Method for manufacturing patient-customized wound dressing integrated with microneedles, and patient-customized wound dressing integrated with microneedles, manufactured through same

Abstract

A method for manufacturing a patient-customized wound dressing integrated with microneedles, and a patient-customized wound dressing integrated with microneedles, manufactured through same, are provided. A wound dressing is manufactured through 3D bioprinting by using a photopolymerizable biocompatible biodegradable bioink, and then microneedles are formed on the wound dressing through two-photon polymerization (2PP) printing by using the photopolymerizable biocompatible biodegradable bioink, and thus the patient-customized wound dressing integrated with microneedles is manufactured.

Description

Method for manufacturing a patient-specific wound dressing with embedded microneedles and a patient-specific wound dressing with embedded microneedles manufactured thereby

[0001] The present invention relates to a method for manufacturing a patient-specific wound dressing with embedded microneedles and a patient-specific wound dressing with embedded microneedles manufactured thereby.

[0002] Wound dressings are medical devices used to prevent contamination and protect wounds. Applying them to a wound site is known to absorb exudates, maintain a moist environment, and prevent scab formation, thus accelerating wound healing.

[0003] According to various recent studies, when there are microscopic pores in the wound dressing, the thickness of the granulation tissue increases and organization progresses rapidly through angiogenesis, ultimately reducing surface strain and expanding the wound closure area.

[0004] Meanwhile, the recent COVID-19 outbreak has resulted in approximately 740 million confirmed cases and 7 million deaths worldwide. Consequently, numerous vaccines have been urgently developed and distributed to reduce new COVID-19 cases and deaths. However, thrombosis, a reported side effect of COVID-19 vaccination, is believed to be caused by the vaccine being injected into the bloodstream. Furthermore, the cold chain system, which requires refrigerated and frozen storage for vaccines and injections, poses a significant economic burden.

[0005] Therefore, to address this issue, microneedles, a transdermal drug delivery system in the form of patches that utilize fine needles to deliver drugs through the stratum corneum, the skin's barrier layer, are being developed. Microneedles can be self-applied, making drug administration easier and reducing the risk of needle-related side effects. Furthermore, they allow the drug to be absorbed into the skin's capillaries, rapidly delivering it throughout the body, thus reducing the dosage required.

[0006] However, because the thickness of the human stratum corneum can vary depending on the patient's age, gender, and race, a so-called personalized treatment is necessary, where the shape of the microneedles is modified to suit the affected area. Furthermore, the treatment must be designed to minimize scarring and external infection while the drug is absorbed, and to promote rapid wound healing.

[0007] One embodiment is to provide a method for manufacturing a patient-specific wound dressing having embedded microneedles.

[0008] Another embodiment seeks to provide a patient-specific wound dressing with embedded microneedles.

[0009] A method for manufacturing a patient-specific wound dressing having microneedles embedded therein according to one embodiment includes a step of manufacturing a wound dressing by a 3D bioprinting method using a photopolymerizable biocompatible biodegradable bioink, and a step of forming microneedles in the wound dressing by a 2PP (2 photon polymerization) printing method using the photopolymerizable biocompatible biodegradable bioink.

[0010] According to another embodiment, a patient-specific wound dressing having microneedles embedded therein comprises a wound dressing manufactured by a 3D bioprinting method in which a plurality of struts made of a photopolymerizable biocompatible biodegradable bioink are cross-laminated to have a pore size of 200 to 500 μm, and a microneedle formed on the struts of the wound dressing and formed by a 2PP (2 photon polymerization) printing method, the wound dressing being made of the photopolymerizable biocompatible biodegradable bioink.

[0011] Patient-specific wound dressings with embedded microneedles are manufactured using biocompatible, biodegradable bioink, enabling stable implantation into the patient's wound site.

[0012] Furthermore, the use of photocurable materials facilitates 3D bioprinting and two-photon polymerization (TPR) printing, facilitating the production of patient-specific wound dressings with embedded microneedles. Furthermore, the mechanical properties of the photocurable bioink can be more easily controlled by mixing it, compared to conventional bioinks, enabling precise and rapid production.

[0013] Furthermore, because the wound dressing is manufactured through 3D bioprinting, the pores within the wound dressing can be controlled to be micro-uniform pores of the order of 200 μm.

[0014] Commercially available wound dressings are manufactured through molding and extrusion, making customized treatments and the inclusion of micro-uniform pores impossible. However, wound dressings manufactured through 3D bioprinting can be formed to incorporate micro-uniform pores of any desired size, such as 200 μm. Consequently, the mobility of keratinocytes and fibroblasts is enhanced, accelerating wound healing. Furthermore, the increased mobility of vascular cells facilitates rapid vascularization, significantly accelerating wound healing.

[0015] Because microneedles are formed through two-photon polymerization, nanoscale (100 nm) microneedles can be manufactured, and printing is possible at various scales, up to millimeter-scale. Incorporating microneedles used as transdermal drug delivery systems into wound dressings allows them to perform not only wound dressing functions but also the functions of conventional injectables and oral medications.

[0016] In addition, since 3D bioprinting technology and two-photon polymerization are combined, it is possible to implement complex shapes, and the wound dressing can be manufactured by adjusting the pores, thickness, microneedle size, and height according to the type and size of the patient's wound, enabling customized treatment for the patient.

[0017] Figure 1 is a graph showing the results of evaluating biodegradability according to the degree of substitution and concentration of GelMA.

[0018] Figure 2 shows the results of measuring the laser gain while varying the photoinitiator to LAP and I2959 and the printing speed of 2PP.

[0019] Figure 3 shows photographs of a strut and wound dressing formed when the nozzle size is 400 μm, the air pressure is 100 kPa, and the GelMA concentration is 40%.

[0020] Figure 4 is an image showing the change in the thickness of the strut according to the change in nozzle size, air pressure strength, and GelMA concentration.

[0021] Figure 5 is an image showing the results of measuring the wound covering effect according to the pore size of the wound covering material.

[0022] Figure 6 shows the results when microneedles are manufactured continuously in one part and the results when microneedles are manufactured by dividing them into two parts.

[0023] Figure 7 is an image of a patient-specific wound dressing with embedded microneedles manufactured according to one embodiment.

[0024] Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily practice the invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. Since embodiments according to the concept of the present invention can have various modifications and can have various forms, embodiments are illustrated in the drawings and described in detail in the present specification. However, this is not intended to limit embodiments according to the concept of the present invention to a specific disclosed form, but includes modifications, equivalents, or substitutes included in the spirit and technical scope of the present invention.

[0025] Throughout this specification, whenever a part is referred to as "including" a component, this does not exclude other components, but rather implies the inclusion of other components, unless otherwise specifically stated. Furthermore, throughout this specification, singular forms also include plural forms, unless otherwise specifically stated.

[0026] When a range of numerical values ​​is stated herein, unless the specific range is otherwise specified, the values ​​have the precision of the significant figures provided according to the standard rules in chemistry for significant figures. For example, the number 10 includes the range of 5.0 to 14.9, and the number 10.0 includes the range of 9.50 to 10.49.

[0027] The following describes a method for manufacturing a patient-specific wound dressing having embedded microneedles according to an embodiment of the present invention.

[0028] Patient-specific wound dressings with embedded microneedles are manufactured using a combination of 3D bioprinting and two-photon polymerization.

[0029] First, a wound dressing is manufactured using 3D bioprinting. 3D bioprinting can create complex shapes at the microscale.

[0030] Wound dressings are manufactured using photopolymerizable biocompatible biodegradable bioink.

[0031] Photocurable biocompatible bioinks may include gelatin methacrylate (GelMA), collagen methacrylate, and others. GelMA is a type of gelatin chemically modified with methacrylate groups. Gelatin itself is a protein derived from collagen found in animal connective tissue. GelMA is low-cost, biocompatible, and biodegradable, has a fast curing speed, and its mechanical properties can be enhanced depending on the ratio of photoinitiators. It is a material amenable to 3D bioprinting and two-photon polymerization (2-photon polymerization) printing.

[0032] Preferably, GelMA having a substitution degree of 70% to 90% is dissolved in triple-distilled water at a concentration of 20% to 40% and used.

[0033] GelMA's degree of substitution can be controlled by maintaining the reaction molar ratio of gelatin and methacrylic anhydride and the pH (7-9). A degree of substitution of 70% means that 70% of the methacrylate has reacted with the gelatin, and 90% means that 90% of the methacrylate has reacted and bonded with the gelatin. If the degree of substitution is less than 70%, the physical properties are too low, making printing or photocrosslinking difficult. On the other hand, if the degree of substitution is more than 90%, such as 100%, the physical properties are too high and the gel becomes too hard during crosslinking.

[0034] Figure 1 is a graph showing the results of evaluating biodegradability according to the degree of substitution and concentration of GelMA. The results in Figure 1 demonstrate that as the degree of substitution and concentration increase, the time required for biodegradation increases. Therefore, it can be seen that the degradation period of a wound dressing can be controlled by adjusting the degree of substitution and concentration to suit the period required for wound healing.

[0035] The materials listed in Table 1 below can be used as photoinitiators for bioprinting.

[0036] Prepolymer PhotoinitiatorwavelegnthtimeGelMA5-20%LAP 0.1%405nmfast (≤180s)VA-086 1%405nmfast (≤180s)Igacure 2959 1%380nmslow (≤180s)Eosin Y 0.01mM / TEA 0.1% / NVP 37nM520nmvery slow (≤180s)

[0037] Among the above photoinitiators, Irgacure 2959 (2-Hydroxy-4′-(2-hydroxyethoxy)-2-methylpropiophenone) (I2959), which has a laser gain of approximately 0.1% to 0.5%, can be advantageous for production because it enables curing with a small amount of laser gain. Figure 2 shows the results of measuring the laser gain by varying the photoinitiator between LAP and I2959 and the printing speed of 2PP.

[0038] For LAP photoinitiators, the minimum required laser gain is high, resulting in longer printing times and greater energy consumption. Conversely, I2959 exhibits a low minimum laser gain of approximately 0.1%, enabling curing with less energy, making it advantageous for production.

[0039] The photoinitiator can be added to the dissolved GelMA solution at a concentration of 0.1%.

[0040] After injecting a solution in which GelMA and I2959 are dissolved at a set concentration into a syringe for 3D bioprinting, the first layer is completed by printing while controlling the spacing between struts through a discharge nozzle, and then UV irradiation is performed to complete the first layer, and the second layer is completed by printing while controlling the spacing between struts in a direction intersecting the first layer, and then UV irradiation is performed alternately to form a wound dressing with a pore size of 200 to 500 μm.

[0041] Figure 3 shows an example of a photograph of a strut and a wound dressing formed when the nozzle size is 400 μm, the air pressure is 100 kPa, and the GelMA concentration is 40%.

[0042] It can be seen from the results in Fig. 4 that the thickness of the strut can be adjusted depending on the size of the discharge nozzle, the strength of the air pressure, and the concentration of GelMA.

[0043] The results in Fig. 4 show that the thickness of the strut can be controlled by setting the nozzle size to 300 to 500 μm, setting the pneumatic pressure to 20 kPa to 100 kPa, and changing the concentration of GelMA.

[0044] The thickness of the strut can be formed to be 0.3 mm to 0.5 mm and the height of each layer to be laminated can be formed to be 0.2 mm to 0.3 mm.

[0045] When discharging one strut and then discharging the strut next to it, the gap between the struts can be set to 200 ㎛ to 2 mm to control the density of the internal structure.

[0046] When the lamination of the first layer is complete, it is cured by irradiating with UV light of 380 nm wavelength for 30 seconds.

[0047] Next, the gap between the struts is controlled in the direction intersecting the first layer, and then printed, UV irradiated to complete the second layer, and then cured by irradiating with UV at a wavelength of 380 nm for about 30 seconds.

[0048] By alternately laminating the first and second layers, a wound dressing having a total thickness of 0.5 mm to 3 mm and a gap of 200 to 500 μm can be completed.

[0049] Wounds refer to skin injuries such as burns, cuts, bruises, lacerations, and abrasions. Wound dressings, also known as wet dressings, are medical devices designed to prevent contamination and skin protection at the wound site, absorb exudates, and prevent bleeding or fluid loss. The regenerative effect can be controlled depending on the size or thickness of the pores. In other words, depending on the type of patient's wound, the gap size (density) can be controlled by controlling the spacing between struts, the thickness of the wound dressing can be controlled by controlling the number of layers, and the biodegradability can be controlled by controlling the degree of substitution or concentration of the bioink used. Therefore, it is possible to form a wound dressing customized for each patient.

[0050] Furthermore, wound dressings can be applied not only to wounds, but also to all cases where improvement of skin conditions is required, such as wounds, atopy, and keloids. If necessary, additional medications necessary for improving skin conditions can be included in the wound dressing.

[0051] Figure 5 shows the results of measuring the effectiveness of wound dressing according to the size of the gap. The results in Figure 5 were derived according to the following experimental method.

[0052] First, mice (C57BL / 7) were anesthetized with 2% isoflurane in 50% oxygen at 1 L / min. Wounds were created on the back using a dermatological punch (8 mm). Depending on the experimental group, non-porous wound dressings, 200 μm pore wound dressings, and 500 μm pore wound dressings were implanted into the wound sites. The control group was left unimplanted after the wounds were created. After the wound models were created, ketoprofen, an analgesic, was administered subcutaneously (5 mg / kg) once daily for 3 days. Penicillin, an antitussive, was administered subcutaneously (1 mg / kg) once daily for 3 days. After the wound models were created, mice in all groups were sacrificed, and wound tissues were removed and subjected to histopathological analysis.

[0053] The analysis results are illustrated in Fig. 5, and it can be confirmed that when the pore size is 200 to 500㎛, it is effective in wound healing, and in particular, when the pore size is about 200㎛, it is advantageous in terms of improving the content and distribution of epi, dermal, muscle, and collagen in a form similar to actual skin tissue.

[0054] Conventional wound dressings are manufactured using molding and extrusion methods, so it is impossible to adjust the size of the pores or control the thickness according to the patient's needs, and in particular, it is impossible to uniformly embed micropores. On the other hand, when manufacturing wound dressings using 3D bioprinting, the size of the pores can be adjusted and uniformly embedded, and the thickness can be easily controlled.

[0055] Next, microneedles embedded in the wound dressing are manufactured.

[0056] Microneedles are manufactured using 2PP (2 Photon Polymerization) printing method.

[0057] 2PP printers use a pulsed femtosecond laser focused on a narrow section of a special resin vault. This focused spot, called a voxel, creates a 3D object by sequentially curing nanometer- and micrometer-sized voxels layer by layer along a predefined path. These voxels can be as large as a few millimeters while maintaining nanometer resolution.

[0058] After inserting the wound dressing into the 2PP printer, bioink for forming the wound dressing is injected, and the diameter and height of the microneedles to be manufactured are input to match the coordinates of the manufactured wound dressing strut. The microneedles are then printed.

[0059] The shape of the microneedle is input in two parts to allow the residual material inside to escape.

[0060] On the left side of Figure 6, the result when the microneedles are manufactured continuously in one part is shown, and on the right side, the result when the microneedles are manufactured by dividing them into two parts is shown.

[0061] As shown in the example on the left, when microneedles are manufactured continuously in one part, it can be seen that the shape of the microneedles collapses and is not manufactured in the desired shape due to the bioink remaining without complete hardening.

[0062] On the other hand, as shown in the example on the right, when the microneedle is first manufactured by dividing it into two parts and then providing a dwell time after the lower part is completely cured so that the remaining photocurable biocompatible biodegradable bioink can come out, and then the tip part is formed on top of it, it can be confirmed that the shape of the microneedle is manufactured straight into the desired shape.

[0063] The height ratio of the lower portion to the tip portion is preferably 1:1 to 2:1. More preferably, the height ratio of the lower portion to the tip portion may be approximately 2:1. If it is less than 1:1, a round needle with a dull tip shape is formed, and if it is more than 2:1, the lower layer may collapse, reducing the overall height of the needle.

[0064] When printing 2PP, the laser gain is set to approximately 30% and the printing speed is set to 50 to 250 ㎛ / s. If the printing speed is less than 50 ㎛ / s, the printing speed is slower than the bioink curing speed, so the output shape is thick compared to the input. If the printing speed is more than 250 ㎛ / s, the printing speed is faster than the bioink curing speed, so the output shape is thin compared to the input.

[0065] After obtaining the printed result, the residual material is washed away by shaking in PBS (Phosphate Buffer Saline) at about 40 degrees for about 20 minutes, and a patient-specific wound dressing with embedded microneedles is completed as illustrated in Fig. 7.

[0066] Microneedles can be embedded with drugs by uniformly mixing the drug in bioink and then using 2PP printing, or they can be delivered by coating the drug on the microneedle after completing the microneedle.

[0067] Medications may be selected based on the patient's condition and may include medications used to treat skin conditions such as wounds, atopy, and keloids. Examples include lidocaine (a local anesthetic), imiquimod (an immunomodulator), and calcineurin inhibitors (topical calcineurin inhibitors), but these are merely examples.

[0068] When drugs are incorporated into microneedles, the concentration of GelMA can be adjusted to control viscosity or a viscosity modifier can be used to achieve uniform drug dispersion within the bioink. Furthermore, the drug can be uniformly dispersed within GelMA through microparticle formation.

[0069] The problem of conventional microneedles being manufactured through rolling and drawing, which requires a long production period and the need to continuously change and purchase expensive molds, can be solved by applying the 2PP printing method.

[0070] Although the preferred embodiments of the present invention have been described in detail above, the scope of the present invention is not limited thereto, and various modifications and improvements made by those skilled in the art using the basic concept of the present invention defined in the following claims also fall within the scope of the present invention.

[0071] The present invention is applicable to the field of medical devices, particularly to the field of wound dressings including microneedles.

Claims

1. A step of manufacturing a wound dressing using a 3D bioprinting method using a photopolymerizable biocompatible biodegradable bioink; and A method for manufacturing a patient-specific wound dressing having embedded microneedles, comprising the step of forming microneedles in the wound dressing by a 2PP (2 photon polymerization) printing method using the photocurable biocompatible biodegradable bioink.

2. In paragraph 1, The above 3D bioprinting method is a method for manufacturing a patient-specific wound dressing with embedded microneedles using the FDM (Fused Deposition Modeling) 3D bioprinting method.

3. In paragraph 1, The above wound dressing material is printed by controlling the spacing between struts and then irradiated with UV to complete the first layer. A method for manufacturing a patient-specific wound dressing having microneedles embedded therein, wherein the steps of printing while controlling the spacing between struts in a direction intersecting the first layer and then completing the second layer by UV irradiation are alternately performed so that the pores of the wound dressing are 200 to 500 μm.

4. In paragraph 1, The above photocurable biocompatible biodegradable bioink comprises gelatin methacrylate methacrylate and a photoinitiator, A method for manufacturing a patient-tailored wound dressing having microneedles in which the methacrylate of the gelatin methacrylate has a substitution degree of 70 to 90%.

5. In paragraph 4, A method for manufacturing a patient-specific wound dressing having microneedles having a concentration of 20 to 40% of the gelatin methacrylate.

6. In paragraph 4, The above photoinitiator is a method for manufacturing a patient-specific wound dressing having embedded microneedles having a minimum laser gain of 0.1%.

7. In paragraph 6, The above photoinitiator is a method for manufacturing a patient-specific wound dressing having microneedles embedded therein, wherein the microneedles are Irgacure 2959.

8. In paragraph 1, The above microneedles are provided with a residence time after the lower part is manufactured so that the remaining photocurable biocompatible biodegradable bioink can escape after the lower part is cured. A method for manufacturing a patient-specific wound dressing having microneedles embedded therein forming a tip portion on the lower surface.

9. In paragraph 7, A method for manufacturing a patient-specific wound dressing having microneedles having a height ratio of the lower portion to the tip portion of 1:1 to 2:

1.

10. In paragraph 1, The above microneedles are a method for manufacturing a patient-specific wound dressing having drug-containing or drug-coated microneedles embedded therein.

11. In paragraph 1, A method for manufacturing a patient-tailored wound dressing having microneedles embedded therein, wherein the pores of the wound dressing, the laminated thickness of the wound dressing, the diameter of the microneedles, and the height of the microneedles are controlled according to the depth or range of the patient's wound.

12. A wound dressing manufactured by a 3D bioprinting method in which a plurality of struts made of a photopolymerizable biocompatible biodegradable bioink are cross-laminated and have a pore size of 200 to 500 μm; and A patient-tailored wound dressing comprising microneedles formed on the struts of the wound dressing and formed by a 2PP (2 photon polymerization) printing method, the microneedles comprising the photocurable biocompatible biodegradable bioink.

13. In paragraph 12, The photocurable biocompatible biodegradable bioink comprises gelatin methacrylate, and the methacrylate of the gelatin methacrylate has a substitution degree of 70 to 90%, and is a patient-tailored wound dressing having microneedles embedded therein.

14. In paragraph 13, A patient-specific wound dressing with microneedles having a concentration of 20 to 40% of the above gelatin methacrylate.

15. In paragraph 12, The above microneedles include a lower portion and a tip portion, A patient-tailored wound dressing having microneedles having a height ratio of the lower portion to the tip portion of 1:1 to 2:

1.

16. In paragraph 12, The above microneedles are patient-tailored wound dressings containing drug-containing or drug-coated microneedles.

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