Tropoelastin for use in treatment of acne scar

Abstract

To provide use of a camera in treatment of an acne scar.SOLUTION: Provided is use of a camera for detecting reduction in volume of an acne scar.SELECTED DRAWING: Figure 5-1

Description

[Technical Field]

[0001] The present disclosure relates to methods of reducing the appearance of acne scars, such as depressions, ice pick scars, rolling atrophic acne scars, and boxcar scars, using compositions comprising tropoelastin. [Background technology]

[0002] The reference to prior art herein is not an admission or suggestion that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art could reasonably be expected to be understood, considered relevant, and / or combined with other pieces of prior art by those skilled in the art.

[0003] Acne scars can be the result of infected wounds caused by clogged skin pores engorged with excess oil, dead skin cells, and bacteria. The pores expand, causing damage to the hair follicle walls. Shallow lesions are usually minor and may heal quickly. However, deeper cuts in the pore walls can allow infected material to leak into the surrounding tissue, resulting in deeper lesions. Therefore, the skin may attempt to repair these lesions by forming new collagen fibers. In some cases, visible scars can develop in prominent locations, such as the face, neck, or chest, which can be a source of concern for individuals. Several variables affect the severity of scars, including their thickness and color. These repairs may not be as smooth and flawless as the original skin. Furthermore, healing can result in undesirable discoloration of the skin within the scar.

[0004] There are several types of acne scars, including but not limited to hypertrophic scars, ice pick scars, boxcar scars, rolling atrophic scars, and depressed scars. In some cases, scars can cause discoloration of the skin, and exposure to ultraviolet light can cause the scar to darken and increase in elevation, giving the scar fibrous tissue a silvery appearance.

[0005] While several treatments have been introduced to prevent and treat acne, the scars that remain can be difficult to manage and control. For example, common skin treatments include the use of topical retinoids to lighten the brown, red, or purple discoloration left by acne, laser treatments, dermabrasion, and punch grafting. Therefore, there is a need to treat unsightly scars and improve their appearance. There is also a desire to reduce the depth, area, and volume of depressions that can be caused by acne. Summary of the Invention

[0006] The present disclosure generally relates to compositions comprising tropoelastin and methods of using such compositions for the treatment of acne scars (e.g., fibrous acne scars). The methods may include administering a composition comprising tropoelastin to an area of ​​skin bearing acne scars. In embodiments, the methods include treating an area of ​​skin bearing acne scars to improve the color and / or appearance and / or reduce the depth, area, and / or volume of acne scars in an area of ​​skin of a patient in need thereof. The treatment methods disclosed herein may improve the color and / or appearance of acne scars in an area of ​​skin of a patient in need thereof. Additionally or alternatively, the treatment methods may reduce the depth, area, and / or volume of acne scars in an area of ​​skin of a patient in need thereof.

[0007] In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 400 mg / ml of tropoelastin. In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 20 mg / ml, about 30 mg / ml, about 40 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 mg / ml, about 180 mg / ml, about 190 mg / ml, about 200 mg / ml, about The compositions may comprise 210 mg / ml, about 220 mg / ml, about 230 mg / ml, about 240 mg / ml, about 250 mg / ml, about 260 mg / ml, about 270 mg / ml, about 280 mg / ml, about 290 mg / ml, 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.

[0008] In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 300 mg / ml of tropoelastin. In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 250 mg / ml of tropoelastin. In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 200 mg / ml of tropoelastin. In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 150 mg / ml of tropoelastin. In some embodiments of each or any of the above or below embodiments, the composition comprises from about 1 mg / ml to about 100 mg / ml of tropoelastin.

[0009] In some embodiments of each or any of the above or below embodiments, the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid. In some embodiments of each or any of the above or below embodiments, the composition comprises about 1 mg / ml to about 100 mg / ml tropoelastin cross-linked with about 0.4% to about 1% derivatized hyaluronic acid (HA). In some embodiments of each or any of the above or below embodiments, the composition comprises about 30 mg / ml recombinant human tropoelastin cross-linked with about 0.5% derivatized hyaluronic acid. In some embodiments of each or any of the above or below embodiments, the composition further comprises a buffer (e.g., phosphate-buffered saline).

[0010] In some embodiments of each or any of the foregoing or following embodiments, the composition comprising tropoelastin is administered around the scar, such as under the scar and / or around the edges of the scar.

[0011] In some embodiments of each or any of the above or below embodiments, the acne scar is subclassified as an ice pick scar, a boxcar scar, or a rolling atrophic scar. In some embodiments of each or any of the above or below embodiments, the acne scar is an ice pick scar. In some embodiments of each or any of the above or below embodiments, the acne scar is a box scar. In some embodiments of each or any of the above or below embodiments, the scar is a rolling atrophic acne scar. In some embodiments of each or any of the above or below embodiments, the scar is a hypertrophic scar. In some embodiments of each or any of the above or below embodiments, the scar comprises fibrous tissue around the edges or base of the scar.

[0012] In some embodiments of each or any of the above or below embodiments, the acne scar has a depth of about 0.1 mm to about 5 mm. In some embodiments of each or any of the above or below embodiments, the acne scar has a depth of 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 within a range between any two of the foregoing values.

[0013] In some embodiments of each or any of the above or below embodiments, the acne scar is less than about 0.05 mm 2 ~approx. 400mm 2 In some embodiments of each or any of the above or below embodiments, the acne scar has an affected area of ​​about 0.05 mm 2 , approximately 0.50 mm 2 , 1.0mm 2 , about 5mm 2 , about 10mm 2 , about 15mm 2 , about 20mm 2 , about 25mm 2 , about 30mm 2 , about 35mm 2 , approximately 40 mm 2 , about 45mm 2 , approximately 50 mm 2 , about 55mm 2 , about 60mm 2 , about 65mm 2 , about 70mm 2 , about 75mm 2 , about 80mm 2 , about 85mm 2 , about 90mm 2 , about 95mm 2 , approximately 100 mm 2 , about 125mm 2 , about 150mm 2 , about 175mm 2 , about 200mm 2 , about 225mm 2 , about 250mm 2 , about 275mm 2 , about 300mm 2 , about 325mm 2, about 350mm 2 , about 375mm 2 , or about 400 mm 2 or has an affected area of ​​any value within a range between any two of the aforementioned values.

[0014] In some embodiments of each or any of the above or below embodiments, the acne scar is less than about 0.01 mm 3 ~approx. 2,000mm 3 In some embodiments of each or any of the above or below embodiments, the acne scar has a volume of about 0.01 mm 3 , 1mm 3 , about 10mm 3 , about 20mm 3 , about 30mm 3 , approximately 40 mm 3 , approximately 50 mm 3 , about 60mm 3 , about 70mm 3 , about 80mm 3 , about 90mm 3 , approximately 100 mm 3 , about 125mm 3 , about 150mm 3 , about 175mm 3 , about 200mm 3 , about 225mm 3 , about 250mm 3 , about 275mm 3 , about 300mm 3 , about 325mm 3 , about 350mm 3 , about 375mm 3 , approximately 400 mm 3 , about 425mm 3 , approximately 450 mm 3 , about 475mm 3 , approximately 500 mm 3 , about 525mm 3 , about 550mm 3 , about 575mm 3 , approximately 600 mm 3 , about 625mm 3 , approximately 650 mm 3 , about 675mm 3 , about 700mm 3 , about 725mm 3 , about 750mm3 , about 775mm 3 , approximately 800 mm 3 , about 825mm 3 , about 850mm 3 , about 875mm 3 , approximately 900 mm 3 , about 925mm 3 , about 950mm 3 , 975mm 3 , approximately 1,000 mm 3 , approximately 1,100 mm 3 , approx. 1,200mm 3 , approx. 1,300mm 3 , approximately 1,400 mm 3 , approximately 1,500 mm 3 , approximately 1,600 mm 3 , approx. 1,700mm 3 , approximately 1,800 mm 3 , approximately 1,900 mm 3 or approximately 2,000 mm 3 or any volume within a range between any two of the aforementioned values.

[0015] In some embodiments of each or any of the above or below embodiments, the method further comprises disrupting fibrous strands beneath the acne scar. In some embodiments of each or any of the above or below embodiments, the disrupting occurs prior to administering the composition to a patient in need thereof. In some embodiments of each or any of the above or below embodiments, the disrupting of the fibrous strands forms a dermal pocket beneath the acne scar. In some embodiments of each or any of the above or below embodiments, the disrupting is performed with an 18-32G needle, such as an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle. In some embodiments of each or any of the above or below embodiments, administering comprises injecting the composition into the dermal pocket. In some embodiments of each or any of the above or below embodiments, the composition comprising tropoelastin is also positioned around the scar, such as beneath and around the scar edges. By placing a composition comprising tropoelastin evenly around the scar throughout the dermis surrounding the scar, it may be ensured that the tropoelastin product is around the scarred area.

[0016] In some embodiments of each or any of the above or below embodiments, the composition is administered as an injection under the acne scar. In some embodiments of each or any of the above or below embodiments, the composition is administered in a volume of about 10 μL to about 100 μL per implant / injection. In some embodiments of each or any of the above or below embodiments, the composition is administered 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 a volume within a range defined by any two of the foregoing values. In some embodiments, multiple injections are administered into the acne scar, and the total administered volume is about 200 μL, about 300 μL, about 400 μL, or about 500 μL.

[0017] In some embodiments of each or any of the above or below embodiments, the injection is performed using a retrograde linear threading technique in a cross-hatched configuration to ensure that all fibrous strands within the acne scar are disrupted. In some embodiments of each or any of the above or below embodiments, the needle is inserted parallel to the skin at an angle of approximately 30°, with the needle configured with a bevel that faces upward. In some embodiments of each or any of the above or below embodiments, the needle is inserted multiple times to disrupt the fibrous strands and form a dermal pocket. In some embodiments of each or any of the above or below embodiments, uniform pressure is applied to inject the composition as the needle is withdrawn from the dermal pocket.

[0018] In some embodiments of each or any of the above or below embodiments, the administration of the composition is repeated, administering one or more bolus injections into the scar. In some embodiments of each or any of the above or below embodiments, the maximum volume of 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 below embodiments, the maximum volume of 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 below embodiments, the maximum volume of composition administered as a treatment is about 100 μL to about 500 μL per square cm. In some embodiments of each or any of the foregoing or following embodiments, the maximum volume of composition administered as a treatment is about 100 μL per square cm, about 150 μL per square cm, about 200 μL per square cm, about 250 μL per square cm, about 300 μL per square cm, about 350 μL per square cm, about 400 μL per square cm, about 450 μL per square cm, 500 μL per square cm, or any amount between the ranges defined by any two of the foregoing values.

[0019] In some embodiments of each or any of the foregoing or following embodiments, the patient in need thereof has a skin type on the Fitzpatrick Skin Type Scale of I, II, III, IV, V, or VI. In some embodiments of each or any of the foregoing or following embodiments, the scarring comprises a grade of 1 to 5. The grades of scarring are as 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).

[0020] In some embodiments of each or any of the above or below embodiments, the acne scar is subclassified as an ice pick scar, a boxcar scar, or a rolling atrophic scar. In some embodiments of each or any of the above or below embodiments, the acne scar is an ice pick scar. In some embodiments of each or any of the above or below embodiments, the acne scar is a box scar. In some embodiments of each or any of the above or below embodiments, the scar is a rolling atrophic acne scar. In some embodiments of each or any of the above or below embodiments, the scar is a hypertrophic scar. In some embodiments of each or any of the above or below embodiments, the acne scar comprises fibrous tissue around the edges and / or base of the scar.

[0021] In some embodiments of each or any of the above or below embodiments, the acne scar has a depth of about 0.1 mm to about 5 mm. In some embodiments of each or any of the above or below embodiments, the acne scar has a depth of 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. In some embodiments of each or any of the above or below embodiments, the acne scar has a depth of about 0.05 mm 2 ~approx. 400mm 2 In some embodiments of each or any of the above or below embodiments, the acne scar has an affected area of ​​about 0.01 mm 3 ~approx. 2,000mm 3 It has a volume of

[0022] In some embodiments of each or any of the above or below embodiments, the acne scar is less than about 0.01 mm 3 , 1mm 3 , about 10mm 3 , about 20mm 3 , about 30mm 3 , approximately 40 mm 3 , approximately 50 mm 3 , about 60mm 3 , about 70mm 3 , about 80mm 3 , about 90mm 3 , approximately 100 mm 3 , about 125mm 3 , about 150mm 3 , about 175mm 3 , about 200mm 3 , about 225mm 3 , about 250mm 3 , about 275mm 3 , about 300mm 3 , about 325mm 3 , about 350mm 3 , about 375mm 3 , approximately 400 mm 3 , about 425mm 3 , approximately 450 mm 3 , about 475mm 3 , approximately 500 mm3 , about 525mm 3 , about 550mm 3 , about 575mm 3 , approximately 600 mm 3 , about 625mm 3 , approximately 650 mm 3 , about 675mm 3 , about 700mm 3 , about 725mm 3 , about 750mm 3 , about 775mm 3 , approximately 800 mm 3 , about 825mm 3 , about 850mm 3 , about 875mm 3 , approximately 900 mm 3 , about 925mm 3 , about 950mm 3 , 975mm 3 , approximately 1,000 mm 3 , approximately 1,100 mm 3 , approx. 1,200mm 3 , approx. 1,300mm 3 , approximately 1,400 mm 3 , approximately 1,500 mm 3 , approximately 1,600 mm 3 , approx. 1,700mm 3 , approximately 1,800 mm 3 , approximately 1,900 mm 3 or approximately 2,000 mm 3 or any volume within a range between any two of the aforementioned values.

[0023] In some embodiments of each or any of the foregoing or following embodiments, the skin is * a * b * and skin color defined by color coordinates, * In some embodiments of each or any of the above or below embodiments, the method further reduces L *In some embodiments of each or any of the foregoing or following embodiments, the method further comprises reducing L by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or by any amount defined by a range between any two of the foregoing values. * In some embodiments of each or any of the above or below embodiments, the method further comprises: * In some embodiments of each or any of the foregoing or following embodiments, the method further comprises increasing a * In some embodiments of each or any of the foregoing or following embodiments, the method further comprises increasing by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or by any amount defined by a range between any two of the foregoing values. * In some embodiments of each or any of the above or below embodiments, the scar comprises a silvery coloration prior to administration of the composition. In some embodiments of each or any of the above or below embodiments, administration of the composition reduces the silvery coloration and increases the red and / or pink coloration of the scar. In some embodiments of each or any of the above or below embodiments, the method comprises administering 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; * by about 1%, about 5%, about 10%, about 15%, about 20%, about 25% or by more than about 50%, or by any amount defined by a range between any two of the preceding values. In some embodiments of each or any of the foregoing embodiments, the scar comprises a colour which differs from the patient's natural skin tone, and administration of the composition results in a reduction or fading of the colour of the scar so that the colour of the scar blends with the patient's natural skin tone.

[0024] In some embodiments of each or any of the above or below embodiments, the acne scars are scars on the face, back, or torso. In some embodiments of each or any of the above or below embodiments, after administration of the composition, the depth, area, and / or volume of the acne scars are reduced.

[0025] In some embodiments of each or any of the foregoing or following embodiments, the method supports skin remodeling and repair of atrophic scars in the maturation stage to reduce the appearance of acne scars.

[0026] In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar area by more than about 90%. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar area by more than about 90%.

[0027] In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar volume by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar volume by more than about 90%. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar volume by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar volume by more than about 90%.

[0028] In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar depth by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the method provides a reduction in acne scar depth of more than about 90%. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar depth by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between the ranges described by any two of the above values. In some embodiments of each or any of the above or below embodiments, the composition provides a reduction in acne scar depth of more than about 90%.

[0029] In some embodiments of each or any of the above or below embodiments, where a patient in need thereof has an area of ​​acne scar on the skin, the method provides a reduction in the depression volume and area of ​​the 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 by more than about 90%, or any amount between the ranges described by any two of the foregoing values. In some embodiments of each or any of the above or below embodiments, where a patient in need thereof has an area of ​​acne scar on the skin, the method provides a reduction in the depression volume and area of ​​the skin contour in the area of ​​the acne scar by more than about 90%. In each or some embodiments of any of the above or below embodiments, the composition provides a reduction in the volume and area of ​​skin contour depression in 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 described by any two of the preceding values. In each or some embodiments of any of the above or below embodiments, the composition provides a reduction in the volume and area of ​​skin contour depression in the area of ​​acne scars by greater than about 90%.

[0030] In some embodiments of each or any of the foregoing or following embodiments, an individual can achieve near complete removal of acne scars with the treatments and methods described herein, reducing acne depth, volume, and area by greater than about 90%.

[0031] In some embodiments of each or any of the foregoing or following embodiments, the method improves skin color. In some embodiments, improving skin color comprises: * by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or by any amount defined by a range between any two of the aforementioned values; and / or *In some embodiments of each or any of the foregoing or following embodiments, L may be increased by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or by any amount defined by a range between any two of the foregoing values. * is reduced by more than about 50%. In some embodiments of each or any of the above or below embodiments, a * is increased by greater than about 50%. In some embodiments of each or any of the above or below embodiments, the composition provides an improvement in skin color.

[0032] In some embodiments of each or any of the above or below embodiments, the methods and compositions increase the volume and area of ​​the skin contour elevation 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 by more than about 90%, or any amount between the ranges described by any two of the foregoing values. In some embodiments of each or any of the above or below embodiments, the volume and area of ​​the skin contour elevation in the area of ​​the acne scar is increased by more than about 90%.

[0033] In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions flatten the contours of the skin in treatment areas that include acne scars or depressions.

[0034] In some embodiments of each or any of the foregoing or following embodiments, the methods and compositions provide for the reduction of L * In some embodiments of each or any of the above or below embodiments, the method and composition reduces a in the composition-treated site compared to the control-treated site. * Increasing from green to red color scale.

[0035] The present disclosure also provides methods for treating (e.g., repairing) the contours of skin affected by acne scars. The methods may include administering a composition comprising tropoelastin to an area of ​​skin having the contours of skin affected by acne scars. In one embodiment, the methods include treating an area of ​​skin having the contours of skin affected by acne scars to reduce the depth, volume, and / or area of ​​the acne scars. [Brief explanation of the drawings]

[0036] Various features of exemplary embodiments of the present disclosure are described below with reference to the drawings, which are intended to illustrate, but not limit, the present disclosure, including the following figures:

[0037] [Figure 1] FIG. 1 shows a flow chart of patient treatment.

[0038] [Figure 2] 2A-2D show the clinical grading of acne scars at screening and day 1. Grading was based on the acne scar scale as described by Tan et al. 2010 (Journal of Cutaneous Medicine and Surgery, Vol 14, No 4 (July / August) (incorporated herein by reference). Scale: 0 = no visible acne scar; 1 = acne scar barely visible from a distance of 2.5 m; 2 = easily noticeable acne scar, involving less than half of the affected area; 3 = easily noticeable acne scar, involving more than half of the affected area; 4 = easily noticeable acne scar, involving the entire area; and 5 = easily noticeable acne scar, involving the entire area. Shown are the sides with the TE implant (recombinant human tropoelastin 30 mg / ml cross-linked with 0.5% derivatized hyaluronic acid) (Figure 2A) and the saline control side (intradermal (id) implant in isotonic saline) (Figure 2B) at the screening visit. Shown are the TE implant side on day 1 (Figure 2C) and the saline control side on day 1 (Figure 2D).

[0039] [Figure 3] Figure 3 shows the blinded third-party review (BTPR) assessment of scars using the Global Impression of Change Scale (PAS1), scale: -3 = much worse; -2 = moderately worse; -1 = slightly worse; 0 = no change; 1 = slightly improved, 2 = moderately improved; 3 = much improved.

[0040] [Figure 4] Figure 4 shows the correlation between screening and baseline visits.

[0041] [Figure 5] Figures 5A and 5B show the results for all camera settings for area and volume, and the results from the cameras increase with increasing severity score, thus suggesting that the cameras are measuring similar components.

[0042] [Figure 6] 6A and 6B show the relationship between GIC(BTPR) and results for different camera settings. DETAILED DESCRIPTION OF THE INVENTION

[0043] Acne is a chronic inflammatory disease that can result from bacterial colonization of the pores and hair follicles of the skin on the face, neck, chest, and back. Bacterial colonization can be caused by bacteria such as Propionibacterium acnes. Acne can also be caused by increased sebum secretion, changes in keratinocytes, and inflammation. However, sometimes the trigger for acne development is unclear.

[0044] Acne can begin during early adolescence and adulthood, a period of increased oil production that can support the growth and colonization of several types of bacteria. Increased oil production may also be caused by hormones, stress, and even diet.

[0045] Problems associated with acne include burning, itching, and pain, which can affect quality of life. Although there are treatments available to prevent and cure acne, people can be left with after-effects of acne, such as unsightly, permanent acne scars, which can be very visible. As acne affects people of all ages, from pre-teens to adults, acne scars can affect pre-teens as well as adults, leading to loss of confidence and low self-esteem.

[0046] There are various degrees of scarring that can occur as a result of acne. Scarring can include rolling atrophic, ice pick, boxcar, and other types of deep depressions in the skin. Acne scars vary in depth and severity. Previous treatments described include subcision, punch excision, laser resurfacing, dermabrasion, and chemical peels. In some cases, scarring can also cause discoloration of the skin.

[0047] Disclosed herein are methods for treating acne scars that may help reduce skin depressions, reduce skin discoloration, and / or even out skin contours.

[0048] Unless otherwise defined, 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.

[0049] As used in the context of describing the present invention (particularly in the context of the claims which follow), the terms "a," "an," "the," and similar reference words are intended to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0050] As used herein, "about" when referring to measurable values ​​is meant to encompass a variation of +20% or +10%, more preferably +5%, even more preferably +1%, and even more preferably +0.1% from the particular value.

[0051] As used herein, unless the context requires otherwise, the term "comprise" and variations of this term, such as "comprising," "comprises," and "comprised," are not intended to exclude additional additives, ingredients, integers, or steps.

[0052] As used herein, "scarring," "fibrosis," or "fibrotic response" may refer to the formation of fibrous (scar) tissue in response to injury or medical intervention.

[0053] As used herein, "scar" ("mark") may refer to a mark left on the skin or in body tissues by the development of fibrous connective tissue following healing of a wound, such as a blemish or acne. As described herein, scars may be the result of acne.

[0054] The term "tropoelastin" refers to the protein from which elastin is formed. Tropoelastin may be monomeric. Tropoelastin is generally not covalently or otherwise cross-linked. Tropoelastin may reversibly form coacervates. Tropoelastin is therefore distinct from elastin, as elastin consists of covalently cross-linked tropoelastin that cannot reversibly coacervate. Tropoelastin may be human tropoelastin. Tropoelastin may be synthetic, e.g., recombinantly expressed or otherwise derived, or may be naturally derived, such as from porcine aorta. As is generally known in the art, tropoelastin may exist in the form of various fragments. In each or some of any of the above or below embodiments, the compositions provided in the methods herein comprise monomeric tropoelastin. In each or some of any of the above or below embodiments, the monomeric tropoelastin is cross-linked to HA. In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin comprises a sequence set forth in any one of SEQ ID NOs: 1-15.

[0055] In some embodiments of each or any of the foregoing or following embodiments, the methods of the invention utilize the SHEL826A tropoelastin analogue (WO 1999 / 03886) for a variety of uses described herein, including for the compositions used in the described methods. The amino acid sequence of SHEL826A is as follows:

[0056] [ka]

[0057] In some embodiments of each or any of the foregoing or following embodiments, the isoform of tropoelastin is the SHEL isoform (WO 1994 / 14958; incorporated herein by reference in its entirety): [ka] or protease-resistant derivatives of SHEL or SHELδ26A isoforms (WO 2000 / 04043; incorporated herein by reference in its entirety). As described in WO 2000 / 04043, the protein sequences of tropoelastin described may have mutated sequences that result in reduced or eliminated susceptibility to proteolytic digestion. Without limitation, the amino acid sequence of tropoelastin may have reduced or eliminated susceptibility to, for example, serine proteases, thrombin, kallikrein, metalloproteases, gelatinase A, gelatinase B, serum proteins, trypsin, or elastase. In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin comprises the sequence set forth in SEQ ID NO: 3 (SHELδ26A isoform): [ka] In some embodiments, the tropoelastin comprises the sequence shown below (SHELδmod isoform): [ka]

[0058] Tropoelastin analogs generally have a sequence that is homologous to the human tropoelastin sequence. The percent identity between a pair of sequences can be calculated by the algorithm implemented in the BESTFIT computer program. Another algorithm for calculating sequence difference is adapted for rapid database searching and is implemented in the BLAST computer program. Compared to the human sequence, the tropoelastin polypeptide sequence may have about 60% identity at the amino acid level, 70% or more identity at the amino acid level, 80% or more identity at the amino acid level, 90% or more identity at the amino acid level, 95% or more identity at the amino acid level, 97% or more identity at the amino acid level, or greater than 99% identity at the amino acid level.

[0059] Conservative amino acid substitutions (e.g., Glu / Asp, Val / Ile, Ser / Thr, Arg / Lys, Gln / Asn) may also be considered when making comparisons, as the chemical similarity of these pairs of amino acid residues is often expected to result in functional equivalence. Amino acid substitutions that are expected to maintain the biological function of a polypeptide will maintain the chemical properties of the substituted amino acid residue, such as hydrophobicity, hydrophilicity, side chain charge, or size.

[0060] Recombinant forms of tropoelastin can be produced as shown in WO1999 / 03886. These sequences include: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] and [ka]

[0061] Tropoelastin is available in a form linked (e.g., covalently bonded) to another molecule, such as a biopolymer such as hyaluronic acid. In some embodiments, the tropoelastin is crosslinked to hyaluronic acid. In some embodiments, the composition comprises monomeric tropoelastin. In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin comprises the amino acid sequence set forth in any one of SEQ ID NOs: 1-15.

[0062] Where tropoelastin is linked to other molecules, it is particularly preferred that the linkage does not interfere with or limit the biological properties of the unlinked form of tropoelastin.

[0063] The purpose of linking tropoelastin to other molecules is typically to enable tropoelastin to be localized to an area and minimize the likelihood that tropoelastin will diffuse or otherwise move away from that area.

[0064] In some embodiments of each or any of the foregoing or following embodiments, the tropoelastin has a particular degree of purity in terms of the amount of tropoelastin in the composition relative to the amount of other proteins or molecules in the composition. In one embodiment, the tropoelastin is in the composition having a purity of at least 75%, preferably 85% purity, and more preferably greater than 90% or 95% purity. Fragments of tropoelastin, i.e., truncated forms of tropoelastin isoforms that arise unintentionally during the manufacture of tropoelastin, may be considered impurities in this context.

[0065] It will be further appreciated that in certain embodiments, 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, more than about 80% of the full length, more than about 90% of the full length, or more than about 95% of the full length of the relevant tropoelastin isoform.

[0066] The term "hyaluronic acid" or "HA" can include hyaluronic acid and any of its hyaluronate salts, such as sodium hyaluronate (sodium salt), potassium hyaluronate, magnesium hyaluronate, and calcium hyaluronate. Hyaluronic acid from a variety of sources can be used herein. For example, hyaluronic acid may be extracted from animal tissue, harvested as a product of bacterial fermentation, or produced in commercial quantities by bioprocessing techniques. In some embodiments, the compositions provided in the methods herein comprise monomeric tropoelastin. In some embodiments, the monomeric tropoelastin is crosslinked to HA. In each or some of the above or below embodiments, the tropoelastin comprises the sequence set forth in any one of SEQ ID NOS: 1-15. In each or some of the above or below embodiments, the tropoelastin comprises the sequence set forth in SEQ ID NOS: 1.

[0067] In some embodiments of each or any of the above or below embodiments, the composition comprises 1 to 100 mg / ml tropoelastin cross-linked with about 0.1% to about 10% derivatized hyaluronic acid (HA). In some embodiments of each or any of the above or below embodiments, the composition comprises 1 to 100 mg / ml tropoelastin cross-linked with about 0.4% to about 1% derivatized hyaluronic acid (HA). In some embodiments of each or any of the above or below embodiments, the tropoelastin is cross-linked with about 0.4%, about 0.5%, about 0.6%, about 0.8%, about 0.9%, or about 1% derivatized hyaluronic acid (HA). In some embodiments, the composition comprises 30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid. In some embodiments of each or any of the above or below embodiments, the composition further comprises a buffer, wherein the buffer is phosphate buffered saline. In some embodiments, the composition comprises derivatized or underivatized HA to control the extent to which the HA crosslinks with itself and / or with monomeric proteins. In some embodiments of each or any of the above or below embodiments, the derivatized HA crosslinks with TE. In some embodiments, the tropoelastin is monomeric. In some embodiments of each or any of the above or below embodiments, monomeric tropoelastin is released from the composition.

[0068] In some embodiments of each or any of the foregoing or following embodiments, the HA may comprise at least one linkable moiety, e.g., at least one cross-linkable moiety, such as a carboxyl group, a hydroxyl group, an amine, a thiol, an alcohol, an alkene, an alkyne, a cyano group, or an azide, and / or modifications, derivatives, or combinations thereof.

[0069] In some embodiments of each or any of the foregoing or following embodiments, the HA may comprise a spacer group, which is capable of linking to the same and / or a second molecule, such as a second biomolecule or biopolymer.

[0070] 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 may be used in the range of 25 to 7,500 disaccharide units or residues.

[0071] In some embodiments of each or any of the foregoing or following embodiments, the HA may be low molecular weight or high molecular weight HA. High molecular weight HA (also referred to as "HMW HA") as described herein generally has a molecular weight of at least about 1 million daltons (mw≧10 6 As used herein, low molecular weight HA (sometimes referred to herein as "LMW HA") generally refers to hyaluronic acid having a molecular weight of less than about 1.0 MDa.

[0072] In some embodiments of each or any of the foregoing or following embodiments, the 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.

[0073] The term "Fitzpatrick Scale" is given its plain and ordinary meaning in the context of this paper and may refer, without limitation, to a scientific classification of skin types. The Fitzpatrick Scale has several different types, from Type 1 to Type 6. This scale is used by dermatologists and cosmetic medical professionals to determine which treatments are best for different skin types. The scale was developed to measure how skin reacts to ultraviolet light, such as sun exposure. Furthermore, this knowledge can be used by cosmetic doctors and laser technicians before performing laser and other types of treatments. Type 1 - Typically has light ivory skin, burns and peels in every sun exposure, but does not tan. Type 2 - Has light, fair skin, burns easily and rarely tans in the sun. Type 3 - Typically has beige skin, burns occasionally in the sun, but can tan. Type 4 - Has olive or light brown skin, and does not freckle even in the sun. This person rarely burns and usually tans. Type 5 - Dark brown or black skin tone, rarely burns and always tans when exposed to the sun. Type 6 - Black, the darkest skin tone. This person never burns and tans easily when exposed to the sun. This useful scale can be used by dermatologists to measure specific skin reactions to the sun and more quickly identify potentially malignant sun spots. Cosmetic physicians can also use this scale to determine the effectiveness of treatments for different skin types. In each or some embodiments of any of the above or below embodiments, the method for treating acne scars can be used on individuals who may have any one of skin type classifications of Types 1 to 6 on the Fitzpatrick scale.

[0074] The term "intradermal implant" refers to an implant that may be placed below the epidermis. This may be, for example and without limitation, an area of ​​the skin such as the dermis, subdermal, or subcutaneous layer. In some embodiments of each or any of the above or below embodiments, the implant may be placed intradermally.

[0075] In some embodiments of each or any of the foregoing or following embodiments, the implant may be placed within the subcutaneous layer. This placement may be in addition to intradermal placement of the implant.

[0076] "Retrograde linear threading" is a method for placing an implant thread into target tissue. First, a needle is inserted. The implant is then deployed by simultaneously withdrawing the needle and depressing the syringe plunger.

[0077] "Cross-hatching" is a method of placing the implant threads in a pattern that creates a "mat" within the target tissue. As the needle is moved through the tissue to complete the linear threading in the cross-hatching arrangement, fibrous tissue in the needle's path or track is disrupted.

[0078] As used herein, "acne" refers to a skin condition that occurs when hair follicles become clogged with dead skin cells and oils from the skin. It may be characterized by blackheads or whiteheads, breakouts, and oily skin. In some cases, acne can lead to scarring. In some embodiments of each or any of the above or below embodiments, the patient in need thereof has not only acne but also acne scars.

[0079] "Acne scars" as described herein may be caused by inflammation in the skin. Acne scars may result from abnormal healing following inflammation caused by acne. "Atrophic acne scars" may be caused by loss of collagen from the healing response and are the most common cause of acne scars.

[0080] "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.

[0081] "Rolling atrophic acne scars" are depressed scars that heal below the normal layer of skin tissue.

[0082] "Boxcar scars" are a type of acne scar that can appear as depressions in the skin. They are defined by sharp edges that may run straight into the skin and are usually a different size than the acne lesion from which they originate. Boxcar scars are a type of atrophic acne scar.

[0083] "Hyperpigmentation" refers to darkening of the skin caused by increased melanin. Causes of hyperpigmentation include, but are not limited to, sunburn, inflammation, skin injury, and acne. Skin may respond to injury by overproduction of melanin produced by melanocytes. In some embodiments of each or any of the above or below embodiments, the scar contains a silvery coloration prior to administration of the composition. In some embodiments of each or any of the above or below embodiments, administration of the composition reduces the silvery coloration and increases the dark red or pink coloration of the scar. In some embodiments of each or any of the above or below embodiments, the method comprises administering L * by 1%, 5%, 10%, 15%, 20%, 25% or more than 50%, or by any amount defined by a range between any two of the aforementioned values; * by 1%, 5%, 10%, 15%, 20%, 25%, or greater than 50%, or by any amount defined by a range between any two of the aforementioned values. The methods described herein can also be used to treat acne scars and reduce skin discoloration caused by acne.

[0084] The "CIELAB color space" is used to define skin color and color changes that may occur after treatment of the skin with a composition containing tropoelastin. * a * b * The Lab color space (also known as the International Commission on Illumination and sometimes abbreviated as "Lab" color space) is a color space defined by the International Commission on Illumination (CIE) in 1976. Colors are represented by three values: L * is the brightness from black (0) to white (100), a * ranges from green (-) to red (+), b * ranges from blue (-) to yellow (+).

[0085] How to Treat Scars Provided herein are methods for treating acne scars (e.g., fibrous acne scars) in a patient in need thereof, including, for example, improving the color and / or appearance of the acne scar. The method may include administering a composition comprising tropoelastin to an area of ​​the patient's skin bearing a scar, including, for example, administering adjacent to the scar or directly or underneath the scar. In another embodiment, the composition comprising tropoelastin is also placed around the scar, such as underneath and around the scar's edges. The depth, affected area, and / or volume of the acne scar are reduced after administration of the composition (including compared to an otherwise identical composition lacking tropoelastin, such as a saline control). Additionally or alternatively, the disclosed methods may increase the volume and area of ​​skin contour elevation in the area of ​​the acne scar (including compared to an otherwise identical composition lacking tropoelastin, such as a saline control).

[0086] The method may further include disrupting fibrous elements of the acne scar, such as fibrous strands or elements (e.g., fibrous tissue) underlying the scar, with a needle to cut or release fibrous strands that deeply anchor the surface of the skin into a depression. In embodiments, disruption of the fibrous elements forms a dermal pocket beneath the acne scar, and the composition is administered into the dermal pocket. After disruption of the scar tissue, the dermal pocket may then be filled with the disclosed composition.

[0087] Scar disruption can be performed with an 18G-32G needle, such as an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle. Disruption of fibrous elements may be performed on scars such as, but not limited to, rolling atrophic scars, boxcar scars, or icepick scars. Administration involves injecting the composition into a dermal pocket. The composition is administered as an injection under the acne scar. Tropoelastin-containing compositions may also be placed around the scar, such as under the scar and / or around the scar's edges. Placing the tropoelastin-containing composition evenly or uniformly around the scar throughout the dermis surrounding the scar may ensure that the tropoelastin product is around the scarred area, allowing for more effective treatment. The composition is administered in a volume of about 10 μL to about 100 μL per injection. Injections are performed using a retrograde linear threading technique in a cross-hatched configuration to ensure that all fibrous strands within the acne scar are destroyed.

[0088] In some embodiments, disruption of fibrous strands is performed on atrophic scars.

[0089] The disruption of fibrous strands may be performed using needles, which anchor the skin to the underlying tissue and disrupt strands that may contribute to the collapse, to create a pocket to make room for placement of the tropoelastin composition under the acne scar where the fibrous strands are located. The tropoelastin composition will therefore be available to skin tissue cells immediately surrounding the scar so that they can grow into and around the product, which will remodel the fibrous elements of the scar.

[0090] The methods disclosed herein may result in remodeling of the fibrous elements surrounding the scar.

[0091] For basic or classic subcision, the needle can be as large as, for example, 18G, usually 21G or 23G, although 27G or 30G needles can also be used as they are small enough to allow for some degree of subcision but allow for creating a pocket or space around the wound and in the dermal layer for placement of the product.

[0092] The needle is inserted parallel to the skin at an angle of approximately 30°, with the needle including a bevel, the bevel facing upward. The needle is inserted multiple times to disrupt the fibrous strands and form a dermal pocket. As the needle is withdrawn from the dermal pocket, uniform pressure is applied to inject the composition. Administration of the composition is repeated, administering one or more bolus injections into the scar.

[0093] The methods disclosed herein can advantageously reduce the depth, affected surface area, and / or volume of acne scars. Indeed, both small and large depressions were shown to improve 168 days after administration of the composition (e.g., 30 mg / ml tropoelastin cross-linked with 0.5% dHA), along with increased smoothing and / or smoothing of skin contours. Surprisingly, this could also lead to remodeling and repair of mature atrophic scars, reducing the appearance of scars.

[0094] The methods disclosed herein can be used to improve the appearance of atrophic acne scars. As described herein, treatments may be administered on days 0, 28, and 56. Such treatments have surprisingly led to improvements in skin appearance and tone in several patients, including those with rolling, boxcar, or icepick acne scars. In some embodiments where the scar has a silvery tone, the methods disclosed herein reduce the silvery tone of the scar and / or increase the red or pink tone of the scar.

[0095] The compositions disclosed herein may contain from about 1 mg / ml to about 400 mg / ml of 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, 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, 440 mg / ml, 450 mg / ml, 460 mg / ml, 470 mg / ml, 480 mg / ml, 490 mg / ml, 500 mg / ml, 510 mg / ml, 520 mg / ml, 530 mg / ml, 540 mg / ml, 550 mg / ml, 560 mg / ml, 570 mg / ml, 580 mg / ml, 590 mg / ml, 6 The composition may contain tropoelastin (90mg / ml, 200mg / ml, 210mg / ml, 220mg / ml, 230mg / ml, 240mg / ml, 250mg / ml, 260mg / ml, 270mg / ml, 280mg / ml, 290mg / ml, 300mg / ml, 310mg / ml, 320mg / ml, 330mg / ml, 340mg / ml, 350mg / ml, 360mg / ml, 370mg / ml, 380mg / ml, 390mg / ml or 400mg / ml).

[0096] The compositions disclosed herein may also include hyaluronic acid (HA). In a further embodiment, the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid. In a further embodiment, the composition comprises about 30 mg / ml human tropoelastin (e.g., recombinant human tropoelastin) cross-linked with about 0.5% derivatized hyaluronic acid. The composition may further include a buffer, such as phosphate-buffered saline.

[0097] Also provided herein are pharmaceutical formulations that include the disclosed compositions that include tropoelastin.

[0098] The maximum volume of the compositions disclosed herein to be administered is about 100 μL to about 5 mL (eg, about 100 μL to about 500 μL per square cm).

[0099] In an embodiment, a patient in need thereof has a skin type on the Fitzpatrick Skin Type Scale of I, II, III, IV, V, or VI.

[0100] Scars treated by the methods disclosed herein may comprise any one of the grades 0, 1, 2, 3, 4, or 5 according to 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: none; no visible acne scars; 1: almost none; scars barely visible even from 2.5 meters; 2: mild; easily noticeable; less than half of the affected area (e.g., face, back, or chest); 3: moderate; more than half of the affected area (e.g., face, back, or chest); 4: severe; entire area involved; 5: very severe; entire area with significant atrophic or hypertrophic scarring.

[0101] In embodiments, the acne scar may be an ice pick scar, a boxcar scar, a rolling atrophic acne scar, a dilating rolling atrophic acne scar, or a hypertrophic scar. The scar may be on the face, back, or torso of the subject.

[0102] Acne scars treated by the methods disclosed herein can have a depth of about 0.1 mm to about 5 mm (e.g., a depth of 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 within a range between any two of the aforementioned values).

[0103] Acne scars treated by the methods disclosed herein are approximately 0.05 mm 2 ~approx. 400mm 2 The affected area may be 100 mm or less.

[0104] Acne scars treated by the methods disclosed herein are approximately 0.01 mm 3 ~2,000mm 3 volume (e.g., about 0.01 mm 3 , about 1mm 3Approximately 10mm 3 Approximately 20mm 3 Approximately 30mm 3 Approximately 40mm 3 Approximately 50mm 3 Approximately 60mm 3 Approximately 70mm 3 Approximately 80mm 3 Approximately 90mm 3 Approximately 100mm 3 Approximately 125mm 3 Approximately 150mm 3 Approximately 175mm 3 Approximately 200mm 3 Approximately 225mm 3 Approximately 250mm 3 Approximately 275mm 3 Approximately 300mm 3 Approximately 325mm 3 Approximately 350mm 3 Approximately 375mm 3 Approximately 400mm 3 Approximately 425mm 3 Approximately 450mm 3 Approximately 475mm 3 Approximately 500mm 3 Approximately 525mm 3 Approximately 550mm 3 Approximately 575mm 3 Approximately 600mm 3 Approximately 625mm 3 Approximately 650mm 3 Approximately 675mm 3 Approximately 700mm 3 Approximately 725mm 3 Approximately 750mm 3 Approximately 775V, approximately 800mm 3 Approximately 825mm 3 Approximately 850mm 3 Approximately 875mm 3 Approximately 900mm 3 Approximately 925mm 3 Approximately 950mm 3 975mm 3 Approximately 1,000 mm 3 Approximately 1,100 mm 3 Approximately 1,200 mm 3 Approximately 1,300 mm 3 Approximately 1,400 mm 3 Approximately 1,500 mm3 , approximately 1,600 mm 3 , approx. 1,700mm 3 , approximately 1,800 mm 3 , approximately 1,900 mm 3 , approximately 2,000 mm 3 or any volume in a range between any two of the aforementioned values).

[0105] Scars treated by the methods disclosed herein are categorized by CIE L * a * b * It is possible to reduce skin color as defined by color coordinates (e.g., L * (decreases by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or any amount defined by a range between any two of the aforementioned values). * by more than about 50%.

[0106] The methods disclosed herein can be used to reduce a protein by, for example, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or any amount defined by a range between any two of the aforementioned values. * In a preferred embodiment, the method disclosed herein further increases * by more than about 50%.

[0107] In embodiments, the scar comprises a color that differs from the patient's natural skin tone, and the compositions disclosed herein result in the color of the scar being reduced or lightened in color intensity such that the color of the scar blends with the patient's natural skin tone.

[0108] The compositions disclosed herein may improve the appearance of a scar (e.g., reduce the depth, volume, surface area, and / or color of a scar by, for example, 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 lacking tropoelastin or saline) 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 bearing a scar.

[0109] 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 is understood that modifications can be made in the procedures set forth without departing from the spirit of the invention. [Example]

[0110] Example 1 Evaluation of the clinical efficacy, durability, tissue compatibility, and safety of TE implants for the treatment of atrophic rolling acne scars Study design and randomization A study was conducted to test and evaluate the clinical efficacy, durability, tissue compatibility, and safety of a TE implant (30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid) after dermal grafting for the treatment of atrophic rolling acne scars.

[0111] Thirty-four patients, both male and female, aged 24 to 55 years, participated in a study of TE implants (30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid; hereafter referred to as "TE implants") for the treatment of acne scars. However, one of the 34 patients withdrew consent before treatment. Thirty-three patients underwent testing on an area of ​​skin approximately 2 cm x 2 cm around the temples and cheekbones on each side of the face. Each side contained two or more moderate to severe rolling, distending, atrophic acne scars. Treatment was performed on both sides of the face as follows: a) a tropoelastin intradermal (id) implant of 30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid ("TE implant"); and b) Saline control (intradermal (id) implant of isotonic saline) ("Saline control").

[0112] Each patient received a TE implant on either the right or left side of their face as their own control, and a saline control on the opposite side of their face. All patients received three treatments of TE implants and saline control (days 0, 28, and 56). At each treatment visit, the TE implant was administered on the same side as on day 0 (saline control was administered on the same side as on day 0). Each treatment consisted of multiple separate direct intradermal injections of approximately 25–50 μl of TE implant into the dermis of a 2 cm x 2 cm treatment area. To ensure disruption of fibrous bundles within the scar, injections were performed using a retrograde linear threading technique in a cross-hatched arrangement. Additionally, one or more bolus injections into the dermis of rolling atrophic acne scars may be administered to ensure optimal scar response. The maximum total volume of TE implant or saline control administered to each treatment area at each treatment time point was approximately 250 μl, not exceeding 500 μl.

[0113] Implant site examination was performed on day 14. All patients were followed for safety until day 168.

[0114] Patients were blinded to which side of the face or body the TE implant or saline control was implanted on. The investigators were not blinded. An independent clinical reviewer was blinded to the post-treatment images on day 168 compared with the pre-treatment images on day 0.

[0115] Test procedure and follow-up screening A screening period of up to 28 days preceded the initial implantation of the study device to determine patient eligibility and baseline parameters. During this period, written, signed, and dated informed consent was obtained from each patient. Pertinent medical histories were taken, a physical examination was performed, and vital signs were recorded. Additional testing included a 12-lead electrocardiogram, breath testing for alcohol use, urine drug testing (covering amphetamine, cocaine, opiates, cannabis, barbiturates, and benzodiazepine use), clinical examination of the intended treatment area, 2D and 3D photography of the intended treatment area, screening of the intended treatment area for the Global Acne Scar Severity Scale (Tan et al., 2010, incorporated herein by reference in its entirety), serum pregnancy testing, blood testing for APTT and PT clotting, blood and urine collection for laboratory safety testing, and blood testing for HepB, HepC, and HIV 1 and 2. Patients were then screened to determine their eligibility for the study, and eligible patients were asked to return to the clinic to begin the study (treatment visit 1, day 0).

[0116] Treatment with investigational devices On outpatient treatment 1 (day 0), eligible patients participated in their initial device implantation. Prior to implantation, the following procedures were performed: - Review of eligibility criteria - Record of changes in concomitant medications - Pre-transplant vital signs - Breath testing for alcohol use -Urine testing for drugs of abuse - Blood collection for anti-tropoelastin antibody analysis - Clinical examination of the area to be treated -Baseline 2D photography of the treatment area -Baseline 3D photography of the treatment area - Pre-treatment assessment of each treatment site by the investigator on the Global Scale for Acne Scar Assessment (Tan et al. 2010 (Journal of Cutaneous Medicine and Surgery, Vol 14, No 4 (July / August), 2010; incorporated herein by reference). - Topical application of EMLA cream (at least 60 minutes before TE or saline control implant). -Urine pregnancy test for women of childbearing potential.

[0117] After these procedures, patients had the test device (TE implant or saline control implant) implanted at the treatment site. Sixty minutes after the TE implant and saline control implant, the injection site was physically inspected for any reaction, and post-treatment 2D photographs were taken.

[0118] On day 14, the implant site was examined and the following procedures were performed by clinical staff: -Review of adverse event (AE) diary cards. - Clinical examination of the treatment area - 2D photography of the treatment area - 3D photography of the treatment area -Blood for serum anti-tropoelastin antibody analysis

[0119] The second visit for the therapeutic implant took place on day 28 ± 3, and the third visit for the therapeutic implant took place on day 56 ± 3. The same procedures as those performed on day 0 were followed.

[0120] Patients were provided with a diary to record any injection site reactions, such as redness, swelling, itching, or tenderness, between each study visit.

[0121] Observation Patients returned to the study site on day 84 ± 3 for follow-up procedures. The following activities were performed: - Recording changes in concomitant medications - Recording of adverse events and clinical examination of treatment areas -Physical examination and vital signs - Breathalyzer tests for alcohol -Urine testing for drugs of abuse - Blood collection for anti-tropoelastin antibody analysis - 2D photography of the treatment area - 3D photography of the treatment area -Urine pregnancy test for women of childbearing potential - Patient and investigator assessment of treatment sites on the Global Impression of Change scale and patient ACNE-Q scale

[0122] An additional follow-up visit was performed on day 168 ± 7, during which the following activities were performed: - Recording changes in concomitant medications - Recording of adverse events and clinical examination of treatment areas -Physical examination and vital signs -12-lead electrocardiogram - Breathalyzer tests for alcohol -Urine testing for drugs of abuse - Blood collection for anti-tropoelastin antibody analysis - 2D photography of the treatment area - 3D photography of the treatment area -Urine pregnancy test for women of childbearing potential - Laboratory safety testing of blood and urine at screening - Patient and investigator global impression of change at the treatment site and patient assessment of the ACNE-Q scale

[0123] At day 168, a blinded independent reviewer also assessed the treatment sites on the Global Impression of Change scale by comparing the day 168 and day 0 photographs.

[0124] Research objectives The primary objective of this study was to establish the clinical efficacy of TE implants in men and women with atrophic acne scars.

[0125] The secondary objectives of this study were to: -Evaluation of histological changes in atrophic acne scars treated with TE implants (30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid). - Confirmation of local and systemic AE profiles of TE implants.

[0126] Safety Goals The safety objective of this study was to evaluate the safety and tolerability of the TE implant.

[0127] Exploratory Objectives The following exploratory objectives were considered: -Analyzing the clinical significance of acne scars - Classification of acne scars analyzed by a blinded independent reviewer (BRPR) - Correlation of 3D camera data with Global Scale for Acne Scar Severity, ACNE-Q acne scar score, and BTPR treatment score

[0128] Participation criteria To be eligible for inclusion in this study, patients had to meet all of the following criteria: 1. Female / male patients with matching treatment areas of approximately 2cm x 2cm on either side of the face, on the temples or cheekbones, each containing at least two rolling atrophic acne scars that are distensible when stretched between the fingers and classified as moderate to severe on the Global Scale for Acne Scar Assessment. 2. Acne scars in areas of otherwise normal, healthy skin. 3. Age: 18 to 55 years old 4. Able to provide voluntary informed consent 5. Your overall condition is good. 6. Sexually active female patients will be of no childbearing potential (i.e., surgically sterilized or postmenopausal), abstain from sexual intercourse, or use a reliable method of contraception (e.g., hormonal contraceptives, condoms, IUDs) for at least 30 days prior to treatment and during the study, except for long-term follow-up. During the long-term follow-up period, female patients of childbearing potential will be encouraged, but not required, to use contraception. 7. Fitzpatrick skin type I, II, III, IV or V.

[0129] Exclusion criteria Patients who met any of the following criteria were excluded from the study. 1. Active acne lesions on the face (or back and torso for patients receiving treatment on those areas as well). 2. Current or previous treatment of atrophic acne scars with fillers, lasers, or deep chemical peels that penetrate the dermis, or any other medical or surgical treatment that, in the opinion of the investigator, would reasonably affect the results of the current clinical study. 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). 4. Female patients with a positive pregnancy test, women who do not agree to adequate contraception and pregnancy testing during the study period, or women who are planning to become pregnant during the study period. 5. Participation in a clinical trial of a pharmacological agent within 1 month prior to screening. 6.Subjects with clinically significant hematological or biochemical findings at screening. 7. Screening test positive for hepatitis B, hepatitis C, or HIV. 8. Patients with bleeding disorders, anticoagulants, thrombocytopenia, or clinically significant prolongation of APTT or PT. 9. Chronic use of aspirin, other nonsteroidal anti-inflammatory drugs, or other antiplatelet drugs. 10. History of keloid formation. 11. History of granulomatous or connective tissue disease. 12. Have used systemic corticosteroids within the past 12 weeks. 13.Currently using a topical retinoid or have used a topical retinoid within the past 8 weeks. 14.Diabetes mellitus or other metabolic disorder that, in the opinion of the investigator, may interfere with the patient's response to treatment. 15. Severe medical condition determined by the investigator to be likely to require systemic corticosteroid administration. 16. Pregnant or breastfeeding women. 17. Previous administration of tropoelastin. 18. History of anaphylactic or allergic reactions, including known hypersensitivity to lidocaine. 19. Have used an investigational drug in the planned implant site within the past 12 months.

[0130] treatment Thirty-three patients were screened, enrolled, randomized, and received at least one TE implant during the study. One patient (patient ID number: 001-120) was enrolled but withdrew consent before treatment on Day 0. Five patients did not receive implant treatment after the first 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 Set (FAS) and Safety Set (SS) populations for analysis. The 27 patients who received all three intended facial treatments formed Photo Analysis Set 1 (PAS1).

[0131] Demographic and baseline characteristics Patient ages ranged from 24 to 55 years, with a mean age of 38.0 years (SD = 8.71). Twenty-two patients were male and 11 were female. Sixteen patients were Caucasian, two were Mediterranean, 14 were Asian, and one was classified as "other." All 11 women were of childbearing potential; each had a negative pregnancy test performed at the screening visit. Four patients had Fitzpatrick skin type II, 13 had skin type III, 12 had skin type IV, and four had skin type V.

[0132] Assessment of scars using the global scale for assessing acne scars At the screening visit and on day 0, patients' acne scars were assessed using the following scale shown in Table 1 to ensure patients met the inclusion criteria for scar severity and to ensure an equivalent contralateral treatment site. This scale was developed by Tan et al. 2010 (Journal of Cutaneous Medicine and Surgery, Vol 14, No 4 (July / August) (incorporated herein by reference). Clinician grading of acne scars is shown in Figures 2A-2D. [Table 1]

[0133] As shown, six patients in the FAS (full analysis set) received either no or only one facial implant of TE implants and saline control, and the remaining 27 received three facial implants of TE implants and saline control.

[0134] For FAS, the mean volume injected per TE implant per visit was 0.33 mL. For comparison, the mean control volume injected per implant visit was 0.45 mL. The cumulative injected volume of TE across all implant visits ranged from 0.10 mL to 1.43 mL. The median cumulative injected volume of TE was 0.90 mL. The cumulative injected volume of the saline control across all implant visits ranged from 0.05 mL to 1.83 mL. The median cumulative injected volume of the saline control was 1.31 mL.

[0135] Main effect analysis For each of five scar lesions on both sides of the face, 3D photo analysis was used to evaluate various characteristics of the treatment area based on three images. One patient only had two images taken and recorded for that area, so the data for this patient were based on only those two images.

[0136] The characteristics of the lesions measured photographically were as follows: -Color L * -Color a * -color b * -Volume (mm 3 ) -Area (mm 2 ) - Depth (mm)

[0137] Volume, area, and depth were each assessed with a camera setting of 6.0 mm. The median of three images for each lesion characteristic was used to generate summary statistics for reporting and analysis. The sum of the median values ​​of the five lesions on each side of the face was then used as the summary score for patient / side analysis. An example is shown below. - Characteristics = volume; Lesion j score = median (Image 1 characteristics, Image 2 characteristics, Image 3 characteristics), where j = 1–5; Summary score = Lesion 1 score + Lesion 2 score + Lesion 3 score + Lesion 4 score + Lesion 5 score.

[0138] The change from baseline in the summary score for each side of the face was then calculated as the summary score for that side of the face on day 168 minus the summary score for that side of the face on day 0.

[0139] The difference in change from baseline to day 168 between the TE implant-treated and saline control-treated sides was also calculated.

[0140] Simple summary statistics for summary scores and change from baseline in summary scores are provided herein. In general, both TE implant-treated and saline control-treated sites showed evidence of improvement from baseline, with TE implant-treated sites showing greater improvement compared to saline control-treated sites.

[0141] Lesion dimensional data were also modeled using regression analysis. Change from baseline was used as the dependent variable, and treatment side (TE implant or saline control implant) and baseline lesion summary score were used as independent (explanatory) variables. Results are presented in Table 2 (PAS1) for change from baseline to Day 168. As per simple summary statistics, model results showed significant reductions in depth, volume, and area for both TE and saline control implants, with a consistently greater reduction from baseline in depth, volume, and area measurements for TE implant-treated sites compared to saline control-treated sites. [Table 2]

[0142] Whole Treatment Site (PAN) Analysis. In addition to measurements taken on individual lesions in the treatment site, the following characteristics were also assessed throughout the entire treatment site to determine the effect of the treatment implant on the overall contour deformation of the treatment site (hereafter referred to as PAN analysis):

[0143] Color imaging (as mentioned earlier, color changes across the treatment area reflect color changes at the individual lesion level). -Color L * (black to white scale) -Color a * (Green to red scale) -color b *(Blue to Yellow Scale)

[0144] Measurement of depression (using a 10.0 mm camera setting to detect contour changes across the treatment area - note that this setting does not measure individual acne scar lesions). - Depth of contour depression of the entire treatment area (mm) - Area of ​​depression in the contour of the entire treatment area (mm 2 ) - Volume of the contour depression of the entire treatment area (mm 3 )

[0145] Prominence measurement (using a 10.0 mm camera setting to detect contour changes across the treatment area - note that individual acne scar lesions are not measured at this setting). - Height of the raised area of ​​the treatment area (mm) - Area of ​​the raised area of ​​the treated area (mm 2 ) - Volume of the bump in the treatment area (mm 3 )

[0146] All camera measurements of the PAN-treated sites are described herein. Similar to individual lesion data, scores were provided based on three images for each characteristic. For the purpose of deriving a summary score for each patient / side, the median of the three image scores was used. The change from baseline for each patient / side was then calculated as the median score on Day 1 minus the median score on Day 1. Changes from baseline in the measured color characteristics may be affected by seasonal changes during the study period—these are facial treatment sites exposed to the sun, so skin color changes between winter and summer, and vice versa. Due to the design and mechanics of the 3D camera system (the camera hood is placed directly on the skin), images are taken under constant lighting, so lighting changes during photography do not affect the resulting images. To account for seasonal changes in skin color, the difference between the implant-treated and saline control-treated sites was calculated at both baseline and Day 168. This change in difference was used to calculate color L in the PAN-treated site analysis. * , color a * , color b *The following are brief summary statistics (for all patients with data in the safety set):

[0147] Similar to the lesion analysis, regression modeling was performed using change from baseline (or change difference from baseline) as the dependent variable and treatment side (TE implant or saline control) and baseline value (or difference in baseline value) as independent (explanatory) variables. The results of the analysis of change from baseline to day 168 are shown in the table below.

[0148] The results showed that the PAN-treated sites of the TE implants showed a significant improvement in L * The color scale from black to white was significantly reduced, and * A significant increase in the color scale from green to red is also seen. Additionally, a significant decrease in the volume and area of ​​larger contoured skin depressions and a corresponding increase in the volume and area of ​​protuberances across the PAN-treated sites is also seen for the TE implants compared to the saline control. [Table 3]

[0149] Assessment of scarring using the Global Impression of Change scale. A blinded independent reviewer (BTPR) was asked to blindly review the photographs taken on days 168 and 0 to assess the change in appearance of the treated areas on the Global Impression of Change (GIC) scale. In the BTPR, only the treated areas and the immediately surrounding areas of the face were photographically reviewed, patient details were not provided, and patients were randomized so that treatment patterns were not discernible. The scales used were as follows: [Table 4]

[0150] The results of the BRPR assessment of PAS1 are described herein and displayed in Figure 3 (BTPR assessment).

[0151] In the PAS1 population, BTPR noted that 70% of the treatment sites examined showed improvement at 168 days in the TE implant site and 41% of the treatment sites examined showed improvement in the saline control site.

[0152] Two further analyses were performed. The first compared the percentage of TE implant-treated sites where the BTPR noted any improvement with saline control-treated sites. The percentage difference was calculated and tested for equality. The results are shown in Table 5. The number of TE implant-treated sites where the blinded reviewer noted improvement was 26% higher than the saline control sites at Day 168 (p=0.033).

[0153] The second analysis used a paired t-test comparison of GIC scores (range -3 to +3) from the TE implant-treated side versus the saline control-treated side. These results are shown below in Table 6. The mean difference in GIC scores between tropoelastin implants in the saline control site, as assessed by BTPR at day 168, was 0.48 (95% CI -0.04 to 1.00, p=0.068). [Table 5]

[0154] GIC scores are measured from -3 to +3. Scores from +1 to +3 are grouped as improvement, and scores from -3 to 0 are grouped as worsening / no improvement. The table shows the number of patients rated as improved (n) over the total number rated (N). The difference is the percentage showing improvement in the TE implant sites minus the percentage showing improvement in the saline control sites. The p-value tests whether the percentage difference (TE implant minus saline control) is zero. [Table 6]

[0155] GIC scores are measured from -3 to +3. Scores from +1 to +3 are grouped as improvement, and scores from -3 to 0 are grouped as worsening / no improvement. This table summarizes the pairwise differences in GIC (TE implant - saline control). A positive difference indicates higher GIC in the TE implant sites compared to the saline control sites. The p-value tests whether the pairwise difference (TE implant - saline control) is zero.

[0156] AcneQ Survey At baseline (day 1) and days 84, 168, and 336, patients were asked to complete the Acne-Q questionnaire. This questionnaire consisted of 10 questions regarding the patient's perception of how bothersome their acne scars were. Each question was rated on a 4-point scale: 1 = not at all, 2 = a little, 3 = quite a lot, and 4 = extremely. The 10 questions asked were as follows: 1. How concerned are you about how your acne scars look from a distance? 2. Acne scars from the past How to cure Are you concerned about (more bumps and dents than you would like)? 3. How bothered are you by the size of your acne scars? 4. photograph How bothered are you by the appearance of acne scars in photos? 5. How bothersome are the amount of acne scars? 6. Acne scar color and skin color difference How concerned are you? 7. bright How bothered are you by how your acne scars look under the light? 8. mirror How concerned are you about the appearance of your acne scars in the mirror? 9. Acne scars How to stand out How concerned are you? 10. Acne scars Up close How concerned are you about your appearance?

[0157] The scale is described by Klassen et al. (Acne-Q (Copyright), A Guide for Researchers and Clinicians, Users Guide Version 1.0, September 2018, McMaster University; incorporated herein by reference).

[0158] Summary statistics for acne scar scale in the PAS1 population are presented herein.

[0159] The acne scar scale is scored so that a higher total represents a "better" result from the patient's perspective. At baseline, there was no statistically significant difference in patient scores on both sides of the face in the PAS1 population, with the TE implant-treated site scoring a mean score of 36.7 and the saline control-treated site scoring a mean score of 35.4. At day 168, patients in the PAS1 population scored the TE implant-treated site (57.4 points) higher than the saline control-treated site (52.0 points), and the difference, 5.370 points, was statistically significantly different from zero (p=0.014). By day 168, the change from baseline scores was statistically significantly higher than zero for both TE implant-treated and saline control-treated sites. Compared with the saline control sites, the change in the TE implant sites was generally greater on average, but the difference between the two treatment sites was not statistically significantly different from zero (in the PAS1 population, the difference was 4.074, p=0.120). [Table 7]

[0160] Higher Acne-Q scar scores represent a "better" response from the patient. A positive change from baseline in Acne-Q scar score indicates that the patient noted improvement based on the questionnaire items.

[0161] Secondary Objective Analysis Blinded independent reviewers were also asked to classify the scars as follows:

[0162] · Expansive rolling atrophic acne scars: The kind that disappear when stretched between your fingers.

[0163] Boxcar or boxcar-like scars: Classic boxcar scars and scars with characteristic fibrous edges that can be seen when stretched between the fingers.

[0164] · Ice pick scars: The classic ice pick acne scar.

[0165] Overall, at baseline, 61% and 69% of scars identified as clinically most significant by BTPR were classified as boxcar scars on the TE implant and saline control-treated sides, respectively. A lower proportion of scars identified as clinically most significant by BTPR, 37% and 26%, were classified as rolling scars on the TE implant and saline control sides, respectively. This may indicate that boxcar scars are more likely to present as the clinically most significant scar type. The remaining 2% on the TE implant side and 5% on the saline control-treated side were classified as icepick scars.

[0166] To analyze acne scars by scar type, we followed the same procedures used for the primary efficacy analysis. These analyses were limited to volume, depth, and impact measurements at the 6.0 mm camera horizontal setting. For each lesion identified by BTPR as one of the three most clinically relevant acne scars, the median of three images for each lesion characteristic was used. However, because patients may have different numbers of identified lesions, the average of the median values ​​of the identified lesions on each side of the face, rather than the sum, was used as the summary score for patient / side analysis.

[0167] The change from baseline for the summary score for each side of the face was then calculated as the summary score for that side of the face on day 168 minus the summary score for that side of the face on day 0.

[0168] The difference in change from baseline to Day 168 between the TE implant-treated and saline control-treated sides was also calculated. As previously mentioned, in some cases, BTPR confirmed the presence of one scar type and the absence of the other among the three most clinically relevant acne scars on one side of the face, so not all patients had data from both sides included in this analysis. This should be taken into consideration when interpreting differences in this analysis. Analyses were performed separately for boxcar and rolling lesions.

[0169] Simple summary statistics for summary scores and change from baseline in summary scores were provided for boxcar lesions (PAS1) and for rolling lesions (PAS1).

[0170] BTPR lesion data for boxcar and rolling acne scars were also modeled using regression analysis, similar to the primary efficacy analysis. Results are provided for change from baseline to day 168 at the 6.0 mm camera setting for PAS1 boxcar and PAS1 rolling scars. Model results showed that TE implant-treated sites consistently demonstrated greater reductions from baseline in depth, volume, and area measurements compared with saline control-treated sites.

[0171] The results are repeated below for the boxcar lesions in Table 8 (changes through day 168). For boxcar lesions identified by BTPR, findings were generally consistent with those from the primary efficacy analysis, although in this case there were more findings that were at or near statistical significance in the differences between TE implant and saline control treated sites, indicating a surprisingly large effect of TE compared to saline control on scars containing fibrous tissue. [Table 8]

[0172] Correlation of 3D camera data with a global measure of acne scar severity As part of the study, a 6-point Global Scale for Acne Scar Severity (GSASS or SCAR-S, Tan et al. 2010; incorporated herein by reference in its entirety) was administered by the investigator at screening and day 0 for both the left and right treatment areas of the face as a criterion for inclusion in the study. The scale was as shown in Table 9. [Table 9]

[0173] We assessed the correlation between GSASS scores on day 0 and photographic measurements of scar lesions obtained from Day 1 (Day 2) images. The majority of GSASS scores on day 0 were in category 3 or 4 (>90%) cases; therefore, the spread of data for this variable may not provide an adequate estimate of the true correlation between GSASS and serial photographic measurements.

[0174] A simple linear regression model was performed to estimate the slope of the linear relationship between photometric measurements (the dependent variable) and GSASS (the independent variable). The interpretation of the slope estimate is conventional: a one-unit change in GSASS (from category X to category X+1) results in a change in photometric measurements equal to the slope estimate. That is, as GSASS increases, so does the photometric measurement, and so the slope estimate was expected to be positive. This was indeed the case, as shown in Table 10 below. [Table 10]

[0175] The p-value tests whether the slope estimate is equal to zero and is equivalent to the p-value when the Pearson correlation coefficient is zero. R-squared is the square of the Pearson correlation coefficient.

[0176] In all cases, the slope estimates were positive and significant for each of the photomeasurements by camera setting, with the greatest statistical significance observed for volumetric and area measurements (at each camera setting tested). The highest R-squared values ​​were observed for area and volume at each camera software setting. This is not surprising, given that GSASS is an assessment of scar appearance from a distance. It should be noted that a simple linear regression model does not necessarily account for correlations among patients. That is, each patient provided both left and right values ​​for analysis, which may not be independent of each other, a fundamental assumption of ordinary least squares regression. As previously mentioned, the majority of the data on the x-axis (GSASS) clustered around two values, which may also affect the "generalizability" of the results.

[0177] Correlation of 3D camera data with pre- and post-treatment scores by a blinded independent reviewer.

[0178] A blinded third-party reviewer (BTPR) was asked to review the photographs taken on days 168 and 0 in a blinded manner to assess changes in the appearance of the treatment sites relative to the GIC scale. For the BTPR, only the treatment site and the immediately adjacent areas of the face were visible in the reviewed photographs. Patient details were not provided, and patients were randomly assigned, so treatment patterns could not be discerned. BTPRs were also asked to identify the three most clinically meaningful acne scars based on the baseline photographs provided, but no ranking was performed. As part of additional exploratory analyses, the correlation between the BTPR GIC score and the change from baseline in BTPR-identified lesions measured using 3D camera software was examined.

[0179] Similar to previous data exploration, a series of simple linear regression models were developed with the change from baseline in photometry as the dependent variable and the BTPR GIC score as the independent variable. Because higher GIC scores indicate improvement by visual inspection, the expected slope of the line would be negative, indicating that a per-unit increase in GIC score would result in a decrease in the measured parameter equal to the estimated slope. This was indeed the case for all photometry parameters at each camera setting investigated, as seen in Table 11 below. In all cases, p-values ​​were <0.05. The slope estimates may represent initial estimates of clinically relevant changes in volume, area, and depth. [Table 11]

[0180] The pP value tests whether the slope estimate is equal to zero and is equivalent to the p value when the Pearson correlation coefficient is zero. R-squared is the square of the Pearson correlation coefficient.

[0181] discussion

[0182] TE implants were found to reduce the volume, area, and depth of atrophic acne scars on treated faces based on 3D photographic analysis and improve their appearance based on feedback from blinded, independent reviewers.

[0183] 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.

[0184] 3D photographic assessment of the facial treatment areas was performed at baseline and day 168 using various camera software settings to measure the color, depth, area, and volume of acne lesions and the overall treatment area characteristics. The 3D photographic assessment included assessment of skin characteristics at the level encompassing individual acne scars (camera horizontal size setting 6.0 mm) and at the level of the overall skin contour (camera horizontal size setting 10.0 mm; smaller depressions were not detected).

[0185] Modeling of the results showed a statistically significant reduction in scar volume, area, and depth over time after treatment with the TE implant for the measurements analyzed (6.0 mm setting). Of note, the greatest differences for the TE implant versus the saline control were seen in camera software settings encompassing individual acne scar depressions and overall skin contour.

[0186] Facial acne lesions treated with TE implants showed the following changes in the PAS1 population: The reduction in acne lesion depth from baseline to Day 168 was -0.43 mm (95% CI -0.56 mm to -0.30 mm, p<0.001) using the 6.0 mm camera software setting, representing a 21% reduction from baseline. This reduction was statistically significantly greater than the reduction in acne lesions observed in the saline control sites (p=0.029). - Reduction in acne lesion area from baseline to day 168 was -19.10mm using a 6.0mm camera software setting 2 (95%CI:-23.76mm 2 ~-14.44mm 2 , p<0.001)—which represented a 24% reduction from baseline. This reduction was statistically significantly greater than the reduction in acne lesions observed in the saline control sites (p<0.001). - Reduction in acne lesion volume from baseline to day 168 was -6.83mm using the 6.0mm camera software setting 3 (95%CI:-8.91mm 3 ~-4.75mm 3, p<0.001)—which represented a 30% reduction from baseline. This reduction was statistically significantly greater than the reduction in acne lesions observed in the saline control sites (p=0.010).

[0187] Modeling also demonstrated statistically significant differences in color characteristics and overall skin contour improvement in favor of the TE implant sites. Color analysis was performed using the change from baseline difference between the TE implant-treated and saline control-treated sites due to seasonal effects on facial skin color. Key findings included: - Color L between TE implant sites and saline control sites from baseline to day 168 * The difference change in characteristics was -1.11 (95% CI: -1.69 to -0.54, p<0.001). - Color a between TE implant sites and saline control sites from baseline to day 168 * The difference in characteristic change was +0.79 (95% CI: +0.33 to +1.27, p=0.002). - Color between TE implant sites and saline control sites from baseline to day 168b * The difference in characteristics was -0.63 (95% CI: -0.92 to -0.34, p<0.001).

[0188] Modeling also demonstrated a statistically significant improvement in skin contour across the treatment area, as measured by the larger 10.0mm camera horizontal size setting. The key findings from the PAS1 set were: - Reduction in skin contour depression area at TE implant treatment sites from baseline to day 168: -50.12mm 3 (95%CI:-66.02mm 3 ~-34.21mm 3 , p<0.001, representing a 47% reduction from baseline). This was statistically significantly different from the reduction observed in the saline control-treated sites (p<0.001) (Table 3). - Reduction in contour depression volume at TE implant treatment sites from baseline to day 168: -22.15mm 3 (95%CI:-30.82mm 3 ~-13.48mm 3 , p<0.001, representing a 50% reduction from baseline). This reduction was statistically significantly greater than that observed in the saline control treatment sites (p=0.014) (Table 3). - Increase in skin contour ridge area at TE implant treatment sites from baseline to day 168: +53.75mm 2 (95%CI: +40.50mm 2 ~+67.01mm 2 , p<0.001, representing a 28% increase from baseline). This was statistically significantly different from the decrease observed in the saline control-treated sites (p<0.001) (Table 3). - Increase in skin contour volume at TE implant treatment sites from baseline to day 168: +23.82mm 3 (95%CI: +14.84mm 3 ~+32.80mm 3 , p<0.001, representing a 27% increase from baseline). This was statistically significantly different from the decrease observed in the saline control-treated sites (p<0.001) (Table 3). -Neither treatment had a significant effect on either contour depression depth or contour elevation height.

[0189] Additionally, there was a statistically significant difference (favoring the TE implant) between the TE implant-treated and saline control-treated sites using blinded independent reviewer-based assessment via the Global Impression of Change scale. In the PAS1 population, at 168 days: - BTPR showed improvement in 70% of TE implant-treated sites and 41% of saline control-treated sites (percentage difference, 30%, p=0.033) (Table 5). - The mean difference in GIC assessment by BTPR was 0.48 in favor of TE implants (p=0.068) (Table 6).

[0190] The acne scar scale of the ACNE-Q questionnaire was derived according to the authors' instructions (Klassen et al.; incorporated herein by reference). Based on patient responses, acne scar scale scores were similar for both the left and right sides of the face at baseline. By day 168, the acne scar scale scores for the TE implant-treated side of the face were significantly higher than the scores for the saline control side (difference = 5.438 points, p = 0.005). The change from baseline in acne scar scale was also calculated. At day 168, both the TE implant and saline control sites showed significant improvement from baseline values ​​(p < 0.001 for both sides). Note that the ACNE-Q questionnaire has not been validated for change from baseline at this time.

[0191] To assess the clinical significance of measurements obtained from the 3D camera data, the correlation of acne scar size measured by the 3D camera was assessed against the GSASS and Acne‐Q scar scales on day 0, and the change in acne scar size measured by the 3D camera was assessed against the GIC score provided by the BTPR.

[0192] Analysis of the relationship of the GSASS assessment performed on day 0 to the depth, volume, and area measurements performed on day 0 using the 6.0 mm camera setting revealed that all three measurements were correlated as follows: - Each GSASS unit increase was associated with a 0.36 mm increase in scar depth across the five measured lesions (95% CI: 0.08 mm to 0.64 mm, p=0.014) (Table 10). - When the GSASS advances by one unit, the scar area of ​​the five measured lesions increases by 25.83 mm 2 increased (95%CI: 9.68mm 2 ~41.98mm 2 , p=0.002) (Table 10). - With one GSASS unit advance, the scar volume of the five measured lesions was 10.11 mm 3 increased (95% CI: 3.44 mm 3 ~16.78mm 3, p=0.004) (Table 10).

[0193] The above correlations between acne scar measurements obtained from the 3D camera and all three clinical assessment tools clearly demonstrate that the 3D camera measurements are clinically meaningful, and such correlations may be useful in calculating sample sizes for future clinical studies. This data can also be used to derive the average step-up in GIC. Using acne scar area measurements with the camera 6.0 setting, the following changes were observed: Day 168: The TE implant group had a mean decrease of -19.0 mm from baseline. 2 This was a decrease of approximately 3.7 steps (step value -5.2 mm) for the GIC. 2 The saline control group had a decrease of -4.2 mm from baseline. 2 This represents a change in GIC of approximately 0.8 steps.

[0194] Analysis showed that measurements of acne scar area showed clinically meaningful differences between TE implant-treated and saline-treated areas when the camera was set to 6.0 mm. Volume measurements performed at the 6.0 mm setting also showed clinically meaningful differences between TE implant-treated and saline control-treated areas.

[0195] Seventy percent of BTPR assessments showed improvement in the TE implant-treated sites and 41% in the saline control-treated sites (percentage difference, 31%, p=0.012).

[0196] Based on patient responses, acne scar scale scores from the ACNE-Q questionnaire were similar for both the left and right sides of the face at baseline. By day 168, the acne scar scale scores on the TE implant-treated side of the face were significantly higher than those on the saline control side (difference = 5.438 points, p = 0.005). Changes from baseline in acne scar scale scores were also calculated. Both the TE implant and saline control sites showed significant improvements from baseline (p < 0.001 for both sides).

[0197] Example 2 : Use of TE implants for acne scars For the treatment of acne scars, a composition containing rH-tropoelastin cross-linked with derivatized hyaluronic acid to form a biomaterial matrix (30 mg / ml TE cross-linked with 0.5% dHA) was used. This composition was shown to support the repair of atrophic scars during the remodeling and maturation stages and reduce the appearance of scars.

[0198] Patients were treated in a 2cm x 2cm area containing at least two rolling atrophic scars. The composition was administered at a total volume of 0.5 ml per treatment on days 0, 28, and 56. Follow-up visits were then conducted on days 7, 84, and 168. The study involved men and women aged 18 to 55. Efficacy assessment was performed using an Antera® 3D camera.

[0199] Patients also served as their own controls using a saline control on another area of ​​skin that did not receive the TE composition.

[0200] Before treatment, patients reviewed their scars and performed a self-assessment of their acne scars. After treatment, patients also rated the appearance of their acne scars. A scar assessment score was obtained on day 0 for comparison at the end of treatment.

[0201] A Miravex Antera 3D camera system was used to allow analysis of depression, elevation, and color across the treatment area and on a lesion-by-lesion basis. Treatment areas were evaluated at a pre-screening visit to ensure that equivalent treatment areas could be selected bilaterally.

[0202] As shown in the tests, this composition produced surprising results in a reduction in the depth and size of acne scars, as well as an improvement in skin tone. For example, patients noticed a smoother, less dimpled, improved texture, and improved scar margins.

[0203] The remarkable results, measured with a 3D camera, included a 24% reduction in acne scar area by day 168 and a 21% reduction by day 336 compared to the control. The TE implant also achieved a 45-50% reduction in contour depression volume and improved skin color by day 336 after treatment compared to the control.

[0204] Regarding skin tone, the L of the TE implant-treated areas compared to the control-treated areas at both 168 and 336 days was significantly higher. * There was a significant decrease in the black to white color scale, with a decrease in the a of the TE implant-treated sites compared to the control-treated sites at both 168 and 336 days. * There was a significant increase in the green to red color scale.

[0205] Further Considerations In some embodiments, any claim herein may depend on any one of the independent claims or any one of the dependent claims. In one aspect, any claim (e.g., a dependent claim or an independent claim) may be combined with any one or more other claims (e.g., a dependent claim or an independent claim). In one aspect, a claim may include some or all of the terms (e.g., steps, operations, means, or components) recited in a claim, sentence, phrase, or paragraph. In one aspect, a claim may include some or all of the terms recited in one or more claims, sentences, phrases, or paragraphs. In one aspect, some of the terms in each claim, sentence, phrase, or paragraph may be deleted. In one aspect, additional terms or elements may be added to a claim, sentence, phrase, or paragraph. In one aspect, the subject technology may be implemented without utilizing some of the components, elements, functions, or operations described herein. In one aspect, the subject technology may be implemented using additional components, elements, functions, or operations.

[0206] The subject technology is exemplified, for example, according to various aspects described below. Various examples of aspects of the subject technology are described as numbered clauses (1, 2, 3, etc.) for convenience. These are provided as examples and are not intended to limit the subject technology. Note that any of the dependent claims can be combined in any combination and placed within a respective independent claim, e.g., clause 1 or clause 20. Other clauses can be presented in a similar manner.

[0207] Section 1. A method of treating an area of ​​skin bearing acne scars to improve the color and / or appearance and / or reduce the depth, area, and / or volume of acne scars in an area of ​​skin of a patient in need of treatment, comprising administering a composition comprising tropoelastin to the area of ​​skin bearing acne scars.

[0208] Item 2. The method of item 1, wherein the composition comprises from about 1 mg / ml to about 400 mg / ml of tropoelastin.

[0209] Section 3 The composition is 1mg / ml, 5mg / ml, 10mg / ml, 20mg / ml, 30mg / ml, 40mg / ml, 50mg / ml, 60mg / ml, 70mg / ml, 80mg / ml, 90mg / ml, 100mg / ml, 110mg / ml , 120mg / ml, 130mg / ml, 140mg / ml, 150mg / ml, 160mg / ml, 170mg / ml, 180mg / ml, 190mg / ml, 200mg / ml, 210mg / ml, 220mg / ml, 230mg / ml, 3. The method of claim 1 or 2, comprising 240mg / ml, 250mg / ml, 260mg / ml, 270mg / ml, 280mg / ml, 290mg / ml, 300mg / ml, 310mg / ml, 320mg / ml, 330mg / ml, 340mg / ml, 350mg / ml, 360mg / ml, 370mg / ml, 380mg / ml, 390mg / ml or 400mg / ml tropoelastin, or any amount of tropoelastin between the ranges defined by any two of the foregoing values.

[0210] Item 4. The method of any one of items 1 to 3, wherein the composition comprises from about 1 mg / ml to about 300 mg / ml of tropoelastin.

[0211] Item 5. The method of any one of items 1 to 4, wherein the composition comprises from about 1 mg / ml to about 250 mg / ml of tropoelastin.

[0212] Item 6. The method of any one of items 1 to 5, wherein the composition comprises from about 1 mg / ml to about 200 mg / ml of tropoelastin.

[0213] Item 7. The method of any one of items 1 to 6, wherein the composition comprises from about 1 mg / ml to about 150 mg / ml of tropoelastin.

[0214] Item 8. The method of any one of items 1 to 7, wherein the composition comprises from about 1 mg / ml to about 100 mg / ml of tropoelastin.

[0215] Item 9. The method of any one of items 1 to 8, wherein the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid.

[0216] Item 10. The method of any one of items 1 to 9, wherein the composition comprises about 1 to about 100 mg / ml tropoelastin crosslinked with about 0.4% to about 1% derivatized hyaluronic acid (HA).

[0217] Clause 11. The method of any one of clauses 1-9, wherein the composition comprises 30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid.

[0218] Item 12. The method of any one of items 1-11, wherein the composition further comprises phosphate buffered saline.

[0219] Clause 13. The method of any one of clauses 1 to 12, wherein the composition comprising tropoelastin is administered around the scar, such as underneath the scar and / or around the edges of the scar.

[0220] Clause 14. The method of any one of clauses 1 to 13, wherein the acne scar is subclassified as an ice pick scar, a boxcar scar, or a rolling atrophic scar.

[0221] Item 15. The method according to any one of items 1 to 14, wherein the acne scar is an ice pick scar.

[0222] Item 16. The method according to any one of items 1 to 14, wherein the acne scar is a box scar.

[0223] Item 17. The method according to any one of items 1 to 14, wherein the scar is a rolling atrophic acne scar.

[0224] Item 18. The method of any one of items 1 to 14, wherein the scar is a hypertrophic scar.

[0225] Clause 19. The method of any one of clauses 1 to 18, wherein the scar comprises fibrous tissue around or below the edge of the scar.

[0226] Item 20: The method according to any one of items 1 to 19, wherein the acne scar has a depth of about 0.1 mm to about 5 mm.

[0227] Section 21: Acne scars are approximately 0.05 mm 2 ~approx. 400mm 2 21. The method according to any one of items 1 to 20, wherein the affected area is 100% or more.

[0228] Section 22: Acne scars are approximately 0.01 mm 3 ~2,000mm 3 22. The method according to any one of items 1 to 21, wherein the volume of the mixture is

[0229] Clause 23. The method of any one of clauses 1-22, wherein the method further comprises the step of disrupting fibrous strands beneath the acne scar.

[0230] Clause 24. The method of clause 23, wherein the destroying step occurs prior to administration of the composition comprising tropoelastin to a patient in need thereof.

[0231] Clause 25: The method of clause 23 or 24, wherein the step of disrupting the fibrous strands forms a dermal pocket beneath the acne scar.

[0232] Clause 26. The method of clause 25, wherein the disrupting step is performed with an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle.

[0233] Clause 27. The method of clause 25 or 26, wherein administering comprises injecting the composition into a dermal pocket.

[0234] Clause 28. The method of any one of clauses 1-27, wherein the composition is administered as an injection beneath the acne scar.

[0235] Clause 29. The method of any one of clauses 1-13, wherein the composition is administered in a volume of about 10 μL to about 100 μL per implant / injection.

[0236] Clause 30: The method of any one of clauses 28-29, wherein the injection is given using a retrograde linear threading technique in a cross-hatched configuration to disrupt fibrous strands within the acne scar.

[0237] 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 degrees parallel to the skin, the needle including a bevel, and the bevel facing upward.

[0238] Clause 32. The method of clause 31, wherein needles are inserted multiple times into an area of ​​skin having acne scars to break down fibrous strands and form dermal pockets.

[0239] Clause 33. The method of clause 32, wherein uniform pressure is applied to inject the composition as the needle is withdrawn from the dermal pocket.

[0240] Clause 34. The method of any one of clauses 1 to 33, wherein the administration of the composition is repeated, administering one or more bolus injections into the scar.

[0241] Item 35. The method of any one of items 1 to 34, wherein the maximum volume of the composition administered is about 100 μL to about 5 mL.

[0242] Item 36. The method of any one of items 1 to 35, wherein the maximum volume of the composition administered is about 100 μL to about 500 μL per square centimeter.

[0243] Clause 37. The method of any one of clauses 1 to 35, wherein the patient in need thereof has a skin type on the Fitzpatrick Skin Type Scale of I, II, III, IV, V or VI.

[0244] Clause 38. The method of any one of clauses 1 to 37, wherein the scar comprises a grade of 1, 2, 3, 4 or 5.

[0245] Section 39: If the skin is CIE L * a * b * and skin color defined by color coordinates, * Item 39. The method according to any one of items 1 to 38, wherein the method reduces

[0246] Section 40: The method is * 40. The method of claim 39, wherein the amount of α-heptane monophosphate (α-HT) is reduced by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or more than about 50%, or by any amount defined by a range between any two of the aforementioned values.

[0247] Section 41a * 41. The method according to claim 39 or 40, further increasing

[0248] Section 42a * by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or by any amount defined by a range between any two of the foregoing values.

[0249] Clause 43. The method of any one of clauses 1-42, wherein the scar comprises a silvery coloration before administering the composition.

[0250] Clause 44. The method of clause 43, wherein administering the composition reduces silvery staining and increases red or pink staining of the scar.

[0251] Section 45 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; *by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or by more than about 50%, or by any amount defined by a range between any two of the aforementioned values.

[0252] Clause 46. A method according to any one of clauses 1 to 45, wherein the scar comprises a colour which differs from the patient's natural skin tone, and wherein administering the composition causes the colour of the scar to be reduced or faded in intensity such that the colour of the scar integrates with the patient's natural skin tone.

[0253] Clause 47: The method of any one of clauses 1 to 46, wherein the acne scar is a scar on the face, back, or torso.

[0254] Item 48. The method of any one of items 1 to 47, wherein the depth, area and / or volume of acne scars is reduced after administration of the composition.

[0255] Clause 49. The method of any one of clauses 1 to 48, wherein the treatment supports skin remodeling and repair of atrophic scars during the maturation stage, thereby reducing the appearance of acne scars.

[0256] Clause 50: The method of any one of clauses 1-49, wherein the treatment reduces 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 described by any two of the foregoing values.

[0257] Clause 51. The method of any one of clauses 1-50, wherein treatment reduces acne scar volume 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 described by any two of the foregoing values.

[0258] Clause 52: The method of any one of clauses 1-51, wherein the treatment reduces acne scar depth 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 described by any two of the foregoing values.

[0259] Clause 53: The method of any one of clauses 1-52, wherein the treatment reduces the volume and area of ​​skin contour depressions in areas of skin having 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 described by any two of the foregoing values.

[0260] Clause 54. The method of any one of clauses 1 to 53, wherein the treatment further improves the skin color of acne scars.

[0261] Clause 55: The method of any one of clauses 1-54, wherein the treatment increases the volume and area of ​​skin contour elevation in areas of skin having 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 described by any two of the foregoing values.

[0262] Clause 56. The method of any one of clauses 53 to 55, wherein the treatment flattens the skin contour in areas of skin having acne scars.

[0263] Item 57. The effect of the treatment on L in areas of skin with acne scars compared to a control treatment. * 57. The method of any one of paragraphs 1 to 56, wherein the black to white scale is reduced.

[0264] Clause 58: A method of restoring the contours of skin affected by acne scars in a subject in need thereof, comprising administering a composition comprising tropoelastin to an area of ​​skin having the contours of skin affected by acne scars.

[0265] Clause 59. The method of clause 58, wherein the composition comprises from about 1 mg / ml to about 400 mg / ml of tropoelastin.

[0266] Section 60 The composition is 1mg / ml, 5mg / ml, 10mg / ml, 20mg / ml, 30mg / ml, 40mg / ml, 50mg / ml, 60mg / ml, 70mg / ml, 80mg / ml, 90mg / ml, 100mg / ml, 110mg / ml, 120mg / ml, 130mg / ml, 140mg / ml, 150mg / ml, 160mg / ml, 170mg / ml, 180mg / ml, 190mg / ml, 200mg / ml, 210mg / ml, 220mg / ml, 230mg / ml, 2 50. The method of claim 58 or 59, comprising 40mg / ml, 250mg / ml, 260mg / ml, 270mg / ml, 280mg / ml, 290mg / ml, 300mg / ml, 310mg / ml, 320mg / ml, 330mg / ml, 340mg / ml, 350mg / ml, 360mg / ml, 370mg / ml, 380mg / ml, 390mg / ml or 400mg / ml of tropoelastin, or any amount between the ranges defined by any two of the foregoing values.

[0267] Clause 61. The method of any one of clauses 58-60, wherein the composition comprises from about 1 mg / ml to about 300 mg / ml of tropoelastin.

[0268] Clause 62: The method of any one of clauses 58-61, wherein the composition comprises from about 1 mg / ml to about 250 mg / ml of tropoelastin.

[0269] Clause 63: The method of any one of clauses 58-62, wherein the composition comprises from about 1 mg / ml to about 200 mg / ml of tropoelastin.

[0270] Clause 64. The method of any one of clauses 58-63, wherein the composition comprises from about 1 mg / ml to about 150 mg / ml of tropoelastin.

[0271] Clause 65: The method of any one of clauses 58-64, wherein the composition comprises from about 1 mg / ml to about 100 mg / ml of tropoelastin.

[0272] Clause 66. The method of any one of clauses 58-65, wherein the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid.

[0273] Clause 67. The method of any one of clauses 58-66, wherein the composition comprises about 1 to about 100 mg / ml tropoelastin crosslinked with about 0.4% to about 1% derivatized hyaluronic acid (HA).

[0274] Clause 68. The method of any one of clauses 58-67, wherein the composition comprises 30 mg / ml recombinant human tropoelastin cross-linked with 0.5% derivatized hyaluronic acid.

[0275] Clause 69. The method of any one of clauses 58 to 68, wherein the composition is administered around the scar, such as underneath the scar and / or around the edge of the scar.

[0276] The foregoing description is provided to enable one skilled in the art to practice the various configurations described herein. While the subject technology has been particularly described with reference to various diagrams and configurations, it should be understood that these are for purposes of illustration only and should not be taken as limiting the scope of the subject technology.

[0277] There may be many other ways to implement the subject technology. The various functions and elements described herein may be arranged differently than shown without departing from the scope of the subject technology. Various modifications to these configurations will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other configurations. Thus, those skilled in the art will be able to make numerous changes and modifications to the subject technology without departing from the scope of the subject technology.

[0278] It is understood that the specific order or hierarchy of steps in the disclosed processes is an illustration of example approaches. Based on design preferences, it is understood that the specific order or hierarchy of steps in the processes may be rearranged. Some of the steps may even be performed simultaneously. The accompanying method claims present elements of the various steps in a sample order, and are not intended to be limited to the specific order or hierarchy presented.

[0279] As used herein, the phrase "at least one" preceding a list of items, with the term "and" or "or" separating any of the items, modifies the list as a whole, not each member (i.e., each item) of the list. The phrase "at least one" does not require the selection of at least one of each listed item; rather, the phrase allows for the inclusion of at least one of any one of the items, and / or at least one of any combination of the items, and / or at least one of each of the items. By way of example, the phrases "at least one of A, B, and C" or "at least one of A, B, or C" refer, respectively, to A only, B only, or C only; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0280] Terms such as "upper," "lower," "front," and "rear," as used in this disclosure, should be understood to refer to any frame of reference, rather than the typical gravity frame of reference. Thus, upper, lower, front, and rear surfaces may extend upward, downward, diagonally, or horizontally in the gravity frame.

[0281] Furthermore, to the extent that terms such as "include," "have," and the like are used in this specification or the claims, such terms are intended to be inclusive in the same manner as "comprise" is interpreted when it is employed as a transitional word in a claim.

[0282] The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments.

[0283] Reference to an element in the singular is intended to mean "one or more," not "one and only one," unless otherwise specified. Masculine pronouns (e.g., he) include feminine and neuter pronouns (e.g., she and its), and vice versa. The term "some" means one or more. Underlined and / or italicized headings and subheadings are used for convenience only and do not limit the subject technology, and should not be referenced in connection with interpreting the description of the subject technology. All structural and functional equivalents to the elements of the various configurations described throughout this disclosure that are known or later become known to those skilled in the art are expressly incorporated herein by reference and are intended to be encompassed by the subject technology. Furthermore, nothing disclosed herein is intended to be dedicated to the public, regardless of whether such disclosure is expressly stated in the description above. [Sequence List Free Text]

[0284] SEQ ID NO: 1 <223> SHELdelta26A SEQ ID NO: 2 <223> SHEL isoforms SEQ ID NO: 3 <223> SHELdelta26A isoform SEQ ID NO:4 <223> SHEL deltamod isoforms SEQ ID NOs: 5 to 15 <223> Synthetic sequences

Claims

1. 1. A method of treating an area of ​​skin bearing acne scars to improve the color and / or appearance and / or reduce the depth, area and / or volume of acne scars in an area of ​​skin in a patient in need of treatment, comprising administering a composition comprising tropoelastin to the area of ​​skin bearing acne scars.

2. 10. The method of claim 1, wherein the composition comprises from about 1 mg / ml to about 400 mg / ml of tropoelastin.

3. 3. The method of any one of claims 1-2, wherein the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid.

4. 4. The method of any one of claims 1 to 3, wherein the composition comprises from about 1 to about 100 mg / ml tropoelastin crosslinked with from about 0.4% to about 1% derivatized hyaluronic acid (HA).

5. A method according to any preceding claim, wherein the composition comprising tropoelastin is administered around the scar, preferably underneath the scar and / or around the scar margin.

6. 6. The method of any one of claims 1 to 5, wherein the acne scar is subclassified as an ice pick scar, a boxcar scar, or a rolling atrophic scar.

7. The method of any one of claims 1 to 6, wherein the acne scar has a depth of about 0.1 mm to about 5 mm.

8. Acne scars are approximately 0.05 mm ２ ~ approx. 400 mm ２ The method according to any one of claims 1 to 7, wherein the affected area is

9. Acne scars are approximately 0.01 mm ３ ~2,000mm ３ The method according to any one of claims 1 to 8, wherein the volume of the mixture is

10. 10. The method of any one of claims 1 to 9, further comprising the step of disrupting fibrous strands underlying acne scars.

11. 11. The method of claim 10, wherein the destroying step occurs prior to administration of the composition comprising tropoelastin to a patient in need thereof.

12. 12. The method of claim 10 or 11, wherein the step of disrupting the fibrous strands forms a dermal pocket beneath the acne scar.

13. 11. The method of claim 10, wherein the disrupting step is performed with an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle.

14. 13. The method of claim 11 or 12, wherein the administering step comprises injecting the composition into a dermal pocket.

15. 15. The method of any one of claims 1 to 14, wherein the composition is administered as an injection beneath the acne scar.

16. 16. The method of any one of claims 1 to 15, wherein the composition is administered in a volume of about 10 μL to about 100 μL per implant / injection.

17. 17. A method according to any preceding claim, wherein the administration of the composition is repeated, administering one or more bolus injections into the scar.

18. 18. The method of any one of claims 1 to 17, wherein the maximum volume of the composition administered is from about 100 μL to about 5 mL.

19. The method of any one of claims 1 to 18, wherein the patient in need thereof has a skin type on the Fitzpatrick skin type scale of I, II, III, IV, V or VI.

20. 20. The method of any one of claims 1 to 19, wherein the scar comprises a grade of 1, 2, 3, 4 or 5.

21. 21. The method of any one of claims 1 to 20, wherein after administration of the composition, the depth, area and / or volume of acne scars is reduced.

22. 22. The method of any one of claims 1 to 21, wherein the treatment supports skin remodeling and repair of atrophic scars during the maturation stage to reduce the appearance of acne scars.

23. 23. The method of any one of claims 1 to 22, wherein treatment reduces acne scar area by at least about 10%.

24. 24. The method of any one of claims 1 to 23, wherein treatment reduces acne scar volume by at least about 10%.

25. 25. The method of any one of claims 1 to 24, wherein treatment reduces acne scar depth by at least about 10%.

26. 26. The method of any one of claims 1 to 25, wherein the treatment reduces the volume and area of ​​skin contour depressions in areas of skin having acne scars by at least about 10%.

27. 27. The method of any one of claims 1 to 26, wherein the treatment further improves the skin color of acne scars.

28. 28. The method of any one of claims 1 to 27, wherein the treatment increases the volume and area of ​​skin contour elevations in areas of skin having acne scars by at least about 10%.

29. 1. A method for restoring skin contours affected by acne scars in a subject in need thereof, comprising administering a composition comprising tropoelastin to an area of ​​skin having skin contours affected by acne scars.

30. 30. The method of claim 29, wherein the composition comprises from about 1 mg / ml to about 400 mg / ml of tropoelastin.

31. 31. The method of any one of claims 29-30, wherein the tropoelastin is cross-linked with about 0.1% to about 10% derivatized hyaluronic acid.

32. 32. The method of any one of claims 29 to 31, wherein the composition comprises from about 1 to about 100 mg / ml tropoelastin crosslinked with from about 0.4% to about 1% derivatized hyaluronic acid (HA).

33. A method according to any one of claims 29 to 32, wherein the composition is administered around the scar, such as underneath the scar and / or around the edges of the scar.

Images