WO2023056171A1 - Printable personalized drug delivery patch - Google Patents

Abstract

A personalized drug delivery system is based on a printable patterned patch by printing therapeutic agents and/or chemical species on the patch with a printer under dermoscopy guidance. A uniform hydroxypropyl cellulose (HPC) membrane was used as a skin adhesive and a loading layer, while an ultra-thin porous poly (lactic-co-glycolic acid) (PLGA) membrane formed a breathable and waterproof protective layer for the HPC membrane. A fluorinated ethylene propylene (FEP) substrate was used for the PLGA and HPC membranes and is removable after delivery of the patch to the skin. Both fat/oil- and water-soluble therapeutic agents can be printed on the patch with high precision and resolution. The drug distribution and penetration performance of the patches depend on corresponding grayscale values of lesion locations. This patch may be used for potential clinical applications, especially for the treatment of skin diseases, cosmetic enhancements, or modifications of skin tissue.

Description

PRINTABLE PERSONALIZED DRUG DELIVERY PATCH

Related Application

[0001] This Application claims priority to U.S. Provisional Patent Application No. 63/250,859 filed on September 30, 2021, which is hereby incorporated by reference in its entirety. Priority is claimed pursuant to 35 U.S.C. § 119 and any other applicable statute.

Technical Field

[0002] The technical field generally relates to patches used to delivery drugs or therapeutics to skin tissue. More specifically, the technical field relates to a personalized or customizable patch used for treating skin conditions or otherwise applying drugs or therapeutic agents to skin tissue.

Background

[0003] Skin diseases are among the most common of all human health afflictions, and thousands of skin conditions have been discovered, affecting nearly one billion people globally. Nevertheless, most skin conditions are treatable, by methods that can be divided into five main categories, namely topical, systemic, surgical, and physical therapy, as well as phototherapy. Of these, topical therapy, which delivers a drug locally to its site of action in the skin, has been the favored route for dermatological therapy for the past few decades and has become increasingly popular due to its convenience, limited side effects, and affordability. Topical medications for skin conditions are available in an extensive range of formulations, including creams, lotions, ointments, gels, liquids, foams, powders, and patches. However, many challenges remain to be overcome for topical drug delivery, including how to achieve accurate drug delivery to specific lesion locations and how to precisely control the local therapeutic dosage.

[0004] Topical drugs applied directly to the skin can cause undesirable side effects, such as itching, peeling, stinging, burning, erythema, rash, irritation, skin discoloration, skin damage, allergies, or contact dermatitis. It is therefore of paramount importance to develop precise drug delivery systems that can restrict the delivery of topical drugs to the area affected by a skin condition, to reduce the risk of side effects to the surrounding healthy skin. However, this presents a challenge, as skin lesions often have indistinct and irregular boundaries with the surrounding normal skin, and each patient has their own individual characteristics. One of how this challenge can be addressed is through the use of non-invasive skin imaging techniques. One such technique is dermoscopy, which is now widely used in the diagnosis of skin conditions and can provide guidance for treatment as well as enabling the monitoring of therapeutic responses. Dermoscopy can help to precisely locate skin lesions; it can also be used to assess their level of severity, as skin conditions frequently cause skin discoloration, and this color difference is often closely linked with disease severity. With various skin conditions, especially skin pigmentation disorders, the shade of skin color of the lesion is often an indicator of the disease severity level. It can also help to inform clinicians of the optimal dosage of therapeutic drugs, which is defined as the dosage that provides the desired therapeutic effect with the minimum of side effects.

Summary

[0005] In one embodiment, a personalized drug delivery system is disclosed that is based on a printable patch that is created by printing therapeutic agents (i.e., drugs) using a printer device (e.g., modified from an inkjet printer) with dermoscopy guidance for the topical therapy. This printable patch consists of three thin layers, fabricated through a layer-by-layer manner using a spin coating technique. The bottom layer of the patch includes fluorinated ethylene propylene (FEP), a copolymer of tetrafluoroethylene and hexafluoropropylene, which acts as a flexible and tough substrate. This hydrophobic membrane can adjust the thermal-moisture equilibrium between the skin and the outer environment. A middle layer of the patch includes a layer of poly (lactic-co-glycolic acid) (PLGA) and serves as a breathable and waterproof protective barrier with the top layer of hydroxy propyl cellulose (HPC) as a skin contact adhesive that is also used for drug loading. The obtained multilayer FEP/PLGA/HPC multi-layer membrane and the drug solution serve as substitutes of the traditional paper and ink, respectively, in the context of inkjet printing on paper. The drug printing is carried out under the guidance of and in response to the personalized imaging of skin conditions by a smartphone-based simple dermoscopy. The drug distribution of the specific pattern printed on the patch can depend on the location and severity of the skin lesions. Such a personalized drug delivery system could be suitable for the high-precision, topical treatment of a variety of skin diseases, such as pigmentations, vitiligo, skin infections, skin scars, bum injuries, and skin cancers.

[0006] In one embodiment, a patch for delivering a therapeutic agent and/or chemical species to skin tissue includes a substrate layer comprising fluorinated ethylene propylene (FEP); a layer of poly (lactic-co-glycolic acid) (PLGA) disposed on the substrate layer; and a layer of hydroxypropyl cellulose (HPC) disposed on the layer of PLGA, wherein the layer of HPC comprises a printed pattern of the therapeutic agent and/or chemical species contained thereon or therein. The printed pattern is a pattern of skin pigmentation or other dermoscopic pattern that is obtained with a dermoscopic imager device or similar imager device.

[0007] In another embodiment, a patch system is disclosed for delivering a therapeutic agent and/or chemical species to skin tissue. The system includes a printer device having one or more fluid-jet cartridges comprising a reservoir for holding the therapeutic agent and/or chemical species and a printhead having a plurality of nozzles configured to eject droplets of the therapeutic agent and/or chemical species and a patch for delivering the therapeutic agent and/or chemical species to skin tissue. The patch, in one embodiment, includes a substrate layer comprising fluorinated ethylene propylene (FEP); a layer of poly (lactic-co-glycolic acid) (PLGA) disposed on the substrate layer; and a layer of hydroxypropyl cellulose (HPC) disposed on the layer of PLGA, wherein the layer of HPC comprises a printed pattern of the therapeutic agent and/or chemical species contained thereon or therein. The patch has the printed pattern printed thereon or therein with the printer device.

[0008] In another method, a method of delivering a therapeutic agent and/or chemical species to skin tissue of a subject includes obtaining one or more images of skin tissue with a dermoscopic imager device, the one or more images of skin tissue comprising a pattern of skin pigmentation or other dermoscopic pattern. An unprinted patch is then provided that includes a substrate layer comprising fluorinated ethylene propylene (FEP), a layer of poly (lactic-co-glycolic acid) (PLGA) disposed on the substrate layer, and a layer of hydroxypropyl cellulose (HPC) disposed on the layer of PLGA. A pattern of the therapeutic agent and/or chemical species is then printed onto or in the layer of HPC using a printer device, wherein the printed pattern corresponds to the pattem(s) in the obtained one or more images of skin tissue obtained with the dermoscopic imager device (or similar imager device). The printed patch is then contacted with the skin tissue of the subject wherein the layer of HPC containing the pattern of the therapeutic agent and/or chemical species comes into contact with the skin tissue of the subject.

Brief Description of the Drawings

[0009] FIG. 1 A illustrates a schematic illustration of the process used to manufacture a printable patch for personalized drug delivery as well as the final patch being applied to skin tissue (right). As seen in FIG. 1 A, a spin coating method is used to fabricate the printable patch (multilayer FEP/PLGA/HPC membrane). The membrane exhibited a typical three-layer sandwich structure, wherein the FEP film or layer is used as the substrate provides sufficient mechanical strength, while the porous PLGA layer or membrane acts as the protective barrier that is breathable and waterproof, and the HPC layer acts as the drug loading layer and displays strong skin adhesion and excellent drug loading efficiency.

[0010] FIG. IB illustrates an example of the application process of the printable patch for personalized precision drug delivery for the treatment of skin conditions. The printable patch and drug solution are used for printing using an inkjet-type printer. A drug-loaded patch incorporates specific patterns of the therapeutic agent and/or chemical species based on images of the skin tissue obtained from a dermoscope or similar imaging device. The pattern of the therapeutic agent and/or chemical species is fabricated on the actual patch using the printer.

[0011] FIG. 2A is a photograph of a large-area FEP/PLGA/HPC membrane with a size of 10 cm x 10 cm.

[0012] FIG. 2B is an image showing the separability test of the FEP/PLGA/HPC membrane.

[0013] FIG. 2C is a schematic illustration of the sandwich structure of the patch and SEM images of the PLGA layer. Inset, statistical analysis of the diameter of 300 pores using Gauss fitting. Scale bars, 5 pm (left) and 2 pm (right).

[0014] FIG. 2D is an image showing the cross-sectional morphologies of the FEP layer (scale bar, 100 pm), the PLGA layer (scale bar, 1 pm), and the HPC layer (scale bar, 5 pm). Insets, contact angle images of the FEP layer (0 = 110.6°) and PLGA layers (fi = 96.2°). [0015] FIG. 2E is a schematic illustration of the uniaxial tensile test along with photographs of the sample before and after the test, and typical stress-strain curves of PLGA, HPC, and PLGA/HPC membranes.

[0016] FIG. 2F is a schematic illustration of the 180° peeling test along with photographs of the sample before and after the test, and typical peeling force-displacement curves of PLGA/HPC membranes when attached to the skin.

[0017] FIG. 3 A is a schematic illustration of the structure of an inkjet printer cartridge according to one embodiment.

[0018] FIG. 3B is a photograph (top) and SEM image (bottom) of the nozzle plate of the inkjet printer cartridge. Scale bars, 200 pm (top), 50 pm (bottom). [0019] FIG. 3C is a graph showing the fluorescence (FL) spectrum of salicylic acid (SA) solution under an excitation wavelength of 365 nm and linear fitting of the FL intensities of the SA solution with different concentrations (0. 1-10 pg/ml). Inset, a photograph of the SA solution under UV light irradiation.

[0020] FIG. 3D illustrates the pattern used for drug printing consists of sixteen typical square shades of gray with gradient grayscale values, and corresponding photographs of the multilayer FEP/PLGA/HPC membrane after drug printing and under UV light irradiation. Scale bars, 1 cm.

[0021] FIG. 3E illustrates a graph of linear fitting of the FL intensities of the re-dissolved SA solution from the square drug patterns with different grayscale values (n = 10).

[0022] FIG. 3F illustrates SEM images of the square drug pattern corresponding to the square shades of gray with different grayscale values (0, 85, 170, and 255). Scale bars, 2 gm. [0023] FIG. 3G illustrates a grayscale image of the University of California, Los Angeles (UCLA) Bruins® logo, and corresponding photographs of the multilayer FEP/PLGA/HPC membrane after drug printing, under UV light irradiation, and stuck on the skin under UV physiotherapy lamp irradiation.

[0024] FIG. 4A is a schematic diagram of the components of one embodiment of a dermoscope. A mobile phone (Smartphone) is used in conjunction with an opto-mechanical attachment that includes a microlens and polarizing filter that is used to obtains image(s) of skin tissue.

[0025] FIG. 4B shows a typical dermoscopy image (left), mirrored grayscale image (middle), and corresponding 3D models (right) established by MATLAB of the skin from a volunteer case of skin pigmentation of a human volunteer. Scale bars, 1 cm.

[0026] FIG. 4C illustrates a printing pattern consisting of sixteen dermoscopy images from four cases of skin pigmentation, and their corresponding mirrored grayscale images. [0027] FIG. 4D are typical images of the drug printed patch using a colored SA solution as the ink under daylight (left) and UV irradiation (right).

[0028] FIG. 4E is a magnified dermoscopy image of typical skin pigmentation (left), and corresponding microscope images of the colored-drug printed patch. Scale bars, 1 mm (the first two), 100 pm (the last two). The high concentration image is from the middle square region in colored drug printing image of FIG. 4E. The low concentration image is from the outer square region in colored drug printing image of FIG. 4E. [0029] FIG. 4F is a typical image of the mice after drug penetration for 12 h, and corresponding FL microscopy images of the cross-section of skin after the drug penetration test. Scale bar, 200 pm.

[0030] FIG. 4G is a quantitative analysis of the drug penetration performance of drug- printed patches. Data are presented as means ± s.d. (n = 5).

[0031] FIGS. 5A-5C are exemplary dermoscopy images (left) and corresponding mirrored grayscale images (right) of both the circular and square pigmentation patterns on the left (L) and right (R) sides of the backs of mice without any treatment (FIG. 5A), treated with the printable patch without drug (FIG. 5B), and treated with the underdosage (10 pL of 1% (w/v)) SA solution (FIG. 5C), at different time points (0, 2, 4, 6, 8, and 10 days).

[0032] FIG. 5D shows dermoscopy images (left) and corresponding mirrored grayscale images (right) of the circular and square pigmentation patterns on the left (L) and right (R) sides of the backs of mice from five different cases (No. 1-5) treated with the overdosage (10 pL of 20% (w/v)) SA solution.

[0033] FIG. 5E illustrates dermoscopy images and corresponding mirrored grayscale images of both the circular and square pigmentation patterns on the left (L) and right (R) sides of the backs of mice from five different cases (No. 1-5) treated with the patch with personalized printed drug every 2 days, and corresponding photographs (right) of the patch under UV physiotherapy lamp irradiation.

[0034] FIGS. 5F and 5G illustrate the evolution of the average grayscale values of the dermoscopy images according to these pigmentation patterns (FIG. 5F) and the corresponding semi-quantitative analysis of the amount of melanin (FIG. 5G). Data are presented as means ± s.d. (n = 5). Statistical significance was evaluated by one-way analysis of variance (ANOVA). ***P < 0.001.

[0035] FIG. 6 illustrates the optical transmittance spectra of the FEP, PLGA, HPC, PLGA/HPC, and FEP/PLGA/HPC membranes.

[0036] FIG. 7 is a SEM image of the FEP layer. Scale bar, 5 pm.

[0037] FIG. 8 is a SEM image of the PLGA layer spin coated on the silicon wafer. Scale bar, 5 pm. Inset, contact angle image ( = 86.3°).

[0038] FIG. 9 is a SEM image of the HPC layer. Scale bar, 5 pm.

[0039] FIGS. 10A-10C are SEM images of the cross-sectional morphology' of the HPC layer of various thicknesses, obtained by adjusting the rotation speeds of spin coating at 2,000 rpm (FIG. 10A), 1,000 rpm (FIG. 10B), and 500 rpm (FIG. IOC), respectively. Scale bars, 5 pm.

[0040] FIG. 11 illustrates a photograph of a free-standing multilayer FEP/PLGA/HPC membrane of size of 10 cm x 10 cm.

[0041] FIG. 12 illustrates the tensile strengths of the PLGA, HPC, and PLGA/HPC membranes. Data are presented as means ± s.d. (n = 5). Statistical significance was evaluated by one-way analysis of variance (ANOVA).

0.001.

[0042] FIG. 13 is a photograph of the SA solution in daylight.

[0043] FIGS. 14A-14B are a schematic illustration of the standard grayscale palette. A standard grayscale palette with 256 squares of varying shades of gray with gradient grayscale values in the range of 0 to 255 (FIG. 14A). FIG. 14B shows the corresponding 3D models of the standard grayscale palette using the grayscale value as the Z-axis (height).

[0044] FIG. 15 illustrates drug distribution with fluorescence microscopy photos of the square drug pattern corresponding to the squares of shades of gray with different grayscale values (0, 85, 170, and 255). Scale bars, 200 pm.

[0045] FIG. 16 illustrates a SEM image of the HPC layer after drug printing using a solution of salicylic acid as the ink. Scale bar, 1 pm.

[0046] FIG. 17A illustrates the absorption spectra of the phenol and colored phenol solutions. Inset, a photograph of the colored phenol solution.

[0047] FIG. 17B illustrates the absorption spectra of the colored phenol solution at different concentrations (0, 10, 20, and 40 mg/mL). Inset, a linear fitting of the absorbance at 499 nm of different concentrations of the colored phenol solution .

[0048] FIG. 17C illustrates a typical photograph of the multilayer FEP/PLGA/HPC membrane following drug printing using colored phenol solution as the ink.

[0049] FIG. 17D is a linear fitting of the absorbance of the re-dissolved colored phenol solution from the square drug patterns with different grayscale values (n = 10).

[0050] FIG. 17E shows SEM images of the square drug pattern corresponding to the shades of gray with different grayscale values (0, 85, 170, and 255). Scale bars, 2 pm. Similar high-quality drug patterns, an excellent linear relationship between the absorbance and grayscale values, and uniform drug distribution were obtained, further indicating the outstanding drug printing performance of the multilayer FEP/PLGA/HPC membranes. [0051] FIG. 18 shows a visual examination of the deformability of the membrane/patch. Photographs of the drug-printed PLGA/HPC membrane sticking on the skin against hundreds of repeated pinching-and-stretching deformations.

[0052] FIG. 19 shows the protection performance of the membrane/patch. Photographs of the drug-printed PLGA/HPC membrane sticking to the skin for 12 h after washing with water and wiping with a napkin.

[0053] FIG. 20A illustrates a printing pattern composed of four squares of different shades of gray with gradient grayscale values (0, 85, 170, 255), selected from the standard grayscale palette.

[0054] FIG. 20B is a photograph of a salicylic acid patch with the pattern repeated twelve times under UV physiotherapy lamp irradiation.

[0055] FIG. 21 shows the results of a drug penetration test. Photographs of the drug- printed patch under UV physiotherapy lamp irradiation during the drug penetration test. Scale bar, 1 cm.

[0056] FIG. 22 shows the results of a drug penetration test. Typical photographs of mice under UV physiotherapy lamp irradiation following drug penetration for various lengths of time (10 min, 30 min, 1 h, 3 h, 6 h, and 12 h). Scale bar, 1 cm.

[0057] FIG. 23 are typical photographs of the well-established animal model with circular and square pigmentation patterns on the left and right sides, respectively, of the backs of mice.

[0058] FIG. 24 illustrates typical photographs of pigmentation pattern-bearing mice from five cases (No. 1-5) before and after topical treatment with the patch after personalized drug printing.

[0059] FIG. 25 illustrates the results of histological examination. Hematoxylin and eosin (H&E)-stained images obtained from sections of skin tissues from the mice (Blank: mice without pigmentation; Control, pigmentation pattern-bearing mice that received no treatment, Patch, pigmentation pattern-bearing mice only treated only with the printable patch;

Underdosage, pigmentation pattern-bearing mice treated with underdosage salicylic acid solution; Overdosage, pigmentation pattern-bearing mice treated with overdosage salicylic acid solution; Treatment, pigmentation pattern-bearing mice treated with the patch after personalized drug printing). Scale bars, 100 pm for all panels.

[0060] FIG. 26A shows 3D reconstruction models of drug distribution of the drug-printed patch from five different mice (No. 1-5) during treatment. [0061] FIG. 26B illustrates the area and intensity of fluorescence of the drug on these drug-printed patches.

[0062] FIGS. 27A-27F illustrate the results of skin lesion segmentation and lesion area quantitation. FIGS. 27A-27E show skin lesion segmentation from the dermoscopy images and corresponding mirrored grayscale images of both the circular and square pigmentation patterns on the left (L) and right (R) sides of the backs of mice with no treatment (FIG. 27 A), treated with the printable patch (FIG. 27B), treated with the underdosage salicylic acid solution (FIG. 27C), treated with the overdosage salicylic acid solution (FIG. 27D), and treated with the drug-printed patch (FIG. 27E), at different time points (0, 2, 4, 6, 8, and 10 days). FIG. 27F shows the progression of the lesion area according to these segmented pigmentation lesions.

[0063] FIGS. 28A-28E illustrate the 3D reconstruction models of the segmented pigmentation lesions from the dermoscopy images of mice with no treatment (FIG. 28A), treated with the printable patch (FIG. 28B), treated with the underdosage salicylic acid solution (FIG. 28C), treated with the overdosage salicylic acid solution (FIG. 28D), and treated with the drug-printed patch (FIG. 28E) at different time points (0, 2, 4, 6, 8, and 10 days), using the grayscale value as the Z-axis (height).

[0064] FIG. 29 show the quantitative analysis of drug-printed patches. The theoretically and experimentally determined amounts of drug printed on a 1 cm² patch (n = 5), and the calculated maximum amount of drug that can be printed on a 1 cm² patch is approximately 350 pg. Ei to Ei are the corresponding experimentally drug loading efficiencies, and the theoretical maximum drug loading efficiency is approximately 33.6%.

[0065] FIGS. 30A-30D illustrates the therapeutic performance of the non-printed drug patch. FIG. 30A shows typical photographs of the non-printed drug patch under visible and UV light irradiation. The patch was fabricated by the drop spreading of different volumes of 10% (w/v) SA solution. Scale bars, 1 cm. FIG. 30B includes typical fluorescence microscopy images under white and UV light illumination of the area with high and low drug concentrations on the non-printed drug patch, respectively. Scale bars, 200 pm. FIG. 30C are dermoscopy images of the circular and square pigmentation patterns on the left (L) and right (R) sides of the back of the mice treated with the non-printed drug patch every 2 days, which was fabricated by the drop spreading of different volumes (No. 1-5: 0, 1, 2, 5, and 10 pL) of 10% (w/v) SA solution. FIG. 30D shows the evolution of the average grayscale values of the dermoscopy images according to these pigmentation patterns and the corresponding semi- quantitative analysis of the amount of melanin.

[0066] FIG. 31 illustrates water vapor transmission rate of the PLGA and PLGA/HPC membranes. Data are presented as means ± s.d. (n = 5). Statistical significance was evaluated by one-way analysis of variance (ANOVA). ***P < 0.001.

[0067] FIGS. 32A-32E illustrates the therapeutic performance in a mouse model of pigmentation. Illustrated are typical mirrored grayscale images of both the circular and square pigmentation patterns on the left (L) and right (R) sides of the backs of mice without any treatment (FIG. 32A), treated with the printable patch without drug (FIG. 32B), treated with the underdosage (10 pL of 1% (w/v)) SA solution (FIG. 32C), treated with the overdosage (10 pL of 20% (w/v)) SA solution (FIG. 32D), and treated with the personalized printed drug patch every 2 days (FIG. 32E), at different time points.

Detailed Description of Illustrated Embodiments

[0068] FIGS. 1A and IB illustrate an embodiment for a patch 2 for delivering a therapeutic agent and/or chemical species 50 to skin tissue 100. The therapeutic agent 50 may include a drug or other medicament. The therapeutic agent 50 may also include macromolecules, cells, and drug formulations for personalized topical medications or treatments. The patch 2 may be used with hydrophilic and/or hydrophobic therapeutic agents 50. In some embodiments, the patch 2 contains only a single therapeutic agent 50, although in other embodiments, the patch 2 may include a plurality of therapeutic agents 50. These may be co-located at the same location(s) on the patch 2 or at different locations. Chemical species other than therapeutic agents 50 or in addition to therapeutics 50 may be loaded in the patch 2 for application onto or into skin tissue 100 in some embodiments. This may include, for example, excipients, adjuvants, dyes or inks (even invisible dyes or inks that are only visible with the application of certain types of light such as ultraviolet light) that may be used to transfer images, graphics, and the like to skin tissue 100 similar to a tattoo. For example, chemical species may be located on the patch 2 to aid in placement of the patch 2 onto the skin tissue 100. Chemical species may be used as markers or fiducial points to aid in placement of the patch 2 so that the pattem(s) of the therapeutic agent 50 found on/in the patch 2 may properly align with the corresponding pattern of skin pigmentation or other dermoscopic pattern on the skin tissue 100. [0069] The patch 2, in one embodiment, includes a substrate layer 10 comprising fluorinated ethylene propylene (FEP). This substrate layer 10 forms a base on which the other two layers 12, 14 are deposited on and can be removed from the patch 2 after contact/appli cation of the patch 2 onto skin tissue 100. While FEP is used as one preferrable material for the substrate layer 10, other polymer-based materials may also be used for the patch 2. The patch 2 further includes, in one embodiment, a layer of poly (lactic-co-gly colic acid) (PLGA) 12 disposed on the substrate layer 10. The PLGA layer 12 is a porous layer that allows the passage of air (e.g., breathable - FIG. 31) yet is a waterproof protective layer.

[0070] The patch 2 further includes a layer of hydroxypropyl cellulose (HPC) 14 disposed on the layer of PLGA. The HPC layer 14 includes the therapeutic agent and/or chemical species 50 contained thereon or therein. For instance, the layer of HPC 14 includes a printed pattern (e.g., FIG. IB) of the therapeutic agent and/or chemical species 50 contained thereon or therein. The printed pattern on the HPC layer 14 is generated using the printer device 70 as seen in FIG. IB and explained herein. In one embodiment, the substrate layer 10 has a thickness of < 150 pm, the layer of PLGA 12 has a thickness of < 200 nm, and the HPC layer 14 has a thickness of < 10 nm.

[0071] In one embodiment, a system 20 is provided that includes the patch 2 along with a dermoscopic imager device 80 configured to one or more capture image(s) of the skin tissue 100 along with a printer device 70. As explained herein, the dermoscopic imager device 80 may include an opto-mechanical attachment 82 that uses the camera of a mobile phone 84 (e.g., Smartphone) as is illustrated in FIG. IB. The opto-mechanical attachment 82 may be removeable from the mobile phone 84 and may include one or more light sources along with one or more lenses and/or polarizers. Alternatively, the light source of the mobile phone 84 (or other light source) may be used to illuminate the skin tissue 100 for images. The dermoscopic imager device 80 captures one or more images 90 of the skin tissue 100 (as seen in FIG. IB). The images 90 that are obtained include a pattern of skin pigmentation or other dermoscopic pattern. The pattern may correspond to a particular skin condition that is to be treated (e.g., FIG. IB). The pattem(s) that are captured in the images 90 may be converted to a file that contains grayscale images of the pattern. This may be obtained in image processing software or an application in the mobile phone 84 or dermoscopic imager device 80. The corresponding grayscale values for the pattern or lesion on the skin tissue 100 that is obtained by the images 90 from the imager device 80 correspond to a quantitative measurement of the visual interpretation of the skin pigmentation. A print file is created by the image processing software or application that, as explained below, is used to print a corresponding pattern onto the HPC layer 14 of the patch 12 using the printing device 70. The pattern that is pnnted on to the HPC layer 14 includes a shape and distribution of therapeutic agents 50 and/or chemicals based on pigmentation pattern obtained with the imager device 80. Thus, the shape, distribution, and density of therapeutic agents 50 and/or chemicals is specifically tailored to match the pigmentation or other pattern that exits on the skin 100 of the subject. [0072] Alternatively, components of the system 20 may include only parts of the patch 2, imager device 80, a printer device 70. For example, the system 20 may include an imager device 80 with opto-mechanical attachment 82 that is used by the patient or subject at home. The obtained images 90 of the skin patterns and/or lesions may be taken and transferred to a remote location (e.g., laboratory, physician’s office, or the like) where the actual patch(es) 2 are printed using a printer 70. Once printed, the patch(es) 2 may be delivered or made available to the subject for use.

[0073] The image(s) 90 that is/are obtained with the dermoscopic imager device 80 are then used to generate the patch 2 loaded with the therapeutic agent and/or chemical species 50 having the corresponding pattern that was captured in the one or more images 90. This is accomplished using a printer device 70 that is used to print the therapeutic agent(s) and/or chemical species 50 onto the material (e.g., HPC layer 14) that forms the patch 2 in the pattern. The printer device 70 is, in one preferred embodiment, a fluid-jet (e.g., ink-jet) type printer that has a cartridge or reservoir 72 that holds the therapeutic agent(s) and/or chemical species 50 and a printhead 74 that ejects droplets or small volumes of the therapeutic agent(s) and/or chemical species 50. The printhead 74 may include a thermal heater 76 that heats the therapeutic agent(s) and/or chemical species 50 and ejects the same out of nozzles 78. Multiple cartridges 72 may be provided, for example, when multiple or different therapeutic agents and/or chemical species 50 are printed using a single printer device 70. The printer device 70 prints the pattern in accordance with the created print file placing the therapeutic agent(s) and/or chemical species 50 in the specific locations on the surface of the layer of HPC 14 of the patch 2.

[0074] The patch 2 is thus fabricated or printed after one or more images 90 of skin tissue 100 are obtained with a dermoscopic imager device 80, wherein the one or more images 90 of skin tissue 100 include a pattern of skin pigmentation or other dermoscopic pattern. The pattern is then printed with the therapeutic agent and/or chemical species 50 onto or in the layer of HPC 14 of the patch 2 using a printer device 70, wherein the printed pattern that contains therapeutic agent and/or chemical species 50 corresponds to the pattern obtained from the one or more images 90 of skin tissue 10 obtained with the dermoscopic imager device 80. In this regard, the size and shape of the pattem(s) of therapeutic agent and/or chemical species 50 that is printed on the patch 2 substantially corresponds to the size and shape of the lesion(s) on the skin tissue 100.

[0075] Multiple patches 2 may be printed on a larger “sheet” of the patch 2 material and then cut into individual patches 2. After the patch 2 is printed, the patch 2 is applied to skin tissue 100 to place the pattern of therapeutic agent(s) and/or chemical species 50 onto the skin tissue 100. Preferably, the patch 2 is positioned such that the pattern of therapeutic agent(s) and/or chemical species 50 substantially overlaps and aligns with the corresponding lesion pattern located on the skin tissue 100. Fiducial or other landmarks may be provided or formed on the skin tissue 100 and/or patch 2 to aid the user in placing the patch 2 into the skin tissue 100. The patch 2 may be applied by the subject or a trained medical professional. After the patch 2 is applied, in one embodiment, the substrate layer 10 may be removed from the patch 2 leaving the other layers 12, 14 disposed on the skin tissue 100.

[0076] The patch 2 may remain on the skin tissue 100 for several minutes, several hours, or longer. In some applications, there may be a need to apply multiple printed patches 2 over the treated area over a period of days. For example, a patch 2 may be worn during the daytime or nighttime and removed and replaced with a new patch 2. The new or additional patches 2 may be applied in a continuous manner or there may be an intervening period of time where no patch 2 is applied to the skin tissue 100 (e.g., patches 2 are applied and worn every other day).

[0077] Experimental

[0078] Preparation and characterization of the printable patch

[0079] The patch 2 was fabricated by depositing of PLGA and HPC on the FEP substrate 10 by spin coating (FIG. 1 A). FIG. 2A shows a typical photograph of the prepared patch in an extensive scale (10 cm x 10 cm) with excellent transparency (FIG. 6), uniformity, and flatness. The separability test (FIG. 2B) revealed that the middle PLGA layer 12 was tightly bound to the top HPC layer 14 but could be easily peeled off from the bottom FEP substrate 10 due to its non-stick surface. Surface and cross-sectional morphologies of the patch 2 were further investigated by the scanning electron microscope (SEM) and optical microscope (FIGS. 2C, 2D, and FIGS. 7-10A-10C). The FEP substrate 10 exhibited a smooth and uniform surface (FIG. 7) and had a thickness of -100 pm (FIG. 2D), which is close to that of regular printer paper. The FEP substrate 10 also demonstrated good surface hydrophobicity with a contact angle (;?) of 110.6° (inset in FIG. 2D).

[0080] Of note, the prepared PLGA layer 12 (or membrane) exhibited a uniform porous structure with high porosity. The diameter of these pores ranged from hundreds of nanometers to several micrometers with an average value of 0.89 ± 0.26 pm (FIG. 2C). The formation of such structure may be due to the balance between the surface tension of PLGA solution on the hydrophobic FEP surface 10 which causes surface shrinkage of the liquid, and the rotation which causes the liquid to spread out during the spin coating process. Once the solvent evaporation rate and the diffusion rate reach equilibrium, the PLGA layer 12 with a porous structure can be formed. The PLGA layer 12 also contained an ultra-thin structure with a thickness of less than 200 nm (FIG. 2D), and its contact angle was 96.2° (inset in FIG. 2D) which was slightly higher than that of the flat PLGA layer 12 (FIG. 8) owing to the lotus effect. This hydrophobic PLGA membrane 12 can adjust the thermal-moisture equilibrium between the skin 100 and the outer environment. Thus, the fabricated PLGA layer 12 or membrane was both breathable (FIG. 31) and waterproof, making it an appropriate candidate for the backing layer of drug patches for use in topical drug delivery applications as the backing layer of drug patches for use in topical drug delivery applications. Moreover, HPC, another polymer that has been widely used in drug delivery as a binder or a polymer coating, was chosen as the component of the drug loading layer 14 with a thickness of ~7 pm (FIG. 9 and FIG. 2D). To enable different drug loading capacities, the thickness of the HPC layer 14 can be tuned within the range of several to tens of micrometers by modifying the spin coating process (FIGS. 10A-10C).

[0081] The free-standing patch 12 that was fabricated exhibited good flexibility and toughness (FIG. 11). In practical applications, the FEP layer 10 can be peeled off after the drug patch 12 had stuck to the skin 100, thus the mechanical properties of the remaining PLGA/HPC layers/membranes 12, 14 are critical to the long-term topical drug delivery process. As expected, the combined PLGA/HPC layers/membranes 12, 14 showed higher tensile strength and toughness than the PLGA and HPC layers 12, 14 alone, with a maximum tensile strength of 16.1 MPa (FIG. 2E and FIG. 12). The synchronous tensile fracture of the PLGA layer 12 and HPC layer 14 in the combined PLGA/HPC layer/membrane further validated their tight bonding. Moreover, a standard 180° peeling test was conducted to measure the interfacial toughness of the HPC layer 14 bonded on the skin 100 (FIG. 2F). Good adhesion was observed, with the measured force reaching a plateau with an average value of ~0.2 N once the peeling process reached a steady state.

[0082] Printable performance of the patch

[0083] Next, an ordinary' inkjet printer (Hewlett-Packard HP-5278) was used to load the drug 50 and test the printable performance of the patch 12. The inkjet printer cartridge 72 mainly consists of a therapeutic agent/drug 50 reservoir(s), electronic chip(s), a heater 76, and a nozzle plate with nozzles 78 (FIG. 3 A) that form the printhead 74. During the printing process, the heater 76 is warmed by a resistor that responds to a signal from the printer 70; the heater vaporizes the therapeutic agent or chemical species 50 (in a very short time - e g., less than 10 microseconds) to form tiny bubbles inside the nozzle 78 which are then forced out onto the patch 12. The morphology of the nozzle plate was then characterized. Two rows of hole-like structures with a diameter of -25 pm can be observed (FIG. 3B), which is sufficient for the printing of therapeutic agents and/or chemical species 50 in a solution state or dispersion state with sub-micron sized particles. Of, other nozzle/printhead configurations may be used.

[0084] As an example of a therapeutic agent 50, salicylic acid (SA) has been approved by the United States Food and Drug Administration (FDA) for to its keratolytic, bacteriostatic, fungicidal, and photoprotective properties; it has been widely used for the topical treatment of various skin conditions such as warts, psoriasis, calluses, acne, ichthyosis, dandruff, and especially for the chemical peeling of pigmentation disorders. For this drug printing, 10% (w/v) SA dissolved in ethanol solution was employed as a model therapeutic agent 50 (FIG. 3C and FIG. 13). The fluorescence (FL) spectrum of the SA solution exhibited a significant characteristic emission peak at 439 nm under an excitation wavelength of 365 nm. A linear relationship was obtained between the FL intensity at 439 nm and the concentration of SA solution in the range of 0.1-10 pg/ml, which was subsequently used for the quantitative analysis of SA.

[0085] Sixteen typical squares of various shades of gray with gradient grayscale values were selected from the standard grayscale palette range, 0-255 (FIGS. 14A-14B) for the follow-up drug printing (FIG. 3D). The ink in the printer cartridge 72 was replaced with the SA solution, which was then printed onto a 5 cm x 5 cm printable patch 2 fabricated as described above. The patch 2 maintained good shape fidelity and exhibited no visible changes before or after drug printing, indicating its excellent printability . Clear patterns of the printed therapeutic agent 50, with a high degree of sharpness and good printing quality, were observed from the patch 2 under ultraviolet (UV) light irradiation. For the quantitative analysis, each square was carefully cut out of the patch 2 and immersed in an ethanol solution to re-dissolve the SA; the FL intensity of the resulting solution was then evaluated (FIG. 3E). A statistical analysis of the data from ten randomly selected patches 12 showed that a robust linear relationship exited between the FL intensity at 439 nm and the grayscale value. The surface morphology and the distribution of patterns of therapeutic agent 50 corresponding to different grayscale values (0, 85, 170, and 255) were further characterized both at macro- and micro-scales by FL microscopy (FIG. 15) and SEM (FIG. 3F). All of the squares exhibited uniform drug distribution, whereas the square possessed more drug deposition corresponding to a lower grayscale value. In particular, the SA after printing was not only absorbed on the surface of layer 14, but also immersed with HPC, which has both water solubility and fat solubility as the versatile drug loading layer (FIG. 16). In addition to the fat-soluble SA, a water-soluble drug, phenol, was tested for drug printing and was found to have the similar printable performances (FIGS. 17A-17E).

[0086] The possibility of printing more complex patterns using this drug printing system (FIG. 3G) was also demonstrated. A University of California, Los Angeles (UCLA) Bruins® logo was printed on a 5 cm x 5 cm patch 2 with a smallest feature of 25 pm in diameter. Moreover, the obtained drug patch 2 can be conveniently and conformally attached to the skin 100 after cleaning with 75% alcohol. After the outermost FEP layer 10 was peeled off, the remaining drug-printed PLGA/HPC layer/membrane 12, 14 firmly adhered to the skin 100 and could maintain excellent flexibility, deformability (FIG. 18), and waterproof capabilities (FIG. 19) for up to 12 hours.

[0087] Dermoscopy-guided drug printing

[0088] A self-made dermoscope imager device 80 was used that incorporated a Smartphone mobile phone 84 together with a mobile phone microscope or opto-mechanical attachment 82 that included a microlens and polarizing filter (FIG. 4A), which was used to obtain images 90 of skin pigmentation under cross-polarized lighting (FIG. 4A). A typical dermoscopy image 90, mirrored grayscale image, and corresponding three-dimensional (3D) models of the skin pigmentation from the skin 100 of a volunteer are shown in FIG. 4B. A clear picture with good subsurface details and low reflectance from the air/tissue interface was captured. Generally, the severity of skin pigmentations and the amount of pigment can be estimated by observing the color and lightness of the dermoscopy image 90. Thus, the corresponding grayscale values were recorded as a quantitative measurement of the visual interpretation of the skin pigmentation. The 3D reconstruction further quantitatively displayed the pigmentation distribution based on the grayscale value of each pixel. [0089] The large-scale printing capability of the printable patch 2 using a drug printing technique was also demonstrated. Dermoscopy images 90 from four cases of skin pigmentation were duplicated four times to form the drug printing pattern (FIG. 4C). To better evaluate the print quality and observe the drug distribution, a colored solution of SA was used as the ink. Clear drug patterns with excellent print quality and accurate drug distribution based on the shape and grayscale values of the printing pattern were obtained on a 10 cm x 10 cm patch (FIG. 4D). The accuracy and resolution of this drug printing technique were explored further (FIG. 4E). A magnified dermoscopy image 90 was mirror printed on the patch 2 with accurate drug distribution. The enlarged microscopy image of the area in darker positions showed denser drug printing dots, indicating a higher drug concentration. Print resolution is usually measured in dots per inch (25.4 mm) (DPI); the higher the DPI, the better the resolution in terms of sharpness and detail. The diameter of a single drug dot was determined to be ~25 pm, thus the print resolution can be calculated as -1000 DPI, indicating that the printed drug dots show good stability on the HPC layer 14 with limited diffusion. [0090] The drug penetration performance of drug-printed patches 2 was also evaluated. Four typical squares of shades of gray with gradient gray scale values of 0, 85, 170, and 255 were selected out to form the print patterns (FIGS. 20A-20B). Large-scale printing of the repeated patterns (12 times/patch) on 8 cm * 10 cm patches 2 with high-quality and uniform drug distribution was achieved using the same SA ink. For the quantitative analysis, these squares were cut from the patch 2, and their drug amount and drug-loading efficiency were then evaluated (FIG. 29). After that, 30 nude mice were selected and randomly divided into six groups (n=5) for the follow-up drug penetration test. The skin on the back of each mouse was cleaned using 75% alcohol and a drug-printed patch was then applied on the back of each mouse under UV irradiation (FIG. 21). The drug squares with higher drug concentrations, corresponding to the printing pattern with lower gray scale values, showed better drug penetration performances, and the FL intensity of the drug in the skin of the mice gradually increased over time, indicating progressive drug penetration (FIG. 22). Importantly, the drug rapidly entered the specifically intended part of the skin without obvious spread to the surrounding skin 100. The penetration capability was further investigated by measuring the penetration depth of the therapeutic agent 50. FIG. 4F shows typical FL images of skin crosssections following 12 h treatment with the drug-printed patches 2. The drug square corresponding to the printing pattern with a grayscale value of 0 exhibited the greatest penetration depth of more than 500 pm, while the penetration depths corresponding to the grayscale values of 85 and 170 were close to 200 pm and 100 pm, respectively. As expected, the drug squares corresponding to the shades of gray with lower grayscale values showed higher drug concentrations, resulting in deeper penetration into the skin. For the quantitative analysis, drug concentration in the skin 100 showed an increasing trend with the drug penetration time and increased amounts of the drug in the patch 2, corresponding to the patterns seen with decreasing grayscale values (FIG. 4G).

[0091] Therapeutic performance in a mouse model of pigmentation

[0092] The printable patch 2 was then applied for the topical therapy of skin pigmentation disorders to evaluate its therapeutic performance. An animal model of skin pigmentation disorder was established using 1,3-dihydroxyacetone (DHA)-based self-tanning drops. DHA is a non-toxic physiological substance produced in the body, which darkens the skin via the Maillard reaction with protein in the stratum comeum. The pigments produced, known as melanoidins, are highly stable, with pigment loss only occurring during the sloughing of the stratum comeum. The well-established mouse model, with circular and square pigmentation patterns on the left and right sides of the back, respectively, are shown in FIG. 23. Next, 25 nude mice with pigmentation patterns were selected, randomly divided into five groups (n = 5), and subjected to various treatments, including: (1) no treatment, (2) treated with the printable patch 2 without drug, (3) treated with drug underdosage (10 uL of 1% (w/v) SA solution), (4) treated with drug overdosage (10 pL of 20% (w/v) SA solution), and (5) treated every 2 days with the printable patch 2 with personalized printed drug.

[0093] The produced pigments are highly stable, therefore the pigmentation patterns obtained in the control group did not show any significant changes within 10 days (FIG. 5 A). After being treated with the printable patches 2 for 12 h every two days for 10 days, the pigmentation patterns showed a slight tendency to fade (FIG. 5B), which may have been due to the viscosity of the HPC layer 14 causing accelerated cell shedding from the surface of the stratum comeum. Owing to the good chemical peeling performance of SA on the skin 100, the pigmentation patterns in mice treated with underdosed SA solution every two days also showed a gradually fading trend over 10 days but with poor treatment efficiency (FIG. 5C). Although chemical peeling is a non-invasive procedure that is usually very safe and effective, it does carry some risks and uncertainties, such as infection, scarring, and abnormal pigmentation. FIG. 5D shows five mice that exhibited side effects resulting from the overdosage SA solution. These pigmentation patterns all faded by a significant amount in a short time and eventually disappeared, further confirming the excellent chemical skin peeling performance of the SA solution. However, because the local drug dosage level and treatment boundaries were difficult to control, the overdosage SA solution inevitably caused severe side effects to the skin of the mice following treatment, including scarring in case No. 1, skin damage in case No. 2, redness in case No. 3, infection in case No. 4, and abnormal pigmentation in case No. 5. Additionally, non-printed drug patches fabricated by conventional method (drop spreading) were also used for treatment (FIGS. 30A-30D). Irregular accumulation of large drug crystals (200 pm) can be observed from these patches, resulting in uncontrollable local drug dosage and distribution, which ultimately results in poor therapeutic efficacy or severe side effects.

[0094] The therapeutic performance of the printable patch 2 with personalized drug printing guided by dermoscopy imaging to treat the patterned pigmentations was also evaluated. As shown in FIG. 5E, five mice with differing pigmentation severity levels were treated with the drug-printed patches 2 for 12 h every two days. The drug distribution on the patches 2 matched very well with the pigment distribution of the corresponding skin lesions (FIGS. 26A-26B). For case No. 1, the pigmentation exhibited significant improvement after the first treatment at day 2 in the initial process, while the average grayscale value increased significantly from (L: 175.3, R: 174.7) to (L: 230.7, R: 227.6) and the amount of melanin reduced from (L: 339.2, R: 357.3) to (L: 142.6, R: 145.2). Drug-printed patches 2 guided by dermoscopy imaging of residual pigmentation were then applied for further treatment, and these pigmentations were completely removed after two treatment sessions. Similar treatment outcomes were also observed with cases No. 2 and No. 3. In cases where the pigmentation was stronger, the location of the pigment was deeper, or the stratum comeum was thick or dense, the treatment process usually required multiple treatments. For cases No. 4 and No.5, the pigmentation exhibited only a slight improvement after the first course of treatment, and the remaining pigmentations were further treated with drug-printed patches 2 according to the real-time dermoscopy imaging. Following several courses of treatment, the pigmentations were all completely cleared within 10 days (FIG. 24). Most importantly, in all of these cases, there was no noticeable color difference between the skin 100 that received pigmentation treatment and the surrounding normal skin 100.

[0095] Histological sections of the skin 100 of the mice from all five groups following treatment are shown in FIG. 25, and similar results to the dermoscopy images were seen. Clear pigment distribution can be observed in the stratum comeum of the pigmentation pattern-bearing mice, while the mice treated only with the patch or the underdosage SA solution showed a slight thinning of the stratum comeum; serious side effects were observed in the mice treated with the overdosage SA solution, such as the thinning of and damage to the epidermis. However, the mice treated with the patch 2 with personalized drug printing showed noticeable thinning of the stratum comeum without any damage to the epidermis. [0096] Semi-quantitative analyses of the evolutionary processes of these pigmentations was conducted using a dermoscopy image analysis tool and a skin melanin analyzer. The evolution of the grayscale values of the dermoscopy images calculated from their corresponding mirrored grayscale images (FIGS. 32A-32E), according to the pigmentation and corresponding amounts of melanin observed with different treatment processes, were tracked and are presented in FIG. 5F-5G, respectively. In the “Control”, “Patch”, and “Underdosage” groups, the grayscale values of all these pigmentation patterns showed a slight increasing trend, while the amount of melanin showed a slightly decreasing trend but with no significant differences between two adjacent time points. These results were consistent with the trends shown in the corresponding dermoscopy images (FIG. 5A-5C). In the “Overdosage” group, the grayscale values displayed a sharp increase, while the amount of melanin showed a precipitous decline following treatment, which was caused by the excellent therapeutic effect of SA. In the “Treatment” group, both the grayscale values and the amount of melanin exhibited considerable improvement following the first few courses of treatment and gradually tended to the value of normal skin.

[0097] Finally, a computerized image analysis technique was used to segment the pigmentation lesions in the dermoscopy images and quantify the area of these lesions (FIGS. 27A-27F). All of the skin pigmentation lesions were segmented from the surrounding skin with high accuracy, based on Otsu’s thresholding segmentation algorithm, and their corresponding pigment distributions were displayed as 3D reconstructed models (FIGS. 28A- 28E). The area of these segmented pigmentation lesions showed similar trends to the semi- quantitative results described above for the grayscale values and amounts of melanin. Most importantly, the area of the lesions in all mice in the “Treatment” group was reduced to almost zero, indicating the complete improvement of these pigmentation disorders.

[0098] A personalized topical drug delivery system 20 based on a printable patch 2 combines a patch 2 with drug printing technology using a conventional inkjet-type printer 70 under dermoscopy guidance with an imager device 80. High-quality drug patterns with good precision can be achieved for printing both fat and water-soluble therapeutic agents 50 on the patches 2. The drug distribution of these printed patches 2 and their drug penetration performances are heavily dependent on the grayscale value distribution of the patterns used for printing. The drug-printed patches 2 enable the personalized treatment of skin pigmentation (or diseased tissue), with both high efficacy and limited side effects. This printing drug delivery system can be adapted to print other therapeutic agents 50, including macromolecules, cells, and drug formulations for personalized topical medications.

Moreover, future combinations of this system 20 with artificial intelligence (Al)-based skin diagnostic technology are expected to achieve further improvements in its accuracy and efficiency for the topical treatment of skin conditions.

[0099] Methods

[00100] Materials. Fluorinated ethylene propylene (FEP) film sheets with a thickness of 0. 1 mm, cut into 280 mm x 200 mm (length x width) pieces, were purchased from The 3D Club (CA, USA). Poly(lactic-co-glycolic acid) (PLGA) (50:50, MW: 40,000-70,000), di chloromethane (DCM), hydroxypropyl cellulose (HPC, MW: -80,000), salicylic acid (SA), phenol, dihydroxyacetone (DHA), and erythrulose were purchased from Sigma- Aldrich (St. Louis, MO, USA). Edible colorings were obtained from Ktdoms (CA, USA). All chemicals used were of analytical reagent grade and used without further purification.

[00101] Preparation of membranes. The FEP/PLGA/HPC membranes were fabricated by a simple spin-coating technique using a programmable high-speed spin coater (VTC-100PA- HCHS, MTI Corporation, USA). A 5% (w/v) solution of PLGA was prepared by dissolving 0.5 g of PLGA in 10 mL DCM and stirring the solution for 30 min. A 10% (w/v) solution of HPC was prepared by dissolving 5 g of HPC in 50 mL ethanol and stirring the solution for 2 h to obtain a clear solution, before using the solution for the spin-coating process. Briefly, 0.5 mL 5% (w/v) PLGA solution was poured dropwise onto an FEP film and spun at 3,000 rpm for 2 min to prepare a porous PLGA membrane. After leaving the film to stand for 5 min, 1 mL of 10% (w/v) HPC solution was dispensed onto the substrate using a volume-controlled pipette. Immediately after dispensing the solution, the spin coater was run at 500 rpm for 30 s, followed by 1,000 rpm for 90 s. Finally, the resulting multilayer membrane or patch 2 was dried in an oven at 50 °C for 2 h. A PLGA membrane with a flat surface was fabricated by dropping 0.5 mL of 5% (w/v) PLGA solution onto a silicon wafer, which was then spun at 3,000 rpm for 2 min. HPC membranes of various thicknesses were obtained by adjusting the rotation speeds of spin coating (at 500, 1,000, and 2,000 rpm). These samples were analyzed as prepared following spin coating, without any further post-processing.

[00102] Characterization of membranes. Scanning electron microscope (SEM) images of the membranes were obtained using a field emission SEM (Supra 40VP, ZEISS, Germany) after gold coating for 120 s (EM-SCD500, Leica, Germany). The absorbance and transmittance spectra were acquired using a TU-1810 ultraviolet-visible (UV-Vis) spectrophotometer (Purkinje General Instrument Co. Ltd. Beijing, China) using QS-grade quartz cuvettes at room temperature. The water contact angle measurement was evaluated by the sessile drop method using a contact angle goniometer (OCA20LHT-TEC700-HTFC1500, Dataphysics, Germany). The breathability of the patch 2 was conducted following the standard upright cup method (ASTM E96) and was expressed as the water vapor transmission rate, which is typically measured in grams per square meter per day (g/m²/day) (FIG. 31). Fluorescence (FL) spectra were collected using an FLS980 fluorescence spectrophotometer (Edinburgh Instruments, UK) with an excitation wavelength of 365 nm and FL intensities recorded at 439 nm. All mechanical tests were performed using a universal mechanical testing machine (Instron 5542, Norwood, MA, USA). Each membrane was cut to a size of 2 cm x 1 cm, positioned between the two grips of the machine, and subjected to tensile mechanical stretching. The crosshead speed was set at 1 mm/min using 2 N load cells with wedge grips. Stress-strain curves were recorded until the sample was completely broken.

[00103] The interfacial toughness of various membranes with the skin 100 was measured using the 180° peeling test. Skin samples were obtained from 6-week-old mice after the subcutaneous fat was removed and excess hair shaved using a disposable razor. The skin samples were washed at room temperature and then attached to a glass plate with epoxy adhesives for semi dry adhesion testing. During the peeling test, the skin surface was cleansed with alcohol wipes, while the top surface of the PLGA/HPC membrane was constrained on a mechanical induction fixture and then stuck on the skin. The measured peeling force of the membrane gave the interfacial toughness. Peeling force-displacement curves were recorded under a constant peeling speed of 1 mm/min. For each test, at least five samples were tested, and all tests were performed in ambient air at room temperature.

[00104] Drug/ therapeutic agent printing. A commercial ink cartridge 72 was disassembled and thoroughly washed with deionized water and ethanol to remove all of the ink. It was then dried in air at room temperature. A 1 mL sample of 10% (w/v) SA solution was injected into the modified ink cartridge 72. The sealed cartridge 72 was then installed on an HP-5278 thermal inkjet printer 70 (HP Inc., CA, USA), ready for printing the therapeutic agent 50 on the printable patch 2 using high-quality photo print mode once the printer 70 had been calibrated. For the quantitative analysis, square patches 2 of the drug-printed membrane (1 cm x 1 cm) were cut out and immersed in 1 rnL ethanol for 30 min to re-dissolve the SA. After centrifugation at 1,000 rpm for 10 min, the supernatant was diluted 50 times with ethanol prior to measuring the fluorescence intensity. To facilitate observation and quantification of phenol printing, an edible coloring with a specific absorption peak at 499 nm was used to mark the distribution of phenol after printing, and 1 mL of 10% (w/v) colored phenol solution was injected into the modified ink cartridge for drug printing, following the steps as outlined above. The drug-printed patches 2 were observed under a UV physiotherapy lamp (310 nm, Philips, The Netherlands) and a fluorescence microscope (Leica, Germany). The areas and FL intensities of the therapeutic agent 50 on these drug-printed patches 2 were calculated using ImageJ software.

[00105] Skin penetration tests. To study the drug penetration performances of the drug- printed patches, the drug patches 2 with different concentrations of SA were attached to the skin on the backs of mice for various lengths of time (10 min, 30 min, 1 h, 3 h, 6 h, and 12 h). SA was used to facilitate the subsequent observations. After being stuck to the skin 100 for the relevant time, the patches 2 were peeled off and the skin 100 was scrubbed with 75% alcohol to remove residual drugs 50. Typical images of the skin 100 were captured by a camera under UV irradiation (310 nm, Philips, The Netherlands). The mice were then euthanized, and the skin tissues 100 were collected and sectioned, while the penetration depth was recorded with a camera under fluorescence microscopy (Leica, Germany). For the quantitative analysis, each skin tissue sample (1 cm x 1 cm) with the various drug concentrations was dissolved with lysis buffer, and the concentration of the drug was determined from the fluorescence spectrum.

[00106] Animal experiments. Female Balb/c nude mice (aged 6-8 weeks, weighing 18-22 g) were purchased from Shanghai Slac Laboratory Animal Co., Ltd. (Shanghai, China). All animal experiments were conducted in conformity with the guidelines of the National Institutes of Health Clinical Center Animal Care and Use Committee (NIH CC/ACUC). To establish the pigmentation animal model, 15% (w/v) DHA solution in ethanol and 3% (w/v) erythrulose solution were painted on the skin 100 on the backs of the mice (n = 25) three times, according to the preset pattern, and irradiated under UV light (310 nm, Philips, The Netherlands) at an intensity of 12 W for 30 min. After 12 h, the mice with patterned pigmentations were randomly divided into five groups (n = 5) and subjected to various conditions, including (1) no treatment, (2) treated with the patch only, (3) treated with the underdosage SA solution, (4) treated with the overdosage SA solution, and (5) treated every 2 days with the personalized, printed drug patch. Next, 10 pL solutions of SA at concentrations of 1% (w/v) and 20% (w/v), were applied as the underdosage and overdosage drug concentrations, respectively, by being dropped carefully onto the skin and spread evenly. The mice were euthanized after treatment and any skin samples with pigmentations were harvested, fixed in 10% neutral buffered formalin, processed routinely into paraffin, sectioned at 5 pm, and stained with hematoxylin and eosin (H&E), and examined under digital microscopy.

[00107] Computerized image analysis. Dermoscopy images were collected using a simple, self-made dermoscope in the RGB (red, green, blue) color model, and any nonuniform background illumination was corrected. These images 90 were loaded using the cv2.imread function from OpenCV (Open Source Computer Vision Library) in Python. The cv2. split function was then used to extract the individual red (R), green (G), and blue (B) channels from the RGB images 90. The resulting separated R, G, and B image layers were collected for threshold-based lesion segmentation. The cv2.threshold function was then used to apply the thresholding, and the optimal threshold was obtained based on Otsu’s thresholding algorithm. Briefly, the pixels in an image can be dichotomized into two classes, Ci (background) and Ci (objects), by a threshold at level k. Then, the class mean levels (mi and mi) and the probabilities of class occurrence (pi and pi) of these two classes can be given as

[00108] ppn_± + p₂m₂ — ^mG (1)

[00109] pi + p₂ = 1 (2)

[00110] where mo is the total mean level of the original image 90, and the class variances are given by

[00111] o^-2 — Pi(m — m_c)² + p₂(m₂ — m_G)² (3)

[00112] and, due to (1)

[00113] a² = p₁p₂(m₁ - m₂)² (4)

[00114] where

[00115] Pi = Ito Pi (5) [00116] (6)

Pl

[00118] The optimal threshold value that maximizes o² calculated by this algorithm was selected for the following analysis. Image thresholding was further processed using the function cv2.threshold(img, 0, 255, cv2.THRESH_BINARY + cv2.THRESH_OTSU). The grayscale values of the pixels greater than or equal to the threshold k* were set to 255, and those less than the threshold k* were set to 0. Two objects were returned by the function cv2.threshold(img, 0, 255, cv2.THRESH_BINARY + cv2.THRESH_OTSU), one is the threshold C, calculated by the Otsu algorithm, and the other is the array after thresholding. Subsequently, the latter is defined as a mask, in which the pixel value of Ci (background) is 0 and that of C2 (objects) is 255. The pixel values of 255 in the mask were then replaced with 1, and then the mask was multiplied by the R, G, and B image layers to obtain the lesion area of each channel. Then, the obtained R, G, and B image layers were combined to form the final output of the pigmentation lesion segmented from the original RGB image. All the RGB images 90 were converted to grayscale images by the cv2.cvtColor function using the formula

[00119] Gray — 0.299/? + 0.587G + 0.114B (8)

[00120] For each segmented lesion image, the lesion area was calculated from the percentage of grayscale pixels in the total pixels, while the total area of skin in each dermoscopy image was 100 mm². Corresponding 3D reconstruction models of these segmented pigmentation lesions were established in MATLAB by using the grayscale value as the Z-axis (height).

[00121] Statistical analysis. All the data were presented as means ± standard deviation (s.d.). To test the significance of the observed differences between the study groups, one-way analysis by variance (ANOVA) statistics was applied, and a value ofP < 0.05 was considered to be statistically significant.

[00122] While embodiments of the present invention have been shown and described, various modifications may be made without departing from the scope of the present invention. For example, various printer 70 types and models may be used to print the pattem(s) of therapeutic agent(s) or chemical species 50 on the patch 2. The printing system described herein may be used in a home environment or may be used in a medical setting (e.g., physician’s office). In addition, the system 20 may include, for example, the printer 70, the imager device 80, and one or more unprinted patches. The invention, therefore, should not be limited, except to the following claims, and their equivalents.

Claims

What is claimed is:

1. A patch for delivering a therapeutic agent and/ or chemical species to skin tissue comprising: a substrate layer comprising fluorinated ethylene propylene (FEP); a layer of poly (lactic-co-gly colic acid) (PLGA) disposed on the substrate layer; and a layer of hydroxy propyl cellulose (HPC) disposed on the layer of PLGA, wherein the layer of HPC comprises a printed pattern of the therapeutic agent and/or chemical species contained thereon or therein.

2. The patch of claim 1 , wherein the substrate layer is removable from the patch.

3. The patch of claim 1, wherein the printed pattern of the therapeutic agent and/or chemical species comprises multiple therapeutic agents and/or chemical species.

4. The patch of claim 1, wherein the printed pattern of the therapeutic agent and/or chemical species substantially matches a pattern of diseased and/or pigmented skin located on the skin tissue.

5. The patch of claim 1, wherein the therapeutic agent and/or chemical species comprises a hydrophilic therapeutic agent and/or chemical species.

6. The patch of claim 1, wherein the therapeutic agent and/or chemical species comprises a hydrophobic therapeutic agent and/or chemical species.

7. The patch of claim 1, wherein the substrate layer has a thickness of < 150 pm, the layer of PLGA has a thickness of < 200 nm, and the HPC layer has a thickness of < 10 nm.

8. A method of using the patch of any of claims 1-7, comprising: placing the patch with the layer of HPC on the skin tissue of a subject; and removing the substrate layer.

27

9. A patch system for delivering a therapeutic agent and/or chemical species to skin tissue comprising: a printer device having one or more fluid-jet cartridges comprising a reservoir for holding the therapeutic agent and/or chemical species and a printhead having a plurality of nozzles configured to eject droplets of the therapeutic agent and/or chemical species from the printhead; and a patch for delivering the therapeutic agent and/or chemical species to skin tissue comprising: a substrate layer comprising fluorinated ethylene propylene (FEP); a layer of poly (lactic-co-glycolic acid) (PLGA) disposed on the substrate layer; and a layer of hydroxypropyl cellulose (HPC) disposed on the layer of PLGA, wherein the layer of HPC comprises a printed pattern of the therapeutic agent and/or chemical species contained thereon or therein.

10. The patch system of claim 9, further comprising a dermoscopic imager device configured to capture one or more image(s) of the skin tissue.

11. The patch system of claim 10, wherein the one or more captured image(s) comprise a pattern of skin pigmentation or other dermoscopic pattern.

12. The patch system of claim 10, wherein the dermoscopic imager device generates a printer file that corresponds to the pattern of skin pigmentation or other dermoscopic pattern in the one or more captured image(s).

13. The patch system of claim 10, wherein the dermoscopic imager device comprises a mobile phone.

14. A method of delivering a therapeutic agent and/or chemical species to skin tissue of a subject comprising: obtaining one or more images of skin tissue with a dermoscopic imager device, the one or more images of skin tissue comprising a pattern of skin pigmentation or other dermoscopic pattern; providing a patch comprising a substrate layer comprising fluorinated ethylene propylene (FEP), a layer of poly (lactic-co-gly colic acid) (PLGA) disposed on the substrate layer, and a layer of hydroxy propyl cellulose (HPC) disposed on the layer of PLGA; printing a pattern of the therapeutic agent and/or chemical species onto or in the layer of HPC using a printer device, wherein the printed pattern corresponds to the pattern in the obtained one or more images of skin tissue obtained with the dermoscopic imager device; and contacting the layer of HPC from the patch containing the pattern of the therapeutic agent and/or chemical species onto the skin tissue of the subject.

15. The method of claim 14, further comprising removing the substrate layer from the layer of HPC and layer of PLGA of the patch.

16. The method of claim 14, wherein the printed pattern of the therapeutic agent and/or chemical species comprises multiple therapeutic agents and/or multiple chemical species.

17. The method of claim 14, wherein the printed pattern of the therapeutic agent and/or chemical species substantially matches a pattern of diseased and/or pigmented skin located on the skin tissue.

18. The method of claim 14, wherein the therapeutic agent and/or chemical species comprises a hydrophilic therapeutic agent and/or chemical species.

19. The method of claim 14, wherein the therapeutic agent and/or chemical species comprises a hydrophobic therapeutic agent and/or chemical species.

20. The method of claim 14, wherein the therapeutic agent and/or chemical species comprises multiple therapeutic agents and/or chemical species.