Treatments for acne scarring

Abstract

The present disclosure provides methods for treating acne scars to improve the color and / or appearance of the acne scars, and / or to reduce the depth, affected area, and / or volume of the acne scars. Such methods can include applying a composition comprising tropoelastin to an area of skin having an acne scar, and optionally disrupting the fiber bundles underlying the acne scar and applying the composition beneath the acne scar.

Description

Technical Field

[0001] This disclosure relates to a method for improving the appearance of acne scars, such as pitted, icepick, roller, and van-shaped acne scars, using a composition containing elastin. Background Technology

[0002] References to any prior art in this specification are not an admission or implication that such prior art forms part of common general knowledge within any jurisdiction, or that such prior art may reasonably be contemplated by a person skilled in the art as relevant and / or combined with other parts of the prior art.

[0003] Acne scars form when skin pores become clogged with excess oil, dead skin cells, and bacteria, leading to infected scabs from these blockages. Swelling pores can cause the walls of small pores to crack. Superficial lesions are usually small and heal quickly. However, when deep cracks exist within the pore walls, infected material can spill into the surrounding tissue, causing deeper damage. The skin may then attempt to repair these lesions by forming new collagen fibers. In some cases, visible scars may appear in prominent locations such as the face, neck, and chest, which can be a source of distress for the individual. Many variables can influence the severity of a scar, such as its thickness and pigmentation. These repairs may not be as smooth and perfect as the original skin. Furthermore, healing can result in undesirable pigmentation within the scar tissue.

[0004] There are several types of acne scars. These types, without limitation, include hypertrophic scars, ice pick scars, boxcar scars, roller scars, and atrophic scars. In some cases, scars can cause skin discoloration; UV exposure can darken scars and make them more noticeable; and the fibrous tissue within the scar can appear silvery.

[0005] Several types of treatments for the prevention and treatment of acne have been described in this art; however, residual scars can be difficult to manage and control. For example, conventional skin treatments include the use of topical retinoids to fade brown, red, or purple discoloration left by acne, laser therapy, dermabrasion, and trephine grafts. Therefore, there is a need to treat unsightly scars and improve their appearance. It is also desirable to reduce the depth, affected area, and volume of pits that may be caused by acne. Summary of the Invention

[0006] This disclosure primarily relates to compositions comprising elastin and methods of using such compositions to treat acne scars (e.g., fibrotic acne scars). The method may include applying the elastin-containing composition to a skin area with acne scars. In one embodiment, the method includes treating the skin area with acne scars to improve the color and / or appearance of the acne scars in the skin area of ​​a patient in need, and / or reduce the depth, affected area, and / or volume of the acne scars. The treatment methods disclosed herein can improve the color and / or appearance of acne scars in the skin area of ​​a patient in need. Additionally or alternatively, the treatment methods can reduce the depth, affected area, and / or volume of acne scars in the skin area of ​​a patient in need.

[0007] In some embodiments of the various or any of the above or below embodiments, the composition comprises elastin between about 1 mg / mL and about 400 mg / mL. In some embodiments of the various or any of the above or below embodiments, the composition comprises 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, or more. L, approximately 210 mg / mL, approximately 220 mg / mL, approximately 230 mg / mL, approximately 240 mg / mL, approximately 250 mg / mL, approximately 260 mg / mL, approximately 270 mg / mL, approximately 280 mg / mL, approximately 290 mg / mL, approximately 300 mg / mL, approximately 310 mg / mL, approximately 320 mg / mL, approximately 330 mg / mL, approximately 340 mg / mL, approximately 350 mg / mL, approximately 360 mg / mL, approximately 370 mg / mL, approximately 380 mg / mL, approximately 390 mg / mL, or approximately 400 mg / mL of tropoelastin, or any amount of tropoelastin within the range defined by any two of the foregoing values.

[0008] In some embodiments of the various or any of the above or below embodiments, the composition comprises tropoelastin between about 1 mg / mL and about 300 mg / mL. In some embodiments of the various or any of the above or below embodiments, the composition comprises tropoelastin between about 1 mg / mL and about 250 mg / mL. In some embodiments of the various or any of the above or below embodiments, the composition comprises tropoelastin between about 1 mg / mL and about 200 mg / mL. In some embodiments of the various or any of the above or below embodiments, the composition comprises tropoelastin between about 1 mg / mL and about 150 mg / mL. In some embodiments of the various or any of the above or below embodiments, the composition comprises tropoelastin between about 1 mg / mL and about 100 mg / mL.

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

[0010] In some embodiments of any of the above or below embodiments, the composition comprising elastin is applied around the scar, for example, below the scar and / or around the edge of the scar.

[0011] In some embodiments of the above or any of the following embodiments, acne scars are subdivided into ice pick scars, boxcar scars, or roller atrophic scars. In some embodiments of the above or any of the following embodiments, the acne scar is an ice pick scar. In some embodiments of the above or any of the following embodiments, the acne scar is a boxcar scar. In some embodiments of the above or any of the following embodiments, the scar is a roller atrophic acne scar. In some embodiments of the above or any of the following embodiments, the scar is a hypertrophic scar. In some embodiments of the above or any of the following embodiments, the scar includes fibrotic tissue around the edge or base of the scar.

[0012] In some embodiments of the various or any of the above or below embodiments, the depth of the acne scar is from about 0.1 mm to about 5 mm. In some embodiments of the various or any of the above or below embodiments, the depth of the acne scar is about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth within the range of any two of the foregoing values.

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

[0014] In some embodiments of the above or any of the following embodiments, the volume of the acne scar is approximately 0.01 mm. 3 Approximately 2,000 mm 3 In some embodiments of each or any of the above or following embodiments, the volume of the acne scar is approximately 0.01 mm. 3 1mm 3 Approximately 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 775mm 3 Approximately 800mm 3 Approximately 825mm 3 Approximately 850mm 3 Approximately 875mm3 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 mm 3 Approximately 1,600 mm 3 Approximately 1,700 mm 3 Approximately 1,800 mm 3 Approximately 1,900 mm 3 or approximately 2,000 mm 3 , or any volume within the range between any two of the aforementioned values.

[0015] In some embodiments of any of the above or below embodiments, the method further includes the step of disrupting the fibrous bundles beneath the acne scar. In some embodiments of any of the above or below embodiments, disruption is performed before application of the composition to a patient in need. In some embodiments of any of the above or below embodiments, the step of disrupting the fibrous bundles creates a dermal pocket beneath the acne scar. In some embodiments of any of the above or below embodiments, disruption is performed using an 18G to 32G needle, such as an 18G, 21G, 23G, 25G, 27G, 29G, or 30G needle. In some embodiments of any of the above or below embodiments, application includes injecting the composition into the dermal pocket. In some embodiments of any of the above or below embodiments, the composition containing elastin is also placed around the scar, for example, below the scar and around the edges of the scar. Uniformly placing the composition containing elastin around the scar throughout the dermis near the scar ensures that the elastin product is positioned around the scar area.

[0016] In some embodiments of any of the above or below embodiments, the composition is applied as an injectable substance under the acne scar. In some embodiments of any of the above or below embodiments, the composition is applied in a volume of about 10 μL to about 100 μL per implantation / injection. In some embodiments of each or any of the above or below embodiments, the composition is applied in a volume of about 10 μL, about 20 μL, about 30 μL, about 40 μL, about 50 μL, about 60 μL, about 70 μL, about 80 μL, about 90 μL, or about 100 μL, or within a range defined by any two of the foregoing values. In some embodiments, the acne scar is treated with more than one injection, and the total application volume is about 200 μL, about 300 μL, about 400 μL, or about 500 μL.

[0017] In some embodiments of the above or any of the following embodiments, retrograde linear threading is used with a cross-hatching injection arrangement to ensure the destruction of all fibrous bundles within the acne scar. In some embodiments of the above or any of the following embodiments, the needle is inserted at an angle of approximately 30° parallel to the skin, with the needle at an angle and facing upwards. In some embodiments of the above or any of the following embodiments, the needle is inserted more than once to break the fibrous bundles and create a dermal capsule. In some embodiments of the above or any of the following embodiments, uniform pressure is applied while the needle is withdrawn from the dermal capsule to inject the composition.

[0018] In some embodiments of the various or any of the above or below embodiments, the composition is repeatedly applied, and wherein it is applied in a bolus injection once or more into the scar. In some embodiments of the various or any of the above or below embodiments, the maximum volume of the composition administered as a treatment is between about 100 μL and about 5 mL. In some embodiments of the various or any of the above or below embodiments, the maximum volume of the composition administered as a treatment is about 100 μL, about 500 μL, about 1 mL, about 1.5 mL, about 2 mL, about 2.5 mL, about 3 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5 mL, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the maximum volume of the composition administered as a treatment is about 100 μL / cm³. 2 Approximately 500 μL / cm 2 Between. In some embodiments of each or any of the above or below embodiments, the maximum volume of the composition administered as treatment is about 100 μL / cm. 2 Approximately 150 μL / cm 2Approximately 200 μL / cm 2 Approximately 250 μL / cm 2 Approximately 300 μL / cm 2 Approximately 350 μL / cm 2 Approximately 400 μL / cm 2 Approximately 450 μL / cm 2 Approximately 500 μL / cm 2 Or any quantity between any two of the aforementioned values.

[0019] In some embodiments of the above or any of the embodiments described above or below, the patient's skin type is classified as type I, II, III, IV, V, or VI in the Fitzpatrick skin classification. In some embodiments of the above or any of the embodiments described above or below, the scar is classified as grade 1 through 5. The scar grading was described by Tan et al. in “Global Scale for Acne Scar Severity (SCAR-S)” (Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference in 2010).

[0020] In some embodiments of the above or any of the following embodiments, acne scars are subdivided into ice pick scars, boxcar scars, or roller atrophic scars. In some embodiments of the above or any of the following embodiments, the acne scar is an ice pick scar. In some embodiments of the above or any of the following embodiments, the acne scar is a boxcar scar. In some embodiments of the above or any of the following embodiments, the scar is a roller atrophic acne scar. In some embodiments of the above or any of the following embodiments, the scar is a hypertrophic scar. In some embodiments of the above or any of the following embodiments, the acne scar includes fibrotic tissue around the scar margin and / or the scar base.

[0021] In some embodiments of the various or any of the above or below embodiments, the depth of the acne scar is from about 0.1 mm to about 5 mm. In some embodiments of the various or any of the above or below embodiments, the depth of the acne scar is about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth within the range of any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the affected area of ​​the acne scar is about 0.05 mm².2 Approximately 400mm 2 In some embodiments of the above or any of the following embodiments, the volume of the acne scar is approximately 0.01 mm. 3 Up to 2,000mm 3 .

[0022] In some embodiments of the above or any of the following embodiments, the volume of the acne scar is approximately 0.01 mm. 3 1mm 3 Approximately 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 775mm 3 Approximately 800mm 3 Approximately 825mm 3 Approximately 850mm 3 Approximately 875mm3 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 mm 3 Approximately 1,600 mm 3 Approximately 1,700 mm 3 Approximately 1,800 mm 3 Approximately 1,900 mm 3 or approximately 2,000 mm 3 , or any volume within the range between any two of the aforementioned values.

[0023] In some embodiments of the various or any of the above or below embodiments, the skin has a skin color defined by CIE L*a*b* color coordinates, wherein the method further reduces L*. In some embodiments of the various or any of the above or below embodiments, the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the method reduces L* by more than about 50%. In some embodiments of the various or any of the above or below embodiments, the method further increases a*. In some embodiments of the various or any of the above or below embodiments, the method increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the method increases a* by more than about 50%. In some embodiments of any of the above or below embodiments, the scar has a silvery tint prior to application of the composition. In some embodiments of any of the above or below embodiments, application of the composition reduces the silvery tint of the scar and increases its red and / or pink tint. In some embodiments of any of the above or below embodiments, the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values, and increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values. In some embodiments of any of the above or below embodiments, the scar has a color different from the patient's natural skin color, wherein application of the composition reduces or fades the scar's color in terms of color intensity, making the scar's color blend with the patient's natural skin color.

[0024] In some embodiments of the above or any of the following embodiments, the acne scars are facial scars, back scars, or trunk scars. In some embodiments of the above or any of the following embodiments, the depth, affected area, and / or volume of the acne scars are reduced after application of the composition.

[0025] In some embodiments of the above or any of the following embodiments, the method helps to repair atrophic scars in the skin remodeling and maturation stage, thereby improving the appearance of acne scars.

[0026] In some embodiments of any of the above or below embodiments, the method reduces the area of ​​acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of any of the above or below embodiments, the method reduces the area of ​​acne scars by greater than about 90%. In some embodiments of any of the above or below embodiments, the composition reduces the area of ​​acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of any of the above or below embodiments, the composition reduces the area of ​​acne scars by greater than about 90%.

[0027] In some embodiments of the various or any of the above or below embodiments, the method reduces the volume of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the method reduces the volume of acne scars by greater than about 90%. In some embodiments of the various or any of the above or below embodiments, the composition reduces the volume of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the composition reduces the volume of acne scars by greater than about 90%.

[0028] In some embodiments of the various or any of the above or below embodiments, the method reduces the depth of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the method reduces the depth of acne scars by greater than about 90%. In some embodiments of the various or any of the above or below embodiments, the composition reduces the depth of acne scars by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the composition reduces the depth of acne scars by greater than about 90%.

[0029] In some embodiments of the various or any of the above or below embodiments, wherein the patient in need has skin with acne scars, the method reduces the volume and area of ​​the depression in the skin contour of the acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, wherein the patient in need has skin with acne scars, the method reduces the volume and area of ​​the depression in the skin contour of the acne scar area by greater than about 90%. In some embodiments of the various or any of the above or below embodiments, the composition reduces the volume and area of ​​the depression in the skin contour of the acne scar area by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or greater than about 90%, or any amount between any two of the foregoing values. In some embodiments of any of the above or below embodiments, the composition reduces the volume and area of ​​the skin contour depression in the acne scar region by more than about 90%.

[0030] In some embodiments of the above or any of the following embodiments, an individual may almost completely remove acne scars through the treatments and methods described herein, wherein the depth, volume, and area of ​​the acne are reduced by more than about 90%.

[0031] In some embodiments of the various or any of the above or below embodiments, the method improves skin tone. In some embodiments, improving skin tone includes reducing L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values, and / or increasing a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, L* is reduced by more than about 50%. In some embodiments of the various or any of the above or below embodiments, a* is increased by more than about 50%. In some embodiments of the various or any of the above or below embodiments, the composition improves skin tone.

[0032] In some embodiments of the various or any of the above or below embodiments, the method and composition increase the volume and area of ​​the raised skin contour in the acne scar region 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 any two of the foregoing values. In some embodiments of the various or any of the above or below embodiments, the increase in volume and area of ​​the raised skin contour in the acne scar region is greater than about 90%.

[0033] In some embodiments of any of the above or below embodiments, the method and composition flatten the skin contour in the treatment area, wherein the treatment area includes acne scars or depressions.

[0034] In some embodiments of the above or any of the above or below embodiments, the method and composition reduce the L* black to white grade in the treatment area compared to the control treatment area. In some embodiments of the above or any of the above or below embodiments, the method and composition increase the a* green to red color grade in the composition treatment area compared to the control treatment area.

[0035] This disclosure also provides a method for treating (e.g., repairing) skin contours affected by acne scars. The method may include applying a composition comprising elastin to a skin region having a skin contour affected by acne scars. In one embodiment, the method includes treating a skin region having a skin contour affected by acne scars to reduce the depth, volume, and / or area of ​​the acne scars. Attached Figure Description

[0036] The various features of the illustrative embodiments of this disclosure are described below with reference to the accompanying drawings. The illustrated embodiments are intended to illustrate the disclosure and not limit it. The drawings include the following figures.

[0037] Figure 1 The flowchart for patient deployment is shown.

[0038] Figures 2A to 2DClinical grading of acne scars at screening and day 1 is shown. This grading is based on the acne scar grading published by Tan et al. in 2010 (Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference). Grades: 0 = Invisible acne scar; 1 = Almost invisible acne scar at 2.5m distance; 2 = Easily identifiable acne scar covering less than half of the affected area; 3 = Easily identifiable acne scar covering more than half of the affected area; 4 = Easily identifiable acne scar covering the entire area; the entire area involves scarring with significant atrophy. As shown in the figure, this is the side with the TE implant (30 mg / mL recombinant human elastin crosslinked with 0.5% derived hyaluronic acid) during screening follow-up. Figure 2A ) and saline control side (intradermal (id) saline implant) Figure 2B As shown in the image, this is the side with the TE implant during day 1. Figure 2C ) and the saline control side during day 1 ( Figure 2D ).

[0039] Figure 3 The image shows a third-party blinded review (BTPR) assessment (PAS1) of the scar using the overall impression change grading method. Grading: -3 = significantly worse; -2 = moderately worse; -1 = slightly worse; 0 = no change; 1 = slightly better; 2 = moderately better; 3 = significantly better.

[0040] Figure 4 The correlation between screening follow-up and baseline follow-up is shown.

[0041] Figure 5A and Figure 5B The results for all camera settings are shown, with the results from the cameras increasing as the severity score increases, thus indicating that the cameras measured similar constructions.

[0042] Figure 6A and Figure 6B This shows the relationship between the results of GIC (BTPR) and different camera settings. Detailed Implementation

[0043] Acne is a chronic inflammatory condition that can result from bacterial colonization of the pores and follicles of the skin on the face, neck, chest, and back. For example, bacterial colonization can be caused by bacteria such as Propionibacterium acnes. Acne can also be caused by increased sebum production, changes in keratinization, and inflammation. However, sometimes the cause of an acne breakout is unclear.

[0044] Acne can begin in early adolescence and persist into adulthood, during which time increased sebum production can contribute to the growth and colonization of several types of bacteria. Hormones, stress, and even diet can also trigger increased sebum production.

[0045] Acne-related problems include pain, itching, and discomfort, and can also affect quality of life. While treatments are available to prevent and cure acne, people often suffer the consequences, such as unsightly and permanent acne scars that can be very noticeable. Because acne affects people from adolescence to adulthood, acne scars can impact both teenagers and adults, leading to loss of confidence and low self-esteem.

[0046] Acne can cause scarring of varying degrees. Scars can include roller scars, ice pick scars, boxcar scars, and other types of deep pits in the skin. The depth and extent of acne scars can vary. Previous treatments, such as subcutaneous peeling, trephine excision, laser resurfacing, dermabrasion, and chemical peels, have been described above. In some cases, scarring can also cause skin discoloration.

[0047] This article discloses methods for treating acne scars that can help reduce skin pitting, reduce skin discoloration, and / or even flatten the skin contour.

[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 pertains.

[0049] The terms “a,” “an,” “the,” and similar designations used in the context of describing the invention (particularly in the context of the following claims) are to be interpreted as covering both the singular and the plural, unless otherwise stated herein or clearly contradicted by the context.

[0050] When referring to measurable values, “about” as used herein means a change of +20% or +10%, more preferably +5%, even more preferably +1%, and still more preferably +0.1% relative to a specified value.

[0051] Unless the context otherwise requires, the term “comprise” as used herein and variations thereof, such as “comprising,” “comprises,” and “comprised,” are not intended to exclude other additives, components, integers, or steps.

[0052] As used in this article, “scar,” “fibrosis,” or “fibrotic response” can refer to fibrous (scar) tissue that forms in response to injury or medical intervention.

[0053] As used in this article, "scar" can refer to a mark left on the skin or within body tissues, where wounds such as scabs or acne have healed and have developed fibrous connective tissue. As discussed in this article, acne can cause scarring.

[0054] The term "tropoelastin" refers to a protein that forms elastin. Tropoelastin can be a monomer. Tropoelastin is typically not cross-linked, covalently linked, or otherwise formed. Tropoelastin can reversibly coagulate. Therefore, tropoelastin differs from elastin because elastin is composed of covalently cross-linked tropoelastin that cannot reversibly coagulate. Tropoelastin can be human tropoelastin. Tropoelastin can be synthetic, for example, it can be derived from recombinant expression or other synthesis, or it can be obtained from a natural source such as porcine aorta. As is generally known in the art, tropoelastin can exist in the form of various fragments. In some embodiments of the various or any of the above or below embodiments, the compositions provided in the methods described herein comprise monomeric tropoelastin. In some embodiments of the various or any of the above or below embodiments, the monomeric tropoelastin is cross-linked with HA. In some embodiments of the various or any of the above or below embodiments, the tropoelastin comprises a sequence as shown in any of SEQ ID NO:1-15.

[0055] In various or any of the embodiments described above or below, the method of the present invention utilizes the SHELδ26A tropoelastin analog (WO 1999 / 03886) for use in the various applications described herein, including the compositions used in the method. The amino acid sequence of SHELδ26A is as follows:

[0056] (SEQ ID NO:1).

[0057] In various or any of the embodiments described above or below, the original elastin isotype is the SHEL isotype (WO 1994 / 14958; the entire contents of which are incorporated herein by reference):

[0058] (SEQ IS NO:2) or a protease-resistant derivative of the same type as SHEL or SHELδ26A (WO2000 / 04043; the entire contents of which are incorporated herein by reference). As described in WO2000 / 04043, the protein sequence of the protoelastin may have a mutated sequence that reduces or eliminates its sensitivity to proteolytic digestion.Non-limitingly, the amino acid sequence of protoelastin is reduced or eliminated in terms of sensitivity to serine proteases, thrombin, kallikrein, metalloproteinases, gelatinase A, gelatinase B, serum proteins, trypsin, or elastase. For example, in some embodiments of various or any of the above or below embodiments, protoelastin includes the sequence shown in SEQ ID NO:3 (SHELδ26A isotype):

[0059] (SEQ ID NO:3). In some embodiments, the proelastin includes the sequence shown below (SHELδmod isotype):

[0060] (SEQ ID NO:4).

[0061] Protoelasin analogues typically have sequences homologous to the human protoelasin sequence. The percentage of identity between a pair of sequences can be calculated using an algorithm executed in the BESTFIT computer program. Another algorithm for calculating sequence divergence has been adapted for rapid database searches and executed in the BLAST computer program. Protoelasin polypeptide sequences can exhibit amino acid-level identity of approximately 60%, 70% or more, 80% or more, 90% or more, 95% or more, 97% or more, or greater than 99% compared to the human sequence.

[0062] When making comparisons, conserved amino acid substitutions (e.g., Glu / Asp, Val / lle, Ser / Thr, Arg / Lys, Gln / Asn) can also be considered, as the chemical similarity of these amino acid residue pairs is expected to make them functionally equivalent in many cases. Amino acid substitutions that are expected to preserve the biological function of the peptide will also preserve the chemical properties of the substituted amino acid residues, such as hydrophobicity, hydrophilicity, side chain charge, or size.

[0063] Recombinant forms of proelastin can be generated based on the sequences described in WO 1999 / 03886. These sequences include:

[0064] (SEQ ID NO:5);

[0065] (SEQ ID NO:6);

[0066] (SEQ ID NO:7);

[0067] SAMGGVPGALAAAKAAKYGAAVPGVLGGLAGVGIPGGVVGAGPAAAAAAAKAAQFGLVGAAGLGLGVGGLGVPGVGGLGIPPAAAAAKAAKYAGALGGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK(SEQ ID NO:8);

[0068] SAMGALVGLGVPGLGVGAGVPGFGAGADEGVRRSLSPELREGDPSSSQHLPSTPSSPRVPGALAAAKAAKYGAAVPGVLGGLGALGGVGIPGGVVGAGPAAAAAAAKAAAKAAQFGLVGAAGLGGLGVGGLGVPGVGGLGGIPPAAAAKAAKYGAAGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK(SEQ ID NO:9);

[0069] GIPPAAAAKAAKYGAAGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK(SEQ IDNO:10);

[0070] GAAGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK(SEQ ID NO:11);

[0071] GADEGVRRSLSPELREGDPSSSQHLPSTPSSPRV(SEQ ID NO:12);

[0072] GADEGVRRSLSPELREGDPSSSQHLPSTPSSPRF(SEQ ID NO:13);

[0073] AAAGLGAGIPGLGVGVGVPGLGVGAGVPGLGVGAGVPGFGAGADEGVRRSLSPELREGDPSSSQHLPSTPSSPRVPGALAAAKAAKYGAAVPGVLGGLGALGGVGIPGGVVGAGPAAAAAAAKAAAKAAQFGLVGAAGLGGLGVGGLGVPGVGGLGGIPPAAAAKAAKYGAAGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK(SEQID NO:14); and

[0074] AAAGLGAGIPGLGVGVGVPGLGVGAGVPGLGVGAGVPGFGAVPGALAAAKAAKYGAAVPGVLGLGALGGVGIPGGVVGAGPAAAAAAAKAAAKAAQFGLVGAAGLGLGVGGLGVPGVGGLGGIPPAAAAKAAKYGAAGLGGVLGGAGQFPLGGVAARPGFGLSPIFPGGACLGKACGRKRK (SEQ ID NO: 15).

[0075] Fibroelastin can be used in the form of linkages (e.g., covalent linkages) with other molecules such as biopolymers of hyaluronic acid. In some embodiments, fibroelastin is cross-linked with hyaluronic acid. In some embodiments, the composition comprises monomeric fibroelastin. In some embodiments of various or any of the above or following embodiments, fibroelastin comprises a sequence as shown in any of SEQ ID NO:1-15.

[0076] Particularly preferred is that when tropoelastin is linked to other molecules, the link does not impede or limit the biological properties of the unlinked form of tropoelastin.

[0077] The purpose of linking tropoelastin to other molecules is usually to enable tropoelastin to be localized to a certain region and to minimize the possibility of tropoelastin diffusing from that region or migrating in other ways.

[0078] In some embodiments of the various or any of the above or below embodiments, the tropoelastin has a specified degree of purity relative to the amount of tropoelastin in the composition, compared to the amounts of other proteins or molecules in the composition. In one embodiment, the tropoelastin is in a composition having a purity of at least 75%, preferably 85%, more preferably greater than 90% or 95%. In this context, fragments of tropoelastin, i.e., truncated forms of the tropoelastin isotype unintentionally generated during tropoelastin manufacturing, may be considered impurities.

[0079] It should also be understood that in some embodiments, tropoelastin may be provided in the form of a composition comprising tropoelastin, preferably a full-length isoform of tropoelastin, or substantially tropoelastin, preferably a full-length isoform of tropoelastin. In some embodiments of any of the above or below embodiments, the tropoelastin will be at least about 65% of the length of the relevant tropoelastin isoform, greater than about 80% of the full length, greater than about 90% of the full length, or greater than about 95% of the full length.

[0080] The term "hyaluronic acid" or "HA" can include hyaluronic acid and any hyaluronic acid salt, including, for example, 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 can be extracted from animal tissues, obtained as a product of bacterial fermentation, or manufactured in commercial batches using bioprocessing techniques. In some embodiments, the composition provided in the methods herein comprises monomeric fibroelastin. In some embodiments, the monomeric fibroelastin is cross-linked with HA. In some embodiments of various or any of the above or following embodiments, the fibroelastin comprises a sequence as shown in any of SEQ ID NO:1-15. In some embodiments of various or any of the above or following embodiments, the fibroelastin comprises a sequence as shown in SEQ ID NO:1.

[0081] In some embodiments of any of the above or below embodiments, the composition comprises 1 mg / mL to 100 mg / mL of tropoelastin crosslinked with about 0.1% to about 10% of derived hyaluronic acid (HA). In some embodiments of any of the above or below embodiments, the composition comprises 1 mg / mL to 100 mg / mL of tropoelastin crosslinked with about 0.4% to about 1% of derived hyaluronic acid (HA). In some embodiments of any of the above or below embodiments, the tropoelastin is crosslinked with about 0.4%, about 0.5%, about 0.6%, about 0.8%, about 0.9%, or about 1% of derived hyaluronic acid (HA). In some embodiments, the composition comprises 30 mg / mL of recombinant human tropoelastin crosslinked with 0.5% of derived hyaluronic acid. In some embodiments of any of the above or below embodiments, the composition further comprises a buffer solution, wherein the buffer solution is a phosphate-buffered saline solution. In some embodiments, the composition comprises derived HA or non-derived HA to control the degree of crosslinking of the HA with itself and / or monomeric proteins. In some embodiments of each or any of the above or below embodiments, the derived HA is crosslinked with TE. In some embodiments, the protoelastin is a monomer. In some embodiments of each or any of the above or below embodiments, the monomeric protoelastin is released from the composition.

[0082] In some embodiments of any of the above or below embodiments, the HA may include at least one connectable portion, such as at least one crosslinkable portion, such as a carboxyl, hydroxyl, amine, thiol, alcohol, olefin, alkyne, cyano or azide, and / or a modifier, derivative or combination thereof.

[0083] In some embodiments of any of the above or below embodiments, the HA may include a spacer group such that the spacer group can be linked to the same molecule and / or a second molecule such as a second biomolecule or biopolymer.

[0084] HA can be in the range of about 25 to about 10,000 disaccharide units or residues. In some embodiments of the various or any of the above or below embodiments, hyaluronic acid in the range of 25 to 7,500 disaccharide units or residues can be used.

[0085] In any of the embodiments described above or below, the HA may be a low molecular weight HA or a high molecular weight HA. The high molecular weight HA (also referred to as "HMW HA") described herein generally refers to a molecular weight of at least about 1.0 million Daltons (mw ≥ 10). 6 Hyaluronic acid with a molecular weight of approximately 1 MDa to about 4.0 MDa. The low molecular weight HA used in this article (sometimes referred to as "LMW HA") generally describes hyaluronic acid with a molecular weight of less than about 1.0 MDa.

[0086] In some embodiments of each or any of the above or below embodiments, HA may be activated and / or modified with activators such as EDC or allyl glycidyl ether and / or modifiers such as NHS, HOBt or bromine.

[0087] The term "Fitzpatrick classification" is given a straightforward and general meaning, and in this context and without limitation, can refer to a scientific classification of skin types. The Fitzpatrick classification has several different types, from type 1 to type 6. Dermatologists and cosmetic medicine practitioners use this classification to determine which treatment is most appropriate for different skin types. The classification was developed to determine the skin's response to ultraviolet radiation, such as sunlight. Furthermore, cosmetic doctors and laser technicians can learn this basic information before applying lasers or other types of treatments. Type 1 – Typically light ivory skin that always burns and peels when exposed to sunlight but never tans. Type 2 – Light fair skin that burns quickly when exposed to sunlight but rarely tans. Type 3 – Typically light beige skin that can burn when exposed to sunlight and is capable of tanning. Type 4 – Olive or light brown skin that does not develop freckles when exposed to sunlight. These individuals rarely get sunburned and tan frequently. Type 5 - Dark brown or black skin tone, rarely sunburned in the sun, and always tans. Type 6 - Black and the darkest skin tone. These individuals never sunburn when exposed to sunlight and tan quickly. Dermatologists can use this useful classification to assess the sun response of certain skin types and to more quickly identify potentially malignant sunspots. Cosmetic physicians can also use this classification to determine the effectiveness of treatments for different skin types. In any of the above or any of the following embodiments, methods for treating acne scars may be used for individuals with any of the skin types classified as types 1 through 6 in the Fitzpatrick classification.

[0088] The term "intradermal implant" refers to an implant that can be placed under the epidermis. Without limitation, the implant can be located in a skin region, such as the dermis, subcutaneous layer, or subdermal layer. In various or any of the embodiments described above or below, the implant can be placed intradermally.

[0089] In some embodiments of the above or any of the following embodiments, the implant may be placed in the subcutaneous layer. This placement method can also be used in addition to intradermal placement of the implant.

[0090] "Retrograde suture technique" is a method used to place implant sutures into target tissue. First, a needle is inserted. Second, while withdrawing the needle, the implant is placed by pressing the plunger of the syringe.

[0091] "Cross-laid threading" is a method of placing implant threads within target tissue in a pattern that creates a "mat" shape. The needle moves through the tissue to complete the threading by cross-laid arrangement, which disrupts the fibrous tissue along the needle's path.

[0092] As used herein, "acne" refers to a skin condition that occurs when dead skin cells and sebum clog hair follicles. Acne is characterized by blackheads or whiteheads, papules, and oily skin. In some cases, acne can lead to scarring. In various or any of the embodiments described above or below, patients in need have acne and acne scars.

[0093] As described in this article, "acne scars" can be caused by inflammation within the skin. Acne scars can also result from abnormal healing following inflammation caused by acne. "Atrophic acne scars" can be caused by the loss of collagen during the healing process, and collagen loss during the healing process is the most common cause of acne scar formation.

[0094] 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.

[0095] "Rolling atrophic acne scars" are jagged scars that heal beneath the normal skin tissue layer.

[0096] "Boxcar scars" are a type of acne scar that presents as indentations on the skin. Boxcar scars are characterized by well-defined edges that extend directly into the skin and are typically different in size from the acne lesion that formed the scar. Boxcar scars are a type of atrophic acne scar.

[0097] Hyperpigmentation is skin darkening caused by increased melanin production. Non-limitingly, causes of hyperpigmentation include sun damage, inflammation, skin injury, and acne. Skin can respond to damage by overproducing melanin, which is produced by melanocytes. In some embodiments of the various or any of the above or below embodiments, the scar has a silvery tint prior to the application of the composition. In some embodiments of the various or any of the above or below embodiments, the application of the composition reduces the silvery tint of the scar and increases its dark red or pink tint. In some embodiments of the various or any of the above or below embodiments, the method reduces L* by about 1%, 5%, 10%, 15%, 20%, 25%, or greater than 50%, or any amount defined by a range between any two of the foregoing values, and increases a* by 1%, 5%, 10%, 15%, 20%, 25%, or greater than 50%, or any amount defined by a range between any two of the foregoing values. The methods described herein can also be used to treat acne scars and reduce skin discoloration caused by acne.

[0098] The CIELAB color space is used to define the skin tone and color changes that will occur after skin is treated with a composition containing elastin. The CIELAB color space (also known as CIE L*a*b* or sometimes simply "Lab" color space) is a color space defined by the International Commission on Illumination (CIE) in 1976. The CIELAB color space represents colors as three values: L* for brightness from black (0) to white (100), a* for green (-) to red (+), and b* for blue (-) to yellow (+).

[0099] Methods to treat scars

[0100] This document provides methods for treating acne scars (e.g., fibrotic acne scars) in patients in need, including, for example, improving the color and / or appearance of the acne scars. The method may include applying a composition containing elastin to a skin area of ​​a patient with scars, including, for example, applying the composition near or directly into or below the scar. In other embodiments, the composition containing elastin may also be placed around the scar, such as below the scar and around the edges of the scar. After application of the composition, the depth, affected area, and / or volume of the acne scar are reduced (including compared to a composition identical in all aspects except for the lack of elastin, such as a saline control). Additionally or alternatively, the disclosed methods may increase the raised volume and raised area of ​​the skin contour in the acne scar area (including compared to a composition identical in all aspects except for the lack of elastin, such as a saline control).

[0101] The method may also include needle puncture to destroy fibrotic units in acne scars, such as fibrous bundles or units (e.g., fibrotic tissue) beneath the scar, to cut or release the fibrous bundles that deeply tether the skin surface into depressions. In one embodiment, destruction of the fibrotic units allows a dermal capsule to form beneath the acne scar, and the composition is applied to the dermal capsule. After destroying the scar tissue, the dermal capsule can be filled with the disclosed composition.

[0102] Scar destruction can be performed using 18G to 32G needles, such as 18G, 21G, 23G, 25G, 27G, 29G, or 30G needles. Non-limitingly, fibrotic units can be destroyed in scars such as roller scars, boxcar scars, or ice pick scars. Application involves injecting the composition into the dermal follicle. The composition is applied as an injectable below the acne scar. The composition containing elastin is placed around the scar, such as below the scar and / or around the edge of the scar. Placing the composition containing elastin uniformly or evenly throughout the dermis near the scar ensures that the elastin product is around the scar area and allows for more effective treatment. The composition is administered in volumes of approximately 10 μL to approximately 100 μL per implantation / injection. Injection is performed using a retrograde suture technique with a cross-laid arrangement to ensure destruction of all fibrous bundles within the acne scar.

[0103] In some implementations, the fibrous bundles of atrophic scars are destroyed.

[0104] Fiber bundles tether the skin to underlying tissues and cause depressions. These bundles can be disrupted using needles to create cysts, thus making room for a fibrous elastin composition to be placed under the acne scar, where the fiber bundles are located. Therefore, the fibrous elastin composition can be used on skin tissue cells immediately surrounding the scar, allowing them to grow within and around the product, which will remodel the fibrotic units of the scar.

[0105] The method disclosed in this paper can remodel fibrotic units near scars.

[0106] For basic or classic subcutaneous dissection, needles can be as large as 18G, typically 21G or 23G, however, 27G or 30G needles can also be used because they are small enough to perform some subcutaneous dissections and to create sacs or spaces around the scar and in the dermis for placing the product.

[0107] The needle is inserted at an angle of approximately 30° parallel to the skin, with the needle angled upwards. The needle is inserted more than once to break the fiber bundles and create a dermal capsule. While withdrawing the needle from the dermal capsule, uniform pressure is applied to inject the composition. The composition is applied repeatedly, with one or more boluses applied to the scar.

[0108] The methods disclosed herein can advantageously reduce the depth, affected surface area, and / or volume of acne scars. Indeed, on day 168 following application of the composition (e.g., 30 mg / mL tropoelastin crosslinked with 0.5% dHA), improvements were observed in both small and large pits, along with improved smoothness and / or levelness of the skin contour. Surprisingly, this also resulted in the repair of atrophic scars in the skin remodeling and maturation phase, thereby improving the appearance of the scars.

[0109] The methods disclosed herein can be used to improve the appearance of atrophic acne scars. As described herein, treatment can be applied on day 0, day 28, and day 56. Surprisingly, this treatment resulted in improved skin appearance and color in several patients, including those with roller, boxcar, or icepick acne scars. In some embodiments where the scar pigmentation includes silver, the methods disclosed herein reduce the silver pigmentation of the scar and / or increase the red or pink pigmentation of the scar.

[0110] The compositions disclosed herein may contain from about 1 mg / mL to about 400 mg / mL of elastin (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, or 400 mg / mL of elastin.

[0111] The compositions disclosed herein may also contain hyaluronic acid (HA). In other embodiments, elastin is cross-linked with about 0.1% to about 10% of the derived hyaluronic acid. In yet another embodiment, the composition comprises 30 mg / mL of human elastin (e.g., recombinant human elastin) cross-linked with about 0.5% of the derived hyaluronic acid. The composition may also contain a buffer, such as phosphate-buffered saline.

[0112] This article also provides pharmaceutical formulations containing the disclosed composition comprising tropoelastin.

[0113] The maximum application volume of the compositions disclosed herein is between about 100 μL and about 5 mL (e.g., at about 100 μL / cm). 2 Approximately 500 μL / cm 2 between).

[0114] In one implementation, the patient in need has a skin type classified as type I, II, III, IV, V, or VI in the Fitzpatrick skin classification system.

[0115] Scars treated using the methods disclosed herein can include any of the grades 0, 1, 2, 3, 4, or 5 described by Tan et al. in their 2010 Global Scale for Acne Scar Severity (SCAR-S) (Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference). The grades are as follows: 0: Clean; invisible acne scars; 1: Very mild; acne scars barely visible from 2.5 m away; 2: Mild; easily identifiable; involving less than half of the affected area (e.g., face, back, or chest); 3: Moderate; involving more than half of the affected area (e.g., face, back, or chest); 4: Severe; involving the entire area; 5: Extremely severe; scars with significant atrophic or hypertrophic appearance throughout the entire area.

[0116] In one implementation, the acne scar may be an ice pick scar, a van scar, a roller scar, an expandable roller scar, or a hypertrophic scar. The scar may be located on the subject's face, back, or torso.

[0117] The depth of acne scars treated by the methods disclosed herein can be from about 0.1 mm to about 5 mm (e.g., about 0.1 mm, about 0.5 mm, about 1.0 mm, about 1.5 mm, about 2 mm, about 2.5 mm, about 3.0 mm, about 3.5 mm, about 4.0 mm, about 4.5 mm, about 5 mm, or any depth within the range of any two of the foregoing values).

[0118] The affected area of ​​acne scars treated using the method disclosed in this article can be approximately 0.05 mm. 2 Approximately 400mm 2 .

[0119] The acne scars treated using the method disclosed in this article can be approximately 0.01 mm in size.3 Up to 2,000mm 3 (For example, approximately 0.01 mm) 3 Approximately 1mm 3 Approximately 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 3Approximately 1,200 mm 3 Approximately 1,300 mm 3 Approximately 1,400 mm 3 Approximately 1,500 mm 3 Approximately 1,600 mm 3 Approximately 1,700 mm 3 Approximately 1,800 mm 3 Approximately 1,900 mm 3 or approximately 2,000 mm 3 (or any volume within the range between any two of the aforementioned values).

[0120] Scars treated by the methods disclosed herein can lighten skin tone defined by CIE L*a*b* color coordinates (e.g., reducing L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or greater than about 50%, or any amount defined by a range between any two of the foregoing values). In a preferred embodiment, the methods disclosed herein reduce L* by greater than about 50%.

[0121] The methods disclosed herein can also increase a*, including by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or more than about 50%, or any amount defined by a range between any two of the foregoing values. In a preferred embodiment, the methods disclosed herein increase a* by more than about 50%.

[0122] In one embodiment, the scar has a color different from the patient's natural skin color, and the compositions disclosed herein cause the scar's color to decrease or fade in terms of color intensity, so that the scar's color becomes integrated with the patient's natural skin color.

[0123] The compositions disclosed herein can improve the appearance of scars (e.g., a reduction in scar depth, volume, surface area, and / or color by about 5%, about 10%, 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) within about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 55%, about 80%, about 85%, about 90%, about 95%, about 100%, or more after injection into a scarred area of ​​skin.

[0124] The following embodiments, sequence listing, and drawings are provided to aid in understanding the invention, and the true scope of the invention is set forth in the appended claims. It should be understood that modifications may be made to the processes without departing from the spirit of the invention.

[0125] Example

[0126] Example 1. Evaluate the clinical efficacy, persistence, tissue compatibility and safety of TE implants for the treatment of atrophic roller acne scars.

[0127] Research Design and Randomization

[0128] The study aimed to test and evaluate the clinical efficacy, persistence, tissue compatibility, and safety of TE implants (30 mg / mL recombinant human elastin crosslinked with 0.5% derived hyaluronic acid) after dermal implantation for the treatment of atrophic roller acne scars.

[0129] Thirty-four male and female patients aged 24 to 55 years participated in a study of the TE implant (30 mg / mL recombinant human elastin crosslinked with 0.5% derived hyaluronic acid; "TE implant") for the treatment of acne scars. However, one of the 34 patients withdrew permission before treatment. Thirty-three patients were tested on approximately 2 cm × 2 cm skin areas measured around the temples and cheekbones on both sides of the face, each area containing at least two moderate to severe roller-shaped, expandable, atrophic acne scars. The following treatment was applied to both sides of the face:

[0130] a) Intradermal (id) implant of endothelial elastin: 30 mg / mL recombinant human endothelial elastin cross-linked with 0.5% derived hyaluronic acid (“TE implant”); and

[0131] b) Saline control (intradermal (id) implant with isotonic saline) (“Saline control”).

[0132] Each patient served as their own control, with the TE implant placed on either the right or left side of the face, and the saline control placed on the opposite side. All patients received three treatments with either the TE implant or the saline control (on days 0, 28, and 56). At each treatment follow-up, the TE implant was administered to the same side as on day 0 (and the saline control to the same side as on day 0). Each treatment involved multiple, discontinuous, direct intradermal injections of approximately 25 μL to 50 μL of the TE implant into the dermis of a 2 cm × 2 cm treatment area. Injections were performed using a retrograde suture technique with a cross-laid arrangement to ensure complete disruption of fibrous bundles within the scar. Additionally, treatment may include one or more boluses into the dermis of the roller-shaped atrophic acne scar to ensure optimal scar response. The maximum total volume of the TE implant or saline control in each treatment area at each treatment time point was approximately 250 μL and no more than 500 μL.

[0133] An examination of the implantation site was conducted on day 14. For safety reasons, all patients were followed up until day 168.

[0134] Patients were unaware of which side of their face or body received the TE implant and the saline control. The researchers were aware. Third-party clinical reviewers were unaware of the images taken on day 0 (pre-treatment) and day 168 (post-treatment).

[0135] Research process and follow-up

[0136] filter

[0137] Prior to initial implantation using a research approach, a 28-day screening period was used to determine patient eligibility and baseline parameters. During this period, written, signed, and dated informed consent was obtained from each patient. Relevant medical history items were recorded, physical examinations were performed, and vital signs were recorded. Other tests performed at this time included: 12-lead ECG, breath test for alcohol, urine drug test (covering the use of amphetamines, cocaine, opioids, cannabis, barbiturates, and benzodiazepines), clinical examination of the intended treatment area, 2-D and 3-D photographs of the intended treatment area, scoring of the intended treatment area in the overall acne scar severity rating (Tan et al., 2010, the entire contents of which are incorporated herein by reference), serum pregnancy test, blood tests for APTT and PT coagulation, laboratory safety tests for blood and urine samples, Hep B, Hep C, and blood tests for HIV 1 and HIV 2. These tests were then used to determine whether patients were eligible for the study, and eligible patients were asked to respond in order to begin the study (treatment follow-up 1, day 0).

[0138] Treatment using research methods

[0139] At treatment follow-up 1 (day 0), eligible patients participated in the initial method implantation. The following procedures were performed prior to implantation:

[0140] - Review of eligibility criteria;

[0141] - Change the record of accompanying medications;

[0142] -Pre-implantation vital signs;

[0143] - Breath test for alcohol consumption;

[0144] - Urine tests for drug abuse;

[0145] - Blood draws for antigen-elastin antibody analysis;

[0146] - Clinical testing of the intended treatment area;

[0147] - Baseline 2D photograph of the treatment area;

[0148] - Baseline 3D photograph of the treatment area;

[0149] - Researchers conducted pre-treatment assessments of each treatment area based on the Global Scale for Acne Scar Assessment (Tan et al., 2010, Journal of Cutaneous Medicine and Surgery, Vol. 14, No. 4 (July / August), incorporated herein by reference;

[0150] - (Apply EMLA cream topically at least 60 minutes before TE or saline control implantation;

[0151] - Urine pregnancy test for women of childbearing age;

[0152] Following these procedures, the treatment area was implanted using research methods (TE implantation or saline control implantation). Sixty minutes after TE implantation and saline control implantation, the full response at the injection site was physically examined, and 2D photographs were taken post-treatment.

[0153] On day 14, an implantation site review is conducted, and clinical staff perform the following procedures:

[0154] - Review of the adverse reaction (AE) diary card;

[0155] - Clinical testing of the treatment area;

[0156] - 2D photograph of the treatment area;

[0157] - 3D photographs of the treatment area;

[0158] -Analysis of serum antigen elastin antibody in blood;

[0159] A second treatment implantation follow-up was performed on day 28±3, and a third treatment implantation follow-up was performed on day 56±3. The same procedure as that performed on day 0 was used.

[0160] Provide patients with a diary to record any injection site reactions such as redness, swelling, itching, and tenderness between each study follow-up.

[0161] track

[0162] The patient returned to the study site on day 84±3 for follow-up procedures. The following activities were performed:

[0163] -Records of changes accompanying the medication

[0164] -Recordation of adverse reactions and clinical testing of the treatment area

[0165] - Physical examination and vital signs

[0166] - Breath test for alcohol consumption

[0167] - Urine tests for drug abuse

[0168] - Blood draw for antigen-elastin antibody analysis

[0169] - 2D photograph of the treatment area

[0170] - 3D photograph of the treatment area

[0171] - Urine pregnancy test for women of childbearing age

[0172] - Patients and researchers assessed the treatment area based on changes in overall impression and the patient's acne-Q rating.

[0173] An additional follow-up visit was conducted on day 168±7. The following activities were performed:

[0174] - Records of changes that occur with the accompanying medication

[0175] -Recordation of adverse reactions and clinical testing of the treatment area

[0176] - Physical examination and vital signs

[0177] -12-lead ECG

[0178] - Breath test for alcohol consumption

[0179] - Urine tests for drug abuse

[0180] - Blood draw for antigen-elastin antibody analysis

[0181] - 2D photograph of the treatment area

[0182] - 3D photograph of the treatment area

[0183] - Urine pregnancy test for women of childbearing age

[0184] Laboratory safety tests for screening blood and urine

[0185] - Patients and researchers assessed the treatment area based on changes in overall impression and the patient's acne-Q rating.

[0186] On day 168, third-party blind reviewers also assessed the treatment area based on the level of change in overall impression by comparing photos taken on day 168 with those taken on day 0.

[0187] Research Objective

[0188] The primary objective of this study was to determine the clinical efficacy of TE implants in men and women with atrophic acne scars.

[0189] The secondary objectives of this study are as follows:

[0190] - Evaluate the histological changes of atrophic acne scars caused by TE implants (30 mg / mL recombinant human elastin crosslinked with 0.5% derived hyaluronic acid).

[0191] - Confirm the local and systemic AE profiles of the TE implant.

[0192] security purposes

[0193] The safety objective of this study was to evaluate the safety and tolerability of TE implants.

[0194] Exploratory purpose

[0195] The following exploratory objectives were tested:

[0196] -Analysis of the clinical significance of acne scars

[0197] - Classification of acne scars analyzed by a third-party blind reviewer (BRPR)

[0198] - Correlation between 3D camera data and overall acne scar severity level, Acne-Q acne scar score, and BTPR treatment score

[0199] Inclusion criteria

[0200] Patients eligible for inclusion in this study must meet all of the following criteria:

[0201] 1. Female / male patients with matching treatment areas of approximately 2cm x 2cm on the temples or cheekbones on both sides of the face, each treatment area containing at least two roller-shaped atrophic acne scars that can expand when stretched between fingers, and classified as moderate to severe in the overall acne scar rating assessment.

[0202] 2. Acne scars in areas of normal, healthy skin.

[0203] 3. Age: 18 to 55 years old.

[0204] 4. Able to provide a voluntary informed consent form.

[0205] 5. Good health condition.

[0206] 6. In addition to long-term follow-up, sexually active female patients will be non-fertile (i.e., surgically sterilized or postmenopausal), abstain from sexual activity, or use a reliable method of contraception (e.g., hormonal contraceptives, condoms, IUD) for at least 30 days before administration and during the study period. During long-term follow-up, contraceptive use will be recommended to fertile female patients, but it is not mandatory.

[0207] 7. Fitzpatrick skin type: type I, type II, type III, type IV, or type V.

[0208] Exclusion criteria

[0209] Patients were excluded from this study if they met any of the following criteria:

[0210] 1. Active, persistent acne lesions on the face (or, for patients who will also be treated in these areas, the back and torso).

[0211] 2. The current or previous treatment of atrophic acne scars with fillers, lasers, deep chemical peels that reach the dermis, or any other medical or surgical treatments can reasonably be considered by the researchers to influence the results of current clinical studies.

[0212] 3. Known hypersensitivity to elastin, hyaluronic acid, or any other component of the TE implant (30 mg / mL recombinant human elastin crosslinked with 0.5% derived hyaluronic acid).

[0213] 4. Women who test positive for pregnancy, women who do not agree to appropriate contraception and pregnancy testing during the study, or women who plan to become pregnant during the trial.

[0214] 5. Participated in clinical trials of pharmacological reagents within one month prior to screening.

[0215] 6. Clinically significant hematological or biochemical test results at the time of screening.

[0216] 7. The screening test was positive for hepatitis B, hepatitis C, or HIV.

[0217] 8. Bleeding diathesis, anticoagulant medication, thrombocytopenia, or clinically significant prolonged APTT or PT.

[0218] 9. Long-term use of aspirin, other nonsteroidal anti-inflammatory drugs, or other antiplatelet agents.

[0219] 10. History of keloid formation.

[0220] 11. History of granulomatous or connective tissue disease.

[0221] 12. Systemic use of corticosteroids within the past 12 weeks.

[0222] 13. Currently using topical retinoids, or using topical retinoids within the past 8 weeks.

[0223] 14. Diabetes or other metabolic disorders, which researchers believe can interfere with a patient's response to treatment.

[0224] 15. In the researchers' view, any serious medical condition that is likely to require systemic use of corticosteroids.

[0225] 16. Pregnant or breastfeeding women.

[0226] 17. Previously administered elastin.

[0227] 18. History of allergies or allergic reactions, including any known allergy to lidocaine.

[0228] 19. Use of any investigational products at the intended implantation site within the preceding 12 months.

[0229] deploy

[0230] During the study, 33 patients were screened, recruited, randomized, and received at least one TE implantation. One patient (Patient ID: 001-120) was enrolled but withdrew their consent before treatment on day 0. Five patients did not receive any further implantations after their initial treatment follow-up on day 0. The remaining 27 patients received all three planned facial treatments. All 33 randomized patients were included in the full analysis group (FAS) and the safety group (SS) used for the analysis. The 27 patients who received all three planned facial treatments formed Photoanalysis Group 1 (PAS1).

[0231] Personnel statistics and baseline characteristics

[0232] The patients' ages ranged from 24 to 55 years, with a mean age of 38.0 years (SD = 8.71). There were 22 males and 11 females. Sixteen patients were Caucasian, two were Mediterranean, 14 were Asian, and one was classified as "other." All 11 women were fertile, and each had a negative pregnancy test result at screening follow-up. Four patients had Fitzpatrick type II skin, 13 had Fitzpatrick type III skin, 12 had Fitzpatrick type IV skin, and four had Fitzpatrick type V skin.

[0233] Scar assessment results using overall acne scar grading assessment

[0234] At screening follow-up and day 0, patients' acne scars were graded using the following grading system shown in Table 1 to ensure that patients met the inclusion criteria for scar severity and to ensure comparable contralateral treated areas. This grading system was developed by Tan et al. in 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 to 2D .

[0235] Table 1: Acne scar assessment results based on Tan et al. (responses are also shown in Figure 2)

[0236] Exposure and medication adherence

[0237] category Fraction describe clean 0 Invisible acne scars Very light 1 Acne scars that are almost invisible from 2.5m away Mild 2 Easily identifiable acne scars; covering less than half of the affected area. moderate 3 Involving more than half of the affected area Severe 4 Involving the entire area Extremely severe 5 The entire area has obvious roller-shaped atrophic scars.

[0238] As mentioned above, six patients in the FAS (full analysis group) did not receive the TE implant and saline control or received only one facial implant in the TE implant and saline control group, while the remaining 27 patients received three facial implants in the TE implant and saline control group.

[0239] For FAS, the average volume of each TE implant injection at follow-up was 0.33 mL. In comparison, the average control volume of each TE implant injection at follow-up was 0.45 mL.

[0240] The cumulative TE volume injected during the entire implantation follow-up period ranged from 0.10 mL to 1.43 mL. The median cumulative TE volume injected was 0.90 mL. The cumulative saline control volume injected during the entire implantation follow-up period ranged from 0.05 mL to 1.83 mL. The median cumulative saline control volume injected was 1.31 mL.

[0241] Preliminary efficacy analysis

[0242] Based on three images of each of five scar lesions on both sides of the face, 3D photoanalysis was used to evaluate various features of the treatment area. Only two images of that area were taken and recorded for each patient, therefore the patient's data are based solely on those two images.

[0243] The damage characteristics determined by photographs are as follows:

[0244] -Color L*

[0245] -Color a*

[0246] -Color b*

[0247] -Volume (mm) 3 )

[0248] -Area (mm) 2 )

[0249] -Depth (mm)

[0250] Volume, area, and depth were assessed with the camera set to 6.0 mm. To generate summary statistics for reporting and analysis, the median of three images for each lesion feature was used. The sum of the medians of the five lesions on both sides of the face was then used as the overall score for the patient / side analysis. An example is shown below:

[0251] - Feature = Volume; Damage score j = Median (Image 1 feature, Image 2 feature, Image 3 feature), where j = 1 to 5; Total score = Damage 1 score + Damage 2 score + Damage 3 score + Damage 4 score + Damage 5 score.

[0252] Then, the total score of one side of the face on day 168 was subtracted from the total score of that side of the face on day 0 to calculate the change in the total score of each side of the face relative to the baseline.

[0253] The difference in change from baseline to day 168 was also calculated between the TE implant treatment side and the saline control side.

[0254] This article provides a brief summary of the overall score statistics and the change in overall score relative to baseline. Generally, both the TE implant and saline control areas showed evidence of improvement compared to baseline, with the TE implant treatment area showing greater improvement compared to the saline control area.

[0255] Regression analysis was also used to model the lesion size data. Changes relative to baseline were used as the dependent variable, and the treated side (TE implant or saline control implant) and the baseline total lesion score were used as independent variables (illustrative). Table 2 presents the results of changes relative to baseline at day 168 (PAS1). Based on simple summary statistics, the model results showed significant reductions in depth, volume, and area for both the TE implant and the saline control implant, with the depth, volume, and area measurements in the TE implant treatment area consistently showing a significant reduction relative to baseline compared to the saline control treatment area.

[0256] Table 2: Regression model evaluation of changes in lesion area, volume, and depth on day 168 relative to baseline for PAS1.

[0257]

[0258]

[0259] Whole-area treatment area (PAN) analysis. In addition to measuring individual lesions within the treatment area, the following characteristics are assessed for the whole treatment area to determine the impact of the treatment implant on the overall contour deformation within the treatment area, hereinafter referred to as PAN analysis:

[0260] Color images (as previously mentioned, color changes on the treated area reflect color changes at individual lesion levels)

[0261] - Color L* (scale from black to white)

[0262] - Color a* (scale from green to red)

[0263] - Color b* (scale from blue to yellow)

[0264] Depression measurement (using a camera set to 10.0mm to detect contour changes on the treatment site; note that individual acne scar lesions were not measured under this setting):

[0265] - Depth of the contour indentation in the treatment area (mm)

[0266] - The area of ​​the contour depression on the treatment area (mm) 2 )

[0267] - The volume of the contour depression on the treatment area (mm) 3 )

[0268] Elevation measurement (using a camera set to 10.0mm to detect contour changes on the treatment site; note that individual acne scar lesions were not measured under this setting).

[0269] - Height of the bulge in the treatment area (mm)

[0270] - Area of ​​the raised area on the treatment zone (mm) 2 )

[0271] - The volume of the bulge in the treatment area (mm) 3 )

[0272] This article describes all camera measurements of the PAN treatment areas. As with individual lesion data, scores were provided based on three images of each feature. To obtain the total 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 by subtracting the median score from the median score on day 168. The changes in color features measured relative to baseline may be affected by seasonal variations during the study period, as these are sun-exposed facial treatment areas where skin color changes from winter to summer and vice versa. Due to the structure and mechanism of the 3D camera system used (the camera shield is placed directly on the skin), images are captured under constant light, so variations in light at the time of photographing do not affect the resulting images. To illustrate seasonal variations in skin color, the difference between the implant-treated side and the saline control side was calculated at baseline and day 168. This change in difference was used as a measure of validity for color L*, color a*, and color b* in the PAN treatment area analysis. A simplified summary of the statistics is shown below (data available for all patients in the safety group).

[0273] Similar to the damage analysis, regression modeling uses the change relative to baseline (or the change in the difference relative to baseline) as the dependent variable, and the treatment side (TE implant or saline control) and the baseline value (or the difference in the baseline value) as independent variables (illustrative). The following table shows the analysis results of the change relative to baseline on day 168.

[0274] The results showed that, compared with the saline control, the L* black-to-white scale was significantly reduced and the a* green-to-red color scale was significantly increased in the PAN treatment area with the TE implant. Furthermore, it was observed that, compared with the saline control, the TE implant significantly reduced the volume and area of ​​larger contour skin depressions and correspondingly increased the volume and area of ​​bulges in the PAN treatment area.

[0275] Table 3: Evaluation of regression model for changes in PAN color, indentation volume, and bulge volume relative to baseline on day 168 for PAS1.

[0276]

[0277] Scar assessment is performed using the level of change in overall impression.

[0278] A third-party blind reviewer (BTPR) was required to review photographs taken on day 168 and day 0 in a blinded manner to assess changes in appearance of the treated area based on the Global Impression Change (GIC) grading. For the BTPR, only the treated area and the immediate surrounding area of ​​the face were visible in the reviewed photographs; no detailed patient information was provided, and patients were randomized to make the treatment pattern indistinguishable. The grading used is as follows.

[0279] Table 4: Scar Assessment Level

[0280] Significant variation Moderate variation Slight deterioration No change Slightly better moderate improvement Significantly improved -3 -2 -1 0 1 2 3

[0281] This article describes the BRPR evaluation results of PAS1 and presents them. Figure 3 (BTPR assessment) in progress.

[0282] In the PAS1 group, BTPR noted that on day 168, 70% of the treated areas at the TE implant site showed improvement, compared to 41% of the treated areas at the saline control site.

[0283] Two additional analyses were performed. The first analysis compared the percentage of treatment areas showing any improvement at the TE implant site to the saline control site, as indicated by the BTPR. The difference in percentages was calculated, and a test was performed to determine whether the difference in percentages was equal to zero. The results are shown in Table 5. At day 168, the blinded reviewers noted a difference of 26% in the number of treatment areas showing any improvement at the TE implant site compared to the saline control site (p = 0.033).

[0284] The second analysis used paired t-tests to compare GIC scores (range -3 to +3) between the TE implant treatment side and the saline control treatment side. These results are presented in Table 6 below. As assessed by BTPR on day 168, the mean difference in GIC scores between the TE implant site and the saline control site was 0.48 (95% CI -0.04 to 1.00, p = 0.068).

[0285] Table 5: GIC scores of treatment areas with any improvement as indicated by third-party blind reviewers (BTPR) (photo analysis group 1).

[0286]

[0287] The GIC score was graded from -3 to +3. Scores from +1 to +3 were grouped as improved, while scores from -3 to 0 were grouped as worsened / no improvement. This represents the number (n) of patients assessed as improved relative to the total number of assessments (N). The difference represents the percentage of significant improvement at the TE implant site minus the percentage of significant improvement at the saline control site. A p-value test was used to determine whether the percentage difference (TE implant - saline control) was zero.

[0288] Table 6: GIC scores of the treatment areas by third-party blind reviewers (BTPR) (photo analysis group 1).

[0289]

[0290] GIC scores were graded from -3 to +3. Scores from +1 to +3 were grouped as improved, while scores from -3 to 0 were grouped as worsened / no improvement. The table summarizes the paired differences in GIC (TE implant - saline control). Positive differences indicate a higher GIC at the TE implant site compared to the saline control site. A p-value test was used to determine whether the paired differences (TE implant - saline control) were zero.

[0291] Acne Q&A

[0292] At baseline (day 1), and on days 84, 168, and 336, patients were asked to complete the Acne-Q Questionnaire. The questionnaire consisted of 10 questions that addressed how much their acne scars bothered them. Each question was rated on a four-point scale: 1 = None, 2 = Very little, 3 = Quite a bit, 4 = Very a bit. The ten questions are listed below:

[0293] 1. Your acne scars From a distance How much does it seem to bother you?

[0294] 2. Your acne scars so far heal How bothered are you by the shape (more raised or jagged than you would like)?

[0295] 3. How bothered are you by the size of your acne scars?

[0296] 4. photo What do your acne scars look like? How bothered are you?

[0297] 5. The acne scars you have quantity How much of a disturbance is it to you?

[0298] 6. The color between your acne scars and your skin tone difference How much of a disturbance is it to you?

[0299] 7. In Bright light What do your acne scars look like? How bothersome are they to you?

[0300] 8. Your acne scars are in Mirror How does it seem to bother you?

[0301] 9. Your acne scars Obviousness How much of a disturbance is it to you?

[0302] 10. Your acne scars close up How much does it seem to bother you?

[0303] Klassen et al. (acne-) The level is described in A Guide for Researchers and Clinicians, User Guide Version 1.0, September 2018, McMaster University; cited and incorporated herein by reference.

[0304] This article presents summary statistics on acne scar grading in the PAS1 group.

[0305] Acne scars were scored, with a higher total score indicating a "better" outcome from the patient's perspective. At baseline, there was no statistically significant difference in scores between the two sides of the face in the PAS1 group, with a mean score of 36.7 for the TE implant treatment area and 35.4 for the saline control area. At day 168, patients in the PAS1 group scored higher on their TE implant treatment area (57.4) than on their saline control area (52.0), a difference of 5.370, which was statistically significant from zero (p = 0.014).

[0306] By day 168, the changes in scores relative to baseline were statistically significant for both the TE implant treatment area and the saline control treatment area. Although the changes at the TE implant site were generally larger on average compared to the saline control site, the differences between the two treatment areas were not statistically significant from zero (4.074 for the PAS1 population, p = 0.120).

[0307] Table 7: Acne-Q acne scar scores of the PAS1 group at various time points.

[0308]

[0309] A higher Acne-Q scar score represents a “better” response in patients. A positive change in the Acne-Q scar score relative to baseline indicates that patients report improvement based on questionnaire items.

[0310] Secondary objective analysis

[0311] The third-party blind reviewers were also required to classify the scars as follows:

[0312] - Expandable roller type atrophic acne scars: They will no longer be visible when stretched between your fingers.

[0313] - Van-shaped or van-like scars: Even when stretched between fingers, typical van-shaped scars and scars with distinctive fibrotic edges will remain visible.

[0314] - Ice pick scars: Classic ice pick acne scars.

[0315] Overall, at baseline, 61% and 69% of the scars identified as clinically most prominent by BTPR on the TE implant side and saline control side, respectively, were classified as van-shaped scars. Lower percentages (37% and 26%) of the scars identified as clinically most prominent by BTPR on the TE implant side and saline control side, respectively, were classified as roller-shaped scars. This suggests that van-shaped scars are more likely to be the most prominent scar type. The remaining 2% of scars on the TE implant side and the remaining 5% on the saline control side were classified as ice pick scars.

[0316] To analyze acne scars by scar type, the same procedures used for preliminary efficacy analysis were followed. These analyses were limited to volume, depth, and affected area measured in a 6.0mm camera lateral size setting. For each lesion identified by BTPR as one of the three most clinically relevant acne scar types, the median of three images for each lesion characteristic was used. However, because patients may have a different number of identified lesions, the average of the median values ​​of the lesions identified on each side of the face was used as the total score for the patient / side analysis, rather than the sum of the median values.

[0317] Then, the total score of one side of the face on day 168 was subtracted from the total score of that side of the face on day 0 to calculate the change in the total score of each side of the face relative to the baseline.

[0318] The difference in change from baseline to day 168 between the TE implant-treated side and the saline control side was also calculated. As mentioned earlier, not all patients have bilateral data for this analysis, because in some cases, BTPR identified one of the three most clinically relevant acne scar types on one side of the face but not on the other. This should be taken into account when interpreting the differences in this analysis. Van-type and roller-type injuries were analyzed separately.

[0319] For (PAS1) van-type damage and (PAS1) roller-type damage, simple summary statistics of the total score and the change in the total score relative to the baseline are provided.

[0320] BTPR lesion data for van and roller acne scars were also modeled using regression analysis in accordance with principal efficacy analysis. Results of changes from baseline to day 168 for PAS1 van and roller scars were provided with a camera setting of 6.0 mm. Model results showed that depth, volume, and area measurements in the TE implant treatment area were consistently significantly reduced relative to baseline compared to the saline control treatment area.

[0321] Table 8 below replicates the results for van-type injuries (up to day 168). For van-type injuries identified by BTPR, the test results are generally consistent with those of the primary efficacy analysis, although in this case, there are more or near-statistically significant test results in the differences between the TE implant and the saline control treatment areas, suggesting that TE has a surprisingly greater effect on scars containing fibrotic tissue compared to the saline control.

[0322] Table 8: Regression model estimates of changes in damage area, volume, and depth of BTPR van models from baseline to day 168 (PAS1 group)

[0323]

[0324] Correlation between 3D camera data and overall acne scar severity level

[0325] As part of the study, for both the left and right sides of the facial treatment area, the researchers used six grades from the Global Acne Scar Severity Rating (GSASS or Scar-S, Tan et al. 2010; the entire contents of that literature are incorporated herein by reference) as inclusion criteria at screening and on day 0. The grades are shown in Table 9.

[0326] Table 9: Overall Severity Level of Acne Scars

[0327] category score describe clean 0 Invisible acne scars Very light 1 Acne scars that are almost invisible from 2.5m away Mild 2 Easy to identify; involves less than half of the affected area moderate 3 Involving more than half of the affected area Severe 4 Involving the entire area Extremely severe 5 The entire area has obvious atrophic scars.

[0328] The correlation between GSASS scores on day 0 and photographic measurements of scar lesions on day 1) was assessed. On day 0, the majority of cases had GSASS scores of 3 or 4 (>90%); therefore, the data distribution for this variable may not provide a proper estimate of the true correlation between GSASS and sequential photographic measurements.

[0329] A simple linear regression model was run to estimate the slope of the linear relationship between photo measurements (dependent variable) and GSASS (independent variable). The slope estimate is conventionally understood as the change in photo measurements resulting from a one-unit change in GSASS (from category X to category X+1). It is expected that as GSASS increases, photo measurements also increase, and therefore the slope estimate should be positive. This is indeed the case, as shown in Table 10 below:

[0330] Table 10: Regression estimation for GSASS modeling based on photo data collected on day 0.

[0331]

[0332] The p-value test checks whether the estimated slope is equal to zero and equal to the p-value of a Pearson correlation coefficient of zero. R 2 This is the square of the Pearson correlation coefficient.

[0333] In all cases, the slope estimates were positive, and the measurements by camera setting were significant, with the highest statistical significance observed in the volume and area measurements (for each camera setting tested). For each camera software setting, the highest R-values ​​for area and volume were observed. 2 The high value is not surprising, as GSASS assesses scar visibility from a distance. It should be noted that simple linear regression models do not necessarily consider patient correlations; that is, each patient provides both left and right values ​​for the analysis, which may not be independent of each other—one of the fundamental assumptions of ordinary least squares regression. As mentioned earlier, most of the data is clustered around the two values ​​on the x-axis (GSASS), which can also affect the "generalization" of the results.

[0334] Correlation between 3D camera data and pre- / post-treatment scores by third-party blind reviewers.

[0335] A third-party blind reviewer (BTPR) was required to review photographs taken on day 168 and day 0 in a blinded manner to assess changes in appearance of the treated area according to the GIC grade. For the BTPR, only the treated area and the immediate surrounding area on the face were observable in the reviewed photographs. Patient details were not provided, and patients were randomized to make treatment patterns indistinguishable. The BTPR was also asked to identify three clinically most significant acne scars based on the provided baseline photographs, but without ranking. As part of an additional exploratory analysis, the correlation between the BTPR GIC score and the changes in lesions relative to baseline as determined by the BTPR using 3D camera software was examined.

[0336] Based on previous data, a series of simple linear regression models were developed, with the change in photographic measurements relative to baseline as the dependent variable and the BTPR GIC score as the independent variable. Since a higher GIC score indicates visual improvement, it was expected that the slope of the line would be negative, indicating that each unit increase in the GIC score would lead to a decrease in the measured parameter equal to the slope estimate. This was indeed the case for all photographic measurements, across all tested camera settings, as shown in Table 11 below. In all cases, p-values ​​< 0.05. The slope estimates represent initial estimates of clinically relevant changes in volume, area, and depth.

[0337] Table 11. Regression estimates of the change in damage from baseline to day 168 relative to the BTPR-selected camera data based on the GIC score model.

[0338]

[0339] The p-value test checks whether the estimated slope is equal to zero and equal to the p-value of a Pearson correlation coefficient of zero. R 2 This is the square of the Pearson correlation coefficient.

[0340] discuss

[0341] 3D photoanalysis revealed that the TE implant reduced the volume, area, and depth of treated facial atrophic acne scars, and feedback from third-party blind reviewers showed that the appearance of acne scars was improved.

[0342] The study also found that the TE implant was safe and well-tolerated for men and women with facial atrophic acne scars who received three implants over a 56-day period.

[0343] At baseline and day 168, 3D photographic evaluations of the facial treatment areas were performed using various camera software settings, during which acne lesions and characteristics of the entire treatment area, including color, depth, area, and volume, were determined. The 3D photographic evaluation included assessing skin features at a level incorporating individual acne scars (camera lateral dimension set to 6.0 mm) and at a level across the entire skin contour (camera lateral dimension set to 10.0 mm, where no smaller depressions were detected).

[0344] The modeling results indicate that, based on analytical measurements (6.0 mm setting), scar volume, area, and depth decreased statistically significantly over time after treatment with TE implants. Notably, under camera software settings, the greatest differences between TE implants and saline controls included individual acne scar depressions and the entire skin contour.

[0345] Facial acne lesions treated with TE implants showed the following changes in the PAS1 population:

[0346] - The reduction in acne lesion depth from baseline to day 168, measured using a 6.0mm camera software setting, was -0.43 mm (95% CI: -0.56 mm to -0.30 mm, p < 0.001), representing a 21% reduction relative to baseline. This reduction was statistically significant compared to the reduction observed in acne lesions at saline control sites (p = 0.029).

[0347] - The reduction in acne lesion area from baseline to day 168, measured using a 6.0mm camera with software settings, was -19.10mm. 2 (At 95% CI, it is -23.76mm) 2 Up to -14.44mm 2(p < 0.001), which represents a 24% reduction relative to baseline. This reduction was statistically significant compared to the reduction observed in acne lesions at the saline control site (p < 0.001).

[0348] - The reduction in acne lesion volume from baseline to day 168, measured using a 6.0mm camera with software settings, was -6.83mm. 3 (95% CI: -8.91mm) 3 Up to -4.75mm 3 (p < 0.001), which indicates a 30% reduction relative to baseline. This reduction was statistically significant compared to the reduction observed in acne lesions at the saline control site (p = 0.010).

[0349] Modeling also revealed statistically significant differences in color characteristics and improvements in skin contour across the entire treated area, each more favorable for the TE implant site. Color analysis was performed to assess the change from baseline in the difference between the TE implant-treated area and the saline control treated area, considering seasonal variations in facial skin color. Key results included:

[0350] - The change in the color L* characteristic between the TE implant site and the saline control site from baseline to day 168 was -1.11 (from -1.69 to -0.54 at 95% CI, p < 0.001).

[0351] - The change in the color a* characteristic between the TE implant site and the saline control site from baseline to day 168 was +0.79 (+0.33 to +1.27 at 95% CI, p = 0.002).

[0352] - The change in the color b* characteristic between the TE implant site and the saline control site from baseline to day 168 was -0.63 (from -0.92 to -0.34 at 95% CI, p < 0.001).

[0353] As measured using a larger 10.0mm camera lateral dimension setting, modeling also showed a statistically significant improvement in skin contour across the entire treatment area. Key results from the PAS1 group include:

[0354] - From baseline to day 168, the reduction in skin contour depression area at the TE implant treatment site was -50.12 mm. 3 (95% CI: -66.02mm) 3 Up to -34.21mm 3 (p<0.001; indicating a 47% reduction relative to baseline). This is statistically significantly different from the reduction observed in the saline control area (p<0.001). (Table 3).

[0355] - From baseline to day 168, the reduction in skin contour depression volume at the TE implant treatment area was -22.15 mm. 3 (30.82 mm at 95% CI) 3 Up to -13.48mm 3 (p<0.001; indicating a 50% reduction relative to baseline). This is statistically significantly different from the reduction observed in the saline control area (p=0.014). (Table 3).

[0356] - From baseline to day 168, the increase in skin contour elevation area at the TE implant treatment site was +53.75 mm. 2 (at 95% CI, it is +40.50mm) 2 Up to +67.01mm 2 (p<0.001; indicating an increase of 28% relative to baseline). This is statistically significantly different from the reduction observed in the saline control area (p<0.001). (Table 3).

[0357] - From baseline to day 168, the increase in skin contour elevation volume at the TE implant treatment area was +23.82 mm. 3 (at 95% CI, it is +14.84 mm) 3 Up to +32.80mm 3 (p<0.001; indicating an increase of 27% relative to baseline). This is statistically significantly different from the reduction observed in the saline control area (p<0.001). (Table 3).

[0358] - Neither treatment had a significant effect on either the depth of the contour depression or the height of the contour elevation.

[0359] Using a third-party blinded reviewer's assessment based on the level of change in overall impression, there was also a statistically significant difference between the TE implant treatment area and the saline control treatment area (TE implant side was favorable). In the PAS1 group, on day 168:

[0360] - 70% of BTPR assessments indicated improvement in the TE implant treatment area, and 41% of BTPR assessments indicated improvement in the saline control treatment area (percentage difference, 30%, p = 0.033). (Table 5).

[0361] - The mean difference in GIC assessment for BTPR was 0.48, and TE implants were favorable (p = 0.068). (Table 6).

[0362] Acne scar grading using the Acne-Q questionnaire was derived according to the authors' description (Klassen et al.; incorporated herein by reference). Based on patient responses, acne scar grading scores were similar on both the left and right sides of the face at baseline. By day 168, the acne scar grading score on the TE implant treatment side of the face was significantly higher than that on the saline control side (difference = 5.438 points, p = 0.005). Changes in acne scar grading relative to baseline were also calculated. At day 168, both the TE implant site and the saline control site showed significant improvement relative to baseline (p < 0.001 for both sides). It should be noted that changes relative to baseline were not confirmed by the Acne-Q questionnaire at this point.

[0363] To evaluate the clinical significance of measurements obtained from 3D camera data, on day 0, the correlation between acne scar size measured by 3D camera and GSASS and acne-Q scar grade was assessed; and the change in acne scar size measured by 3D camera was evaluated against the GIC score provided by BTPR.

[0364] Analysis of the relationship between the GSASS assessment conducted on day 0 and the depth, volume, and area measurements taken on day 0 using a 6.0mm camera setup revealed correlations with all three of the following measurements:

[0365] - A single step size in GSASS was associated with a 0.36 mm increase in scar depth across the five measured injuries (0.08 mm to 0.64 mm at 95% CI, p = 0.014). (Table 10).

[0366] - A single step size in GSASS resulted in a 25.83 mm increase in scar area across five measured injuries. 2 The correlation (9.68 mm at 95% CI) is relevant. 2 up to 41.98mm 2 (p = 0.002). (Table 10).

[0367] - A single step size in GSASS resulted in a 10.11 mm increase in scar volume across five measured injuries. 3 The correlation (at 95% CI) was 3.44 mm. 3 Up to 16.78mm 3 (p = 0.004). (Table 10).

[0368] The correlation between acne scar measurements obtained from a 3D camera and the above-mentioned correlations with all three clinical assessment tools clearly demonstrates the clinical significance of 3D camera measurements, and that this correlation can be used to calculate sample size for future clinical studies. This data can also be used to obtain the average step-up in the GIC. Using camera 6.0 settings to measure the area of ​​acne scars, the following changes were observed:

[0369] On day 168; the TE implant group showed a mean reduction of -19.0 mm relative to baseline. 2 This represents approximately 3.7 steps of change in GIC (based on -5.2mm). 2 (the step size value), while the saline control group showed a decrease of -4.2 mm relative to baseline. 2 This indicates a change of approximately 0.8 steps in GIC.

[0370] Analysis revealed that, for measurements of acne scar areas, a 6.0mm camera setting demonstrated a clinically significant difference between the TE implant treatment area and the saline control treatment area. Volume measurements performed using the 6.0mm setting also demonstrated a clinically significant difference between the TE implant treatment area and the saline control treatment area.

[0371] 70% of BTPR assessments indicated improvement in the TE implant treatment area, and 41% of BTPR assessments indicated improvement in the saline control treatment area (percentage difference, 31%, p = 0.012).

[0372] Based on patient responses, at baseline, the Acne-Q Questionnaire acne scar grade scores on the left and right sides of the face were similar. By day 168, the acne scar grade score on the TE implant treatment side of the face was significantly higher than that on the saline control side (difference = 5.438 points, p = 0.005). Changes in acne scar grade relative to baseline were also calculated. Both the TE implant site and the saline control site showed significant improvement relative to baseline (p < 0.001 for both sides).

[0373] Example 2 Uses of TE implants for acne scars

[0374] To treat acne scars, a composition was used comprising rH elastin crosslinked with derived hyaluronic acid to form a biomaterial matrix (30 mg / mL TE crosslinked with 0.5% dHA). This composition has been shown to aid in the repair of atrophic scars in the skin remodeling and maturation stages, thereby improving the appearance of acne scars.

[0375] Patients were treated in an area measuring 2cm × 2cm containing at least two roller-shaped atrophic scars. The composition was applied on days 0, 28, and 56, with a total volume of 0.5mL per treatment. Follow-up was then conducted on days 7, 84, and 168. The study included men and women aged 18 to 55 years. 3D camera performance evaluation.

[0376] Patients also served as their own controls, using saline as a control in other skin areas that were not treated with the TE composition.

[0377] Before treatment, patients reviewed their scars and performed a self-assessment of their acne scars. After treatment, patients further evaluated the appearance of their acne scars. Scar assessment scores were obtained on Day 0 for comparison at the end of treatment.

[0378] Using the Miravex Antera 3D camera system, depressions, bulges, and color can be analyzed within the treatment area and on a per-lesion basis. Treatment area assessment is performed during pre-screening follow-up to ensure selection of bilaterally equivalent treatment areas.

[0379] As studies have shown, this composition has achieved remarkable results in reducing the depth and size of acne scar areas and improving skin tone. For example, patients report smoother, less jagged, improved texture and improved scar edges.

[0380] Surprising results measured using a 3D camera included a 24% reduction in acne scar area at day 168 and a 21% reduction at day 336 compared to the control. A 45% to 50% reduction in contoured depression volume and improved skin tone were also achieved at day 336 post-TE implant treatment, compared to the control.

[0381] Regarding skin color, on days 168 and 336, the L* black-to-white scale was significantly lower in the TE implant treatment area compared to the control treatment area, and on days 168 and 336, the a* green-to-red scale was significantly increased in the TE implant treatment area compared to the control treatment area.

[0382] Further consideration

[0383] In some implementations, any provision of this document may be subordinate to any independent provision or any dependent provision. In one aspect, any provision (e.g., dependent or independent provision) may be combined with any other one or more provisions (e.g., dependent or independent provisions). In one aspect, a claim may include some or all of the words (e.g., steps, operations, apparatus, or components) recited in a provision, sentence, phrase, or paragraph. In one aspect, a claim may include some or all of the words recited in one or more provisions, sentences, phrases, or paragraphs. In one aspect, some words may be removed from each provision, sentence, phrase, or paragraph. In one aspect, additional words or elements may be added to a provision, sentence, phrase, or paragraph. In one aspect, the subject matter may be implemented without utilizing some of the components, elements, functions, or operations described herein. In one aspect, the subject matter may be implemented using other components, elements, functions, or operations.

[0384] For example, the subject matter technique is illustrated by various aspects described below. For convenience, various examples of aspects of the subject matter technique are described as numbered clauses (1, 2, 3, etc.). These are provided as examples and do not limit the subject matter technique. It should be noted that any dependent clauses may be combined in any combination and placed within separate clauses such as Clause 1 or Clause 20. Other clauses may be presented in a similar manner.

[0385] Clause 1. A method for treating a skin area with acne scars to improve the color and / or appearance of acne scars in a skin area of ​​a patient in need, and / or reduce the depth, affected area and / or volume of acne scars, the method comprising applying a composition comprising elastin to the skin area with acne scars.

[0386] Clause 2. The method according to Clause 1, wherein the composition comprises between about 1 mg / mL and about 400 mg / mL of elastin.

[0387] Clause 3. The method according to Clause 1 or 2, wherein the composition comprises 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 2 10 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL or 400 mg / mL of tropoelastin, or any amount of tropoelastin between any two of the aforementioned values.

[0388] Clause 4. The method according to any one of Clauses 1 to 3, wherein the composition comprises between about 1 mg / mL and about 300 mg / mL of elastin.

[0389] Clause 5. The method according to any one of Clauses 1 to 4, wherein the composition comprises between about 1 mg / mL and about 250 mg / mL of elastin.

[0390] Clause 6. The method according to any one of Clauses 1 to 5, wherein the composition comprises between about 1 mg / mL and about 200 mg / mL of elastin.

[0391] Clause 7. The method according to any one of Clauses 1 to 6, wherein the composition comprises between about 1 mg / mL and about 150 mg / mL of elastin.

[0392] Clause 8. The method according to any one of Clauses 1 to 7, wherein the composition comprises between about 1 mg / mL and about 100 mg / mL of elastin.

[0393] Clause 9. The method according to any one of Clauses 1 to 8, wherein the elastin is cross-linked with about 0.1% to about 10% of the derived hyaluronic acid.

[0394] Clause 10. The method according to any one of Clauses 1 to 9, wherein the composition comprises between about 1 mg / mL and about 100 mg / mL of elastin, the elastin being cross-linked with about 0.4% to about 1% of derived hyaluronic acid (HA).

[0395] Clause 11. The method according to any one of Clauses 1 to 9, wherein the composition comprises 30 mg / mL of recombinant human elastin crosslinked with 0.5% of derived hyaluronic acid.

[0396] Clause 12. The method according to any one of Clauses 1 to 11, wherein the composition further comprises phosphate-buffered saline.

[0397] Clause 13. The method according to any one of Clauses 1 to 12, wherein the composition comprising endoelastin is applied around the scar, for example, under the scar and / or around the edge of the scar.

[0398] Clause 14. The method according to any one of Clauses 1 to 13, wherein acne scars are subdivided into ice pick scars, boxcar scars, or roller scars.

[0399] Clause 15. The method according to any one of Clauses 1 to 14, wherein the acne scar is an ice pick scar.

[0400] Clause 16. The method according to any one of Clauses 1 to 14, wherein the acne scar is a box-shaped scar.

[0401] Clause 17. The method according to any one of Clauses 1 to 14, wherein the scar is a roller-shaped atrophic acne scar.

[0402] Clause 18. The method according to any one of Clauses 1 to 14, wherein the scar is a hypertrophic scar.

[0403] Clause 19. The method according to any one of Clauses 1 to 18, wherein the scar comprises fibrotic tissue around or beneath the edge of the scar.

[0404] Clause 20. The method according to any one of Clauses 1 to 19, wherein the depth of the acne scar is from about 0.1 mm to about 5 mm.

[0405] Clause 21. The method according to any one of Clauses 1 to 20, wherein the affected area of ​​the acne scar is approximately 0.05 mm. 2 Approximately 400mm 2 .

[0406] Clause 22. The method according to any one of Clauses 1 to 21, wherein the volume of the acne scar is about 0.01 mm. 3 Up to 2,000mm3 .

[0407] Clause 23. The method according to any one of Clauses 1 to 22, wherein the method further comprises the step of destroying the fibrous bundles beneath the acne scar.

[0408] Clause 24. The method according to Clause 23, wherein a destruction step is performed prior to administering the composition containing tropoelastin to a patient in need.

[0409] Clause 25. The method described in accordance with Clause 23 or 24, wherein the step of destroying the fiber bundles creates a dermal cyst beneath the acne scar.

[0410] Clause 26. The method according to Clause 25, wherein the destructive steps are performed using 18G, 21G, 23G, 25G, 27G, 29G or 30G needles.

[0411] Clause 27. The method according to Clause 25 or 26, wherein application comprises injecting the composition into a dermal capsule.

[0412] Clause 28. The method according to any one of Clauses 1 to 27, wherein the composition is applied as an injectable substance under the acne scar.

[0413] Clause 29. The method according to any one of Clauses 1 to 13, wherein the composition is administered in a volume of about 10 μL to about 100 μL per implantation / injection.

[0414] Clause 30. The method according to any one of Clauses 28 to 29, wherein retrograde threading technique is used to perform injections with a cross-thread arrangement to destroy fibrous bundles within acne scars.

[0415] Clause 31. The method according to Clause 30, wherein the needle is inserted into the skin area with acne scars at an angle of about 30° parallel to the skin, and wherein the needle is at an angle and the angle is upward.

[0416] Clause 32. The method according to Clause 31, wherein a needle is inserted into the skin area with acne scars more than once to break the fiber bundles and create a dermal cyst.

[0417] Clause 33. The method according to Clause 32, wherein uniform pressure is applied while the needle is withdrawn from the dermal sac to inject the composition.

[0418] Clause 34. The method according to any one of Clauses 1 to 33, wherein the composition is applied repeatedly, and wherein the composition is applied once or more in a bolus to the scar.

[0419] Clause 35. The method according to any one of Clauses 1 to 34, wherein the maximum volume of the composition applied is between about 100 μL and about 5 mL.

[0420] Clause 36. The method according to any one of Clauses 1 to 35, wherein the maximum volume of the composition applied is about 100 μL / cm³. 2 Approximately 500 μL / cm 2 between.

[0421] Clause 37. The method according to any one of Clauses 1 to 35, wherein the patient in need has a skin type of type I, II, III, IV, V or VI in the Fitzpatrick skin type classification.

[0422] Clause 38. The method according to any one of Clauses 1 to 37, wherein the scar includes grade 1, grade 2, grade 3, grade 4 or grade 5.

[0423] Clause 39. The method according to any one of Clauses 1 to 38, wherein the skin has a skin color defined by CIE L*a*b* color coordinates, wherein the method further reduces L*.

[0424] Clause 40. The method according to Clause 39, wherein the method reduces L* 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 foregoing values.

[0425] Clause 41. The method described in accordance with Clause 39 or 40, wherein the method further increases a*.

[0426] Clause 42. The method according to Clause 41, wherein the method increases a* 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 foregoing values.

[0427] Clause 43. The method according to any one of Clauses 1 to 42, wherein the scar has a silver coloration prior to application of the composition.

[0428] Clause 44. The method according to Clause 43, wherein the application of the composition reduces the silver coloration of the scar and increases the red and / or pink coloration of the scar.

[0429] Clause 45. The method according to Clause 44, wherein the method reduces L* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or more than about 50%, or any amount defined by the range between any two of the foregoing values, and increases a* by about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or more than about 50%, or any amount defined by the range between any two of the foregoing values.

[0430] Clause 46. The method according to any one of Clauses 1 to 45, wherein the scar has color, wherein the color is different from the patient's natural skin color, and wherein the application of the composition causes the color of the scar to decrease or fade in terms of color intensity, such that the color of the scar becomes one with the patient's natural skin color.

[0431] Clause 47. The method according to any one of Clauses 1 to 46, wherein the acne scar is a facial scar, a back scar, or a trunk scar.

[0432] Clause 48. The method according to any one of Clauses 1 to 47, wherein after application of the composition, the depth, affected area and / or volume of acne scars are reduced.

[0433] Clause 49. The method according to any one of Clauses 1 to 48, wherein the treatment helps to repair atrophic scars in the skin remodeling and maturation stage, thereby improving the appearance of acne scars.

[0434] Clause 50. The method according to any one of Clauses 1 to 49, wherein the treatment reduces the area of ​​acne scars 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 any two of the foregoing values.

[0435] Clause 51. The method according to any one of Clauses 1 to 50, wherein the treatment reduces the volume of the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between any two of the foregoing values.

[0436] Clause 52. The method according to any one of Clauses 1 to 51, wherein the treatment reduces the depth of the acne scar by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or more than about 90%, or any amount between any two of the foregoing values.

[0437] Clause 53. The method according to any one of Clauses 1 to 52, wherein the treatment reduces the volume and area of ​​the depression of the skin contour in the skin region with acne scars 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 any two of the foregoing values.

[0438] Clause 54. The method according to any one of Clauses 1 to 53, wherein the treatment further improves the skin tone of the acne scars.

[0439] Clause 55. The method according to any one of Clauses 1 to 54, wherein the treatment increases the volume and area of ​​the raised skin contour in the skin region with acne scars 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 any two of the foregoing values.

[0440] Clause 56. The method according to any one of Clauses 53 to 55, wherein the treatment flattens the skin contour in the skin area with acne scars.

[0441] Clause 57. The method according to any one of Clauses 1 to 56, wherein the treatment reduces the L* black-to-white scale in the skin area with acne scars compared to a control treatment.

[0442] Clause 58. A method for repairing the skin contour affected by acne scars in a subject in need, the method comprising: applying a composition comprising elastin to a skin area having the skin contour affected by acne scars.

[0443] Clause 59. The method according to Clause 58, wherein the composition comprises between about 1 mg / mL and about 400 mg / mL of elastin.

[0444] Clause 60. The method according to Clause 58 or 59, wherein the composition comprises 1 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 30 mg / mL, 40 mg / mL, 50 mg / mL, 60 mg / mL, 70 mg / mL, 80 mg / mL, 90 mg / mL, 100 mg / mL, 110 mg / mL, 120 mg / mL, 130 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL, 180 mg / mL, 190 mg / mL, 200 mg / mL, 210 mg / mL, 220 mg / mL, 230 mg / mL, 240 mg / mL, 250 mg / mL, 260 mg / mL, 270 mg / mL, 280 mg / mL, 290 mg / mL, 300 mg / mL, 310 mg / mL, 320 mg / mL, 330 mg / mL, 340 mg / mL, 350 mg / mL, 360 mg / mL, 370 mg / mL, 380 mg / mL, 390 mg / mL or 400 mg / mL of tropoelastin, or any amount of tropoelastin within the range defined by any two of the foregoing values.

[0445] Clause 61. The method according to any one of Clauses 58 to 60, wherein the composition comprises between about 1 mg / mL and about 300 mg / mL of elastin.

[0446] Clause 62. The method according to any one of Clauses 58 to 61, wherein the composition comprises between about 1 mg / mL and about 250 mg / mL of elastin.

[0447] Clause 63. The method according to any one of Clauses 58 to 62, wherein the composition comprises between about 1 mg / mL and about 200 mg / mL of elastin.

[0448] Clause 64. The method according to any one of Clauses 58 to 63, wherein the composition comprises between about 1 mg / mL and about 150 mg / mL of elastin.

[0449] Clause 65. The method according to any one of Clauses 58 to 64, wherein the composition comprises between about 1 mg / mL and about 100 mg / mL of elastin.

[0450] Clause 66. The method according to any one of Clauses 58 to 65, wherein the elastin is cross-linked with about 0.1% to about 10% of the derived hyaluronic acid.

[0451] Clause 67. The method according to any one of Clauses 58 to 66, wherein the composition comprises between about 1 mg / mL and about 100 mg / mL of elastin, the elastin being cross-linked with about 0.4% to about 1% of derived hyaluronic acid (HA).

[0452] Clause 68. The method according to any one of Clauses 58 to 67, wherein the composition comprises 30 mg / mL of recombinant human elastin crosslinked with 0.5% of derived hyaluronic acid.

[0453] Clause 69. The method according to any one of Clauses 58 to 68, wherein the composition is applied around the scar, for example below the scar and / or around the edge of the scar.

[0454] The above description is provided to enable those skilled in the art to practice the various configurations described herein. Although the subject matter has been specifically described with reference to various accompanying drawings and configurations, it should be understood that these are for illustrative purposes only and should not be considered as limiting the scope of the subject matter.

[0455] Many other ways may be used to implement the techniques described herein. Various functions and elements may differ from those described herein without departing from the scope of the techniques described herein. These various modifications to the configurations will be apparent to those skilled in the art, and the general principles defined herein can be applied to other configurations. Therefore, those skilled in the art can make many changes and modifications to the techniques described herein without departing from the scope of the techniques described herein.

[0456] It should be understood that the specific order or hierarchy of steps in the disclosed process is an illustration of an exemplary method. It should be understood that the specific order or hierarchy of steps in the process can be rearranged based on design preferences. Some steps may be performed simultaneously. The appended method claims present the elements of each step in an exemplary order, but are not intended to limit one to the presented specific order or hierarchy.

[0457] As used herein, the phrase “at least one” preceding a series of items, and the terms “and” or “or” used to separate any items, modify the list as a whole, not each member of the list (i.e., each item). The phrase “at least one” does not require selection of at least one of each of the listed items; rather, the phrase can encompass the meaning of at least one of any one item, and / or at least one of any combination of items, and / or at least one of each item. For example, the phrases “at least one A, B, and C” or “at least one A, B, or C” each refer to only A, only B, or only C; any combination of A, B, and C; and / or at least one of each of A, B, and C.

[0458] Terms such as “top,” “bottom,” “front,” and “back” used in this disclosure should be understood as referring to any frame of reference, rather than a conventional gravitational frame of reference. Therefore, the top surface, bottom surface, front surface, and back surface can extend upwards, downwards, diagonally, or horizontally in a gravitational frame of reference.

[0459] Furthermore, with regard to the terms “comprising,” “having,” etc., used in the specification or claims, these terms are intended to be inclusive in the same way as the term “comprising,” as indicated when “comprising” is used as a transitional word in the claims.

[0460] The term "exemplary" as used herein means "used as an example, illustration, or explanation." Any "exemplary" implementation described herein is not necessarily to be construed as preferred or advantageous over some other implementations.

[0461] Unless otherwise specified, elements referred to in the singular are not intended to mean "one and only one," but rather "one or more." Male pronouns (e.g., his) include female and neuter pronouns (e.g., her and its), and vice versa. The term "some" means one or more. Underlined and / or italicized headings and subheadings are used for convenience only, do not limit the subject matter, and are not intended to be interpreted in conjunction with the description of the subject matter. All structural and functional equivalents of elements in the various configurations described herein that are known or will be known hereafter by one of ordinary skill in the art are expressly incorporated herein by reference and are intended to be covered by the subject matter. Furthermore, nothing disclosed herein is intended to be offered to the public, whether or not such disclosure is expressly stated in the foregoing description. SEQUENCE LISTING <110> Allergan Pharmaceuticals International Ltd. <120> Fibroelastin used to treat acne scars <130> 122320-5930 <150> 62 / 891,232 <151> 2019-08-23 <160> 15 <170> PatentIn version 3.5 <210> 1 <211> 698 <212> PRT <213> Artificial Sequence <220> <223> SHELδ26A <400> 1 Gly Gly Val Pro Gly Ala Ile Pro Gly Gly Val Pro Gly Gly Val Phe 1 5 10 15 Tyr Pro Gly Ala Gly Leu Gly Ala Leu Gly Gly Gly Ala Leu Gly Pro 20 25 30 Gly Gly Lys Pro Leu Lys Pro Val Pro Gly Gly Leu Ala Gly Ala Gly 35 40 45 Leu Gly Ala Gly Leu Gly Ala Phe Pro Ala Val Thr Phe Pro Gly Ala 50 55 60 Leu Val Pro Gly Gly Val Ala Asp Ala Ala Ala Ala Tyr Lys Ala Ala 65 70 75 80 Lys Ala Gly Ala Gly Leu Gly Gly Val Pro Gly Val Gly Gly Leu Gly 85 90 95 Val Ser Ala Gly Ala Val Val Pro Gln Pro Gly Ala Gly Val Lys Pro 100 105 110 Gly Lys Val Pro Gly Val Gly Leu Pro Gly Val Tyr Pro Gly Gly Val 115 120 125 Leu Pro Gly Ala Arg Phe Pro Gly Val Gly Val Leu Pro Gly Val Pro 130 135 140 Thr Gly Ala Gly Val Lys Pro Lys Ala Pro Gly Val Gly Gly Ala Phe 145 150 155 160 Ala Gly Ile Pro Gly Val Gly Pro Phe Gly Gly Pro Gln Pro Gly Val 165 170 175 Pro Leu Gly Tyr Pro Ile Lys Ala Pro Lys Leu Pro Gly Gly Tyr Gly 180 185 190 Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro Gly Gly 195 200 205 Val Ala Gly Ala Ala Gly Lys Ala Gly Tyr Pro Thr Gly Thr Gly Val 210 215 220 Gly Pro Gln Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Phe 225 230 235 240 Gly Ala Gly Ala Ala Gly Val Leu Pro Gly Val Gly Gly Ala Gly Val 245 250 255 Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly Gly Ile Ala Gly Val 260 265 270 Gly Thr Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala 275 280 285 Lys Tyr Gly Ala Ala Ala Gly Leu Val Pro Gly Gly Pro Gly Phe Gly 290 295 300 Pro Gly Val Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val 305 310 315 320 Pro Gly Ala Gly Ile Pro Val Val Pro Gly Ala Gly Ile Pro Gly Ala 325 330 335 Ala Val Pro Gly Val Val Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala 340 345 350 Lys Ala Ala Lys Tyr Gly Ala Arg Pro Gly Val Gly Val Gly Gly Ile 355 360 365 Pro Thr Tyr Gly Val Gly Ala Gly Gly Phe Pro Gly Phe Gly Val Gly 370 375 380 Val Gly Gly Ile Pro Gly Val Ala Gly Val Pro Ser Val Gly Gly Val 385 390 395 400 Pro Gly Val Gly Gly Val Pro Gly Val Gly Ile Ser Pro Glu Ala Gln 405 410 415 Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala 420 425 430 Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val 435 440 445 Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly 450 455 460 Val Ala Pro Gly Val Gly Leu Ala Pro Gly Val Gly Val Ala Pro Gly 465 470 475 480 Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Ile Gly Pro Gly 485 490 495 Gly Val Ala Ala Ala Ala Lys Ser Ala Ala Lys Val Ala Ala Lys Ala 500 505 510 Gln Leu Arg Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly 515 520 525 Val Gly Val Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly 530 535 540 Leu Gly Val Gly Ala Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala 545 550 555 560 Leu Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val 565 570 575 Leu Gly Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val 580 585 590 Val Gly Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala 595 600 605 Lys Ala Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu 610 615 620 Gly Val Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile 625 630 635 640 Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu 645 650 655 Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala 660 665 670 Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys 675 680 685 Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 690 695 <210> 2 <211> 733 <212> PRT <213> Artificial Sequence <220> <223> SHEL Isoform <400> 2 Ser Met Gly Gly Val Pro Gly Ala Ile Pro Gly Gly Val Pro Gly Gly 1 5 10 15 Val Phe Tyr Pro Gly Ala Gly Leu Gly Ala Leu Gly Gly Gly Ala Leu 20 25 30 Gly Pro Gly Gly Lys Pro Leu Lys Pro Val Pro Gly Gly Leu Ala Gly 35 40 45 Ala Gly Leu Gly Ala Gly Leu Gly Ala Phe Pro Ala Val Thr Phe Pro 50 55 60 Gly Ala Leu Val Pro Gly Gly Val Ala Asp Ala Ala Ala Ala Tyr Lys 65 70 75 80 Ala Ala Lys Ala Gly Ala Gly Leu Gly Gly Val Pro Gly Val Gly Gly 85 90 95 Leu Gly Val Ser Ala Gly Ala Val Val Pro Gln Pro Gly Ala Gly Val 100 105 110 Lys Pro Gly Lys Val Pro Gly Val Gly Leu Pro Gly Val Tyr Pro Gly 115 120 125 Gly Val Leu Pro Gly Ala Arg Phe Pro Gly Val Gly Val Leu Pro Gly 130 135 140 Val Pro Thr Gly Ala Gly Val Lys Pro Lys Ala Pro Gly Val Gly Gly 145 150 155 160 Ala Phe Ala Gly Ile Pro Gly Val Gly Pro Phe Gly Gly Pro Gln Pro 165 170 175 Gly Val Pro Leu Gly Tyr Pro Ile Lys Ala Pro Lys Leu Pro Gly Gly 180 185 190 Tyr Gly Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro 195 200 205 Gly Gly Val Ala Gly Ala Ala Gly Lys Ala Gly Tyr Pro Thr Gly Thr 210 215 220 Gly Val Gly Pro Gln Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala 225 230 235 240 Lys Phe Gly Ala Gly Ala Ala Gly Val Leu Pro Gly Val Gly Gly Ala 245 250 255 Gly Val Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly Gly Ile Ala 260 265 270 Gly Val Gly Thr Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys 275 280 285 Ala Ala Lys Tyr Gly Ala Ala Ala Gly Leu Val Pro Gly Gly Pro Gly 290 295 300 Phe Gly Pro Gly Val Val Gly Val Pro Gly Ala Gly Val Pro Gly Val 305 310 315 320 Gly Val Pro Gly Ala Gly Ile Pro Val Val Pro Gly Ala Gly Ile Pro 325 330 335 Gly Ala Ala Val Pro Gly Val Val Ser Pro Glu Ala Ala Ala Lys Ala 340 345 350 Ala Ala Lys Ala Ala Lys Tyr Gly Ala Arg Pro Gly Val Gly Val Gly 355 360 365 Gly Ile Pro Thr Tyr Gly Val Gly Ala Gly Gly Phe Pro Gly Phe Gly 370 375 380 Val Gly Val Gly Gly Ile Pro Gly Val Ala Gly Val Pro Ser Val Gly 385 390 395 400 Gly Val Pro Gly Val Gly Gly Val Pro Gly Val Gly Ile Ser Pro Glu 405 410 415 Ala Gln Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Val Gly Thr 420 425 430 Pro Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly 435 440 445 Leu Val Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly 450 455 460 Val Gly Val Ala Pro Gly Val Gly Leu Ala Pro Gly Val Gly Val Ala 465 470 475 480 Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Ile Gly 485 490 495 Pro Gly Gly Val Ala Ala Ala Ala Lys Ser Ala Ala Lys Val Ala Ala 500 505 510 Lys Ala Gln Leu Arg Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly 515 520 525 Leu Gly Val Gly Val Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val 530 535 540 Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Phe Gly Ala Gly Ala 545 550 555 560 Asp Glu Gly Val Arg Arg Ser Leu Ser Pro Glu Leu Arg Glu Gly Asp 565 570 575 Pro Ser Ser Ser Gln His Leu Pro Ser Thr Pro Ser Ser Pro Arg Val 580 585 590 Pro Gly Ala Leu Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val 595 600 605 Pro Gly Val Leu Gly Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro 610 615 620 Gly Gly Val Val Gly Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys 625 630 635 640 Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu 645 650 655 Gly Gly Leu Gly Val Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu 660 665 670 Gly Gly Ile Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala 675 680 685 Ala Gly Leu Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly 690 695 700 Gly Val Ala Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly 705 710 715 720 Gly Ala Cys Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 725 730 <210> 3 <211> 698 <212> PRT <213> Artificial Sequence <220> <223> SHELδ26A Isoform <400> 3 Gly Gly Val Pro Gly Ala Ile Pro Gly Gly Val Pro Gly Gly Val Phe 1 5 10 15 Tyr Pro Gly Ala Gly Leu Gly Ala Leu Gly Gly Gly Ala Leu Gly Pro 20 25 30 Gly Gly Lys Pro Leu Lys Pro Val Pro Gly Gly Leu Ala Gly Ala Gly 35 40 45 Leu Gly Ala Gly Leu Gly Ala Phe Pro Ala Val Thr Phe Pro Gly Ala 50 55 60 Leu Val Pro Gly Gly Val Ala Asp Ala Ala Ala Ala Tyr Lys Ala Ala 65 70 75 80 Lys Ala Gly Ala Gly Leu Gly Gly Val Pro Gly Val Gly Gly Leu Gly 85 90 95 Val Ser Ala Gly Ala Val Val Pro Gln Pro Gly Ala Gly Val Lys Pro 100 105 110 Gly Lys Val Pro Gly Val Gly Leu Pro Gly Val Tyr Pro Gly Gly Val 115 120 125 Leu Pro Gly Ala Arg Phe Pro Gly Val Gly Val Leu Pro Gly Val Pro 130 135 140 Thr Gly Ala Gly Val Lys Pro Lys Ala Pro Gly Val Gly Gly Ala Phe 145 150 155 160 Ala Gly Ile Pro Gly Val Gly Pro Phe Gly Gly Pro Gln Pro Gly Val 165 170 175 Pro Leu Gly Tyr Pro Ile Lys Ala Pro Lys Leu Pro Gly Gly Tyr Gly 180 185 190 Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro Gly Gly 195 200 205 Val Ala Gly Ala Ala Gly Lys Ala Gly Tyr Pro Thr Gly Thr Gly Val 210 215 220 Gly Pro Gln Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Phe 225 230 235 240 Gly Ala Gly Ala Ala Gly Val Leu Pro Gly Val Gly Gly Ala Gly Val 245 250 255 Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly Gly Ile Ala Gly Val 260 265 270 Gly Thr Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala 275 280 285 Lys Tyr Gly Ala Ala Ala Gly Leu Val Pro Gly Gly Pro Gly Phe Gly 290 295 300 Pro Gly Val Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val 305 310 315 320 Pro Gly Ala Gly Ile Pro Val Val Pro Gly Ala Gly Ile Pro Gly Ala 325 330 335 Ala Val Pro Gly Val Val Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala 340 345 350 Lys Ala Ala Lys Tyr Gly Ala Arg Pro Gly Val Gly Val Gly Gly Ile 355 360 365 Pro Thr Tyr Gly Val Gly Ala Gly Gly Phe Pro Gly Phe Gly Val Gly 370 375 380 Val Gly Gly Ile Pro Gly Val Ala Gly Val Pro Ser Val Gly Gly Val 385 390 395 400 Pro Gly Val Gly Gly Val Pro Gly Val Gly Ile Ser Pro Glu Ala Gln 405 410 415 Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala 420 425 430 Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val 435 440 445 Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly 450 455 460 Val Ala Pro Gly Val Gly Leu Ala Pro Gly Val Gly Val Ala Pro Gly 465 470 475 480 Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Ile Gly Pro Gly 485 490 495 Gly Val Ala Ala Ala Ala Lys Ser Ala Ala Lys Val Ala Ala Lys Ala 500 505 510 Gln Leu Arg Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly 515 520 525 Val Gly Val Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly 530 535 540 Leu Gly Val Gly Ala Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala 545 550 555 560 Leu Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val 565 570 575 Leu Gly Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val 580 585 590 Val Gly Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala 595 600 605 Lys Ala Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu 610 615 620 Gly Val Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile 625 630 635 640 Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu 645 650 655 Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala 660 665 670 Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys 675 680 685 Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 690 695 <210> 4 <211> 660 <212> PRT <213> Artificial Sequence <220> <223> SHELδmod isotype <400> 4 Gly Gly Val Pro Gly Ala Val Pro Gly Gly Val Pro Gly Gly Val Phe 1 5 10 15 Tyr Pro Gly Ala Gly Phe Gly Ala Val Pro Gly Gly Val Ala Asp Ala 20 25 30 Ala Ala Ala Tyr Lys Ala Ala Lys Ala Gly Ala Gly Leu Gly Gly Val 35 40 45 Pro Gly Val Gly Gly Leu Gly Val Ser Ala Gly Ala Val Val Pro Gln 50 55 60 Pro Gly Ala Gly Val Lys Pro Gly Lys Val Pro Gly Val Gly Leu Pro 65 70 75 80 Gly Val Tyr Pro Gly Phe Gly Ala Val Pro Gly Ala Arg Phe Pro Gly 85 90 95 Val Gly Val Leu Pro Gly Val Pro Thr Gly Ala Gly Val Lys Pro Lys 100 105 110 Ala Pro Gly Val Gly Gly Ala Phe Ala Gly Ile Pro Gly Val Gly Pro 115 120 125 Phe Gly Gly Pro Gln Pro Gly Val Pro Leu Gly Tyr Pro Ile Lys Ala 130 135 140 Pro Lys Leu Pro Gly Gly Tyr Gly Leu Pro Tyr Thr Thr Gly Lys Leu 145 150 155 160 Pro Tyr Gly Tyr Gly Pro Gly Gly Val Ala Gly Ala Ala Gly Lys Ala 165 170 175 Gly Tyr Pro Thr Gly Thr Gly Val Gly Pro Gln Ala Ala Ala Ala Ala 180 185 190 Ala Ala Lys Ala Ala Ala Lys Phe Gly Ala Gly Ala Ala Gly Phe Gly 195 200 205 Ala Val Pro Gly Val Gly Gly Ala Gly Val Pro Gly Val Pro Gly Ala 210 215 220 Ile Pro Gly Ile Gly Gly Ile Ala Gly Val Gly Thr Pro Ala Ala Ala 225 230 235 240 Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Ala 245 250 255 Gly Leu Val Pro Gly Gly Pro Gly Phe Gly Pro Gly Val Val Gly Val 260 265 270 Pro Gly Phe Gly Ala Val Pro Gly Val Gly Val Pro Gly Ala Gly Ile 275 280 285 Pro Val Val Pro Gly Ala Gly Ile Pro Gly Ala Ala Gly Phe Gly Ala 290 295 300 Val Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Lys Tyr 305 310 315 320 Gly Ala Arg Pro Gly Val Gly Val Gly Gly Ile Pro Thr Tyr Gly Val 325 330 335 Gly Ala Gly Gly Phe Pro Gly Phe Gly Val Gly Val Gly Gly Ile Pro 340 345 350 Gly Val Ala Gly Val Pro Ser Val Gly Gly Val Pro Gly Val Gly Gly 355 360 365 Val Pro Gly Val Gly Ile Ser Pro Glu Ala Gln Ala Ala Ala Ala Ala 370 375 380 Lys Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala Ala Ala Ala Ala Lys 385 390 395 400 Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val Pro Gly Val Gly Val 405 410 415 Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val 420 425 430 Gly Leu Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro 435 440 445 Gly Val Gly Val Ala Pro Gly Ile Gly Pro Gly Gly Val Ala Ala Ala 450 455 460 Ala Lys Ser Ala Ala Lys Val Ala Ala Lys Ala Gln Leu Arg Ala Ala 465 470 475 480 Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly Val Gly Val Gly Val 485 490 495 Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Leu Gly Val Gly Ala 500 505 510 Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala Leu Ala Ala Ala Lys 515 520 525 Ala Ala Lys Tyr Gly Ala Val Pro Gly Val Leu Gly Gly Leu Gly Ala 530 535 540 Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly Ala Gly Pro Ala 545 550 555 560 Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly 565 570 575 Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val Gly Gly Leu Gly 580 585 590 Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro Ala Ala Ala Ala 595 600 605 Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly Val Leu Gly Gly 610 615 620 Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg Pro Gly Phe Gly 625 630 635 640 Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly Lys Ala Cys Gly 645 650 655 Arg Lys Arg Lys 660 <210> 5 <211> 732 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 5 Ser Met Gly Gly Val Pro Gly Ala Ile Pro Gly Gly Val Pro Gly Gly 1 5 10 15 Val Phe Tyr Pro Gly Ala Gly Leu Gly Ala Leu Gly Gly Gly Ala Leu 20 25 30 Gly Pro Gly Gly Lys Pro Leu Lys Pro Val Pro Gly Gly Leu Ala Gly 35 40 45 Ala Gly Leu Gly Ala Gly Leu Gly Ala Phe Pro Ala Val Thr Phe Pro 50 55 60 Gly Ala Leu Val Pro Gly Gly Val Ala Asp Ala Ala Ala Ala Tyr Lys 65 70 75 80 Ala Ala Lys Ala Gly Ala Gly Leu Gly Gly Val Pro Gly Val Gly Gly 85 90 95 Leu Gly Val Ser Ala Gly Ala Val Val Pro Gln Pro Gly Ala Gly Val 100 105 110 Lys Pro Gly Lys Val Pro Gly Val Gly Leu Pro Gly Val Tyr Pro Gly 115 120 125 Gly Val Leu Pro Gly Ala Arg Phe Pro Gly Val Gly Val Leu Pro Gly 130 135 140 Val Pro Thr Gly Ala Gly Val Lys Pro Lys Ala Pro Gly Val Gly Gly 145 150 155 160 Ala Phe Ala Gly Ile Pro Gly Val Gly Pro Phe Gly Gly Pro Gln Pro 165 170 175 Gly Val Pro Leu Gly Tyr Pro Ile Lys Ala Pro Lys Leu Pro Gly Gly 180 185 190 Tyr Gly Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro 195 200 205 Gly Gly Val Ala Gly Ala Ala Gly Lys Ala Gly Tyr Pro Thr Gly Thr 210 215 220 Gly Val Gly Pro Gln Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala 225 230 235 240 Lys Phe Gly Ala Gly Ala Ala Gly Val Leu Pro Gly Val Gly Gly Ala 245 250 255 Gly Val Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly Gly Ile Ala 260 265 270 Gly Val Gly Thr Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys 275 280 285 Ala Ala Lys Tyr Gly Ala Ala Ala Gly Leu Val Pro Gly Gly Pro Gly 290 295 300 Phe Gly Pro Gly Val Val Gly Val Pro Gly Ala Gly Val Pro Gly Val 305 310 315 320 Gly Val Pro Gly Ala Gly Ile Pro Val Val Pro Gly Ala Gly Ile Pro 325 330 335 Gly Ala Ala Val Pro Gly Val Val Ser Pro Glu Ala Ala Ala Lys Ala 340 345 350 Ala Ala Lys Ala Ala Lys Tyr Gly Ala Arg Pro Gly Val Gly Val Gly 355 360 365 Gly Ile Pro Thr Tyr Gly Val Gly Ala Gly Gly Phe Pro Gly Phe Gly 370 375 380 Val Gly Val Gly Gly Ile Pro Gly Val Ala Gly Val Pro Ser Val Gly 385 390 395 400 Gly Val Pro Gly Val Gly Gly Val Pro Gly Val Gly Ile Ser Pro Glu 405 410 415 Ala Gln Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Val Gly Thr 420 425 430 Pro Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly 435 440 445 Leu Val Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly 450 455 460 Val Gly Val Ala Pro Gly Val Gly Leu Ala Pro Gly Val Gly Val Ala 465 470 475 480 Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Ile Gly 485 490 495 Pro Gly Gly Val Ala Ala Ala Ala Lys Ser Ala Ala Lys Val Ala Ala 500 505 510 Lys Ala Gln Leu Arg Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly 515 520 525 Leu Gly Val Gly Val Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val 530 535 540 Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Phe Gly Ala Gly Ala 545 550 555 560 Asp Glu Gly Val Arg Arg Ser Leu Ser Pro Glu Leu Arg Glu Gly Asp 565 570 575 Pro Ser Ser Ser Gln His Leu Pro Ser Thr Pro Ser Ser Pro Arg Val 580 585 590 Pro Gly Ala Leu Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val 595 600 605 Pro Gly Val Leu Gly Gly Leu Gly Ala Leu Gly Val Gly Ile Pro Gly 610 615 620 Gly Val Val Gly Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala 625 630 635 640 Ala Ala Lys Ala Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly 645 650 655 Gly Leu Gly Val Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly 660 665 670 Gly Ile Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala 675 680 685 Gly Leu Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly 690 695 700 Val Ala Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly 705 710 715 720 Ala Cys Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 725 730 <210> 6 <211> 698 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 6 Gly Gly Val Pro Gly Ala Ile Pro Gly Gly Val Pro Gly Gly Val Phe 1 5 10 15 Tyr Pro Gly Ala Gly Leu Gly Ala Leu Gly Gly Gly Ala Leu Gly Pro 20 25 30 Gly Gly Lys Pro Leu Lys Pro Val Pro Gly Gly Leu Ala Gly Ala Gly 35 40 45 Leu Gly Ala Gly Leu Gly Ala Phe Pro Ala Val Thr Phe Pro Gly Ala 50 55 60 Leu Val Pro Gly Gly Val Ala Asp Ala Ala Ala Ala Tyr Lys Ala Ala 65 70 75 80 Lys Ala Gly Ala Gly Leu Gly Gly Val Pro Gly Val Gly Gly Leu Gly 85 90 95 Val Ser Ala Gly Ala Val Val Pro Gln Pro Gly Ala Gly Val Lys Pro 100 105 110 Gly Lys Val Pro Gly Val Gly Leu Pro Gly Val Tyr Pro Gly Gly Val 115 120 125 Leu Pro Gly Ala Arg Phe Pro Gly Val Gly Val Leu Pro Gly Val Pro 130 135 140 Thr Gly Ala Gly Val Lys Pro Lys Ala Pro Gly Val Gly Gly Ala Phe 145 150 155 160 Ala Gly Ile Pro Gly Val Gly Pro Phe Gly Gly Pro Gln Pro Gly Val 165 170 175 Pro Leu Gly Tyr Pro Ile Lys Ala Pro Lys Leu Pro Gly Gly Tyr Gly 180 185 190 Leu Pro Tyr Thr Thr Gly Lys Leu Pro Tyr Gly Tyr Gly Pro Gly Gly 195 200 205 Val Ala Gly Ala Ala Gly Lys Ala Gly Tyr Pro Thr Gly Thr Gly Val 210 215 220 Gly Pro Gln Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Phe 225 230 235 240 Gly Ala Gly Ala Ala Gly Val Leu Pro Gly Val Gly Gly Ala Gly Val 245 250 255 Pro Gly Val Pro Gly Ala Ile Pro Gly Ile Gly Gly Ile Ala Gly Val 260 265 270 Gly Thr Pro Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala 275 280 285 Lys Tyr Gly Ala Ala Ala Gly Leu Val Pro Gly Gly Pro Gly Phe Gly 290 295 300 Pro Gly Val Val Gly Val Pro Gly Ala Gly Val Pro Gly Val Gly Val 305 310 315 320 Pro Gly Ala Gly Ile Pro Val Val Pro Gly Ala Gly Ile Pro Gly Ala 325 330 335 Ala Val Pro Gly Val Val Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala 340 345 350 Lys Ala Ala Lys Tyr Gly Ala Arg Pro Gly Val Gly Val Gly Gly Ile 355 360 365 Pro Thr Tyr Gly Val Gly Ala Gly Gly Phe Pro Gly Phe Gly Val Gly 370 375 380 Val Gly Gly Ile Pro Gly Val Ala Gly Val Pro Ser Val Gly Gly Val 385 390 395 400 Pro Gly Val Gly Gly Val Pro Gly Val Gly Ile Ser Pro Glu Ala Gln 405 410 415 Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala 420 425 430 Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val 435 440 445 Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly 450 455 460 Val Ala Pro Gly Val Gly Leu Ala Pro Gly Val Gly Val Ala Pro Gly 465 470 475 480 Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Ile Gly Pro Gly 485 490 495 Gly Val Ala Ala Ala Ala Lys Ser Ala Ala Lys Val Ala Ala Lys Ala 500 505 510 Gln Leu Arg Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly 515 520 525 Val Gly Val Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly 530 535 540 Leu Gly Val Gly Ala Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala 545 550 555 560 Leu Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val 565 570 575 Leu Gly Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val 580 585 590 Val Gly Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala 595 600 605 Lys Ala Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu 610 615 620 Gly Val Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile 625 630 635 640 Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu 645 650 655 Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala 660 665 670 Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys 675 680 685 Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 690 695 <210> 7 <211> 660 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 7 Met Gly Gly Val Pro Gly Ala Val Pro Gly Gly Val Pro Gly Gly Val 1 5 10 15 Phe Tyr Pro Gly Ala Gly Phe Gly Ala Val Pro Gly Gly Val Ala Asp 20 25 30 Ala Ala Ala Ala Tyr Lys Ala Ala Lys Ala Gly Ala Gly Leu Gly Gly 35 40 45 Val Pro Gly Val Gly Gly Leu Gly Val Ser Ala Gly Ala Val Val Pro 50 55 60 Gln Pro Gly Ala Gly Val Lys Pro Gly Lys Val Pro Gly Val Gly Leu 65 70 75 80 Pro Gly Val Tyr Pro Gly Phe Gly Ala Val Pro Gly Ala Arg Phe Pro 85 90 95 Gly Val Gly Val Leu Pro Gly Val Pro Thr Gly Ala Gly Val Lys Pro 100 105 110 Lys Ala Pro Gly Val Gly Gly Ala Phe Ala Gly Ile Pro Gly Val Gly 115 120 125 Pro Phe Gly Gly Pro Gln Pro Gly Val Pro Leu Gly Tyr Pro Ile Lys 130 135 140 Ala Pro Lys Leu Pro Gly Gly Tyr Gly Leu Pro Tyr Thr Thr Gly Lys 145 150 155 160 Leu Pro Tyr Gly Tyr Gly Pro Gly Gly Val Ala Ala Ala Gly Lys Ala 165 170 175 Gly Tyr Pro Thr Gly Thr Gly Val Gly Pro Gln Ala Ala Ala Ala Ala 180 185 190 Ala Ala Lys Ala Ala Ala Lys Phe Gly Ala Gly Ala Ala Gly Phe Gly 195 200 205 Ala Val Pro Gly Val Gly Gly Ala Gly Val Pro Gly Val Pro Gly Ala 210 215 220 Ile Pro Gly Ile Gly Gly Ile Ala Gly Val Gly Thr Pro Ala Ala Ala 225 230 235 240 Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Ala 245 250 255 Gly Leu Val Pro Gly Gly Pro Gly Phe Gly Pro Gly Val Val Gly Val 260 265 270 Pro Gly Phe Gly Ala Val Pro Gly Val Gly Val Pro Gly Ala Gly Ile 275 280 285 Pro Val Val Pro Gly Ala Gly Ile Pro Gly Ala Ala Gly Phe Gly Ala 290 295 300 Val Ser Pro Glu Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Lys Tyr 305 310 315 320 Gly Ala Arg Pro Gly Val Gly Val Gly Gly Ile Pro Thr Tyr Gly Val 325 330 335 Gly Ala Gly Phe Phe Pro Gly Phe Gly Val Gly Val Gly Gly Ile Pro 340 345 350 Gly Val Ala Gly Val Pro Ser Val Gly Gly Val Pro Gly Val Gly Gly 355 360 365 Val Pro Gly Val Gly Ile Ser Pro Glu Ala Gln Ala Ala Ala Ala Ala 370 375 380 Lys Ala Ala Lys Tyr Gly Val Gly Thr Pro Ala Ala Ala Ala Ala Lys 385 390 395 400 Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu Val Pro Gly Val Gly Val 405 410 415 Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro Gly Val 420 425 430 Gly Leu Ala Pro Gly Val Gly Val Ala Pro Gly Val Gly Val Ala Pro 435 440 445 Gly Val Gly Val Ala Pro Gly Ile Gly Pro Gly Gly Val Ala Ala Ala 450 455 460 Ala Lys Ser Ala Ala Lys Val Ala Ala Lys Ala Gln Leu Arg Ala Ala 465 470 475 480 Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly Val Gly Val Gly Val 485 490 495 Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Leu Gly Val Gly Ala 500 505 510 Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala Leu Ala Ala Ala Lys 515 520 525 Ala Ala Lys Tyr Gly Ala Val Pro Gly Val Leu Gly Gly Leu Gly Ala 530 535 540 Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly Ala Gly Pro Ala 545 550 555 560 Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly 565 570 575 Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val Gly Gly Leu Gly 580 585 590 Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro Ala Ala Ala Ala 595 600 605 Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly Val Leu Gly Gly 610 615 620 Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg Pro Gly Phe Gly 625 630 635 640 Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly Lys Ala Cys Gly 645 650 655 Arg Lys Arg Lys 660 <210> 8 <211> 147 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 8 Ser Ala Met Gly Gly Val Pro Gly Ala Leu Ala Ala Ala Lys Ala Ala 1 5 10 15 Lys Tyr Gly Ala Ala Val Pro Gly Val Leu Gly Gly Leu Gly Ala Leu 20 25 30 Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly Ala Gly Pro Ala Ala 35 40 45 Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala Gln Phe Gly Leu 50 55 60 Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val Gly Gly Leu Gly Val 65 70 75 80 Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro Ala Ala Ala Ala Lys 85 90 95 Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly Val Leu Gly Gly Ala 100 105 110 Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg Pro Gly Phe Gly Leu 115 120 125 Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly Lys Ala Cys Gly Arg 130 135 140 Lys Arg Lys 145 <210> 9 <211> 200 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 9 Ser Ala Met Gly Ala Leu Val Gly Leu Gly Val Pro Gly Leu Gly Val 1 5 10 15 Gly Ala Gly Val Pro Gly Phe Gly Ala Gly Ala Asp Glu Gly Val Arg 20 25 30 Arg Ser Leu Ser Pro Glu Leu Arg Glu Gly Asp Pro Ser Ser Ser Gln 35 40 45 His Leu Pro Ser Thr Pro Ser Ser Pro Arg Val Pro Gly Ala Leu Ala 50 55 60 Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val Leu Gly 65 70 75 80 Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly 85 90 95 Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala 100 105 110 Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val 115 120 125 Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro 130 135 140 Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly 145 150 155 160 Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg 165 170 175 Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly 180 185 190 Lys Ala Cys Gly Arg Lys Arg Lys 195 200 <210> 10 <211> 60 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 10 Gly Ile Pro Pro Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala 1 5 10 15 Gly Leu Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly 20 25 30 Val Ala Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly 35 40 45 Ala Cys Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 50 55 60 <210> 11 <211> 47 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 11 Gly Ala Ala Gly Leu Gly Gly Val Leu Gly Gly Ala Gly Gln Phe Pro 1 5 10 15 Leu Gly Gly Val Ala Ala Arg Pro Gly Phe Gly Leu Ser Pro Ile Phe 20 25 30 Pro Gly Gly Ala Cys Leu Gly Lys Ala Cys Gly Arg Lys Arg Lys 35 40 45 <210> 12 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 12 Gly Ala Asp Glu Gly Val Arg Arg Ser Leu Ser Pro Glu Leu Arg Glu 1 5 10 15 Gly Asp Pro Ser Ser Ser Gln His Leu Pro Ser Thr Pro Ser Ser Pro 20 25 30 Arg Val <210> 13 <211> 34 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 13 Gly Ala Asp Glu Gly Val Arg Arg Ser Leu Ser Pro Glu Leu Arg Glu 1 5 10 15 Gly Asp Pro Ser Ser Ser Gln His Leu Pro Ser Thr Pro Ser Ser Pro 20 25 30 Arg Phe <210> 14 <211> 216 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <400> 14 Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly Val Gly Val 1 5 10 15 Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Leu Gly Val 20 25 30 Gly Ala Gly Val Pro Gly Phe Gly Ala Gly Ala Asp Glu Gly Val Arg 35 40 45 Arg Ser Leu Ser Pro Glu Leu Arg Glu Gly Asp Pro Ser Ser Ser Gln 50 55 60 His Leu Pro Ser Thr Pro Ser Ser Pro Arg Val Pro Gly Ala Leu Ala 65 70 75 80 Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val Leu Gly 85 90 95 Gly Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly 100 105 110 Ala Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala 115 120 125 Ala Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val 130 135 140 Gly Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro 145 150 155 160 Ala Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly 165 170 175 Val Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg 180 185 190 Pro Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly 195 200 205 Lys Ala Cys Gly Arg Lys Arg Lys 210 215 <210> 15 <211> 183 <212> PRT <213> Artificial Sequence <220> <223> Synthetic sequence <400> 15 Ala Ala Ala Gly Leu Gly Ala Gly Ile Pro Gly Leu Gly Val Gly Val 1 5 10 15 Gly Val Pro Gly Leu Gly Val Gly Ala Gly Val Pro Gly Leu Gly Val 20 25 30 Gly Ala Gly Val Pro Gly Phe Gly Ala Val Pro Gly Ala Leu Ala Ala 35 40 45 Ala Lys Ala Ala Lys Tyr Gly Ala Ala Val Pro Gly Val Leu Gly Gly 50 55 60 Leu Gly Ala Leu Gly Gly Val Gly Ile Pro Gly Gly Val Val Gly Ala 65 70 75 80 Gly Pro Ala Ala Ala Ala Ala Ala Ala Lys Ala Ala Ala Lys Ala Ala 85 90 95 Gln Phe Gly Leu Val Gly Ala Ala Gly Leu Gly Gly Leu Gly Val Gly 100 105 110 Gly Leu Gly Val Pro Gly Val Gly Gly Leu Gly Gly Ile Pro Pro Ala 115 120 125 Ala Ala Ala Lys Ala Ala Lys Tyr Gly Ala Ala Gly Leu Gly Gly Val 130 135 140 Leu Gly Gly Ala Gly Gln Phe Pro Leu Gly Gly Val Ala Ala Arg Pro 145 150 155 160 Gly Phe Gly Leu Ser Pro Ile Phe Pro Gly Gly Ala Cys Leu Gly Lys 165 170 175 Ala Cys Gly Arg Lys Arg Lys 180

Claims

1. Use of a composition comprising elastin and hyaluronic acid in the preparation of a medicament for treating skin areas with acne scars in a subject of need, for improving one or more of the following in the skin areas of the patient of need: improving the color and / or appearance of the acne scars, reducing the depth of the acne scars, reducing the area affected by the acne scars, and reducing the volume of the acne scars, wherein the composition comprising elastin and hyaluronic acid comprises 30 mg / mL of elastin crosslinked with 0.5% of a derived hyaluronic acid HA.

2. The use according to claim 1, wherein the composition comprising elastin and hyaluronic acid is applied around the scar, and / or wherein the acne scar is subdivided into ice pick scars, boxcar scars, or roller scars.

3. The use according to claim 2, wherein the composition comprising elastin and hyaluronic acid is applied below the scar and / or around the edge of the scar.

4. The use according to claim 1, wherein the depth of the acne scar is 0.1 mm to 5 mm, and / or the affected area of ​​the acne scar is 0.05 mm. 2 Up to 400 mm 2 And / or the volume of the acne scar is 0.01 mm. 3 Up to 2,000 mm 3 .

5. The use according to claim 1, wherein the composition comprising elastin and hyaluronic acid is applied as an injectable substance under the acne scar, and the maximum volume of the composition comprising elastin and hyaluronic acid applied is 100 µL to 5 mL.

6. The use according to claim 5, wherein the composition comprising elastin and hyaluronic acid is applied as an injectable substance under the acne scar, and the total volume of the composition comprising elastin and hyaluronic acid applied to each 2cm x 2cm area of ​​skin is 0.5 mL.

7. The use according to claim 5, wherein the composition comprising elastin and hyaluronic acid is applied on day 0, day 28±3, and day 56±3.

8. The use according to claim 1, wherein the composition comprising elastin and hyaluronic acid is repeatedly applied, and wherein it is applied once or more in the scar.

9. The use according to claim 1, wherein the skin type of the patient in need is type I, II, III, IV, V or VI in the Fitzpatrick skin classification, and / or the scar includes grade 1, 2, 3, 4 or 5.

10. The use according to claim 1, wherein after application of the composition comprising elastin and hyaluronic acid, the depth, affected area and / or volume of the acne scar is reduced.

11. The use according to claim 1, wherein the treatment helps repair atrophic scars in the skin remodeling and maturation stage, thereby improving the appearance of the acne scars.

12. The use according to claim 1, wherein the treatment reduces the area of ​​the acne scar by at least 10%, and / or the treatment reduces the volume of the acne scar by at least 10%, and / or the treatment reduces the depth of the acne scar by at least 10%.

13. The use according to claim 1, wherein the treatment reduces the volume and area of ​​the depression in the skin contour of the skin region having the acne scar by at least 10%, or the treatment further improves the skin color of the acne scar.

14. The use according to claim 1, wherein the treatment increases the volume and area of ​​the raised skin contour in the acne scar area by at least 10%.

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

16. Use of a composition comprising 30 mg / mL of tropoelastin crosslinked with 0.5% of a derived hyaluronic acid in the preparation of a medicament for treating the skin contours of a subject in need affected by acne scars.

17. The use according to claim 16, wherein the composition is applied around the scar.

18. The use according to claim 17, wherein the composition is applied below the scar and / or around the edge of the scar.

19. Use of a composition comprising elastin and hyaluronic acid in the preparation of a medicament for treating acne scars in a skin region of a patient in need; The composition comprising elastin and hyaluronic acid contains 30 mg / mL of elastin, and The elastin is cross-linked with 0.5% of the derived hyaluronic acid (HA).

20. The use according to claim 19, wherein the composition comprising elastin and hyaluronic acid is applied as an injectable substance under the acne scar, and the maximum volume of the composition comprising elastin and hyaluronic acid applied to a 2cm x 2cm area of ​​skin at day 0, day 28±3, and day 56±3 is 0.5 mL.

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