Abstract:
One aspect of the invention provides a method for alleviating acne including: applying a therapeutic substance to an area of skin having follicles, said therapeutic substance comprising a plurality of metal nanoparticles within a carrier; using a device to impart mechanical energy to deliver some of said therapeutic substance into a plurality of follicles; removing the composition remaining on the skin surface while leaving the therapeutic substance in said follicles; and irradiating the skin to which the composition was applied with light energy effective to treat acne.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     The application is a continuation of U.S. patent application Ser. No. 14/627,470, filed Feb. 20, 2015, which application is a continuation of U.S. patent application Ser. No. 12/787,655, filed May 26, 2010, now issued as U.S. Pat. No. 8,961,450, which application claims the benefit of U.S. Provisional Patent Application Ser. No. 61/181,228, filed May 26, 2009. The disclosures of each of the foregoing patent applications are incorporated herein in their entireties by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention is directed to a method and apparatus for delivering a substance, e.g., a therapeutic substance, to sebaceous glands and/or hair follicles. 
     BACKGROUND INFORMATION 
       FIG. 1  shows a hair follicle structure  100 , which includes a hair follicle  110 , hair shaft  120  and one or more associated sebaceous glands  130 . A small gap  125  is generally present between the hair shaft  120  and the sides of the follicle  110  in the upper portion of the follicle structure  100  leading to the skin surface  115 . One or more sebaceous glands  130  are often connected to this gap via a duct  135 , as shown in  FIG. 1 . 
     Sebaceous glands  130  secrete an oily substance called sebum  140 , which is a mixture of lipids and debris from dead cells shed by the gland  130 . The sebum  140  is deposited into the upper portion (infundibulum) of the hair follicle  110 , and eventually may rise up to the skin surface  115 . Sebum  140  can lubricate and protect hair shafts  120 , act as a moisturizer, and can also help to seal the follicle opening  125  from external substances. 
     Sebum accumulation and/or blockage of the duct  135  between the sebaceous gland  130  and the hair follicle  110  by sebum  140  can be a major cause of the common skin condition acne vulgaris (generally referred to as ‘acne’). Sebum blockages can enlarge to form blackheads or whiteheads. Redness, swelling, and infection may also occur. These acne symptoms can be aesthetically undesirable and socially stigmatizing, and they can also lead to the formation of disfiguring scars. 
     Present approaches for alleviating acne symptoms and avoiding more serious complications include application of topical solutions of substances such as benzoyl peroxide (available over-the-counter or by prescription) or salicylic acid, or prescription antibiotics such as erythromycin, clindamycin, or tetracycline derivatives. Topical retinoids can also be applied to alleviate acne symptoms. Retinoids include tretinoin (brand name Retin-A), adapalene, and tazarotene and the non-prescription retinol or derivatives. Retinoids appear to influence cells in the follicle lining, which can help to prevent hyperkeratinization of these cells that can lead to blockages. 
     The effectiveness of such topical treatments, particularly solutions containing retinoids, may generally be limited by the ability of the topical solutions to penetrate deeply into the follicle  110  and into the sebaceous gland  130  itself. Accumulation of sebum  140  and debris in the hair follicle  110  and/or duct  135  leading into the sebaceous gland  130  can inhibit penetration of topical solutions into the follicle region where they may be more efficacious. 
     Oral intake of isotretinoin, a retinoid (available under the brand names ACCUTANE®, SOTRET®, CLARUS™, etc.) has been shown to provide long-term reduction of acne symptoms or severity thereof. Isotretinoin can be very effective for treating severe cases of acne. However, oral administration of isotretinoin is believed to cause significant side effects, including liver damage and birth defects when used by pregnant women. For these reasons, treatment of acne using oral administration of isotretinoin generally requires close monitoring and a specified timetable for treatment cycles. 
     Other techniques that can be used to treat acne with varying degrees of effectiveness include phototherapy (e.g., photodynamic therapy (“PDT”) or treatment with various lasers or intense pulsed light sources). PDT generally involves topical application of a solution containing 5-aminolevulinic acid (ALA) or other photosensitizer precurosors or photosensitizers, followed by irradiation with optical energy to activate the photosensitizer and selectively affect certain tissues where the photosensitizer is present. PDT techniques for treating acne are described, e.g., in U.S. Pat. No. 6,897,238, and various substances that may be used as photosensitizers in PDT procedures are described, e.g., in U.S. Pat. No. 6,034,267. 
     Follicular keratosis is a common condition that is characterized by excess production of keratin that can block follicles, and produce symptoms such as rashes, swelling, pain and/or ingrown hairs. Although there is no known cure for follicular keratosis, symptoms can be relieved through application of substances such as topical solutions of vitamin A or benzoyl peroxide. 
     Topical solutions, lotions, etc. are also marketed for application to the scalp to stimulate hair growth, reduce a rate of hair loss, etc. These solutions can contain substances such as minoxidil, azealic acid, and/or dyhydrotestosterone (DHT) blockers. Such solutions may be more effective and/or may be used in lower concentrations if they can be delivered more effectively to the follicle area or certain portions thereof. PDT techniques can also be used to treat hair loss as described, e.g., in U.S. Pat. No. 7,090,691. Better penetration of compounds used in such PDT techniques into the follicle can improve the effectiveness of such techniques. 
     Thus, in view of the above-described deficiencies, a method and apparatus would be desirable for improved acne treatment and treatment of other skin conditions via more effective application of topical substances into the hair follicle region and optionally into the sebaceous gland. More effective delivery of such substances can allow lower concentrations to be used, can improve efficacy, and can also provide an alternative to more dangerous treatments, such as oral application of isotretinoin. 
     SUMMARY OF THE INVENTION 
     The present invention is directed to meeting the aforementioned needs and addressing the deficiencies particularly discussed above and generally in the prior art. Embodiments of the present invention provide a system, method and apparatus for delivering substances, e.g., therapeutic substances, into the hair follicle region, e.g., proximal to or into sebaceous glands, located in skin tissue. This can be achieved by directing a substance into the follicle under pressure. Optionally, a portion of the sebum present in the hair follicle may be heated and/or removed, e.g. using a vacuum, before introducing the therapeutic substance. 
     In one aspect of the present invention, an apparatus is provided for applying a therapeutic substance under pressure to follicle areas of skin, e.g., to follicle openings and/or sebaceous glands. Such application can improve the penetration of the substance into certain skin structures, which may improve their efficacy. The therapeutic substances can include, but are not limited to, topical solutions or lotions that can be used to treat acne, hair loss, follicular keratosis, or for photodynamic therapy procedures. 
     The apparatus can include a delivery arrangement and an outlet structured to deliver the therapeutic substance contained therein under pressure to the skin surface. The therapeutic substance can be contained within a reservoir or cartridge provided in the apparatus, which may be in communication with a source of pressurized gas or the like that is configured to propel the therapeutic substance through the outlet and into the skin. Alternatively, the therapeutic substance can be provided to the delivery arrangement in the apparatus under pressure from a remote source. 
     The outlet can be configured as a single opening through the lower surface of the apparatus that can be round, oval, a slit, or as a plurality of such openings. The openings can have a small dimension, e.g., a hole diameter or slit width, that is small to facilitate introduction of the substance into the skin at a high pressure. For instance, a hole diameter or slit width can be less than about 1000 μm, e.g., less than about 500 μm, or as small as about 50 μm, or optionally less than about 50 μm. Smaller dimensions can be used in applications for which delivery of the substance into the skin at a higher pressure is desirable. 
     One or more vacuum conduits can be provided at least partially along a lower surface of the apparatus, to improve the physical contact between the lower surface and the skin during application of the therapeutic substance(s). One or more pressure conduits can also be provided at least partially along a lower surface of the apparatus and configured to be in communication with a source of pressurized gas. The pressure conduit(s) can facilitate motion of the apparatus over the skin surface, e.g., by intermittently breaking a suction force between the vacuum conduits on the lower surface of the apparatus and the skin surface. 
     In further embodiments of the present invention, the apparatus can also include a heating arrangement, such as a resistance heater, a source of optical radiation or ultrasound, or the like. The heating arrangement can be configured to contact the skin and/or heat a portion of the lower surface of the apparatus, to thereby heat the skin surface and loosen sebum and/or other debris that may be present in pores, follicles, etc. The skin is preferably heated to a temperature less than 65° C. to avoid generating thermal damage to the heated tissue. The loosened material may then be partially removed from the skin when the one or more vacuum conduits on the lower surface pass over the heated skin. A collection arrangement can be provided in the apparatus or affixed thereto to trap such material removed from the skin through the vacuum conduit(s), thereby preventing such material from being transported into the low-pressure source and possibly contaminating or obstructing it. 
     In a still further embodiment, the apparatus can include a vibrating arrangement mechanically coupled or affixed to the housing. The vibrating arrangement can be configured to induce vibrations in the housing, including the lower surface thereof that contacts the skin when in use. Such vibrations can facilitate movement of the apparatus over the skin surface when a low pressure is present in the vacuum conduit and/or facilitate loosening of sebum and/or other debris that may be present in pores, follicles, etc. 
     In another aspect, embodiments of the present invention provide a method for introducing a therapeutic substance into a skin structure such as a follicle, pore, or sebaceous gland. The method includes optionally heating a surface region to loosen sebum or other debris that may be present near the skin surface. A low-pressure arrangement can then be passed over the heated skin tissue to loosen and/or partially remove some of the sebum and/or debris. A source of a pressurized therapeutic substance can then be passed over the skin surface to direct at least a portion of the substance into pores, follicles, or other skin structures. 
     In yet another embodiment, the invention provides a method for treating a subject having a skin condition. Skin conditions include acne, hair loss, follicular hyper keratosis, etc. The method comprises delivering a therapeutically effective amount of a substance under elevated pressure through at least one opening in a substrate onto the skin tissue of the subject; and providing at least one low-pressure channel along a lower surface of the substrate proximal to at least a portion of the at least one opening, wherein the low-pressure channel is configured to maintain the lower surface of the substrate proximal to the surface of the skin tissue when a reduced pressure is provided in the low-pressure channel, thereby treating the subject for a skin condition. 
     In still another aspect, the invention provides kits that include various embodiments of the apparatus described herein and instructions for using the various embodiments of the apparatus in accordance with the methods of the invention described herein. 
     These and other objects, features and advantages of the present invention will become more apparent from the following detailed description taken in conjunction with the drawings. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       So that those having ordinary skill in the art to which the present application appertains will more readily understand how to make and use the same, reference may be had to the drawings wherein: 
         FIG. 1  is an illustration of a hair follicle structure; 
         FIG. 2 a    is a schematic cross-sectional illustration of an exemplary apparatus in accordance with an embodiment of the present invention; 
         FIG. 2 b    is an illustration of the lower surface of the apparatus shown in  FIG. 2   a;    
         FIG. 2 c    is an illustration of a further configuration of the lower surface of the apparatus shown in  FIG. 2   a;    
         FIG. 2 d    is an illustration of a still further configuration of the lower surface of the apparatus shown in  FIG. 2   a;    
         FIG. 3 a    is a schematic cross-sectional illustration of an exemplary apparatus in accordance with another embodiment of the present invention; 
         FIG. 3 b    is an illustration of the lower surface of the apparatus shown in  FIG. 3   a;    
         FIG. 3 c    is an illustration of a further configuration of the lower surface of the apparatus shown in  FIG. 3   a;    
         FIG. 4 a    is a schematic cross-sectional illustration of an exemplary apparatus in accordance with still another embodiment of the present invention; 
         FIG. 4 b    is an illustration of the lower surface of the apparatus shown in  FIG. 4   a;    
         FIG. 4 c    is an illustration of a further configuration of the lower surface of the apparatus shown in  FIG. 4   a;    
         FIG. 4 d    is a schematic illustration of the apparatus shown in  FIG. 4 a    being used to remove sebum from, and apply a therapeutic substance to, a region of skin tissue; and 
         FIG. 5  is a schematic cross-sectional illustration of an exemplary apparatus in accordance with a further embodiment of the present invention. 
     
    
    
     While the present invention will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments and is not limited by the particular embodiments illustrated in the figures. 
     DETAILED DESCRIPTION 
     A schematic side view of an apparatus  200  that can be used to deliver substances into a hair follicle and optionally to an associated sebaceous gland is shown in  FIG. 2 a   . The apparatus  200  includes a housing  210 , a vacuum conduit  220 , and a delivery arrangement  230 . A lower surface  260  of the apparatus  200  is configured to contact the skin surface  250 . In certain embodiments, the housing  210  can be shaped to be easily held in the hand and traversed over an area of skin  250  to be treated. The delivery arrangement  230  can include a reservoir, cartridge, tube, duct, or the like, or a combination thereof, that may be located within or formed as part of the housing  210 , and that is configured to contain a portion of the therapeutic substance. The therapeutic substance in the delivery arrangement  230  can be pressurized using an external pressure source that can provide a pressurized gas or the like through a delivery tube  235 . The delivery arrangement  230  can also be provided in communication with an external source or reservoir of a therapeutic substance (not shown) configured to supply the therapeutic substance through the delivery tube  235 . Vacuum conduit  220  can be provided in communication with a vacuum or low-pressure source (not shown) through a vacuum tube  225 . A vibrating arrangement  212  may also be affixed to or provided in mechanical contact with the housing  210 . 
     An exemplary configuration of the lower surface  260  of the apparatus  200  is shown in  FIG. 2 b   . The lower portion of the vacuum conduit  220  and the lower surface  260  form a low-pressure channel  222 , which can be generally proximal to the perimeter of the lower surface  260 . The outlet  280  of the delivery arrangement  230  is located in the central region of the lower surface  260 . The outside diameter of the lower surface  260  is preferably small enough to allow the lower surface  260  to conform to local variations in the shape of the skin surface  250 , and large enough to facilitate treatment of larger areas of the skin  250 . For example, the outside diameter of the lower surface  260  can be between about 1 inch and about 3 inches, although smaller or larger diameters can be provided in certain embodiments. The shape of the lower surface  260  can be substantially circular, as shown in  FIG. 2 b   . In further embodiments, the lower surface  260  can be ovoid, elliptical, or polygonal in shape, or any other shape appropriate for a particular application. The lower surface  260  can be substantially flat, or it may be slightly convex, concave, or otherwise contoured to more closely adapt to the shape of a skin surface  250  to be treated. 
     In use, the apparatus  200  can be placed against the skin  250  and a low pressure or vacuum provided in the vacuum conduit  220 . The low pressure or vacuum can be controlled, e.g., using a conventional valve arrangement or the like. The low pressure in the vacuum conduit  220  and low-pressure channel  222  can facilitate close contact and/or adherence between the lower surface  260  of the apparatus  200  and the skin surface  250 . A therapeutic substance can be provided under elevated pressure in the delivery arrangement  230 , e.g., using the delivery tube  235 . The therapeutic substance can be provided in the form of an aqueous solution, another type of liquid solution, a lotion, a suspension or emulsion, or the like. The therapeutic substance can then be delivered into hair follicle regions in the skin  250  located proximal to the outlet  280  of the delivery arrangement  230 . The elevated pressure provided in the delivery arrangement  230  can facilitate such delivery. In certain embodiments, one or more low-pressure channels  222  and/or vacuum conduits  220  can be used to recover a portion of the therapeutic substance from the skin surface that is delivered by the delivery arrangement  230  but not absorbed into the skin openings. Such recovery can be used, e.g., to eliminate a presence of excess therapeutic substance on the skin surface after treatment and/or to recover expensive therapeutic substances or components thereof, such as gold nanoparticles or the like. 
     In certain embodiments, the pressure in the delivery arrangement  230  can be varied over time, e.g., to provide a pulsed delivery of the therapeutic substance. For example, the delivery arrangement  230  can be exposed to intervals of high pressure that may have a regular period or frequency, or which may be randomly timed. The pressure variations or pulses can facilitate introduction of the therapeutic substance into the openings of the skin tissue, such as the follicles and pores. The intervals can be of short duration, e.g., on the order of a second or less. In certain embodiments, longer intervals of high pressure may be used. Such variations in pressure applied to the therapeutic substance during delivery may be used with any of the various embodiments of the present invention described herein. 
     The low pressure provided in the vacuum conduit  220  and low-pressure channel  222  can also help prevent a portion of the therapeutic substance from escaping out the sides of the lower surface  260  of the apparatus  200  when it is delivered under pressure, while preferably not removing a significant amount of the therapeutic substance that was introduced into the skin through the outlet  280 . The size, shape and/or geometry of the low-pressure channel  222  can be selected to optimize these different functions when the device is passed over the skin at reasonable/typical operating speeds. For example, a portion of the therapeutic substance that is forced through the outlet  280  but does not penetrate or absorb into the follicle areas of the skin  250  may be recovered through the low-pressure channel  222  and vacuum conduit  220 . 
     The apparatus can be traversed over the skin surface  250  to treat a larger area of skin. The presence of low pressure in the vacuum conduit can impede mobility of the apparatus  200  over the skin surface  250 . However, it has been observed that providing a pressurized source such as that present at the outlet  280  of the delivery arrangement  230  provides an intermittent breaking and recovery of the vacuum seal between the low-pressure channel  222  at the lower surface  260  of the apparatus  200  and the skin surface. Such behavior can manifest as a vibration of the apparatus  200 , and facilitates easy motion of the apparatus  200  over the skin surface  250 . 
     In a further embodiment, the apparatus  200  can include a pressure conduit  270  configured to be proximal to at least a portion of the vacuum conduit  220  on the lower surface  260  of the apparatus  200 , as shown in  FIG. 2 c   . The pressure conduit  270  can have a form generally similar to that of the low-pressure channel  222  shown in  FIG. 2 a   . A source of pressurized gas, such as air, nitrogen, or the like, can be provided to the pressure conduit  270  using a hose, tubing or the like. The pressure in the pressure conduit  270  can be controlled using a conventional valve arrangement. In use, the low-pressure channel  222  can provide good adherence between the apparatus  200  and skin surface  250 , as described above. The pressure in the pressure conduit  270  can be controlled and/or adjusted to modify this adherence and allow the apparatus  200  to be easily traversed over the skin  250 , substantially independent of the pressurized therapeutic substance provided through the outlet  280  of the delivery arrangement  230 . 
     In certain embodiments, the relative locations of the low-pressure channel  222  and pressure conduit  270  can be reversed from that shown in  FIG. 2 c   , such that the pressure conduit  270  lies outside of the low-pressure channel  222 , e.g., closer to the outer edge of the lower surface  260  of the apparatus  200 . In still further embodiments, the low-pressure channel  222  and/or the pressure conduit  270 , if present, can be provided as a plurality of openings on the lower surface  260  of the apparatus  200 , e.g., as a plurality of rectangular or curved slots, rather than as continuous channels such as those shown in  FIGS. 2 b    and  2   c.    
     Pressure provided to the pressure conduit  270  (if present) and/or the delivery arrangement  230 , and vacuum in the vacuum conduit  220  and low-pressure channel  222  can be controlled individually to provide good adherence of the apparatus  200  to the skin  250  and desired delivery of the therapeutic substance to the skin  250 , while also facilitating motion of the apparatus  200  over the skin surface  250 . For example, the amount of pressure or vacuum applied to these conduits can be set or varied using conventional valve arrangements and/or pressure controllers. The pressures and/or vacuum may optionally be pulsed to facilitate such motion. 
     The outlet  280  of the delivery arrangement  230  can be provided as a single opening, similar to that shown in  FIG. 2 b   . Alternatively, the outlet  280  can be configured as a plurality of smaller openings or nozzles, as shown in  FIG. 2 d   . The smaller openings of the outlet  280  can be used to deliver the therapeutic substance at higher local pressures, which can facilitate infiltration of such substance into the follicle region and optionally into sebaceous glands. For example, the outflow pores may have a lateral size or diameter that is between about 50 μm and about 500 μm. Accordingly, the streams of the therapeutic substance that may be provided through the optional openings or nozzles can have a size that is less than about 1000 μm, e.g., less than about 500 μm, or as small as about 50 μm, or optionally less than about 50 μm. The delivery stream or streams can be used to force solutions or substances into the at least partially open sebaceous follicles. 
     The vibrating arrangement  212  may optionally be provided in the apparatus  200 . The vibrating arrangement  212  can be mechanically coupled to the housing  210 , and configured to generate vibrations in the housing, e.g., on the lower surface  260 , when the device  200  is in use. The vibrating arrangement  212  can include, e.g., an eccentric weight provided on a rotating shaft, a piezoelectric element, or any conventional device configured to produce vibrations. Vibrations generated by the vibration arrangement  212  can facilitate translation of the apparatus  200  over the skin tissue  250  when in use. They can also assist in breaking up, loosening, and/or removing sebum and/or other debris that may be present near the surface of the skin  250 . Such removal of sebum and/or debris is described in more detail below. 
     The vibrating arrangement  212  can have an amplitude of vibration in the range of about 50-1000 μm, or between about 100-500 μm. The frequency of the induced vibrations can be between about 1 Hz and about 10 kHz. Other vibration parameters may be used in certain embodiments. Particular vibration parameters can be selected based on properties of the apparatus  200 , e.g., the size of the apparatus  200  and/or the lower surface  260 , the size and shape of the vacuum conduit  220  and/or the delivery arrangement  230 , the pressures provided in these structures, etc. The vibrating arrangement  212  can include circuitry configured to adjust the amplitude and/or frequency of the vibrations. The vibration arrangement  212  can optionally be included with other embodiments of the present invention described herein. 
     In a further embodiment, an apparatus  300  shown in  FIG. 3 a    can be provided for delivering substances into a hair follicle and optionally to an associated sebaceous gland. The apparatus  300 , similar to the apparatus  200  shown in  FIG. 2 a   , includes a housing  310 , a vacuum conduit  320 , and a delivery arrangement  330 . A handle  340  can be attached to the housing  310  or formed as part of the housing  310  to facilitate manipulation of the apparatus  300 . The delivery arrangement  330  can be provided in communication with a source or reservoir of a therapeutic substance (not shown) through a delivery tube  335 , and the vacuum conduit  320  and low-pressure channel  322  can be provided in communication with a vacuum or low-pressure source (not shown) through a vacuum tube  325 . 
     An exemplary configuration of the lower surface  360  of the apparatus  300  is shown in  FIG. 3 b   . The lower surface  360  can have a substantially square or rectangular shape, as shown in  FIG. 3 b   , and other shapes may also be used. The lower portion of the vacuum conduit  320  and the lower surface  360  form the low-pressure channel  322 , which may be generally proximal to the perimeter of the lower surface  360 . The outlet  380  of the delivery arrangement  330  can be configured as an elongated slit extending through the lower surface  360 . Such a slit can provide a high delivery pressure for the therapeutic substance delivered through the delivery arrangement  330 , and the delivery can easily be applied over a large area of skin when the lower surface  360  of the device  300  is traversed over a skin surface in the direction of the arrow shown in  FIG. 3   b.    
     In a further embodiment, shown in  FIG. 3 c   , the outlet  380  of the delivery arrangement  330  can be configured as a plurality of elongated slits extending through the lower surface  360 . The slits can be arranged in one or more rows, as shown in  FIG. 3 c   , or other configurations may also be used. Such slits can also provide a high delivery pressure for the therapeutic substance delivered through the delivery arrangement  330 . 
     In another embodiment, the apparatus  300  can include a pressure conduit similar to the pressure conduit  270  shown in  FIG. 2 c   . This pressure conduit can be provided proximal to the low-pressure channel  322  on the lower surface  360  of the apparatus  300 , and a gas pressure in the pressure conduit can be controlled and/or adjusted to facilitate traversal of the apparatus  300  over the skin surface, substantially independent of the pressurized therapeutic substance provided through the outlet  380 . 
     A further embodiment of an apparatus  400  that can be used to deliver substances into a hair follicle and optionally an associated sebaceous gland is shown schematically in  FIG. 4 a   . The apparatus  400  includes a housing  410 , a vacuum conduit  420 , and a delivery arrangement  430 . A lower surface  460  of the apparatus  400  can be, e.g., affixed to the housing  410  or formed as an integral part thereof. An outlet  480  can be provided that allows material located in the delivery arrangement  430  to pass through the lower surface  460 . The lower portion of the vacuum conduit  420  and the lower surface  460  form a low-pressure channel  422 . The housing  410  can include a handle  440  that facilitates manipulation of the apparatus  400 , e.g., to translate it over an area of skin to be treated. The delivery arrangement  430  can be provided in communication with a source or reservoir of a therapeutic substance (not shown) through a delivery tube  435 . 
     The vacuum conduit  420  and low-pressure channel  422  can be provided in communication with a vacuum pump or low-pressure source (not shown) through a vacuum tube  425 . The pressure within the low-pressure channel  422  is preferably low enough to substantially maintain good contact between the skin and the lower surface  460  of the apparatus  400  when in use. Any pressure that is lower than atmospheric pressure may be provided in the vacuum conduit  420 . The pressure is preferably greater than about 11 psi (e.g., greater than about −0.8 atmospheres). Exposure of the skin tissue to pressures lower than this may generate some petechial hemorrhage and/or bruising of the skin. However, application of a pressurized environment (e.g., a pressure greater than atmospheric pressure) proximal to the region of tissue exposed to such lower pressure can reduce the likelihood of bruising or hemorrhage. Such higher pressure can be provided, e.g., by the pressurized substance being delivered from the delivery arrangement  430  through the conduit  480  and/or by a pressurized outlet provided in proximity to the low-pressure channel  422 , e.g., similar to the pressurized conduit  270  shown in  FIG. 2   c.    
     The apparatus  400  further includes a heating arrangement  490 . The heating arrangement  490  can include a conventional resistance heater or other heating device, and preferably includes an on/off switch and a controller, e.g., a thermostatic controller or the like. The heating arrangement  490  can provide contact or radiant energy heating of the skin tissue near the surface. For example, the heating arrangement  490  may include electrical resistance heating, infrared or other optical heating (e.g., using a plurality of LEDs, laser diodes, lamps), ultrasound, or other sources configured to emit energy at one or more wavelengths absorbed by the skin and/or the sebum, phase-change or chemical reaction heating (e.g., providing one or more warm or exothermically reactive substances in a chamber within the device), etc. 
     The size, duration, temperature (for conductive contact heating) or exposure parameters of irradiance, wavelength(s) and exposure time for radiant heating of the heating arrangement  490  are preferably selected such that the sebum and debris are sufficiently heated to loosen them and/or facilitate their removal when the apparatus  400  is moved over the skin at reasonable/typical operating speeds. Such speeds can be, e.g., on the order of about 1 cm/sec, although higher or lower speeds can also be used. The heating arrangement  490  can facilitate introduction of the therapeutic substance into the follicle region and optionally into sebaceous glands by heating and loosening accumulated sebum in the follicle region. A portion of this sebum may also be removed using the apparatus  400 , as described in more detail below. 
     An exemplary configuration of the lower surface  460  of the apparatus  400  is shown in  FIG. 4 b   . The outlet  480  of the delivery arrangement  430  is located in the central region of the lower surface  460 . The lower portion of the vacuum conduit  420  and the lower surface  460  form the low-pressure channel  422  in the lower surface  460  that may be generally proximal to the perimeter of the lower surface  460 . A portion  422   a  of the low-pressure channel  422  proximal to the heating arrangement  490  may be wider than other parts of the low-pressure channel  422  to facilitate removal of sebum in the skin, as described in more detail below. In certain embodiments, two or more low-pressure channels  422  may be provided. Thus, for example, the wider portion  422   a  of the low-pressure channel  422  shown in  FIG. 4 b    can optionally be provided as a second channel that is separate from the narrower portion of the low-pressure channel  422 . 
     A surface of the heating arrangement  490  is preferably configured to be substantially coplanar with the lower surface  460 , such that it will contact the skin surface when the lower surface  460  of the device  400  is placed on the skin. In another embodiment, the heating arrangement  490  can be located above a portion of the lower surface  460 , e.g., within the housing  410 , and configured to heat a portion of the lower surface  460  and a region of skin contacting the heated portion of the lower surface  460 . 
     In a further embodiment, the apparatus  400  can include a pressure conduit  470  proximal to at least a portion of the low-pressure channel  422  on the lower surface  460  of the apparatus  400 , as shown in  FIG. 4 c   . The pressure conduit  470  can be similar to the pressure conduit  270  shown in  FIG. 2 c   , and may be provided to facilitate translation of the apparatus  400  over a skin surface when a vacuum or low pressure is present in the low-pressure channel  422  and/or to reduce or prevent bruising of skin that is exposed to the low pressure. A source of pressurized gas, such as air, nitrogen, or the like, can be provided to the pressure conduit  470  using a hose, tubing or the like, and the gas pressure can be controlled using a conventional valve arrangement. Pressure provided to the pressure conduit  470  may optionally be pulsed to facilitate translation of the apparatus  400 . 
     The geometry of the pressure conduit  470  and its location relative to the vacuum conduit  420  may be varied from the configuration shown in  FIG. 4 c   . In general, portions of the pressure conduit  470  that pass through the lower surface  460  of the apparatus  400  are preferably located proximal to portions of the low-pressure channel  422 . For example, the pressure conduit  470  may be configured as a plurality of channels provided substantially parallel to portions of the low-pressure channel  422  on the lower surface  460 . Such proximity can facilitate intermittent interruption of a vacuum seal that may be formed between the low-pressure channel  422  and the skin surface as described above, and allow the apparatus  400  to more easily be translated over the skin when a low pressure is present in the vacuum conduit  420 . 
       FIG. 4 d    illustrates an exemplary use of the apparatus  400  to deliver a therapeutic material  433  into one or more sebaceous glands  495  located in the skin  450 . The apparatus  400  is placed on the surface of the skin  450 . The low-pressure channel  422  facilitates good contact between the lower surface  460  of the apparatus  400  and the skin  450  when a low pressure is provided in the vacuum conduit  420 . The apparatus  400  can be translated over the surface of the skin  450  in the direction indicated by the arrow in  FIG. 4   d.    
     The heating arrangement  490  provided in a forward location of the apparatus will first contact a target area of the skin  450 , and can be controlled to heat sebum  492  and any associated debris located in the target area. Such heating can loosen the sebum  492 , e.g., by melting or reducing the viscosity of wax esters of the sebum  492  that may be present in or proximal to sebaceous glands  495  that block access to the follicle opening and sebaceous gland  495 . 
     For example, the target area of the skin  450  can be heated to a temperature of between about 37° C. and about 47° C. Heating of the skin tissue  450  to higher temperatures can also be performed. Heating temperatures may preferably be greater than about 35° C., which may be slightly lower than the body&#39;s core temperature but greater than a typical surface temperature of the skin  450 . Preferably, the target area of the skin  450  is heated to a temperature that is less than about 65° C., to avoid the likelihood of generating irreversible thermal damage in surrounding dermis tissues. Sebaceous glands  495  are generally located about 1-2 mm deep below the surface of the skin  450 . Heat transfer by conduction through the skin  450  to the level of the sebaceous gland  495  may require several seconds or more, depending on depth of the features being heated. 
     Preheating of skin tissue  450  to be treated can optionally be performed prior to using an apparatus in accordance with certain embodiments of the present invention described herein. For example, radiant heating or contact heating using, e.g., a heated pad, a hot towel, or the like can be performed on the skin  450  prior to application of an apparatus  200 ,  300 ,  400  to the heated skin  450 . In certain embodiments, such preheating can be performed instead of providing a heating arrangement  490  in the exemplary apparatus  400 . Alternatively, such preheating can be performed in addition to using such a heating arrangement  490 . 
     As the apparatus  400  is traversed over the skin  450 , a forward portion  422   a  of the low-pressure channel  422  (which may optionally be wider than other parts of the low-pressure channel  422 ) passes over the heated tissue, and the low pressure can facilitate loosening and/or removal of a portion of the heated sebum  492  and/or debris from sebaceous glands  495 , follicles, and/or pores in the skin  450 . The vacuum procedure can also remove some blockages that may be present in the duct of the sebaceous gland  495  and/or in follicles, which may be achieved with other embodiments of the present invention described herein that do not include a heating arrangement  490 . 
     Removal of sebum  492  and/or other debris in the follicle region can be enhanced, e.g., by applying a force in the vicinity of a hair follicle that has a lateral component (e.g., parallel to the skin surface), such that material in the infidibulum can be squeezed out. Such force may be applied by edges of the lower surface  460  of the apparatus  400  as it is translated over the skin  450 . The low pressure in the low-pressure channel  422  can pull the skin  450  against the lower surface  460  of the apparatus  400  as it is translated, thus increasing the effectiveness of such removal. 
     The outlet  480  of the delivery arrangement  430  can be located behind the wide portion  422   a  of the low-pressure channel  422  (relative to the preferred translation direction of the apparatus  400  indicated by the arrow in  FIG. 4 d   ), as shown in  FIG. 4 b   . The width of the outlet  480  is preferably similar to that of the wide portion  422   a  of the low-pressure channel  422 , e.g., it may be slightly narrower as shown in  FIG. 4 b   . As the apparatus  400  continues to be traversed over the skin  450 , a therapeutic substance  433  provided under pressure in the delivery arrangement  430  can be forced through the conduit  480  and into the follicle region of the target area, e.g., into the sebaceous glands  495  from which some sebum  492  and debris may have previously been loosened and/or removed. Removal of sebum  492  can generate a more open pathway that facilitates penetration of such therapeutic substance  433  more deeply into the follicle and/or sebaceous gland  495 . 
     The therapeutic substance  433  is preferably provided in the delivery arrangement  430  under pressure. In certain embodiments, multiple delivery arrangements  430  and/or outlets  480  can be provided that are configured to deliver two or more different types of therapeutic substances  433 . The delivery arrangement  430  may include a reservoir, cartridge, or the like that may be located within the housing  410  or formed as part of the housing  410  that is configured to contain the therapeutic substance  433 . The therapeutic substance  433  can be pressurized using, e.g., a pressure source such as a manual or electric pump, a piston, a pressurized gas line provided in communication with the delivery arrangement  433 , or the like. 
     In certain embodiments, the outlet  480  can be provided in the form of one or more smaller nozzles, orifices, jets, or slits through the lower surface  460  that are configured to direct one or more small streams of the therapeutic substance  433  onto the skin surface  450  and into the follicle region and/or sebaceous glands  495 . Such nozzles or jets can be provided in a substantially linear array (e.g., in a single row) to expose a large portion of the skin surface to the streams when the apparatus is traversed over the skin surface. Alternatively, the jets or nozzles can be arranged in a two-dimensional array (e.g., two or more rows of nozzles, jets, slits, etc.) to provide greater exposure of the skin surface  450  to the plurality of streams of pressurized therapeutic substance  433  as the apparatus  400  is translated over the skin surface  450 . 
     In further exemplary embodiments, the apparatus  400  can include a plurality of low-pressure channels  422  and/or delivery arrangements  430  and outlets  480 , which may be configured such that a particular follicle or pore is exposed to more than one cycle of low-pressure removal and delivery of pressurized substance(s) as the apparatus  400  is translated over the follicle or pore. Multiple heating arrangements  490  can also be provided. Such exemplary configurations can improve the effectiveness for skin heating, removal of sebum, and/or delivery of therapeutic material(s). Alternatively, the apparatus  400  (or any apparatus in accordance with embodiments of the present invention) may be translated over a region of skin to be treated a plurality of times to generate multiple cycles of heating, sebum removal, and/or delivery of therapeutic substances. 
     A further embodiment of an apparatus  500  in accordance with the present invention is shown in  FIG. 5 . The apparatus  500  includes a housing  510 , a vacuum conduit  520 , a low-pressure channel  522  (optionally including a wide portion  522   a ), a delivery arrangement  530 , and a heating arrangement  590 . The housing  510  can include a handle  540  that facilitates manipulation of the apparatus  500 . A lower surface  560  of the apparatus  500  can be affixed to the housing  510  or formed as an integral part thereof. 
     The delivery arrangement  530  can include a reservoir, cartridge, enclosure or the like adapted to hold a therapeutic substance  533 . The delivery arrangement  530  can be provided in communication with a pressure source through delivery tube  535 , such that the therapeutic substance  533  can be delivered under pressure from an outlet  580  located on the lower surface  560  of the apparatus  500  and into the skin. A control conduit  538  may also be provided in communication with the delivery arrangement  530 , e.g., as shown in  FIG. 5 . A distal end of the control conduit  538  can pass through the lower surface  560  of the apparatus  500  at one or more locations thereon. 
     The control conduit  538  can act as a control valve for pressurizing the therapeutic substance  533  in the delivery arrangement  530 . For example, when the lower surface  560  of the apparatus  500  is placed in contact with a skin surface, the distal end of the control conduit  538  can be blocked, allowing a pressurized gas provided through the delivery tube  535  to force some of the therapeutic substance  533  through the outlet  580 . When the lower surface  560  of the apparatus  500  is not in contact with a skin surface, the pressurized gas will more readily flow through the control conduit  538  and out of the unobstructed distal end thereof, thereby preventing the therapeutic substance  533  from being pushed out of the outlet  580  when it is not proximal to a skin surface. A manual switch or valve may also be provided, in addition to or instead of the control conduit  538 , to control the delivery of pressurized therapeutic substance  533  through the outlet  580  and into a region of skin to be treated. The control conduit  538  can also be provided with other embodiments of the present invention described herein to control application of the therapeutic substance  533 . 
     A collection arrangement  528  may also be provided in communication with a vacuum tube  525  and the vacuum conduit  520 . The collection arrangement  528  can be configured to trap sebum or other material that may be withdrawn from the skin being treated through the vacuum conduit  520 , while preventing the sebum from passing through the vacuum tube  525  that provides low pressure to the vacuum conduit  520  and low-pressure channel  522 . The collection arrangement  528  can be provided within the housing  510  of the apparatus  500  as shown in  FIG. 5 , or external to the housing  510 . The collection arrangement  538  may also be provided with other embodiments of the present invention described herein. 
     An apparatus for delivering a substance to hair follicles, pores and/or sebaceous glands in the skin, in accordance with the various embodiments of the present invention described herein, can be provided as a disposable device. For example, such an apparatus can be provided as a housing that includes one or more vacuum conduits and delivery arrangements with associated outlets, as described herein. The apparatus can be configured to be attached to a low-pressure or vacuum source and a pressure source through a vacuum tube and a delivery tube, respectively. The housing can be configured to accept one or more cartridges, vials, or the like containing one or more therapeutic materials. The housing can also be configured to accept a removable and reusable heating arrangement affixed thereto. A collection arrangement can also be included in the housing. 
     In use, a cartridge containing a therapeutic substance can be affixed to the device such that the substance is in communication with the delivery arrangement. A high-pressure source and a low-pressure source can also be attached to the device. An optional heating arrangement can also be affixed to the device. The device can then be applied to a skin surface as described herein, to apply the therapeutic substance into pores and/or follicle regions of the skin, and optionally to loosen and/or remove a portion of the sebum present. After use, the cartridge and heating arrangement can be removed from the device, and the device disconnected from the low- and high-pressure sources. The device can then be discarded, while the heating arrangement and/or cartridge can be used with a new device for a further treatment. 
     Any therapeutic substance that can produce a desirable effect when delivered into a hair follicle and/or into a sebaceous gland (e.g., not just limited to acne treatments) may be used in embodiments of the present invention. Such therapeutic substances can penetrate more effectively into the follicle and/or sebaceous gland, as compared with a conventional topical application, using the exemplary method and apparatus described herein. 
     For example, one therapeutic substance that may be used is a topical retinoid (e.g., tretinoin) for treatment of acne conditions. ALA or other compounds used in PDT for acne treatment, hair loss treatment, or the like, such as those described in U.S. Pat. Nos. 6,897,238, 6,034,267, and 7,090,691, may also be used. Topical solutions of vitamin A or benzoyl peroxide may be used to treat follicular keratosis. Other therapeutic substances that are marketed as topical solutions for various uses such as treating hair loss or various dermatological conditions may also be used with embodiments of the present invention. For example, solutions for treating hair loss that contain substances such as minoxidil, azealic acid, and/or dyhydrotestosterone (DHT) blockers may be used. Therapeutic substances containing antimicrobial metal nanoparticles may also be used. Therapeutic substances containing chromophores, e.g. exogenous chromophores, such as those described in U.S. Pat. No. 7,494,503 for use in PDT procedures can also be used with embodiments of the present invention. Such substances and/or procedures using such substances may be more effective if they can be delivered more effectively to the follicle area or certain portions thereof. 
     Various therapeutic substances, including any mentioned herein or combinations thereof, can also be applied using embodiments of the present invention. Accordingly, amounts and/or concentrations of such applied therapeutic substances may be reduced and still provide similar effectiveness. This approach may also improve the efficacy of topical solutions and/or reduce the occurrence of undesirable side effects, because the therapeutic substances can be delivered more specifically into the regions of the follicle to be treated. In some applications, using sufficient degrees of preheating, vacuum, and pressurized delivery may allow some amount of the therapeutic substances to be delivered into the sebaceous gland. 
     The foregoing merely illustrates the principles of the invention. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous techniques which, although not explicitly described herein, embody the principles of the invention and are thus within the spirit and scope of the invention. All patents and publications cited herein are incorporated herein by reference in their entireties.