TWI832115B - Anti-curling film - Google Patents

Abstract

An anti-curling film is provided. The anti-curling film includes a first portion and a second portion covering the first portion. The first portion includes polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methacrylate (PEGMA) and a photoinitiator. The second portion includes polycaprolactone (PCL), gelatin, hyaluronic acid (HA), alginate (AA), polyvinyl alcohol (PVA) or a combination thereof.

Description

Anti-curl film

The present disclosure relates to a film material, and in particular to an anti-curl film material.

Currently, adhesive and water-absorbent films used clinically often absorb a large amount of tissue fluid, causing the material to dissolve and disintegrate, or the film to curl and detach due to volume swelling, causing difficulties in clinical use and hampering the accuracy of treatment. low, or even ineffective.

Currently common solutions, for example, use water-absorbing or hydrophobic polymers alone. In addition, due to the easy curling characteristics of the materials themselves, most of them can only be used on specific organs, resulting in poor clinical operability. Moreover, the product manufacturing process and related verification require high costs, and the market acceptance is low.

Therefore, it is desirable to develop a film that can avoid curling during the process of adhering to tissue.

Clinical surgical membranes often absorb a large amount of tissue fluid during the process of attaching to organs when repairing clinical wounds, causing the membrane to swell and curl, resulting in poor clinical operability. The membrane may even be detached from the tissue surface due to structural damage after swelling. Therapeutic effect.

According to an embodiment of the present disclosure, an anti-curling film is provided, including: a first part including polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methyl methacrylate ( polyethylene glycol methacrylate (PEGMA) and a photoinitiator; and a second part covering the first part, wherein the second part includes polycaprolactone (PCL), gelatin (gelatin), hyaluronic acid (hyaluronic acid), HA), alginate (AA), polyvinyl alcohol (PVA), or combinations thereof.

In some embodiments, the grafting rate of polyethylene glycol methyl methacrylate (PEGMA) is between 65% and 72%.

In some embodiments, the weight ratio of polylactic acid (PLA), polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA) ranges from 0.5:1:1 to 0.5:1:6 .

In some embodiments, the first portion includes a first layer and a second layer. In some embodiments, the first layer includes polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA), and the polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA) weight ratio is between 1:6 and 1:12. In some embodiments, the second layer includes polyethylene glycol methyl methacrylate (PEGMA) and polylactic acid (PLA), and a combination of polyethylene glycol methyl methacrylate (PEGMA) and polylactic acid (PLA) The weight ratio is between 1:1 and 3:1.

In some embodiments, the weight ratio of polyethylene glycol methyl methacrylate (PEGMA), polylactic acid (PLA) and the photoinitiator is between 1:1:0.005 and 3:1:0.015. In some embodiments, the weight ratio of polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methyl methacrylate (PEGMA) and the photoinitiator is between 2:1:7:0.03 to 3:1:12:0.06. In some embodiments, when the content of polyethylene glycol methyl methacrylate (PEGMA) is too low, film formation may not be possible. In some embodiments, when the content of polyethylene glycol methyl methacrylate (PEGMA) is too high, the adhesion effect between the overall film layer and the tissue will be affected. In some embodiments, if the weight ratio of the photoinitiator is too low, it will affect the adhesion effect between the entire film layer and the tissue. If the weight ratio of the photoinitiator is too high, it will easily produce toxicity and cause tissue inflammation. In some embodiments, when the weight ratio of polycaprolactone (PCL) is too low, film formation may be affected, or if it is too high, the film may lose its adhesion effect due to the functional groups for attachment being coated in the PCL polymer.

In some embodiments, the second part includes a first layer and a second layer. In some embodiments, the first layer includes polycaprolactone (PCL), gelatin, algin (AA), or combinations thereof. In some embodiments, the second layer includes polycaprolactone (PCL), hyaluronic acid (HA), polyvinyl alcohol (PVA), or combinations thereof. In some embodiments, the first layer includes polycaprolactone (PCL) and gelatin (gelatin), and the weight ratio of polycaprolactone to gelatin is between 0.14:1 and 1:1. In some embodiments, the first layer includes polycaprolactone (PCL) and algin (AA), and the weight ratio of polycaprolactone to algin is between 8:1 and 4:1. In some embodiments, the first layer includes polycaprolactone (PCL), gelatin (gelatin) and algin (AA), and the weight ratio of polycaprolactone, gelatin and algin is between 1:1:0.1 to 1:1.85:0.125. In some embodiments, the first layer includes algin (AA), and the weight percentage of algin is between 1 wt% and 5 wt%. In some embodiments, the second layer includes polycaprolactone (PCL) and hyaluronic acid (HA), and the weight ratio of polycaprolactone to hyaluronic acid is between 10:1 and 35:1. In some embodiments, the second layer includes polycaprolactone (PCL) and polyvinyl alcohol (PVA), and the weight ratio of polycaprolactone to polyvinyl alcohol is between 1:0.1 and 1:0.16. In some embodiments, the second layer includes polycaprolactone (PCL), hyaluronic acid (HA) and polyvinyl alcohol (PVA), and the weight ratio of polycaprolactone, hyaluronic acid and polyvinyl alcohol is between Between 10:1:0.5 and 35:1:1. In some embodiments, when the content of gelatin and algin (AA) in the second part is too low, although the tissue fluid on the tissue surface can be quickly absorbed, the second part is easily dissolved by the tissue fluid and cannot maintain its stable structure. (Easy to be washed away by tissue fluid, which reduces the time it stays on the surface of the organ to repair/adhere, and loses its protective function, causing the film to curl again); in some embodiments, when the gelatin (gelatin), algin (algin) in the second part When the AA) content is too high, after the film is formed, the material is hard due to the high polymer content, and the polymer cannot quickly adsorb tissue fluid in a short time during operation (the space between molecules is relatively dense, and it takes a long time for water molecules such as tissue fluid to enter), leading to absorption. The effect of interstitial fluid is reduced, and it is easy for the diaphragm to warp when it adheres to the tissue, or the high polymer content and long-term absorption of the tissue will cause excessive swelling and thickness. After the warping and thickness are exceeded, the film will easily become loose due to tissue peristalsis. If it separates or slides, it loses its adhesion effect and cannot achieve the protective effect. In some embodiments, after absorbing tissue fluid, the second part can remain on the tissue surface for 24-48 hours without being washed away by body fluids.

In some embodiments, the second part includes gelatin (gelatin) and algin (AA) or includes gelatin (gelatin). In some embodiments, the second part includes gelatin and algin (AA), and the weight ratio of gelatin to algin is between 4:1 and 14.5:1. In some embodiments, the second part includes gelatin, and the weight percentage of gelatin is between 10wt% and 29.9wt%.

In some embodiments, the area ratio of the first part to the second part is between 5:100 and 65:100.

According to an embodiment of the present disclosure, an anti-curling film is provided, including: the second part of the above-mentioned anti-curling film.

This disclosure is directed to a film material (photo-cured layer - the first part of the anti-curling film) with tissue adhesion and water absorption (hydrophilicity), using a protective method (covering it with a protective layer - the second part of the anti-curling film). Part) and produce a specific area ratio to limit the amount of water absorbed when the water-absorbent film material is attached to the tissue surface (for example, liver, gastrointestinal tract, etc.). When the water-absorbent film material is used clinically and attached to the surface of internal organs in the body, it can effectively reduce the phenomenon of curling caused by the volume expansion of the water-absorbent film material caused by absorbing a large amount of tissue fluid. It can also effectively avoid the curling of the film material and the tissue surface. A situation causing disengagement occurs.

This disclosure is mainly to solve the curling condition caused by water absorption of the film. It uses the specific area ratio between the film layers to effectively control the water absorption state of the film, reduce the efficiency of water absorption during the tissue attachment reaction, and combines light-sensitive curing into the material. The design strengthens the adhesion effect between the film and the tissue surface through UV light irradiation of a fixed wavelength, so that while UV light promotes the adhesion speed of the film, while the polymer material reduces water absorption, the molecules rearrange and reduce curling in the film. The generation of stress will eliminate the occurrence of curling state.

Please refer to Figures 1 and 2. According to an embodiment of the present disclosure, an anti-curling film 10 is provided. Figure 1 is a top view of the anti-curl film 10. Figure 2 is a schematic cross-sectional view taken along the A-A’ section line in Figure 1.

As shown in Figures 1 and 2, the anti-curling film 10 includes a photocurable layer 12 and a protective layer 14. The protective layer 14 covers the photocurable layer 12 . The word "covering" here means that the lower photocurable layer 12 does not exceed the scope of the upper protective layer 14 when viewed from the above views or cross-sectional views. The photocurable layer 12 includes polylactic acid (PLA), polycaprolactone (PCL), and polyethylene glycol methacrylate (PEGMA).

In the embodiment shown in FIGS. 1 and 2 , the photocurable layer 12 is a double layer. For example, the photocurable layer 12 includes a first layer 16 and a second layer 18 , but the present disclosure is not limited thereto. In some embodiments, the first layer 16 includes polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA), and the polycaprolactone (PCL) and polyethylene glycol methyl methacrylate The weight ratio of (PEGMA) is between about 1:6 and about 1:12. When the weight ratio of polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA) is too low (for example, lower than 1:6), the configuration of the first layer 16 may not be formed. If the weight ratio is too high (for example, higher than 1:12), the first layer 16 will separate from the second layer 18 and cannot be effectively combined. In some embodiments, the second layer 18 includes polylactic acid (PLA) and polyethylene glycol methyl methacrylate (PEGMA), and a combination of polyethylene glycol methyl methacrylate (PEGMA) and polylactic acid (PLA). The weight ratio ranges from about 1:1 to about 3:1. When the weight ratio of polyethylene glycol methyl methacrylate (PEGMA) and polylactic acid (PLA) is too low (for example, less than 1:1), the configuration of the second layer 18 will not be formed. If the weight ratio is too high, (for example, higher than 3:1), the second layer 18 cannot be effectively combined with the first layer 16 .

In some embodiments, the photocurable layer 12 is a single layer. For example, the photocurable layer 12 includes polylactic acid (PLA), polycaprolactone (PCL), and polyethylene glycol methyl methacrylate (PEGMA). In some embodiments, the weight ratio of polylactic acid (PLA), polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA) in the photocurable layer 12 ranges from about 0.5:1:1 to About 0.5:1:6. When the weight ratio of the above three raw materials is based on PCL, if the ratio range of PLA and PEGMA is lower than the above ratio, the photocurable layer may not be able to effectively form a film, resulting in cracking and damage. If the ratio range is higher than the above ratio, the photocuring effect may decrease or even fail. On the other hand, if PEGMA in the photocurable layer exceeds the weight percentage of PCL and PLA by more than 50%, the photocurable layer may not be effectively formed, resulting in film damage and process failure.

In the embodiments shown in Figures 1 and 2, the photocurable layer 12 further includes a photoinitiator, such as Irgacure 2959, Irgacure 819 DW, or Irgacure 127. In some embodiments, the weight ratio of polyethylene glycol methyl methacrylate (PEGMA), polylactic acid (PLA) and photoinitiator ranges from about 1:1:0.005 to about 3:1:0.015. In some embodiments, the weight ratio of polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methyl methacrylate (PEGMA) and photoinitiator is approximately 2:1:7:0.03 to approximately 3:1:12:0.06.

In the embodiment shown in FIGS. 1 and 2 , the protective layer 14 is a double layer. For example, the protective layer 14 includes a first layer 20 and a second layer 22 , but the present disclosure is not limited thereto. In some embodiments, the first layer 20 includes polycaprolactone (PCL), gelatin, algin (AA), or combinations thereof. In some embodiments, the second layer 22 includes polycaprolactone (PCL), hyaluronic acid (HA), polyvinyl alcohol (PVA), or combinations thereof. In some embodiments, the first layer includes polycaprolactone (PCL) and gelatin, and the weight ratio of polycaprolactone to gelatin is between about 0.14:1 and about 1:1. In some embodiments, the first layer includes polycaprolactone (PCL) and algin (AA), and the weight ratio of polycaprolactone to algin is between about 8:1 and about 4:1. In some embodiments, the first layer includes polycaprolactone (PCL), gelatin (gelatin) and algin (AA), and the weight ratio of polycaprolactone, gelatin and algin is approximately 1:1:0.1 to approximately 1:1.85:0.125. In some embodiments, the first layer includes algin (AA), and the weight percentage of algin is between about 1 wt% and about 5 wt%. In some embodiments, the second layer includes polycaprolactone (PCL) and hyaluronic acid (HA), and the weight ratio of polycaprolactone to hyaluronic acid is between about 10:1 and about 35:1. . In some embodiments, the second layer includes polycaprolactone (PCL) and polyvinyl alcohol (PVA), and the weight ratio of polycaprolactone to polyvinyl alcohol is between about 1:0.1 and about 1:0.16. . In some embodiments, the second layer includes polycaprolactone (PCL), hyaluronic acid (HA) and polyvinyl alcohol (PVA), and the weight ratio of polycaprolactone, hyaluronic acid and polyvinyl alcohol is between Between approximately 10:1:0.5 and approximately 35:1:1.

In some embodiments, the protective layer 14 is a single layer. For example, the protective layer 14 includes polycaprolactone (PCL), gelatin (gelatin), hyaluronic acid (HA), alginate (AA), Polyvinyl alcohol (PVA), or combinations thereof. In some embodiments, the protective layer 14 includes gelatin and algin (AA). In some embodiments, the protective layer 14 includes gelatin. In some embodiments, the protective layer 14 includes gelatin and algin (AA), and the weight ratio of gelatin to algin is between about 4:1 and about 14.5:1. In some embodiments, the protective layer 14 includes gelatin, and the weight percentage of gelatin is between about 10 wt% and about 29.9 wt%.

In some embodiments, the grafting rate of polyethylene glycol methyl methacrylate (PEGMA) ranges from about 65% to about 72%. If the grafting rate is lower than the minimum percentage disclosed in the present disclosure, the effect of the subsequent reaction with the photoinitiator may be reduced. Even after molding in the post-processing process, the amount of exposed reaction functional groups will be too small to allow effective reaction. On the contrary, if the grafting rate is too high, one of the possible problems is the production of excess reactive functional groups, which will cause toxic reactions in future clinical applications and cause inflammation in patients. The other is excessive photocuring reaction. As a result, the light-cured layer will lose its softness and conformability when implanted into the human body in the future, or even produce sharper corners that rub against tissue, resulting in adverse reactions such as inflammation or tissue injury, causing pain to the patient after recovery.

In some embodiments, the area ratio of the photocurable layer 12 to the protective layer 14 is between about 5:100 and about 65:100. If the area of the protective layer 14 is fixed, the area ratio of the photocurable layer 12 to the protective layer 14 is too large. If the area of the protective layer 14 is fixed and the area ratio of the photo-cured layer 12 to the protective layer 14 is too high, the effect of the protective layer 14 on absorbing tissue fluid will be affected (the protective effect is poor). , causing the photocurable layer 12 to swell and curl. In some embodiments, when the area of the protective layer 14 is 100 square centimeters, the photocurable layer 12 is 6.25 square centimeters. In some embodiments, when the area of the protective layer 14 is 100 square centimeters, the photocurable layer 12 is 64 square centimeters.

In some embodiments, the protective layer 14 may be implemented separately.

This disclosure is directed to a film material (photo-cured layer - the first part of the anti-curling film) with tissue adhesion and water absorption (hydrophilicity), using a protective method (covering it with a protective layer - the second part of the anti-curling film). Part) and produce a specific area ratio to limit the amount of water absorbed when the water-absorbent film material is attached to the tissue surface (for example, liver, gastrointestinal tract, etc.). When the water-absorbent film material is used clinically and attached to the surface of internal organs in the body, it can effectively reduce the phenomenon of curling caused by the volume expansion of the water-absorbent film material caused by absorbing a large amount of tissue fluid. It can also effectively avoid the curling of the film material and the tissue surface. A situation causing disengagement occurs.

This disclosure is mainly to solve the curling condition caused by water absorption of the film, and utilizes the specific area ratio between the film layers (photo-cured layer 12 and protective layer 14) to effectively control the water absorption state of the film and reduce the efficiency of water absorption during the tissue adhesion reaction process. , and incorporates a photo-sensitive curing design into the material. During implementation, UV light of a fixed wavelength is irradiated to enhance the adhesion effect between the film and the tissue surface, so that while UV light promotes the adhesion speed of the film, the polymer in the photo-cured layer (The polymer, as mentioned above, can be a film formed by blending PCL/PEGMA or PLA/PEGMA). When the amount of water absorption is reduced, the molecules are rearranged, reducing the generation of curling stress in the film, thereby eliminating the occurrence of curling.

Preparation Example 1

Preparation of polyethylene glycol methyl methacrylate (PEGMA)

(1) Place 50 grams of polyethylene glycol (PEG) (molecular weight 8,000) into the reaction tank and dissolve it in 350 ml of tetrahydrofuran (THF). And pass in high-purity nitrogen to remove water vapor. (2) Dissolve methacrylic anhydride (MA) in 100 ml of tetrahydrofuran (THF), and slowly drop it into the above polyethylene glycol (PEG) solution. Polyethylene glycol (PEG) and methyl The ratio of acrylic anhydride (MA) is 1:5. (3) Continue to pass nitrogen gas and maintain the reaction temperature at 80 degrees Celsius for 8 hours. Next, add diethyl ether 10 times larger than the original volume for precipitation purification, and then filter the precipitated sample. (4) Dissolve the precipitated sample back into 100 ml of tetrahydrofuran (THF) at 60 degrees Celsius. After performing the above step (3), filter the sample and bake it in an exhaust cabinet at room temperature of 22 to 27 degrees. After drying, polyethylene glycol methyl methacrylate (PEGMA) can be obtained. The obtained polyethylene glycol methyl methacrylate (PEGMA) was subjected to NMR analysis. The double bond structure signals of MA appeared at 5.57ppm and 6.12ppm on the NMR spectrum, which confirmed that polyethylene glycol (PEG) and Methacrylic anhydride (MA) has been synthesized to form polyethylene glycol methyl methacrylate (PEGMA). The yield is about 89.02%, and the synthetic grafting rate is about 68.45%.

Preparation Example 2

Preparation of photocured layer

First, a solution (solution 1) containing 1g polycaprolactone (PCL) and 10g polyethylene glycol methyl methacrylate (PEGMA) was prepared, and a solution containing 2g polylactic acid (PLA) and 2g polyethylene glycol methyl The solution of methyl acrylate (PEGMA) (solution 2), solution 1 and solution 2 all use dichloromethane (DCM) as the solvent. After configuring Solution 1 and Solution 2, add starter I2959 to the two solutions respectively in amounts of 0.05 and 0.01g, and wait for 16 to 24 hours for the two solutions to be completely dissolved.

Next, solution 2 was coated on the Teflon flat substrate to form a film, and the coating thickness was set to 150 microns. After completing the film formation of solution 2, wait for about 10 minutes, and then pour solution 1 onto the film formed by solution 2 (first apply solution 2 to form a film, and then apply solution 1 on the film formed by solution 2. Film formation), solution 1 is evenly coated to form a film, and the thickness is set to 150 microns. After the dichloromethane (DCM) evaporates for 16 to 24 hours, the photocured layer can be obtained.

Preparation Example 3

Preparation of protective layer

First, prepare a solution containing 4g polycaprolactone (PCL) and 0.5g alginic acid (AA). PCL uses dichloromethane (DCM) as the solvent, and AA is deionized water (DDW) in an oven at 50 degrees environment for dissolution. After the respective preparations are completed, the two are mixed, stirred and emulsified to complete the preparation (solution 1).

Prepare a solution (solution 2) containing 4g polycaprolactone (PCL) and 0.1g polyvinyl alcohol (PVA). PCL uses dichloromethane (DCM) as the solvent, and PVA uses deionized water (DDW). Dissolve in an oven at 50 degrees. After the respective preparations are completed, the two are mixed, stirred and emulsified to complete the preparation (solution 2).

Next, solution 2 was coated on the Teflon flat substrate to form a film, and the coating thickness was set to 150 microns. After completing the film formation of solution 2, wait for about 10 minutes, and then pour solution 1 onto the film formed by solution 2 (first apply solution 2 to form a film, and then apply solution 1 on the film formed by solution 2. Film formation), solution 1 is evenly coated to form a film, and the thickness is set to 150 microns. After the dichloromethane (DCM) evaporates for 16 to 24 hours, the protective layer can be obtained.

Preparation Example 4

Preparation of anti-curl films

The anti-curling film mainly coats the photo-cured film of Preparation Example 2 on a protective layer containing components such as polycaprolactone (PCL), gelatin (gelatin), hyaluronic acid (HA), etc., so that the protective layer and the photo-cured layer Combined to form the same film, the coating sequence is to first prepare the protective layer, and then apply the photo-cured layer on the protective layer according to the steps of Preparation Example 2. After the solvent evaporates for 16 to 24 hours, an anti-curling film can be obtained .

Example 1

Test and analysis of the adhesion strength of the light-cured layer (attached to pig intestines) before and after sterilization

First, according to clinical sterility requirements, the light-cured layer is sterilized with ethylene oxide (EO). After sterilization, the samples were subjected to in vitro tissue adhesion test analysis according to the requirements of ASTM F2258 and ASTM F2255. Before analysis, the photocured layer was cut according to the size and operation method required by ASTM content, and then attached to the mold and intestinal tissue respectively. Irradiate with UV light 1 cm above the photo-cured layer for 10 minutes continuously. Record the light source intensity every minute. The UV light intensity decreases from 600mW to 520mW. The wavelength of UV light used is 365nm (UV light required for photo-curing) Wavelength range 270~400 nm). Carry out attachment test analysis after irradiating with UV light source for 60 seconds. The analysis results of ASTM F2258 are shown in Figure 3. The commercial product is Tissuemed's TissuePatch™. The original specification is 10*10cm and the thickness is about 40um. The size for analyzing the adhesion strength is the same as the sample in this example. The size cutting operation is carried out according to the requirements of ASTM text. The adhesion strengths of unsterilized, sterilized for 4 hours, sterilized for 8 hours, and commercially available TissuePatch™ were 30.92±5.01mJ, 22.96±3.86mJ, 26.13±1.32mJ, and 3.01±1.73mJ respectively. The analysis results of ASTM F2255 are shown in Figure 4. The adhesion strengths of unsterilized, sterilized for 4 hours, sterilized for 8 hours, and commercially available products are 38.72±17.35mJ, 42.49±10.93mJ, 49.30±14.43mJ, and 11.20±1.28 respectively. mJ.

Example 2

Test and analysis of the adhesion strength of the light-cured layer (attached to pig liver) before and after sterilization

First, according to clinical sterility requirements, the light-cured layer is sterilized with ethylene oxide (EO). After sterilization, the samples were subjected to in vitro tissue adhesion test analysis according to the requirements of ASTM F2258 and ASTM F2255. Before analysis, the light-cured layer was attached to the liver. The attachment dimensions were the same as in Example 1 above, and the dimensions and operation methods were carried out according to the requirements of ASTM text. Irradiate with UV light at a distance of 1 cm above the light-cured layer for 10 minutes. Record the light source intensity every minute. The UV light intensity drops from 600mW to 520mW. Carry out attachment test analysis after irradiating with UV light source for 60 seconds. The analysis results of ASTM F2258 are shown in Figure 5. Tests were conducted on non-sterilized, sterilized and commercially available products (TissuePatch™). The adhesion strengths were 78.06±5.02mJ, 113.18±35.75mJ and 4.43±2.94mJ respectively. The analysis results of ASTM F2255 are shown in Figure 6. The adhesion strengths of unsterilized, sterilized and commercial products are 47.85±6.97mJ, 33.03±8.01mJ and 27.61±10.37mJ respectively.

Example 3

Test and analysis of adhesion strength of anti-curl film (attached to pig intestines)

According to the requirements of ASTM F2258 and ASTM F2255, the anti-curling film prepared in Preparation Example 4 was subjected to in vitro tissue adhesion test analysis. Anti-curl film was attached to intestinal tissue prior to analysis. Irradiate with UV light at a distance of 1 cm above the anti-curl film for 10 minutes. Record the light source intensity every minute. The UV light intensity drops from 600mW to 520mW. Carry out attachment test analysis after irradiating with UV light source for 60 seconds. The analysis results of ASTM F2258 are shown in Figure 7. The adhesion strengths of the anti-curl film prepared in Preparation Example 3 and the commercial product TissuePatch™ are 19.53±3.74mJ and 3.01±1.73mJ respectively. The analysis results of ASTM F2255 are shown in Figure 8. The adhesion strengths of the anti-curl film prepared in Preparation Example 4 and the commercial product are 17.13±0.15mJ and 19.78±10.97mJ respectively. It can be seen from the above analysis results that the adhesion strength of the anti-curl film of the present disclosure is stable and better than that of commercially available products.

Example 4

Water absorption and swelling test analysis of light-cured layer (attached to pig liver)

The light-curing layer (test size is 2.5*2.5cm and 8*8cm respectively) is attached to the liver and continuously irradiated with UV light for curing. The irradiation times were 30 seconds, 60 seconds, 90 seconds, 180 seconds, 240 seconds and 300 seconds respectively. After the irradiation is completed, a fixed volume of 200 microliters (μL) of physiological saline is given for a water absorption and hydration test. After 30 minutes of the same water absorption time, observe the swelling thickness of the photocured layer under a microscope. The analysis results are shown in Figure 9. It can be seen from Figure 9 that after 180 seconds of UV light irradiation, the thickness of the photocured layer has reached equilibrium and no longer increases significantly. When irradiated for 300 seconds, the thickness has almost no change. After further converting the percentage of swelling, (Wt after swelling - W0 before swelling)/W0*100 before swelling = swelling degree %, the change curve of the obtained swelling degree (percentage) is shown in Figure 10. As can be seen from Figure 10, after 180 to 300 seconds of irradiation, the turbidity of the photo-cured layer is approximately 55.31 to 58.65% of the original thickness, and after 180 seconds of irradiation, the change slows down significantly. This can also be verified by UV irradiation. It can make the photo-cured layer moist and stable for at least 180 seconds.

Example 5

Water absorption and swelling test analysis of anti-curl film (attached to pig liver)

The following is a water absorption and swelling test and analysis of the anti-curling film prepared in Preparation Example 4. The test was divided into a control group (without protective layer) and an experimental group (covered with protective layer). The control group sample was attached to the liver, irradiated with UV light for 60 seconds, and soaked in physiological saline for 30 minutes. Because the sample was not protected by a protective layer, the sample appeared curled and detached from the tissue surface. The experimental groups were divided into Experiment 1 group and Experiment 2 group. The anti-curl film used in Experiment 1 has a protective layer area of 10x10 cm and a photo-curing layer area of 2.5x2.5 cm. The anti-curl film used in Experiment 2 has a protective layer area of 10x10 cm and a photo-curing layer area of 8x8 cm. The anti-curling film was attached to the liver and irradiated with UV light. The irradiation times were 60 seconds, 180 seconds and 300 seconds respectively. After the irradiation is completed, soak the liver tissue in physiological saline for 16 to 18 hours. It can be seen from the test results that the experimental group 1 will not curl or fall off after being exposed to UV light for 180 seconds and soaked for 16 to 18 hours. Similarly, in Experiment 2, after being exposed to UV light for 60 seconds and soaked for 16 to 18 hours, there was no curling or shedding. The above test results verify that the photo-cured layer, under the effective protection of the protective layer (the photo-cured layer area accounts for 6.25% to 64% of the protective layer area), can effectively eliminate the curling of the film due to water absorption.

Example 6

Cytotoxicity (biocompatibility) analysis of anti-curling films

The following cytotoxicity analysis was performed on the anti-curl film prepared in Preparation Example 4 according to ISO 10993-5. The film was placed in Dulbecco's modified Minimal Essential Medium (DMEM) containing 10% fetal bovine serum (FBS) at 37 degrees Celsius for extraction. After 24 hours of incubation, the extract was co-cultured with L929 fibroblasts. The co-culture time is 24 hours. The cell survival rate after co-culture of L929 fibroblasts and sample extract was greater than 70%, indicating that the disclosed anti-curling film has no toxicity and good biocompatibility.

Example 7

Implantation test of anti-curling film in rabbits (attached to liver)

The following is a verification of the efficacy of the anti-curling film implanted in rabbits. The test was divided into a control group (without protective layer) and an experimental group (covered with protective layer). The area of the photocured layer used in the control group was 1.5x1.5 cm. The anti-curl film used by the experimental group has a protective layer area of 2.5x.2.5 cm and a photo-curing layer area of 1.5x1.5 cm. After the two groups were irradiated with UV light for 180 seconds at the same time, the patch reactions were observed respectively. At this time, the control group had obviously curled up and partially detached from the tissue surface. After suturing, wait 48 hours before sacrificing samples for observation. It can be seen from the results that the patch in the control group was slightly sticky. Although it still existed at the location of the surgical liver, the patch was folded due to curling. On the other hand, the patch in the experimental group showed no sticking and could be stably attached to the surface of the liver without any curling or detachment.

Example 8

Implantation test of anti-curling film in pigs (attached to the intestines)

The following is a verification of the efficacy of the anti-curling film implanted in pigs. Step 1: Locate the intestinal injury. Step 2: Aseptically remove the anti-curl film. Step 3: Curl the film and use minimally invasive surgical instruments to deliver the anti-curling film into the body. Step 4: Attach it to the wound and confirm that it is completely covered. Step 5: Use a specific UV light wavelength light source for irradiation. Step 6: The illumination time is 180 seconds. After completing the above 6 steps, suture and disinfect the abdominal micro-trauma incision according to the general clinical postoperative operation methods, and wait for one month for animal sampling and observation.

The animals were sacrificed for sampling one month later, and the wound was observed using a minimally invasive surgical endoscope before sacrifice. Observation results show that after one month, the anti-curling film did not produce any adverse reactions such as sticking to the intestinal wound, and there were faint traces of the film above the wound. This confirms that the anti-curling film can be stably attached. There will be no curling or other adverse reactions on intestinal wounds. The above results prove that the disclosed anti-curling film can not only effectively solve the problem of patch curling due to water absorption and swelling caused by commonly used clinical water-absorbent patch films after being implanted in the body, but can also avoid other possible sequelae.

Example 9

Implantation test of anti-curling film in pigs (attached to intestines, stomach and liver) (observation by appearance)

The following is a verification of the efficacy of the anti-curling film implanted in pigs for 1 month and 3 months. The implanted organs are intestine, stomach and liver. Samples were taken for observation after 1 month and 3 months respectively. After sampling and observing one month later, it was found that there was no sticking or leakage in any organ. After 3 months of sampling and observation, it was found that the appearance of the intestinal tract was normal, while there was some sticky tissue in the stomach and liver. During the sampling process, the adherent proliferative tissue in the stomach can be separated without external intervention. This adhesion after surgery is a normal reaction and is not an undesirable adhesion in clinical practice. As for the adhesion that occurs in the liver, it only needs to be gently removed to remove the adhesion. Since the liver is an organ prone to adhesion, any surgical operation may cause adhesion. Is it due to the anti-curling film? Caused by this, slice analysis is still needed to clearly determine the results. In summary, in terms of the adhesion index score performance, the anti-curling film disclosed in the present disclosure has the best effect on intestinal organs, and the stomach and liver can still be used as candidate organs and application locations for future clinical indications.

Example 10

Implantation test of anti-curling film in pigs (attached to intestines, stomach and liver) (observed by tissue staining)

In this example, samples were taken one month later, and the tissues were sectioned and stained for observation. Staining of the intestine, stomach, and liver was performed, including H&E (Hematoxylin & Eosin staining), MGT (Masson's Trichrome Stain; Masson's trichrome staining) and immunohistochemistry (Immunohistochemistry, IHC) CD45 inflammatory response. dyeing. The H&E staining results of the intestinal tissue sections showed (as shown in Figure 11) that the wound was effectively covered by the material, and the wound had been repaired to achieve a sealing effect, which was consistent with the appearance observed during sampling. The H&E staining results of gastric tissue sections (as shown in Figure 12) are the same as those of intestinal tissue. The wound has been completely covered by material, and the tissue at the wound has also been repaired. It is consistent with the appearance observed at the time of sampling and does not Leakage and tissue proliferation occur. The H&E staining results of the liver tissue sections showed (as shown in Figure 13) (because it is difficult to stop bleeding in the liver, in order to avoid multiple variables affecting the experiment, the film was only implanted into the body and attached without creating a wound). The film was still Can stably exist on the surface of tissues. Through H&E staining observation, it can be found that the light-cured patch can stably exist on the tissue surface, and can accurately and stably seal and stop leakage at the postoperative wound (no sutures are used to fix the patch or repair the wound). This verification The light-curing patch has the function of being attached to prevent leakage. In addition, when observing the tissue section above the film, no adverse hyperplasia tissue performance was observed, which was consistent with the appearance observation during sampling and also verified the anti-adhesion effect of the light-cured patch.

In order to verify the efficacy of the light-cured patch and the status of tissue repair, MGT staining was performed on each of the above-mentioned tissues. MGT staining can mainly observe collagen produced by connective tissue. The tissue sections of the intestine (as shown in Figure 14), stomach (as shown in Figure 15), and liver (as shown in Figure 16) were observed by MGT staining. The results show in the 100X photo in the figure that the wound has been There is a blue-green collagen reaction, which means that after the wound is sealed and leak-proofed by the light-cured patch, the film can serve as a repair bridge, allowing fibroblasts to repair defects between wounds along the material, thereby producing extracellular matrix. of collagen. It can also be observed that the material is surrounded by blue-green connective tissue, and the material has begun to appear damaged. This phenomenon can be inferred that the material begins to undergo a degradation reaction after being covered by tissue.

After completing the H&E and MGT section analysis, the tissues of the intestine, stomach, and liver were stained for CD45 by immunohistochemistry (IHC). IHC uses the specific binding between antibodies and antigens to detect the expression amount and location of target proteins in tissues or cells. CD45 was stained brown (DAB) for identification, and nuclei were stained with Hematoxylin for identification. CD45 is expressed on all white blood cells and is also said to help identify all hematopoietic cells except mature red blood cells and platelets. The following describes the results of CD45 in the intestine, stomach, and liver tissues under a 10X microscope. Observed under the 10X field of view, the results showed that there was only an obvious brown (DAB) precipitated immune reaction around the material, while there was no significant immune inflammatory reaction in the wounds of the intestines and stomach. The inflammatory reaction was further observed under 100X and 400X microscopes. The results showed that under 100X, only the intestines had a slight inflammatory reaction, and there was no serious immune reaction in other organs. This means that one month after the light-cured patch is implanted, after the acute inflammation period in the first two weeks, the tissue has begun to enter the repair phase (M2 phase).

Based on the above analysis, the performance of the disclosed anti-curling film after implantation in the body is in line with the expected anti-leakage effect, and there is no adverse reaction of sticking. It can be seen from the analysis results of tissue sections that the tissue has begun to repair one month after implantation in the body, and the efficacy verification in large animals has been quite successful.

10: Anti-curl film 12:Light curing layer 14:Protective layer 16: The first layer of photo-cured layer 18: The second layer of photo-cured layer 20: The first layer of protective layer 22: The second layer of protection

Figure 1 is a top view of an anti-curl film according to an embodiment of the present disclosure; Figure 2 is a schematic cross-sectional view of an anti-curl film according to an embodiment of the present disclosure along the A-A’ section line in Figure 1; Figure 3 is a test analysis (ASTM F2258) of the adhesion strength of the photo-cured layer (attached to pig intestines) before and after sterilization, according to an embodiment of the present disclosure; Figure 4 is a test analysis (ASTM F2255) of the adhesion strength of the photo-cured layer (attached to pig intestines) before and after sterilization, according to an embodiment of the present disclosure; Figure 5 is a test analysis (ASTM F2258) of the adhesion strength of the light-cured layer (attached to pig liver) before and after sterilization according to an embodiment of the present disclosure; Figure 6 shows the adhesion strength test analysis (ASTM F2255) of the light-cured layer (attached to pig liver) before and after sterilization according to an embodiment of the present disclosure; Figure 7 is a test analysis (ASTM F2258) of the adhesion strength of the anti-curl film (attached to pig intestines) according to an embodiment of the present disclosure; Figure 8 is a test analysis (ASTM F2255) of the adhesion strength of the anti-curl film (attached to pig intestines) according to an embodiment of the present disclosure; Figure 9 shows the water absorption and swelling test analysis of the light-cured layer (attached to the pig liver) according to an embodiment of the present disclosure; Figure 10 is an analysis of the swelling degree of the light-cured layer (attached to pig liver) according to an embodiment of the present disclosure; Figure 11 shows the H&E staining results of intestinal tissue sections according to an embodiment of the present disclosure; Figure 12 shows the H&E staining results of gastric tissue sections according to an embodiment of the present disclosure; Figure 13 shows the H&E staining results of liver tissue sections according to an embodiment of the present disclosure; Figure 14 shows the MGT staining results of intestinal tissue sections according to an embodiment of the present disclosure; Figure 15 shows the MGT staining results of gastric tissue sections according to an embodiment of the present disclosure; and Figure 16 shows the MGT staining results of liver tissue sections according to an embodiment of the present disclosure.

10: Anti-curl film

12:Light curing layer

14:Protective layer

Claims (18)

An anti-curling film, including: a first part including polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methacrylate (PEGMA) and a light Initiator, wherein the weight ratio of polylactic acid (PLA), polycaprolactone (PCL), polyethylene glycol methyl methacrylate (PEGMA) and the photoinitiator is between 2:1:7:0.03 and Between 3:1:12:0.06; and a second part covering the first part, wherein the second part includes polycaprolactone (PCL), gelatin (gelatin), hyaluronic acid (HA), Alginate (AA), polyvinyl alcohol (PVA), or a combination thereof, wherein when the second part includes gelatin (gelatin) and algin (AA), the weight ratio of gelatin to algin is between Between 4:1 and 14.5:1, and the area ratio of the first part to the second part is between 5:100 and 65:100. The anti-curl film of claim 1, wherein the grafting rate of polyethylene glycol methyl methacrylate (PEGMA) is between 65% and 72%. The anti-curl film of claim 1, wherein the weight ratio of polylactic acid (PLA), polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PFGMA) is between 0.5:1:1 and 0.5 :1:6. The anti-curl film of claim 1, wherein the first part includes a first layer and a second layer. The anti-curl film of claim 4, wherein the first layer includes polycaprolactone (PCL) and polyethylene glycol methyl methacrylate (PEGMA), and the polycaprolactone and polyethylene glycol methyl methacrylate The weight ratio of methyl acrylate is between 1:6 and 1:12. The anti-curl film of claim 4, wherein the second layer includes polyethylene glycol methyl methacrylate (PEGMA) and polylactic acid (PLA), and polyethylene glycol methyl methacrylate (PEGMA) and The weight ratio of polylactic acid (PLA) is between 1:1 and 3:1. The anti-curl film of claim 1, wherein the weight ratio of polyethylene glycol methyl methacrylate (PEGMA), polylactic acid (PLA) and the photoinitiator is between 1:1:0.005 and 3:1 : between 0.015. The anti-curl film of claim 1, wherein the second part includes a first layer and a second layer. The anti-curl film of claim 8, wherein the first layer includes polycaprolactone (PCL), gelatin, algin (AA), or a combination thereof. The anti-curl film of claim 8, wherein the second layer includes polycaprolactone (PCL), hyaluronic acid (HA), polyvinyl alcohol (PVA), or a combination thereof. The anti-curl film of claim 9, wherein the first layer includes polycaprolactone (PCL) and gelatin (gelatin), and the weight ratio of polycaprolactone to gelatin is between 0.14:1 and 1:1. between. The anti-curl film of claim 9, wherein the first layer includes polycaprolactone (PCL) and algin (AA), and the weight ratio of polycaprolactone to algin is between 8:1 and 4: between 1. The anti-curl film of claim 9, wherein the first layer includes polycaprolactone (PCL), gelatin (gelatin) and algin (AA), and the weight ratio of polycaprolactone, gelatin and algin is between Between 1:1:0.1 and 1:1.85:0.125. The anti-curl film of claim 9, wherein the first layer includes algin (AA), and the weight percentage of algin is between 1 wt% and 5 wt%. The anti-curling film of claim 10, wherein the second layer includes polycaprolactone (PCL) and hyaluronic acid (HA), and the weight ratio of polycaprolactone to hyaluronic acid is between 10:1 and Between 35:1. The anti-curl film of claim 10, wherein the second layer includes polycaprolactone (PCL) and polyvinyl alcohol (PVA), and the weight ratio of polycaprolactone to polyvinyl alcohol is between 1:0.1 and 1: Between 0.16. The anti-curl film of claim 10, wherein the second layer includes polycaprolactone (PCL), hyaluronic acid (HA) and polyvinyl alcohol (PVA), and polycaprolactone, hyaluronic acid and polyvinyl alcohol (PVA) The weight ratio of vinyl alcohol ranges from 10:1:0.5 to 35:1:1. The anti-curl film of claim 1, wherein when the second part includes gelatin, the weight percentage of gelatin is between 10wt% and 29.9wt%.

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