Implantable microneedle anastomosis stent as well as preparation method and application thereof

Abstract

The invention discloses an implantable microneedle anastomosis stent as well as a preparation method and application thereof. The implantable microneedle anastomosis stent is composed of a stent body and a microneedle array loaded with medicine. The middle part of the stent main body is of a tubular structure, and two ends are gradually expanded to facilitate anastomosis and fixation; the micro-needle array loaded with the medicine is coated outside the stent main body; the invention aims to treat diseases and promote the healing of the intestinal anastomotic stoma through precise local drug delivery, and has wide clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of biomedical implants and drug delivery technology, specifically an implantable microneedle anastomosis stent and its preparation method, as well as its application in the preparation of postoperative adjuvant treatment devices for resectable intestinal diseases, which can realize postoperative intestinal anastomosis and local drug delivery. Background Technology

[0002] The treatment of intestinal diseases, particularly colorectal cancer, Crohn's disease, and ulcerative colitis, has become a significant public health issue worldwide. For severe cases that are difficult to control with non-invasive treatments, bowel resection is considered the gold standard, removing diseased tissue and re-establishing intestinal anastomoses. However, the success of bowel anastomosis depends not only on precise surgical techniques but also on comprehensive postoperative management, especially the effective implementation of postoperative adjuvant therapy. The goal of postoperative adjuvant therapy is to enhance recovery and reduce complications through optimized drug treatment regimens and meticulous care. Postoperative drug therapy is particularly important in this process, helping to prevent disease recurrence and further manage intestinal inflammation or damage.

[0003] While existing systemic drug administration (such as oral and injectable medications) has made some progress in alleviating inflammation and reducing relapses, many challenges remain. First, medication adherence is a common problem, with patients often failing to take medications as prescribed, leading to reduced efficacy. Second, drug absorption is often uneven, especially after bowel resection, where digestive function is impaired, further limiting efficacy. Finally, drug side effects and toxicity remain major concerns with systemic administration, often causing discomfort and worsening the condition. Therefore, existing drug treatments, especially systemic administration, suffer from limited efficacy and significant side effects, urgently requiring a more precise and localized drug delivery method.

[0004] In intestinal anastomosis, traditional manual suturing remains the most common method. However, this method is not only technically demanding and cumbersome, but also prone to postoperative complications such as anastomotic leakage, anastomotic stenosis, and local infection. Although some innovative anastomosis techniques, such as bioadhesive patches, sealants, and anastomotic stents, have been proposed and achieved some clinical application results, these techniques mainly focus on the closure and sealing of the anastomosis, lacking effective postoperative drug treatment options, especially in promoting anastomotic healing and preventing local inflammation. Particularly after intestinal surgery, due to damage to the intestinal mucosa and impaired drug absorption, existing drug delivery methods often fail to achieve ideal therapeutic effects. While some studies have attempted to achieve local drug treatment through implantable drug delivery systems, these systems face challenges related to mucosal barriers, the timeliness of drug release, and biocompatibility. Furthermore, in traditional post-anastomosis treatments, although intravenous infusion can be an effective treatment in the short term, it cannot precisely target specific areas and has a low therapeutic index. Long-term use still suffers from problems such as short-lasting drug efficacy and patient intolerance.

[0005] Therefore, developing an innovative implantable drug delivery system capable of postoperative local drug delivery, precise drug release, and promotion of anastomotic healing has become an urgent need in intestinal surgery. Current research mainly focuses on improving anastomosis techniques and reducing anastomosis failure, but research on postoperative drug delivery systems remains scarce, especially implantable devices with high-precision drug release capabilities. Although some intestinal implantable systems have attempted to address the problem of local drug delivery, these systems still face many technical challenges due to the influence of the mucosal barrier on drug transport, the issue of on-demand release of stimulus-responsive drugs, and the problem of ensuring biocompatibility. Therefore, developing an implantable microneedle anastomosis scaffold that can meet the requirements of precise drug delivery after intestinal anastomosis, has high safety, and good biocompatibility has become a current research hotspot and challenge. Summary of the Invention

[0006] To address the problems of time-consuming and labor-intensive traditional manual anastomosis surgery, numerous complications, poor postoperative drug delivery accuracy, and low therapeutic index, this invention provides an implantable microneedle anastomosis scaffold, its preparation method, and its application. This scaffold can be used for postoperative intestinal anastomosis and local drug release, and is particularly suitable for the treatment of resectable intestinal lesions and intestinal diseases related to anastomotic inflammation.

[0007] The main body of the stent of this invention is manufactured using 3D printing technology, and has an adjustable size and structure to adapt to different clinical application scenarios. The stent is externally mounted with a biodegradable drug-loaded microneedle array. These microneedles can penetrate the intestinal mucosa layer, achieving localized controlled release of the drug at the lesion site, thereby achieving an effective therapeutic effect.

[0008] The technical solution of the present invention is as follows: An implantable microneedle anastomosis stent (MAS) consists of a stent body and a drug-loaded microneedle array; The middle part of the main body of the support is a tubular structure, and the two ends gradually expand to facilitate fitting and fixation. Preferably, the two ends are funnel-shaped openings. The drug-loaded microneedle array is wrapped around the outside of the stent body, preferably around the central tubular structure of the stent body; The scaffold body is made of a biodegradable polymer selected from one or more of the following: polyglycolic acid, polylactic acid-glycolic acid copolymer, polylactic acid, polycaprolactone; preferably polyglycolic acid with good biodegradability and biocompatibility. The drug-loaded microneedle array uses a biodegradable polymer as the microneedle body and loads the drug through chemical bonding or physical mixing; wherein, the biodegradable polymer is, for example, polyvinyl alcohol, polylactic acid, polycaprolactone, polyhydroxyalkanoates, etc.; the drug is selected from one or more of the following: Small molecule drugs, such as olsalazine (Os), mesalazine, sulfasalazine, etc. Protein drugs, such as anti-tumor necrosis factor α Antibodies or anti-interleukin-12 / 23 antibodies, etc.; Nucleic acid drugs, such as small interfering RNA, messenger RNA, and circular RNA; Nanomedicines, such as nanoparticles, nanoantibodies, and nanocarriers; Active pharmaceutical ingredients, such as probiotics, Salmonella, and yeast cells.

[0009] Furthermore, the microneedle body can be one or more of the following: Drugs modified with phenylboronic acid are used as cross-linking agents and combined with polyvinyl alcohol to form polymer prodrug microneedles; The microneedle body is formed by combining tris(4-sulfophenyl)boronic acid as a crosslinking agent with polyvinyl alcohol; The microneedle body is formed by combining terephthalic acid as a crosslinking agent with polyvinyl alcohol.

[0010] Furthermore, in the drug-loaded microneedles, the drug-modified phenylboronic acid groups react with polyvinyl alcohol to form a three-dimensional network structure, and the microneedles have a stimulus-responsive drug release function; for example, the drug selected is the clinical anti-inflammatory drug Os, whose carboxyl groups at both ends are modified with phenylboronic acid groups to act as cross-linking agents; the phenylboronic acid groups are modified to 4-(bromomethyl)phenylboronic acid, which undergoes a nucleophilic reaction with Os to generate a disubstituted product.

[0011] The method for preparing the implantable microneedle anastomosis scaffold of the present invention includes: (1) Preparation of the scaffold body The scaffold body was prepared using biodegradable polymers as raw materials through hot melt extrusion and 3D printing. For example, using a high-temperature melt extrusion 3D printing device, polyglycolic acid powder is added into the printing cylinder, heated to a molten state, and extruded through a nozzle under a set pressure to obtain the main body of the support structure. The size and structure of the main body of the support can be customized according to actual needs; the parameters of the support for small animal experiments are: length 10mm, diameter of the tubular structure in the middle 2.25mm, and diameter of the flared openings at both ends 3.25mm. (2) Preparation of drug-loaded microneedle arrays A drug and a biodegradable polymer are dispersed in a solvent to form a drug-loaded polymer precursor solution, which is then injected into a mold and subjected to molding and curing processes to form a microneedle array structure. The curing process may include one or more of the following: vacuuming, pressurizing, centrifugation, drying, or lyophilization. The target drug or its precursor drug can be directly loaded through physical mixing, or a drug or drug precursor modified with specific functional groups can be obtained through chemical reactions to achieve subsequent drug loading or cross-linking functions. For example: Select the target drug Os, and chemically modify the drug by reacting 4-bromomethylphenylboronic acid with the carboxyl groups at both ends of Os to form a phenylboronic ester bond structure. The reaction conditions are: dimethylformamide as solvent, potassium carbonate as alkaline catalyst, room temperature, and 24 hours to obtain an Os prodrug solution; mix an equal volume of 1-10 mg / mL Os prodrug solution with a 2%-10% (w / w) polyvinyl alcohol solution, and quickly blow it evenly to form a homogeneous drug-loaded polymer precursor solution (the concentration can be adjusted according to the drug loading and release time). The molded microneedles can be pyramidal, conical, cylindrical, or other shapes. The array arrangement can be customized according to requirements. The amount of precursor solution is determined according to the cavity volume of the microneedle mold to ensure that the microneedle cavity is completely filled and forms a complete needle structure. Specifically, small microneedles require at least 2.4 ml of pre-solution, while large microneedles require at least 240 ml of pre-solution. When the microneedles in the microneedle array are pyramidal, their base width is 100–400 μm, their height is 150–900 μm, and their tip spacing is 150–800 μm. Specifically, a standard microneedle array consists of 20×20 microneedles, with a base width of approximately 400 μm, a tip spacing of approximately 800 μm, and a height of approximately 900 μm, and the microneedle patch size is approximately 16 mm×16 mm; a small microneedle array consists of 98×98 microneedles, with a base width of approximately 100 μm, a tip spacing of approximately 150 μm, and a height of approximately 150 μm, and the patch size is approximately 20 mm×20 mm; a large microneedle array consists of 100×100 microneedles, with a base width of approximately 400 μm, a tip spacing of approximately 800 μm, and a height of approximately 900 μm, and the patch size is approximately 79.2 mm×79.2 mm. (3) Assemble implantable microneedle anastomosis scaffold The drug-loaded microneedle array prepared in step (2) is fixed to the outside of the scaffold body in step (1) to form an integrated implantable microneedle anastomosis scaffold. Drug-loaded microneedle arrays can be fixed to the middle or other parts of the scaffold body through adhesion, coating, embedding, or cross-linking. Specifically, the microneedle array is cut to a matching size and then coated onto the middle of the scaffold using a precursor mixture solution or biological adhesive (such as biomedical glue). After coating, it is dried and cured under constant temperature conditions to firmly bond the microneedle array with the scaffold, forming an integral structure. For small animal experiments, the microneedle array can be designed as an approximately 22×60 array structure; for large animal experiments, the array can be an approximately 15×80 structure to match intestinal anastomosis scaffolds of different sizes. The resulting integrated microneedle intestinal anastomosis scaffold has good structural stability and drug loading uniformity, enabling local drug sustained release and anastomosis assistance functions.

[0012] The performance tests of the implantable microneedle anastomosis scaffold (MAS) described in this invention are as follows: Performance testing included radial strength measurements and a simulated intestinal leakage prevention experiment.

[0013] Radial strength tests were performed on the simple support and MAS using a static material testing machine (ZwickRoell, ProLine Z10), specifically including compression and tensile tests.

[0014] In the compression test, the specimen is placed in the center of the sample fixture, and the force value when the support buckles is recorded during the compression process.

[0015] Specifically, the load cell capacity, initial gap, and displacement rate are set as follows: For 3D printed simple scaffolds and MAS, the load cell capacity is set to 200 N, the initial gap is about 5 mm, and the displacement rate is 1 mm / min; for commercial scaffolds and MAS, the load cell capacity is set to 10 kN, the initial gap is about 22 mm, and the displacement rate is 5 mm / min.

[0016] In the tensile test, two steel wires are passed through the center of the support, and the two ends of the steel wires are knotted and fixed to the test device. Forces are applied to each wire, and the force value when the support breaks is recorded.

[0017] Specifically, preloads of 6 N and 20 N were applied at loading rates of 5 mm / min and 20 mm / min, respectively.

[0018] A microfluidic device was used to simulate intestinal leakage prevention experiments, with either a simple scaffold or a minimally invasive stent (MAS) and surgical sutures serving as the control group. Piglet intestinal segments were cut with a scalpel and reconnected using sutures, a simple scaffold, or a MAS, respectively. Both ends of the intestine were fixed to the incision ends of 15 mL centrifuge tubes. Holes were drilled in the centrifuge tube caps and connected to a 10 mL syringe, with an additional hole at the bottom for liquid outflow.

[0019] Specifically, phosphate-buffered saline (PBS) was injected into the syringe, and the flow rate of the microfluidic device was set to 1 mL / min, with a total volume of 10 mL. After starting the microfluidic device, PBS was collected at 0, 3, 5, 7, and 10 minutes, and the cumulative volume was calculated by weighing.

[0020] The drug delivery system of the implantable microneedle anastomosis stent described in this invention includes the following functions: (1) Stimulus-responsive drug delivery system The drug delivery system comprises an inflammatory stimulus-responsive release structure based on an Os polymer prodrug microneedle array. The microneedle array is fabricated by adjusting the volume ratio of the Os prodrug solution to the polymer matrix solution (e.g., 1:0.5, 1:1, or 1:2), enabling controlled drug release in an environment containing an oxidizing stimulus, such as hydrogen peroxide (H₂O₂). The drug release process is modulated by changes in external oxidative conditions, thereby achieving dynamic control of the drug release rate.

[0021] The drug release of microneedle arrays with different proportions over time was evaluated in 1 mM H2O2 solution. The concentration-dependent release and degradation behavior of the microneedle arrays at different hydrogen peroxide concentrations (0, 0.1, 1, 10 mM) was investigated. Pulsed release experiments, conducted by alternating exposure to PBS and 1 mM H2O2 solution (1 hour per cycle), demonstrated that the system can achieve periodic, pulsated drug release behavior.

[0022] (2) Application of drugs to inflamed tissues and drug release behavior

[0023] The drug delivery system based on Os polymer prodrug microneedle array can achieve local release of drugs and penetration delivery of drugs into the intestinal mucosa in tissue microenvironments of different types or severities of inflammation.

[0024] Large-sized microneedle patches were selected, which can be directly attached to postoperative lesions in patients, including mildly and severely inflamed intestinal mucosa areas, to evaluate adhesion and drug release behavior in inflamed tissues of patients with intestinal diseases. Intestinal mucosal layer permeation experiments were conducted using microneedle patches physically mixed with fluorescein isothiocyanate, with a corresponding Os polymer prodrug membrane serving as a control group, to verify the effect of the microneedle structure on enhancing drug tissue permeability.

[0025] (3) Multi-type drug loading platform

[0026] The drug delivery system is compatible with various types of drugs loaded into microneedle arrays, including small molecule drugs, protein drugs, nanomedicines, and bioactive biological carriers. Drugs are loaded into the microneedle array by mixing drug solutions, suspensions, or drug particles with a polymer matrix solution of the microneedle array, using methods such as impregnation, vacuum adsorption, chemical covalent bonding, or physical adsorption.

[0027] Small-sized microneedle patches loaded with different types of drugs were prepared using previously established methods. In the final drying step, when the solution was almost dry but the needles were still covered, different drug solutions were added, including fluorescently labeled protein drugs (IgG-FITC), nanomedicines (LNPs-FITC), and bioactive drugs (such as Salmonella VPN20009). When the nanomedicines were lipid nanoparticles, nucleic acid drugs could also be loaded.

[0028] The implantable microneedle anastomosis scaffold described in this invention can be used to prepare postoperative treatment devices for intestinal diseases. The evaluation method for its application effect is as follows: (1) Therapeutic application and efficacy evaluation of radiation colitis model Microneedle intestinal anastomosis stents can be used to treat radiation-induced colitis in mice, primarily by promoting postoperative anastomosis and local drug delivery to relieve inflammation. Specifically, a mouse model of radiation-induced colitis was established by irradiating the intestinal tract with X-rays (e.g., 225 kV, 17.7 mA, 8 Gy). Three days prior to surgery, mice were given a residue-free liquid diet to cleanse the intestines before resection of the colonic lesions and stent anastomosis. Experimental animals were divided into four groups: suture group, suture + oral medication group, stent alone group, and MAS group.

[0029] In the suture + drug group, an equimolar amount of Os solution (0.47 mg / animal) containing the drug in the microneedle patch was administered orally. In the stent-only group and the MAS group, corresponding stents were implanted at the anastomosis site postoperatively. Postoperatively, the animals were fed liquid diets and received intramuscular injections of ceftriaxone sodium (100 mg / kg) for anti-infection treatment.

[0030] On postoperative day 7, H&E staining was performed on the anastomosis site and major organ tissues to assess the degree of inflammation. The anastomosis site tissues were then... γ -H2AX and COX-2 immunofluorescence staining, and TNF-α α Immunohistochemical detection of IL-6. Tissue samples from the implantation site of the MAS group were collected on postoperative days 1, 3, 7 and 14. H&E staining and immunohistochemical analysis of tight junction protein-1 (ZO-1) and cadherin type E were performed to assess epithelial repair and barrier integrity.

[0031] (2) Therapeutic application and efficacy evaluation of ischemic inflammatory injury model

[0032] Microneedle intestinal anastomosis scaffolds can be used to treat ischemic inflammatory damage to the intestines of miniature pigs. Specifically, an ischemic intestinal injury model was established using adult miniature pigs (approximately 25–30 kg). Local ischemia was induced by severing and clamping the four mesenteric vessels supplying the small intestine for 45 minutes, followed by resection of the degenerated and necrotic dark red intestinal segment. Experimental animals were divided into a conventional suture group, a suture + oral Os group, a scaffold alone group, and a MAS group as controls.

[0033] The suture + Os group received an equimolar amount of Os (41.21 mg / head) orally, equivalent to the amount of medication in the microneedle patch, serving as a systemic drug control. The stent-only group and the MAS group underwent implantation of a biodegradable, commercially available polyglycolic acid / barium sulfate composite stent at the anastomosis site. To prevent postoperative infection, ceftriaxone sodium (100 mg / kg) was administered intramuscularly every other day.

[0034] On postoperative day 7, CT imaging was performed to assess the structure of the implanted stent and the anastomosis site. On postoperative day 8, the animal was euthanized and a segment of intestine was harvested for H&E staining to assess anastomotic healing and tissue repair.

[0035] The beneficial effects of this invention are as follows: 1. Precise local treatment: The implantable microneedle anastomosis stent of this invention can accurately deliver drugs to the intestinal anastomosis site, avoiding the side effects of traditional systemic drug administration, realizing the precise release of drugs where they are needed, and improving the treatment effect.

[0036] 2. Controllable drug release: The stimulation-responsive drug release mechanism of the microneedle array enables the drug to be released automatically according to the degree of local inflammation, avoiding the problems of drug overdose or uneven release, and providing a safe and effective treatment option.

[0037] 3. Reduced Operational Complexity: Compared to traditional manual suture anastomosis, this invention reduces sutures, simplifies surgical procedures, and decreases the need for specialized personnel. This stent enables precise drug delivery without complex medical procedures, making it suitable for widespread clinical application, especially for postoperative patient self-management.

[0038] 4. Reduced risk of drug burst release: The microneedle system of this invention avoids the drug burst release phenomenon that may occur in traditional drug delivery methods through a stimulus-responsive drug release mechanism, ensuring long-term stable drug release and improving patient medication safety.

[0039] 5. Wide applicability: This device can provide local and efficient drug delivery, and is suitable for postoperative adjuvant treatment of various intestinal diseases. It can also provide precise treatment in different clinical scenarios, and has significant advantages in preventing complications after intestinal anastomosis.

[0040] 6. Optimize traditional treatment methods: This invention optimizes and replaces traditional intestinal anastomosis treatment methods, while improving treatment outcomes and reducing postoperative complications. It provides an innovative and highly operable postoperative treatment plan with broad clinical application prospects. Attached Figure Description

[0041] Figure 1 : Schematic diagram of the drug preparation process of Embodiment 1 of the present invention. a) Schematic diagram of the synthesis process of Os prodrug, with the inset showing the synthesized Os prodrug solution. b) Schematic diagram of the synthesis process of polymer prodrug, with the inset showing the synthesized polymer prodrug solution.

[0042] Figure 2Characterization of the microneedles and MAS in Embodiment 1 of the present invention. a) Characterization of polymer prodrug microneedle patches: i) Photograph of the polymer prodrug microneedle patch (scale bar, 100 μm); ii) Scanning electron microscope (SEM) image of the microneedle array (scale bar, 100 μm); iii) Magnified view of a single microneedle (scale bar, 50 μm). b) Characterization of large-size polymer prodrug microneedles: i) Photograph of the polymer prodrug microneedle patch (scale bar, 500 μm); ii) SEM image of the polymer prodrug microneedle (scale bar, 500 μm); iii) Magnified view of a single microneedle (scale bar, 500 μm). c) Morphological characterization of MAS: i) Digital photograph of the prepared polymer prodrug MAS (scale bar, 2 mm); ii) SEM image of the MAS (scale bar, 1 mm); iii) SEM image of the microneedle array on the MAS (scale bar, 200 μm).

[0043] Figure 3 Performance test results of Embodiment 1 of the present invention. a) Radial compression test curves of the stent and MAS. The first two are 3D printed stent and MAS, and the last two are clinically approved stent and MAS; the inset shows photographs of the test. Fmax represents the maximum force that the stent / MAS can withstand during the test. b) Radial tensile test curves of the stent and MAS. The first two are 3D printed stent and MAS, and the last two are clinically approved stent and MAS; the inset shows photographs of the test. Fmax represents the maximum force that the stent / MAS can withstand during the test. c) Schematic diagram of the radial compressive force (RCF) and radial tensile force (RTF) measurement system of MAS. d) Quantification of RCF and RTF of stent and MAS in 3D printed (S) and clinically approved (L) configurations (n=3). e) Schematic diagram of intestinal leakage prevention simulation based on microfluidic device, where leakage occurs at the suture site (a) and the other end of the intestine (b). f) Weight of PBS flowing out from site b at different time points (n=3). The stent group and MAS group used clinically approved intestinal anastomosis stents. Data are expressed as mean ± standard deviation.

[0044] Figure 4Example 2 of this invention presents the results of drug release and degradation. a) Polymer prodrugs exhibiting H2O2-responsive release behavior. Phenylboronic acid ester bonds can be broken through oxidation and hydrolysis processes, thereby releasing Os. b) Drug release kinetics of polymer prodrug microneedles with three different formulations. c) Cumulative drug release curves of polymer prodrug microneedle patches in PBS at different H2O2 concentrations (n=3). d) Micrographs showing the change in microneedle morphology over time. Single-row polymer prodrug microneedles were incubated in PBS with different H2O2 concentrations and photographed at 0, 12, and 24 hours (n=3). Scale bar, 100 μm. e) SEM images of polymer prodrug MAS and microneedle arrays after incubation in 1 mM H2O2 for 1, 3, and 14 days. Scale bar, 1 mm (top); Scale bar, 100 μm (bottom). f) Pulsed release curves of polymer prodrug microneedle patches in PBS with and without H2O2 (n=3). Blue indicates 0 mM, and purple indicates 1 mM.

[0045] Figure 5 Results of the application of this invention to inflamed tissue in Example 2. a) Digital photographs of polymer prodrug microneedle patches applied to intestinal tissue of Crohn's disease patients. Normal tissue was treated with conventional polymer prodrug microneedles, while inflamed tissue was treated with RhB-loaded polymer prodrug and PVA microneedles. Scale bar, 5 mm. Red triangles indicate tissue type, and green triangles indicate microneedle type. b) Heating and epithelial (H&E) images of intestinal tissue of Crohn's disease patients after microneedle administration. i) Polymer prodrug microneedles for normal tissue of colorectal cancer patients; ii) Polymer prodrug microneedles for inflamed tissue; iii) PVA microneedles for inflamed tissue. Scale bar, 1 mm. Black arrows and labels indicate microneedle holes. c) Cumulative prodrug release curves (n=3) after polymer prodrug microneedles were applied to different intestinal tissues of Crohn's disease patients. d) Representative fluorescence microscopy images of FITC release and distribution of polymer prodrug films and microneedle patches 2 hours after insertion, applied to low-inflammatory and high-inflammatory intestinal tissues of Crohn's disease (10 years and 2 months) and radiation enteritis patients, respectively. Scale bar, 2 mm. e) Quantitative analysis of the FITC fluorescence intensity released from polymer prodrug microneedles and films under low-inflammatory and high-inflammatory conditions.

[0046] Figure 6Example 2 of this invention describes a multi-type drug loading platform. a) Confocal image of the polymer prodrug microneedle patch (blue: polymer prodrug) loaded with model protein (yellow: IgG-FITC), nanoparticles (green: LNP-FITC), and bacteria (red: Salmonella-Cy5). Scale bar, 50 μm. b) Circular dichroism (CDD) spectra of IgG and IgG released from microneedles in PBS. c) Circular dichroism (CDD) spectra of IgG and IgG released from microneedles in PBS containing 0.1 mM H2O2. d) Dynamic light scattering results of LNPs and their release in PBS. e) Dynamic light scattering results of LNPs and their release in PBS containing 0.1 mM H2O2. f) Colony photographs of Salmonella released from the polymer prodrug microneedle patch on LB agar plates (n=3). g) Corresponding colony counts of Salmonella (n=3).

[0047] Figure 7 Example 3 of this invention describes the results of its application in treating radiation-induced colitis in mice. a) Schematic diagram of the treatment process of the polymer prodrug MAS in a mouse model of radiation-induced colitis. b) Digital photograph of the mouse colon after stent implantation. c) H&E histological scores of colon tissue at the implantation site in mice after radiation (n=4). Black arrows and labels indicate specific features. d) γ-H2AX immunofluorescence staining statistics (n=4); e) COX-2 immunofluorescence staining statistics (n=4). f) IL-6 immunofluorescence staining statistics (n=4); g) TNF-α immunofluorescence staining statistics (n=4). Scale bar, 100 µm. 3D-printed intestinal anastomosis stents were used in both the stent group and the MAS group. h) H&E staining for mucosal regeneration. i) IHC staining for ZO-1 in barrier repair. j) IHC staining for E-cadherin in barrier repair. Samples are intestinal sections collected at 1, 3, 7, and 14 days after MAS implantation. Black arrows and labels indicate specific features or processes. Scale bar, 100 μm.

[0048] Figure 8Example 3 of this invention describes the treatment results of ischemic inflammatory bowel injury in miniature pigs. a) Schematic diagram of the treatment process of a miniature pig model of ischemic inflammatory bowel injury using polymeric prodrug MAS. b) Digital photograph of the MAS used for implantation into the intestine of miniature pigs. c) CT images of miniature pigs after different treatments (day 7). Arrows and labels indicate pathological features, stent / MAS, and intestine. d) H&E images of miniature pigs on day 7 after different treatments. Black arrows and labels indicate specific features. Scale bar, 100 µm. e) Statistical data on mean villus length and villus number in the same area (n=3). f) Changes in hs-CRP levels in the blood of miniature pigs after different treatments (n=3). The stent group and MAS group used clinically approved intestinal anastomosis stents.

[0049] Figure 9 : Schematic diagram of the preparation method of MAS of the present invention.

[0050] Figure 10 : Schematic diagram of the application of MAS in intestinal diseases according to the present invention. Detailed Implementation

[0051] The present invention is further described below through specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0052] In the following examples, experimental methods without specific conditions were performed according to conventional methods and conditions, or according to the product instructions; unless otherwise specified, all reagents and raw materials used were commercially available.

[0053] The following are the reagents, instruments, and their suppliers involved in the embodiments of this invention: A high-temperature melt extrusion 3D printer (envisionTEC 3D-BIOPLOTTER) was used to fabricate intestinal anastomosis scaffolds. PGA powder (Sigma, CAS: 26124-68-5) was used to print the scaffold. Osalazine sodium (Macklin, CAS: 6054-98-4), 4-(bromomethyl)phenylboronic acid (Macklin, CAS: 68162-47-0), and potassium carbonate (TCI, CAS: 584-08-7) were used to synthesize the salazine prodrug. Dimethylformamide (DMF, Thermo Fisher, CAS: 68-12-2) was used as a solvent. Polyvinyl alcohol (Sigma, CAS: 9002-89-5) was used to prepare polyprodrug microneedle patches. BALB / c mice (male, approximately 6-8 weeks old) were purchased from Hangzhou Ziyuan Laboratory Animal Technology Co., Ltd.; Panamanian piglets (male, weighing 25-30 kg) were purchased from Wujiang Tianyu Biotechnology Co., Ltd.; and human intestinal tissue was obtained from a clinical donor with the approval of the Ethics Committee of Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine.

[0054] Example 1: Preparation and Characterization of Microneedle Anastomotic Scaffold

[0055] In this embodiment, the microneedles are composed of an inflammatory-responsive polymer prodrug matrix, and the scaffold is composed of polyglycolic acid. First, the anti-inflammatory drug olsalazine is modified with 4-bromomethylphenylboronic acid via a nucleophilic substitution reaction (…). Figure 1 (a) Preferably, 1 equivalent of ossalazine sodium is weighed and mixed with 5 equivalents of 4-(bromomethyl)phenylboronic acid and 5 equivalents of potassium carbonate, then added to N,N-dimethylformamide (DMF) to make the total volume of the system 10 mL. The reaction is carried out under an inert atmosphere. The reaction flask is connected to an argon-filled balloon, and the air is completely removed and an inert protective atmosphere is established by alternating vacuum and argon filling several times. Then, the reaction system is magnetically stirred at room temperature for 24 h to allow the nucleophilic sites on the ossalazine molecule to react with 4-(bromomethyl)phenylboronic acid to form a phenylboronic ester bond structure to generate the target prodrug. After the reaction is completed, ice water is slowly added dropwise to the reaction solution, and a yellow solid precipitates in the system. The obtained solid is collected by centrifugation and washed repeatedly with ice water several times to remove inorganic salts and unreacted raw materials. Finally, the wet solid is freeze-dried to obtain a bright yellow crude ossalazine prodrug powder. The crude product was dissolved in methanol to prepare a solution with a mass concentration of 10 mg / mL, which was then used as the injection solution for preparative high-performance liquid chromatography (HPLC) purification. Preferably, a C18 reversed-phase preparative column (e.g., a 19×250 mm C18 column) was used, with the column temperature controlled at 25 °C, the detection wavelength at 254 nm, and the flow rate at 10 mL / min. The mobile phase consisted of acetonitrile containing 0.1% trifluoroacetic acid and water, with an initial volume ratio of acetonitrile:water = 66:34, followed by linear gradient elution to 80:20 over 14 min. 1 mL of the injection solution was injected each time, and the eluent fraction with the strongest absorption intensity in the chromatogram was collected as the target product fraction. The collected fraction was subjected to rotary evaporation to remove acetonitrile, causing the product to precipitate in the aqueous phase. This product was then centrifuged again and freeze-dried to obtain an orange-yellow solid powder, i.e., high-purity oxalacil prodrug. The obtained prodrug can be stored under low temperature and light-protected conditions for later use.

[0056] Subsequently, the prodrug, acting as a linker, crosslinks with PVA rich in polyol groups to form a polyprodrug matrix. Figure 1(b) Preferably, a pre-solution of the polymeric prodrug for microneedle formation is first prepared. A 5 mg / mL oxalafil prodrug solution is rapidly mixed with a 2% PVA aqueous solution at a 1:1 volume ratio, causing the boric acid groups on the prodrug molecule to condense and crosslink with the polyhydroxyl groups on the PVA chain, forming an inflammatory-responsive polymeric prodrug matrix sol, i.e., the microneedle precursor solution. This precursor solution is then poured into a pre-prepared microneedle mold. The container containing the mold is placed in a vacuum desiccator and evacuated to remove residual air bubbles and promote complete filling of the microneedle cavity to the bottom. After maintaining the vacuum for a period of time, atmospheric pressure is restored, and the mixture is allowed to dry at room temperature until the solvent has largely evaporated and the system has solidified. Demolding yields the polymeric prodrug microneedle array patch.

[0057] In practice, the preparation of small-sized microneedle arrays requires at least approximately 2.4 mL of the aforementioned precursor solution, while large-sized microneedle arrays require at least approximately 240 mL of precursor solution to ensure complete filling of the mold cavity and formation of a complete microneedle structure. Furthermore, by adjusting the prodrug and PVA concentrations, polyprodrug hydrogels can also be prepared for comparison or other drug delivery methods. For example, mixing a 10 mg / mL oxalafil prodrug solution with a 10% PVA aqueous solution at a 1:1 volume ratio, stirring thoroughly in a glass bottle, and allowing it to stand will form a polyprodrug hydrogel with certain mechanical strength and self-supporting properties, suitable for in vitro drug release or performance testing.

[0058] like Figure 2 As shown in Figure a, the microneedle patches suitable for mouse and in vitro experiments are pyramid-shaped, with each microneedle having a base width of 100 μm, a height of 150 μm, and a spacing of 150 μm. Larger microneedle patches for miniature pig and human tissue experiments were prepared using the same method, with microneedles having a base width of 400 μm, a height of 900 μm, and a spacing of 800 μm. Figure 2 (b)

[0059] A biodegradable polymer, polyglycolic acid (PGA), was used as the raw material to fabricate the scaffold body using melt extrusion 3D printing technology. Specifically, the PGA raw material was added to the barrel of an extrusion 3D printing device and heated to a molten state. The printing temperature was, for example, 200–260 °C, and the extrusion pressure was, for example, 0.5–2.0 bar. In this embodiment, the printing temperature was approximately 230 °C, and the extrusion pressure was approximately 1.0 bar. The material was continuously extruded through a nozzle and deposited layer by layer along a preset path to obtain a scaffold body with a tubular structure in the middle and gradually expanding ends. This design helps to fix the scaffold at the intestinal incision site and prevent the loss of intestinal contents. The total length of the scaffold body was 10 mm, the diameter of the central tubular structure was 2.25 mm, and the diameter of the expanded ends was 3.25 mm. After printing, the scaffold body was cooled to room temperature for later use.

[0060] Subsequently, we modified and loaded the pre-drug-coated microneedle patch into the central region of the intestinal anastomosis scaffold, ultimately obtaining MAS ( Figure 2 (c) This design focuses drug delivery on the site most relevant to inflammation, ensuring precise release, while both ends contact healthy tissue to secure the scaffold. In this way, the conformity between the microneedle patch and the scaffold is enhanced, mechanical stability is improved, and the manufacturing process is simplified, thus ensuring production consistency.

[0061] Microneedle patches suitable for mouse experiments were arranged in an array of approximately 22 × 60 on a scaffold, with a prodrug loading of approximately 0.82 mg; while microneedle patches suitable for miniature pig experiments were arranged in an array of approximately 15 × 80, with a prodrug loading of approximately 72 mg. To evaluate the mechanical strength of the MAS design, we measured radial compressive force (RCF) and radial tensile force (RTF), representing resistance to abdominal and intestinal pressures, respectively. In the compression test ( Figure 3 a and Figure 3 In the mouse experiment, the RCF of the 3D-printed scaffold increased from 15.12 ± 4.09 N (scaffold) to 29.51 ± 3.98 N (MAS). P =0.0120); the RCF of the commercial scaffold in the mini pig experiment increased from 296.89±11.50N to 330.61±14.79N (MAS, P =0.0356). In the tensile test ( Figure 3 b and Figure 3 The RTF of the 3D printed scaffold is 28.51±5.28N (scaffold) and 35.99±6.08N (MAS). P =0.1829); the RTF of commercial stents was 508.66±37.72N (stent) and 616.48±162.73N (MAS, P =0.3262). These results indicate that both the scaffold and the MAS exhibit good mechanical strength sufficient to maintain structural integrity under physiological conditions.

[0062] To evaluate the leak-proof capability of MAS, we used a microfluidic-assisted flow model to simulate intestinal fluid dynamics. Figure 3 (e). Miniature pig intestines were processed through a surgical incision and sutured or a stent was implanted, followed by PBS perfusion, and fluid output at the distal (b) end was measured. Figure 3 (f) In the suture group, leakage occurred at the anastomosis, resulting in the inability to detect fluid at the distal end (b). In contrast, the stent group ( P =0.0031) and MAS group ( P=0.0001) effectively prevented leakage and increased fluid output over time at the distal end (b).

[0063] Example 2: Drug delivery system based on implantable microneedle anastomotic scaffold

[0064] One of the pathological characteristics of intestinal inflammation is the excessive generation of reactive oxygen species (ROS), which exacerbates the inflammatory cascade and leads to tissue damage. H2O2 is a particularly abundant and stable molecule among these, playing a crucial role in key physiological and pathological processes. To leverage this increased oxidative stress, this invention employs a hydrogen peroxide-responsive system as a powerful strategy for precise drug delivery to the lesion site. In this system, the phenylboronic acid ester bonds in the polyprodrug matrix are designed to preferentially respond to hydrogen peroxide, triggering an oxidation reaction followed by hydrolysis, resulting in the cleavage of the phenylboronic acid ester groups at both ends of the prodrug. Figure 4 (a) This process promotes the degradation of the polymer prodrug network and enables the controlled release of the Os drug, with the release rate influenced by both time and H2O2 concentration.

[0065] (1) Stimulus-responsive drug delivery system

[0066] To investigate the release kinetics of polymer prodrug microneedles, we prepared three microneedle formulations with different prodrug-to-PVA ratios and incubated them in PBS containing 1 mM H2O2 to evaluate the drug release behavior. The results showed that, compared to the formulation with a high prodrug content, the microneedles with a high PVA ratio accelerated the release of Os. Figure 4 (b) This indicates that by adjusting the formulation, the system can be customized to achieve specific drug release characteristics according to different inflammation levels. Next, we evaluated the drug release behavior of a 1:1 prodrug-PVA microneedle at different concentrations of H2O2, using H2O2 concentrations of 0, 0.1, 1, and 10 mM respectively. Figure 4 (c) Compared to the reduced drug release in the PBS group, Os was rapidly released within 24 hours at a high concentration of 10 mM H2O2, demonstrating proof-of-concept for the system's release behavior. In contrast, at pathological H2O2 concentrations (0.1 mM and 1 mM), Os release was gradual and sustained, indicating that the drug can remain available for extended periods under inflammatory conditions. Over time, images showed that the microneedles gradually became less distinct in the presence of H2O2 solution, with their shape and color becoming blurred, indicating that the matrix was uniformly eroded along the entire microneedle rather than dissolving from the tip. Figure 4 (d). To further evaluate the morphological changes under oxidative stress, we characterized MAS using SEM after incubation with 1 mM H2O2 ( Figure 4(e). The overall structure remained intact, demonstrating good short-term stability. Although the microneedle array began releasing the drug on day 1, its geometry remained unchanged, but by day 3 it showed significant shrinkage and edge blurring, indicating significant microneedle degradation. By day 14, the microneedle array had almost completely disappeared, leaving only a thin residual base. These results indicate that MAS exhibits short-term stability under oxidative stress, while microneedles degrade under long-term exposure. Furthermore, by alternately placing the microneedles in PBS containing and without H2O2, we achieved pulsed Os release characteristics and maintained this characteristic over multiple cycles. Figure 4 (f). This ROS-dependent release behavior holds promise for responding to different levels of inflammation and achieving repeated responsive releases, thereby optimizing therapeutic control.

[0067] (2) Application of drugs to inflamed tissues and drug release behavior

[0068] To evaluate the clinical translational potential of MAS, we investigated its penetration and stimulus-response behavior in intestinal tissue from patients with inflammatory bowel disease. Tissue samples were obtained from Crohn's disease cases and collected during bowel resection surgery, including both high- and low-inflammatory areas. First, a prodrug-coated microneedle patch was applied to the well-defined mucosal layer of low-inflammatory intestinal tissue. The microneedle patch gradually deposited into the mucosal layer and almost completely integrated over time. Figure 5 (a) Similarly, the polyprodrug-loaded microneedle patch also adhered effectively to the lesion mucosal layer of highly inflamed tissue. In contrast, the PVA microneedle patch deformed rapidly upon contact with intestinal tissue, highlighting the important role of the prodrug cross-linking agent in maintaining structural stability, especially under physiological conditions. Further H&E staining confirmed that the polyprodrug-loaded microneedle patch could penetrate the mucosal layer of normal colon cancer tissue and Crohn's disease inflamed tissue, showing obvious puncture marks. In contrast, the penetration ability of the PVA microneedle patch was limited, forming only slight puncture points on the mucosal surface, mainly due to the mechanical deformation of PVA upon contact with moist tissue. Figure 5 (b) Next, we evaluated the drug release performance of the prodrug-containing microneedle patch in co-culture with intestinal tissue from Crohn's disease patients and compared it in tissues with different levels of inflammation. Compared with low-inflammatory tissues, high-inflammatory tissues induced more Os release ( P =0.0236), this difference was significant after 24 hours of co-culture ( Figure 5 (c). To further evaluate the advantages of the prodrugated microneedle patch, we compared its performance with that of the prodrugated film and evaluated the release and distribution of fluorescein isothiocyanate (FITC) in tissues of patients with different types and severities of intestinal inflammation. Figure 5(d). The results showed that, compared with low-inflammatory tissues, both the prodrug film and microneedles exhibited enhanced FITC release in high-inflammatory samples, indicating that drug release from the prodrug matrix is ​​inflammation-dependent. Figure 5 (e). Polymeric prodrug films mainly restrict fluorescence signals to the mucosal surface, while polymeric prodrug microneedles show a significant advantage, promoting deeper and more uniform penetration of FITC into the mucosal layer.

[0069] (3) Multi-type drug loading platform

[0070] Besides anastomotic inflammation, complex intestinal diseases (such as ulcerative colitis, colon cancer, and inflammatory bowel disease) often require the combined use of multiple therapeutic agents. Based on its ability to penetrate the mucosal barrier and alleviate anastomotic inflammation, the MAS of this invention is also being studied as a multifunctional drug delivery platform capable of delivering various therapeutic agents (such as proteins, nanoparticles, and bacteria). We mixed IgG proteins, lipid nanoparticles (LNPs), and Salmonella VNP20009, among other drugs, into a microneedle precursor solution, followed by vacuum treatment and drying to ultimately form a microneedle array. Confocal fluorescence microscopy confirmed that the loaded therapeutic agents were uniformly distributed within the drug-eluting prodrug microneedles. Figure 6 (a). To further confirm the stability and integrity of the released therapeutic agent, we performed three additional characterization tests. Circular dichroism spectroscopy of the released IgG confirmed that this method maintained the β-structure of the protein (…). Figure 6 (bc). Dynamic light scattering results show that the released LNPs can maintain uniformity and stability. Figure 6 (in the middle). Furthermore, the loading process had minimal impact on bacterial activity, and Salmonella plate culture results showed good colony formation. Figure 6 (fg).

[0071] Example 3: Application of microneedle intestinal anastomosis stent in the treatment of resectable intestinal diseases

[0072] (1) Application of microneedle anastomosis scaffold in the treatment of a mouse model of radiation colitis

[0073] Treatment of many intestinal diseases involves radiation therapy, such as resectable colorectal cancer, which can lead to anastomotic inflammation, affecting postoperative recovery and prognosis. To evaluate the therapeutic effect of MAS in vivo, we conducted experiments in a radiation-induced mouse colitis model. Briefly, BALB / c mice were irradiated with X-rays to induce colitis, followed by colectomy. Figure 7(a) Following resection, the control group underwent intestinal anastomosis using conventional suturing methods, which met clinical standards of care. The other control group received an oral dose equivalent to the Os in the polyprotic microneedle patch (suture + Os) after suturing. Subsequently, blank stents and MAS were implanted at the postoperative site, with the extended ends of the stents supporting the intestinal wall to prevent leakage. Figure 7 (b) Postoperatively, we monitored the health of the mice and collected fecal samples for further analysis. Colonic tissue was collected on postoperative day 7 for pathological analysis. Histological scoring based on H&E staining showed ( Figure 7 In the c) group, MAS implantation significantly alleviated colonic inflammation, with a score of 0.75±0.25, which was significantly lower than that in the blank stent group (4.75±0.48). P <0.0001), suture + Os group (3.5±0.64, P =0.0014) and the suture group (6.25±0.25, P <0.0001), compared to the untreated group (0±0, P There was no significant difference compared to (=0.6658).

[0074] To further explore the mechanism of MAS-mediated inflammation relief, we used immunofluorescence staining for analysis. Radiation-induced ROS generation or persistent inflammation can cause DNA damage and trigger phosphorylation of proteins like γ-H2AX, which can be repaired after inflammation subsides. The suture group after radiation showed a significantly increased level of γ-H2AX (10.4±1.5%), significantly higher than the untreated group (0.3±0.1%). Figure 7 (d). The suture + Os group (5.9±0.8%) and the stent implantation group (8.4±1.1%) partially restored the structure of the mucosal layer, but still showed signs of DNA damage. In contrast, MAS not only restored the integrity of the mucosal structure, but also significantly reduced γ-H2AX levels (1.4±0.4%). In addition, as the final active ingredient of the anti-inflammatory prodrug Os, mesalazine alleviates inflammation by inhibiting COX proteins such as COX-2. Compared with the suture group after irradiation showing 56.9±4.9% COX-2 expression, the COX-2 level in the MAS group was significantly reduced, at only 3.7±1.2% ( P <0.0001), significantly lower than the suture + Os group (30.6±4.0%). P =0.0007) and stent group (36.3±4.7%, P <0.0001 indicates the effect of drug release ( Figure 7 (e). Furthermore, radiation colitis can trigger an inflammatory response, accompanied by elevated levels of pro-inflammatory cytokines such as TNF-α and IL-6. Figure 7 f and Figure 7As shown in Figure g, immunohistochemical staining of the colon revealed significantly increased levels of IL-6 and TNF-α expression in the irradiated suture group compared to the untreated group. P <0.0001). After oral administration of Os, the suture + Os group showed a slight reduction in IL-6 compared to the suture group ( P =0.0243) and TNF-α ( P =0.0005). The MAS implantation group effectively reduced the expression of IL-6 (=0.0005). P =0.0044) and TNF-α ( P The level of (=0.0003) compared to the blank stent group further demonstrates the efficacy of the prodrug-based MAS. To assess the progress of mucosal regeneration after MAS implantation, we performed H&E and immunohistochemical (IHC) analyses on days 1, 3, 7, and 14. H&E staining showed ( Figure 7 (h), significant mucosal damage was observed on day 1, with gradual structural recovery beginning on day 3, near-normal morphology by day 7, and almost complete recovery by day 14. This is in response to the tight junction protein ZO-1 ( Figure 7 (i) and E-cadherin ( Figure 7 IHC staining of the samples (j) showed significant loss of connectivity from day 1 to day 3, large-scale remodeling began on day 7, and almost complete recovery was achieved by day 14, indicating the re-establishment of barrier integrity. These results suggest that MAS implantation promotes mucosal regeneration and can restore barrier function in a timely manner, thereby supporting efficient drug delivery without delaying barrier recovery.

[0075] (2) Application of microneedle anastomosis scaffold in the treatment of ischemic inflammatory injury in miniature pigs

[0076] To further evaluate the in vivo effects of MAS in large animals, we developed a miniature pig model of ischemic inflammatory intestinal injury. Figure 8 (a). In clinical practice, acute ischemic intestinal obstruction and intestinal necrosis lead to impaired blood supply and trigger an inflammatory response that persists even after resection of the affected intestinal segment. In this study, after intestinal resection, an anastomotic stent was implanted at the anastomosis site. The stent was loaded with large-sized prodrug-coated microneedles and combined with clinically used intestinal anastomotic stents to further validate the feasibility of this strategy. In short, Panamanian miniature pigs underwent laparotomy and temporary clamping of mesenteric vessels to induce ischemia. Subsequently, the blackened lesion was excised, an anastomotic stent was implanted, and the stent was securely fixed to the intestinal tissue using surgical sutures. Figure 8 (b) As a control group, suture methods were used, and patients were given oral medication or not postoperatively.

[0077] Postoperatively, the condition of the anastomosis site in the miniature pig intestine was monitored using computed tomography (CT) imaging. CT images showed structural abnormalities at the anastomosis site; both the scaffold group and the MAS group maintained relatively intact structures. Figure 8 (c) Sagittal plots showed that in the suture group, regardless of whether the same dose of Os was administered orally, intestinal wall edema and mesenteric exudate were observed, indicating that the inflammation was not effectively relieved. Similarly, the stent implantation group not only showed significant mesenteric exudate but also increased intestinal contents. In contrast, the MAS group showed minimal mesenteric exudate and reduced intestinal contents, suggesting that reducing inflammation contributes to the recovery of intestinal function.

[0078] On postoperative day 8, we collected intestinal tissue from the anastomosis site for detailed pathological evaluation. H&E stained images showed signs of ischemic inflammatory damage, particularly in the sutured group, including mucosal atrophy, edema, lymphoid follicle hyperplasia, and even destruction of glandular structures and muscle layer. Figure 8 (d). Neither the suture group nor the stent group effectively relieved these symptoms after oral medication. However, MAS treatment significantly alleviated severe atrophy and deformity symptoms, with a reduction in glandular number compared to the stent group. P =0.0010) and length ( P =0.0030) all increased ( Figure 8 (e). Magnified H&E images further confirmed that MAS treatment significantly alleviated inflammatory symptoms, as evidenced by a reduction in inflammatory cell infiltration, glandular destruction, congestion, and glandular stasis and deformation.

[0079] During this period, we also collected blood samples daily for routine and biochemical analyses. High-sensitivity C-reactive protein (hs-CRP), an acute-phase protein reflecting the level of inflammation in tissue damage, showed elevated levels in all groups postoperatively, especially on the first postoperative day. P >0.05)( Figure 8 (f). On day 5, hs-CRP levels in the MAS group began to show significant differences compared to other groups (f). P <0.05), and showed a decreasing trend. By day 7, the stent-implanted group maintained a higher hs-CRP level (1.4±0.3%), while the MAS group showed a significant decrease in hs-CRP level (0.5±0.1%), consistent with other results, indicating that the inflammation was relieved.

Claims

1. An implantable microneedle anastomosis stent, characterized in that, It consists of a scaffold body and a drug-loaded microneedle array; The middle part of the stent body is a tubular structure, which gradually expands at both ends to facilitate anastomosis and fixation; the drug-loaded microneedle array covers the outside of the stent body; The main body of the scaffold is made of a biodegradable polymer; The drug-loaded microneedle array uses a biodegradable polymer as the microneedle body and loads the drug through chemical bonding or physical mixing.

2. The implantable microneedle anastomosis stent as described in claim 1, characterized in that, The stent body has a tubular structure in the middle and flared openings at both ends; the drug-loaded microneedle array covers the middle of the stent body and the outer surface of the tubular structure.

3. The implantable microneedle anastomosis stent as described in any one of claims 1 or 2, characterized in that, The biodegradable polymer used for the stent body is selected from one or more of the following: polyglycolic acid, polylactic acid-glycolic acid copolymer, polylactic acid, and polycaprolactone.

4. The implantable microneedle anastomosis stent as described in any one of claims 1 or 2, characterized in that, The biodegradable polymer used for the microneedle body is selected from one or more of the following: polyvinyl alcohol, polylactic acid, polycaprolactone, and polyhydroxyalkanoates.

5. The implantable microneedle anastomosis stent as described in any one of claims 1 or 2, characterized in that, The drug is selected from one or more of the following: small molecule drugs, protein drugs, nucleic acid drugs, nanomedicines, and active drugs.

6. The method for preparing the implantable microneedle anastomosis scaffold as described in claim 1, characterized in that, include: (1) Preparation of the scaffold body The scaffold body is prepared using biodegradable polymers as raw materials through melt molding, extrusion molding, 3D printing, or a combination thereof. The dimensions and structure of the main support structure are customized according to actual needs; (2) Preparation of drug-loaded microneedle arrays The drug and biodegradable polymer are dispersed in a solvent to form a drug-loaded polymer precursor solution, which is then injected into a mold and formed into a microneedle array structure through molding and curing. (3) Assemble implantable microneedle anastomosis scaffold The drug-loaded microneedle array prepared in step (2) is fixed to the outside of the scaffold body prepared in step (1) to form an integrated implantable microneedle anastomosis scaffold.

7. The preparation method according to claim 6, characterized in that, In step (2), olsalazine is used as the target drug. The carboxyl groups at both ends of olsalazine are reacted with 4-bromomethylphenylboronic acid to prepare an olsalazine prodrug with a phenylboronic acid ester bond structure. Then, the olsalazine prodrug and polyvinyl alcohol are dispersed in a solvent to form a drug-loaded polymer precursor solution.

8. The preparation method according to claim 6, characterized in that, The microneedles in the microneedle array are pyramid-shaped, with a base width of 100–400 μm, a height of 150–900 μm, and a tip spacing of 150–800 μm.

9. The application of the implantable microneedle anastomosis stent as described in claim 1 in the preparation of a medical device for adjuvant treatment after resectable intestinal diseases.

Images