Multifunctional medical patch for gastrointestinal tract and manufacturing method therefor

Abstract

The present invention relates to a multifunctional medical patch for the gastrointestinal tract and a manufacturing method therefor and, more specifically, to a multifunctional medical patch for the gastrointestinal tract, the patch being composed of three layers including an unrolling layer, a guard layer, and a therapeutic layer, wherein the unrolling layer is composed of polyethylene glycol dimethacrylate (PEGDM) and undergoes a swelling phenomenon upon contact with liquid at the target site, the guard layer, located between the unrolling layer and the medical layer, is composed of triethylene glycol dimethacrylate (TEGDM), and the therapeutic layer contains a mucous membrane adhesive material and a medical material and adheres to a target site.

Description

Multifunctional medical patch for the gastrointestinal tract and method for manufacturing the same

[0001] The present invention relates to a multifunctional medical patch for the gastrointestinal tract and a method for manufacturing the same.

[0002] The gastrointestinal tract presents a challenging environment for treatment due to its complex anatomical structure and physiological conditions. It is saturated with mucus, has a curved surface, and lesions can develop in various locations. To overcome these challenges and achieve treatment, research has been conducted on various treatment methods, including conventional endoscopy, capsule endoscopy, and nanoparticle applications.

[0003] Among these, research on capsule endoscopy-based treatments has primarily focused on this approach due to its advantages, including non-invasiveness, ease of operation, and short recovery time. For example, a capsule has been developed to deliver insulin-loaded microneedles (MN) into the gastrointestinal tract. While capsules offer higher drug absorption rates than subcutaneous injections, microneedles can only be delivered once at a specific pH level, limiting their ability to deliver therapeutic agents to multiple lesion sites and precise delivery into the gastrointestinal tract. Furthermore, a magnetically actuated capsule has been developed to deliver multiple drug-loaded gelatin microneedle patches. The capsule moves rapidly and utilizes an external magnetic field to deliver the patches into the gastrointestinal tract. However, weak adhesion between the patch and the intestinal surface reduces drug delivery efficiency, and the open capsule opening leaves the patch unprotected from substances present in the gastrointestinal tract. Furthermore, a technique has been developed to deliver multiple chitosan-catechol patches using a magnetically actuated capsule with an open-close mechanism. These improved patches demonstrated improved adhesion to the intestinal surface compared to gelatin microneedle patches, and were partially protected by the capsule during transit via an open-close mechanism. However, complete patch protection by the capsule with an open-close mechanism is impossible due to the influx of low-viscosity liquids into the gastrointestinal tract, and the flat nature of the patch makes effective delivery difficult on curved gastrointestinal surfaces. Furthermore, the lack of an imaging module within the patch delivery capsule hinders visualization of the gastrointestinal tract during the treatment process.

[0004] Therefore, to improve these existing problems, the characteristics of drug-loaded patches and active patch delivery capsules must be improved. To achieve this, first, the gastrointestinal therapeutic patch must have therapeutic properties and deliver the drug in close contact with the gastrointestinal surface with various curvatures. Second, the active capsule must be actively activated by an external magnetic field, protect the patch loaded into the capsule even in the wet gastrointestinal environment, and enable active patch delivery to multiple target lesion sites. Finally, the capsule must incorporate an imaging module to observe the interior of the gastrointestinal tract, identify target lesions, and deliver the patch.

[0005] However, technologies that reflect these improvements have not yet been developed.

[0006] Accordingly, the inventors of the present invention have developed a multifunctional medical patch for the gastrointestinal tract and a self-actuating capsule by considering the improvements necessary for the characteristics of a drug delivery patch and an active capsule, and the multifunctional medical patch for the gastrointestinal tract of the present invention is composed of an unrolling layer, a guard layer, and a medical layer, and has the characteristic that multiple patches can be loaded onto a wired endoscope or capsule endoscope and delivered due to its excellent rolling performance, and has the characteristic that it can be delivered in close contact with the curved inner surface of the gastrointestinal tract due to its unrolling performance, and has sufficient adhesion to the surface of the gastrointestinal tract due to its mucosal adhesiveness, and can perform various medical functions by including a material having a medical function, thereby completing the present invention.

[0007] Accordingly, the purpose of the present invention is to provide a multifunctional medical patch for the gastrointestinal tract, which comprises three layers: an unrolling layer, a guard layer, and a therapeutic layer, wherein the unrolling layer is composed of PEGDM (polyethylene glycol dimethacrylate) and causes a swelling phenomenon when in contact with a liquid at a target site, the guard layer is located between the unrolling layer and the therapeutic layer and is composed of TEGDM (triethylene glycol dimethacrylate), and the therapeutic layer contains a mucoadhesive material and a medical material and is characterized by being adhered to the target site.

[0008] Another object of the present invention is to provide a method for manufacturing the multifunctional medical patch for the gastrointestinal tract of the present invention.

[0009] In order to achieve the above object of the present invention, the present invention provides a multifunctional medical patch for the gastrointestinal tract, which is composed of three layers: an unrolling layer, a guard layer, and a therapeutic layer, wherein the unrolling layer is composed of PEGDM (polyethylene glycol dimethacrylate) and causes a swelling phenomenon when in contact with a liquid at a target site, the guard layer is located between the unrolling layer and the therapeutic layer and is composed of TEGDM (triethylene glycol dimethacrylate), and the therapeutic layer contains a mucoadhesive material and a medical material and is characterized in that it adheres to the target site.

[0010] In one embodiment of the present invention, the multifunctional medical patch for the gastrointestinal tract may be delivered to a target site in the gastrointestinal tract in a rolled form.

[0011] In one embodiment of the present invention, the rolled outer layer may be rolled to become a therapeutic layer.

[0012] In one embodiment of the present invention, the delivery may be such that one or more multifunctional medical patches for the gastrointestinal tract in a rolled form are mounted on a wire endoscope or capsule endoscope and delivered to the target site.

[0013] In one embodiment of the present invention, the mucoadhesive material may be at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof.

[0014] In one embodiment of the present invention, the medical material may be at least one selected from the group consisting of an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

[0015] In one embodiment of the present invention, the multifunctional medical patch for the gastrointestinal tract may be delivered and adhered to a target area in a rolled form, and the unrolled layer may be swelled by a liquid in the gastrointestinal tract to completely unfold to fit the curved surface of the target area, and the medical material may be strongly adhered by a mucoadhesive material contained in the medical layer, and the medical material may be released to the target area.

[0016] In addition, the present invention provides a method for manufacturing a multifunctional medical patch for the gastrointestinal tract, comprising the steps of: (1) irradiating a TEGDM (triethylene glycol dimethacrylate) solution with ultraviolet rays to manufacture a guard layer; (2) dispensing a PEGDM (polyethylene glycol dimethacrylate) solution onto the guard layer manufactured in step (1) and irradiating the solution with ultraviolet rays to manufacture an unrolling layer on the guard layer; (3) placing the two-layer structure of the guard layer and the unrolling layer manufactured in step (2) into a resin mold with the guard layer facing upward, pouring a mixed solution of a mucoadhesive material and a medical material thereon, and then freeze-drying to manufacture a therapeutic layer on the guard layer; and (4) separating a multifunctional medical patch for the gastrointestinal tract, the multifunctional medical patch comprising three layers of the unrolling layer, the guard layer, and the therapeutic layer, from the mold.

[0017] In one embodiment of the present invention, the multifunctional medical patch for the gastrointestinal tract separated from the mold in step (4) may further include a step of rolling the multifunctional medical patch for the gastrointestinal tract into a cylindrical shape with the medical layer facing outward, inserting the multifunctional medical patch into a cylindrical resin mold, and heating the rolled-up shape.

[0018] In one embodiment of the present invention, the heating may be performed using a heating gun at a temperature of 150°C to 250°C for 5 to 15 seconds.

[0019] In one embodiment of the present invention, the mucoadhesive material may be at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof.

[0020] In one embodiment of the present invention, the medical material may be at least one selected from the group consisting of an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

[0021] The multifunctional medical patch for the gastrointestinal tract according to the present invention can be delivered to a target site by mounting multiple multifunctional medical patches for the gastrointestinal tract on a wired endoscope or capsule endoscope due to its excellent rolling performance, and can be completely adhered to the inner surface of the curved gastrointestinal tract due to the characteristic of the unrolling layer being deployed when absorbing liquid at the target site, and not only has excellent adhesion to the surface of the gastrointestinal tract due to the use of a mucoadhesive material contained in the medical layer, but also contains a medical material, so that it can effectively perform various medical functions.

[0022] FIG. 1 is a schematic diagram showing the structure of a multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention, wherein (a) the structure of the deployable TheraS of the present invention is shown, (b) the unrolled state and the rolled state of TheraS are shown, (c) a magnetically actuated capsule equipped with four TheraS are shown, (d) the components of the magnetically actuated capsule are shown, and (e-g) a schematic diagram showing the delivery and treatment process in the gastrointestinal tract using the magnetically actuated capsule equipped with TheraS of the present invention.

[0023] FIG. 2 illustrates a manufacturing process of a multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention, (a) illustrating a manufacturing process of a two-layer structure by UV irradiation of TEGDM and PEGDM, (b) illustrating a sequential manufacturing process of a chitosan-catechol layer containing magnetic nanoparticles (MNPs) and an anticancer agent (DOX) on the two-layer structure, and (c) illustrating a manufacturing process of rolled TheraS through heat treatment and a process of mounting it on a capsule device.

[0024] FIG. 3 shows the results of a characteristic analysis of the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention, wherein (a) and (b) are photographs of the unrolling state and rolling state of TheraS observed with a digital camera, (c) and (d) are images of the cross-section of TheraS observed with an SEM and a confocal microscope, (e) confirms the process of TheraS of the present invention unfolding on the surface of the small intestine, (f) shows the ATR-FT-IR spectra of the medical layer, the guard layer, and the unrolling layer of TheraS of the present invention, (g) shows the results of analyzing the adhesion between a gelatin sheet and TheraS of the present invention on the surface of the small intestine or stomach (n=10), and (h) confirms the temperature change of TheraS of the present invention under the application of AMF at the initial room temperature (RT: 16.5°C) and body temperature (BT: 37.0°C), and the shaded part shows the cell death temperature and thermal tissue ablation temperature when the initial temperature is BT (n=5).

[0025] Figure 4 shows (a) the results of analyzing the release profile of a model drug (rhodamine) from TheraS after contact with the surface of the small intestine of a pig, (b) the results of analyzing the degree of rhodamine release from TheraS over time on the surface of the small intestine of a pig (n=5), and (c) the results of analyzing the degree of DOX drug release from TheraS after contact with the small intestine of a pig with or without AMF application (n=5).

[0026] Figure 5 shows the initial and final states of a pig's stomach before and after delivery of four TheraS to the target site using (a) and (b) the self-actuating capsules, and (c) to (f) show photographs captured using a camera mounted on the capsule showing the TheraS of the present invention being delivered to the pig's stomach.

[0027] FIG. 6 shows the results of hemostatic performance analysis for TheraS of the present invention, (a) showing an image of hemolyzed blood after a whole blood coagulation test in a 96-well plate, (b) showing the results of comparative analysis of whole blood coagulation performance for control blood, gelatin sheet, gelatin-chitosan sheet, and TheraS of the present invention (n = 5), (c) showing confirmation of coagulated blood of each sample on the plate, and (d) showing an image of platelets attached to the gelatin sheet, gelatin-chitosan sheet, and TheraS of the present invention confirmed by SEM analysis.

[0028] Figure 7 confirms the in vitro therapeutic effect of TheraS of the present invention using HT-29 cells, (a) to (f) the degree of HT-29 cell survival after 24 hours in the control group, TheraS (MNPs- and DOX-) treatment group, TheraS (DOX-) treatment group, and the TheraS treatment group with or without AMF application and with or without AMF application, respectively, and (g) the HT-29 cell survival rate is shown as a CCK-8 analysis graph (n = 5). *p<0.005, **p<0.0005, ns p>0.05, and all scale bars are 500 μm.

[0029] In Fig. 8, (a) and (b) show the region of the small intestine of a pig subjected to thermal resection using TheraS under AMF, (c) and (d) show the region of the stomach of a pig subjected to thermal resection using TheraS under AMF, and (e) and (f) show H&E staining images of coagulative necrosis (CN) and normal tissue (NT) in the small intestine and stomach of a pig after thermal resection using TheraS under AMF.

[0030] The present invention is characterized by providing a multifunctional medical patch for the gastrointestinal tract and a method for manufacturing the same.

[0031] Specifically, the multifunctional medical patch for the gastrointestinal tract according to the present invention is composed of three layers: an unrolling layer, a guard layer, and a therapeutic layer. The unrolling layer is composed of PEGDM (polyethylene glycol dimethacrylate) and causes a swelling phenomenon when in contact with a liquid at a target site. The guard layer is located between the unrolling layer and the therapeutic layer and is composed of TEGDM (triethylene glycol dimethacrylate). The therapeutic layer includes a mucoadhesive material and a medical material and is characterized by adhering to the target site.

[0032] The multifunctional medical patch for the gastrointestinal tract according to the present invention has the characteristic of being delivered to a target area in the gastrointestinal tract in a rolled form. At this time, the multifunctional medical patch for the gastrointestinal tract in a rolled form is rolled so that the outer layer, i.e., the outer layer, becomes a therapeutic layer.

[0033] In addition, the above delivery can be delivered to a target site by mounting one or more multifunctional medical patches for the gastrointestinal tract in a rolled form on a wired endoscope or capsule endoscope. In one embodiment of the present invention, four multifunctional medical patches for the gastrointestinal tract are mounted on a magnetically driven capsule endoscope and delivered to a target site.

[0034] As described above, the composition of the multifunctional medical patch for the gastrointestinal tract of the present invention is composed of a total of three layers. The unrolling layer is composed of PEGDM (polyethylene glycol dimethacrylate), the guard layer located between the unrolling layer and the medical layer is composed of TEGDM (triethylene glycol dimethacrylate), and the medical layer includes a mucoadhesive material and a medical material.

[0035] The materials that can be used as the above mucosal adhesive material are not limited thereto, but at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof may be used.

[0036] The above medical material may be a drug for treating a disease or a marker / sensing material capable of monitoring an in vivo condition or environment, and specifically, the medical material may be at least one selected from the group consisting of, but not limited to, an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

[0037] When a biocompatible ink or fluorescent material is used as the medical material of the present invention, the patch of the present invention has the function of performing tattooing.

[0038] India ink, etc. can be used as biocompatible ink, and rhodamine, etc. can be used as fluorescent material.

[0039] In addition, when a disease treatment drug is used as the above medical material, the drug is released from the patch of the present invention to the target site, i.e., the lesion site, in the gastrointestinal tract, thereby improving and treating the disease.

[0040] In one embodiment of the present invention, anticancer activity and hemostatic activity were confirmed by adding an anticancer agent and a hemostatic agent.

[0041] Hemostatic agents include chitosan, catechol, or epinephrine, and tissue regeneration factors such as collagen, fibrin, and alginate can also be used. Using tissue regeneration factors in conjunction with hemostatic agents can achieve tissue regeneration after hemostasis.

[0042] In one embodiment of the present invention, the anticancer activity was confirmed using doxorubicin (DOX) as an anticancer agent, and further, it was confirmed that when magnetic nanoparticles (e.g., iron oxide nanoparticles) are added, hyperthermia and drug release promotion effects can also be obtained.

[0043] A sensing material can be used as a medical material of the present invention, for example, by using a reactive oxygen species (ROS) sensing material / nanoparticle or a pH sensing material / nanoparticle, the condition within the gastrointestinal tract can be confirmed and analyzed.

[0044] At this time, for ROS sensing, PVP (polyvinylpyrrolidone), gold, or silica can be used, and by using indium tin oxide, gold, Wo3, etc. as pH sensing materials, the pH status in the body can be observed by color change according to pH concentration.

[0045] Next, the functional operation of the multifunctional medical patch for the gastrointestinal tract according to the present invention at the target site is described as follows.

[0046] As described above, when a multifunctional gastrointestinal medical patch in a rolling form is mounted on a gastrointestinal endoscope or a capsule endoscope and delivered to a target site, the multifunctional gastrointestinal medical patch in a rolling form adhered to the surface of the target site in the gastrointestinal tract begins to unfold as the unrolling layer begins to swell when the liquid in the gastrointestinal tract reaches the unrolling layer located at the innermost part of the rolling form. By the swelling of the unrolling layer, the medical patch of the present invention is completely unfolded to fit the curved surface of the gastrointestinal tract at the target site, and is strongly adhered to the curved surface of the gastrointestinal tract by the mucoadhesive material contained in the medical layer. Thereafter, the medical material contained in the medical layer is released to the target site, thereby exerting the intended medical effect.

[0047] In addition, the present invention can provide a method for manufacturing a multifunctional medical patch for the gastrointestinal tract of the present invention, the method preferably comprising the steps of: (1) irradiating a TEGDM (triethylene glycol dimethacrylate) solution with ultraviolet rays to manufacture a guard layer; (2) dispensing a PEGDM (polyethylene glycol dimethacrylate) solution onto the guard layer manufactured in step (1) and irradiating the solution with ultraviolet rays to manufacture an unrolling layer on the guard layer; (3) placing the two-layer structure of the guard layer and the unrolling layer manufactured in step (2) into a resin mold with the guard layer facing upward, pouring a mixed solution of a mucoadhesive material and a medical material thereon, and then freeze-drying to manufacture a therapeutic layer on the guard layer; and (4) separating a multifunctional medical patch for the gastrointestinal tract composed of three layers of an unrolling layer, a guard layer, and a therapeutic layer from the mold.

[0048] In addition, the multifunctional medical patch for the gastrointestinal tract separated from the mold in the above step (4) may further include a step of rolling the multifunctional medical patch for the gastrointestinal tract into a cylindrical shape with the medical layer facing outward, inserting the multifunctional medical patch into a cylindrical resin mold, and heating the rolled-up shape.

[0049] In the above method, the heating for manufacturing a multifunctional medical patch for the gastrointestinal tract in a rolled form can be performed using a heating gun at a temperature of 150°C to 250°C for 5 to 15 seconds, and in the embodiment of the present invention, the heating treatment was performed at a temperature of 200°C for 10 seconds.

[0050] In the above method, the mucoadhesive material may be at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof.

[0051] In addition, in the above method, the medical material may be at least one selected from the group consisting of an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

[0052] A more detailed description of the method for manufacturing a multifunctional medical patch for the gastrointestinal tract according to the present invention is described in the examples below.

[0053] Furthermore, the inventors of the present invention have confirmed through experiments of examples whether the multifunctional medical patch for the gastrointestinal tract of the present invention can be usefully used as an actual medical patch. According to one embodiment of the present invention, when a patch containing a hemostatic agent was used, it was confirmed that excellent hemostatic performance was exhibited in the gastrointestinal tract. In addition, when a patch containing an anticancer agent was used, it was confirmed that excellent anticancer activity was exhibited by effectively killing cancer cells in an analysis using HT-29 human colon cancer cells. It was also confirmed that the multifunctional medical patch for the gastrointestinal tract of the present invention generates heat under an alternating magnetic field (AMF) to induce local tissue necrosis, thereby enabling thermal ablation.

[0054] Hereinafter, the present invention will be described in more detail through examples. These examples are intended to more specifically illustrate the present invention, and the scope of the present invention is not limited to these examples.

[0055]

[0056] <Preparation example and experimental method>

[0057] Manufacturing of a multifunctional medical patch for the gastrointestinal tract (TheraS)

[0058] The multifunctional gastrointestinal medical patch (TheraS) according to the present invention was manufactured to consist of three layers. First, a two-layer structure consisting of a guard layer and an unrolling layer was manufactured using ultraviolet (UV) curing (Fig. 2a). Solutions of triethylene glycol dimethacrylate (TEGDM, Mw 286.3, Merck) and polyethylene glycol dimethacrylate (PEGDM, Mn 750, Merck) were prepared by mixing them with the photoinitiator 2-hydroxy-2-methylpropiophenone at a concentration of 1% v / v. To prepare the guard layer, 7 μL of TEGDM was dispensed onto a slide glass, and a silane-coated cover glass was placed on top. Afterwards, UV irradiation (365 nm, 230 mW cm-2) was performed for 60 s using an ANUJ6186 head and an ANUJ6428 lens (Panasonic Industry, Japan). After removing the cover glass, 6 μL of PEGDM solution was dispensed onto the guard layer, and a silane-coated cover glass was placed on top. Afterwards, UV irradiation (365 nm, 230 mW cm-2) was applied for 30 s. Finally, the cover glass and slide glass were removed to obtain a two-layer structure consisting of a guard layer and an unrolling layer.

[0059] The manufacturing process of the two-layered therapeutic layer is shown in Fig. 2b. A chitosan-catechol solution containing MNPs and DOX was prepared. That is, 1 g of chitosan (medium molecular weight, Merck) was mixed with 5 mL of 5 N HCl (Duksan, Korea) and 44.5 mL of DI water, and the pH was adjusted to 5.5. Then, 1.18 g and 1.24 g of hydrocaffeic acid (Merck) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (Merck) were dissolved in 5 mL and 20 mL of ethanol, respectively, and the chitosan solution was added thereto, respectively. Afterwards, the mixture was dialyzed against 10 mM NaCl solution and DI water at pH 3.5 for 48 h and 4 h, respectively. The solution was then lyophilized at -80°C. The produced chitosan-catechol base material was dissolved in 2 wt% DI water, and 1 wt% chitosan-coated MNPs and 1 mg / mL -1 The final chitosan-catechol solution containing MNPs and DOX was obtained by adding DOX. The mold for fabricating the final TheraS was fabricated using resin (Transparent Resin V4, Formlabs) with a stereolithography (SLA) 3D printer (Form3, Formlabs). Next, the fabricated two-layer structure was placed in the resin mold with the guard layer facing upward. The chitosan-catechol solution containing the fabricated MNPs and DOX was then poured onto the guard layer of the two-layer structure and freeze-dried at -80°C. The three-layer structure was then separated from the resin mold to obtain the final TheraS. In addition, TheraS with different fluorescent substances in each layer for fluorescent visualization was fabricated using a similar process. Here, the TEGDM solution was syto9 (3 μg mL -1 , Invitrogen) was used in combination with PEGDM solution, and DAPI (3 μg mL -1, Thermo Scientific) were used in combination, and the chitosan-catechol solution containing MNPs and DOX was used in combination with rhodamine B (0.1 mg mL-1, Merck).

[0060] The process of manufacturing the rolled TheraS and mounting it into a capsule is illustrated in Fig. 2c. The manufactured TheraS was rolled into a cylinder using tweezers with the therapeutic layer facing outward, and then inserted into a cylindrical 3D-printed resin mold. To maintain the rolled state of the TheraS, the TheraS within the mold was heated at 200°C for 10 seconds using a heat gun. Subsequently, the rolled TheraS was inserted into the capsule channel. Finally, four rolled TheraS were prepared and placed in each capsule channel.

[0061]

[0062] Morphological analysis of the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention

[0063] The overall appearance of the multifunctional gastrointestinal medical patch (TheraS) according to the present invention in an unrolled (unfolded) and rolled (rolled) state, as well as the process of TheraS unfolding in the small intestine, were photographed using a DSLR camera (EOS-800D, CANON). In addition, cross-sectional images of TheraS and fluorescently labeled patches were photographed and analyzed using a field-effect scanning electron microscope (FE-SEM) (SU8020, Hitachi) and a confocal microscope (FV1200, Olympus), respectively, at the DGIST Institute for Advanced Semiconductor Convergence Technology (INST).

[0064]

[0065] FT-IR spectral analysis of the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention

[0066] To determine the chemical composition of the multifunctional gastrointestinal medical patch (TheraS) according to the present invention, FT-IR spectra were analyzed using an ATR-FT-IR microscope (Nicolet Continuum, Thermo Scientific) at DGIST INST. Individual layers were prepared to investigate the chemical composition of each TheraS layer. First, 6 μL of PEGDM solution was dispensed onto a slide glass to produce a single annealed layer, and a silane-coated cover glass was placed on top. Subsequently, UV irradiation (365 nm, 230 mW cm -2 ) was applied for 60 seconds to create a single PEGDM layer. Next, a single guard layer was prepared by irradiating the TEGDM solution with UV for 30 seconds. Finally, a chitosan-catechol solution containing MNPs and DOX was poured into a resin mold and freeze-dried at -80°C to prepare a therapeutic layer. The FT-IR spectrum was analyzed for each individual layer prepared above.

[0067]

[0068] Adhesion analysis

[0069] The adhesive force between the multifunctional gastrointestinal medical patch (TheraS) of the present invention and porcine small intestine (BIOZOA Biological Supply, Korea) was analyzed using a motorized stage (KZL06050-N1-FD, Suruga Seiki, Japan) and a load cell (DBCM-5, Bongshin, Korea). To this end, the load cell was first fixed on top, and the porcine small intestine was fixed to the motorized stage. Next, the unfolded TheraS, connected to the load cell by a string, was positioned on the surface of the porcine intestine. After a certain contact interval, the stage was moved downward at a constant speed, and the adhesive force applied to the load cell was measured. The LabVIEW program (National Instruments, USA) was used to record the force measurements. In addition, an experiment was conducted to compare the adhesive strength of TheraS of the present invention on the porcine small intestine with the adhesive strength of a gelatin sheet widely used for drug delivery. The gelatin sheet was prepared by pouring a 10% gelatin (bovine skin, Deoksan, Korea) solution into a 35 mm dish and drying overnight. To obtain the final gelatin sheet, the dried gelatin was cut to the same size as TheraS, but the cut size can be cut to a desired size as needed. The TheraS and the gelatin sheet were kept in contact with the surface of the porcine small intestine for 60 and 120 seconds, respectively. The adhesive strength between the small intestine and the sheet was measured as the motorized stage moved downward. This measurement was repeated 10 sets. The adhesive strength between the porcine stomach (BIOZOA Biological Supply, Korea) and the sheet was also measured.

[0070]

[0071] Analysis of temperature changes in the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention under an alternating magnetic field (AMF).

[0072] The temperature change of the patch of the present invention was measured under an alternating magnetic field. For this purpose, TheraS was immersed in phosphate-buffered saline (PBS) and an alternating magnetic field (320 A, 325 kHz) was applied for 20 minutes. The temperature change of TheraS was measured and recorded every 2 minutes using a thermal imaging camera (GTC 400 C, BOSCH). The measurements were performed under two different initial temperature conditions: room temperature (RT, 16.5°C) and body temperature (BT, 37.0°C). In addition, for each initial condition, the temperature change was measured by repeating the experiment five times during the alternating magnetic field exposure.

[0073]

[0074] Drug release analysis of the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention

[0075] To visually confirm the drug release process of TheraS of the present invention, TheraS containing rhodamine, a model drug, was placed on the surface of the small intestine of a pig. Assuming that TheraS was in an unfolded state, the unfolded sheet was placed on the small intestine. TheraS was separated after 2, 4, 6, 8, and 10 minutes of contact, and the rhodamine released onto the surface of the small intestine of the pig was observed using a DSLR camera. The experiment was performed with and without application of AMF (320 A, 325 kHz) for the first 2 minutes. In addition, the area of ​​rhodamine released onto the surface of the small intestine was quantitatively measured using ImageJ software (National Institutes of Health, USA). Each experiment was repeated three times.

[0076] In addition, to evaluate the amount of DOX released from TheraS of the present invention, the amount of DOX loaded on TheraS before and after contact with the surface of the small intestine of a pig was evaluated. After contacting the original TheraS and the separated TheraS with the surface of the small intestine, they were completely dissolved in a shaking incubator (JSSI-100C, JSR, Korea) at 50℃ and 300 rpm for 2 minutes. The concentration of DOX dissolved in the original solution and the separated TheraS solution was measured at 490 nm using a UV-vis spectrophotometer (SPECTROstar Nano, BMG LABTECH). The amount of DOX delivered to the surface of the small intestine of a pig through TheraS was quantitatively measured using a drug release test, and each experiment was repeated 5 times.

[0077]

[0078] Unrolling test in pig stomach

[0079] To evaluate the unrolling performance of the TheraS of the present invention, unrolling motion tests were performed on pig stomach sections with various curvatures. Four sections of pig stomachs with different curvatures were prepared, and rhodamine-loaded rolling TheraS was placed on the wet stomach surface. The process of spreading and adhering TheraS to the stomach surface was recorded using a DSLR camera. After TheraS was fully spread on the pig stomach surface, it was kept for 10 minutes and then separated. A plan view of the stomach sample showing the drug released from TheraS was observed using a DSLR camera. A cross-section of the pig stomach sample was also observed. In addition, stomach samples were frozen with OCT compound in a cryomold, and then the frozen samples were sliced ​​into 100 μm sections using a cryostat microtome (Leica / CM3050S) at the INST of DGIST. The thinly cut sections were placed on glass slides and imaged and analyzed using a confocal microscope (LSM900, Carl Zeiss) at the INST of DGIST.

[0080]

[0081] Magnetically actuated capsule for delivery of the multifunctional medical patch (TheraS) for the gastrointestinal tract of the present invention

[0082] The magnetically actuated capsule designed to deliver the TheraS of the present invention to a target lesion site was constructed with an Ecoflex lid assembly. It consisted of four deployable TheraS capsule cameras, rods, bodies, and heads; a pushing bar; metal pins; and a permanent magnet. In addition, the center rod, capsule body, and pushing bar were manufactured using an SLA 3D printer containing transparent resin. The permanent magnet attached to the pushing bar consisted of two axially magnetized ring magnets (MAGNA, Japan) with inner diameters, outer diameters, and heights of 2.5, 8, and 2.5 mm, respectively, and one radially magnetized ring magnet (JLMAGNET, Korea) with inner diameters, outer diameters, and heights of 2.3, 8, and 1 mm, respectively. Two hemispherical metal pins with a diameter of 1.5 mm (Nailmall, Korea) were attached to the pushing bar. The Ecoflex lid assembly was prepared by pouring Ecoflex 00-30 (Smooth-On Inc, USA) mixed with lipophilic blue dye into a resin mold and drying at 60°C for 2 h. The resin mold was fabricated using an SLA 3D printer, and silane-coated after UV exposure (405 nm, 9.1 W) for 60 min and heat treatment (120°C) for 120 min. A wired capsule camera (OV6946 endoscope module, Dothecamera) with a diameter of 2 mm and a height of 4 mm was used to capture images of the inside of the gastrointestinal tract. The camera was assembled at the center of the channel entrance, and the wire passed through the central rod and exited from the capsule head.

[0083]

[0084] In vitro delivery test of the multifunctional gastrointestinal medical patch (TheraS) of the present invention

[0085] To verify the delivery of the TheraS of the present invention to the stomach and small intestine of a pig, an in vitro test was conducted using a magnetically actuated capsule. The magnetically actuated capsule was moved via the EMA system to deliver the loaded TheraS. First, the pig's stomach was placed on a 3D-printed stomach-shaped test bed. Next, the capsule was moved to the target lesion location during the translation mode, and then, during the sheet delivery mode, the capsule extruded and positioned the TheraS. During this process, the TheraS was extruded from the lower channel closest to the stomach surface using a uniform field applied obliquely downward. By repeating this process, four TheraS capsules contained within the capsule were delivered to specific locations in the pig's stomach. Furthermore, the unfolding motion of the delivered TheraS was simultaneously recorded using a DSLR and a capsule camera. Experiments were also conducted on a pig small intestine secured to a 3D-printed small intestine-shaped phantom using the same method.

[0086]

[0087] Analysis of the hemostatic performance of the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention

[0088] To evaluate the hemostatic performance of TheraS of the present invention, whole blood coagulation tests and platelet adhesion tests were performed. For this purpose, 0.2 mL of human citrated blood was poured into TheraS, and 20 μL of 0.2 M CaCl2 was added for blood coagulation. The mixture was then incubated at 37°C and 30 rpm for 0, 2, 4, 6, 8, and 10 minutes. The sample was then hemolyzed with 20 mL of DI water, and the absorbance was measured at 540 nm using a UV-vis spectrophotometer. The hemostatic performance of control blood, gelatin sheets, and gelatin-chitosan sheets was processed and compared using the same procedure. Gelatin-chitosan microneedle patches were prepared as follows: a solution containing 10% gelatin (from bovine skin, Deoksan, Korea) and 2% chitosan (medium molecular weight, 75–85% deacetylated) in a 2:1 ratio was poured into a 35-mm dish and dried overnight. The dried gelatin-chitosan sheets were cut to the same size (7 × 10 mm) as the TheraS, and each experiment was repeated five times.

[0089] Additionally, to perform platelet adhesion tests, citrated blood was centrifuged at 2,500 rpm for 5 minutes to obtain platelet-rich plasma (PRP). 100 μL of PRP was then added to TheraS and incubated at 37 °C for 20 minutes. The samples were washed three times with PBS and fixed with a 0.1% glutaraldehyde solution for 2 hours. The samples were then dried to obtain SEM images. Similarly, gelatin and gelatin-chitosan sheets were processed in the same manner to compare platelet adhesion.

[0090]

[0091] Cytotoxicity test of the multifunctional gastrointestinal medical patch (TheraS) of the present invention on HT-29 cells

[0092] The anticancer efficacy of TheraS of the present invention was evaluated in HT-29 cells (human colon cancer cell line, ATCC, USA). HT-29 cells were cultured in RPMI 1640 medium (Gibco) containing 10% fetal bovine serum (Gibco) and 1% penicillin-streptomycin (Gibco), seeded at a density of 1 × 10^6 cells per 35 mm cell culture dish, and counted using a cell counting kit-8 (CCK-8). Before applying TheraS, cells were cultured for 24 hours under 5% CO2 culture conditions. Five sets of cell viability experiments were performed for each experimental group as follows. The experiments were conducted in five groups: control group, TheraS without MNPs and DOX (TheraS(MNPs- and DOX-)), TheraS without DOX but with or without AMF (TheraS(DOX-)), and TheraS AMF with or without AMF. In addition, the AMF treatment group was exposed to AMF (320 A, 325 kHz) for 10 min. After exposure to each experimental condition for 24 h, the cell viability of each group was analyzed. Additionally, the nuclei of living cells were stained with DAPI, and fluorescence images of the cells were obtained using a fluorescence microscope (LSM700, Zeiss). The overall cell viability of each experimental group was measured at 450 nm using the CCK-8 assay, and the statistical significance for each group was analyzed using the p-test and one-way ANOVA, and the results of p<0.005 were considered significant.

[0093]

[0094] Thermal ablation using the multifunctional medical patch for the gastrointestinal tract (TheraS) of the present invention

[0095] The thermal ablation performance of TheraS of the present invention was evaluated using samples from the small intestine and stomach of a pig. First, TheraS was fully unfolded and placed in the pig intestine, then treated with AMF (320 A, 325 kHz). After 40 minutes of AMF application, TheraS was separated from the surface of the pig intestine, and the heat-treated small intestine surface was observed using a DSLR camera. Next, the unfolded TheraS was placed in the stomach of a pig, and AMF was applied for 40 minutes. After TheraS was removed, the stomach surface was observed using a DSLR camera.

[0096] Additionally, histological analysis was performed on the surface of the small intestine of pigs that underwent thermal resection using TheraS. Heat-treated intestinal sections were stained with hematoxylin and eosin (H&E). Specifically, heat-treated intestinal specimens were fixed in a formaldehyde solution, dehydrated in ethanol and xylene, and embedded in paraffin. The resulting tissue-embedded paraffin blocks were cut into 4-μm-thick slices using a rotary microtome (RM2255, Leica, Germany) at the DGIST INST. Each section was placed on a slide, deparaffinized in xylene, and dehydrated in ethanol. After staining with H&E for 10 and 2 minutes, respectively, the sections were washed in ethanol and xylene, and dried. For histological analysis, each processed section was observed under a fluorescence microscope (Nikon-Eclipse-90i). Paraffin blocks of thermally removed gastric tissue were prepared using a similar method, and paraffin sections were prepared. Each section was stained with H&E and histologically analyzed using a fluorescence microscope.

[0097]

[0098] Statistical analysis

[0099] All statistical data analyses were performed using Microsoft Excel, and data are presented as the mean ± standard deviation (SD) from at least three independent experiments. Statistical significance for each experimental group was analyzed using the p-test and one-way analysis of variance (ANOVA). Cases marked with an "*" or "**" at p<0.005 or p<0.0005 were considered statistically significant.

[0100]

[0101] <Example 1>

[0102] Manufacturing and Characterization of the Multifunctional Medical Patch for the Gastrointestinal Tract of the Present Invention (TheraS)

[0103] TheraS designed in the present invention was manufactured by sequentially UV curing TEGDM and PEGDM solutions, followed by pouring a chitosan-catechol solution containing MNPs and DOX, and freeze-drying (Figs. 2a and 2b). The manufactured TheraS was then rolled and mounted in the proposed capsule (Fig. 2c). PEGDM and TEGDM used in the TheraS of the present invention are bioinert materials that can be easily manufactured into various shapes through UV curing. Photopolymerized PEGDM swells upon contact with liquid, making it suitable for drug delivery to curved surfaces such as the eye. In addition, chitosan-catechol, used as the therapeutic layer, is a key material for mussel adhesives and has excellent adhesive properties even in humid environments, as well as high strength, high rigidity, and water resistance.

[0104] Furthermore, chitosan-catechol binds strongly to the gastrointestinal mucus due to its biodegradability and dissolves in the gastrointestinal tract after treatment. Due to its excellent hemostatic properties, chitosan-catechol can also be used in hemostatic treatments. The MNPs loaded into the therapeutic layer were coated with chitosan to ensure biocompatibility.

[0105] Furthermore, the characteristics of TheraS according to the present invention were analyzed. The element distribution of TheraS of the present invention was observed through energy dispersive X-ray spectroscopy (EDS, SU8020, Hitachi). As a result, Fe mapping confirmed that the chitosan-coated MNPs were uniformly distributed in the treatment layer. The magnetization values ​​(M) of the chitosan-coated MNPs and TheraS were analyzed using a vibrating sampling magnetometer (VSM, model 7407, Lake Shore Cryotronics), and as a result, they were approximately 84.25 emu / g and 3.74 emu / g, respectively.

[0106] In addition, images of the TheraS of the present invention in an unfolded and rolled state were confirmed using a digital single-lens reflex (DSLR) camera (EOS-800D, CANON) as shown in FIGS. 3a and 3b, respectively. A cross-sectional image of TheraS was obtained using a field emission scanning electron microscope (FE-SEM) as shown in FIG. 3c.

[0107] As a result of observation, the size of the unfolded TheraS was 10 × 7 mm, and the thicknesses of the unrolled layer, guard layer, and therapeutic layer were confirmed to be approximately 16 μm, 8 μm, and 0.7 mm, respectively. In addition, the cross-sectional fluorescence images of TheraS manufactured using a PEGDM solution containing 4',6-diamidino-2-phenylindole (DAPI), a TEGDM solution containing syto9, and a chitosan-catechol solution containing MNPs and DOX containing rhodamine B were observed using a confocal microscope (Fig. 3d).

[0108] In addition, the unfolding process of TheraS after being delivered to the small intestine surface was observed, and the process is shown in Fig. 3e. First, the rolled TheraS was placed on the wet surface of the small intestine, and when the small intestine mucus (pH 6.8) reached the unrolling layer of TheraS, the layer began to swell, followed by bending and stress relaxation, indicating the initiation of unfolding, or unrolling, of TheraS, and then gradually and eventually completely unrolled and adhered to the small intestine surface. In addition, the unfolding process of TheraS was confirmed in the small intestine of pigs (pH 8.0) using artificial intestinal fluid (pH 8.0) and in the stomach of pigs (pH 2.0) using artificial gastric fluid (pH 2.0).

[0109] As a result, it was confirmed that the TheraS of the present invention unfolds after being placed on the surface of various gastrointestinal environments having various pH values ​​(small intestine: pH 6.6-8.0, large intestine: pH 6.5, and stomach: pH 1-2.5).

[0110] In addition, it was confirmed that TheraS of the present invention has excellent adhesiveness to the surface of the gastrointestinal tract, and this adhesive performance was found to be superior to that of a gelatin sheet.

[0111]

[0112] <Example 2>

[0113] Confirmation of drug release of the multifunctional medical patch for the gastrointestinal tract of the present invention in an alternating magnetic field (AMF)

[0114] To evaluate the drug release profile of the multifunctional gastrointestinal medical patch (TheraS) of the present invention on the gastrointestinal surface, the rhodamine-loaded TheraS was placed on the surface of the small intestine of a pig for a specific period of time, then removed, and the profile of the gastrointestinal surface was analyzed. The drug release profile of TheraS was observed for the group to which AMF was applied for the initial 2 minutes and the group to which it was not applied.

[0115] As a result, as can be seen in Fig. 4a, the drug release area of ​​TheraS in both the group with and without AMF application was found to increase with contact time, and in particular, the group with AMF application was found to have a larger drug release area than the group without AMF application. In addition, the drug release area of ​​TheraS delivered to the surface of the small intestine of a pig was measured using ImageJ software. When TheraS was brought into contact with the surface of the small intestine of a pig for 10 minutes, it was found that approximately 75.68% and 95.85% of the total area of ​​TheraS were released in the group without AMF application and the group with AMF application, respectively (Fig. 4b). Through this, the inventors of the present invention were able to find out that applying AMF can further enhance drug release from TheraS of the present invention, thereby increasing the amount of drug delivered to the surface of the gastrointestinal tract.

[0116] Furthermore, to measure the release of DOX drug from TheraS of the present invention, the unfolded TheraS was brought into contact with the surface of the small intestine of a pig for a specific period of time and then separated. The amount of DOX remaining in the TheraS was then measured using a UV-vis spectrophotometer after completely dissolving the TheraS in DI water before and after contact with the surface of the small intestine of the pig. The amount of DOX delivered to the small intestine of the pig was calculated by subtracting the amount of DOX remaining in the TheraS after drug delivery from the amount originally loaded on the TheraS.

[0117] As a result, when TheraS was in contact with the surface of the porcine small intestine for 10 minutes, approximately 46.63% and 61.05% of DOX were released from TheraS in the groups without and with AMF, respectively (Fig. 4c). Therefore, these results also indicate that the application of AMF can enhance the drug release level from TheraS, ultimately leading to greater drug delivery to the gastrointestinal surface.

[0118]

[0119] <Example 3>

[0120] Analysis of the delivery efficacy of the multifunctional medical patch for the gastrointestinal tract of the present invention in vitro

[0121] Next, the inventors conducted in vitro tests using a porcine stomach to demonstrate targeted delivery using a capsule to verify whether the multifunctional gastrointestinal medical patch (TheraS) of the present invention can be magnetically actuated to a desired location and deliver TheraS. To this end, the inventors first attached a porcine stomach to a 3D-printed phantom and actuated the magnetically actuated capsule using an EMA system (Fig. 5a).

[0122] As a result, the capsule was moved to the target lesion site by the external magnetic field, the TheraS equipped with the pushing bar was pushed, the Ecoflex lid assembly was folded, the capsule channel was opened, and the TheraS was released, and similarly, the remaining three TheraS were successfully delivered into the pig stomach (Fig. 5b).

[0123] Furthermore, the inventors of the present invention recorded images of the stomach surface where the TheraS of the present invention was delivered in real time using a camera mounted on the capsule during an in vitro analysis process, and these images are shown in Figures 5c to 5f. By confirming that each TheraS was gradually released and attached to the stomach surface after being delivered to the target site, the inventors confirmed that delivery of multiple TheraS to multiple target sites was possible.

[0124]

[0125] <Example 4>

[0126] Analysis of the hemostatic performance of the multifunctional medical patch for the gastrointestinal tract of the present invention

[0127] Gastrointestinal bleeding refers to bleeding caused by damage to the mucous membranes of organs such as the esophagus, stomach, small intestine, and colon. It is known to be caused by peptic ulcers, polypectomy, and colon cancer. Therefore, the inventors of the present invention conducted whole blood coagulation tests and platelet adhesion experiments to analyze the hemostatic performance of TheraS of the present invention. To this end, whole blood coagulation tests were performed on a total of four groups: control blood, gelatin sheets, gelatin-chitosan sheets, and TheraS treatment groups of the present invention.

[0128] As a result, it was found that the longer the whole blood was applied to each experimental group, the more clots were formed on the surface of each sample, which increased the capture of red blood cells. Conversely, when deionized (DI) water was added, the heavily coagulated samples showed a lighter color due to reduced hemolysis (Fig. 6a). In particular, in the group treated with TheraS of the present invention, a remarkable blood coagulation phenomenon was observed when exposed to whole blood for more than 4 minutes. This blood coagulation phenomenon was found to be faster and more effective in the TheraS treated group of the present invention compared to the other experimental groups.

[0129] Additionally, hemoglobin absorbance was measured at 540 nm using a UV-vis spectrophotometer, with lower absorbance indicating a higher coagulation rate.

[0130] As a result of the analysis, as shown in Fig. 6b, 10 minutes after application of the sample, the optical density (OD) values ​​of the control blood, gelatin sheet, gelatin-chitosan sheet, and TheraS treatment groups were 1.428, 1.039, 0.407, and 0.077, respectively, confirming that TheraS of the present invention has a significantly superior blood coagulation effect compared to other experimental groups. The appearance of hemolyzed blood after coagulation in each experimental group is shown in Fig. 6c.

[0131]

[0132] Additionally, a platelet adhesion test was conducted to observe the tendency of platelets to adhere to the TheraS surface of the present invention. To this end, three experimental groups were tested: a gelatin sheet, a gelatin-chitosan sheet, and a TheraS treatment group. Platelet aggregation in each group was observed using SEM.

[0133] As a result, as shown in Fig. 6d, it was confirmed that a greater number of platelets were attached to the TheraS of the present invention than to the gelatin and gelatin-chitosan sheets.

[0134]

[0135] Through this, it was found that the multifunctional gastrointestinal medical patch of the present invention, which contains chitosan-catechol in the therapeutic layer, exhibits excellent hemostatic performance by promoting red blood cell coagulation and platelet activation, thereby rapidly inducing hemostasis. Therefore, it was found that the multifunctional gastrointestinal medical patch of the present invention can be effectively used in the treatment of gastrointestinal bleeding.

[0136]

[0137] <Example 5>

[0138] Analysis of the cancer treatment effect of the multifunctional medical patch for the gastrointestinal tract of the present invention

[0139] Furthermore, the inventors of the present invention conducted a cytotoxicity test using HT-29 human colon cancer cells to confirm whether the multifunctional gastrointestinal medical patch (TheraS) of the present invention has a therapeutic effect on cancer. For this purpose, the cells were cultured in a cell culture plate and treated with TheraS of the present invention for 24 hours. Cell viability was evaluated in a total of six experimental groups: a control group, a group containing TheraS without MNPs and DOX (TheraS(MNPs-and DOX-)), a group containing TheraS without DOX (TheraS(DOX-) with or without AMF), and a group treated with TheraS with or without AMF.

[0140] For the analysis, the nuclei of cells in each experimental group were stained with DAPI and observed under a fluorescence microscope.

[0141] As a result, as shown in Figures 7a-7f, TheraS without MNPs and DOX did not significantly affect cell viability due to the biocompatibility of chitosan-catechol and the bioinertness of PEGDM and TEGDM in the therapeutic layer. In TheraS (DOX-) without an alternating magnetic field (AMF), a small number of cell deaths were confirmed due to the chitosan-coated MNPs. In TheraS (DOX-) with an AMF applied, a greater number of cell deaths were induced, confirming that the TheraS of the present invention with an AMF applied can effectively kill cancer cells by inducing hyperthermia. In addition, it was confirmed that the TheraS group without an AMF applied had a significant number of cell deaths due to the release of DOX drug. In addition, in the TheraS group with an AMF applied, it was confirmed that TheraS can induce the most extensive and effective apoptosis of cancer cells by inducing hyperthermia under an AMF and simultaneously releasing DOX.

[0142] For the experimental results as described above, the cell viability of each experimental group was quantitatively analyzed using the CCK-8 assay. As shown in Fig. 7g, the TheraS (MNPs- and DOX-) treatment group showed a cell viability of approximately 94.96%, which seems to have shown only minimal cytotoxicity because there were no MNPs or DOX. The TheraS (DOX-) treatment group without AMF application showed a cell viability of approximately 73.94%, which seems to have been influenced by the chitosan-coated MNPs in inhibiting cell growth. In contrast, the TheraS (DOX-) treatment group with AMF application showed a cell viability of approximately 42.94%, which seems to have induced tumor cell death through hyperthermia under the AMF, while the TheraS treatment group without AMF application showed a cell viability of approximately 48.03%, which seems to have been due to the released drug DOX. Furthermore, the TheraS treatment group with AMF applied showed the best anticancer efficacy with a cell viability rate of approximately 35.37%. This was because effective cancer cell death induction occurred through DOX drug release along with hyperthermia induction under AMF conditions.

[0143]

[0144] <Example 6>

[0145] Analysis of the feasibility of thermal ablation using the multifunctional medical patch for the gastrointestinal tract of the present invention under an alternating magnetic field (AMF).

[0146] To evaluate the thermal ablation potential of the multifunctional gastrointestinal medical patch (TheraS) of the present invention, the inventors performed thermal ablation. The experiment was conducted by placing TheraS spread over the surface of the small intestine of a pig subjected to AMF. After the TheraS was unrolled, AMF was applied for 40 minutes, and then the TheraS was detached, after which the small intestine surface was observed.

[0147] Under AMF, the area heated by TheraS was clearly distinct from the normal tissue (NT) area on the intestinal surface (Figs. 8a and 8b). The white areas on the intestinal surface of the pig represent areas of coagulative necrosis (CN), a well-known phenomenon observed in tissues exposed to temperatures above 50°C.

[0148] The results of thermal ablation performed on a pig stomach using TheraS of the present invention under AMF are shown in FIGS. 8c and 8d. It was confirmed that tissue necrosis occurred on the surface of the pig stomach to which TheraS was delivered due to the heat generated by TheraS under AMF, and the ablated area turned brown, unlike the pig small intestine.

[0149] In addition, the thermal ablation ability of TheraS in the porcine small intestine was analyzed through hematoxylin and eosin (H&E) staining. As shown in Fig. 8e, the CN region appeared brighter than the NT region, indicating that TheraS was delivered and heat was generated under the AMF, resulting in thermal ablation on the intestinal surface. Similarly, a clear distinction between normal and necrotic regions was observed in the thermally ablated porcine stomach region (Fig. 8f). In particular, since temperatures above 100°C may cause tissue boiling or carbonization, it is appropriate to perform thermal ablation in the temperature range of 50 to 100°C. Therefore, in the present invention, TheraS was applied under the AMF starting from an initial temperature of 37°C and gradually increasing the temperature to approximately 60°C within 40 minutes, indicating that appropriate thermal ablation was possible in the target region.

[0150] Through these results, the inventors of the present invention were able to determine that the multifunctional medical patch for the gastrointestinal tract of the present invention can be usefully used in the treatment of cancer or tumors, as it can perform thermal ablation by generating heat under AMF and inducing local tissue necrosis.

[0151]

[0152] Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than restrictive. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. A multifunctional medical patch for the gastrointestinal tract consisting of three layers: an unrolling layer, a guard layer, and a therapeutic layer. The above unrolling layer is composed of PEGDM (polyethylene glycol dimethacrylate) and causes swelling when in contact with liquid at the target area. The above guard layer is located between the unrolling layer and the medical layer and is composed of TEGDM (triethylene glycol dimethacrylate). A multifunctional medical patch for the gastrointestinal tract, wherein the medical layer comprises a mucoadhesive material and a medical material and is characterized by adhesion to a target area.

2. In paragraph 1, The above multifunctional medical patch for the gastrointestinal tract is a multifunctional medical patch for the gastrointestinal tract, characterized in that it is delivered to a target site in the gastrointestinal tract in a rolled form.

3. In paragraph 2, A multifunctional medical patch for the gastrointestinal tract, characterized in that the outer layer in the rolled form is rolled to become a therapeutic layer.

4. In paragraph 2, The above delivery is a multifunctional medical patch for the gastrointestinal tract, characterized in that one or more multifunctional medical patches for the gastrointestinal tract in a rolled form are mounted on a wire endoscope or capsule endoscope and delivered to a target site.

5. In paragraph 1, A multifunctional medical patch for the gastrointestinal tract, characterized in that the mucosal adhesive material is at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof.

6. In paragraph 1, A multifunctional medical patch for the gastrointestinal tract, characterized in that the medical material is at least one selected from the group consisting of an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

7. In paragraph 1, The above multifunctional medical patch for the gastrointestinal tract is, A multifunctional medical patch for the gastrointestinal tract, characterized in that it is delivered to a target area in a rolled form and adhered, the unrolled layer swells due to gastrointestinal liquid to completely unfold to fit the curved surface of the target area, and is strongly adhered by a mucoadhesive material contained in the medical layer, and the medical material is released to the target area. 8.(1) A step of manufacturing a guard layer by irradiating ultraviolet rays to a TEGDM (triethylene glycol dimethacrylate) solution; (2) a step of dispensing a PEGDM (polyethylene glycol dimethacrylate) solution onto the guard layer manufactured in step (1) and irradiating it with ultraviolet rays to manufacture an unrolling layer on the guard layer; (3) a step of placing the two-layer structure of the guard layer and the unrolling layer manufactured in the step (2) into a resin mold with the guard layer facing upward, pouring a mixed solution of a mucosal adhesive material and a medical material thereon, and then freeze-drying to manufacture a therapeutic layer on the guard layer; and (4) a step of separating a multifunctional medical patch for the gastrointestinal tract, comprising three layers: an unrolling layer, a guard layer, and a therapeutic layer, from the mold; A method for manufacturing a multifunctional medical patch for the gastrointestinal tract.

9. In paragraph 8, A method for manufacturing a multifunctional medical patch for the gastrointestinal tract, characterized in that the method further comprises the step of rolling the multifunctional medical patch for the gastrointestinal tract separated from the mold in the step (4) into a cylinder with the medical layer facing outward, inserting it into a cylindrical resin mold, and heating it to manufacture a multifunctional medical patch for the gastrointestinal tract in a rolled shape.

10. In paragraph 9, A method for manufacturing a multifunctional medical patch for the gastrointestinal tract, characterized in that the heating is performed using a heating gun at a temperature of 150°C to 250°C for 5 to 15 seconds.

11. In paragraph 9, A method for manufacturing a multifunctional medical patch for the gastrointestinal tract, characterized in that the mucosal adhesive material is at least one selected from the group consisting of chitosan, catechol, tannic acid, alginate, guar gum, xanthan gum, pectin, galactomannan, glucomannan, hyaluronic acid, glycosaminoglycans, gelatin, polyethylene glycol, polyethyleneoxide, polyacrylic acid, polymethacrylic acid, polyvinyl pyrrolidone, polyvinyl amine, and derivatives thereof.

12. In paragraph 9, A method for manufacturing a multifunctional medical patch for the gastrointestinal tract, characterized in that the medical material is at least one selected from the group consisting of an anticancer agent, a magnetic nanoparticle, a hemostatic agent, a tissue regeneration factor, a biocompatible ink, a fluorescent material, an active oxygen sensing material, and a pH sensing material.

Images