Radix lithospermi composite dressing as well as preparation method and application thereof

Abstract

The invention provides a lithospermum composite dressing as well as a preparation method and application thereof. Relates to the technical field of medical biology. The lithospermum composite dressing comprises a drug sustained-release layer and an elastic non-woven fabric backing, the drug sustained-release layer comprises alkannin, chitosan and gelatin, and the elastic model of the elastic non-woven fabric backing is 50-100 MPa. In the drug sustained-release layer provided by the embodiment of the invention, the alkannin and the chitosan are jointly used as antibacterial agents, and the alkannin makes up the weaker inhibition of the chitosan on Gbacteria, so that a dual antibacterial mechanism is formed. The shikonin is loaded on the gelatin bracket, so that the slow release of the shikonin can be controlled, and the shikonin can be continuously released due to the thermosensitivity (37 DEG C slow dissolution) of the gelatin (the release rate reaches 85% after 72 hours in an in-vitro release experiment). The anti-inflammatory / blood vessel promoting effect of the alkannin, the antibacterial / hemostatic effect of the chitosan and the mechanical toughness of the gelatin can form the coordination of the triple functions of anti-infection, repair and structural support.

Description

Technical Field

[0001] The embodiments of the present invention relate to the field of medical biotechnology, and in particular to a lithospermum composite dressing and a preparation method and application thereof. Background Art

[0002] Skin is the body's natural barrier against external environmental factors. Injuries caused by trauma, surgery, burns, or chronic illness can compromise skin integrity and impair its normal function. Wound dressings play a crucial role in the repair of skin wounds.

[0003] Currently, China performs over 2 million interventional surgeries annually (with an annual growth rate of 15%), with 8.7% of these surgeries resulting from puncture site complications. Taking femoral artery puncture as an example, the average time for hemostasis after femoral artery puncture is 32 minutes, while traditional dressings require sandbag compression for 6 hours. The local infection rate after vascular intervention is 5.2%, much higher than that of open surgery (2.1%). Furthermore, the incidence of delayed puncture site healing in patients receiving anticoagulant therapy reaches 23%.

[0004] Traditional interventional surgical dressings face the following technical bottlenecks: A. Insufficient physical properties: The moisture permeability of traditional gauze dressings is <1500g / m² / 24h (ideal value >2500), which causes local moisture; Elastic bandage pressure can easily cause skin ischemic damage (incidence rate 12%); B. Lack of drug synergy: Existing hemostatic materials (such as gelatin sponge) lack antibacterial components and need to be used in combination with antibiotics; Healing-promoting components (such as growth factors) have a half-life of < 2 hours in the body and cannot have a sustained effect.

[0005] Other traditional dressings have the following limitations: ① Physical barrier type: non-woven fabric air permeability <1000g / m² / 24h (ideal value >2000).

[0006] ② Biological dressings: Allogeneic skin has the risk of immune rejection and has high preservation costs.

[0007] ③Drug carriers: The drug loading capacity of traditional hydrogels is <5%, and the burst release effect is obvious.

[0008] This shows that a new wound dressing is urgently needed. Summary of the Invention

[0009] The embodiment of the present invention provides a lithospermum composite dressing and a preparation method and application thereof. The dressing is suitable for the puncture site of interventional surgery and can also be promoted and applied to the care of various surgical wounds, chronic ulcers, etc.

[0010] A first aspect of an embodiment of the present invention provides a method for determining the amount of coenzyme Q10 in a biological sample, the method comprising: The drug sustained-release layer comprises shikonin, chitosan and gelatin, and the elastic model of the elastic non-woven fabric backing is 50-100 MPa.

[0011] Optionally, the lithospermum composite dressing further comprises: an intelligent response layer, the intelligent response layer comprising a pH-sensitive hydrogel, the pH-sensitive hydrogel responding to changes in the local pH value of the wound, with a swelling degree varying between 300-500% and a fluid absorption rate of 1500%.

[0012] Optionally, the lithospermum composite dressing further comprises: a polyurethane breathable membrane, the polyurethane breathable membrane having a thickness of 50-80 μm, a water vapor permeability of 2800 g / m² / 24h, and an anti-bacterial penetration rate of >99.99%.

[0013] Optionally, the lithospermum composite dressing further comprises: a millimeter wave absorbing layer, the millimeter wave absorbing layer being filled with silicon carbide micropowder, the millimeter wave absorbing layer being used to absorb millimeter waves with a wavelength of 8-12 mm, thereby increasing blood flow by 20%, accelerating blood circulation at the puncture site, and promoting tissue metabolism and repair.

[0014] Optionally, the lithospermum composite dressing further comprises: a cooling phase change layer, the cooling phase change layer comprises: a phase change material, the phase change temperature of the phase change material is 40° C., and the cold storage capacity is 120 J / g.

[0015] The second aspect of the embodiment of the present invention provides a method for preparing the lithospermum composite dressing according to any one of the first aspects. The method comprises: preparing shikonin solution; preparing chitosan solution; Prepare gelatin solution; Mix the prepared chitosan solution and gelatin solution; Adding shikonin solution to the mixed chitosan-gelatin solution and stirring for 10-15 minutes to uniformly disperse shikonin in the mixed solution to obtain a shikonin-chitosan-gelatin solution, wherein the weight proportion of shikonin is 0.5-2%, the weight proportion of chitosan is 3-8%, and the weight proportion of gelatin is 5-15%; The shikonin-chitosan-gelatin solution is pre-frozen at a temperature of -40°C for 2-4 hours to completely freeze the solution into a solid state; Freeze-dry the pre-frozen samples; Cutting the freeze-dried dressing sample into a suitable size and shape to obtain a drug sustained-release layer; The drug sustained-release layer and the elastic non-woven fabric backing are assembled to obtain the lithospermum officinale composite dressing.

[0016] Optionally, the method further includes: mixing shikonin and anhydrous ethanol to obtain a shikonin ethanol solution; The ethanol solution of shikonin was quickly injected into supercritical CO2. Ethanol, as a good solvent, was quickly extracted by supercritical CO2. Shikonin precipitated due to a sudden drop in solubility, and shikonin nanocrystals were obtained. The shikonin nanocrystals are loaded into a drug sustained-release layer.

[0017] A third aspect of the embodiments of the present invention provides use of the lithospermum composite dressing described in any one of the first aspects in preparing a dressing for treating post-femoral artery puncture surgery.

[0018] A fourth aspect of the embodiments of the present invention provides use of the lithospermum composite dressing described in the first aspect in preparing a dressing for treating burn wounds.

[0019] In this embodiment of the present invention, shikonin and chitosan act together as antimicrobial agents in the sustained-release drug layer. Shikonin compensates for chitosan's weak inhibition of G⁺ bacteria, creating a dual antimicrobial mechanism. The gelatin scaffold loaded with shikonin allows for controlled sustained release, and the thermosensitivity of gelatin (slow dissolution at 37°C) enables sustained release (up to 85% release rate over 72 hours in in vitro release experiments). The anti-inflammatory / angiogenic effects of shikonin, the antimicrobial / hemostatic effects of chitosan, and the mechanical toughness of gelatin create a triple functional synergy: anti-infection, repair, and structural support. The elastic nonwoven backing has an elastic modulus of 50-100 MPa, adapting to the dynamic stresses at the femoral artery puncture site and promoting postoperative wound healing. DETAILED DESCRIPTION

[0020] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the present invention is further described in detail below in conjunction with specific embodiments.

[0021] The inventors have discovered that the current related dressings generally have the following problems: (1) Insufficient protection: Traditional dressings are difficult to balance in terms of preventing bacterial penetration and breathability, and cannot effectively provide a good external protective environment for the puncture site, which can easily lead to an increased risk of infection.

[0022] (2) Poor sustained drug release: Existing dressings lack precise control over drug loading and release, and are unable to achieve sustained and stable drug release, thus affecting the therapeutic effect.

[0023] (3) Lack of intelligent response: It cannot make corresponding adjustments based on the physiological state of the wound (such as changes in pH value), making it difficult to meet the needs of wound care at different stages.

[0024] (4) Limited healing function: The function of promoting blood circulation and tissue repair at the puncture site is weak, resulting in a longer wound healing time.

[0025] Based on this, the embodiment of the present invention proposes a lithospermum composite dressing, a drug sustained-release layer and an elastic non-woven fabric backing, wherein the drug sustained-release layer includes shikonin, chitosan and gelatin, and the elastic model of the elastic non-woven fabric backing is: 50-100MPa.

[0026] Shikonin is a naphthoquinone compound extracted from the root of Lithospermum erythrorhizon. It has the following effects: anti-inflammatory effect: inhibiting inflammatory factors such as TNF-α and IL-6; promoting angiogenesis: activating the VEGF pathway and accelerating the formation of granulation tissue; broad-spectrum antibacterial effect: MIC against Staphylococcus aureus and Escherichia coli is ≤50μg / mL.

[0027] Chitosan is a natural polymer material with the following properties: film-forming + hemostatic properties: forming a breathable and moisturizing film, with positive charge adsorbing red blood cells to promote blood coagulation; antibacterial properties: the inhibition rate of common wound bacteria is >70% (passed ASTM E2149 test).

[0028] Gelatin has the following properties: mechanical toughness + biodegradability: it can provide a scaffold structure with an elongation at break ≥120%; cell affinity: it can promote a 35% increase in the adhesion rate of fibroblasts.

[0029] In the drug sustained-release layer provided in the embodiment of the present invention, shikonin and chitosan act together as antibacterial agents. Shikonin compensates for the weak inhibition of chitosan on G⁺ bacteria, forming a dual antibacterial mechanism.

[0030] The gelatin scaffold loaded with shikonin can achieve the controlled sustained release of shikonin. The thermosensitivity of gelatin (slow dissolution at 37°C) can achieve the sustained release of shikonin (the release rate in the in vitro release experiment reached 85% within 72 hours).

[0031] The anti-inflammatory / angiogenic effects of shikonin, the antibacterial / hemostatic effects of chitosan, and the mechanical toughness of gelatin can form a triple functional synergy of "anti-infection-repair-structural support".

[0032] In the examples of the present invention, in order to verify the effect of the drug sustained-release layer, antibacterial test and cell proliferation experiment were carried out. The experimental results are shown in Table 1, Table 2 and Table 3.

[0033] Table 1 Antibacterial test results (ASTM E2149 standard)

[0034] As can be seen from Table 1, the drug sustained-release layer obtained by the synergistic use of shikonin, chitosan and gelatin has a significantly higher antibacterial rate than that of the single group (p<0.05), proving that the three can synergistically achieve better antibacterial effects.

[0035] Table 2 Antibacterial efficacy test results of drug sustained-release layer

[0036] As can be seen from Table 2, the drug sustained-release layer obtained by the synergistic use of shikonin, chitosan and gelatin has an inhibition zone diameter of 18 mm against Escherichia coli, compared with 12 mm for the traditional preparation. This verifies that the drug sustained-release layer can synergistically achieve a better antibacterial effect.

[0037] Table 3 Cell proliferation assay results (MTT assay, NIH3T3 fibroblasts)

[0038] As can be seen from Table 3, the drug sustained-release layer containing shikonin can significantly promote cell proliferation. Western Blot verification shows that shikonin promotes cell proliferation by activating the ERK pathway.

[0039] In the examples of the present invention, the physical properties of the drug-release layer were also tested, demonstrating a water absorption rate exceeding 600% (gelatin provides a porous structure), which is superior to a single chitosan membrane (which has a water absorption rate of approximately 300%). The tensile strength of the drug-release layer was 3.2 MPa, meeting the mechanical strength requirements for wound dressings as specified in ISO 13485.

[0040] In the embodiment of the present invention, in the drug sustained-release layer, the proportion of shikonin is 0.5-2%, the proportion of chitosan is 3-8%, and the proportion of gelatin is 5-15%.

[0041] In the embodiment of the present invention, HPLC detection showed that the release of shikonin in the drug sustained-release layer conformed to the Higuchi model (R²=0.983).

[0042] In the field of drug release, the Higuchi model is a classic model for describing drug release rates from matrix systems. It is applicable when the drug loading exceeds the solubility of the matrix medium. The model assumes that undissolved drug is completely converted to dissolved drug and ultimately released from the matrix into the surrounding fluid. Its formula calculates the cumulative amount of drug released per unit surface area over time t. The Higuchi model provides an important theoretical framework for the development of modern drug delivery technologies, helping to predict drug release rates and guide the design of pharmaceutical formulations. For example, it is widely used in in vitro release testing of semisolid formulations (such as creams, gels, and ointments) to evaluate the release behavior of active ingredients from the matrix.

[0043] In the embodiment of the present invention, the lithospermum composite dressing is a multi-layer composite structure, which includes not only a drug sustained-release layer but also an elastic non-woven fabric backing.

[0044] In the embodiment of the present invention, the elastic nonwoven backing is designed to be suitable for non-postoperative puncture sites during interventional surgery. The elastic modulus of the elastic nonwoven backing is 50-100 MPa, which can adapt to the dynamic stress of the femoral artery puncture site and promote postoperative incision healing.

[0045] In an embodiment of the present invention, the elastic non-woven fabric backing further comprises: a self-adhesive silicone edge with a peel strength of 0.3 N / cm, which reduces skin damage during postoperative dressing changes.

[0046] In an embodiment of the present invention, the lithospermum composite dressing further includes: an intelligent response layer, wherein the intelligent response layer includes a pH-sensitive hydrogel, which responds to changes in the local pH value of the wound, with a swelling degree varying between 300-500% and a fluid absorption rate of 1500%.

[0047] pH-sensitive hydrogel wound dressing achieves precise regulation of swelling degree between 300-500% through the synergistic effect of charge transformation of ionized groups, dynamic adjustment of network structure and intelligent response system.

[0048] The pH of the wound surface during the inflammatory phase is 4-6. In infected wounds, lactic acid is produced by bacterial metabolism, lowering the pH to 4-6. The carboxylic acid groups in the hydrogel are protonated, causing the network to shrink and reducing exudate absorption.

[0049] During the wound healing phase (pH 7-8): As inflammation subsides, the pH returns to neutral. Carboxyl groups deprotonate, the network expands, and the swelling increases to 300-500%. This absorbs excess exudate and maintains a moist environment, promoting fibroblast migration and collagen deposition.

[0050] In this embodiment of the present invention, the pH-sensitive hydrogel is an acrylic acid-acrylamide copolymer. This composite hydrogel of polyacrylamide (PAM) and polymethacrylic acid (PDMAEMA) provides mechanical strength through a primary network and pH sensitivity through a secondary network. At pH 4, protonation of the PDMAEMA segments causes the network to shrink and the swelling to decrease. At pH 7.4, electrostatic repulsion from the carboxylate groups increases the swelling to 300-500%.

[0051] In an embodiment of the present invention, the lithospermum composite dressing further comprises: a polyurethane breathable membrane, the polyurethane breathable membrane has a thickness of 50-80 μm, a water vapor permeability of 2800 g / m² / 24h, and an anti-bacterial penetration rate of >99.99%.

[0052] In this embodiment of the present invention, the polyurethane breathable membrane is located on the outer layer of the lithospermum composite dressing, isolating it from external contaminants and maintaining the wound microenvironmental humidity (40-60% RH). The drug sustained-release layer is located in the middle layer of the lithospermum composite dressing, enabling zero-order release of shikonin (92% cumulative release rate over 72 hours). The intelligent response layer is located in the inner layer of the lithospermum composite dressing, triggering swelling at a wound pH of 5.5-7.0 and absorbing exudate (absorption rate of 1500%).

[0053] In an embodiment of the present invention, the lithospermum composite dressing further includes: a millimeter wave absorption layer, which is filled with silicon carbide micropowder. The millimeter wave absorption layer is used to absorb millimeter waves with a wavelength of 8-12 mm, increase blood flow by 20%, accelerate blood circulation at the puncture site, and promote tissue metabolism and repair.

[0054] The high thermal conductivity of silicon carbide micropowder (490 W / m·K, approximately three times that of silicon) enables rapid and even heat distribution, reduces blood viscosity, and reduces red blood cell aggregation, thereby increasing blood flow. This effect has been shown in animal models to increase local blood flow by 15-25%.

[0055] In addition, the high thermal conductivity and low thermal expansion coefficient (4.3×10⁻) of silicon carbide powder 6 / ℃) can optimize the wound microenvironment by: Temperature gradient regulation: Micropowder conducts heat quickly to avoid local overheating (≤42°C) and maintain a repair-promoting temperature window of 37-39°C. This temperature range can increase the fibroblast proliferation rate by 40% and increase collagen synthesis by 3 times.

[0056] Improved metabolic efficiency: Local temperature increases accelerate enzymatic reactions (e.g., increasing the activity of matrix metalloproteinases (MMPs) by 20-30%), promoting the degradation of necrotic tissue and the deposition of new matrix. Simultaneously, temperature increases shift the oxygen dissociation curve to the right, enhancing hemoglobin's ability to release oxygen and improving tissue hypoxia.

[0057] Immune regulation: Moderate heat stimulation (38-40°C) can inhibit the release of pro-inflammatory factors (such as TNF-α, IL-6), while promoting the secretion of anti-inflammatory factors (IL-10), shortening the inflammatory phase of the wound by 30-50%, and entering the proliferation phase earlier.

[0058] In the embodiment of the present invention, it is determined through laser Doppler blood flowmetry that the millimeter wave absorption layer can increase the blood flow rate by 20%.

[0059] In an embodiment of the present invention, the lithospermum composite dressing may further include: a hemostatic microsphere composite layer loaded with prothrombin to shorten the coagulation time to 8 minutes (15 minutes for traditional dressings).

[0060] In an embodiment of the present invention, the lithospermum composite dressing further comprises a cooling phase change layer, wherein the cooling phase change layer comprises a phase change material, wherein the phase change temperature of the phase change material is 40° C., and the cold storage capacity is 120 J / g.

[0061] In the embodiments of the present invention, the cooling phase change layer primarily utilizes the temperature regulation function of the phase change material (maintaining a constant local temperature on the wound surface by absorbing or releasing latent heat) and its moisturizing and protective properties to help create a suitable wound healing microenvironment (avoiding excessive temperatures that aggravate tissue damage or excessive dryness that impairs repair). Phase change materials suitable for burn dressings must meet requirements such as good biocompatibility, a phase change temperature close to normal human body temperature (35-37°C), moderate latent heat, and high stability. Common types are as follows: 1. Paraffin phase change materials Paraffin is one of the most commonly used organic phase change materials. It has a wide phase change temperature range (controllable within 30-40°C by adjusting its composition), a high latent heat (typically 150-250 J / g), good chemical stability, and low cost. Paraffin is often combined with polymer substrates (such as alginate, chitosan, and polyurethane) to create a cooling phase change layer with temperature-regulating properties. For example, paraffin microcapsules can be embedded in a dressing matrix. When the local temperature of the wound surface rises, the paraffin melts and absorbs heat, preventing it from overheating. When the temperature drops, it solidifies and releases heat, maintaining a constant temperature on the wound surface.

[0062] 2. Fatty acids and derivatives Common types include stearic acid, palmitic acid, lauric acid, and their mixtures (the phase transition temperature can be adjusted to 35-37°C through compounding). They have excellent biocompatibility (some fatty acids are metabolites of the human body), a high latent heat of phase change (150-200 J / g), and possess certain antibacterial and moisturizing properties. They also have a strong affinity for natural polymer dressing substrates (such as collagen and gelatin). They can be encapsulated through emulsification and microencapsulation techniques and then combined with burn dressings to regulate temperature and help maintain a moist wound environment.

[0063] 3. Polyethylene glycol (PEG) and its derivatives PEG is a water-soluble polymer with a phase transition temperature that can be adjusted by molecular weight (e.g., PEG 6000 has a phase transition temperature of approximately 25-30°C, and PEG 10000 has a phase transition temperature of approximately 37-40°C). It also has a moderate latent heat (150-200 J / g), excellent biocompatibility (widely used in medical materials), and possesses certain moisturizing and repair-promoting properties. PEG is highly compatible with water and most polar polymers. It can be directly blended with dressing matrices (such as carboxymethyl cellulose and hyaluronic acid) or formulated into hydrogel-type phase-change dressings, which combine temperature regulation and moisturizing properties.

[0064] 4. Hydrated salt phase change materials Common types include sodium acetate trihydrate (phase transition temperature approximately 58°C, requiring compounding to lower the temperature) and calcium chloride hexahydrate (adjusted to 35-37°C by adding nucleating agents and thickeners). Hydrated salt phase change materials have extremely high latent heat (200-300 J / g) and are low-cost, but are prone to "supercooling" (failure to solidify below the phase transition point) and "phase separation" (separation of components after long-term use). Nucleating agents (such as borax) and thickeners (such as sodium carboxymethyl cellulose) are required to improve stability. Biocompatibility requires rigorous verification (some salts may be irritating to wound surfaces) and are currently more commonly used in composite systems with biocompatible substrates.

[0065] 5. Natural lipids Common types include beeswax, hydrogenated products of vegetable oils (such as olive oil and castor oil), or animal fat derivatives. Their phase transition temperature is close to human body temperature (30-38°C), offering excellent biocompatibility, natural moisturizing and occlusive properties, reducing moisture loss from wounds while regulating local temperature through phase transition. Naturally sourced and well tolerated by the human body, they are suitable dressing bases for superficial burns, providing both temperature regulation and physical barrier properties.

[0066] In an embodiment of the present invention, the finished product of the lithospermum composite dressing can have independent functional layers (intelligent response layer, polyurethane breathable membrane, millimeter wave absorption layer, hemostatic microsphere composite layer, cooling phase change layer, etc.). Medical staff can assemble different functional layers according to actual clinical needs during clinical use.

[0067] In an embodiment of the present invention, the finished product of the lithospermum composite dressing can be a composite dressing of different models and functions assembled by assembling one or more of the various functional layers (intelligent response layer, polyurethane breathable membrane, millimeter wave absorption layer, hemostatic microsphere composite layer, cooling phase change layer, etc.) and the base layer of the lithospermum composite dressing (drug sustained-release layer and elastic non-woven fabric backing) to adapt to different clinical needs.

[0068] In this embodiment of the present invention, the polyurethane breathable membrane provides excellent external protection, enhancing bacterial penetration resistance and air permeability. The drug-release layer enables precise and sustained drug release, improving therapeutic efficacy. The intelligent response layer exhibits intelligent response capabilities, adjusting its properties based on changes in wound pH. It triggers swelling and absorbs exudate at a pH between 5.5 and 7.0. The millimeter wave absorption layer promotes blood circulation at the puncture site, accelerating wound healing.

[0069] In this embodiment of the present invention, the polyurethane breathable membrane serves as the outer protective layer. Its thickness is 50-80 μm, its water vapor transmission rate is 2800 g / m² / 24h, and its bacterial penetration rate is >99.99% (ASTM F1671). The elastic non-woven fabric backing, serving as the functional reinforcement layer, is 120-150 μm thick and has an elastic modulus of 50-100 MPa. The self-adhesive silicone edge of the elastic non-woven fabric backing (30-50 μm thick) has a peel strength of 0.3 N / cm.

[0070] In the examples of the present invention, the clinical efficacy of the lithospermum erythrorhizon composite dressing was also clinically verified, and the results were as follows: ①Burn Department (3 hospitals, n=200): The average healing time was 9.2 days (14.5 days in the control group).

[0071] Scar hyperplasia was reduced by 42% (determined by Vancouver Scar Scale score).

[0072] ②Interventional Department (n=150): The time to hemostasis was shortened by 56% (the average time to hemostasis for the lithospermum composite dressing was 8 minutes, while the average time to hemostasis for the control group was 18 minutes).

[0073] The puncture site infection rate dropped from 5.2% to 1.3%.

[0074] The embodiment of the present invention integrates interdisciplinary technologies (materials science, natural medicinal chemistry, and biomedical engineering) to construct a composite dressing with the characteristics of intelligent response, precise controlled release, and microenvironment regulation. While maintaining the advantages of traditional Chinese medicine, it solves the core problems of existing dressings in terms of antibacterial timeliness, healing efficacy, and mechanical adaptability, and is suitable for the treatment needs of complex wounds in multiple departments.

[0075] The polyurethane breathable membrane, serving as the outer protective layer of the Lithospermum officinale composite dressing, maintains a high water vapor transmission rate (2800g / m² / 24h), maintaining normal moisture exchange within the skin. It also boasts an ultra-high bacterial penetration rate (>99.99%, per ASTM F1671), effectively blocking external bacteria and reducing the risk of infection at the puncture site. For example, it provides a reliable initial protective barrier at the puncture site after interventional surgery.

[0076] The elastic nonwoven backing layer of the comfrey composite dressing provides a degree of elasticity to accommodate the skin's tensile changes during movement, with an elastic modulus of 50-100 MPa. The self-adhesive silicone edge, with a thickness of 30-50 μm and a peel strength of 0.3 N / cm, ensures a close fit and prevents displacement. In practice, the dressing remains firmly fixed to the puncture site even during patient movement.

[0077] The drug-release layer, the core of the lithospermum composite dressing, uses gelatin as a carrier, facilitating drug loading and sustained release. The loaded shikonin and chitosan possess antibacterial, anti-inflammatory, and tissue-repair properties. The release pattern demonstrates zero-order kinetics (R² = 0.983), enabling stable and sustained drug release and prolonged therapeutic efficacy.

[0078] The pH-sensitive hydrogel (acrylic acid-acrylamide copolymer) in the smart response layer responds to localized changes in wound pH (pH 5.5-7.0), varying its swelling between 300-500% and absorbing up to 1500% of saline solution. When wound inflammation occurs, the pH shifts, causing the hydrogel to swell, increasing its absorption of exudate while also adjusting the dressing's permeability to create a favorable healing environment.

[0079] The millimeter wave absorption layer, as a special functional layer of the comfrey composite dressing, is filled with silicon carbide micropowder and can absorb millimeter waves with a wavelength of 8-12mm. Laser Doppler detection shows that it can increase blood flow by 20%, accelerate blood circulation at the puncture site, promote tissue metabolism and repair, and help wounds heal faster.

[0080] The present invention also provides a specific application example of the lithospermum composite dressing.

[0081] In the embodiment of the present invention, patients undergoing transradial artery interventional surgery were selected as research subjects, and the lithospermum composite dressing of the present invention was subjected to clinical application testing.

[0082] After the puncture is completed, the lithospermum composite dressing of the present invention is immediately applied to the puncture site, ensuring a close fit. The wound is regularly observed and the dressing is changed based on wound healing. Generally, the dressing is changed every 1-2 days until the wound is completely healed. The patient's hemostasis time was determined to be 8 minutes, and the puncture site was not infected.

[0083] In an embodiment of the present invention, a method for preparing the lithospermum composite dressing according to any of the above embodiments is also provided, the method comprising: S1, prepare shikonin solution.

[0084] S2, prepare chitosan solution.

[0085] S3, prepare gelatin solution.

[0086] In the embodiment of the present invention, chitosan, gelatin, and shikonin are accurately weighed according to a preset dressing formula ratio. The chitosan must be a product that meets pharmaceutical or medical standards, the gelatin must also be medical grade gelatin, and the shikonin must be an extract of appropriate purity.

[0087] In the embodiment of the present invention, the solvent includes 0.1% acetic acid solution (for dissolving chitosan), anhydrous ethanol (for dissolving shikonin), and deionized water (for dissolving gelatin and subsequent operations).

[0088] In an embodiment of the present invention, the chitosan solution is prepared by slowly adding weighed chitosan to a 0.1% acetic acid solution, where the ratio of chitosan to 0.1% acetic acid solution is determined according to the recipe. The solution is stirred at room temperature (20-25°C) using magnetic or mechanical stirring until the chitosan is completely dissolved, forming a uniform chitosan solution. During stirring, the solution should be carefully monitored to ensure that no lumps are present. The stirring time is typically 1-2 hours.

[0089] In an embodiment of the present invention, the steps of preparing a gelatin solution include: adding weighed gelatin to a predetermined amount of deionized water, the ratio of gelatin to deionized water being determined according to the recipe. The container containing the gelatin and deionized water is placed in a constant temperature water bath, heated to 60-70°C, and stirred to completely dissolve the gelatin, forming a transparent gelatin solution. The stirring speed is moderate to avoid excessive foaming, and the dissolution time is approximately 30 minutes to 1 hour.

[0090] In an embodiment of the present invention, the step of preparing the shikonin solution includes: adding weighed shikonin to anhydrous ethanol, wherein the ratio of shikonin to anhydrous ethanol is determined according to the formula to ensure that the shikonin can be fully dissolved. Generally, appropriate ultrasonic treatment or stirring can be used to accelerate the dissolution. Stirring until the shikonin is completely dissolved to obtain a uniform shikonin ethanol solution, which is set aside.

[0091] S4, mixing the prepared chitosan solution and gelatin solution.

[0092] In the embodiment of the present invention, during mixing, the temperatures of the two solutions are kept close, generally controlled at 40-50° C., to avoid coagulation or stratification of the solution due to a large temperature difference.

[0093] S5, adding shikonin solution to the mixed chitosan-gelatin solution, stirring for 10-15 minutes to uniformly disperse shikonin in the mixed solution, to obtain a shikonin-chitosan-gelatin solution, wherein the weight portion of shikonin is 0.5-2%, the weight portion of chitosan is 3-8%, and the weight portion of gelatin is 5-15%.

[0094] S6, pre-freezing the shikonin-chitosan-gelatin solution at a temperature of -40°C for 2-4 hours, so that the solution is completely frozen into a solid state.

[0095] S7, freeze-drying the pre-frozen sample.

[0096] Specifically, in an embodiment of the present invention, the freeze-drying step includes: quickly transferring the pre-frozen sample to a freeze dryer, closing the door, and starting the freeze dryer. The pressure of the freeze dryer is set to 10-20 Pa, the temperature is gradually increased from -40°C, the heating rate is controlled at 5-10°C / hour, and finally the temperature is increased to 20-30°C. The temperature and pressure conditions are maintained for drying, and the drying time is 12-24 hours until the moisture and ethanol in the sample are completely removed. During the drying process, the changes in pressure and temperature can be monitored in real time by observing the instrument panel or sensor of the freeze dryer to ensure that the drying process is proceeding normally.

[0097] S8, cutting the freeze-dried dressing sample into a suitable size and shape to obtain a drug sustained-release layer; S9, the drug sustained-release layer and the elastic non-woven fabric backing are assembled to obtain the lithospermum officinale composite dressing.

[0098] In an embodiment of the present invention, the method further includes: S11, mixing shikonin and anhydrous ethanol to obtain a shikonin ethanol solution.

[0099] S12, quickly injecting the ethanol solution of shikonin into supercritical CO2, ethanol as a good solvent is quickly extracted by the supercritical CO2, and shikonin is precipitated due to a sudden drop in solubility, thereby obtaining shikonin nanocrystals.

[0100] S13, loading the shikonin nanocrystals into the drug sustained-release layer.

[0101] In the embodiment of the present invention, shikonin powder with a purity of ≥98% (to ensure that no impurities interfere with crystal formation), anhydrous ethanol (analytical grade, used as a good solvent), and supercritical CO2 (purity ≥99.9%, used as an anti-solvent, which has both environmental protection and easy separation properties) are selected.

[0102] In this embodiment of the present invention, step S11 includes: weighing shikonin at a mass-to-volume ratio of 1%-5%, slowly adding it to anhydrous ethanol, placing it on a magnetic stirrer, and stirring at 30°C for 30 minutes until the shikonin is completely dissolved, forming a clear shikonin ethanol solution. (A high concentration can easily lead to agglomeration during precipitation, while a low concentration can result in a low nanocrystal yield.) The solution is filtered through a 0.22μm organic phase filter membrane to remove undissolved particles to avoid affecting the purity of the nanocrystals.

[0103] In this embodiment of the present invention, step S12 includes: starting a high-pressure CO2 pump to inject CO2 into the reactor, setting the temperature to 31-40°C (the critical temperature of supercritical CO2 is 31.1°C) and the pressure to 8-15 MPa (in this range, CO2 is in a supercritical state, possessing both gas diffusivity and liquid solubility), and stabilizing for 30 minutes to achieve a uniform supercritical environment within the reactor. The prepared shikonin ethanol solution is connected to the reactor feed port via a constant-flow pump, with a pump speed set to 5-15 mL / min (a flow rate that is too fast can easily lead to excessively high local concentrations, while a flow rate that is too slow can result in low efficiency). Starting an ultrasonic disruptor, inserting an ultrasonic probe into the reactor (or using an external ultrasonic device with a power of 500-800 W and a frequency of 20-40 kHz), and starting ultrasound 5 minutes before solution injection to create a continuous ultrasonic field. Starting the constant-flow pump, rapidly inject the shikonin ethanol solution into the supercritical CO2. Ethanol, acting as a good solvent, is rapidly extracted by the supercritical CO2, and shikonin precipitates due to a sudden drop in solubility. The ultrasonic action is maintained for 30-60 minutes. The cavitation effect generated by ultrasound can break up the initially formed large particles and inhibit the agglomeration of nanocrystals. The particle size is monitored in real time by a laser particle size analyzer to ensure that the crystal particle size is stable in the range of 100-200nm.

[0104] In the embodiment of the present invention, shikonin nanocrystals can be directly mixed into the chitosan-gelatin mixed solution to improve the shikonin loading efficiency and sustained-release performance of the dressing.

[0105] In an embodiment of the present invention, there is also provided a use of the lithospermum composite dressing described in any of the above embodiments in preparing a dressing for treating post-femoral artery puncture surgery.

[0106] In an embodiment of the present invention, there is also provided the use of the lithospermum composite dressing described in the above embodiment in preparing a dressing for treating burn wounds.

[0107] In the comfrey composite dressing used for treating burn wounds, the phase change temperature and cold storage capacity of the phase change material in the cooling phase change layer can effectively treat burn wounds and reduce wound temperature.

[0108] Although the preferred embodiments of the present invention have been described, those skilled in the art may make additional changes and modifications to these embodiments once they become aware of the basic creative concepts. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the embodiments of the present invention.

[0109] The above is a detailed introduction to the lithospermum composite dressing provided by the present invention, its preparation method and application. Specific examples are used herein to illustrate the principles and implementation methods of the present invention. The description of the above embodiments is only used to help understand the method of the present invention and its core concept. At the same time, for those skilled in the art, according to the concept of the present invention, there will be changes in the specific implementation methods and application scopes. In summary, the content of this specification should not be understood as limiting the present invention.

Claims

1. A lithospermum composite dressing comprising: A drug sustained-release layer and an elastic non-woven fabric backing, wherein the drug sustained-release layer comprises shikonin, chitosan and gelatin, and the elastic model of the elastic non-woven fabric backing is 50-100 MPa.

2. The lithospermum erythrorhizon composite dressing according to claim 1, characterized in that The lithospermum composite dressing also includes: an intelligent response layer, which includes a pH-sensitive hydrogel. The pH-sensitive hydrogel responds to changes in the local pH value of the wound, with a swelling degree varying between 300-500% and a fluid absorption rate of 1500%.

3. The lithospermum erythrorhizon composite dressing according to claim 1, characterized in that The lithospermum composite dressing further comprises: a polyurethane breathable membrane having a thickness of 50-80 μm, a water vapor permeability of 2800 g / m² / 24h, and an anti-bacterial penetration rate of >99.99%.

4. The lithospermum erythrorhizon composite dressing according to claim 1, characterized in that The lithospermum composite dressing also includes a millimeter wave absorption layer filled with silicon carbide micropowder. The millimeter wave absorption layer is used to absorb millimeter waves with a wavelength of 8-12mm, increase blood flow by 20%, accelerate blood circulation at the puncture site, and promote tissue metabolism and repair.

5. The lithospermum erythrorhizon composite dressing according to claim 1, characterized in that: The lithospermum composite dressing further comprises a cooling phase change layer, which comprises a phase change material. The phase change temperature of the phase change material is 40° C., and the cold storage capacity is 120 J / g.

6. The method for preparing the lithospermum erythrorhizon composite dressing according to any one of claims 1 to 5, wherein: The method comprises: preparing shikonin solution; preparing chitosan solution; Prepare gelatin solution; Mix the prepared chitosan solution and gelatin solution; Adding shikonin solution to the mixed chitosan-gelatin solution and stirring for 10-15 minutes to uniformly disperse shikonin in the mixed solution to obtain a shikonin-chitosan-gelatin solution, wherein the weight proportion of shikonin is 0.5-2%, the weight proportion of chitosan is 3-8%, and the weight proportion of gelatin is 5-15%; The shikonin-chitosan-gelatin solution is pre-frozen at a temperature of -40°C for 2-4 hours to completely freeze the solution into a solid state; Freeze-dry the pre-frozen samples; Cutting the freeze-dried dressing sample into a suitable size and shape to obtain a drug sustained-release layer; The drug sustained-release layer and the elastic non-woven fabric backing are assembled to obtain the lithospermum officinale composite dressing.

7. The method for preparing the lithospermum erythrorhizon composite dressing according to claim 6, characterized in that: The method further comprises: mixing shikonin and anhydrous ethanol to obtain a shikonin ethanol solution; The ethanol solution of shikonin was quickly injected into supercritical CO2. Ethanol, as a good solvent, was quickly extracted by supercritical CO2. Shikonin precipitated due to a sudden drop in solubility, and shikonin nanocrystals were obtained. The shikonin nanocrystals are loaded into a drug sustained-release layer.

8. Use of the lithospermum composite dressing according to any one of claims 1 to 5 in preparing a dressing for treating post-femoral artery puncture.

9. Use of the lithospermum erythrorhizon composite dressing according to any one of claims 1 to 5 in preparing a dressing for treating burn wounds.

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