Microneedle for intradermal filling

Abstract

A device comprising: a sleeve body defining an inner bore and terminating at a distal opening; a hollow microneedle defining a lumen and terminating at a distal tip, where the microneedle is configured to be reciprocally displaceable within the bore such that the tip extends and retracts through the distal opening; and a plunger having a shaft operable to advance a seal along the lumen to deliver an amount of a specified composition within the lumen along the lumen and through an outlet at a distal portion of the microneedle.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 446,390, filed on February 17, 2023, entitled “MICRONEEDLE FOR INTRADERMAL FILLING,” the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention generally relates to devices and methods for delivering dermal filler compositions into the skin of a subject using a microneedle device. Background Art

[0003] The skin is composed of the upper epidermis and dermis. Beneath these layers lies the subcutaneous tissue (also known as the subcutaneous fat layer, sub-cutis, or subcutaneous tissue). The subcutaneous tissue is not usually classified as a layer of the skin.

[0004] The uppermost layer of the epidermis is composed of a stratified squamous epithelium and an underlying basement membrane. It contains no blood vessels and is nourished by diffusion from the dermis. This layer of skin acts as a barrier between the body and the external environment, retaining water and preventing the penetration of harmful chemicals and pathogens. The thickness of the epidermis in the skin of the adult face and neck is typically between 30 μm and 60 μm (micrometer), depending on the specific location in the body. The thinnest epidermis is typically found behind the ear, with a thickness of approximately 29.5 μm, while the thickest epidermis is typically found on the upper lip, with a thickness of approximately 62.6 μm. The average skin thickness on the face and neck (where wrinkles, lines, and folds are common) is 1.26 millimeters (mm).

[0005] The dermis lies beneath the epidermis and contains a variety of structures, including blood vessels, nerves, hair follicles, smooth muscle, glands, and lymphatic tissue. The dermis (or corium) in the skin of the face and neck is typically 700–2000 μm thick and is the primary component of human skin. It is composed of a dense network of connective tissue, primarily collagen fibrils for support and elastin fibers for flexibility.

[0006] The subcutaneous tissue lies beneath the dermis and is important for attaching the skin to the underlying bones and muscles, as well as providing it with blood vessels and nerves. The subcutaneous tissue is composed of loose connective tissue and elastin, and contains fibroblasts, macrophages, and adipocytes. Adipocytes play a primary role in the fat storage function of the subcutaneous tissue. Fat acts as a filler material and acts as insulation between the body and the external environment.

[0007] Several factors contribute to facial aging, including inherent changes in the skin, the effects of gravity, the activity of facial muscles that lead to the formation of dynamic lines, skin defects or displacements, bone loss, loss of tissue elasticity, and exposure to harsh environmental conditions, particularly sunlight or UV radiation and pollutants. Skin ages when the epidermis begins to thin, causing the junction with the dermis to flatten. Collagen decreases as a person ages, and the collagen bundles that give the skin its volume become looser and lose strength. When skin loses elasticity, it is less able to resist stretching. Combined with the forces of gravity, muscle pull, and tissue changes, the skin begins to wrinkle. Water loss and the breakdown of bonds between cells also reduce the skin's barrier function, which can lead to an increase in pore size.

[0008] Efforts have been made to develop and use compositions to correct skin defects, such as scars and wrinkles, or to augment a subject's tissue in order to improve the appearance of the skin, particularly facial skin. Currently, there are dozens of known dermal fillers used for skin augmentation, including autologous implantable materials, allogeneic products, xenogeneic products, and synthetically derived products.

[0009] Available dermal fillers include biodegradable natural substances (such as collagen, gelatin, hyaluronic acid, dextran, and dried acellular particulate dermal matrix), biodegradable synthetic polymers (such as poly-L-lactic acid, polyethylene oxide, and carboxymethylcellulose), non-biodegradable synthetic polymers (such as polymethyl methacrylate, polyacrylamide, polyalkylimides, and silicone), and combinations thereof.

[0010] Biocompatible ceramic skin fillers such as hydroxyapatite (Ca5(PO4)3(OH)) are known to be effective skin filler materials. Hydroxyapatite is a naturally occurring mineral form of calcium phosphate. Hydroxyapatite contains the mineral components of bone, thus making it biocompatible and non-immunogenic when introduced into a subject. Notably, hydroxyapatite is biodegradable, following the same metabolic pathway as bone fragments produced by common bone fractures, but it is semi-permanent in that it persists for up to 3 years when implanted into a subject. Furthermore, when injected as small microspheres, hydroxyapatite also acts as a scaffold that promotes the formation of new tissue similar to its surrounding environment. In the inner part of the skin, such as the dermis, the deposited hydroxyapatite particles support fibroblast ingrowth and new collagen formation.

[0011] Dermal filler products are typically injected with a needle just below the skin's surface at the site of wrinkles, lines, or folds (or scars or subcutaneous tissue to be augmented). These products essentially plump up the skin from beneath the upper layers. However, administering dermal fillers via injection or implant is uncomfortable and potentially painful for the patient, and requires highly trained medical professionals to perform the procedure.

[0012] The foregoing examples of the related art and limitations associated therewith are intended to be illustrative, not exclusive. Other limitations of the related art will become apparent to those skilled in the art upon reading this specification and studying the accompanying drawings. Summary of the Invention

[0013] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools, and methods, which are exemplary and illustrative, not limiting in scope.

[0014] In one embodiment, a device is provided comprising: a sleeve body defining an inner bore and terminating at a distal opening; a hollow microneedle defining an inner lumen and terminating at a distal pointed tip, wherein the microneedle is configured to be reciprocally displaceable within the inner bore such that the tip extends and retracts through the distal opening; and a plunger having a shaft operable to advance a seal along the inner lumen to deliver a quantity of a specified composition within the lumen, along the inner lumen, and through an outlet at a distal portion of the microneedle.

[0015] In some embodiments, the device further comprises a reservoir attached at the proximal end of the main body sleeve and configured to store a predetermined amount of the designated composition.

[0016] In some embodiments, the microneedle comprises an orifice extending along a sidewall of the microneedle, wherein the orifice provides communication between the reservoir and the lumen, thereby allowing the amount of the designated composition to enter the lumen from the reservoir.

[0017] In some embodiments, the tip is configured to pierce the skin of the subject at the injection site.

[0018] In some embodiments, the distal opening is configured to be positioned against the outer surface of the skin of the subject at the injection site, wherein the microneedle is configured to extend a predetermined distance through the distal opening into the dermis or subcutaneous tissue layer of the subject to deliver the amount of at least a portion of the specified composition at a desired depth within the dermis or subcutaneous tissue layer.

[0019] In some embodiments, the microneedle is made of a material selected from the group consisting of metal, plastic, ceramic material, silicone material, and any combination thereof.

[0020] In some embodiments, the microneedle has a cross-sectional shape selected from the group consisting of circular, rectangular, elliptical, triangular, and polygonal.

[0021] In some embodiments, the tip comprises an end having an angle of convergence equal to 10-60 degrees.

[0022] In some embodiments, the designated composition is a skin augmentation composition.

[0023] In some embodiments, the given composition has a consistency that is liquid, viscous, semi-solid, or solid.

[0024] In some embodiments, the given composition comprises hydroxyapatite or hyaluronic acid.

[0025] In some embodiments, the designated composition comprises solid particles or solid spheres.

[0026] In some embodiments, the device further comprises one or more sensors configured to image or measure the depth of local skin structures at the injection site, wherein the one or more sensors are selected from the group consisting of: an ultrasonic sensor, an optical transducer, and a manometer force transducer.

[0027] In some embodiments, the device further comprises one or more imaging devices configured to image the advancement path of the device at the injection site.

[0028] In some embodiments, the outlet is located at the tip.

[0029] In one embodiment, a method is also provided, comprising: providing a device comprising a sleeve body defining an inner bore and terminating at a distal opening; a hollow microneedle defining an inner cavity and terminating at a distal tip, wherein the microneedle is configured to be capable of reciprocal displacement within the inner bore such that the tip extends and retracts through the distal opening; and a plunger having a shaft operable to advance a seal along the inner cavity to deliver a quantity of a specified composition within the cavity, along the inner cavity, and through an outlet at a distal portion of the microneedle; positioning the device at an injection site about the skin of a subject; displacing the microneedle within the inner bore such that the tip extends a predetermined distance through the distal opening into the dermis or subcutaneous tissue layer of the skin of the subject; and operating the shaft to advance the seal along the inner cavity, thereby delivering at least a portion of the quantity of the specified composition into the dermis or subcutaneous tissue layer along the inner cavity and through the outlet at the tip.

[0030] In some embodiments, the device further comprises a reservoir attached at the proximal end of the body sleeve and configured to store a predetermined amount of the designated composition.

[0031] In some embodiments, the microneedle comprises an orifice extending along a sidewall of the microneedle, wherein the orifice provides communication between the reservoir and the lumen, thereby allowing the amount of the designated composition to enter the lumen from the reservoir.

[0032] In some embodiments, the tip is configured to pierce the skin of the subject at the injection site.

[0033] In some embodiments, the distal opening is configured to be positioned against an outer surface of the skin of the subject at the injection site, wherein the predetermined distance defines a desired depth location within the dermis or subcutaneous tissue layer for delivering the amount of the at least a portion of the specified composition.

[0034] In some embodiments, the microneedle is made of a material selected from the group consisting of metal, plastic, ceramic material, silicone material, and any combination thereof.

[0035] In some embodiments, the microneedle has a cross-sectional shape selected from the group consisting of circular, rectangular, elliptical, triangular, and polygonal.

[0036] In some embodiments, the tip comprises an end having an angle of convergence equal to 10-60 degrees.

[0037] In some embodiments, the designated composition is a dermal filler composition.

[0038] In some embodiments, the given composition has a consistency that is liquid, viscous, semi-solid, or solid.

[0039] In some embodiments, the given composition comprises hydroxyapatite or hyaluronic acid.

[0040] In some embodiments, the designated composition comprises solid particles or solid spheres.

[0041] In some embodiments, the device further comprises one or more sensors configured to image or measure the depth of local skin structures at the injection site, wherein the one or more sensors are selected from the group consisting of: an ultrasonic sensor, an optical transducer, and a manometer force transducer.

[0042] In some embodiments, the device further comprises one or more imaging devices configured to image the advancement path of the device at the injection site.

[0043] In some embodiments, the outlet is located at the tip.

[0044] Further embodiments, features, advantages, and the full scope of applicability of the present invention will become apparent from the detailed description and accompanying drawings given below. However, it should be understood that the detailed description, while indicating preferred embodiments of the present invention, is given by way of illustration only, as various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] The subject matter of the present disclosure will be more fully understood and appreciated based on the following detailed description taken in conjunction with the accompanying drawings, in which corresponding or similar numbers or characters indicate corresponding or similar components. Unless otherwise indicated, these drawings provide exemplary embodiments or aspects of the present disclosure and do not limit the scope of the present disclosure. In these drawings: Figure 1A-1F shows an exemplary microneedle device for intradermal delivery of a dermal filler composition into dermal tissue of a subject according to some embodiments of the present disclosure; Figure 2A-2H The present invention shows the operating steps of a method for intradermally delivering a dermal filler composition into the dermal tissue of a subject using a microneedle device according to some embodiments of the present invention; Figure 3 is a flow chart of the operational steps of a method for intradermally delivering a dermal filler composition into the dermal tissue of a subject using a microneedle device of the present disclosure according to some embodiments of the present disclosure; Figures 4A-4Cshows additional exemplary embodiments of a microneedle device for intradermal delivery of a dermal filler composition into dermal tissue of a subject according to some embodiments of the present disclosure; and Figure 5 is a schematic diagram of an exemplary microneedle system for intradermal delivery of a dermal filler composition into the dermal tissue of a subject using a microneedle device of the present disclosure, according to some embodiments of the present disclosure.

[0046] It will be understood that, for simplicity and clarity of illustration, the elements shown in the figures are not necessarily drawn to scale. For example, for clarity, the dimensions of some of these elements may be exaggerated relative to other elements. In addition, where deemed appropriate, reference numerals may be repeated in the figures to indicate corresponding or similar elements. DETAILED DESCRIPTION

[0047] In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, one skilled in the art will appreciate that the present invention may be practiced without these specific details. In other instances, well-known methods, procedures, and components have not been described in detail in order to avoid obscuring the present disclosure. As used herein, the term "dermis" refers to the dermis layer of the skin.

[0048] Disclosed herein are microneedle devices and methods for intradermally delivering a dermal filler composition into the dermal tissue of a subject using the disclosed microneedle devices. According to the methods of the present invention, the disclosed microneedle devices are deployed along predefined lines or wrinkles where dermal filling, cosmetic repair, or tissue augmentation is desired, and a quantity of the dermal filler composition is injected through the disclosed microneedle devices to one or more predetermined intradermal depths.

[0049] In some embodiments, the microneedle devices of the present disclosure provide definitive intradermal filling of undesirable lines, wrinkles, depressed scars, and folds of a subject's skin using one of several suitable biocompatible filler materials that can be injected into the dermis or subcutaneous tissue layer of the subject's facial or neck skin.

[0050] In some embodiments, the microneedle devices of the present disclosure are particularly suitable for accurate and precise delivery of viscous, dense, semisolid, or solid filling materials (such as calcium hydroxyapatite spheres in powder form).

[0051] In some embodiments, the microneedle devices of the present disclosure provide for precise and accurate delivery of filling compositions into predetermined defective areas of the dermal and subdermal target tissue, thereby preventing waste of dermal filler material, avoiding the need for repeated or multiple administration cycles, and reducing any undesirable side effects associated with delivery into the epidermis, such as the appearance of small solid bumps on the surface of the treated skin, which can cause the skin to appear bumpy and, when the injection is superficial, can ulcerate the epidermis and become a source of infection and inflammation.

[0052] In some embodiments, the microneedle device of the present disclosure provides accurate positioning of the injection depth based on pre-measured skin depth along predetermined lines or wrinkles where dermal filling is desired. In some embodiments, such pre-measurement can be achieved using an ultrasonic sensor (e.g., high-resolution ultrasound (e.g., having a frequency greater than 10 MHz)) to obtain high-resolution imaging of the local skin structure at the desired injection site. In some embodiments, such pre-measurement allows the medical practitioner performing this procedure to accurately measure the depth of the dermis at the injection site and determine one or more optimal injection depths at the measured injection site.

[0053] One aspect of the present invention provides a microneedle device comprising microneedles for intradermal administration of a dermal filler composition, for example, to the dermis and / or subcutaneous tissue layer of human facial or neck skin.

[0054] refer to Figure 1A-1F , which illustrates an exemplary microneedle device 100 for intradermal delivery of a dermal filler composition into dermal tissue of a subject, according to some embodiments of the present disclosure.

[0055] In some embodiments, the microneedle device 100 of the present disclosure comprises at least: - A syringe barrel body 102 defining an inner bore and terminating in a distal opening 102a.

[0056] A reservoir 104 attached to the proximal end 102 b of the cartridge body 102 and configured to store a predetermined amount of a dermal filling composition 108 therein, wherein the reservoir 104 has a refill opening 106 .

[0057] - A hollow microneedle 110, which is within the reservoir 104 and extends through the proximal end 102b into the inner bore defined by the sleeve body 102, wherein the microneedle 110 is configured to be reciprocally displaceable along the inner bore of the sleeve body 102, so that the distal tip 112 of the microneedle 100 can be extended and retracted through the distal opening 102a of the sleeve body 110.

[0058] A port or orifice 114 extending along the sidewall of the microneedle 110 and positioned to provide communication between the reservoir 104 and the cavity 110 c of the microneedle 110 , such that the dermal filling composition 108 can flow or enter the cavity 110 c through the port 114 .

[0059] A plunger 116 having a shaft 116a for advancing a seal 118 along the lumen 110c of the microneedle 110 to (i) collect a quantity 108a of the skin filling composition 108 that is communicated into the lumen 110c of the microneedle 110 through the port 114, and (ii) deliver the quantity 108a of the skin filling composition 108 along the lumen 110c of the microneedle 110 and through the outlet at the tip 112. The plunger shaft 116a is formed with a plunger extension that extends proximally from the proximal end of the microneedle 110 in a sealable engagement therewith.

[0060] As used herein, the term "microneedle" refers to a protruding structure designed to penetrate the skin and facilitate the delivery of various types of compounds into the tissue. According to some embodiments, the microneedles facilitate delivery of the compositions of the present invention to the dermis and / or subcutaneous tissue compartments of the skin.

[0061] Now we will continue to refer to Figure 1A-1F The principles and operation of the microneedle device 100 according to some embodiments of the present disclosure are discussed.

[0062] exist Figure 1A , plunger 116 and seal 118 are shown in an initial position, wherein seal 118 is positioned proximal to port 114. Similarly, tip 112 of microneedle 110 is in a retracted position within cartridge body 110 such that tip 112 does not extend beyond distal opening 102a.

[0063] The microneedle device can be deployed along a predetermined line or wrinkle of the subject's skin for desired dermal augmentation, cosmetic repair, or tissue filling. Once positioned at the desired injection site, the microneedle 110 can be advanced distally, such as Figure 1B As shown, the tip 112 extends a predetermined distance from the distal end 102a of the sleeve body 102. Thus, with the distal opening 102a of the sleeve 102 positioned against the outer surface of the skin at the injection site, the tip 112 penetrates the skin to a predetermined injection depth, which is determined by the distance the tip 112 extends through the opening 102a. In some embodiments, the distance that the microneedle 110 is advanced through the opening 102a can be predetermined based on a pre-measured measurement of the skin structure at the injection site, thereby accurately measuring the depth of the dermis layer at the injection site and determining one or more optimal injection depths at the measured injection site.

[0064] In some embodiments, as Figure 1C-1EAs shown, the plunger 116 can then be advanced to drive the seal 118 in a distal direction, thereby collecting a certain amount 108a of the skin filling composition 108, which flows from the reservoir 104 through the port 114 or into the cavity 110c of the microneedle 110. In some embodiments, the plunger 116 drives the seal 118, thereby delivering the amount 108a distally through the cavity 110c of the microneedle 110 toward the tip 112. Figure 1F In FIG. 1 , seal 118 delivers volume 108a through the outlet of tip 112 at a predetermined injection depth.

[0065] In certain embodiments, the height of the microneedles 110 is 500, 1000, 1500, 2000, 2500, 3000, 4000, 5000, 6000, or 7000 μm. Each possibility represents a separate embodiment of the present invention.

[0066] In certain embodiments, the microneedle 110, the cartridge body 102, and / or the plunger 116 are each formed from a rigid material selected from the group consisting of metals, metal alloys, plastics, ceramic materials, silicone materials, and combinations thereof. In certain embodiments, the metal is stainless steel. Each possibility represents a separate embodiment of the present invention.

[0067] In certain embodiments, the microneedle 110 has a cross-sectional shape selected from the group consisting of: circular, rectangular, elliptical, triangular, and polygonal. Each possibility represents a separate embodiment of the present invention.

[0068] In certain embodiments, the diameter of the tip 112 is the same as the diameter of the microneedle 110. In certain embodiments, the diameter of a section of the tip 112 is greater than the overall diameter of the microneedle 110. In certain embodiments, the diameter of the tip 112 is approximately 5%, approximately 10%, approximately 15%, or approximately 20% greater than the diameter of the microneedle 110. In certain embodiments, the tip 112 defines a tapered or conical end portion having a convergence angle between 10 and 60 degrees, such as 10 degrees, 20 degrees, 30 degrees, 40 degrees, 50 degrees, or 60 degrees. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the tip 112 has a shape selected from the group consisting of a cone, a taper, a pyramid, a triangular pyramid, and a multi-sided pyramid. Each possibility represents a separate embodiment of the present invention.

[0069] In certain embodiments, the tip 112 is hollow and terminates in an outlet or opening, thereby allowing delivery therethrough of the filling composition 108. In certain embodiments, the tip 112 is blocked or sealed and does not terminate in an outlet, thereby allowing delivery of the filling composition through a hole or slit in the microneedle 110 itself.

[0070] In another aspect, the present invention also provides a method 300 for intradermally delivering a dermal filler composition into the dermal tissue of a subject using a microneedle device (such as microneedle device variation 100 or variations 120, 130, and / or 140). Figure 3 Flowchart and Figures 2A-2D Discuss the various steps of method 300. Method 300 can be performed in the order in which the steps are presented, or in a different order (or even in parallel), as long as the order achieves a condition or result required by a step to be obtained from a preceding step.

[0071] although Figure 2A-2D The steps of method 300 are illustrated with reference to exemplary microneedle device 100 , but the details of method 300 are equally applicable to exemplary microneedle device variations 120 , 130 , and / or 140 .

[0072] Method 300 begins at step 302 ( Figure 2A ), wherein the microneedle device 100 can be deployed along a predetermined line or wrinkle around a subject's skin region 200, the skin region 200 including an epidermis layer 202 and a dermis / deeper subcutaneous tissue layer 204. In some embodiments, the microneedle device 100 can be in an initial position, wherein the seal 118 is positioned proximal to the port 114. Similarly, the tip 112 of the microneedle 110 is in a retracted position within the cartridge body 110, such that the tip 112 does not extend beyond the distal opening 102a.

[0073] In some embodiments, in step 304, ultrasonic imaging of the structure of the skin area 200 at the injection site may be performed to accurately measure the depth of the dermis / subcutaneous tissue layer 204 at the injection site and predetermine one or more optimal injection depths at the measured injection site (generally at or near the midpoint of the depth dimension of the dermis / subcutaneous tissue layer).

[0074] In step 306 ( Figure 2B ), the microneedle 110 can be advanced distally, as Figure 1B As shown, the tip 112 is extended a predetermined distance A1 (as determined in step 304) from the distal end 102a of the sleeve body 102. Thus, with the distal opening 102a of the sleeve 102 positioned against the outer surface of the skin at the injection site, the tip 112 penetrates the skin to a predetermined intradermal injection depth (indicated by a horizontal dashed line), which is determined by the distance A1 that the tip 112 extends through the opening 102a.

[0075] In step 308 ( Figure 2C), the plunger 116 can then be advanced to drive the seal 118 in a distal direction, thereby collecting a quantity 108 a of the skin filling composition 108, which flows from the reservoir 104 through the port 114 or into the lumen 110 c of the microneedle 110. In some embodiments, the plunger 116 drives the seal 118, thereby delivering the quantity 108 a distally through the lumen 110 c of the microneedle 110 toward the tip 112.

[0076] In step 310 ( Figure 2D ), the plunger 116 continues to be advanced toward the tip 112 until the seal 118 delivers the amount 108a through the outlet of the tip 112 at or near the predetermined injection depth A1, and the amount 108a begins to be deposited at or near the predetermined injection depth A1, for example, at least a first portion of the amount 108a has been deposited at or near the depth A1.

[0077] In step 312 ( Figure 2E-2F ), the microneedle 110 can begin to be gradually retracted through the distal opening 102a of the sleeve body 102, so that the tip 112 can be retracted along a retraction path that extends around a deep portion of the dermis 204 at the injection site. As the microneedle 110 is gradually retracted, steps 308-310 can be repeated one or more times to deposit another one or more portions of the amount 108a along the retraction path until the entire amount of the amount 108a has been deposited near the predetermined depth.

[0078] It should be noted that the plunger 116 can be operated independently of the microneedle 110, wherein the plunger 116 and the microneedle 110 are capable of relative movement relative to each other and relative to the cartridge body 102, such that, for example, the microneedle 110 can be gradually retracted while the plunger 116 is capable of reciprocating (i.e., advancing and retracting) within the bore of the microneedle 110 and relative to the microneedle 110, or vice versa.

[0079] For example, in some embodiments, optionally, during step 312, plunger 116 can be retracted one or more times to its initial position with seal 118 positioned proximal to port 114 to optionally collect an additional amount of dermal filling composition to replenish amount 108a, as determined necessary or desirable by the healthcare practitioner performing this procedure. Plunger 116 can then be advanced as described above in steps 308-310 to deliver the additional replenishing amount to approximately the predetermined depth.

[0080] In some embodiments, one or more of the plunger 116 and the microneedle 110 can be operated and moved via a variety of manually operated and / or automatically controlled devices and different types of manipulators using a variety of mechanisms and electromechanical elements, including, for example, angular and linear motors, optical or electromagnetic position encoders, universal joints, linkages, pulleys, cables, belts and ribbons, and gears.

[0081] refer to Figure 2G-2H Steps 306-312 of method 300 may be repeated two or more times at the injection site to inject the drug at two or more desired depths (e.g., depth A2 ( Figure 2G ) and / or depth A3 ( Figure 2H )) delivers a skin filling composition to the affected area.

[0082] refer to Figure 4A , which shows an exemplary variation 120 of a microneedle device 100 for intradermally delivering a dermal filler composition into the dermal tissue of a subject according to some embodiments of the present disclosure. The microneedle device variation 120 can be substantially similar to the microneedle device 100 described above and includes a cartridge body 102; a reservoir 104 having a refill opening 106 for storing a dermal filler composition 108; a microneedle 110 having a tip 112 and a port 114; and a plunger 116 having a shaft 116a and a seal 118. The principles and operation of the microneedle device variation 120 are substantially similar to those of the microneedle device 100, as described above with reference to FIG. Figure 1A-1F described.

[0083] In some embodiments, microneedle device variation 120 includes a nose-like protrusion 122 extending laterally from the distal end of sleeve body 102. When microneedle device variation 120 is deployed along a predetermined line or wrinkle around skin area 200 where dermal augmentation, cosmetic repair, or tissue filling is desired, nose-like protrusion 122 is configured to provide a visual indication of the precise location of tip 112. In some embodiments, nose-like protrusion 122 can also provide for smoothing of skin area 200 ahead of microneedle device variation 120 as microneedle device variation 120 is moved along a predetermined path around skin area 200 (e.g., in the direction indicated by the arrow). In some embodiments, nose-like protrusion 122 can also serve as a pointer or arrow to assist a healthcare practitioner performing such a procedure in precisely navigating the device along the wrinkle or line to be treated.

[0084] refer to Figure 4B , which shows an exemplary variation 130 of a microneedle device 110 for intradermally delivering a dermal filler composition into the dermal tissue of a subject according to some embodiments of the present disclosure. The microneedle device variation 130 can be substantially similar to the microneedle device 100 described above and includes a cartridge body 102; a reservoir 104 having a refill opening 106 for storing a dermal filler composition 108; a microneedle 110 having a tip 112 and a port 114; a plunger 116 having a shaft 116a and a seal 118; and a nose 122. The principles and operation of the microneedle device variation 130 are substantially similar to those of the microneedle device 100, as described above with reference to FIG. Figure 1A-1F described.

[0085] In some embodiments, microneedle device variations 130 include one or more imaging devices (e.g., cameras) 126 configured to image skin area 200. In some embodiments, microneedle device variations 130 include a nose-like protrusion 122 extending laterally from the distal end of sleeve body 102. Nose-like protrusion 122 is configured to accommodate one or more ultrasound or other sensors 124.

[0086] In some embodiments, the ultrasonic sensor(s) 124 can be high-resolution ultrasonic sensor(s) (e.g., having a frequency greater than 10 MHz) to obtain high-resolution imaging of the structure of the local skin area 200 at the desired injection site. In some embodiments, such pre-measurements allow the medical practitioner performing the procedure to accurately measure the depth of the dermis at the injection site and determine one or more optimal injection depths at the measured injection site.

[0087] In some embodiments, imaging device(s) 126, optionally with magnification capabilities, may be configured to assist in pinpointing the exact location of a microneedle device variation 130 as it is deployed along a predetermined path (e.g., in the direction marked by the arrows) around a subject's skin area 200.

[0088] refer to Figure 4C , which shows a variation 140 of the microneedle device 100 for intradermally delivering a dermal filler composition into the dermal tissue of a subject according to some embodiments of the present disclosure. The microneedle device variation 140 includes a cartridge body 102; a tapered or conical reservoir 105 having a refill opening 107 for storing a dermal filler composition 108; a microneedle 110 having a tip 112 and a port 115; a plunger 116 having a shaft 116a and a seal 118; and a nose 122. The principles and operation of the microneedle device variation 140 are substantially similar to those of the microneedle device 100, as described above with reference to FIG. Figure 1A-1F described.

[0089] In some embodiments, variation 140 of microneedle device 100 includes at least: - A syringe barrel body 102 defining an inner bore and terminating in a distal opening 102a.

[0090] - A tapered or conical reservoir 105 located along a sidewall of the cartridge body 102 and configured to store a predetermined amount of dermal filling composition 108 therein, wherein the reservoir 105 has a refill opening 107 .

[0091] - A port or orifice 115 extending along the sidewall of the microneedle 110 and positioned to provide communication between the reservoir 105 and the cavity 110c of the microneedle 110 so that the dermal filling composition 108 can flow into the port 115 or into the cavity 110c.

[0092] - A hollow microneedle 110 extending within the inner bore defined by the sleeve body 102, wherein the microneedle 110 is configured to be reciprocally displaceable along the inner bore of the sleeve body 102 such that a distal tip 112 of the microneedle 100 can be extended and retracted through the distal opening 102a of the sleeve body 110.

[0093] A plunger 116 having a shaft 116a for advancing a seal 118 along the lumen 110c of the microneedle 110 to (i) collect a quantity 108a of the skin filling composition 108, which is communicated into the lumen 110c of the microneedle 110 through the port 115, and (ii) deliver the quantity 108a of the skin filling composition along the lumen 110c of the microneedle 110 and through the outlet at the tip 112. The plunger shaft 116a is formed with a plunger extension extending proximally from the proximal end of the microneedle 110 in a sealable engagement therewith.

[0094] Figure 5 is a schematic diagram of an exemplary microneedle system 500 for intradermally delivering a dermal filler composition into the dermal tissue of a subject using a microneedle device of the present disclosure. In some embodiments, according to some embodiments of the present disclosure, the microneedle system 500 is configured to intradermally deliver a dermal filler composition into the dermal tissue of a subject. In some embodiments, the microneedle system 500 includes a microneedle device 504, which may be embodied in Figure 1A-1F and Figure 2A-2H The exemplary microneedle device 100 shown, and / or Figure 4A The exemplary microneedle device variation 120 shown, Figure 4B The exemplary microneedle device variation 130 shown and / or Figure 4C In any of the illustrated exemplary microneedle device variations 140. Generally, the microneedle device 504 includes one or more high-frequency ultrasound transducers 504a and one or more imaging devices 504b.

[0095] In some embodiments, the microneedle system 500 includes a control module 502 configured to control the operation of the microneedle system 500 and the microneedle device 504. The control module 502 may include one or more hardware processors, random access memory (RAM), and one or more non-transitory computer-readable storage devices, such as a storage device 502a. The components of the control module 502 may be co-located or distributed, or the control module 502 may be configured to run as one or more cloud computing "instances," "containers," "virtual machines," or other types of packaged software applications, as are known in the art.

[0096] The storage device 502a may store thereon program instructions and / or components configured to operate the control module 502. The program instructions may include one or more software modules, which may include an operating system with various software components and / or drivers for controlling and managing general system tasks (e.g., memory management, storage device control, power management, etc.), as well as facilitating communication between various hardware components and software components. The control module 502 may operate by loading the instructions of the various software modules into its RAM when the hardware processor(s) including the control module 502 execute the instructions of the various software modules.

[0097] The control module 502 described herein is merely an exemplary embodiment of the present invention and, in practice, may be implemented solely in hardware, solely in software, or in a combination of both hardware and software. The control module 502 may have more or fewer components and modules than shown, may combine two or more of these components, or may have different configurations or arrangements of these components. The control module 502 may include any additional components that enable it to function as an operating computer system, such as a motherboard, data bus, power supply, network interface card, display, input device, etc. In addition, the components of the control module 502 may be co-located or distributed (e.g., co-located or distributed on an external control or computing device), or the system may be configured to run as one or more cloud computing "scenarios," "containers," "virtual machines," or other types of packaged software applications, as is known in the art.

[0098] In some embodiments, microneedle system 500 includes a user interface 506, which may include a display screen, which is optionally a touch screen. User interface 506 is used to provide output to a user and / or receive input from a user.

[0099] In some embodiments, the microneedle system 500 or any of its modules is configured to communicate with one or more external computing devices (not shown), which may include computer processors of local or remote computing devices or remote servers (e.g., cloud-based remote servers). For example, the external computing devices may receive data from the control module 502 and may then send data and / or instructions to the control module 502.

[0100] In some embodiments, the microneedle system 500 includes a communication unit 508 configured to send information to and / or receive information from an external computing device. The sending and receiving of information can be implemented wirelessly and / or wiredly.

[0101] In certain embodiments, the dermal filler composition is solid at room temperature. In certain embodiments, the dermal filler composition is solid at a temperature of 10° C., 20° C., 30° C., 40° C., or 50° C. In certain embodiments, the dermal filler composition is semi-solid at room temperature, or at a temperature of 10° C., 20° C., 30° C., 40° C., or 50° C.

[0102] In some embodiments, the dermal filler composition comprises a dermal filler component substance or material and a dispersant. In certain embodiments, the dermal filler composition consists essentially of a biocompatible dermal filler material and a biocompatible dispersant. In certain embodiments, the dermal filler composition does not comprise a dispersant.

[0103] In some embodiments, the dermal filler composition is solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is solid at room temperature. In certain embodiments, the dermal filler composition is solid at room temperature, the dermal filler material is semi-solid at room temperature, and the dispersant is solid at room temperature. In certain embodiments, the dermal filler composition is solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is semi-solid at room temperature. In certain embodiments, the dermal filler composition is solid at room temperature, the dermal filler material is semi-solid at room temperature, and the dispersant is semi-solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is semi-solid at room temperature, and the dispersant is solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is semi-solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is solid at room temperature, and the dispersant is semi-solid at room temperature. In certain embodiments, the dermal filler composition is semi-solid at room temperature, the dermal filler material is semi-solid at room temperature, and the dispersant is semi-solid at room temperature. In certain embodiments, the dermal filler composition is liquid at room temperature.

[0104] In certain embodiments, the dermal filler composition is solid at room temperature and comprises about 50% to about 75% by weight of a biocompatible dermal filler material, and about 25% to about 50% by weight of a biocompatible dispersant, wherein at least about 20% of the total volume of the microneedles is filled with the dermal filler composition.

[0105] In certain embodiments, the dermal filler composition is solid at room temperature and comprises about 60% to about 65% by weight of a biocompatible dermal filler material, and about 35% to about 40% by weight of a biocompatible dispersant, wherein about 40% to about 50% of the total volume of the microneedles is filled with the dermal filler composition.

[0106] In certain embodiments, the skin filler composition comprises at least about 30% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 35% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 40% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 45% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 50% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 55% by weight of a biocompatible skin filler material. In certain embodiments, the skin filler composition comprises at least about 60% by weight of a biocompatible skin filler material.

[0107] In certain embodiments, the dermal filler composition comprises at least about 20% by weight of at least one biocompatible dispersant. In certain embodiments, the dermal filler composition comprises at least about 25% by weight of at least one biocompatible dispersant. In certain embodiments, the dermal filler composition comprises at least about 30% by weight of at least one biocompatible dispersant. In certain embodiments, the dermal filler composition comprises at least about 30% by weight of at least one biocompatible dispersant. In certain embodiments, the dermal filler composition comprises at least about 35% by weight of at least one biocompatible dispersant.

[0108] In certain embodiments, the dermal filler composition comprises at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60% by weight of a biocompatible dermal filler material; and at least about 20%, at least about 25%, at least about 30%, or at least about 35% by weight of at least one biocompatible dispersant. Each possibility represents a separate embodiment of the present invention.

[0109] In certain embodiments, the skin filler composition comprises 4% by weight of the biocompatible skin filler material for every 3% by weight of the at least one biocompatible dispersant. In certain embodiments, the skin filler composition comprises 5% by weight of the biocompatible skin filler material for every 3% by weight of the at least one biocompatible dispersant. In certain embodiments, the skin filler composition comprises 6% by weight of the biocompatible skin filler material for every 3% by weight of the at least one biocompatible dispersant.

[0110] In certain embodiments, the dermal filler composition comprises from about 50% to about 75% by weight of a biocompatible dermal filler material and from about 25% to about 50% by weight of a biocompatible dispersant. In certain embodiments, the dermal filler composition comprises from about 60% to about 65% by weight of a biocompatible dermal filler material and from about 35% to about 40% by weight of a biocompatible dispersant. In certain embodiments, the dermal filler composition comprises from about 62.5% by weight of a biocompatible dermal filler material and from about 37.5% by weight of a biocompatible dispersant.

[0111] In certain embodiments, at least about 20% of the total volume of the microneedles is filled with a skin filler composition. In certain embodiments, at least about 30% of the total volume of the microneedles is filled with a skin filler composition. In certain embodiments, at least about 40% of the total volume of the microneedles is filled with a skin filler composition. In certain embodiments, at least about 50% of the total volume of the microneedles is filled with a skin filler composition. In certain embodiments, from about 40% to about 50% of the total volume of the microneedles is filled with a skin filler composition.

[0112] In certain embodiments, the biocompatible dispersant disperses at least a portion of the skin filler material into the dermis, subcutaneous tissue, or both. In certain embodiments, the biocompatible dispersant disperses at least a portion of the skin filler material into both the dermis and subcutaneous tissue.

[0113] In certain embodiments, the biocompatible skin filler material is hydroxyapatite. In certain embodiments, the biocompatible skin filler material is hyaluronic acid. In certain embodiments, the biocompatible skin filler material is in the form of solid particles or solid spheres. In certain embodiments, approximately 10% of the particles or spheres have a diameter of up to about 15 μm to about 35 μm. In certain embodiments, approximately 50% of the particles or spheres have a diameter of up to about 35 μm to about 50 μm. In certain embodiments, approximately 90% of the particles or spheres have a diameter of up to about 50 μm to about 70 μm. In certain embodiments, approximately 10% of the particles or spheres have a diameter of up to about 26 μm. In certain embodiments, approximately 50% of the particles or spheres have a diameter of up to about 41 μm. In certain embodiments, approximately 90% of the particles or spheres have a diameter of up to 64 μm.

[0114] In certain embodiments, the biocompatible dispersant is a water-soluble polymer. In certain embodiments, the water-soluble polymer is polyethylene glycol (PEG), polyethylene oxide (PEO), or polyethylene oxide (POE). In certain embodiments, the molecular weight of the water-soluble polymer ranges from about 1,000, about 2,000, about 3,000, about 4,000, about 5,000, about 6,000, about 7,000, about 8,000, about 9,000, or about 10,000 to about 10,000, about 11,000, about 12,000, about 13,000, about 14,000, about 15,000, about 16,000, about 17,000, about 18,000, or about 19,000 g / mole. Each possibility represents a separate embodiment of the present invention. In certain embodiments, the water-soluble polymer is PEG 12,000.

[0115] The present disclosure provides, for the first time, a microneedle-based applicator for delivering a dermal filler composition comprising at least one biocompatible filler material to a subject's skin. The applicator of the present invention provides an effective, comfortable, and easy-to-use delivery system for dermal filler compositions. The present disclosure also provides methods for delivering dermal filler compositions to a subject's skin. The methods of the present invention are particularly useful for filling undesirable folds, wrinkles, or lines in a subject's skin. According to some embodiments, the methods of the present invention enable a subject to use the applicator and method of the present invention without the assistance of a trained medical professional. According to other embodiments, the applicator of the present invention may be supplied as a disposable strip or patch.

[0116] According to some embodiments of the present invention, non-limiting examples of skin imperfections or defects are selected from the group consisting of: undesirable lines, wrinkles, folds, depressed scars, defective areas of the skin or subcutaneous layer, or combinations thereof.

[0117] As used herein, the terms "composition," "composition of the present invention," "filling composition," "soft tissue filling composition," and "dermal filling composition" are used interchangeably and refer to a composition comprising at least one biocompatible dermal filling material. It should be understood that the dermal filling composition according to the present invention is suitable for filling the skin, dermis, subcutaneous tissue layer, or a combination thereof.

[0118] As used herein, the terms "biocompatible skin filler material," "biocompatible soft tissue filler material," "biocompatible agent," and "biocompatible material" are used interchangeably. As used herein, the term "biocompatible material" refers to a biocompatible skin filler material. According to some embodiments, the biocompatible material is an inorganic ceramic material, such as, but not limited to, hydroxyapatite. According to some embodiments, the biocompatible material is water-insoluble. According to some embodiments, the biocompatible material is a calcium phosphate ceramic material. As used herein, the terms "hydroxyapatite," "hydroxyapatite," "calcium hydroxyapatite," and "calcium hydroxyapatite" are interchangeable. According to some embodiments, hydroxyapatite as used herein also refers to a salt or derivative of hydroxyapatite.

[0119] In certain embodiments, the dermal filler material is at least 95% crystalline. In certain embodiments, the dermal filler material is at least 95% crystalline as measured by XRD. In certain embodiments, the dermal filler material is at least 98% pure. In certain embodiments, the dermal filler material has a density of 0.45 g / cm 3 Up to 0.65 g / cm 3 In certain embodiments, the skin filler material has a specific gravity of 0.509 g / cm 3 proportion.

[0120] In certain embodiments, the hydroxyapatite is at least 95% crystalline. In certain embodiments, the hydroxyapatite is at least 95% crystalline as measured by XRD. In certain embodiments, the hydroxyapatite is at least 98% pure. In certain embodiments, the hydroxyapatite has a density of 0.45 g / cm 3 Up to 0.65 g / cm 3 In certain embodiments, hydroxyapatite has a specific gravity of 0.509 g / cm 3 proportion.

[0121] A non-limiting example of a dermal filling composition comprising a biocompatible ceramic material is RADIESSE manufactured by Merz Aesthetics. ® , which comprises calcium hydroxyapatite beads suspended in a gel vehicle consisting primarily of water, glycerol, and sodium carboxymethylcellulose.

[0122] According to some embodiments, the biocompatible material is biodegradable. According to some embodiments, the biocompatible material can undergo biodegradation in no less than 1, 2, 3, or 4 weeks after being administered to a subject. According to some embodiments, the biocompatible material can undergo biodegradation in no less than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after being administered to a subject. According to some embodiments, the biocompatible material can undergo biodegradation in no less than 0.5, 1, 2, or 3 years after being administered to a subject. According to some embodiments, the biocompatible material can undergo biodegradation in no less than several months after being administered to a subject. According to some embodiments, the biocompatible material can undergo biodegradation in no less than 12 months after being administered to a subject.

[0123] According to some embodiments, the biocompatible material is in the form of beads and / or particles. According to some embodiments, the biocompatible material comprises beads and / or particles of the same or different sizes. According to some embodiments, the biocompatible material is in the form of beads and / or particles whose size is adapted to the size of the area to be treated. According to some embodiments, an applicator containing large beads of biocompatible material is suitable for treating deep and / or large lines, wrinkles, or folds.

[0124] According to some embodiments, the biocompatible material comprises beads and / or particles having a size of up to 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 micrometers (µm). According to some embodiments, the biocompatible material comprises beads and / or particles having a size of 25-45 μm. According to some embodiments, the biocompatible material comprises beads and / or particles having a size of 10-50 μm. According to some embodiments, the biocompatible material comprises beads and / or particles having a size of 5-20 μm. According to some embodiments, the biocompatible material comprises beads and / or particles having a size of approximately 40 μm. According to some embodiments, the biocompatible material particles are approximately 10-100 μm, preferably approximately 40 μm.

[0125] According to some embodiments, the dermal filler composition comprises at least 1%, 2%, 3%, 4%, 5%, 10%, 15%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% biocompatible material. According to some embodiments, the dermal filler composition comprises at least 30% biocompatible material.

[0126] According to some embodiments, the composition of the present invention comprises at least one biocompatible filler, at least one biodegradable carrier, and at least one additional skin filling material. According to some embodiments, the composition of the present invention comprises hydroxyapatite and at least one biodegradable carrier. According to some embodiments, the composition of the present invention comprises hydroxyapatite and polyethylene glycol. According to some embodiments, the composition of the present invention comprises hydroxyapatite, polyethylene glycol, and magnesium sulfate.

[0127] According to some embodiments, the biodegradable carrier is selected from the group consisting of salts, biodegradable polymers, and combinations thereof. According to some embodiments, the biodegradable carrier is a salt. According to some embodiments, the salt is a water-soluble salt. According to some embodiments, the salt is selected from the group consisting of sodium sulfate, sodium chloride, magnesium sulfate, magnesium citrate, magnesium chloride, and combinations thereof.

[0128] According to some embodiments, the biodegradable carrier is a biodegradable polymer. According to some embodiments, the biodegradable polymer is a polymer selected from the group consisting of polyethylene glycol (PEG), Polyglactin 910, Polyglecaprone 25, polydioxanone, Lactomer 9-1, Glycomer 631, polygluconate, and combinations thereof. According to some embodiments, the biodegradable carrier is magnesium sulfate and / or polyethylene glycol. According to some embodiments, PEG, as used herein, has a molecular weight of 10 to 50 kDa. According to some embodiments, the biodegradable carrier comprising 10-50 kDa PEG has a thick paste consistency. According to some embodiments, the biodegradable carrier is Polyglactin 910 and / or magnesium sulfate.

[0129] According to some embodiments, the biodegradable carrier is degradable within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 hours of inserting the microneedles into the skin of a subject. According to some embodiments, the biodegradable polymer is degradable within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 hours of inserting the microneedles into the skin of a subject. According to some embodiments, the biodegradable carrier is degradable within 0.5, 1, 2, 3, 4, 5, 6, 7 days of inserting the microneedles into the skin of a subject. According to some embodiments, the biodegradable polymer is degradable within 0.5, 1, 2, 3, 4, 5, 6, 7 days of inserting the microneedles into the skin of a subject. According to some embodiments, the biodegradable carrier undergoes biodegradation in less than 7 days, preferably less than 2 days, and most preferably less than 1 day, of inserting the microneedles into the skin of a subject. According to some embodiments, the biodegradable carrier rapidly biodegrades within hours / days of introduction into the subject, resulting in a uniform distribution of the biocompatible filler material and / or skin filler material in the treated area, thereby achieving uniform filling of the treated skin defect / imperfection. According to some embodiments, after the composition of the present invention is inserted into the subject's skin, the biodegradable carrier undergoes biodegradation, while the biocompatible filler remains within the subject's skin for at least several months, preferably up to one year, and most preferably for more than one year.

[0130] According to some embodiments, inserting microneedles containing a dermal filler composition into a subject's skin causes biodegradation of a rapidly degradable component of the composition, thereby releasing a biocompatible filler into the treated area. According to some embodiments, the rapidly degradable component is a biodegradable carrier, such as, but not limited to, magnesium sulfate and / or polyethylene glycol. It will be appreciated that, according to some embodiments, biodegradation of the component of the composition (e.g., the biodegradable carrier) aids in the uniform spreading of the biocompatible filler throughout the treated area. According to some embodiments, after the rapidly degradable component (e.g., the biodegradable carrier) biodegrades, the biocompatible filler is transferred from the microneedles to the treated area. As used herein, a rapidly degradable component refers to a component of the present compositions that undergoes biodegradation within a few hours or up to seven days after insertion of the present microneedles into the subject's skin. It will be appreciated that the biocompatible filler is not a rapidly degradable component of the present compositions. According to some embodiments, after administration of the present applicator for a desired period of time, the applicator and microneedles are removed from the subject, leaving at least a portion of the composition in the treated area.

[0131] According to some embodiments, the biodegradable carrier comprises water and / or glycerol and / or carboxymethyl cellulose. According to some embodiments, the biodegradable carrier comprises water, glycerol and carboxymethyl cellulose. According to some embodiments, the biodegradable carrier comprises carboxymethyl cellulose.

[0132] According to some embodiments, the compositions of the present invention comprise a biocompatible filler material in the form of beads and / or particles surrounded by at least one biodegradable carrier. According to some embodiments, the compositions of the present invention comprise a biocompatible filler material in the form of beads and / or particles surrounded by at least one biodegradable polymer. According to some embodiments, the compositions of the present invention comprise a biocompatible filler material in the form of beads and / or particles surrounded by at least one salt. According to some embodiments, the compositions of the present invention comprise hydroxyapatite in the form of beads and / or particles surrounded by at least one biodegradable carrier.

[0133] According to some embodiments, beads or particles of a biocompatible filler material (such as but not limited to hydroxyapatite) surrounded by the biodegradable carrier are evenly spread in the treatment area after the biodegradable carrier degrades due to dissolution, enzymatic activity, or the like.

[0134] According to some embodiments, a biodegradable polymer is added to the composition of the present invention to produce a composition having a gel-like, paste-like, or solid consistency. According to some embodiments, the gel-like, paste-like, or solid composition is configured to facilitate insertion and retention in the middle portion of the microneedle of the present invention. According to some embodiments, a salt is added to the composition of the present invention to aid in the uniform dispersion of the biocompatible filler in the composition. According to some embodiments, the addition of a material that attracts water or aqueous solutions (such as glycerol, salts, or polyethylene glycol (PEG), and other such materials or compounds) to the composition of the present invention causes water to diffuse into the composition, thereby aiding in the uniform dispersion of the biocompatible filler in the composition and / or within the treated area.

[0135] As used herein, the terms "skin filler material" and "filler" refer to agents and compositions used to fill skin defects. According to some embodiments, the skin filler material is a dermal and / or subcutaneous tissue filler. Suitable skin filler materials according to the present invention include, but are not limited to, proteins, polysaccharides, lipids, synthetic polymers and combinations thereof. According to some embodiments, the skin filler material according to the present invention is any material known in the art that is suitable for filling unwanted folds, wrinkles, depressed scars or lines in the skin of a subject. According to some embodiments, the skin filler material according to the present invention is any skin filler material configured to be delivered using microneedles. According to some embodiments, the biocompatible filler material is a skin filler material. According to certain embodiments, the skin filler material refers to a biocompatible inert material. The term "inert material" as used herein refers to a non-antigenic, non-carcinogenic, non-teratogenic and non-migratory filling material.

[0136] According to some embodiments, dermal filler materials include allogeneic products, xenogeneic products, and synthetically derived products.

[0137] According to some embodiments, the composition of the present invention further comprises at least one skin filling material selected from the group consisting of biodegradable natural substances, biodegradable synthetic polymers, non-biodegradable synthetic polymers, non-biodegradable natural substances, and combinations thereof.

[0138] According to some embodiments, the biodegradable natural material is selected from the group consisting of, for example, bovine collagen, porcine collagen, recombinant collagen, human collagen, gelatin, hyaluronic acid, hyaluronic acid derivatives, dried acellular granular dermal matrix, allogeneic fat, and combinations thereof.

[0139] According to some embodiments, the biodegradable synthetic polymer is selected from, for example, poly-L-lactic acid, polyethylene oxide, carboxymethyl cellulose, and combinations thereof.

[0140] According to some embodiments, the non-biodegradable synthetic polymer is selected from, for example, polymethyl methacrylate (PMMA), polymethyl methacrylate beads, silicone, silicone rubber, expanded polytetrafluoroethylene (ePTFE), polyacrylamide, polyalkylimide, and combinations thereof.

[0141] According to some embodiments, the dermal filler composition comprises at least one biocompatible filler material, a biodegradable carrier, and at least one type of dermal filler material selected from the group consisting of biodegradable natural substances, biodegradable synthetic polymers, non-biodegradable synthetic polymers, and combinations thereof.

[0142] According to some embodiments, the dermal filler composition comprises hydroxyapatite and at least one type of dermal filler material other than hydroxyapatite. According to some embodiments, the dermal filler composition comprises hydroxyapatite and at least one type of soft tissue filler material selected from the group consisting of: biodegradable natural substances, biodegradable synthetic polymers, non-biodegradable synthetic polymers, non-biodegradable natural substances, and combinations thereof. According to some embodiments, the dermal filler composition comprises hydroxyapatite and at least one type of soft tissue filler material selected from the group consisting of: biodegradable natural substances, biodegradable synthetic polymers, non-biodegradable synthetic polymers, and combinations thereof.

[0143] According to some embodiments, the compositions of the present invention comprise less than 50% by weight of water-soluble dermal filler materials, such as, but not limited to, collagen, hyaluronic acid, and gelatin.

[0144] The dermal filler material included in the composition of the present invention is a valid dermal filler approved by the U.S. Food and Drug Administration, including but not limited to fillers containing structural proteins, polysaccharides, or synthetic polymers. Exemplary embodiments of dermal filler materials to be used include collagen, such as reconstructed bovine collagen products, including but not limited to ZYDERM I®, ZYDERM II®, and ZYPLAST® (Collagen Corporation); natural human collagen COSMODERM™ and COSMOPLAST™ (INAMED); and endogenous collagen from a subject, i.e., AUTOLOGEN® produced by Collagenesis. According to some embodiments, additional examples of dermal fillers can be selected from dermal fillers containing hyaluronic acid, including but not limited to HYLAFORM® gel, manufactured by INAMED and Genzyme Corporations, which is derived from rooster combs; and RESTYLANE®, manufactured by Medicis, a hyaluronic acid derivative derived from fermentation of Streptococcus bacteria. The hyaluronic acid according to the present invention includes non-crosslinked and / or crosslinked hyaluronic acid derivatives known in the art. "Hyaluronic acid" according to the present invention includes both solid and semi-solid forms of hyaluronic acid. According to some embodiments, the collagen according to the present invention is selected from the group consisting of allogeneic collagen, xenogeneic collagen, and combinations thereof. According to other embodiments, the skin filler material is cultured human cadaveric dermis.

[0145] According to some embodiments, the composition of the present invention further comprises a bioactive agent. According to some embodiments, the bioactive agent is selected from the group consisting of: an enzyme, a drug, a toxin, and combinations thereof. According to some embodiments, the composition of the present invention does not contain any bioactive agent.

[0146] According to some embodiments, the enzyme is collagenase for treating scars or keloids, hyaluronidase for treating hyaluronic acid excess, or elastase for skin dilation.

[0147] According to some embodiments, the drug is an analgesic. According to some embodiments, when the applicator of the present invention is used to subcutaneously deliver a dermal filler composition, at least one analgesic is co-delivered by the applicator of the present invention along with the dermal filler composition. According to some embodiments, the dermal filler composition of the present invention further comprises an analgesic. According to some embodiments, the method of the present invention further comprises administering an analgesic. According to some embodiments, any analgesic known in the art may be used in the present invention, such as, but not limited to, lidocaine, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, opioids, or morphinomimetics. According to some embodiments, the analgesic useful in the present invention is lidocaine.

[0148] According to some embodiments, the drug is a drug known in the art to assist in filling undesirable lines, wrinkles, folds, etc. According to some embodiments, examples of drugs suitable for inclusion in the compositions of the present invention include, but are not limited to, anti-psoriatic drugs, muscle relaxants, and combinations thereof.

[0149] According to some embodiments, the drug is a drug for treating or preventing pathological scarring. According to some embodiments, the drug for treating pathological scarring is a corticosteroid. According to some embodiments, the corticosteroid is any corticosteroid known in the art for treating pathological scarring, such as but not limited to triamcinolone.

[0150] According to some embodiments, the toxin is botulinum toxin. According to some embodiments, the composition of the present invention comprises botulinum toxin. According to some embodiments, the composition of the present invention comprises botulinum toxin type A, human albumin, and sodium chloride. According to some embodiments, the applicator of the present invention comprises botulinum toxin.

[0151] According to some embodiments, the dermal filling composition of the present invention further comprises a medical pigment. According to some embodiments, the microneedles of the present invention further comprise a medical pigment. As used herein, the term "medical pigment" refers to a color material suitable for insertion into the skin of a subject. According to some embodiments, the medical pigment has regulatory approval for insertion into the skin of a subject. According to some embodiments, the medical pigment is a pigment known in the art as suitable for micropigmentation treatment. In non-limiting examples, medical pigments suitable for use according to the present invention include, but are not limited to, pigments such as BIOCHROMADERM ® (Biotic Phocea) or Signature Series (Micro-Pigmentation Centre, Inc.) According to some embodiments, possible medical pigments for use with the applicator of the present invention may be selected from: pigments for scar camouflage, areola reconstruction, lip remodeling, and any combination thereof.

[0152] According to some embodiments, the microneedles comprising a medical pigment are suitable for micropigmentation treatment. According to some embodiments, the micropigmentation treatment is selected from the group consisting of scar concealment, concealment and / or blurring of skin pigmentation, nipple and areola sculpting and / or filling, freckle correction, lip coloring, eyebrow coloring, and combinations thereof. According to some embodiments, the microneedles of the present invention comprise a composition comprising a medical pigment. According to some embodiments, the applicator of the present invention further comprises microneedles comprising a medical pigment without a biocompatible filler or skin filling composition.

[0153] As used herein, the terms "subject," "subject in need thereof," and "patient in need thereof" are used interchangeably and, according to some embodiments, refer to a subject in need of skin or subcutaneous layer augmentation, or a combination thereof. According to some embodiments, the subject is a subject having undesirable lines, wrinkles, and folds, such as, but not limited to, the elderly. According to other embodiments, the subject is a subject having scars in need of augmentation or filling. In a non-limiting example, the subject is a subject having facial wrinkles that he or she desires to have filled to achieve a younger-looking, healthier, and fuller-looking facial skin. Notably, the subject may have normal-looking skin and desire to use the applicator / method of the present invention to achieve the appearance of fuller skin in desired areas, such as, but not limited to, the cheeks and lips.

[0154] As used herein, the term "substantially" refers, according to some embodiments, to a complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, a composition "consisting essentially of A and B" would mean that the composition consists entirely of A and B, or, taking into account minor impurities, consists almost entirely of A and B. In some cases, the exact degree of permissible deviation from absolute completeness depends on the specific circumstances. However, generally speaking, nearly complete will result in the same overall result as if absolute and total completeness were achieved.

[0155] The use of "substantially" is equally applicable when used in a negative sense, and according to some embodiments, refers to the complete or nearly complete absence of an action, characteristic, property, state, structure, item, or result. For example, a composition "substantially free of A" would completely lack A or nearly completely lack A, and its effect would be the same as the complete absence of A. In other words, a composition "substantially free of / lacking" an ingredient or element may still actually contain such an item, as long as it has no measurable effect.

[0156] As used herein, the term "about" is used to provide flexibility to a provided numerical value by providing that a given value may be "a little above" or "a little below" the provided numerical value. As used herein, the term "about" also refers to ±10%, preferably ±5%, and most preferably ±1% of the referenced numerical value according to some embodiments.

[0157] As used herein, the terms "subcutaneous" and "subcutaneous layer" are used interchangeably. It should be understood that the applicator and / or microneedle of the present invention is configured to administer the dermal filling composition to the skin or the subcutaneous layer, or a combination thereof. It should be understood that the method of the present invention provides for filling or refilling of the skin or the subcutaneous layer, or a combination thereof.

[0158] According to some embodiments, the present invention provides use of an applicator of the present invention for filling the skin of a subject in need thereof. According to some embodiments, the present invention provides use of an applicator of the present invention for filling undesirable folds, wrinkles, lines or recessed areas in the skin of a subject in need thereof.

[0159] As used herein, the terms "biocompatible filler soft tissue filling material," "biocompatible filler material," and "biocompatible filler" are used interchangeably.

[0160] While certain features of the present invention have been illustrated and described herein, numerous modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. It is therefore intended that the appended claims cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. An apparatus comprising: a sleeve body defining an inner bore and terminating in a distal opening; a hollow microneedle defining an inner lumen and terminating at a distal tip, wherein the microneedle is configured to be reciprocally displaceable within the inner bore such that the tip extends and retracts through the distal opening; and A plunger having a shaft operable to advance the seal along the lumen to deliver an amount of a designated composition within the lumen, along the lumen, and through an outlet at a distal portion of the microneedle. 2 . The device of claim 1 , further comprising a reservoir attached at a proximal end of the body sleeve and configured to store a predetermined amount of the designated composition.

3. The device of claim 2, wherein the microneedle comprises an orifice extending along a sidewall of the microneedle, and wherein the orifice provides communication between the reservoir and the lumen, thereby allowing the amount of the specified composition to enter the lumen from the reservoir.

4. The device of any one of claims 1-3, wherein the tip is configured to pierce the skin of the subject at an injection site.

5. The device of claim 4, wherein the distal opening is configured to be positioned against the outer surface of the skin of the subject at the injection site, and wherein the microneedle is configured to extend a predetermined distance through the distal opening into the dermis or subcutaneous tissue layer of the subject to deliver the amount of at least a portion of the specified composition at a desired depth within the dermis or subcutaneous tissue layer.

6. The device according to any one of claims 1 to 5, wherein the microneedles are made of a material selected from the group consisting of metal, plastic, ceramic material, silicone material, and any combination thereof.

7. The device of any one of claims 1 to 6, wherein the microneedles have a cross-sectional shape selected from the group consisting of circular, rectangular, elliptical, triangular, and polygonal.

8. The device of any one of claims 1-7, wherein the tip comprises an end having an angle of convergence equal to 10-60 degrees.

9. The device according to any one of claims 1 to 8, wherein the designated composition is a skin filling composition.

10. The device according to any one of claims 1 to 9, wherein the designated composition has a consistency that is liquid, viscous, semi-solid or solid.

11. The device of any one of claims 1-10, wherein the designated composition comprises hydroxyapatite or hyaluronic acid.

12. The device according to any one of claims 1 to 11, wherein the designated composition comprises solid particles or solid spheres.

13. The device according to any one of claims 1-12, further comprising one or more sensors configured to image or measure the depth of the local skin structure at the injection site, wherein the one or more sensors are selected from the group consisting of: an ultrasonic sensor, an optical transducer, and a pressure gauge force transducer.

14. The device of any one of claims 1-13, further comprising one or more imaging devices configured to image the advancement path of the device at the injection site.

15. The device of any one of claims 1-14, wherein the outlet is located at the tip.

16. A method comprising: An apparatus is provided, comprising: a sleeve body defining an inner bore and terminating in a distal opening, a hollow microneedle defining an inner lumen and terminating at a distal tip, wherein the microneedle is configured to be reciprocally displaceable within the inner bore such that the tip extends and retracts through the distal opening, and a plunger having a shaft operable to advance the seal along the lumen to deliver an amount of a specified composition within the lumen, along the lumen, and through an outlet at a distal portion of the microneedle; positioning the device at an injection site around the skin of a subject; displacing the microneedle within the inner bore so that the tip extends a predetermined distance through the distal opening into the dermis or subcutaneous tissue layer of the skin of the subject; and The shaft is operated to advance the seal along the lumen, thereby delivering at least a portion of the amount of the designated composition along the lumen and through the outlet at the tip into the dermis or subcutaneous tissue layer.

17. The method of claim 16, wherein the device further comprises a reservoir attached at the proximal end of the body sleeve and configured to store a predetermined amount of the designated composition.

18. The method of claim 17, wherein the microneedle comprises an orifice extending along a sidewall of the microneedle, and wherein the orifice provides communication between the reservoir and the lumen, thereby allowing the amount of the specified composition to pass from the reservoir into the lumen.

19. The method of any one of claims 16-18, wherein the tip is configured to pierce the skin of the subject at the injection site.

20. The method of claim 19, wherein the distal opening is configured to be positioned against an outer surface of the skin of the subject at the injection site, and wherein the predetermined distance defines a desired depth location within the dermis or subcutaneous tissue layer for delivering the at least a portion of the amount of the specified composition.

21. The method according to any one of claims 16 to 20, wherein the microneedles are made of a material selected from the group consisting of metal, plastic, ceramic material, silicone material, and any combination thereof.

22. The method of any one of claims 16-21, wherein the microneedle has a cross-sectional shape selected from the group consisting of circular, rectangular, elliptical, triangular, and polygonal.

23. The method of any one of claims 16-22, wherein the tip comprises an end having an angle of convergence equal to 10-60 degrees.

24. The method of any one of claims 16-23, wherein the designated composition is a dermal filler composition.

25. The method of any one of claims 16-24, wherein the designated composition has a consistency that is liquid, viscous, semi-solid, or solid.

26. The method of any one of claims 16-25, wherein the specified composition comprises hydroxyapatite or hyaluronic acid.

27. The method of any one of claims 16-26, wherein the designated composition comprises solid particles or solid spheres.

28. The method of any one of claims 16-27, wherein the device further comprises one or more sensors configured to image or measure the depth of local skin structures at the injection site, wherein the one or more sensors are selected from the group consisting of: an ultrasonic sensor, an optical transducer, and a manometer force transducer.

29. The method of any one of claims 16-28, wherein the device further comprises one or more imaging devices configured to image the advancement path of the device at the injection site.

30. The method of any one of claims 16-29, wherein the outlet is located at the tip.

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