Intestinal pressure self-adaptive perception cluster type microneedle robot and preparation method

Abstract

The application discloses a kind of intestinal pressure adaptive perception cluster type microneedle robot and preparation method, the cluster type microneedle robot includes microneedle administration unit and middle expansion unit, wherein microneedle administration unit includes drug-loaded microneedle, microneedle base and sheet hydrogel, the drug-loaded microneedle is located on the microneedle base, the microneedle base is equipped with recess, and the recess of the microneedle base is filled with sheet hydrogel;Middle expansion unit includes ring belt controllable rupture shell side wall structure and upper isolation layer, lower isolation layer, the controllable rupture shell side wall structure is in situ bonded with the upper isolation layer, lower isolation layer, and the closed cavity formed is filled with sheet super-fast expansion hydrogel;The middle expansion unit is located between two the microneedle administration unit, and two the microneedle administration unit is in situ bonded with the upper isolation layer, lower isolation layer of the middle expansion unit, and the sheet hydrogel filled in the recess of the microneedle base is encapsulated.

Description

Technical Field

[0001] This invention belongs to the field of microneedle robot technology, specifically relating to a clustered microneedle robot with adaptive intestinal pressure sensing and its preparation method. Background Technology

[0002] Biological macromolecules, such as proteins, peptides, nucleic acids, and some antibody drugs, are highly susceptible to degradation and inactivation due to their large molecular weight, intricate structure, and sensitivity to the external environment. After oral administration, they are easily affected by the complex physiological environment of the gastrointestinal tract. On the one hand, gastric acid, digestive enzymes, and various proteolytic enzymes in the intestine can lead to drug degradation and inactivation; on the other hand, the intestinal mucus layer, epithelial barrier, and tight junction structures significantly limit their transmembrane absorption, resulting in generally low bioavailability and poor absorption efficiency for orally administered biological macromolecules. To improve the oral delivery of these drugs, researchers both domestically and internationally have proposed various improvement strategies, such as using enteric coating and controlled-release systems to avoid the gastric environment, utilizing nanocarriers, liposomes, or polymer microparticles to improve drug stability and mucosal retention, and achieving local active drug delivery through micromechanical devices. However, these methods still generally suffer from limited delivery efficiency, unstable sites of action, significant drug loss, or insufficient safety and degradability.

[0003] Against this backdrop, oral microneedle drug delivery devices have gradually become an important development direction for the oral delivery of biopharmaceuticals. These devices typically carry drugs through microneedles that penetrate the intestinal mucosa and subcutaneous tissue, enabling localized, targeted, and barrier-crossing drug delivery. This, to some extent, avoids long-term exposure of drugs to the complex digestive fluid environment, thus improving delivery efficiency. Extensive research has been conducted both domestically and internationally on this approach, such as using spring-loaded energy release for rapid microneedle insertion, and utilizing chemical reactions, gas expansion, or ultrasonic triggering for microneedle deployment and drug delivery. These approaches have made positive progress in improving insertion efficiency and trigger controllability; however, many devices still suffer from limitations such as complex structures, high risk of in vivo residue, insufficient biodegradability, or strong dependence on precise external triggering conditions.

[0004] Patent WO2024243887A1 discloses a microneedle drug delivery device and its preparation method. The device includes a substrate, a microneedle array, and a liquid-absorbing and swelling material. The substrate supports the microneedle array, and the liquid-absorbing and swelling material is placed between the substrates to form a sandwich structure. This device utilizes a gentle water-absorbing and swelling mechanism and the natural peristaltic behavior of the gastrointestinal tract to insert the microneedles into the intestinal wall, completing drug delivery. It physically overcomes the physiological barrier to oral delivery and absorption of biological drugs, improving the oral bioavailability of biological drugs. All materials used are biodegradable soft materials, ensuring high safety. However, this device also has some drawbacks: Specifically, this type of device relies on the natural peristalsis of the intestine and the expansion of the liquid to achieve microneedle insertion. However, different patients have differences in intestinal lumen diameter and intestinal motility due to age, gender, and disease status. The maximum expansion volume that the original microneedle robot can achieve may not be able to adapt to all intestinal environments, which can easily lead to insufficient microneedle contact. At the same time, the intestinal wall structure is complex and continuously peristaltic, and the contact process between the microneedle and the intestinal wall is prone to be insufficient, resulting in insufficient insertion stability. In addition, the large-sized structure formed after the hydrogel expands is difficult to shrink or disintegrate, and may block the intestine for a long time, making it difficult to be expelled. The risk of small intestinal obstruction cannot be ignored. Summary of the Invention

[0005] Existing microneedle robots mostly employ a single expansion / single force mechanism, lacking an intermediate execution unit capable of actively amplifying mechanical thrust. Consequently, their operational reliability is limited under weak pressure or low-frequency peristalsis conditions. Furthermore, improper expansion structure design can easily lead to premature instability or complete disintegration, making it difficult to simultaneously achieve insertion drive, controlled rupture, and safe subsequent expulsion. While existing ultra-fast expanding hydrogels possess strong mechanical working capabilities, they have not yet formed an integrated structural, material, and process solution for oral microneedle robots, lacking a controllable rupture shell, staged structural response, and overall encapsulation design suitable for intestinal microneedle drug delivery scenarios.

[0006] This invention addresses the shortcomings of existing technologies by providing a clustered microneedle robot with adaptive intestinal pressure sensing and its fabrication method. This robot can sense and adapt to intestinal pressure conditions, actively compensate for insufficient pressure, and controllably rupture under sufficient pressure. It is also suitable for oral encapsulation. The invention constructs a clustered microneedle robot consisting of an upper microneedle drug delivery unit, a middle expansion unit, and a lower microneedle drug delivery unit. The middle expansion unit provides active mechanical compensation during periods of insufficient intestinal pressure and can achieve phased failure and structural switching through controllable rupture of the outer shell during periods of continuous pressure accumulation. This allows the entire system to adaptively respond according to intestinal pressure conditions, completing a sequential process of "expansion—insertion—rupture—disintegration."

[0007] This invention achieves this objective through the following technical solution: A clustered microneedle robot with adaptive intestinal pressure sensing, comprising: A microneedle drug delivery unit includes a drug-loaded microneedle, a microneedle base, and a sheet-like hydrogel. The drug-loaded microneedle is located on the microneedle base, and the microneedle base has grooves. The grooves of the microneedle base are filled with sheet-like hydrogel. The central expansion unit includes a ring-shaped controllable fracture outer shell sidewall structure and an upper isolation layer and a lower isolation layer. The controllable fracture outer shell sidewall structure is bonded to the upper isolation layer and the lower isolation layer in situ, and the closed cavity formed is filled with sheet-like ultra-fast expanding hydrogel. The intermediate expansion unit is located between the two microneedle drug delivery units. The two microneedle drug delivery units are respectively bonded in situ to the upper and lower isolation layers of the intermediate expansion unit to encapsulate the sheet-like hydrogel filling the groove of the microneedle substrate.

[0008] The method for preparing the clustered microneedle robot includes the following steps: S1, respectively fabricate the drug-loaded microneedles, the microneedle substrate, the sheet-like hydrogel, the sheet-like ultra-rapid expansion hydrogel, the upper isolation layer, and the lower isolation layer; S2, the microneedle base is fabricated based on the drug-loaded microneedle, and the sheet-like hydrogel is filled into the groove of the microneedle base to obtain the microneedle drug delivery unit; S3, fabricate the controllable fracture shell sidewall structure, bond the upper and lower isolation layers to the controllable fracture shell sidewall structure in situ, and encapsulate the sheet-like ultra-fast hydrogel inside the controllable fracture shell sidewall structure to obtain the central expansion unit; S4, the upper and lower isolation layers of the central expansion unit are respectively bonded to the microneedle substrates of the two microneedle drug delivery units in situ, and the sheet-like hydrogel is encapsulated to obtain a clustered microneedle robot.

[0009] Furthermore, the drug-loaded microneedles are fabricated as follows: a drug-loaded microneedle raw material solution is prepared using 60% by mass of polyethylene glycol diacrylate with an average molecular weight of 600, 60% by mass of polyethylene glycol with an average molecular weight of 4000, and 2% by volume of 2-hydroxy-2-methylphenylacetone. The mass ratio of polyethylene glycol diacrylate to polyethylene glycol is 0.5:1 to 2:1. The drug solution is then added to the drug-loaded microneedle raw material solution and mixed. Finally, the drug-loaded microneedles are fabricated in a mold using a photocrosslinking method.

[0010] Furthermore, a polyvinyl alcohol solution with a mass fraction of 20% and an average molecular weight of 95,000 was used as the raw material solution for the microneedle substrate and the isolation layer. When preparing the raw material solution, polyvinyl alcohol was added to deionized water and stirred under a water bath at 85-90°C until a homogeneous and transparent solution was formed.

[0011] Furthermore, the sheet hydrogel is prepared as follows: a solution of sodium carboxymethyl cellulose with a mass fraction of 3% and citric acid with a mass fraction of 0.2% is used to prepare the sheet hydrogel raw material; the sheet hydrogel raw material is stirred thoroughly until it is free of gel, placed in a petri dish and pressed into a gel-like sheet, and then dried and cut into sheet hydrogel sheets.

[0012] Furthermore, a raw material solution for the controllable fracture shell sidewall structure was prepared using 7% polyvinyl alcohol with an average molecular weight of 95,000, 2% acrylamide, 0.02%–0.04% N,N'-methylenebisacrylamide, and 0.04%–0.08% 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone. During the preparation process, the mixed solution of polyvinyl alcohol, acrylamide, and N,N'-methylenebisacrylamide was first placed in a water bath at 85–90°C and stirred. After complete dissolution, it was cooled to room temperature, and then the remaining components were added and stirred thoroughly.

[0013] Furthermore, the specific steps for fabricating the ultra-fast expanding hydrogel are as follows: An acidic component solution for the ultra-rapid expansion hydrogel was prepared using a 15%–25% (w / w) acetic acid solution, a 5%–10% (w / w) acrylamide solution, a 0.2%–0.6% (w / w) N,N'-methylenebisacrylamide solution, and a 1%–3% (w / w) gelatin solution, with an acetic acid to acrylamide mass ratio of 2:1 to 4:1. To prepare the acidic component solution, the gelatin was first placed in a water bath at 50–60°C and stirred until completely dissolved. After cooling to room temperature, the remaining components were added and stirred thoroughly. A saturated sodium bicarbonate solution was used as the alkaline component solution for the ultra-rapid expansion hydrogel, and 0.1%–0.2% (w / w) 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone was added as a photoinitiator. Using a dual-barrel syringe system, the acidic and alkaline components of the ultra-fast expanding hydrogel were placed in two separate syringes and mixed through the mixing end of the dual-barrel syringe. After the reaction, a stable foam was rapidly generated. The foam was then spread evenly and cured by UV irradiation at room temperature to obtain a dense gel-like sheet. The sheet was then placed in anhydrous ethanol for solvent replacement, removed, dried under ambient conditions, and cut into sheet-like ultra-fast expanding hydrogels.

[0014] Furthermore, a 5% polyvinyl alcohol solution was used as an in-situ adhesive.

[0015] Furthermore, the fabrication of the microneedle substrate, upper isolation layer, lower isolation layer, controllable fracture shell sidewall structure, and the in-situ bonding treatment all employ the freeze-thaw cycle method.

[0016] The present invention also provides an application of the clustered microneedle robot, wherein the clustered microneedle robot is placed in an enteric-coated capsule as an oral medication.

[0017] Compared with the prior art, the beneficial effects of this invention are as follows: 1. This invention proposes a clustered microneedle robot composed of an upper microneedle drug delivery unit, a middle controllable expansion unit, and a lower microneedle drug delivery unit. Compared with a single microneedle robot, this structure, by setting up an independently encapsulated expansion robot and introducing an ultra-fast expansion hydrogel inside it, enables the system to rely on the mechanical driving force generated by internal expansion to push the microneedle drug delivery unit closer to the intestinal wall in the early stages when local peristalsis is insufficient and pressure accumulation is inadequate. This enhances the reliability of microneedle contact and insertion, and reduces the system's dependence on a single external peristaltic condition.

[0018] 2. This invention establishes a working mechanism of "internal chemical potential driven by external intestinal peristalsis synergistic amplification". The ultra-fast expanding hydrogel inside the central expansion unit can rapidly absorb liquid and increase volume in intestinal fluid, generating thrust; even when the external peristaltic pressure is insufficient, this internal thrust can still push the microneedle drug delivery unit closer to the intestinal wall; when the external pressure further accumulates, it can work synergistically with the internal thrust to cause the controllable rupture shell to reach a preset failure threshold, achieving a phased structural switch.

[0019] 3. This invention features a controllable fracture shell, allowing the central expansion unit to partially fracture rather than completely disintegrate under continuous peristaltic action after initial volume support and thrust output. After the controllable fracture shell partially fractures, the internal ultra-rapidly expanding hydrogel gradually overflows. Under intestinal peristaltic pressure, the overflowing hydrogel maintains a high volume for approximately 30 minutes, continuously providing mechanical support for the microneedle drug delivery unit, ensuring stable contact and continuous insertion of the microneedles into the intestinal wall. As the contact area between the overflowing hydrogel and intestinal fluid further increases, its degradation rate gradually increases, and the volume of the central expansion unit gradually decreases. During this process, because the controllable fracture shell fractures partially rather than completely disintegrates, and because the overflowing hydrogel and polyvinyl alcohol material maintain a certain cross-linking connection, the overall robot structure remains largely intact during the degradation phase. The upper and lower microneedle drug delivery units continue to perform insertion and drug delivery functions, thus achieving a sequential response process of "expansion—insertion—fracture—disintegration." Through the above design, the present invention realizes the phased response process of "early volume support - later volume reduction" of the central expansion unit. While ensuring the continuous insertion of microneedles and drug delivery function, it is conducive to subsequent structural degradation and intestinal excretion, thereby reducing the risk of intestinal retention caused by maintaining an excessively large volume for a long time.

[0020] 4. This invention employs a differentiated material division of labor strategy: the microneedle base membrane uses a high-strength polyvinyl alcohol base membrane to ensure the load-bearing and support during the microneedle insertion stage; the controllable rupture shell uses a medium-strength, stretchable, and locally ruptureable polyvinyl alcohol / acrylamide composite network to balance expansion adaptability and controllable failure; and the ultra-fast expanding hydrogel uses a low-modulus, high-expansion-rate material system to provide rapid volume expansion and mechanical driving capability.

[0021] 5. After being dried under environmental conditions, the overall size of the clustered microneedle robot of the present invention can be adapted to the No. 000 enteric-coated capsule, enabling oral encapsulation; after entering the intestine, it can significantly increase in volume and activate its function in a short time, taking into account both the convenience of oral administration and the functionality of structural deployment.

[0022] 6. The experimental and simulation verification routes of this invention are complete, and can support the feasibility of the clustered microneedle robot in adaptive intestinal pressure sensing and active drug delivery from multiple levels such as material mechanical properties, expansion behavior, fracture behavior, degradation behavior and finite element simulation. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the preparation process of the microneedle drug delivery unit of the present invention; Figure 2 This is a schematic diagram of the preparation process of the sheet-like hydrogel of the present invention; Figure 3 This is a schematic diagram of the fabrication process of the upper and lower isolation layers of the present invention; Figure 4 This is a schematic diagram of the process for preparing the controllable fracture outer shell sidewall of the present invention; Figure 5 This is a schematic diagram of the preparation process of the sheet-like ultra-fast expanding hydrogel of the present invention; Figure 6 This is a schematic diagram of the packaging process for the central expansion unit of the present invention; Figure 7 This is a schematic diagram of the overall structure of the cluster-type microneedle robot of the present invention; Figure 8 This is a schematic diagram showing the verification results of the mechanical properties of the material of this invention; Figure 9 This is a schematic diagram showing the mass change and morphological evolution of the overall robot of the present invention in simulated intestinal fluid; Figure 10 This is a schematic diagram of the expansion, fragmentation, and degradation process of the ultra-fast expanding hydrogel of the present invention in simulated intestinal fluid; Figure 11 This is a schematic diagram illustrating the morphological changes of the clustered microneedle robot of the present invention during in vitro pressure simulation verification. Figure 12 This is a simulation model and boundary condition diagram of the present invention.

[0024] The annotations in the attached figures are explained as follows: 1 is the drug-loaded microneedle body raw material solution; 2 is the microneedle base raw material solution; 3 is the sheet-like hydrogel raw material; 4 is the upper and lower isolation layer raw material solution; 5 is the raw material solution for the controllable rupture outer shell sidewall structure; 6 is the acidic component solution of the ultra-rapid expansion hydrogel; 7 is the alkaline component solution of the ultra-rapid expansion hydrogel; 8 is the in-situ adhesive; 9 is the microneedle drug delivery unit mold; 10 is the microneedle drug delivery unit top cover; 11 is the upper and lower isolation layer mold; 12 is the controllable rupture outer shell sidewall structure; 13 is the controllable rupture outer shell polydimethylsiloxane mold; 14 15 is a sheet-like ultra-rapidly expanding hydrogel; 16 is a sheet-like hydrogel; 17 is the bottom assembly of the central expansion unit; 18 is the encapsulation body of the central expansion unit; 19 is a microneedle drug delivery unit; 20 is a clustered microneedle robot; 21 is a clustered microneedle robot loaded with enteric-coated capsule No. 000; 22 is the central expansion unit after local rupture; 23 is an ultra-rapidly expanding hydrogel that has overflowed and disintegrated; 24 is the intestinal wall region in the simulation model; 25 is the microneedle contact area in the simulation model; 26 is the central expansion unit in the simulation model. Detailed Implementation

[0025] Exemplary embodiments of the present invention will now be described in more detail with reference to the accompanying drawings. While exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the invention to those skilled in the art. It should be noted that, unless otherwise specified, the embodiments and features described herein can be combined with each other. The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0026] See Figures 1 to 12 This invention discloses the fabrication process of a clustered microneedle robot with adaptive intestinal pressure sensing, as detailed below: Preparation of raw material solution and functional solution A drug-loaded microneedle raw material solution 1 was prepared using 60% by mass of polyethylene glycol diacrylate with an average molecular weight of 600, 60% by mass of polyethylene glycol with an average molecular weight of 4000, and 2% by volume of 2-hydroxy-2-methylphenylacetone, along with a drug-containing solution, to form inverted quadrangular pyramidal microneedles. The mass ratio of polyethylene glycol diacrylate to polyethylene glycol was 0.5:1 to 2:1. 2-hydroxy-2-methylphenylacetone served as a photoinitiator for subsequent UV curing during the microneedle forming process. In this embodiment, insulin or smegglutinin was used as the drug.

[0027] A polyvinyl alcohol solution with a mass fraction of 20% and an average molecular weight of 95,000 was used as the microneedle substrate raw material solution 2. During preparation, polyvinyl alcohol was added to deionized water and stirred in a water bath at 85–90°C until a homogeneous and transparent solution was formed.

[0028] A sheet-like hydrogel raw material 3 was prepared using a solution of sodium carboxymethyl cellulose with a mass fraction of 3% and citric acid with a mass fraction of 0.2%, which was used to fill the sheet-like hydrogel 15 inside the microneedle drug delivery unit 18 to provide a slow-swelling effect.

[0029] A 20% polyvinyl alcohol solution, the same as the microneedle basement membrane raw material solution, was used as the isolation layer raw material solution 4 to form the upper and lower isolation layers of the middle expansion unit.

[0030] A controlled-fracture shell sidewall structure feedstock solution 5 was prepared using 7% polyvinyl alcohol (with an average molecular weight of 95,000), 2% acrylamide, 0.02%–0.04% N,N'-methylenebisacrylamide, and 0.04%–0.08% 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone. First, the mixed solution of polyvinyl alcohol, acrylamide, and N,N'-methylenebisacrylamide was placed in a water bath at 85–90°C and stirred until completely dissolved. After cooling to room temperature, the remaining components were added and stirred thoroughly.

[0031] A dual-barrel syringe system was used, in which the acidic tube contained a 15%–25% (w / w) acetic acid solution, a 5%–10% (w / w) acrylamide, a 0.2%–0.6% (w / w) N,N'-methylenebisacrylamide, and a 1%–3% (w / w) gelatin solution as the acidic component solution 6 for the ultra-rapid expansion hydrogel. During preparation, the gelatin was first placed in a 50–60°C water bath and stirred until fully dissolved. After cooling to room temperature, the remaining components were added and stirred thoroughly until homogeneous.

[0032] A saturated sodium bicarbonate solution was placed in an alkaline tube as the alkaline component solution 7 for the ultra-rapid expansion hydrogel, and 0.1% to 0.2% by mass of 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone was added as a photoinitiator.

[0033] A 5% polyvinyl alcohol solution was used as the in-situ adhesive.

[0034] II. Mold Structure and Precast Part Forming like Figure 1As shown, the microneedle drug delivery unit mold 9 is a polydimethylsiloxane mold, whose cavity includes both an inverted quadrangular pyramidal microneedle array and a main groove for forming a semi-capsule-shaped basement membrane cavity. The inverted quadrangular pyramidal holes have a hole spacing of 1200 μm, a hole depth of 1000 μm, and a hole side length of 420 μm; the groove depth is 3.5 mm, the groove length is 27.9 mm, the diameter of the semicircles on both sides of the groove is 6.6 mm, the flange depth is 0.5 mm, and the flange width is 1.5 mm. The microneedle body raw material solution 1, mixed with the drug-loaded solution, is injected into the microneedle array, and vacuum degassing is performed twice, 3 minutes each time, to remove air bubbles in the holes; then, excess solution on the mold surface is removed using a 1 ml syringe or pipette, leaving only the raw material solution in the inverted quadrangular pyramidal holes, and the mold is irradiated with ultraviolet light for 15 seconds to form a pre-cured drug-loaded microneedle array.

[0035] Microneedle base material liquid 2 is injected into the concave mold 9 of the microneedle delivery unit with pre-cured drug-loaded microneedle array until the base cavity is filled; then the microneedle delivery unit cap 10 is slowly closed from one side, and its perimeter is gently pressed to squeeze out excess polyvinyl alcohol solution from the edges. Subsequently, three freeze-thaw cycles are performed, with the low temperature stage at -35°C for 1.5 hours and the high temperature stage at 35°C for 2 hours. After demolding, a microneedle base with drug-loaded microneedles is obtained.

[0036] like Figure 3 As shown, the upper and lower isolation layer mold 11 is a polydimethylsiloxane mold with an elongated oval planar profile, a groove depth of 0.25 mm, a total groove length of 30.9 mm, and a semi-circular diameter of 10.6 mm at both ends. After the upper and lower isolation layer raw material liquid 4 is injected into the mold, it is pressed into shape with a plastic petri dish cover plate, and then subjected to three freeze-thaw cycles at low temperature of -35℃ for 1.5 hours and high temperature of 35℃ for 2 hours. After demolding, the upper isolation layer and the lower isolation layer are obtained respectively.

[0037] The controllable fracture shell sidewall structure 12 is the main wall of the central expansion unit. It is an independent elongated annular sidewall without a top or bottom, retaining only a continuous closed annular sidewall outline. Its planar shape is formed by the smooth connection of the arc segments at both ends and the straight segments on both sides to form a closed annular boundary.

[0038] like Figure 4As shown, the controllable fracture shell polydimethylsiloxane concave mold 13 is a polydimethylsiloxane concave mold that matches the controllable fracture shell sidewall structure 12. The diameter of the semicircles at both ends of the inner contour of the groove is 6.6 mm, the diameter of the semicircles at both ends of the outer contour is 7.6 mm, the distance between the centers of the two semicircles is 20.3 mm, and the thickness of the shell sidewall is 0.5 mm. In use, the controllable fracture shell raw material liquid 5 is injected into the groove, the transparent upper isolation layer concave mold cover 11 is closed, and it is placed in an ice-water bath environment for ultraviolet crosslinking for 20 minutes; then, four freeze-thaw cycles are performed, with the low temperature stage at -35°C for 1.5 hours and the high temperature stage at 45°C for 2 hours. After demolding, an independently formed controllable fracture shell sidewall structure preform can be obtained. The above mold structure can ensure that the obtained shell sidewall structure has a continuous, uniform, circumferentially closed, and thickness-controlled elongated annular structure, providing a geometric basis for the controllable fracture behavior of the subsequent central expansion unit.

[0039] III. Preparation of Functional Hydrogels like Figure 5 As shown, the sheet-like ultra-fast expanding hydrogel 14 was fabricated as follows: Acidic component solution 6 and alkaline component solution 7 were mixed via the mixing end of a double-barrel syringe, and a stable foam was rapidly generated after the reaction. This foam was then evenly spread in a disposable square petri dish and cured by UV irradiation for 2 minutes at room temperature, resulting in a dense, gel-like sheet. The sheet was then placed in anhydrous ethanol for solvent replacement for 2 hours, removed, dried under ambient conditions, and cut into sheet-like ultra-fast expanding hydrogels 14 with a length of 18 mm and a width of 5 mm, which were used as the built-in driving material for the central expansion unit.

[0040] like Figure 2 As shown, the fabrication process of sheet hydrogel 15 is as follows: the sheet hydrogel raw material 3 is thoroughly stirred until there is no gel, placed in a disposable square culture dish and pressed into a gel-like sheet, and then placed in a 40° constant temperature oven to dry for 12 hours. After drying, it is cut into a sheet with the same size as the sheet ultra-rapid expansion hydrogel 14, which is used to fill the inner cavity of the semi-capsule-type base groove of the microneedle drug delivery unit.

[0041] IV. Cluster-based microneedle robot assembly like Figure 6 As shown, the controllable fracture shell sidewall structure 12 and the lower isolation layer are first bonded in situ within the controllable fracture shell polydimethylsiloxane concave mold 13. Specifically, after a small amount of in-situ adhesive 8 is added to the interface between the two, a rapid freeze-thaw cycle is performed, with a low temperature of -35°C and a high temperature of 25°C, and both the low and high temperature times are 1 hour, to form the bottom assembly 16 of the central expansion unit.

[0042] After demolding the bottom assembly 16 of the bottom central expansion unit, a sheet-like ultra-fast expanding hydrogel 14 is filled into its cavity, and then the upper isolation layer is covered on top. The top encapsulation is completed by the same in-situ bonding process as the lower isolation layer, resulting in the central expansion unit encapsulation body 17. Since the controllable fracture shell material is prone to sidewall collapse under water loss conditions, this encapsulation step is preferably carried out in a humid environment by freeze-thaw to maintain the geometric stability of the shell.

[0043] The microneedle substrate is demolded from the microneedle drug delivery unit mold 9, and sheet-like hydrogel 15 is filled into the internal groove cavity to form microneedle drug delivery units 18.

[0044] The overall assembly of the clustered microneedle robot 20 is as follows: Two microneedle drug delivery units 18 are placed above and below the central expansion unit package 17, respectively. A small amount of in-situ adhesive 8 is dropped at each contact interface, and the same in-situ bonding process as the lower isolation layer is used to finally obtain the overall clustered microneedle robot 20, with the structure as shown below. Figure 7 As shown.

[0045] Clustered microneedle robot 21 containing enteric-coated capsule No. 000. After the entire assembly of the clustered microneedle robot 20 was dried for 12 hours, its external dimensions were measured to be: length 2cm, width 0.7cm, height 0.8cm, which is suitable for containing enteric-coated capsule No. 000.

[0046] V. Working Mechanism and Process The clustered microneedle robot 19 of the present invention consists of two microneedle drug delivery units 18 and a central expansion unit 17 located in the middle. Before entering the small intestine, the enteric-coated capsule shell protects the internal clustered robot from interference from the gastric environment; after entering the small intestine, the enteric-coated capsule dissolves and releases the entire clustered robot inside. The sheet-like hydrogel 15 inside the upper and lower microneedle drug delivery units and the sheet-like ultra-fast expanding hydrogel 14 inside the central expansion unit come into contact with intestinal fluid and begin to absorb liquid and expand. Among them, the central expansion unit dominates the early response of the overall structure because the ultra-fast expanding hydrogel it contains has a higher expansion rate and stronger mechanical working ability.

[0047] When the frequency of local peristalsis in the intestine is low, the diameter of the intestinal lumen is large, or the pressure accumulation is insufficient, the sheet-like ultra-fast expanding hydrogel 14 can provide significant volume expansion and internal thrust in a short time, pushing the two microneedle drug delivery units 18 to expand outward, so that the microneedle array can make more full contact with the intestinal wall, thereby achieving active compensation for insufficient external mechanical stimulation.

[0048] As intestinal peristalsis continues and external pressure accumulates further, the internal thrust generated by the expansion of the ultra-rapid hydrogel, together with the external intestinal pressure, acts on the controllable rupture shell, causing the shell to reach the failure threshold and undergo local cracking, forming the central expansion unit 21 after local rupture. At this time, the internal hydrogel gradually overflows, fully contacts the intestinal fluid, and accelerates decomposition, forming an overflowing and decomposed ultra-rapidly expanding hydrogel 22. Since the rupture of the controllable rupture shell is a local crack rather than a complete fragmentation, the two microneedle drug delivery units 18 remain connected as a whole and maintain the function of puncturing and delivering drugs, ultimately realizing the sequential process of expansion-puncture-rupture-disintegration.

[0049] VI. Performance Verification and Effect Description Material mechanical property verification: Mechanical characterization was performed on the key materials constituting the clustered microneedle robot. The results of the material mechanical property verification are as follows: Figure 8 As shown, the tensile test of the polyvinyl alcohol base film yielded a Young's modulus of approximately 470 kPa, with a strain range from 0 to 1, indicating high strength and good support capacity. The tensile test of the controllable fracture shell material yielded a Young's modulus of approximately 91 kPa, with a strain range from 0 to 3, exhibiting moderate strength and high ductility. It can effectively adapt to the volume expansion caused by the strong expansion capacity of the ultra-fast hydrogel, as well as local fracture rather than overall failure under the combined action of internal and external factors. The compression test of the ultra-fast expanding hydrogel yielded a Young's modulus of approximately 3 kPa, exhibiting low modulus and large deformation characteristics, making it suitable as a driving material.

[0050] Verification under drying-rehydration cycle conditions: The mechanical performance of the polyvinyl alcohol base film and the controllable fracture shell was compared in the original wet state and the dried and rehydrated state. The results showed that the tensile strength of the base film increased after dehydration and rehydration; the ultimate strength of the controllable fracture shell remained basically stable in both states, but the tensile strain decreased significantly. These results indicate that the shell material of this invention can balance basic load-bearing capacity with more easily triggered local fracture characteristics under dry storage and rehydration initiation conditions.

[0051] Overall expansion and degradation behavior verification. Mass changes and morphological evolution of the clustered microneedle robots in simulated intestinal fluid, as shown in... Figure 9 As shown, the clustered microneedle robot 19 was placed in artificial simulated intestinal fluid at 37°C, and a mass-time test was conducted with an experimental cycle of 72 hours. The results showed that the overall mass of the stationary robot rapidly increased from 0 to 3 hours, reached swelling equilibrium from 3 to 6 hours and remained relatively stable, and then slowly decreased after 6 hours as the hydrogel inside the central expansion unit gradually overflowed and fragmented. Morphological observation further indicated that the central controllable fracture shell could crack in an early stage, while the robot as a whole remained basically intact during this stage. The overall volume only decreased significantly after the hydrogel gradually disintegrated in the later stage.

[0052] Independent performance verification of the ultra-rapidly expanding hydrogel. The expansion, fragmentation, and degradation process of the ultra-rapidly expanding hydrogel of this invention in simulated intestinal fluid is as follows: Figure 10 As shown, when the sheet-like ultra-rapidly expanding hydrogel 14 was placed alone in artificial simulated intestinal fluid at 37°C, it was found that it rapidly absorbed liquid and expanded within 0 to 20 minutes, reached its maximum mass and maintained its intact structure in about 20 minutes to 1 hour, and gradually crumbled and showed a decrease in mass after 1 hour. These results indicate that the ultra-rapidly expanding hydrogel possesses both rapid early-stage functional capabilities and late-stage degradability.

[0053] In vitro pressure simulation verification. The morphological changes of the clustered microneedle robot of this invention during in vitro pressure simulation verification are as follows: Figure 11 As shown, a negligible-weight plastic sheet was used as a simulated intestinal wall sheet, and the intestinal peristalsis environment was simulated by loading weights and manually controlling the contraction-relaxation rhythm. Under simulated weak-pressure peristalsis, a 50-gram weight, a frequency of 10 times / minute, and a contraction-relaxation time ratio of 3:7 were used; under simulated low-frequency peristalsis, a 100-gram weight, a frequency of 5 times / minute, and a contraction-relaxation time ratio of 3:7 were used; under simulated normal peristalsis, a 100-gram weight, a frequency of 10 times / minute, and a contraction-relaxation time ratio of 3:7 were used. Experimental results show that in the insufficient pressure stage, the central expansion unit can still expand the overall robot volume to more than twice its original dry volume within approximately 8 minutes; after switching to normal peristalsis, the controllable rupture shell can locally crack within a short time, and the internal hydrogel overflows, while the upper and lower microneedle drug delivery units remain intact. This indicates that the present invention can complete the switching between active compensation and controllable rupture stages under different intestinal pressure conditions.

[0054] Simulation verification. Based on the material mechanics parameters obtained from experiments, a structural model including the intestinal wall region 23, the microneedle contact area 24, and the central expansion element 25 was constructed on a finite element platform, as follows: Figure 12 As shown in the figure. The simulation employs time-dependent analysis of solid mechanics, equating the expansion processes of sheet-like hydrogels and sheet-like ultra-rapidly expanding hydrogels to time-dependent thermal expansion. Analytical functions are constructed based on real experimental data curves to describe their expansion processes over time. Boundary loads are used to simulate the periodic pressure outside the intestine. Analysis of the overall displacement field, equivalent stress field, and local high-stress zones verifies the driving effect of the central expansion unit on the microneedle drug delivery unit, the mechanical conditions for microneedle penetration into the intestinal wall, and the feasibility of controlling the rupture of the outer shell to achieve the failure condition.

[0055] The present invention has been described in detail above through embodiments, but the content described is only an exemplary embodiment of the present invention and should not be considered as limiting the scope of the present invention. The scope of protection of the present invention is defined by the claims. Any technical solutions designed by those skilled in the art using the technical solutions described in the present invention, or similar technical solutions designed by those skilled in the art under the inspiration of the technical solutions of the present invention, within the substance and scope of protection of the present invention, to achieve the above-mentioned technical effects, or equivalent changes and improvements made to the scope of the application, should still fall within the patent protection scope of the present invention. It should be noted that, for clarity, descriptions of some components and processes that are not directly and obviously related to the scope of protection of the present invention but are known to those skilled in the art have been omitted in the description of the present invention.

Claims

1. A clustered microneedle robot with adaptive intestinal pressure sensing, characterized in that, include: A microneedle drug delivery unit includes a drug-loaded microneedle, a microneedle base, and a sheet-like hydrogel. The drug-loaded microneedle is located on the microneedle base, and the microneedle base has grooves. The grooves of the microneedle base are filled with sheet-like hydrogel. The central expansion unit includes a ring-shaped controllable fracture outer shell sidewall structure and an upper isolation layer and a lower isolation layer. The controllable fracture outer shell sidewall structure is bonded to the upper isolation layer and the lower isolation layer in situ, and the closed cavity formed is filled with sheet-like ultra-fast expanding hydrogel. The intermediate expansion unit is located between the two microneedle drug delivery units. The two microneedle drug delivery units are respectively bonded in situ to the upper and lower isolation layers of the intermediate expansion unit to encapsulate the sheet-like hydrogel filling the groove of the microneedle substrate.

2. A method for preparing the clustered microneedle robot according to claim 1, characterized in that, Includes the following steps: S1, respectively fabricate the drug-loaded microneedles, the microneedle substrate, the sheet-like hydrogel, the sheet-like ultra-rapid expansion hydrogel, the upper isolation layer, and the lower isolation layer; S2, the microneedle base is fabricated based on the drug-loaded microneedle, and the sheet-like hydrogel is filled into the groove of the microneedle base to obtain the microneedle drug delivery unit; S3, fabricate the controllable fracture shell sidewall structure, bond the upper and lower isolation layers to the controllable fracture shell sidewall structure in situ, and encapsulate the sheet-like ultra-fast hydrogel inside the controllable fracture shell sidewall structure to obtain the central expansion unit; S4, the upper and lower isolation layers of the central expansion unit are respectively bonded to the microneedle substrates of the two microneedle drug delivery units in situ, and the sheet-like hydrogel is encapsulated to obtain a clustered microneedle robot.

3. The method according to claim 2, characterized in that, The drug-loaded microneedles are fabricated as follows: a drug-loaded microneedle raw material solution is prepared using 60% by mass of polyethylene glycol diacrylate with an average molecular weight of 600, 60% by mass of polyethylene glycol with an average molecular weight of 4000, and 2% by volume of 2-hydroxy-2-methylphenylacetone. The mass ratio of polyethylene glycol diacrylate to polyethylene glycol is 0.5:1 to 2:

1. The drug solution is then added to the drug-loaded microneedle raw material solution and mixed. Finally, the drug-loaded microneedles are fabricated in a mold using a photocrosslinking method.

4. The method according to claim 2, characterized in that, A polyvinyl alcohol solution with a mass fraction of 20% and an average molecular weight of 95,000 was used as the raw material solution for the microneedle substrate and the isolation layer. When preparing the raw material solution, polyvinyl alcohol was added to deionized water and stirred in a water bath at 85-90°C until a homogeneous and transparent solution was formed.

5. The method according to claim 2, characterized in that, The sheet-like hydrogel is prepared as follows: a solution of sodium carboxymethyl cellulose with a mass fraction of 3% and citric acid with a mass fraction of 0.2% is used to prepare the sheet-like hydrogel raw material; the sheet-like hydrogel raw material is stirred thoroughly until it is free of gel, placed in a petri dish and pressed into a gel-like sheet, and then dried and cut into sheet-like hydrogel sheets.

6. The method according to claim 2, characterized in that, A controllable fracture shell sidewall structure raw material solution was prepared using 7% polyvinyl alcohol with an average molecular weight of 95,000, 2% acrylamide, 0.02%–0.04% N,N'-methylenebisacrylamide, and 0.04%–0.08% 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone. During the preparation process, the mixed solution of polyvinyl alcohol, acrylamide, and N,N'-methylenebisacrylamide was first placed in a water bath at 85–90°C and stirred. After complete dissolution, it was cooled to room temperature, and then the remaining components were added and stirred thoroughly.

7. The method according to claim 2, characterized in that, The specific steps for creating ultra-fast expanding hydrogels are as follows: An acidic component solution for the ultra-rapid expansion hydrogel was prepared using a 15%–25% (w / w) acetic acid solution, a 5%–10% (w / w) acrylamide solution, a 0.2%–0.6% (w / w) N,N'-methylenebisacrylamide solution, and a 1%–3% (w / w) gelatin solution, with an acetic acid to acrylamide mass ratio of 2:1 to 4:

1. To prepare the acidic component solution, the gelatin was first placed in a water bath at 50–60°C and stirred until fully dissolved. After cooling to room temperature, the remaining components were added and stirred thoroughly. A saturated sodium bicarbonate solution was used as the alkaline component solution for the ultra-rapid expansion hydrogel, and 0.1%–0.2% (w / w) 2-hydroxy-1-[4-(2-hydroxyethoxy)phenyl]-2-methyl-1-propanone was added as a photoinitiator. Using a dual-barrel syringe system, the acidic and alkaline components of the ultra-fast expanding hydrogel were placed in two separate syringes and mixed through the mixing end of the dual-barrel syringe. After the reaction, a stable foam was rapidly generated. The foam was then spread evenly and cured by UV irradiation at room temperature to obtain a dense gel-like sheet. The sheet was then placed in anhydrous ethanol for solvent replacement, removed, dried under ambient conditions, and cut into sheet-like ultra-fast expanding hydrogels.

8. The method according to claim 2, characterized in that, A 5% polyvinyl alcohol solution was used as the in-situ adhesive.

9. The method according to claim 2, characterized in that, The fabrication of the microneedle substrate, upper isolation layer, lower isolation layer, controllable fracture outer shell sidewall structure, and the in-situ bonding treatment all adopt the freeze-thaw cycle method.

10. The application of the clustered microneedle robot according to claim 1, characterized in that, The clustered microneedle robot is placed in an enteric-coated capsule as an oral medication.

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