CN114129505A - Silk fibroin microneedle patch for improving hypertrophic scars and preparation method thereof - Google Patents

Silk fibroin microneedle patch for improving hypertrophic scars and preparation method thereof Download PDF

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Publication number
CN114129505A
CN114129505A CN202111455521.2A CN202111455521A CN114129505A CN 114129505 A CN114129505 A CN 114129505A CN 202111455521 A CN202111455521 A CN 202111455521A CN 114129505 A CN114129505 A CN 114129505A
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microneedle
scar
silk fibroin
microneedle patch
improving
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范琪
张庆
黄志刚
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Chongqing Max Biomedical Technology Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medical Informatics (AREA)
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  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
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Abstract

The invention relates to a scar improving technology, in particular to a silk fibroin micro-needle patch for improving hypertrophic scars and a preparation method thereof. The invention aims to provide a new choice for improving scars. The silk fibroin microneedle patch for improving hypertrophic scars comprises a back lining layer and microneedles distributed on the back lining layer in an array mode, wherein the density of the microneedle array is 10-250 microneedles/cm2The needle body is in a quadrangular pyramid shape or a conical shape, and the height of the needle is 600-1000 mu m; the microneedle is prepared by taking silk fibroin as a raw material. The microneedle patch has good biocompatibility, slowly degrades in scar tissues, continuously plays a role in physical intervention and realizes the improvement of hypertrophic scarsThe purpose is. The microneedle patch does not contain any hormone or other drugs, and has high biological safety. And the scar-removing device has the characteristics of minimally invasive painlessness and convenience in use, can be used by patients, and greatly improves the self-management of scar patients.

Description

Silk fibroin microneedle patch for improving hypertrophic scars and preparation method thereof
Technical Field
The invention relates to a scar improving technology, in particular to a silk fibroin micro-needle patch for improving hypertrophic scars and a preparation method thereof.
Background
Excessive deposition of type I collagen in Hypertrophic Scars (HS) not only increases tissue stiffness, but also serves as a barrier against transdermal drug delivery, so that clinical drug therapy for hypertrophic scars usually requires local injection to help the drug reach the lesion, so as to improve the therapeutic effect. But the defects of local injection are also obvious, on one hand, the injection process brings pain, the acceptance of patients is poor, and the operation of medical staff is seriously depended on; on the other hand, the treatment is difficult to continue due to side effects such as drug allergy or high cost. But not drug treatment schemes such as stretch clothing, silicone gel/patch and the like, and the treatment effect of patients is poor due to long treatment period, slow effect and the like.
The polymer Microneedles (MNs) penetrate into the dermis by penetrating the epidermis to create a micropore array in skin tissues, so that the drugs can be effectively delivered in the dermis, and the tumor, the diabetes, the infection and the like can be treated in a minimally invasive manner. Here, however, we propose for the first time that microneedles can physically modulate the biomechanics and ultrastructure of tissue and create a scar-free environment.
Disclosure of Invention
The invention aims to provide a new choice for improving scars.
The silk fibroin microneedle patch for improving hypertrophic scars comprises a back lining layer and microneedles distributed on the back lining layer in an array mode, wherein the density of the microneedle array is 10-250 microneedles/cm2The needle body is in a quadrangular pyramid shape or a conical shape, and the height of the needle is 600-1000 mu m; the microneedle is prepared by taking silk fibroin as a raw material.
Preferably, the density of the microneedle array is 225 pieces/cm2。
Specifically, the needle height is 1000 μm.
Further, the needle body is of a quadrangular pyramid shape, and the bottom side length of the cone is 300 mu m.
The invention also provides a preparation method of the microneedle patch, which comprises the following steps: pouring a solution of raw materials into a mold under a vacuum condition, performing solution-gel conversion at room temperature, and drying at 25-60 ℃; annealing treatment; pouring 10% -20% of PVA (polyvinyl alcohol) solution into the mold, and centrifuging to enable the PVA solution to be in close contact with the silk fibroin microneedle; drying and demoulding; the raw material is silk fibroin.
In particular, the solution-gel transformation is carried out at room temperature and dried at 60 ℃.
Specifically, the annealing treatment comprises the following steps: keeping for 0.5-12 h in a vacuum environment filled with methanol steam or water vapor. Annealing can promote the internal structure of the silk fibroin to be converted into a beta folding structure, improve the mechanical property of the microneedle, and reduce the water solubility and the degradation rate.
Further, the drying and demolding are as follows: and (3) dehydrating and drying the backing layer at 4-80 ℃, and demolding to obtain the microneedle patch.
Preferably, the drying and demolding temperature is 4 ℃.
Wherein the solution of the raw material is 5-20 w/v% of silk fibroin solution.
Preferably, the solution of the raw material is a 10w/v% silk fibroin solution.
Wherein, before preparation, the die is pretreated by plasma for 30-90 s.
Preferably, the mold is pre-treated with plasma for 90s prior to preparation.
Further, the preparation of the mould comprises the following steps: preparing microneedle male molds with different array densities by using high-strength resin as a base material and adopting 3D printing; and cleaning the male mold for 3D printing by using deionized water, pouring PDMS (polydimethylsiloxane) and a curing agent above the male mold, curing for 2h at 80 ℃, and demolding to obtain the microneedle female mold.
Wherein the mass ratio of the PDMS (polydimethylsiloxane) to the curing agent is 10: 1.
The invention also provides the microneedle patch prepared by the method.
The invention also provides application of the microneedle patch in preparing a medical product for improving the appearance of the hypertrophic scar, improving the microstructure of hypertrophic scar tissue or improving the skin elasticity of the scar part.
The invention has the beneficial effects that: the microneedle patch disclosed by the invention is good in biocompatibility, helps loaded drugs to pass through a collagen barrier and be slowly released in scar tissues, and continuously plays an anti-scar role. The microneedle patch has the characteristics of minimally invasive and painless property, is convenient and quick to use, can be used by a patient, and greatly improves the self-management of scar patients. The untreated scar is red and has obvious difference with normal skin; the color of the skin is gradually improved after the microneedle treatment, and is close to the normal skin. The hyperplastic scar tissue obviously protrudes out of the surface of normal skin, the thickness is gradually increased along with the increase of growth time, and the thickness of the scar is obviously reduced after the intervention of the micro-needle; scar thickness variation after patch treatment was on average 2.8 mm, which was a maximum reduction of 20.5 ± 0.5%. Scar index (SEI) also decreased from a maximum of 4.99 to a minimum of 1.45 after microneedle patch treatment. After treatment, the skin elasticity at the scar site was improved as indicated by a higher rate of stress relaxation per unit time (about 0.19 MPa/S) in the untreated scar tissue than in normal skin (about 0.15 MPa/S) in the stress relaxation test. The stress relaxation rate of the scar after SF MNs (15 x 15) treatment is slower, about 0.16 MPa/S, which is close to that of normal skin.
Drawings
Fig. 1, a process for preparing a microneedle patch. Plasma represents Plasma; SF solution, i.e. silk fibroin solution; vaccum refers to performing under a vacuum environment; gelation represents the solution-gel conversion process; methanol vapor stands for a de-ignition treatment with Methanol vapour; 15% PVA solution means 15% therapeutic concentration of polyvinyl alcohol solution; centrifugation is centrifugal operation; demods means demold; SF microstrips is the silk fibroin microneedle patch.
Figure 2, photographic observation of rabbit ear scar model after treatment.
Figure 3 change in scar thickness in each experimental group after treatment. Changes in HS thickness represent the change in scar thickness in mm; control is the untreated scar group; SF MNs treated HS represents microneedle patch treatment group: wherein 5X 5 indicates the use of an array density of 5X 5 (25 pins/mm)2) The scar group treated with the microneedle patch of (1); 10X 10 indicates the density of the array used is 10X 10 (100 needles/mm)2) The scar group treated with the microneedle patch of (1); 15 × 15 denotes usage matrixColumn density 15X 15 (225 needles/mm)2) The scar group treated by the microneedle patch of (1).
Figure 4 change in microstructure in pathological sections of scar tissue in each experimental group after treatment. H&E represents hematoxylin eosin staining of pathological sections; masson indicates specific staining for collagen fibers in the tissue; sirius staining refers to staining used to distinguish type I and type III glues. Normal indicates Normal skin; untreated HS was the Untreated scar group; SF MNs treated HS represents microneedle patch treatment group: wherein 5X 5 indicates the use of an array density of 5X 5 (25 pins/mm)2) The scar group treated with the microneedle patch of (1); 10X 10 indicates the density of the array used is 10X 10 (100 needles/mm)2) The scar group treated with the microneedle patch of (1); 15X 15 indicates the use of an array density of 15X 15 (225 pins/mm)2) The scar group treated by the microneedle patch of (1).
Figure 5 change in scar index in each experimental group after treatment. Scar elevation index, which is the ratio of Scar tissue thickness to normal skin thickness; normal indicates Normal skin; untreated HS was the Untreated scar group; SF MNs treated HS represents microneedle patch treatment group: wherein 5X 5 indicates the use of an array density of 5X 5 (25 pins/mm)2) The scar group treated with the microneedle patch of (1); 10X 10 indicates the density of the array used is 10X 10 (100 needles/mm)2) The scar group treated with the microneedle patch of (1); 15X 15 indicates the use of an array density of 15X 15 (225 pins/mm)2) The scar group treated by the microneedle patch of (1).
Figure 6, after treatment, the skin elasticity at the scar site was significantly improved, as shown by a gradual approach to normal skin in stress relaxation behavior. Force at the elongation represents the Force required to stretch to a set elongation in newtons (N); the Relaxation rate represents the stress Relaxation rate in megapascals per second (MPa/s). Untreated HS was the Untreated scar group; SF MNs treated HS represents microneedle patch treatment group: wherein 5X 5 indicates the use of an array density of 5X 5 (25 pins/mm)2) The scar group treated with the microneedle patch of (1); 10X 10 indicates the density of the array used is 10X 10 (100 needles/mm)2) For treating scarA scar group; 15X 15 indicates the use of an array density of 15X 15 (225 pins/mm)2) The scar group treated by the microneedle patch of (1).
Detailed Description
Example 1 microneedle patch preparation procedure
Microneedle structure design: three array densities (5X 5, 10X 10, 15X 15 needles/cm)2) The needle body is in a four-pyramid shape, the side length of the bottom of the cone is 300 mu m, and the height of the needle body is 1 mm;
preparing a microneedle male die: preparing microneedle male molds with different array densities by using high-strength resin as a base material and adopting 3D printing;
preparing a microneedle female die: cleaning a male mold for 3D printing with deionized water, pouring PDMS (polydimethylsiloxane) and a curing agent (mass ratio of 10: 1, w/w) above the male mold, curing at 80 ℃ for 2h, and demolding to obtain a microneedle female mold.
The preparation process of the microneedle patch is shown in fig. 1.
Pretreatment of a mold: pretreating the surface of a PDMS female die for 90s by plasma;
polymer solution infusion: pouring silk fibroin solution (10%, w/v) in the processed mould, forcing the polymer solution into a mould micro-cavity under a vacuum environment, carrying out solution-gel conversion at room temperature, and drying at 60 ℃;
annealing treatment: placing the micro-needle in a vacuum environment filled with methanol vapor or water vapor, keeping for 12h, promoting the internal structure of the silk fibroin to be converted into a beta folding structure, improving the mechanical property of the micro-needle, and reducing the water solubility and the degradation rate;
preparing a backing layer: pouring 15% PVA (polyvinyl alcohol) solution above the mould, and centrifuging to make the PVA solution closely contact with the silk fibroin microneedle;
drying and demolding: and (3) dehydrating and drying the backing layer at 4 ℃, and demolding to obtain the microneedle patch.
EXAMPLE 2 microneedle patch treatment of hypertrophic scar in rabbit ears
The treatment method comprises the following steps:
disease models: hypertrophic scar of rabbit ear;
the treatment process comprises the following steps: wiping and disinfecting the local scar with iodine, pressing the sterilized silk fibroin microneedle patch into the scar tissue, fixing with an adhesive tape, and keeping for 30 days;
grouping: control group (scar without microneedle treatment), microneedle treatment group (5 × 5, 10 × 10, 15 × 15).
(II) treatment effect:
and (3) appearance observation: as shown in fig. 2, the untreated scar protrudes significantly from the surface of normal skin, and the scar tissue area is red, which is significantly different from normal skin. The color of the skin is gradually improved after the microneedle array is used for treating, the improvement degree of the scar tissue bulge and the color is gradually increased along with the increase of the density of the microneedle array, and the color of the skin at the scar part is close to that of normal skin in a 15 x 15 group.
And (3) thickness measurement: as shown in fig. 3, the tissue thickness at the designated site was measured with a vernier caliper with an accuracy of 0.01mm and statistically analyzed. The results show that tissue thickness gradually increases with continued growth and change of hypertrophic scars. But the tendency of the thickness to increase after drying with a fine needle was significantly suppressed. The change in scar thickness after 15X 15 patch treatment averaged 2.8 mm, with a 20.5 + -0.5% reduction in total thickness. While the maximum scar thickness in the untreated group exceeded 4.5 mm, with an average increase of 13.3%. The thickness was reduced by 3.2% and 13.2% in the 5 × 5 and 10 × 10 groups, respectively.
Pathological section observation is carried out on scar tissues, the tissue structure and collagen fibers are observed through hematoxylin eosin staining, Masson staining and sirius red staining, and the results are shown in figure 4, wherein the thickness of hyperplastic scar tissues and the collagen deposition amount are obviously higher than those of normal skin, and the arrangement of the collagen fibers is disordered. The ratio of collagen type I (red) to collagen type III (green) in scar (about 5.18: 1) is much higher than normal skin (about 1: 1). After the microneedle patch is used for treatment, the thickness of scar tissue and the collagen content are both obviously reduced, and the proportion of type I collagen and type III collagen is gradually reduced to be close to normal skin. Scar index was calculated by measuring the thickness of the dermal layer of scar tissue and normal dermal layer of skin in tissue sections and statistical analysis, and the result is that scar index (SEI) is positively correlated with scar formation as shown in fig. 5, decreasing from a maximum of 4.99 for untreated HS to a minimum of 1.45 (15 × 15) after microneedle patch treatment.
The scar tissue is further sampled and prepared into a dumbbell-shaped sample piece with the effective length of not 1cm for the detection of the tissue biomechanics. A stress relaxation test is carried out on a tissue sample piece on a universal material testing machine, the tensile rate is set to be 10%, the sample piece is axially stretched at the rate of 1mm/s until the strain is 10%, the stretching is stopped and maintained for 120s, the change curve of the stress along with the time is recorded, and the stress relaxation rate of the tissue is calculated. The results are shown in 6, and the stress reduction per unit time (-0.19 MPa/S) of the untreated scar tissue is higher than that of normal skin (-0.15 MPa/S) in the relaxation process. The stress relaxation rate of the scar after SF MNs (15 multiplied by 15) treatment is slower, about 0.16 MPa/S, which is close to that of normal skin, and shows that the elasticity of the skin at the scar part after treatment is greatly improved.

Claims (10)

1. A silk fibroin microneedle patch for improving hypertrophic scars comprises a back lining layer and microneedles distributed on the back lining layer in an array mode, and is characterized in that the density of microneedle arrays is 10-250 pieces/cm2The needle body is in a quadrangular pyramid shape or a conical shape, and the height of the needle is 600-1000 mu m; the microneedle is prepared by taking silk fibroin as a raw material.
2. A microneedle patch according to claim 1, wherein the needle height is 1000 μm.
3. A microneedle patch according to claim 1 or 2, wherein the needle body is of a quadrangular pyramid shape with a bottom of the pyramid 300 μm in length.
4. A method for preparing a microneedle patch according to any one of claims 1 to 3, comprising the steps of: pouring a solution of raw materials into a mold under a vacuum condition, performing solution-gel conversion at room temperature, and drying at 25-60 ℃; annealing treatment; pouring 10% -20% of PVA (polyvinyl alcohol) solution into the mold, and centrifuging to enable the PVA solution to be in close contact with the silk fibroin microneedle; drying and demoulding; the raw material is silk fibroin.
5. The method of claim 4, wherein the annealing comprises: keeping for 0.5-12 h in a vacuum environment filled with methanol steam or water vapor; annealing can promote the internal structure of the silk fibroin to be converted into a beta folding structure, improve the mechanical property of the microneedle, and reduce the water solubility and the degradation rate.
6. The method of claim 4 or 5, wherein the dry stripping is: and (3) dehydrating and drying the backing layer at 4-80 ℃, and demolding to obtain the microneedle patch.
7. The method according to any one of claims 4 to 6, wherein the solution of the raw material is 5 to 20w/v% of silk fibroin solution.
8. The method according to any one of claims 4 to 7, wherein, before the preparation, the mold is subjected to plasma pretreatment for 30 to 90 seconds;
preferably, the preparation of the mold comprises the following steps: preparing microneedle male molds with different array densities by using high-strength resin as a base material and adopting 3D printing; cleaning a male mold for 3D printing with deionized water, pouring PDMS (polydimethylsiloxane) and a curing agent above the male mold, curing for 2h at 80 ℃, and demolding to obtain a microneedle female mold;
preferably, the mass ratio of the PDMS (polydimethylsiloxane) to the curing agent is 10: 1.
9. The microneedle patch prepared by the method according to any one of claims 4 to 8.
10. Use of the microneedle patch of any one of claims 1-3 or 9 for preparing a medical article for improving the appearance of hypertrophic scar, improving the microstructure of hypertrophic scar tissue or increasing the skin elasticity of scar.
CN202111455521.2A 2021-12-01 2021-12-01 Silk fibroin microneedle patch for improving hypertrophic scars and preparation method thereof Withdrawn CN114129505A (en)

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Application publication date: 20220304