Proelastin for treating acne scars

Abstract

The present disclosure provides troelastin for use in the treatment of acne scars, including in particular methods for treating acne scars to improve the color and / or appearance of, and / or reduce the depth, affected area, and / or volume of, acne scars. Such methods may include applying a composition comprising troelastin to a region of skin having an acne scar, and optionally disrupting fiber bundles under the acne scar, and applying the composition under the acne scar.

Description

[0001] This patent application is a divisional application of the patent application with application number 2020800703481, application date August 21, 2020, and invention name “Tropoelastin for the treatment of acne scars”. Technical Field

[0002] The present disclosure relates to methods of improving the appearance of acne scars, such as depressions, ice pick scars, roller atrophic acne scars, and boxcar scars, using compositions comprising tropoelastin. Background Art

[0003] Reference to any prior art in the specification is not an acknowledgement or implication that the prior art forms part of the common general knowledge in any jurisdiction, or that the prior art could reasonably be expected to be understood by a person skilled in the art, to be relevant and / or to be combined with other parts of the prior art.

[0004] Acne scars are formed by infected scabs caused by clogged skin pores filled with excess oil, dead skin cells and bacteria. The pores swell, causing cracks in the walls of the pores. Shallow injuries are usually small and can heal quickly. But when there are deep cracks in the pore walls, infected substances can overflow into the surrounding tissues, causing deeper injuries. Therefore, the skin may try to repair these injuries by forming new collagen fibers. In some cases, visible scars may be in obvious locations, such as the face, neck and chest, which may become a nuisance to the person concerned. Many variables can affect the severity of scars, such as the thickness and coloring of scars. These repairs may not be as smooth and perfect as the baseline skin (original skin). In addition, healing may cause the skin inside the scar to have undesirable coloring.

[0005] There are several types of acne scars. Without limitation, these types include hypertrophic scars, ice pick scars, boxcar scars, roller-type atrophic scars, and depressed scars. In some cases, scars can cause skin discoloration, UV exposure can cause scars to darken and make them more noticeable, and fibrous tissue in scars can be silver.

[0006] Several types of treatments for the prevention and treatment of acne have been described in the art, however, the scars left behind can be difficult to treat and even more difficult to control. For example, conventional treatments for the skin include the use of topical retinoids to fade the brown, red or purple discoloration left by acne, laser treatments, dermabrasion and trephination. Thus, there is a need to treat unsightly scars and improve their appearance. It is also desirable to reduce the depth, affected area and volume of the depressions that may be caused by acne. Summary of the invention

[0007] The present disclosure generally relates to compositions comprising tropoelastin and methods of using such compositions to treat acne scars (e.g., fibrotic acne scars). The method may include applying a composition comprising tropoelastin to a skin area with acne scars. In one embodiment, the method includes treating a skin area with acne scars to improve the color and / or appearance of acne scars in a skin area of ​​a patient in need, and / or reduce the depth, affected area, and / or volume of acne scars. The treatment methods disclosed herein may improve the color and / or appearance of acne scars in a skin area of ​​a patient in need. Additionally or alternatively, the treatment methods may reduce the depth, affected area, and / or volume of acne scars in a skin area of ​​a patient in need.

[0008] In some embodiments of each or any of the above or following embodiments, the composition comprises between about 1 mg / mL and about 400 mg / mL of tropoelastin. In some embodiments of each or any of the above or following embodiments, the composition comprises between about 1 mg / mL and about 400 mg / mL of tropoelastin.

[0009] mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170

[0010] mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210

[0011] mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250

[0012] mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290

[0013]

[0045] The invention relates to any amount of tropoelastin, wherein the amount of tropoelastin is about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, or about 400 mg / mL of tropoelastin, or any amount of tropoelastin between the ranges defined by any two of the foregoing values.

[0014] In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 300mg / mL. In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 250mg / mL. In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 200mg / mL. In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 150mg / mL. In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 100mg / mL.

[0015] In some embodiments of each or any of the above or following embodiments, tropoelastin is cross-linked with about 0.1% to about 10% of the derived hyaluronic acid. In some embodiments of each or any of the above or following embodiments, the composition comprises tropoelastin between about 1mg / mL to about 100mg / mL cross-linked with about 0.4% to about 1% of the derived hyaluronic acid (HA). In some embodiments of each or any of the above or following embodiments, the composition comprises recombinant human tropoelastin of about 30mg / mL cross-linked with about 0.5% of the derived hyaluronic acid. In some embodiments of each or any of the above or following embodiments, the composition further comprises a buffer (e.g., phosphate buffered saline).

[0016] In some embodiments of each or any of the foregoing or following embodiments, the composition comprising tropoelastin is applied around a scar, such as beneath a scar and / or around the edges of a scar.

[0017] In some embodiments of each or any of the above or following embodiments, acne scars are subdivided into ice pick scars, boxcar scars, or roller atrophic scars. In some embodiments of each or any of the above or following embodiments, the acne scars are ice pick scars. In some embodiments of each or any of the above or following embodiments, the acne scars are boxcar scars. In some embodiments of each or any of the above or following embodiments, the scars are roller atrophic acne scars. In some embodiments of each or any of the above or following embodiments, the scars are hypertrophic scars. In some embodiments of each or any of the above or following embodiments, the scars include fibrotic tissue around the edges or base of the scars.

[0018] In some embodiments of each or any of the above or following embodiments, the depth of the acne scar is about 0.1 mm to about 5 mm. In some embodiments of each or any of the above or following embodiments, the depth of the acne scar is about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth in the range between any two of the foregoing values.

[0019] In some embodiments of each or any of the foregoing or following embodiments, the affected area of ​​the acne scar is about 0.05 mm 2 To about 400mm 2 In some embodiments of each or any of the foregoing or following embodiments, the affected area of ​​the acne scar is about 0.05 mm 2 , about 0.50mm 2 , 1.0mm 2 , about 5mm 2 , about 10mm 2 , about 15mm 2 , about 20mm 2 , about 25mm 2 , about 30mm 2 、Approx. 35mm 2 、Approx. 40mm 2 、Approx. 45mm 2 、About 50mm 2 、Approx. 55mm 2 、Approx. 60mm 2 、Approx. 65mm 2 、Approx. 70mm 2 、Approx. 75mm 2 、Approx. 80mm 2 、Approx. 85mm 2 、Approx. 90mm 2 、Approx. 95mm 2 , about 100mm 2 , about 125mm 2 , about 150mm 2 、Approx. 175mm 2 , about 200mm 2 、Approx. 225mm 2 , about 250mm 2 、Approx. 275mm 2 , about 300mm 2 、Approx. 325mm 2 、About 350mm 2 、Approx. 375mm 2 or about 400mm 2, or any value in the range between any two of the aforementioned values.

[0020] In some embodiments of each or any of the foregoing or following embodiments, the volume of the acne scar is about 0.01 mm 3 About 2,000mm 3 In some embodiments of each or any of the foregoing or following embodiments, the volume of the acne scar is about 0.01 mm 3 , 1mm 3 , about 10mm 3 , about 20mm 3 , about 30mm 3 、Approx. 40mm 3 、About 50mm 3 、Approx. 60mm 3 、Approx. 70mm 3 、Approx. 80mm 3 、Approx. 90mm 3 , about 100mm 3 , about 125mm 3 , about 150mm 3 、Approx. 175mm 3 , about 200mm 3 、Approx. 225mm 3 , about 250mm 3 、Approx. 275mm 3 , about 300mm 3 、Approx. 325mm 3 、About 350mm 3 、Approx. 375mm 3 , about 400mm 3 、Approx. 425mm 3 、Approx. 450mm 3 、Approx. 475mm 3 , about 500mm 3 、Approx. 525mm 3 、About 550mm 3 、About 575mm 3 、About 600mm 3 、Approx. 625mm 3 、About 650mm 3 、Approx. 675mm 3 、About 700mm 3 、Approx. 725mm 3 、About 750mm 3 、Approx. 775mm 3 , about 800mm 3 、Approx. 825mm 3 、About 850mm 3 、Approx. 875mm3 、About 900mm 3 、Approx. 925mm 3 、About 950mm 3 、975mm 3 、Approx. 1,000mm 3 、Approx. 1,100mm 3 、Approx. 1,200mm 3 、Approx. 1,300mm 3 、Approx. 1,400mm 3 、Approx. 1,500mm 3 、Approx. 1,600mm 3 、Approx. 1,700mm 3 、Approx. 1,800mm 3 、Approx. 1,900mm 3 or about 2,000mm 3 , or any volume within the range between any two of the aforementioned values.

[0021] In some embodiments of each or any of the above or following embodiments, the method further comprises the step of destroying the fiber bundle below the acne scar. In some embodiments of each or any of the above or following embodiments, the destruction is performed before the composition is applied to a patient in need. In some embodiments of each or any of the above or following embodiments, the step of destroying the fiber bundle produces a dermal pocket below the acne scar. In some embodiments of each or any of the above or following embodiments, the destruction is performed with an 18G to 32G needle, such as an 18G, 21G, 23G, 25G, 27G, 29G or 30G needle. In some embodiments of each or any of the above or following embodiments, application comprises injecting the composition into the dermal pocket. In some embodiments of each or any of the above or following embodiments, a composition comprising tropoelastin is also placed around the scar, such as below the scar and around the edge of the scar. In the entire dermis near the scar, the composition comprising tropoelastin is evenly placed around the scar to ensure that the tropoelastin product is around the scar area.

[0022] In some embodiments of each or any of the above or following embodiments, the composition is applied as an injection under the acne scar. In some embodiments of each or any of the above or following embodiments, the composition is applied in a volume of about 10 μL to about 100 μL per implantation / injection. In some embodiments of each or any of the above or following embodiments, the composition is applied in a volume of about 10 μL, about 20 μL, about 30 μL, about 40 μL, about 50 μL, about 60 μL, about 70 μL, about 80 μL, about 90 μL or about 100 μL, or in a range defined by any two of the foregoing values. In some embodiments, more than one injection is performed on the acne scar, and the total application volume is about 200 μL, about 300 μL, about 400 μL or about 500 μL.

[0023] In some embodiments of each or any of the above or following embodiments, the injection is performed using a retrograde linear threading technique in a cross-hatching arrangement to ensure that all fiber bundles within the acne scar are destroyed. In some embodiments of each or any of the above or following embodiments, the needle is inserted at an angle of about 30° parallel to the skin, wherein the needle is beveled and the bevel is facing upward. In some embodiments of each or any of the above or following embodiments, the needle is inserted more than once to break the fiber bundles and create a dermal capsule. In some embodiments of each or any of the above or following embodiments, uniform pressure is applied to inject the composition while the needle is withdrawn from the dermal capsule.

[0024] In some embodiments of each or any of the above or following embodiments, the composition is administered repeatedly, and wherein one or more boluses are administered in the scar. In some embodiments of each or any of the above or following embodiments, the maximum volume of the composition administered as a treatment is between about 100 μL and about 5 mL. In some embodiments of each or any of the above or following embodiments, the maximum volume of the composition administered as a treatment is about 100 μL, about 500 μL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5 mL, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the maximum volume of the composition administered as a treatment is about 100 μL / cm 2 to about 500 μL / cm 2 In some embodiments of each or any of the foregoing or following embodiments, the maximum volume of the composition administered as a treatment is about 100 μL / cm 2 , about 150μL / cm 2, about 200μL / cm 2 , about 250μL / cm 2 , about 300μL / cm 2 , about 350μL / cm 2 , about 400μL / cm 2 , about 450μL / cm 2 , about 500μL / cm 2 , or any amount between the ranges defined by any two of the foregoing values.

[0025] In some embodiments of each or any of the foregoing or following embodiments, the skin type of the patient in need thereof is type I, type II, type III, type IV, type V, or type VI in the Fitzpatrick skin classification scale. In some embodiments of each or any of the foregoing or following embodiments, the scar comprises grades 1 to 5. Scar grading is described in Tan et al., "Global Scale for Acne Scar Severity (SCAR-S)" in 2010 (Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference).

[0026] In some embodiments of each or any of the above or following embodiments, acne scars are subdivided into ice pick scars, boxcar scars, or roller-type atrophic scars. In some embodiments of each or any of the above or following embodiments, the acne scars are ice pick scars. In some embodiments of each or any of the above or following embodiments, the acne scars are boxcar scars. In some embodiments of each or any of the above or following embodiments, the scars are roller-type atrophic acne scars. In some embodiments of each or any of the above or following embodiments, the scars are hypertrophic scars. In some embodiments of each or any of the above or following embodiments, the acne scars include fibrotic tissue around the scar edges and / or scar base.

[0027] In some embodiments of each or any of the above or following embodiments, the depth of the acne scar is about 0.1 mm to about 5 mm. In some embodiments of each or any of the above or following embodiments, the depth of the acne scar is about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth in the range between any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the affected area of ​​the acne scar is about 0.05 mm2 To about 400mm 2 In some embodiments of each or any of the foregoing or following embodiments, the volume of the acne scar is about 0.01 mm 3 Up to 2,000mm 3 .

[0028] In some embodiments of each or any of the foregoing or following embodiments, the volume of the acne scar is about 0.01 mm 3 , 1mm 3 , about 10mm 3 , about 20mm 3 , about 30mm 3 、Approx. 40mm 3 、About 50mm 3 、Approx. 60mm 3 、Approx. 70mm 3 、Approx. 80mm 3 、Approx. 90mm 3 , about 100mm 3 , about 125mm 3 , about 150mm 3 、Approx. 175mm 3 , about 200mm 3 、Approx. 225mm 3 , about 250mm 3 、Approx. 275mm 3 , about 300mm 3 、Approx. 325mm 3 、About 350mm 3 、Approx. 375mm 3 , about 400mm 3 、Approx. 425mm 3 、Approx. 450mm 3 、Approx. 475mm 3 , about 500mm 3 、Approx. 525mm 3 、About 550mm 3 、About 575mm 3 、About 600mm 3 、Approx. 625mm 3 、About 650mm 3 、Approx. 675mm 3 、About 700mm 3 、Approx. 725mm 3 、About 750mm 3 、Approx. 775mm 3 , about 800mm 3 、Approx. 825mm 3 、About 850mm 3 、Approx. 875mm3 、About 900mm 3 、Approx. 925mm 3 、About 950mm 3 、975mm 3 、Approx. 1,000mm 3 、Approx. 1,100mm 3 、Approx. 1,200mm 3 、Approx. 1,300mm 3 、Approx. 1,400mm 3 、Approx. 1,500mm 3 、Approx. 1,600mm 3 、Approx. 1,700mm 3 、Approx. 1,800mm 3 、Approx. 1,900mm 3 or about 2,000mm 3 , or any volume within the range between any two of the aforementioned values.

[0029] In some embodiments of each or any of the above or following embodiments, the skin has a skin color defined by CIE L*a*b* color coordinates, wherein the method also reduces L*. In some embodiments of each or any of the above or following embodiments, the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the aforementioned values. In some embodiments of each or any of the above or following embodiments, the method reduces L* by more than about 50%. In some embodiments of each or any of the above or following embodiments, the method also increases a*. In some embodiments of each or any of the above or following embodiments, the method increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the aforementioned values. In some embodiments of each or any of the above or following embodiments, the method increases a* by more than about 50%. In some embodiments of each or any of the above or following embodiments, the scar has a silver coloration prior to application of the composition. In some embodiments of each or any of the above or following embodiments, application of the composition reduces the silver coloration of the scar and increases the red coloration and / or pink coloration of the scar. In some embodiments of each or any of the above or following embodiments, the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values, and increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the scar has a color, wherein the color is different from the patient's natural skin color, wherein application of the composition causes the color of the scar to decrease or fade in color intensity, such that the color of the scar blends with the patient's natural skin color.

[0030] In some embodiments of each or any of the foregoing or following embodiments, the acne scar is a facial scar, a back scar, or a trunk scar. In some embodiments of each or any of the foregoing or following embodiments, after applying the composition, the depth, affected area, and / or volume of the acne scar is reduced.

[0031] In some embodiments of each or any of the foregoing or following embodiments, the method aids in the repair of atrophic scars during the skin remodeling and maturation phase, thereby improving the appearance of acne scars.

[0032] In some embodiments of each or any of the above or following embodiments, the method reduces the area of ​​acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the method reduces the area of ​​acne scars by greater than about 90%. In some embodiments of each or any of the above or following embodiments, the composition reduces the area of ​​acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the composition reduces the area of ​​acne scars by greater than about 90%.

[0033] In some embodiments of each or any of the above or following embodiments, the method reduces the volume of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the method reduces the volume of acne scars by greater than about 90%. In some embodiments of each or any of the above or following embodiments, the composition reduces the volume of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the composition reduces the volume of acne scars by greater than about 90%.

[0034] In some embodiments of each or any of the above or following embodiments, the method reduces the depth of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the method reduces the depth of acne scars by greater than about 90%. In some embodiments of each or any of the above or following embodiments, the composition reduces the depth of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, the composition reduces the depth of acne scars by greater than about 90%.

[0035] In some embodiments of each or any of the above or following embodiments, wherein the skin of a patient in need thereof has an acne scar area, the method reduces the depressed volume and area of ​​the skin contour in the acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the above or following embodiments, wherein the skin of a patient in need thereof has an acne scar area, the method reduces the depressed volume and area of ​​the skin contour in the acne scar area by greater than about 90%. In some embodiments of each or any of the above or following embodiments, the composition reduces the depressed volume and area of ​​the skin contour in the acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the foregoing or following embodiments, the composition reduces the depressed volume and area of ​​skin contour in the area of ​​acne scars by greater than about 90%.

[0036] In some embodiments of each or any of the foregoing or following embodiments, a subject may have nearly complete elimination of acne scars by the treatments and methods described herein, wherein the acne depth, volume, and area are reduced by greater than about 90%.

[0037] In some embodiments of each or any of the above or following embodiments, the method improves skin color. In some embodiments, improving skin color includes reducing L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount limited by the range between any two of the aforementioned values, and / or increasing a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount limited by the range between any two of the aforementioned values. In some embodiments of each or any of the above or following embodiments, L* is reduced by more than about 50%. In some embodiments of each or any of the above or following embodiments, a* is increased by more than about 50%. In some embodiments of each or any of the above or following embodiments, the composition improves skin color.

[0038] In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions increase the volume and area of ​​the raised skin contour in the area of ​​the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values. In some embodiments of each or any of the foregoing or following embodiments, the volume and area of ​​the raised skin contour in the area of ​​the acne scar increases by greater than about 90%.

[0039] In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions flatten skin contours in a treated area, wherein the treated area comprises an acne scar or depression.

[0040] In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions reduce the L* black to white scale in the treated area compared to a control treated area. In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions increase the a* green to red color scale in the composition treated area compared to a control treated area.

[0041] The present disclosure also provides a method for treating (e.g., repairing) a skin contour affected by acne scars. The method may include applying a composition comprising tropoelastin to a skin area having a skin contour affected by acne scars. In one embodiment, the method includes treating a skin area having a skin contour affected by acne scars to reduce acne scar depth, volume, and / or area. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Various features of illustrative embodiments of the present disclosure are described below with reference to the accompanying drawings. The illustrated embodiments are intended to illustrate the present disclosure, not to limit the present disclosure. The drawings include the following figures.

[0043] Figure 1 A flow chart showing patient deployment.

[0044] FIG. 2A to FIG. 2D Clinical grading of acne scars at screening and day 1 is shown. This grading is based on Tan et al. (2010) (Journal of Cutaneous Medicine and

[0045] Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference). Scale: 0 = invisible acne scar; 1 = barely visible acne scar from 2.5 m away; 2 = easily identifiable acne scar involving less than half of the affected area; 3 = easily identifiable acne scar involving more than half of the affected area; 4 = easily identifiable acne scar involving the entire area; the entire area involved has obvious atrophic scarring. As shown in the figure, this is the side with TE implant side (30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derived hyaluronic acid) during the screening follow-up ( Figure 2A ) and saline control side (intradermal (id) saline implant) ( Figure 2B As shown in the figure, this is the side with TE implant during day 1 ( Figure 2C ) and saline control side during day 1 ( Figure 2D ).

[0046] Figure 3 Shows a third-party blind review of scars using the global impression change scale

[0047] (BTPR) Assessment (PAS1). Scale: -3 = significantly worse; -2 = moderately worse; -1 = slightly worse; 0 = no change; 1 = slightly better, 2 = moderately better; 3 = significantly better.

[0048] Figure 4 The correlation between the screening visit and the baseline visit is shown.

[0049] Figure 5A and Figure 5B Results for all camera settings are shown for area and volume, with results from the cameras increasing as the severity score increases, thus indicating that the cameras measure similar constructs.

[0050] Fig. 6A and Figure 6B The relationship between GIC (BTPR) and the results for different camera settings is shown. DETAILED DESCRIPTION

[0051] Acne is a chronic inflammatory disease that can develop from bacterial colonization of the pores and hair follicles on the skin of the face, neck, chest, and back. For example, bacterial colonization can be caused by bacteria such as Propionibacterium acnes. Acne can also be caused by increased sebum production, changes in keratinization, and inflammation. Sometimes, however, the cause of an acne outbreak is unclear.

[0052] Acne can begin in early adolescence and continue into adulthood, during which time increased oil production can facilitate the growth and colonization of several types of bacteria. Hormones, stress, and even diet can also cause increased oil production.

[0053] Problems associated with acne include distress, itching, pain, and can also affect quality of life. Despite the existence of available treatments to prevent and cure acne, people suffer the consequences of their acne, such as unsightly and permanent acne scars, which can also be very visible. As acne affects age groups from teenagers to adults, acne scars affect teenagers as well as adults, can lead to a loss of confidence and can cause low self-esteem.

[0054] There are different degrees of scarring that can occur from acne. Scars can include roller-type atrophic scars, ice pick scars, boxcar scars, and other types of deep depressions in the skin. Acne scars can vary in depth and extent. Previous treatments, such as subcision, trephine excision, laser resurfacing, dermabrasion, and chemical peels, have been described above. In some cases, scarring can also result in skin discoloration.

[0055] Disclosed herein are methods of treating acne scars that may help reduce skin dimpling, reduce skin discoloration, and / or even flatten skin contours.

[0056] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0057] The terms “a,” “an,” “the” and similar referents used in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0058] As used herein, "about" when referring to a measurable value is meant to include variations of +20% or +10%, more preferably +5%, even more preferably +1%, and still more preferably +0.1% relative to the specified value.

[0059] Unless the context requires otherwise, as used herein, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude other additives, components, integers or steps.

[0060] As used herein, "scar," "fibrosis," or "fibrotic response" may refer to fibrous (scar) tissue that forms in response to injury or medical intervention.

[0061] As used herein, "scar" may refer to a mark left on the skin or in body tissue where a wound such as a scab or acne has healed and fibrous connective tissue has developed. As described herein, acne may cause scars.

[0062] The term "tropoelastin" refers to a protein that forms elastin. Tropoelastin may be a monomer. Tropoelastin is not usually cross-linked, covalent or otherwise. Tropoelastin can reversibly coagulate. Therefore, tropoelastin is different from elastin because elastin is composed of covalently cross-linked tropoelastin that cannot reversibly coagulate. Tropoelastin may be human tropoelastin. Tropoelastin may be synthetic, for example, it may be derived from recombinant expression or other synthesis, or it may be obtained from a natural source such as a porcine aorta. As is generally known in the art, tropoelastin may exist in the form of multiple fragments. In some embodiments of each or any of the above or following embodiments, the composition provided in the method described herein comprises monomer tropoelastin. In some embodiments of each or any of the above or following embodiments, the monomer tropoelastin is cross-linked with HA. In some embodiments of each or any of the above or following embodiments, the tropoelastin comprises a sequence as shown in any one of SEQ ID NO: 1-15.

[0063] In some embodiments of each or any of the above or below embodiments, the methods of the invention utilize SHELδ26A tropoelastin analog (WO 1999 / 03886) for various applications described herein, including compositions used in the methods. The amino acid sequence of SHELδ26A is:

[0064]

[0065] In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin isoform is a SHEL isoform (WO 1994 / 14958; the entire contents of which are incorporated herein by reference):

[0066] (SEQ IS NO: 2) or a protease-resistant derivative of SHEL or SHELδ26A isoform (WO 2000 / 04043; the entire contents of which are incorporated herein by reference). As described in WO 2000 / 04043, the protein sequence of the tropoelastin may have a mutated sequence such that sensitivity to proteolytic digestion is reduced or eliminated.Without limitation, the sensitivity of the tropoelastin amino acid sequence to serine proteases, thrombin, kallikrein, metalloproteinases, gelatinase A, gelatinase B, serum proteins, trypsin or elastase is reduced or eliminated, for example, in some embodiments of each or any of the above or following embodiments, the tropoelastin comprises the sequence shown in SEQ ID NO:3 (SHELδ26A isoform):.

[0067] (SEQ ID NO:3). In some embodiments, the tropoelastin comprises the sequence shown below (SHELδmod isoform):

[0068]

[0069] The tropoelastin analogs generally have sequences homologous to human tropoelastin sequences. The percent identity between a pair of sequences can be calculated by an algorithm implemented in the BESTFIT computer program. Another algorithm for calculating sequence divergence has been adapted for rapid database searches and implemented in the BLAST computer program. Compared to human sequences, the tropoelastin polypeptide sequences may have an identity of about 60% at the amino acid level, 70% or more at the amino acid level, 80% or more at the amino acid level, 90% or more at the amino acid level, 95% or more at the amino acid level, 97% or more at the amino acid level, or greater than 99% at the amino acid level.

[0070] When making comparisons, conservative amino acid substitutions (e.g., Glu / Asp, Val / Ile, Ser / Thr, Arg / Lys, Gln / Asn) may also be considered, because it is expected that in many cases, the chemical similarity of these amino acid residue pairs makes functional equivalence. Amino acid substitutions that are expected to retain the biological function of a polypeptide will retain the chemical properties of the replaced amino acid residues, such as hydrophobicity, hydrophilicity, side chain charge or size.

[0071] Recombinant forms of tropoelastin can be produced according to the sequences described in WO 1999 / 03886. These sequences include:

[0072]

[0073]

[0074]

[0075] as well as

[0076]

[0077] Tropoelastin can be used in the form of being connected (e.g., covalently connected) to other molecules such as biopolymers such as hyaluronic acid. In some embodiments, tropoelastin is cross-linked with hyaluronic acid. In some embodiments, the composition comprises monomeric tropoelastin. In some embodiments of each or any of the above or following embodiments, tropoelastin comprises a sequence as shown in any one of SEQ ID NOs: 1-15.

[0078] It is particularly preferred that when tropoelastin is linked to other molecules, the linkage does not hinder or limit the biological properties of the unlinked form of the tropoelastin.

[0079] The purpose of linking tropoelastin to other molecules is generally to enable the localization of the tropoelastin to a certain area and to minimize the possibility of the tropoelastin diffusing or otherwise migrating away from that area.

[0080] In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin has a specified degree of purity relative to the amount of tropoelastin in the composition compared to the amount of other proteins or molecules in the composition. In one embodiment, the tropoelastin is in a composition having at least 75% purity, preferably 85% purity, more preferably greater than 90% or 95% purity. In this context, fragments of tropoelastin, i.e. truncated forms of tropoelastin isoforms that are inadvertently produced by tropoelastin manufacturing, may be considered impurities.

[0081] It will also be appreciated that in certain embodiments, the tropoelastin may be provided in the form of a composition consisting of or consisting essentially of tropoelastin, preferably a full-length isoform of tropoelastin. In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin will be at least about 65% of the length of the relevant tropoelastin isoform, greater than about 80% of the full length, greater than about 90% of the full length, or greater than about 95% of the full length.

[0082] The term "hyaluronic acid" or "HA" may include hyaluronic acid and any hyaluronate salt, including, for example, sodium hyaluronate (sodium salt), potassium hyaluronate, magnesium hyaluronate and calcium hyaluronate. Hyaluronic acid from various sources can be used herein. For example, hyaluronic acid can be extracted from animal tissue, can be obtained as a product of bacterial fermentation, or can be manufactured in commercial batches by bioprocessing technology. In some embodiments, the composition provided in the method herein comprises monomeric tropoelastin. In some embodiments, monomeric tropoelastin is cross-linked with HA. In some embodiments of each or any of the above or following embodiments, the tropoelastin includes a sequence as shown in any one of SEQ ID NO: 1-15. In some embodiments of each or any of the above or following embodiments, the tropoelastin includes a sequence as shown in SEQ ID NO: 1.

[0083] In some embodiments of each or any of the above or following embodiments, the composition comprises 1 mg / mL to 100 mg / mL of tropoelastin cross-linked with about 0.1% to about 10% derived hyaluronic acid (HA). In some embodiments of each or any of the above or following embodiments, the composition comprises 1 mg / mL to 100 mg / mL of tropoelastin cross-linked with about 0.4% to about 1% derived hyaluronic acid (HA). In some embodiments of each or any of the above or following embodiments, tropoelastin is cross-linked with about 0.4%, about 0.5%, about 0.6%, about 0.8%, about 0.9% or about 1% derived hyaluronic acid (HA). In some embodiments, the composition comprises 30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derived hyaluronic acid. In some embodiments of each or any of the above or following embodiments, the composition further comprises a buffer, wherein the buffer is phosphate buffered saline. In some embodiments, the composition comprises derived HA or non-derivatized HA to control the degree of cross-linking of HA with itself and / or monomeric protein. In some embodiments of each or any of the above or following embodiments, the derived HA is cross-linked with TE. In some embodiments, tropoelastin is a monomer. In some embodiments of each or any of the above or following embodiments, monomeric tropoelastin is released from the composition.

[0084] In some embodiments of each or any of the foregoing or following embodiments, HA may include at least one linkable portion, e.g., at least one cross-linkable portion, such as a carboxyl group, a hydroxyl group, an amine, a thiol group, an alcohol, an olefin, an alkyne, a cyano group, or an azide group, and / or modifications, derivatives, or combinations thereof.

[0085] In some embodiments of each or any of the foregoing or following embodiments, the HA can include a spacer such that the spacer can be attached to the same molecule and / or a second molecule, such as a second biomolecule or biopolymer.

[0086] HA may range from about 25 to about 10,000 disaccharide units or residues. In some embodiments of each or any of the foregoing or following embodiments, hyaluronic acid ranging from 25 to 7,500 disaccharide units or residues may be used.

[0087] In some embodiments of each or any of the foregoing or following embodiments, the HA may be a low molecular weight HA or a high molecular weight HA. The high molecular weight HA (also referred to as "HMW HA") described herein generally describes a HA having a molecular weight of at least about 1.0 million Daltons (mw ≥ 10 6As used herein, low molecular weight HA (sometimes referred to herein as "LMW HA") generally describes hyaluronic acid having a molecular weight of less than about 1.0 MDa.

[0088] In some embodiments of each or any of the foregoing or following embodiments, HA may be activated and / or modified with an activating agent such as EDC or allyl glycidyl ether and / or a modifying agent such as NHS, HOBt, or bromine.

[0089] The term "Fitzpatrick scale" is given a straightforward and common meaning, which, in view of this article and without limitation, may refer to a scientific skin type classification. The Fitzpatrick scale has several different types from type 1 to type 6. Dermatologists and cosmetic medicine practitioners use this scale to determine which treatment is most appropriate for different skin types. The scale was developed to determine the skin's reaction to ultraviolet rays such as sunlight. In addition, cosmetic doctors and laser technicians can understand this common sense before applying lasers or other types of treatments. Type 1 - usually light ivory skin, and always burns and peels when exposed to the sun, but never tans. Type 2 - is a light fair complexion, and burns quickly when exposed to the sun, but rarely tans. Type 3 - is usually beige light skin, and can burn when exposed to the sun, and can tan. Type 4 - is olive skin or light brown tones, and will not produce freckles when exposed to the sun. This type of person rarely burns from the sun and often tans. Type 5 - is a dark brown or black skin color, rarely gets sunburned in the sun, and always tans. Type 6 - is black and is the darkest skin color. This type of person never burns when exposed to the sun, and tans quickly. Dermatologists can use this useful scale to judge how certain skins react to the sun and how to identify potential malignant sun spots more quickly. Cosmetic doctors can also use this scale to determine the effectiveness of treatments for different skin types. In some embodiments of each or any of the above or following embodiments, the method of treating acne scars can be used for individuals with any skin type classification of type 1 to type 6 in the Fitzpatrick scale.

[0090] The term "intradermal implant" is an implant that can be placed below the epidermis. Without limitation, the implant can be in a skin region, such as (e.g.) dermis, subcutaneous or hypodermal layer. In some embodiments of each or any of the above or following embodiments, the implant can be placed intradermally.

[0091] In some embodiments of each or any of the foregoing or following embodiments, the implant can be placed in the subcutaneous layer. In addition to placing the implant intradermally, this placement can also be used.

[0092] The "retrograde threading technique" is a method used to place the thread of an implant into the target tissue. First, the needle is inserted. Second, the implant is placed by depressing the plunger of the syringe while the needle is withdrawn.

[0093] "Cross-hook" is a method of placing the threads of the implant in a "mat" pattern within the target tissue. Threading is accomplished by moving the needle through the tissue in a cross-hook arrangement, which disrupts the fibrous tissue in the course or path of the needle.

[0094] "Acne" as used herein refers to a skin disease that occurs when dead skin cells and skin oils clog the hair follicles. Acne is characterized by blackheads or whiteheads, pimples, and oily skin. In some cases, acne may lead to scars. In some embodiments of each or any of the foregoing or following embodiments, the patient in need thereof has acne and acne scars.

[0095] As used herein, "acne scars" may be caused by inflammation in the skin. Acne scars may be abnormal healing following inflammation caused by acne. "Atrophic acne scars" may be caused by the loss of collagen in the healing response, and loss of collagen in the healing response is the most common cause of acne scar formation.

[0096] "Ice pick scars" caused by acne can be narrow, deep scars that extend into the dermis. Ice pick scars are a type of atrophic acne scar.

[0097] "Roller-type atrophic acne scars" are jagged scars that heal beneath the normal layer of skin tissue.

[0098] A "boxcar-type scar" is a type of acne scar that may appear as an indentation in the skin. A boxcar-type scar is defined by a well-defined edge of the scar that may move directly down into the skin and is usually a different size than the acne lesion that formed the scar. A boxcar-type scar is a type of atrophic acne scar.

[0099] "Hyperpigmentation" is the darkening of the skin caused by an increase in melanin. In a non-limiting manner, the causes of hyperpigmentation include sun damage, inflammation, skin damage and acne. The skin can respond to damage by overproducing melanin produced by melanocytes. In some embodiments of each or any of the above or following embodiments, the scar has a silver coloration before applying the composition. In some embodiments of each or any of the above or following embodiments, applying the composition reduces the silver coloration of the scar and increases the dark red or pink coloration of the scar. In some embodiments of each or any of the above or following embodiments, the method reduces L* by about 1%, 5%, 10%, 15%, 20%, 25%, or more than 50%, or any amount limited by the range between any two of the above values, and increases a* by 1%, 5%, 10%, 15%, 20%, 25%, or more than 50%, or any amount limited by the range between any two of the above values. The methods described herein can also be used to treat acne scars and reduce skin discoloration caused by acne.

[0100] The "CIELAB color space" is used to define skin color and color changes that may occur after treating the skin with a composition comprising tropoelastin. The CIELAB color space (also known as CIE L*a*b* or sometimes simply "Lab" color space) is a color space defined by the International Commission on Illumination (CIE) in 1976. The CIELAB color space represents color as three values: L* for lightness from black (0) to white (100), a* from green (-) to red (+), and b* from blue (-) to yellow (+).

[0101] Treatment methods for scars

[0102] Provided herein is a method for treating an acne scar (e.g., a fibrotic acne scar) in a patient in need thereof, including, for example, improving the color and / or appearance of an acne scar. The method may include applying a composition comprising tropoelastin to a skin region of a patient with a scar, including, for example, applying the composition near the scar or directly into the scar or below the scar. In other embodiments, a composition comprising tropoelastin is also placed around the scar, such as below the scar and around the edge of the scar. After applying the composition, the depth, affected area, and / or volume of the acne scar are reduced (including compositions that are otherwise identical except for the lack of tropoelastin, such as compared to saline controls). In addition or alternatively, the disclosed method can increase the raised volume and raised area of ​​the skin contour in the acne scar region (including compositions that are otherwise identical except for the lack of tropoelastin, such as compared to saline controls).

[0103] The method may also include acupuncture to disrupt fibrotic units in the acne scar, such as fiber bundles or units (e.g., fibrotic tissue) beneath the scar to cut or release fiber bundles that deeply tether the skin surface into a depression. In one embodiment, the disruption of the fibrotic unit allows the formation of a dermal sac beneath the acne scar, and the composition is applied to the dermal sac. After the scar tissue is disrupted, the dermal sac can be filled with the disclosed composition.

[0104] Scar destruction can be carried out with 18G to 32G needles, such as 18G, 21G, 23G, 25G, 27G, 29G or 30G needles. In a non-limiting manner, scars such as roller-type atrophic scars, boxcar scars or ice pick scars can be subjected to destruction of fibrotic units. Administration includes injecting the composition into a dermal capsule. The composition is applied below the acne scar as an injection. The composition comprising tropoelastin is placed around the scar, such as below the scar and / or around the edge of the scar. The composition comprising tropoelastin is evenly or uniformly placed in the entire dermis near the scar, which can ensure that the tropoelastin product is around the scar area, and more effective treatment can be achieved. The composition is administered with a volume of about 10 μL to about 100 μL per implantation / injection. Injection is performed using a retrograde threading technique with a cross-line arrangement to ensure that all fiber bundles in the acne scar are destroyed.

[0105] In some embodiments, disruption of fiber bundles is performed on atrophic scars.

[0106] The fiber bundles tether the skin to the underlying tissue and create depressions, and disruption of the fiber bundles can be performed using a needle to disrupt the bundles and create a capsule, thereby leaving space for the tropoelastin composition to be placed under the acne scar, where the fiber bundles are located. Thus, the tropoelastin composition will be available to the skin tissue cells immediately surrounding the scar, so they can grow in and around the article, which will remodel the fibrotic unit of the scar.

[0107] The methods disclosed herein can result in remodeling of fibrotic units adjacent to scars.

[0108] For basic or classic subcision, the needle can be as large as 18G, typically 21G or 23G, however, a 27G or 30G needle may also be used as it is small enough to allow some subcision and also create a pocket or space around the scar and in the dermis for placement of the product.

[0109] The needle is inserted at an angle of about 30° parallel to the skin, with the needle beveled and the bevel facing upward. The needle is inserted more than once to break the fiber bundles and create a dermal pocket. Uniform pressure is applied while the needle is withdrawn from the dermal pocket to inject the composition. The composition is applied repeatedly, and one or more boluses are applied in the scar.

[0110] The methods disclosed herein can advantageously reduce the depth, affected surface area, and / or volume of acne scars. In fact, at day 168 after application of the composition (e.g., 30 mg / mL tropoelastin cross-linked with 0.5% dHA), small as well as large depressions were shown to be improved, and the smoothness and / or levelness of the skin contours were improved. Surprisingly, this also resulted in the repair of atrophic scars that are in the skin remodeling and maturation phase, thereby improving the appearance of the scars.

[0111] The methods disclosed herein can be used to improve the appearance of atrophic acne scars. As described herein, treatment can be applied on day 0, day 28, and day 56. Surprisingly, this treatment resulted in improvements in both the appearance and color of the skin of several patients, including patients with roller-type, boxcar-type, or icepick-type acne scars. In some embodiments, where the coloration of the scar includes silver, the methods disclosed herein reduce the silver coloration of the scar and / or increase the red coloration or pink coloration of the scar.

[0112] The compositions disclosed herein can include from about 1 mg / mL to about 400 mg / mL tropoelastin (e.g., 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, or 400 mg / mL tropoelastin).

[0113] The compositions disclosed herein may also include hyaluronic acid (HA). In other embodiments, tropoelastin is cross-linked with about 0.1% to about 10% of the derived hyaluronic acid. In yet another embodiment, the composition comprises 30 mg / mL human tropoelastin (e.g., recombinant human tropoelastin) cross-linked with about 0.5% of the derived hyaluronic acid. The composition may also include a buffer, e.g., phosphate buffered saline.

[0114] Also provided herein are pharmaceutical formulations containing the disclosed tropoelastin-containing compositions.

[0115] The maximum volume of the compositions disclosed herein for administration is between about 100 μL and about 5 mL (e.g., at about 100 μL / cm 2 to about 500 μL / cm 2 between).

[0116] In one embodiment, the patient in need thereof has a skin type of Type I, Type II, Type III, Type IV, Type V, or Type VI on the Fitzpatrick skin classification scale.

[0117] Scars treated by the methods disclosed herein may include any of the gradings of 0, 1, 2, 3, 4, or 5 described in the "Global Scale for Acne Scar Severity (SCAR-S)" by Tan et al., 2010, Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference. The grading is as follows: 0: clean; no visible acne scar, 1: very light; barely visible acne scar from 2.5 m away, 2: mild; easily identifiable; involving less than half of the affected area (e.g., face, back, or chest); 3: moderate; involving more than half of the affected area (e.g., face, back, or chest); 4: severe; involving the entire area, 5: extremely severe; the entire area has obvious atrophic or hypertrophic scars.

[0118] In one embodiment, the acne scar may be an ice pick scar, a boxcar scar, a roller atrophic acne scar, an expandable roller atrophic acne scar, or a hypertrophic scar. The scar may be located on the face, back, or trunk of the subject.

[0119] Acne scars treated by the methods disclosed herein can have a depth of about 0.1 mm to about 5 mm (e.g., about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth in a range between any two of the foregoing values).

[0120] The affected area of ​​acne scars treated by the methods disclosed herein may be about 0.05 mm 2 To about 400mm 2 .

[0121] The volume of acne scars treated by the methods disclosed herein may be about 0.01 mm 3 Up to 2,000mm 3 (For example, about 0.01 mm 3 , about 1mm 3 , about 10mm 3 , about 20mm 3 , about 30mm 3 、Approx. 40mm 3 、About 50mm 3 、Approx. 60mm 3 、Approx. 70mm 3 、Approx. 80mm 3 、Approx. 90mm 3 , about 100mm 3 , about 125mm 3 , about 150mm 3 、Approx. 175mm 3 , about 200mm 3 、Approx. 225mm 3 , about 250mm 3 、Approx. 275mm 3 , about 300mm 3 、Approx. 325mm 3 、About 350mm 3 、Approx. 375mm 3 , about 400mm 3 、Approx. 425mm 3 、Approx. 450mm 3 、Approx. 475mm 3 , about 500mm 3 、Approx. 525mm 3 、About 550mm 3 、About 575mm 3 、About 600mm 3 、Approx. 625mm 3 、About 650mm 3 、Approx. 675mm 3 、About 700mm 3 、Approx. 725mm 3 、About 750mm 3 , about 775v, about 800mm 3 、Approx. 825mm 3 、About 850mm 3 、Approx. 875mm 3 、About 900mm 3 、Approx. 925mm 3 、About 950mm 3 、975mm 3 、Approx. 1,000mm 3、Approx. 1,100mm 3 、Approx. 1,200mm 3 、Approx. 1,300mm 3 、Approx. 1,400mm 3 、Approx. 1,500mm 3 、Approx. 1,600mm 3 、Approx. 1,700mm 3 、Approx. 1,800mm 3 、Approx. 1,900mm 3 , or about 2,000mm 3 , or any volume in a range between any two of the foregoing values).

[0122] Scars treated by the methods disclosed herein can lighten the skin color defined by the CIE L*a*b* color coordinates (e.g., reducing L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values). In preferred embodiments, the methods disclosed herein reduce L* by greater than about 50%.

[0123] The methods disclosed herein can also increase a*, including an increase of about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount limited by a range between any two of the foregoing values. In a preferred embodiment, the methods disclosed herein increase a* by greater than about 50%.

[0124] In one embodiment, the scar has a color that is different from the patient's natural skin color, and the composition disclosed herein causes the color of the scar to decrease or fade in color intensity such that the color of the scar blends in with the patient's natural skin color.

[0125] The compositions disclosed herein can improve the appearance of scars (e.g., a reduction in depth, volume, surface area, and / or color of scars comprising about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, or more, compared to an otherwise identical composition or saline solution except for the lack of tropoelastin) within about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 12 months after injection into an area of ​​skin having a scar.

[0126] The following examples, sequence listing and figures are provided to aid the understanding of the present invention, the true scope of which is set forth in the appended claims.It should be understood that modifications can be made to the procedures described without departing from the spirit of the present invention.

[0127] Example

[0128] Example 1. To evaluate the clinical efficacy, durability, tissue compatibility, and safety of TE implants for the treatment of atrophic roller-shaped acne scars

[0129] Study Design and Randomization

[0130] A study was conducted to test and evaluate the clinical efficacy, durability, tissue compatibility, and safety of TE implants (30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derived hyaluronic acid) following dermal implantation for the treatment of atrophic roller-shaped acne scars.

[0131] Thirty-four male and female patients between the ages of 24 and 55 participated in a study of TE implants (30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derived hyaluronic acid; "TE implants") for the treatment of acne scars. However, one of the 34 patients withdrew consent before treatment. Thirty-three patients tested skin areas measuring approximately 2 cm x 2 cm around the temples and cheekbones on both sides of the face, where each area included a minimum of two moderate to severe roller-type expansile atrophic acne scars. The following treatments were applied to both sides of the face:

[0132] a) Tropoelastin intradermal (id) implant: 30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid ("TE implant"); and

[0133] b) Saline control (intradermal (id) implant of isotonic saline) ("Saline control").

[0134] Each patient served as their own control, with the TE implant implanted in one of the right or left sides of the face, and the saline control implanted in the opposite side of the face. All patients received three treatments of TE implants and saline controls (on day 0, day 28, and day 56). At each treatment follow-up, the TE implant was applied to the same side used on day 0 (the saline control was applied to the same side used on day 0). Each treatment included multiple, discontinuous, direct intradermal injections of about 25 μL to 50 μL of TE implants each time into the skin dermis of a 2 cm × 2 cm treatment area. Retrograde threading techniques were used to cross-line arrangements for injection to ensure that all fiber bundles within the scar were destroyed. In addition, treatment may include applying one or more bolus injections in the dermis of roller-type atrophic acne scars to ensure optimal scar response. In each treatment area at each treatment time point, the maximum total volume of TE implants or saline controls was about 250 μL and not more than 500 μL.

[0135] Implant site review was performed on Day 14. All patients were followed until Day 168 for safety reasons.

[0136] Patients were unaware of which side of their face or body the TE implant and saline control were implanted. Investigators were aware. Third-party clinical reviewers were blinded for pre-treatment images at Day 0 and post-treatment images at Day 168.

[0137] Research process and tracking

[0138] filter

[0139] Before the initial implantation by the research method, a screening period of up to 28 days was used to determine whether the patient had eligibility and baseline parameters. During this period, written, signed and dated informed consent was obtained from each patient. Relevant medical history items were recorded, physical examinations were performed, and vital signs were recorded. Other tests performed at this time included: 12-lead ECG, breath test for testing alcohol, urine drug test (covering the use of amphetamine, cocaine, opiates, marijuana, barbiturates and benzodiazepines), clinical examination of the expected treatment area, 2-D and 3-D photos of the expected treatment area, score of the expected treatment area in the overall acne scar severity grade (Tan et al., 2010, the entire content of this document is incorporated herein by reference), serum pregnancy test, blood test of APTT and PT coagulation, laboratory safety test of blood and urine samples, Hep B, Hep C, and HIV 1 and HIV 2 blood test. These tests were then used to determine if patients were eligible for the study, and eligible patients were asked to respond to begin the study (Treatment Visit 1, Day 0).

[0140] Treatment using investigational methods

[0141] At Treatment Visit 1 (Day 0), eligible patients underwent primary implantation. Prior to implantation, the following procedures were performed:

[0142] - Review of eligibility criteria;

[0143] - Change the record of concomitant medication;

[0144] - Pre-implantation vital signs;

[0145] - Breath test for alcohol consumption;

[0146] - Urine testing for drugs of abuse;

[0147] -Blood draw for antigen elastin antibody analysis;

[0148] - Clinical examination of the intended treatment area;

[0149] - Baseline 2-D photographs of the treatment area;

[0150] - Baseline 3-D photograph of the treatment area;

[0151] - Pre-treatment assessment of each treatment area by the investigator according to the Global Scale for Acne Scar Assessment (Tan et al., 2010, Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference);

[0152] - Topical application of EMLA cream (at least 60 minutes before TE or saline control implantation);

[0153] - Urine pregnancy test for females of childbearing potential;

[0154] Following these procedures, the patient's treatment area was implanted using the study protocol (TE implant or saline control implant). Sixty minutes after TE and saline control implants, the injection site was physically inspected for overall response and post-treatment 2-D photographs were taken.

[0155] On Day 14, an implant site review was performed and clinical staff performed the following procedures:

[0156] - Review of adverse event (AE) diary cards;

[0157] - Clinical examination of the treatment area;

[0158] - 2-D photos of the treatment area;

[0159] - 3-D photos of the treatment area;

[0160] - Analysis of serum antigen elastin antibodies in blood;

[0161] The second treatment implantation visit was performed on day 28 ± 3, and the third treatment implantation visit was performed on day 56 ± 3. The same procedures as those performed on day 0 were employed.

[0162] Patients were provided with a diary to record any injection site reactions such as redness, swelling, itching, and tenderness between each study visit.

[0163] track

[0164] Patients returned to the study site on day 84 ± 3 for a follow-up procedure. The following activities were performed:

[0165] - Records of changes in medications

[0166] - Records of adverse reactions and clinical examinations in the treatment area

[0167] -Physical examination and vital signs

[0168] - Breath test for alcohol consumption

[0169] - Urine test for drugs of abuse

[0170] -Blood draw for antigen elastin antibody analysis

[0171] - 2-D photos of the treated area

[0172] - 3-D photos of the treated area

[0173] - Urine pregnancy test for women of childbearing potential

[0174] - Patient and investigator assessment of the treated area based on the Global Impression of Change rating and patient assessment based on the Acne-Q rating

[0175] Additional follow-up was conducted on day 168 ± 7. The following activities were performed:

[0176] - Records of changes associated with medications

[0177] - Records of adverse reactions and clinical examinations in the treatment area

[0178] -Physical examination and vital signs

[0179] -12-lead ECG

[0180] - Breath test for alcohol consumption

[0181] - Urine test for drugs of abuse

[0182] -Blood draw for antigen elastin antibody analysis

[0183] - 2-D photos of the treated area

[0184] - 3-D photos of the treated area

[0185] - Urine pregnancy test for women of childbearing potential

[0186] - Screening blood and urine laboratory safety tests

[0187] - Patient and investigator assessment of the treated area based on the Global Impression of Change rating and patient assessment based on the Acne-Q rating

[0188] On Day 168, a third-party blinded reviewer also evaluated the treated area based on the change grade of the global impression by comparing the Day 168 and Day 0 photographs.

[0189] Purpose

[0190] The primary objective of this study was to determine the clinical efficacy of TE implants in men and women with atrophic acne scars.

[0191] The secondary aims of this study are as follows:

[0192] - To evaluate the histological changes of atrophic acne scars with TE implants (30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid).

[0193] - Confirmation of local and systemic AE profiles of TE implants.

[0194] Security purpose

[0195] The safety objective of this study was to evaluate the safety and tolerability of TE implants.

[0196] Exploratory purpose

[0197] The following exploratory objectives were examined:

[0198] -Analysis of the clinical significance of acne scars

[0199] - Classification of acne scars analyzed by a third-party blind reviewer (BRPR)

[0200] - Correlation of 3D camera data with overall acne scar severity rating, Acne-Q acne scar score, and BTPR treatment score

[0201] Inclusion criteria

[0202] Patients eligible for inclusion in this study must meet all of the following criteria:

[0203] 1. Female / male patients with approximately 2 cm x 2 cm matching treatment areas on the temples or cheekbones on both sides of the face, each containing a minimum of two roller-type atrophic acne scars that are dilatable when stretched between the fingers and are classified as moderate to severe in the overall acne scar grade assessment.

[0204] 2. Acne scars on normal healthy skin areas.

[0205] 3. Age: 18 to 55 years old.

[0206] 4. Able to provide voluntary informed consent.

[0207] 5. Good health.

[0208] 6. Except for long-term follow-up, sexually active female patients will not be of childbearing potential (i.e., surgically sterilized or postmenopausal), abstain from sexual activity, or use reliable contraceptive methods (e.g., hormonal contraceptives, condoms, IUDs) for at least 30 days before dosing and during the study. During the long-term follow-up period, female patients of childbearing potential will be advised to use contraception, but this is not mandatory.

[0209] 7. Fitzpatrick skin type I, II, III, IV, or V.

[0210] Exclusion criteria

[0211] Patients were excluded from this study when any of the following criteria were met:

[0212] 1. Active persistent acne lesions on the face (or back and trunk for patients who will also be treated in these areas).

[0213] 2. Current or previous treatment of atrophic acne scars with fillers, laser or deep chemical peels that reach the dermis, or any other medical or surgical treatment that, in the opinion of the investigator, could reasonably be expected to affect the results of the current clinical study.

[0214] 3. Known hypersensitivity to tropoelastin, hyaluronic acid, or any other component of the TE implant (30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid).

[0215] 4. Female patients with a positive pregnancy test, women who do not agree to appropriate contraception and pregnancy testing during the study, or women who plan to become pregnant during the trial.

[0216] 5. Participated in clinical trials of pharmacological agents within 1 month before screening.

[0217] 6. Clinically significant hematological or biochemical test results at screening.

[0218] 7. Tested positive for hepatitis B, hepatitis C, or HIV at screening.

[0219] 8. Bleeding diathesis, anticoagulant drugs, thrombocytopenia, or clinically significant prolongation of APTT or PT.

[0220] 9. Long-term use of aspirin, other non-steroidal anti-inflammatory drugs or other antiplatelet agents.

[0221] 10. History of keloid formation.

[0222] 11. History of granulomatous or connective tissue disease.

[0223] 12. Use of systemic corticosteroids within the past 12 weeks.

[0224] 13. Currently using topical retinoids or have used topical retinoids within the past 8 weeks.

[0225] 14. Diabetes or other metabolic disorders that, in the opinion of the investigator, would interfere with the patient's response to treatment.

[0226] 15. Any serious medical condition that, in the investigator's opinion, would likely require the use of systemic corticosteroids.

[0227] 16. Pregnant or breastfeeding women.

[0228] 17. Previous administration of tropoelastin.

[0229] 18. History of allergies or anaphylactic reactions, including any known hypersensitivity to lidocaine.

[0230] 19. Use of any investigational product at the intended implantation site within the previous 12 months.

[0231] deploy

[0232] During the study, 33 patients were screened, recruited, randomized, and received at least one TE implantation. One patient (patient ID number: 001-120) was enrolled but withdrew consent before treatment on day 0. Five patients did not have any further implants after the initial treatment visit on day 0. The remaining 27 patients received all three intended facial treatments. All 33 randomized patients were included in the full analysis group (FAS) and safety group (SS) populations for analysis. The 27 patients who received all three intended facial treatments formed the photo analysis group 1 (PAS1).

[0233] Demographics and Baseline Characteristics

[0234] Patients ranged in age from 24 to 55 years, with a mean age of 38.0 years (SD=8.71). 22 patients were male and 11 were female. 16 patients were Caucasian, 2 were of Mediterranean origin, 14 were Asian, and one was classified as "other". All 11 women were of fertile potential, and each had a negative pregnancy test at the screening visit. 4 patients had Fitzpatrick skin type II, 13 patients had Fitzpatrick skin type III, 12 patients had Fitzpatrick skin type IV, and 4 patients had Fitzpatrick skin type V.

[0235] Scar assessment results using the overall acne scar rating

[0236] At the screening visit and day 0, patients' acne scars were graded using the following scale shown in Table 1 to ensure that patients met the inclusion criteria for scar severity and to ensure comparable contralateral treatment areas. This scale was developed by Tan et al. in 2010 (Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference). Clinicians' grading of acne scars is shown in FIG. 2A to FIG. 2D .

[0237] Table 1: Acne scar assessment results according to Tan et al. (responses are also shown in Figure 2) Exposure and medication compliance

[0238] category Fraction describe clean 0 Invisible acne scars Very light 1 Acne scars that are barely visible from 2.5m away Mild 2 Easily identifiable acne scars; involving less than half of the affected area Moderate 3 More than half of the affected area Severe 4 Covering the entire area Extreme 5 The entire area has obvious roller-type atrophic scars

[0239] As described above, six patients in the FAS (full analysis group) received no TE implants and saline control or only one facial implant with TE implants and saline control, while the remaining 27 patients received three facial implants with TE implants and saline control.

[0240] For FAS, the mean volume per TE implant injection at follow-up was 0.33 mL. In comparison, the mean volume per TE implant injection at follow-up for controls was 0.45 mL.

[0241] The cumulative TE volume injected during all implant visits ranged from 0.10 mL to 1.43 mL. The median cumulative TE volume injected was 0.90 mL. The cumulative saline control volume injected during all implant visits ranged from 0.05 mL to 1.83 mL. The median cumulative saline control volume injected was 1.31 mL.

[0242] Preliminary efficacy analysis

[0243] Based on three images of each of the five scar lesions on both sides of the face, 3D photo analysis was used to evaluate various features of the treated area. One patient had only two images taken and recorded of the site, so the data for this patient were based on these two images only.

[0244] The damage characteristics determined by photographs are:

[0245] - Color L*

[0246] - Color a*

[0247] - Color b*

[0248] - Volume (mm 3 )

[0249] - Area (mm 2 )

[0250] -Depth (mm)

[0251] Volume, area, and depth were assessed with the camera set to 6.0 mm. To generate summary statistics for reporting and analysis, the median of the three images for each lesion feature was used. The sum of the medians of the five lesions on both sides of the face was then used as the total score for the analysis of the patient / side. An example is shown below:

[0252] - Feature = Volume; Lesion j score = Median (Image 1 Feature, Image 2 Feature, Image 3 Feature), where j = 1 to 5; Total score = Lesion 1 score + Lesion 2 score + Lesion 3 score + Lesion 4 score + Lesion 5 score.

[0253] The change from baseline in the total score for each side of the face was then calculated by subtracting the total score on that side of the face on Day 0 from the total score on that side of the face on Day 168.

[0254] The difference in change from baseline to Day 168 between the TE implant-treated side and the saline control-treated side was also calculated.

[0255] Simple summary statistics of the total score and the change in total score from baseline are provided herein. In general, both TE implant and saline control treated areas showed evidence of improvement compared to baseline, with TE implant treated areas showing greater improvement compared to saline control treated areas.

[0256] Regression analysis was also used to model the lesion size data. The change relative to baseline was used as the dependent variable, and the treatment side (TE implant or saline control implant) and the baseline injury total score were used as independent variables (illustrative). Table 2 provides the results of the change relative to baseline on the 168th day (PAS1). According to simple summary statistics, for both TE implants and saline control implants, the model results show that depth, volume and area are significantly reduced, wherein the depth, volume and area measurements in the TE implant treatment area are always significantly reduced relative to baseline compared with the saline control treatment area.

[0257] Table 2: Regression model evaluation of changes in lesion area, volume, and depth from baseline at Day 168 for PAS1.

[0258]

[0259]

[0260] Overall (PAN) Analysis of the Treatment Area. In addition to the determination of individual lesions in the treatment area, the following characteristics were evaluated for the overall treatment area to determine the effect of the therapeutic implant on the overall contour deformation in the treatment area, hereinafter referred to as PAN analysis:

[0261] Color image (as mentioned before, color changes on the treated area reflect color changes at the individual lesion level)

[0262] - Color L* (scale from black to white)

[0263] - Color a* (scale from green to red)

[0264] - Color b* (scale from blue to yellow)

[0265] Indentation measurements (using the camera set at 10.0 mm to detect contour changes over the treated site, note that at this setting, individual acne scar lesions were not measured):

[0266] - Depth of contour depression on treatment area (mm)

[0267] - Area of ​​the contour depression on the treatment area (mm 2 )

[0268] - Volume of the contour depression on the treatment area (mm 3 )

[0269] Elevation measurements (using a camera set at 10.0 mm to detect contour changes over the treated site, note that at this setting, individual acne scar lesions were not measured).

[0270] - Height of the protuberance over the treatment area (mm)

[0271] - Area of ​​elevation above the treatment area (mm 2 )

[0272] - Volume of the elevation over the treated area (mm 3 )

[0273] This article describes all camera measurements of the PAN treatment area. As with the single lesion data, scores are provided based on three images of each feature. To obtain a total score for each patient / side, the median of the three image scores was used. Then, the median score on day 1 was subtracted from the median score on day 168 to calculate the change from baseline for each patient / side. The changes in the measured color features relative to baseline may be affected by seasonal changes during the study, because these are facial treatment areas exposed to sunlight, and the skin color will change from winter to summer, and vice versa. Due to the structure and mechanism of the 3D camera system used (the camera shield is placed directly on the skin), images are taken with constant light, so changes in light when the photos are taken will not affect the resulting images. To account for seasonal changes in skin color, the difference between the implant-treated side and the saline control-treated side was calculated at baseline and day 168. The change in this difference is used as a measure of the effectiveness of color L*, color a*, and color b* in the PAN treatment area analysis. Simple summary statistics are shown below (all patients in the safety group have data).

[0274] As with the injury analysis, regression modeling used the change from baseline (or change from baseline difference) as the dependent variable, and treatment side (TE implant or saline control) and baseline value (or difference from baseline value) as independent variables (illustrative). The following table shows the results of the analysis of the change from baseline at Day 168.

[0275] The results showed that the L* black to white scale was significantly reduced and the a* green to red color scale was significantly increased in the PAN treated area of ​​the TE implant compared to the saline control. It was also observed that the TE implant resulted in a significant reduction in the volume and area of ​​larger contour skin depressions and a corresponding increase in the volume and area of ​​elevations over the PAN treated area compared to the saline control.

[0276] Table 3: Regression model evaluation of changes from baseline in PAN color, depression volume, and elevation volume at Day 168 for PAS1.

[0277]

[0278] Scar assessment was performed using the global impression change grade.

[0279] A third party blind reviewer (BTPR) was asked to review the Day 168 and Day 0 photos in a blinded manner to assess the change in appearance of the treated area based on the Global Impression of Change (GIC) scale. For the BTPR, only the treated area and the immediate surrounding area in the face were visible in the reviewed photos, no patient details were provided, and patients were randomized so that the treatment mode could not be discerned. The scale used was as follows.

[0280] Table 4: Scar assessment grades

[0281] Significantly worse Moderately worse Slightly worse No change Slightly better Moderate improvement Significantly improved -3 -2 -1 0 1 2 3

[0282] The results of the BRPR evaluation of PAS1 are described herein and are shown in Figure 3 (BTPR assessment) in progress.

[0283] In the PAS1 population, BTPR noted improvement in 70% of the treated area examined at TE implant sites and 41% of the treated area examined at saline control sites at Day 168.

[0284] Two additional analyses were performed. The first analysis compared the percentage of treated areas that the BTPR indicated achieved any improvement in the TE implant treated areas versus the saline control treated areas. The difference in percentages was calculated and tested to see if the difference in percentages was equal to zero. The results are shown in Table 5. At Day 168, the difference in the number of treated areas that the blinded reviewer indicated achieved any improvement in the TE implant sites compared to the saline control sites was 26% (p=0.033).

[0285] The second analysis used a paired t-test to compare the GIC scores of the TE implant treated side with the saline control treated side (range -3 to +3). These results are presented in Table 6 below. As assessed by BTPR at Day 168, the mean difference in GIC scores between the tropoelastin implant site and the saline control site was 0.48 (95% CI -0.04 to 1.00, p = 0.068).

[0286] Table 5: GIC scores of treated areas with any improvement as indicated by a blinded third party reviewer (BTPR) (Photo Analysis Set 1).

[0287]

[0288] GIC scores were determined as -3 to +3. Scores from +1 to +3 were grouped as improved, while scores from -3 to 0 were grouped as worsening / not improved. The table shows the number (n) of patients assessed as improved relative to the total number of assessments (N). The difference represents the percentage of significant improvement at the TE implant site minus the percentage of significant improvement at the saline control site. The p value tests whether the difference in percentage (TE implant-saline control) is zero.

[0289] Table 6: GIC scores of the treated areas by a blind third party reviewer (BTPR) (Photo Analysis Group 1).

[0290]

[0291] The GIC score was determined as -3 to +3. Scores from +1 to +3 were grouped as improved, while scores from -3 to 0 were grouped as worsening / not improved. The table summarizes the paired differences of GIC (TE implant-saline control). A positive difference indicates that the TE implant site has a higher GIC compared to the saline control site. The p value tests whether the paired differences (TE implant-saline control) are zero.

[0292] Acne Q Questionnaire

[0293] At baseline (Day 1) and on Days 84, 168, and 336, patients were asked to complete the Acne-Q questionnaire. The questionnaire consisted of 10 questions concerning the patient's perception of the extent to which their acne scars bothered them. Each question was rated on a four-point scale: 1 = not at all, 2 = a little, 3 = quite a bit, and 4 = very much. The ten questions asked are listed below:

[0294] 1. Your acne scars From a distance How much does it seem to bother you?

[0295] 2. How old are your acne scars? heal How much does it bother you that your hair is raised or jagged in some way (more raised or jagged than you would like)?

[0296] 3. How much does the size of your acne scars bother you?

[0297] 4. photo How do your acne scars look and how much do they bother you?

[0298] 5. The acne scars you have quantity How much does it bother you?

[0299] 6. The difference between the color of your acne scars and your skin tone difference How much does it bother you?

[0300] 7. Bright Light How do your acne scars look and how much do they bother you?

[0301] 8. Where are your acne scars? Mirror How much does it bother you about what it looks like?

[0302] 9. Your acne scars Prominence How much does it bother you?

[0303] 10. Your acne scars Close Range How much does it seem to bother you?

[0304] Klassen et al. (Acne-Q This level is described in A Guide for Researchers and Clinicians, User Guide Version 1.0, September 2018, McMaster University; incorporated herein by reference).

[0305] Summary statistics of acne scar grades for the PAS1 population are shown herein.

[0306] Acne scars were scored, with higher totals indicating "better" results from the patient's perspective. For baseline values, there was no statistically significant difference in the scores between the two sides of the face in the PAS1 population, with the average score for the TE implant-treated area being 36.7 and the average score for the saline control-treated area being 35.4. On Day 168, the PAS1 population patients scored their TE implant-treated area (57.4) higher than their saline control-treated area (52.0), with a difference of 5.370, which was statistically significantly different from zero (p = 0.014).

[0307] The change from baseline score was statistically significantly above zero for both the TE implant treated areas and the saline control treated areas by Day 168. Although the changes at the TE implant sites were generally larger on average compared to the saline control sites, the difference between the two treatment areas was not statistically significantly different from zero (difference 4.074, p=0.120 for the PAS1 population).

[0308] Table 7: Acne-Q acne scar scores of PAS1 population at various time points.

[0309]

[0310] A higher Acne-Q Scar score represents a "better" response for the patient. A positive change from baseline in the Acne-Q Scar score indicates that the patient indicated an improvement based on the questionnaire item.

[0311] Secondary Objective Analysis

[0312] A third-party blind reviewer was also asked to categorize the scars as follows:

[0313] - Expandable roller for atrophic acne scars: when stretched between the fingers, they are no longer visible.

[0314] - Boxcar-type or van-like scars: Typical boxcar-type scars and scars with distinctive fibrotic borders will remain visible even when stretched between the fingers.

[0315] -Icepick Scars: Classic icepick acne scars.

[0316] Overall, at baseline, 61% and 69% of the scars identified as most clinically significant by BTPR were classified as boxcar-type scars on the TE implant side and saline control treatment side, respectively. A lower percentage of 37% and 26% of the scars identified as most clinically significant by BTPR were classified as roller-type scars on the TE implant side and saline control treatment side, respectively. This may indicate that boxcar-type scars are more likely to exist as the most clinically significant scar type. The remaining 2% of scars on the TE implant side and the remaining 5% of scars on the saline control treatment side were classified as icepick type.

[0317] To analyze acne scars by scar type, the same process as used for the primary efficacy analysis was followed. These analyses were limited to volume, depth, and affected area measured at the 6.0 mm camera transverse dimension setting. For each lesion identified by BTPR as one of the three most clinically relevant acne scars, the median of the three images of each lesion feature was used. However, because patients can have different numbers of identified lesions, the average of the medians of the lesions identified on each side of the face was used as the total score for the analysis of the patient / side, rather than the sum being used as the total score for the analysis of the patient / side.

[0318] The change from baseline in the total score for each side of the face was then calculated by subtracting the total score on that side of the face on Day 0 from the total score on that side of the face on Day 168.

[0319] The difference in change from baseline to Day 168 was also calculated between the TE implant treated side and the saline control treated side. As previously mentioned, not all patients had data for both sides for this analysis because in some cases the BTPR identified one of the three most clinically relevant acne scar types on one side of the face but not the other side. This should be considered when interpreting the differences in this analysis. Boxcar-type lesions and roller-type lesions were analyzed separately.

[0320] Simple summary statistics for the total score and the change from baseline in the total score are provided for (PAS1) boxcar-type injuries and (PAS1) roller-type injuries.

[0321] The BTPR lesion data for box-type and roller-type acne scars were also modeled using regression analysis as per the primary efficacy analysis. The change results from baseline to day 168 for PAS1 box-type and PAS1 roller-type were provided at a camera setting of 6.0 mm. The model results showed that the depth, volume, and area measurements in the TE implant treated areas were consistently significantly reduced relative to baseline compared to the saline control treated areas.

[0322] Table 8 below replicates the results for van-type injuries (varied to day 168). For van-type injuries identified by BTPR, the test results were generally consistent with the primary efficacy analysis test results, although in this case there were more statistically significant or near-significant test results in the differences between TE implant and saline control treated areas, suggesting that TE has a surprisingly greater effect on scars containing fibrotic tissue compared to saline controls.

[0323] Table 8: Regression model estimates of changes in lesion area, volume, and depth from baseline to day 168 in BTPR van-type patients (PAS1 group)

[0324]

[0325] Correlation of 3D camera data with overall acne scar severity rating

[0326] As part of the study, the investigator provided six ratings on the Global Acne Scar Severity Scale (GSASS or Scar-S, Tan et al. 2010; the entire contents of which are incorporated herein by reference) for both sides of the facial treatment area, left and right, at screening and day 0 as inclusion criteria for the study. The ratings are shown in Table 9.

[0327] Table 9: Overall acne scar severity rating

[0328] category score describe clean 0 Invisible acne scars Very light 1 Acne scars that are barely visible from 25m away Mild 2 Easily identifiable; involves less than half of the affected area Moderate 3 More than half of the affected area Severe 4 Covering the entire area Extreme 5 The entire area has obvious atrophic scars

[0329] The correlation between the GSASS score on day 0 and the photographic measurements of scar lesions on day 2 was evaluated. On day 0, the majority of cases had a GSASS score of 3 or 4 (>90%), therefore, the data distribution of this variable may not provide an adequate estimate of the true correlation between the GSASS and serial photographic measurements.

[0330] A simple linear regression model was run to estimate the slope of the linear relationship between the photomeasure (dependent variable) and GSASS (independent variable). The slope estimate is understood by convention, i.e., the change in photomeasure resulting from a one unit change in GSASS (a change from category X to category X+1) is equal to the slope estimate. It is expected that as GSASS increases, photomeasures also increase, and therefore it is expected that the slope estimate will be positive. This is indeed the case, as shown in Table 10 below:

[0331] Table 10: Regression estimates for GSASS modeling based on photographic data collected on day 0.

[0332]

[0333] The p-value tests whether the slope estimate is equal to zero and is equal to the p-value for a Pearson correlation coefficient of zero. 2 is the square of the Pearson correlation coefficient.

[0334] In all cases, the slope estimates were positive and significant for each photo measurement by camera setting, with the greatest statistical significance observed from volume and area measurements (at each camera setting tested). The highest R values ​​for area and volume were observed for each camera software setting. 2 values, which is not surprising since GSASS is an assessment of scar visibility from a distance. It should be noted that a simple linear regression model does not necessarily take into account patient correlation, i.e. each patient provides both left and right values ​​for analysis, which may not be independent of each other, which is one of the basic assumptions of ordinary least squares regression. As mentioned previously, most of the data is on the x-axis. (GSASS) is clustered around two values, which may also affect the "generalizability" of the results.

[0335] Correlation of 3D camera data with pre / post-treatment scores by a blinded third-party reviewer.

[0336] A third party blind reviewer (BTPR) was asked to review the photos at Day 168 and Day 0 in a blinded manner to assess the change in appearance of the treated area according to the GIC grade. For the BTPR, only the treated area and the immediately surrounding area in the face were observed in the reviewed photos. No detailed information about the patients was provided, and the patients were randomized so that the treatment mode could not be discerned. The BTPR was also asked to identify the three most clinically significant acne scars based on the baseline photos provided, but not to rank them. As part of an additional exploratory analysis, the correlation between the BTPR GIC score and the change from baseline in the lesions identified by the BTPR as determined using the 3D camera software was examined.

[0337] Based on previous data exploration, a series of simple linear regression models were developed with the change from baseline in the photometric measurements as the dependent variable and the BTPR GIC score as the independent variable. Since higher GIC scores indicate improved visual assessment, it is expected that the slope of the line will be negative, indicating that each unit increase in GIC score will result in a decrease in the measured parameter equal to the slope estimate. This was indeed the case for all photometric parameters at each camera setting tested, as shown in Table 11 below. In each case, the p value was <0.05. The slope estimates can represent initial estimates of clinically relevant changes in volume, area, and depth.

[0338] Table 11. Regression estimates of change from baseline to day 168 for BTPR GIC score modeling relative to BTPR selected lesions from camera data.

[0339]

[0340] The p-value tests whether the slope estimate is equal to zero and is equal to the p-value for a Pearson correlation coefficient of zero. 2 is the square of the Pearson correlation coefficient.

[0341] discuss

[0342] The TE implant was found to reduce the volume, area, and depth of treated facial atrophic acne scars based on 3D photo analysis, and the appearance of acne scars was found to improve based on feedback from third-party blinded reviewers.

[0343] The TE implant was also found to be safe and well-tolerated in men and women with facial atrophic acne scars who received three implants over a 56-day period.

[0344] 3D photo-evaluations of the facial treatment areas were performed using various camera software settings at baseline and Day 168, in which acne lesions as well as the overall treatment area characteristics of color, depth, area, and volume were determined. The 3D photo-evaluations included evaluation of skin characteristics at a level encompassing individual acne scars (camera lateral dimension set to 6.0 mm) and at a level encompassing the overall skin contour (camera lateral dimension set to 10.0 mm, where smaller depressions were not detected).

[0345] The modeled results showed that scar volume, area, and depth were statistically significantly reduced over time after treatment with the TE implant as determined by the assay (6.0 mm setting). Notably, the greatest differences between the TE implant and saline control included individual acne scar indentations and overall skin contours under the camera software setting.

[0346] Facial acne lesions treated with TE implants showed the following changes in the PAS1 population:

[0347] - The reduction in acne lesion depth from baseline to Day 168, measured using the 6.0 mm camera software setting, was -0.43 mm (-0.56 mm to -0.30 mm at 95% CI, p<0.001), representing a 21% reduction relative to baseline. This reduction was statistically significantly greater than the reduction observed in acne lesions at saline control sites (p=0.029).

[0348] -Reduction in acne lesion area from baseline to Day 168 was -19.10 mm using the 6.0 mm camera software setting 2 (95% CI is -23.76 mm 2 To -14.44mm 2 , p<0.001), which represents a 24% reduction relative to baseline. This reduction was statistically significantly greater than the reduction observed in acne lesions in saline control sites (p<0.001).

[0349] -Reduction in acne lesion volume from baseline to Day 168 was -6.83 mm using the 6.0 mm camera software setting 3 (95% CI is -8.91 mm 3 To -4.75mm 3 , p<0.001), which represents a 30% reduction relative to baseline. This reduction was statistically significantly greater than the reduction observed in acne lesions in saline control sites (p=0.010).

[0350] Modeling also showed statistically significant differences in color characteristics and improvements in skin contour across the treated area, each favoring the TE implant site. Because seasonality affects facial skin color, color analysis was performed using the change from baseline in the difference between the TE implant treated area and the saline control treated area. Key results include:

[0351] - Change in the difference in color L* characteristics between TE implant sites and saline control sites from baseline to day 168 was -1.11 (95% CI -1.69 to -0.54, p<0.001)

[0352] - Change in the difference in color a* characteristics between TE implant sites and saline control sites from baseline to day 168 was +0.79 (95% CI +0.33 to +1.27, p=0.002)

[0353] - Change in the difference in color b* characteristics between TE implant sites and saline control sites from baseline to day 168 was -0.63 (95% CI -0.92 to -0.34, p<0.001)

[0354] Modeling also showed statistically significant improvements in skin contour across the treatment area as measured by the larger 10.0 mm camera lateral dimension setting. Key results from the PAS1 group here include:

[0355] - From baseline to Day 168, the reduction in skin contour depression area at the TE implant treatment area was -50.12mm 3 (95% CI is -66.02 mm 3 To -34.21mm 3 , p<0.001; representing a 47% decrease relative to baseline values). This was statistically significantly different from the decrease observed in the saline control treated areas (p<0.001). (Table 3).

[0356] - From baseline to Day 168, the reduction in skin contour depression volume at the TE implant treatment area was -22.15 mm 3 (95% CI is -30.82 mm 3 To -13.48mm 3 , p<0.001; indicating a 50% decrease relative to baseline values). This was statistically significantly different from the decrease observed in the saline control treated areas (p=0.014). (Table 3).

[0357] - Increase in skin contour elevation of +53.75mm in the TE implant treated area from baseline to Day 168 2 (95% CI is +40.50 mm 2 Up to +67.01mm 2 , p<0.001; representing an increase of 28% relative to baseline values). This was statistically significantly different from the decrease observed in the saline control treated areas (p<0.001). (Table 3).

[0358] - Increase in skin contour elevation volume in the TE implant treated area from baseline to day 168 was +23.82mm 3 (95% CI is +14.84 mm 3 Up to +32.80mm 3 , p<0.001; representing an increase of 27% relative to baseline values). This was statistically significantly different from the decrease observed in the saline control treated areas (p<0.001). (Table 3).

[0359] - There was no significant effect of either treatment on either the depth of contour concavity or the height of contour elevation.

[0360] There was also a statistically significant difference between the TE implant treated area and the saline control treated area (TE implant side favored) using a third party blinded reviewer's assessment based on the global impression of change rating. In the PAS1 population, at Day 168:

[0361] - 70% of BTPR assessments indicated improvement in the TE implant treated area and 41% of BTPR assessments indicated improvement in the saline control treated area (percent difference, 30%, p=0.033). (Table 5).

[0362] - The mean difference in GIC assessment for BTPR was 0.48 in favor of TE implants (p=0.068). (Table 6).

[0363] The acne scar grade of the Acne-Q questionnaire was derived according to the authors' instructions (Klassen et al.; incorporated herein by reference). Based on the patient's response, at baseline, the acne scar grade scores of both the left and right sides of the face were similar. By day 168, the acne scar grade score on the TE implant-treated side of the face was significantly higher than the acne scar grade score on the saline control side (difference = 5.438 points, p = 0.005). The change in acne scar grade relative to baseline was also calculated. On day 168, both the TE implant site and the saline control site showed significant improvement relative to baseline values ​​(p < 0.001 on both sides). It should be noted that the Acne-Q questionnaire did not confirm changes relative to baseline at this time.

[0364] To assess the clinical significance of measurements derived from the 3D camera data, the correlation of acne scar size measured with the 3D camera with the GSASS and Acne-Q scar grades was evaluated on day 0; and the change in acne scar size determined by the 3D camera was evaluated against the GIC score provided by the BTPR.

[0365] Analysis of the relationship between the GSASS assessments performed on day 0 and the depth, volume, and area measurements performed on day 0 using the 6.0 mm camera setting revealed correlations with all three measurements as follows:

[0366] - One unit step length in the GSASS was associated with a 0.36 mm increase in scar depth among the five lesions measured (95% CI 0.08 mm to 0.64 mm, p=0.014).

[0367] (Table 10).

[0368] - One unit step length in GSASS was associated with an increase in scar area of ​​25.83 mm among the five lesions measured 2 Correlation (95% CI 9.68 mm 2Up to 41.98mm 2 , p=0.002).

[0369] (Table 10).

[0370] -One unit step in GSASS was associated with a 10.11 mm increase in scar volume among the five lesions measured 3 Correlation (95% CI 3.44 mm 3 Up to 16.78mm 3 ,p=0.004).

[0371] (Table 10).

[0372] The above correlation of the acne scar measurements obtained from the 3D camera with all three clinical assessment tools clearly demonstrates that the 3D camera measurements are clinically meaningful and that this correlation can be used to calculate sample sizes for future clinical studies. This data can also be used to obtain the average step-up in the GIC. The following changes were observed for the area of ​​acne scars measured using the camera 6.0 setting:

[0373] Day 168; TE implant group showed a mean decrease from baseline of -19.0 mm 2 , which represents a change of about 3.7 steps in GIC (based on -5.2 mm 2 The saline control group showed a decrease of -4.2 mm relative to baseline. 2 , which indicates a change of GIC of about 0.8 steps.

[0374] The analysis found that for acne scar area measurements, the 6.0 mm camera setting demonstrated clinically significant differences between the TE implant treated areas and the saline control treated areas. Volume measurements made with the 6.0 mm setting also demonstrated clinically significant differences between the TE implant treated areas and the saline control treated areas.

[0375] 70% of BTPR assessments indicated improvement in the TE implant treated area and 41% of BTPR assessments indicated improvement in the saline control treated area (percent difference, 31%, p=0.012).

[0376] Based on the patient's response, at baseline, the acne scar grade scores of the Acne-Q questionnaire were similar for both the left and right sides of the face. By day 168, the acne scar grade score on the TE implant-treated side of the face was significantly higher than the acne scar grade score on the saline control side (difference = 5.438 points, p = 0.005). The change in acne scar grade relative to baseline was also calculated. Both the TE implant site and the saline control site showed significant improvement relative to baseline values ​​(p < 0.001 on both sides).

[0377] Example 2 : Use of TE implants for acne scars

[0378] For the treatment of acne scars, a composition comprising rH tropoelastin cross-linked with derived hyaluronic acid to form a biomaterial matrix (30 mg / mL TE cross-linked with 0.5% dHA) was used. The composition was shown to aid in the repair of atrophic scars during the skin remodeling and maturation phase, thereby improving the appearance of acne scars.

[0379] Patients were treated with an area measuring 2 cm x 2 cm containing at least 2 roller-type atrophic scars. The composition was applied on days 0, 28, and 56, with a total volume of 0.5 mL per treatment. Follow-up was then performed on days 7, 84, and 168. Males and females aged between 18 and 55 years were studied. 3D camera for efficacy evaluation.

[0380] Patients also served as their own controls, using saline controls on other skin areas that did not receive the TE composition.

[0381] Before treatment, patients reviewed their scars and performed a self-assessment of their acne scars. After treatment, patients further assessed the appearance of their acne scars. Scar assessment scores were obtained on Day 0 for comparison at the end of treatment.

[0382] Using the Miravex Antera 3D camera system, depression, elevation, and color can be analyzed within the treatment area and on a per-lesion basis. Treatment area assessment is performed at the prescreening visit to ensure that bilaterally equivalent treatment areas can be selected.

[0383] As shown in the study, the composition achieved amazing results in reducing the depth and size of the acne scar area and improving the skin tone. For example, patients recognized smoother, less jagged, improved texture, and improved scar edges.

[0384] Surprising results measured by 3D camera included a 24% reduction in the area of ​​acne scars compared to controls at day 168 and a 21% reduction at day 336. A 45% to 50% reduction in contour depression volume and improved skin tone were also achieved at day 336 after TE implant treatment compared to controls.

[0385] Regarding skin color, on both days 168 and 336, the L* black to white scale in the TE implant-treated area decreased significantly compared to the control-treated area, and on both days 168 and 336, the a* green to red color scale in the TE implant-treated area increased significantly compared to the control-treated area.

[0386] Further considerations

[0387] In some embodiments, any clause of this paper can be subordinate to any independent clause or any dependent clause. In one aspect, any clause (for example, dependent or independent clause) can be combined with any other one or more clauses (for example, dependent or independent clause). In one aspect, claim can include some or all words (for example, steps, operations, devices or components) narrated from clauses, sentences, phrases or paragraphs. In one aspect, claim can include some or all words narrated in one or more clauses, sentences, phrases or paragraphs. In one aspect, some words in each clause, sentence, phrase or paragraph can be removed. In one aspect, other words or elements can be added to clauses, sentences, phrases or paragraphs. In one aspect, this subject technology can be realized without utilizing some components, elements, functions or operations described herein. In one aspect, other components, elements, functions or operations can be utilized to realize this subject technology.

[0388] For example, the subject technology is described according to the various aspects described below. For convenience, various examples of various aspects of the subject technology are described as numbered clauses (1, 2, 3, etc.). These are provided as examples, but not limiting the subject technology. It should be noted that any dependent clauses can be combined in any combination and placed in each independent clause such as clause 1 or clause 20. Other clauses can be presented in a similar manner.

[0389] Clause 1. A method of treating an area of ​​skin having acne scars to improve the color and / or appearance of acne scars in an area of ​​skin of a patient in need thereof, and / or to reduce the depth, affected area and / or volume of acne scars, the method comprising applying a composition comprising tropoelastin to the area of ​​skin having acne scars.

[0390] Clause 2. The method of Clause 1, wherein the composition comprises between about 1 mg / mL to about 400 mg / mL tropoelastin.

[0391] Clause 3. The method according to clause 1 or 2, wherein the composition comprises 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL, 400 mg / mL, 410 mg / mL, 420 mg / mL, 430 mg / mL 10 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL or 400 mg / mL of tropoelastin, or any amount of tropoelastin between the range defined by any two of the foregoing values.

[0392] Clause 4. The method according to any one of Clauses 1 to 3, wherein the composition comprises between about 1 mg / mL to about 300 mg / mL tropoelastin.

[0393] Clause 5. The method according to any one of Clauses 1 to 4, wherein the composition comprises between about 1 mg / mL to about 250 mg / mL tropoelastin.

[0394] Clause 6. The method according to any one of Clauses 1 to 5, wherein the composition comprises between about 1 mg / mL to about 200 mg / mL tropoelastin.

[0395] Clause 7. The method according to any one of Clauses 1 to 6, wherein the composition comprises between about 1 mg / mL to about 150 mg / mL tropoelastin.

[0396] Clause 8. The method according to any one of Clauses 1 to 7, wherein the composition comprises between about 1 mg / mL to about 100 mg / mL tropoelastin.

[0397] Clause 9. The method of any one of Clauses 1 to 8, wherein the tropoelastin is cross-linked with about 0.1% to about 10% of the derivatized hyaluronic acid.

[0398] Clause 10. The method of any one of Clauses 1 to 9, wherein the composition comprises between about 1 mg / mL to about 100 mg / mL tropoelastin cross-linked with about 0.4% to about 1% derivatized hyaluronic acid (HA).

[0399] Clause 11. The method of any one of Clauses 1 to 9, wherein the composition comprises 30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid.

[0400] Clause 12. The method according to any one of clauses 1 to 11, wherein the composition further comprises phosphate buffered saline.

[0401] Clause 13. The method according to any one of clauses 1 to 12, wherein the composition comprising tropoelastin is applied around the scar, such as beneath the scar and / or around the edges of the scar.

[0402] Clause 14. The method according to any one of clauses 1 to 13, wherein the acne scars are subdivided into ice pick scars, boxcar scars or roller-type atrophic scars.

[0403] Clause 15. The method according to any one of Clauses 1 to 14, wherein the acne scar is an ice pick scar.

[0404] Clause 16. The method according to any one of Clauses 1 to 14, wherein the acne scar is a box scar.

[0405] Clause 17. The method according to any one of Clauses 1 to 14, wherein the scar is a roller-type atrophic acne scar.

[0406] Clause 18. The method according to any one of Clauses 1 to 14, wherein the scar is a hypertrophic scar.

[0407] Clause 19. The method according to any one of Clauses 1 to 18, wherein the scar comprises fibrotic tissue around or beneath the edges of the scar.

[0408] Clause 20. The method of any one of Clauses 1 to 19, wherein the acne scar has a depth of about 0.1 mm to about 5 mm.

[0409] Clause 21. The method according to any one of clauses 1 to 20, wherein the affected area of ​​the acne scar is about 0.05 mm 2 To about 400mm 2 .

[0410] Clause 22. The method according to any one of clauses 1 to 21, wherein the volume of the acne scar is about 0.01 mm 3 Up to 2,000mm3 .

[0411] Clause 23. The method according to any one of Clauses 1 to 22, wherein the method further comprises the step of disrupting fiber bundles underlying the acne scar.

[0412] Clause 24. The method according to Clause 23, wherein the disrupting step is performed prior to administering the composition comprising tropoelastin to a patient in need thereof.

[0413] Clause 25. The method according to Clause 23 or 24, wherein the step of disrupting the fiber bundles creates a dermal pocket beneath the acne scar.

[0414] Clause 26. The method of Clause 25, wherein the disrupting step is performed with an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle.

[0415] Clause 27. The method according to Clause 25 or 26, wherein administering comprises injecting the composition into the dermal follicle.

[0416] Clause 28. The method according to any one of Clauses 1 to 27, wherein the composition is administered as an injection beneath the acne scar.

[0417] Clause 29. The method according to any one of Clauses 1 to 13, wherein the composition is administered in a volume of about 10 μL to about 100 μL per implantation / injection.

[0418] Clause 30. The method according to any one of Clauses 28 to 29, wherein the injection is performed in a cross-hatching arrangement using a retrograde threading technique to disrupt fiber bundles within the acne scar.

[0419] Clause 31. The method of Clause 30, wherein the needle is inserted into the area of ​​skin having the acne scar at an angle of about 30° parallel to the skin, and wherein the needle is beveled and the bevel is facing upward.

[0420] Clause 32. The method of Clause 31, wherein the needle is inserted more than once into the area of ​​skin having the acne scar to disrupt the fiber bundles and create a dermal pocket.

[0421] Clause 33. The method according to Clause 32, wherein uniform pressure is applied to inject the composition while withdrawing the needle from the dermal follicle.

[0422] Clause 34. The method according to any one of Clauses 1 to 33, wherein the composition is administered repeatedly, and wherein one or more boluses are administered in the scar.

[0423] Clause 35. The method of any one of Clauses 1 to 34, wherein the maximum volume of the composition administered is between about 100 μL and about 5 mL.

[0424] Clause 36. The method according to any one of clauses 1 to 35, wherein the maximum volume of the composition applied is about 100 μL / cm 2 to about 500 μL / cm 2 between.

[0425] Clause 37. The method of any one of Clauses 1 to 35, wherein the patient in need thereof has a skin type of Type I, Type II, Type III, Type IV, Type V, or Type VI on the Fitzpatrick skin classification scale.

[0426] Clause 38. The method of any one of Clauses 1 to 37, wherein the scar comprises grade 1, grade 2, grade 3, grade 4, or grade 5.

[0427] Clause 39. The method of any one of clauses 1 to 38, wherein the skin has a skin tone defined by CIE L*a*b* color coordinates, wherein the method further causes a reduction in L*.

[0428] Clause 40. The method of clause 39, wherein the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values.

[0429] Clause 41. The method according to clause 39 or 40, wherein the method also increases a*.

[0430] Clause 42. A method according to clause 41, wherein the method increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values.

[0431] Clause 43. The method according to any one of Clauses 1 to 42, wherein the scar has a silver coloration prior to applying the composition.

[0432] Clause 44. The method according to Clause 43, wherein applying the composition reduces the silver coloration of the scar and increases the red coloration and / or pink coloration of the scar.

[0433] Item 45. A method according to Item 44, wherein the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values, and increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by the range between any two of the foregoing values.

[0434] Clause 46. The method of any one of clauses 1 to 45, wherein the scar has a color, wherein the color is different from the patient's natural skin color, and wherein applying the composition causes the color of the scar to decrease or fade in color intensity such that the color of the scar blends in with the patient's natural skin color.

[0435] Clause 47. The method according to any one of Clauses 1 to 46, wherein the acne scar is a facial scar, a back scar or a trunk scar.

[0436] Clause 48. The method according to any one of Clauses 1 to 47, wherein the depth, affected area and / or volume of acne scars is reduced following application of the composition.

[0437] Clause 49. The method according to any one of Clauses 1 to 48, wherein the treatment aids in the repair of atrophic scars in the skin remodeling and maturation phase, thereby improving the appearance of acne scars.

[0438] Clause 50. The method of any one of clauses 1 to 49, wherein the treatment reduces the area of ​​the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values.

[0439] Clause 51. The method of any one of clauses 1 to 50, wherein the treatment reduces the volume of the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values.

[0440] Clause 52. The method of any one of clauses 1 to 51, wherein the treatment reduces the depth of the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values.

[0441] Clause 53. The method of any one of clauses 1 to 52, wherein the treatment reduces the depressed volume and area of ​​the skin contour in the skin area with acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values.

[0442] Clause 54. The method of any one of Clauses 1 to 53, wherein the treatment further improves the skin tone of the acne scar.

[0443] Clause 55. The method of any one of clauses 1 to 54, wherein the treatment increases the volume and area of ​​raised skin contours in the skin area with acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between the ranges defined by any two of the foregoing values.

[0444] Clause 56. The method of any one of Clauses 53 to 55, wherein the treatment flattens the skin contour in the area of ​​skin having acne scars.

[0445] Clause 57. The method of any one of Clauses 1 to 56, wherein the treatment reduces the L* black to white scale in the area of ​​skin having acne scars compared to a control treatment.

[0446] Clause 58. A method of restoring skin contour affected by acne scars in a subject in need thereof, the method comprising: applying a composition comprising tropoelastin to an area of ​​skin having skin contour affected by acne scars.

[0447] Clause 59. The method of Clause 58, wherein the composition comprises between about 1 mg / mL to about 400 mg / mL tropoelastin.

[0448] Clause 60. The method of clause 58 or 59, wherein the composition comprises 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL or 400 mg / mL of tropoelastin, or any amount of tropoelastin between the range defined by any two of the foregoing values.

[0449] Clause 61. The method according to any one of Clauses 58 to 60, wherein the composition comprises between about 1 mg / mL to about 300 mg / mL tropoelastin.

[0450] Clause 62. The method according to any one of Clauses 58 to 61, wherein the composition comprises between about 1 mg / mL to about 250 mg / mL tropoelastin.

[0451] Clause 63. The method according to any one of Clauses 58 to 62, wherein the composition comprises between about 1 mg / mL to about 200 mg / mL tropoelastin.

[0452] Clause 64. The method according to any one of Clauses 58 to 63, wherein the composition comprises between about 1 mg / mL to about 150 mg / mL tropoelastin.

[0453] Clause 65. The method according to any one of Clauses 58 to 64, wherein the composition comprises between about 1 mg / mL to about 100 mg / mL tropoelastin.

[0454] Clause 66. The method of any one of Clauses 58 to 65, wherein the tropoelastin is cross-linked with about 0.1% to about 10% of the derivatized hyaluronic acid.

[0455] Clause 67. The method of any one of Clauses 58 to 66, wherein the composition comprises between about 1 mg / mL to about 100 mg / mL tropoelastin cross-linked with about 0.4% to about 1% derivatized hyaluronic acid (HA).

[0456] Clause 68. The method of any one of Clauses 58 to 67, wherein the composition comprises 30 mg / mL recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid.

[0457] Clause 69. The method according to any one of Clauses 58 to 68, wherein the composition is applied around the scar, such as beneath the scar and / or around the edges of the scar.

[0458] The above description is provided to enable those skilled in the art to practice the various configurations described herein. Although the subject technology has been described in detail with reference to various drawings and configurations, it should be understood that these are only for illustrative purposes and should not be considered to limit the scope of the subject technology.

[0459] There may be many other ways to implement the subject technology. Various functions and elements may be different from the functions and elements described herein without departing from the scope of the subject technology. Various modifications of these configurations are apparent to those skilled in the art, and the general principles defined herein may be applied to other configurations. Therefore, without departing from the scope of the subject technology, those of ordinary skill in the art may make many changes and modifications to the subject technology.

[0460] It should be understood that the specific order or hierarchy of steps in the disclosed process is an illustration of an exemplary method. It should be understood that the specific order or hierarchy of steps in the process can be rearranged based on design preferences. Some steps can be performed simultaneously. The attached method claims present the elements of the various steps in an exemplary order, but are not meant to be limited to the specific order or hierarchy presented.

[0461] As used herein, the phrase "at least one of" preceding a series of items, and the terms "and" or "or" used to separate any items, modify the list as a whole, rather than modifying each member of the list (i.e., each item). The phrase "at least one of" does not require selection of at least one of each item listed; rather, the phrase can include the meaning of at least one of any one item, and / or at least one of any combination of items, and / or at least one of each item. For example, the phrase "at least one of A, B, and C" or "at least one of A, B, or C" each refers to only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0462] Terms such as "top", "bottom", "front", "back", etc. used in this disclosure should be understood to refer to an arbitrary reference frame, not the ordinary gravitational reference frame. Thus, the top surface, bottom surface, front surface, and back surface may extend upward, downward, diagonally, or horizontally in the gravitational reference frame.

[0463] Furthermore, to the extent that the terms "including," "having," and the like are used in the specification or claims, these terms are intended to be inclusive in the same manner as the term "comprising," as illustrated when "comprising" is used as a transitional word in a claim.

[0464] The word “exemplary” is used herein to mean “serving as an example, instance, or illustration.” Any “exemplary” embodiment described herein is not necessarily to be construed as preferred or advantageous over some embodiments.

[0465] Unless otherwise specified, elements referred to in the singular are not intended to mean "one and only one", but rather "one or more". Masculine pronouns (e.g., his) include feminine and neuter (e.g., her and its), and vice versa. The term "some" refers to one or more. Underlined and / or italicized titles and subtitles are used for convenience only, do not limit the subject technology, and are not intended to be interpreted in conjunction with the description of the subject technology. All structural and functional equivalents of the elements of the various configurations described throughout the present disclosure that are known or will later be known to those of ordinary skill in the art are expressly incorporated herein by reference and are intended to be covered by the subject technology. In addition, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is explicitly stated in the above description.

Claims

1. A composition comprising tropoelastin cross-linked with about 0.5% of derived hyaluronic acid for use in treating an area of ​​skin having acne scars to improve one or more of the following in the area of ​​skin of a patient in need thereof: color, appearance, reduction in depth of the acne scars, reduction in affected area of ​​the acne scars, and reduction in volume of the acne scars, wherein the composition comprises 30 mg / mL of tropoelastin.

2. The composition for use according to claim 1, wherein the composition comprising tropoelastin is applied around the scar, preferably below the scar and / or around the edge of the scar and / or wherein the acne scar is subdivided into ice pick scars, boxcar scars or roller-type atrophic scars.

3. A composition for use according to any one of claims 1 or 2, wherein the depth of the acne scar is from about 0.1 mm to about 5 mm and / or wherein the affected area of ​​the acne scar is about 0.05 mm 2 To about 400mm 2 and / or wherein the volume of the acne scar is about 0.01 mm 3 Up to 2,000mm 3 .

4. The composition for use according to any one of claims 1 to 3, wherein the composition is administered as an injection beneath the acne scar, preferably in a volume of about 10 μL to about 100 μL per implant / injection, more preferably wherein the maximum volume of the composition administered is between about 100 μL to about 5 mL.

5. The composition for use according to any one of claims 1 to 4, wherein the composition is applied as an injection beneath the acne scar, wherein the maximum volume of the composition applied is from about 100 μL to about 500 μL per square centimeter of skin area.

6. The composition for use according to any one of claims 1 to 5, wherein the composition is administered on day 0, day 28 and day 56.

7. The composition for use according to any one of claims 1 to 6, wherein the composition is administered repeatedly and wherein one or more boluses are administered in the scar.

8. A composition for use according to any one of claims 1 to 7, wherein the skin type of the patient in need thereof is type I, type II, type III, type IV, type V or type VI in the Fitzpatrick skin classification system and / or wherein the scar comprises grade 1, grade 2, grade 3, grade 4 or grade 5.

9. A composition for use according to any one of claims 1 to 8, wherein after application of the composition, the depth, affected area and / or volume of the acne scar is reduced, preferably wherein the treatment aids in the repair of atrophic scars in the skin remodeling and maturation phase, thereby improving the appearance of the acne scar.

10. The composition for use according to any one of claims 1 to 9, wherein the treatment reduces the area of ​​the acne scar by at least about 10% and / or wherein the treatment reduces the volume of the acne scar by at least about 10% and / or wherein the treatment reduces the depth of the acne scar by at least about 10%.

11. A composition for use according to any one of claims 1 to 10, wherein the treatment reduces the depressed volume and area of ​​the skin contour in the area of ​​skin having the acne scar by at least about 10%, optionally wherein the treatment further improves the skin tone of the acne scar.

12. A composition for use according to any one of claims 1 to 11, wherein the treatment increases the volume and area of ​​the raised skin contour in the area of ​​skin having the acne scar by at least about 10%.

13. The composition for use according to claim 1, wherein the hyaluronic acid is activated and / or modified by adding 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and / or N-hydroxysuccinimide (NHS).

Images