. Thus, five 5 millisecond pulses or twenty-five 1 millisecond pulses of this type of diode laser have an ablation effect substantially equivalent to a 25mJ pulse at the same time.

The following examples describe the use of lasers to increase the permeability of the stratum corneum to expel fluids, gases, or other biomolecules and to deliver drugs. These examples do not limit the scope of the present invention, but are merely embodiments.

Example 1

The laser includes a flash bulb (PSC lamp, Webster, NY), an erbium: YAG Crystal (Union Carbide Crystal Products, wasagoul, WA), optical resonance mirror (CVILaser corp., Albuquerque, NM), an infrared transmitting lens (Esco Products inc., oaklidge, NJ) and a number of standard electronic components such as capacitors, resistors, inductors, transistors, diodes, thyristors, fuses and switches, all of which are commercially available from any electronic component supply such as Newark Electronics, Little Rock, AR.

Example 2

Infrared laser emission pulses were obtained using solid-state pulsed erbium: YAG laser and is formed by focusing a laser beam, which is composed of two flat resonator mirrors, one erbium: YAG crystal as active medium and one power source. The wavelength of the laser beam was 2.84 microns. A single pulse is used.

The operating parameters were as follows: the energy per pulse is 40, 80 or 120mJ, the size of the laser beam at the focus is 2mm, and the energy flux is 1.27, 2.55 or 3.82J/cm². The temporal spacing between pulses is 300 mus, producing energy flux rates of 0.42, 0.85 or 1.27 x 10⁴W/cm²。

Transepithelial water loss (TEWL) was measured by the volar appearance of the volunteers' forearms. The front arm is then placed at the focal point of the laser and the laser is discharged. TEWL measurements of the irradiated sites were then collected, with the measurements of the non-irradiated controls being subtracted. The results (presented in FIG. 27) show that at pulse energies of 40, 80 and 120mJ, the barrier function of the stratum corneum is reduced and the resulting water loss is measured as 131, 892 and 1743gm/m, respectively²And/hr. The positive control for strip peel (25 Scotch perforated strips applied continuously and removed quickly from a patch of skin) was determined to be 9.0gm/m²Hr, greater than untouched control; thus the laser is more effective than strip stripping in reducing the barrier function of the stratum corneum.

Clinical assessments were performed 24 hours after irradiation. There was only one small eschar evident at the site of high energy irradiation and no subcutaneous edema. Volunteers were irradiated or in need of medical treatment.

Example 3

Infrared laser emission pulses were obtained using solid-state pulsed erbium: YAG laser and is formed by focusing a laser beam, which is composed of two flat resonator mirrors, one erbium: YAG crystal as active medium and one power source. The wavelength of the laser beam was 2.94 microns. A single pulse is used.

The operating parameters were as follows: the energy per pulse was 60mJ, the size of the laser beam at the focal point was 2mm, and the energy flux was 1.91J/cm². The temporal spacing between pulses was 300. mu.s, producing an energy flux rate of 0.64X 10⁴W/cm²。

The palm portion of the volunteer's forearm was placed at the focus of the laser and the laser was discharged. The ablation site was epicutaneously dosed for two minutes with a 30% lidocaine solution. A 26G-0.5 needle was then inserted into the laser ablation site with no visible pain. After another 6 minute anesthesia treatment, a 22G-1 needle was inserted completely into the laser ablation site with no visible pain. Volunteers were not irradiated and did not require medical treatment.

Example 4

Ablation threshold energy: the normally hydrated (66%) stratum corneum was layered between two microscope slides and exposed to erbium: YAG laser. Ablation marks were determined by placing the sample close to the lamp to see if there was any stratum corneum sloughing at the irradiation site. From this test, the threshold energy of irradiation (for a 2mm irradiation spot) was determined to be about 90-120 mJ. Since energy is consumed to remove the stratum corneum from the epidermis to which it is adhered, the threshold may be higher while the stratum corneum is still covering the epidermis and in the case of normal skin.

Example 5

Differential Scanning Calorimetry (DSC): FIG. 28 shows DSC scans of normally hydrated (66%) human stratum corneum, and sub-ablation using 60mJErbium for pulse energy: YAG laser irradiates the scan of the stratum corneum. Thermal conversion peaks were defined at approximately 65, 80 and 92 ℃, and we measured the heat of conversion (. mu.J), the center of conversion (. degree.C.) and the full width at half maximum of conversion (. degree.C.) (FIGS. 29-31). The results shown are in the normal 66% hydrated stratum corneum, dehydrated 33% stratum corneum, steam heated stratum corneum, erbium: YAG laser irradiated or soaked in chloroform-methanol (a liquid solvent) or β -mercaptoethanol (a protein denaturant). The effect of laser irradiation on the stratum corneum is consistent with visible changes due to thermal damage (i.e. heating with steam) and defatting (depending on the transformation 1, 2 or 3 you see).³H₂The permeability of O and the transdermal resistance test performed on the skin in the same way indicate that the results of these treatments (heat, solvents or denaturants) lead to an increase in permeability. Thus, changes in the stratum corneum induced by these treatments, changes consistent with those seen in laser-irradiated stratum corneum, and changes that do not cause ablation of the stratum corneum, together result in increased permeability.

Example 6

Fourier Transform Infrared (FTIR) spectroscopy: the stratum corneum treated in the same manner as in the DSC test described above was investigated with fourier spectroscopy, except that the energy used was 53-76 mJ. The broad spectrum (see, e.g., FIGS. 32-33) indicates that the absorption bands due to water, proteins, and lipids are altered when the stratum corneum is irradiated. Some of these changes are consistent with visible changes in the stratum corneum that are not laser treated (e.g., dehydration, thermal injury, lipid solubilization, or protein denaturation). For example, the amide I and II bands generated by the presence of proteins (most likely keratin, which makes up the majority of the stratum corneum proteins) move to larger wavenumbers, consistent with the effects of denaturation alone (for the amide II band) or with dehydration and β -mercaptoethanol treatment (for the amide II band) (see, e.g., fig. 34). CH (CH)₂The migration of the vibration band (due to the presence of lipids) to smaller wave numbers indicates that the association between adjacent lipid molecules is disturbed and/or the environment around the lipid molecules is altered in such a way as to alter the vibrational behavior of the molecules (see, e.g., fig. 35).

Example 7

Histology: numerous in vivo tests have been performed on mice and humans. Typically, with erbium: YAG laser selected special pulse energy to irradiate 2mm point on skin, and then immediately or after 24 hours, performing tissue inspection on the irradiated part. Two examples of typical results are shown in figures 36 and 37. Figure 36 shows that the skin of a mouse is irradiated at 80mJ with sufficient energy to render the skin permeable (e.g., to lidocaine) without any signs of stratum corneum ablation. Figure 37 depicts human skin at 24 hours after irradiation at 80 mJ. In this case, there is some change in the appearance of the stratum corneum (perhaps several layers of the stratum corneum have coagulated into a dark black monolayer), while the stratum corneum is still largely intact and not ablated. Irradiation of human skin in vivo and subsequent examination under a dissecting microscope showed that at sub-ablative energies (less than about 90-120mJ), the stratum corneum was still present on the skin. The irradiated skin in vivo turned slightly white, which may be evidence of dehydration or separation of the stratum corneum from the underlying tissue.

Example 8

One way to quantify the reduction of stratum corneum barrier function is to measure the reduction of skin impedance due to laser irradiation. In this test, the reaction was carried out with erbium: a single pulse irradiation energy of a YAG laser using an energy domain irradiates separate 2mm spots on the palm portion of the forearm of the volunteer. An ECG electrode was then placed on the same forearm at the irradiated site and 20cm away from the unirradiated site. The impedance of the skin is then measured with a 100Hz sine wave on the order of 1 volt full amplitude. The results of a series of measurements are shown in FIG. 22, which shows that the impedance of the skin is reduced when the skin is irradiated with an irradiation energy as low as 10mJ by interpolating the data using the fitted curve.

Example 9

Human skin pieces were placed in a diafiltration chamber and treated with erbium: the irradiation can be performed by a single pulse irradiation by a YAG laser. The spot size is 2mm and the pulses can be measured with a calibrated watt-hour meter. After irradiation, the percolator was placed in a 37 ℃ heating apparatus. Phosphate buffered saline was added to the subcutaneous receptor chamber and a small stir bar was inserted into the receptor chamber to maintain continuous mixing of the fluids. Control skin was not irradiated. A small volume of radiolabeled compound (corticosterone or DNA) was then added to the donor chamber and left for 15 minutes (for corticosterone) before removal or throughout the experiment (for DNA). Samples were then removed from the receptor chamber at various times after application of the test compound and measured with a scintillation counter or gamma counter. The results of this test are shown in FIGS. 21 and 26. The results indicate that an increase in permeability can occur at sub-ablative laser pulse energies (see 77 mJ/pulse data for corticosterone). Although the energy used in the DNA experiments may be ablative, permeability is increased when lower energy is used.

Example 10

Histological studies of mice and human skin irradiated in vivo or in vitro have shown that when erbium: the YAG laser pulse energy is less than 100-200mJ with little or no ablation. (see, e.g., FIG. 25). Repetition of this study showed the same results as the previous study. Using tritiated water (³H₂O) in vitro permeation studies, for defined (FIGS. 23 and 24)50mJ (1.6J/cm)²) To 1250mJ (40J/cm)²) The energy of the laser beam is irradiated on the skin, and the ratio can be seen as low as 5J/cm²While the permeability is more or less constant. This indicates that laser irradiation induces an increase in permeability (tritiated water) at sub-ablative energies.

Example 11

Erbium: the output laser of the YAG laser is passed through a hole to limit its diameter to 2 mm. Human skin purchased from a skin bank was placed in a Franz filtration cell. The receptor compartment of the cell was filled with 0.9% buffered saline. The skin in the discontinuous diafiltration chamber was irradiated with a single pulse of standard energy. Control skin was unirradiated. When testing for lidocaine permeability, 254mJ pulses were used and multiple samples were irradiated. In the case of testing for interferon gamma, 285mJ pulses were used and multiple samples were irradiated. In the case of insulin testing, 274mJ pulses were used and multiple samples were irradiated. In the case of cortisone testing, either 77mJ or 117mJ pulses were used and multiple samples were irradiated. In the case of testing for interferon gamma, 285mJ pulses were used and multiple samples were irradiated. After irradiation, a stirring magnet was placed in the receptor chamber of the diafiltration chamber and the chamber was placed in a heating device, maintaining the temperature at 37 ℃. Radiolabeled lidocaine, gamma interferon and insulin were diluted with buffered saline and the resulting 100 μ l solution was poured into the donor compartment of a discontinuous diafiltration chamber. The donor was left on the skin during the test. Samples were removed from the receptor chamber at multiple times after administration and the amount of drug contained was determined using a gamma counter or liquid scintillation counter. The data obtained are graphically presented in FIGS. 39, 40 and 41. From these and similar data, permeability constants can be derived and are listed below:

drug permeability constant, kp (× 10)^-3cm/hr)

Lidocaine 2.62+/-6.9

Gamma-interferon 9.74+/-2.05

Insulin 11.3+/-0.93

Example 12

This data was collected as TEWL results in the same experiment (see example 2 and fig. 27). In the bleach assay, the original skin tone (red) of each spot was determined using a Minolta CR-300 chlorine meter (Minolta inc., NJ). Then, using erbium: the YAG laser melts six 2mm spots on one forearm using energies of 40, 80 and 120 mJ. The spot directly adjacent to the laser-irradiated spot (negative calorimeter control) remained out of contact. A film of 1% hydrocortisone was then applied to six irradiation spots on the treatment arm. An untouched spot on the contralateral arm was treated with a thin layer of Diprolene (β -methasone), a strong steroid, which penetrated the intact stratum corneum in an amount sufficient to cause measurable skin bleaching. A patch of closure consisting of a simple plastic wrap was secured to all points on both arms with gauze and skin tape and left for 2 hours, after which the applied steroid was gently wiped off with a cotton swab. Each of the non-irradiated and irradiated spots was measured using a calorimeter 2, 4, 8, 10, 12, and 26 hours after irradiation, and the results are shown in FIG. 38. Finally, the skin was evaluated clinically as a basis for evaluation after 26 hours of irradiation.

The results of the calorimeter measurements indicated that some skin erythema (reddening) occurred, but the reddening point was less than that seen for the control point not treated with hydrocortisone due to the opposite effect of bleaching the permeated hydrocortisone. The Diprolene control confirmed the validity of the measurement and no problems occurred in the volunteers at the 26 hour evaluation, although in some cases the irradiation site was clearly a small red spot.

Example 13

Mixing erbium: the radiation output of the YAG laser is focused and collimated by optics to produce a spot of, for example, 5mm in size on the skin surface. Visual inspection of a patient's skin at or near the site of the disease may have anything that affects the pharmacokinetics of the drug to be administered (e.g., significant erythema or extensive loss of stratum corneum integrity). This is the point to be irradiated, which is gently decontaminated to remove all debris and any extraneous compounds such as perfume or body oil constituents. A disposable tip attached to the laser is pressed against the skin prior to irradiation to contain all ablated biological debris and to contain all stray irradiation energy from the laser. This was irradiated with a single laser pulse of 950mJ (about 350. mu.s long). The result is a reduction or elimination of the barrier function of the stratum corneum. Subsequently, an amount of a drug, such as hydrocortisone, is applied to the irradiated spot. The drug may be in the form of a paste, which remains at the site of irradiation. Optionally, an occlusion sheet is placed over the drug to retain it at the irradiation site.

Example 14

By using a solid-state pulse Er consisting of two flat resonator mirrors: YAG crystal laser, Er as an effective medium: YAG crystal, power supply, anda method of converging a laser beam forms an infrared laser irradiation pulse. The wavelength of the laser beam was 2.94 microns. The width of the pulse is about 300 mus. The spot size was about 2mm and the energy flux was 5J/cm². A single pulse is used.

Three 2mm diameter spots were made on the flaccid penis. After ablation, alprostadil (available from Pharmacia & Upjohn, Kalamazoo, MI) drug formulations were coated onto small pieces consisting of tissue paper. The sheet was then applied to the perforated area of the skin on the flaccid penis and secured with adhesive tape for 45 minutes. After about 35 minutes, the patient was able to erect for more than 1 hour.

The benefit of this route of administration is that it is painless. A common route of administering alprostadil involves injecting the compound deep into the corpus cavernosum with a hypodermic needle. This step is not only painful, but also can lead to possible infectious contamination of the sharp.

Example 15

By using a solid-state pulse Er consisting of two flat resonator mirrors: YAG crystal laser, Er as an effective medium: YAG crystals, a power supply, and a method of converging a laser beam form infrared laser irradiation pulses. The wavelength of the laser beam is preferably 2.94 microns. The width of the pulse is preferably about 300 mus. The spot size is preferably about 2mm, and about 5J/cm is generated with about 150mJ of pulsed energy²Energy flux of (2).

From TRANSMEDICA^TMEr: the irradiation energy of a single pulse from YAG, operating according to the above parameters, is preferably used to irradiate a 2mm diameter spot on the scalp showing hair loss. Multiple irradiation spots may be used, and after irradiation, minoxidil (e.g., from Pharmacia) may be applied to the scalp near the gap&Rogaine by Upjohn, Kalamazoo, MI) so that the drug stimulates the hair follicle in greater amounts than it is absorbed only across the skin. Alternatively, after ablation, the androgen inhibitor may be administered through a laser ablation site. These male inhibitors can act to counteract the effects of androgens on hair loss.

Example 16

Skin resurfacing is widely used and is a commonly required cosmetic procedure in which laser-generated radiation is used to remove (typically) wrinkles from the face of a patient by ablating about 400 microns of skin (Dover j.s., Hruza g.j., "laser skin resurfacing", Simen, Cutan, med. surg., 15 (3): 177-88, 1996). After treatment, the irradiated area is usually coated with a "mask" made of hydrogel to provide a cool feeling and to prevent undesirable drying of the treated skin and "leakage" of body fluids.

The pain produced by this procedure would be intolerable if local or general anesthetics were not used. Typically, multiple (about to 30) local injections of lidocaine are accomplished prior to irradiation of the skin. These injections themselves take a significant amount of time to act and are themselves relatively painful.

Preferably TRANSMEDIA is used before resurfacing of the skin^TMEr: a single pulse of radiation from a YAG laser can irradiate a 2mm diameter spot on the face requiring multiple applications of lidocaine. The energy used at each laser pulse is preferably 150 mJ. Following irradiation, lidocaine was used as a general anesthetic. Furthermore, by incorporating lidocaine (preferably of the lidocaine-hydrochloric acid hydrophilic type) into hydrosols or other sheets or gel preservation methods and applying these composites (in the physical form of a "mask") to the patient's face before laser irradiation, then applying Er: YAG laser ablates the stratum corneum at the matrix point of the treatment site, and this painless procedure produces sufficient anesthesia. It would also be advantageous to incorporate an analgesic in a hydrosol to prepare patients for fear of a medical procedure. Alternatively, the "mask" can be divided into several anesthetic units suitable for individual application to specific laser treated areas on the face. Finally, another "mask" incorporating a useful drug, such as an antibiotic (e.g., bacitracin, Neosporin, polysporarin, and sulfocaden) or a long-term local or systemic analgesic, such as fentanyl (fentanyl) or demeral, can be applied to the patient after resurfacing of the skin.

Example 17

Hair growth in the nostrils is a common cosmetic problem. The current treatment method is to pull out the hair with tweezers, which is painful and not lasting. By using a solid-state pulse Er consisting of two flat resonator mirrors: YAG crystal laser, Er as an effective medium: YAG crystals, a power supply, and a method of converging a laser beam form infrared laser irradiation pulses. The wavelength of the laser beam is preferably 2.94 microns. The width of the pulse is preferably about 300 mus. The spot size is preferably about 2mm, and about 5J/cm is generated with about 150mJ of pulsed energy²Energy flux of (2).

Preferably used from TRANSMEDICA^TMEr: YAG was operated according to the above parameters to irradiate a 2mm diameter spot on the nasal mucosa showing cosmetic unaesthetic hair growth. Multiple illumination spots may be used. The irradiation itself is sufficient to alter the tissue to inhibit subsequent hair growth, and thus the irradiation itself is sufficient to alter the tissue to inhibit subsequent hair growth. Alternatively, after irradiation, a dye, such as indocyanine green, may be applied, which absorbs different wavelengths of irradiation. After the dye is absorbed by the nostrils, the temperature of the surrounding tissue may be raised using radiation energy at 810nm from a diode laser (GaAlAs laser). This can serve to selectively destroy hair follicles that are in contact with the dye. As a result, the nasal tissue is altered so that no hair is produced, or at least not so quickly as it is manually removed.

While various applications of the present invention have been shown and described, it would be apparent to those skilled in the art that many more modifications than mentioned are possible without departing from the inventive concepts herein.

Claims (80)

1. A method of altering the permeability of the skin with or without partial ablation of the stratum corneum, comprising the steps of:

(a) focusing and irradiating the skin at least as deep as the stratum corneum, but not as deep as the capillary layers, with a laser beam having sufficient energy flux; and are

(b) The laser is excited to create a change site having a diameter of 0.5 microns to 5.0 centimeters.

2. The method of claim 1, wherein the laser beam has a wavelength of 0.2 to 10 microns.

3. The method of claim 1, wherein the laser beam has a wavelength of 1.5 to 3.0 microns.

4. The method of claim 1, wherein the laser beam has a wavelength of 2.94 microns.

5. The method of claim 1, wherein the laser beam is emitted by a laser selected from the group consisting of Er: YAG, pulsed CO₂、Ho：YAG、Er：YAP、Er/Cr：YSGG、Ho：YSGG、Er：GGSG、Er：YLF、Tm：YAG、Ho：YAG、Ho/Nd：YAlO₃Cobalt: MgF₂HF reagent, DF reagent, carbon monoxide, low UV laser and Nd up to three times the frequency: YAG laser.

6. The method of claim 1, wherein the laser beam is formed from an Er: YAG laser emission.

7. The method of claim 1, wherein the laser beam is emitted by a modulated laser selected from the group consisting of continuous wave CO2, Nd: YAG, thulium: YAG, and diode lasers.

8. The method of claim 1, wherein the focal spot of the laser beam on the skin has a diameter of 0.1-5.0 mm.

9. The method of claim 1, wherein the energy fluence of the laser beam on the skin is 0.03 to 100,000J/cm²。

10. The method of claim 1, wherein the energy fluence of the laser beam on the skin is 0.03-9.6J/cm²。

11. The method of claim 1, wherein the pulse width is between 1 femtosecond and 1000 microseconds.

12. The method of claim 1, wherein the pulse width is between 1 and 1000 microseconds.

13. The method of claim 1, wherein a plurality of changes are made to the skin for drug delivery.

14. The method of claim 1, further comprising a beam splitter configured to simultaneously produce multiple spot changes from the laser.

15. The method of claim 14, wherein the beam splitter is selected from a series of partially silvered mirrors, a series of dichroic mirrors, or a series of beam splitting prisms.

16. The method of claim 1, further comprising a means for reflecting the light beam at different angles to create different sites of change on the skin.

17. The method of claim 1, further comprising a means for scanning the laser beam to produce a continuous path change.

18. The method of claim 1, further comprising the step of administering a therapeutically effective amount of a pharmaceutical composition at the site of alteration.

19. The method of claim 18, wherein the pharmaceutical composition is a topically acting drug.

20. The method of claim 19, wherein the pharmaceutical composition is an anesthetic.

21. The method of claim 20, wherein the pharmaceutical composition is lidocaine.

22. The method of claim 19, wherein the pharmaceutical composition is selected from the group consisting of alprostadil (alprostadil), minoxidil (minoxidil), topical antibiotics, antiviral or antifungal agents, chemotherapeutic or anticancer agents, and protein or DNA based biopharmaceuticals.

23. The method of claim 18, wherein the pharmaceutical composition is a systemically acting compound.

24. The method of claim 23, wherein the pharmaceutical composition is an antibiotic.

25. The method of claim 24, wherein the antibiotic is selected from the group consisting of tetracycline, streptomycin, sulfonamides, kanamycin, neomycin, penicillin, and chloramphenicol.

26. The method of claim 23, wherein the pharmaceutical composition is a hormone.

27. The method of claim 26 wherein the hormone is selected from the group consisting of parathyroid hormone, growth hormone, gonadotropins, insulin, ACTH, somatostatin, prolactin, placental lactogen, melanocyte stimulating hormone, thyrotropin, parathyroid hormone, calcitonin, enkephalin, and angiotensin.

28. The method of claim 23, wherein the pharmaceutical composition is selected from the group consisting of steroids, non-steroids, anti-inflammatory agents, systemically acting antibiotics, antivirals, antifungals, and antiemetics.

29. The method of claim 23, wherein the pharmaceutical composition is nitroglycerin.

30. The method of claim 18, wherein the pharmaceutical composition is selected from the group consisting of an antigen, an allergen, and a penetration enhancer.

31. The method of claim 18, wherein the patch containing the pharmaceutical composition is placed at the site of alteration prior to firing the laser.

32. The method of claim 18, wherein the patch containing the pharmaceutical composition is placed at the site of alteration after the laser is fired.

33. A method of delivering a topically acting drug through skin tissue, comprising the steps of:

(a) focusing a laser beam having sufficient energy flux to ablate the skin, at least deep to the stratum corneum, but not deep to the capillary layers;

(b) activating a laser to create an ablation site, the modification site having a diameter of 0.5 microns to 5.0 centimeters; and is

(c) Administering a therapeutically effective amount of a locally acting drug at the site of ablation.

34. The method of claim 33, wherein the laser beam has a wavelength of 0.2 to 10 microns.

35. The method of claim 33, wherein the laser beam has a wavelength of 1.5 to 3.0 microns.

36. The method of claim 33, wherein the laser beam has a wavelength of 2.94 microns.

37. The method of claim 33, wherein the laser beam is emitted by a laser selected from the group consisting of Er: YAG, pulsed CO₂、Ho：YAG、Er：YAP、Er/Cr：YSGG、Ho：YSGG、Er：GGSG、Er：YLF、Tm：YAG、Ho：YAG、Ho/Nd：YAlO₃Cobalt: MgF₂HF reagent, DF reagent, carbon monoxide, low UV laser and Nd up to three times the frequency: YAG laser.

38. The method of claim 33, wherein the laser beam is formed from an Er: YAG laser emission.

39. The method of claim 33, wherein the laser beam is focused on the skin at a spot having a diameter of 0.1-5.0 mm.

40. The method of claim 33, wherein the energy fluence of the laser beam on the skin is between 0.03 and 100,000J/cm²。

41. The method of claim 33, wherein the energy fluence of the laser beam on the skin is 0.03-9.6J/cm²。

42. The method of claim 33, wherein the pulse width is between 1 femtosecond and 1000 microseconds.

43. The method of claim 33, wherein the pulse width is between 1 and 1000 microseconds.

44. The method of claim 33, wherein a plurality of changes are made to the skin for drug delivery.

45. The method of claim 33, further comprising a beam splitter configured to simultaneously produce multiple spot changes from the laser.

46. The method of claim 45, wherein the beam splitter is selected from a series of partially silvered mirrors, a series of dichroic mirrors, or a series of beam splitting prisms.

47. The method of claim 33, further comprising a means for reflecting the light beam at different angles to create different sites of change on the skin.

48. The method of claim 33, further comprising a means for scanning the laser beam to produce a continuous path change.

49. The method of claim 33, further comprising the step of applying a therapeutically effective amount of a pharmaceutical composition to the site of alteration.

50. The method of claim 49, wherein the pharmaceutical composition is a topically acting anesthetic composition.

51. The method of claim 49, wherein a patch containing a locally acting anesthetic is placed over the ablation site prior to activating the laser.

52. The method of claim 49, wherein a patch containing a locally acting anesthetic is placed over the ablation site after the laser is activated.

53. The method of claim 33, further comprising applying a topically acting steroid or steroid anti-inflammatory agent, or an antibiotic, antiviral or antifungal agent, or a biopharmaceutical-based protein or DNA, alprostadil, minoxidil, or a chemotherapeutic or anti-cancer agent at the site of ablation.

54. A method of delivering a drug through skin tissue comprising the steps of:

(a) ablating the skin, at least to the stratum corneum but not to the capillary layers, with a laser beam of sufficient energy flux from a modulated laser; and are

(b) The laser is activated to create an ablation site, the modification site having a diameter of 0.5 microns to 5.0 centimeters.

55. The method of claim 54, wherein the laser beam is emitted by a laser selected from the group consisting of continuous wave CO2, Nd: YAG, thulium: YAG, and diode lasers.

56. The method of claim 54, wherein the laser beam is focused on the skin at a spot having a diameter of 0.1-5.0 mm.

57. The method of claim 54, wherein the energy fluence of the laser beam on the skin is between 0.03 and 100,000J/cm²。

58. The method of claim 54, wherein the energy fluence of the laser beam on the skin is between 0.03 and 9.6J/cm²。

59. The method of claim 54, wherein the pulse width is between 1 femtosecond and 1,000 microseconds.

60. The method of claim 54, wherein the pulse width is between 1 and 1000 microseconds.

61. The method of claim 54, wherein a plurality of changes are made to the skin for drug delivery.

62. The method of claim 54 further comprising a beam splitter configured to simultaneously produce multiple spot changes from the laser.

63. The method of claim 62, wherein the beam splitter is selected from a series of partially silvered mirrors, a series of dichroic mirrors, or a series of beam splitting prisms.

64. The method of claim 54, further comprising a means for reflecting the light beam at different angles to create different ablation sites on the skin.

65. The method of claim 54 further comprising a means for scanning the laser beam to produce a continuous path change.

66. The method of claim 54, further comprising the step of applying a therapeutically effective amount of the pharmaceutical composition to the site of ablation.

67. The method of claim 66, wherein the pharmaceutical composition is a topically acting drug.

68. The method of claim 67, wherein the pharmaceutical composition is an anesthetic.

69. The method of claim 68, wherein the pharmaceutical composition is lidocaine.

70. The method of claim 67, wherein the pharmaceutical composition is selected from the group consisting of alprostadil (alprostadil), minoxidil (minoxidil), topically applied antibiotics, antiviral or antifungal agents, chemotherapy or anticancer agents, and biopharmaceutical-based proteins or DNA.

71. The method of claim 66 wherein the pharmaceutical composition is a systemically acting compound.

72. The method of claim 71, wherein the pharmaceutical composition is an antibiotic.

73. The method of claim 72, wherein the antibiotic is selected from the group consisting of tetracycline, streptomycin, sulfonamides, kanamycin, neomycin, penicillin, and chloramphenicol.

74. The method of claim 71, wherein the pharmaceutical composition is a hormone.

75. The method of claim 74 wherein the hormone is selected from the group consisting of parathyroid hormone, growth hormone, gonadotropins, insulin, ACTH, somatostatin, prolactin, placental lactogen, melanocyte stimulating hormone, thyrotropin, parathyroid hormone, calcitonin, enkephalin, and angiotensin.

76. The method of claim 71 wherein the pharmaceutical composition is selected from the group consisting of steroids, non-steroids, anti-inflammatory agents, systemically acting antibiotics, antivirals, antifungals, and antiemetics.

77. The method of claim 71, wherein the pharmaceutical composition is nitroglycerin.

78. The method of claim 66, wherein the pharmaceutical composition is selected from the group consisting of an antigen, an allergen, and a penetration enhancer.

79. The method of claim 66, wherein the patch containing the pharmaceutical composition is placed at the site of alteration prior to firing the laser.

80. The method of claim 66, wherein the patch containing the pharmaceutical composition is placed at the site of alteration after the laser is fired.