Medicated threaded acupuncture needle for treating tendonitis and application of the same in medical device for treating tendonitis

Abstract

The application provides a drug-loaded threaded acupuncture needle for treating tendonitis, a needle body, a needle-shaped carrier with a puncture function, at least part of the surface of the needle-shaped carrier is provided with a microstructure; a functional coating modified on the surface of the needle body; and a drug composition comprising a clathrate formed by the carrier and a hydrophobic anti-inflammatory drug. The tangeretin beta-cyclodextrin sodium sulfate salt clathrate delivery system constructed by the application adopts a CA (acupuncture) positioning method, which is simple and fast, and can be used for treating tendonitis. In the in vivo experiment, after establishing a tendonitis model of an SD rat, in-situ minimally invasive treatment is performed by using acupuncture, and the results show that the development of tendonitis can be significantly delayed, and excellent treatment effect is shown.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials, specifically relating to a novel spiral-shaped drug-loaded acupuncture needle loaded with cyclodextrin and hesperidin. Background Technology

[0002] Tendinitis is a non-infectious inflammatory reaction, mostly caused by overuse and repetitive, strong stretching of the tendon. The manifestations of tendinitis in different locations are generally similar: localized pain, limited function, and decreased athletic ability are the main symptoms, seriously affecting the patient's quality of life and the athlete's career. The overall incidence of tendinitis is very high; it can occur in any location where there is a tendon or tendon sheath.

[0003] Tendinitis is associated with an inflammatory response characterized by the release of inflammatory cytokines, including interleukins (ILs) such as IL-1 and IL-6, tumor necrosis factor (TNF-α), regulatory factors (matrix metalloproteinases (MMPs) such as MMP-3 and MMP-9), and mediators (cyclooxygenase (COX)-2). Tendon repair typically consists of several phases, including an inflammatory phase, a proliferative phase, and a remodeling phase. The secretion of inflammatory / pro-inflammatory cytokines is observed when local tissue injury occurs. Simultaneously, as a feedback mechanism, anti-inflammatory cytokines, such as IL-10, can recruit fibroblasts to the site of injury, contributing to tissue repair. Persistent tissue inflammation leads to Achilles tendon degeneration, in which increased degeneration-related biomarkers, such as type I collagen (COL1a1), type III collagen (COLⅢa1), decorin (DCN), and tenascin-C (TNC), are involved in tissue remodeling.

[0004] Currently, there are many treatment options for Achilles tendinitis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, physical therapy, extracorporeal shock wave therapy, and surgery. However, drug treatments have side effects, conservative treatments like physical therapy have long treatment cycles and are not always effective, and surgical treatments are invasive and carry risks such as decreased tendon biomechanical properties, tendon adhesions, and re-rupture. Therefore, developing new treatment strategies for tendinitis is crucial.

[0005] In-situ drug delivery is an ideal strategy that plays a vital role in medical treatment. Its advantages include the ability to precisely target drugs to specific areas and create an accumulation effect, significantly improving efficacy and reducing treatment-related side effects.

[0006] Tangeretin, also known as 5,6,7,8,4' Pentamethoxyflavones are polymethoxyflavones widely found in citrus fruits (sweet oranges, mandarins, etc.). Due to their unique biochemical structure, hesperidin is low in polarity and highly lipid-soluble, readily soluble in organic substances such as benzene and ether, thus easily crossing the phospholipid bilayer to enter the cell membrane and exert its effects. Studies have shown that hesperidin possesses more than 80% of the bioactivity of polymethoxyflavones, exhibiting positive effects on various chronic diseases, such as type 2 diabetes, cardiovascular diseases, malignant tumors, and neurodegenerative diseases. It has been widely applied in multiple fields, including biology, medicine, and health foods. Anti-inflammatory activity is one of the most effective functions of hesperidin; while directly clearing inflammatory factors in the body, it can also regulate related inflammatory signaling pathways or enhance endogenous defense mechanisms, thus inhibiting inflammatory responses. However, due to its low polarity and poor water solubility, hesperidin is easily and rapidly degraded and metabolized in vivo, often failing to fully realize its active advantages. Therefore, we need to develop a drug delivery carrier with hydrophilic properties.

[0007] Cyclodextrin (CD) is a natural cyclic oligosaccharide produced by the hydrolysis of starch by amylase. There are three types of natural CD: α-CD, β-CD, and γ-CD, composed of 6, 7, and 8 glucose units linked by 1,4-glycosidic bonds, respectively. They are shaped like truncated cones, barrels, or donuts. The luminal diameters of α-CD, β-CD, and γ-CD are 4.5–5.3 Å, 6.0–6.5 Å, and 7.5–8.3 Å, respectively. They possess a relatively hydrophobic inner surface and a hydrophilic outer surface. Hydrophobic drugs (such as hesperidin) can enter the cavity of cyclodextrin through non-covalent interactions to form inclusion complexes without complex chemical reactions. Therefore, the water solubility and stability of the drug are greatly improved. The inclusion complexes can slowly release the drug locally to achieve therapeutic effects.

[0008] Meanwhile, the physical barriers of the physiological structures of certain tissues or organs (such as intervertebral discs, ligaments, and cartilage) greatly hinder the implementation of lesion localization therapy. Therefore, designing a drug delivery system that can effectively penetrate the physical barriers of various tissues and organs and accurately locate the lesion is a major problem that urgently needs to be solved.

[0009] Chinese acupuncture (CA) is the most mature localized therapy in traditional Chinese medicine, with a clinical application history of thousands of years. Over time, its efficacy has become evident, and its use is popular worldwide. Acupuncture needles are less than 200–300 micrometers in diameter and vary in length to several hundred millimeters. They can penetrate the physical barriers of various tissues and organs, directly contacting diseased tissues to precisely stimulate the lesions and alter their microenvironment, thereby alleviating and treating diseases. Furthermore, the tiny size of Chinese acupuncture needles (CA needles) makes them minimally invasive; patients experience almost no pain during acupuncture treatment, and there is virtually no bleeding at the acupuncture site. CA needles are made of metal, are physically strong, and can be made to several hundred millimeters in length, easily reaching deep tissues and penetrating the physical barriers of tissues through the skin. Currently, acupuncture is widely used to treat diseases of muscles, the intervertebral nerve, the sciatic nerve, and other deep tissues. However, because the medication is usually above the needle tip plane, some medication is lost during the process of penetrating the physical barrier. Therefore, the present invention designs a threaded groove at the tip of the CA needle, so that the drug-loaded coating is lower than the needle tip plane and its specific surface area is increased, thereby greatly increasing the drug content on the needle surface and reducing drug loss during the breakthrough process.

[0010] This invention fully utilizes the advantages of threaded grooves, functional coatings, cyclodextrin carriers, and drug molecules, ingeniously combining chemically modified acupuncture needles with drug-loaded cyclodextrin to construct a novel drug delivery system. This delivery system allows the threaded acupuncture needle to penetrate physical barriers such as the skin to reach the tendon injury area. Through rotation and lifting, the interaction between the needle and the drug-loaded cyclodextrin is disrupted, enabling the drug-loaded inclusion complex to be released in situ and exert its sustained effect. This provides a theoretical basis for the clinical treatment of tendinitis. Summary of the Invention

[0011] The purpose of this invention is to design and prepare a spiral-shaped drug-loaded acupuncture needle loaded with cyclodextrin and hesperidin. The specific technical solution of this invention is as follows:

[0012] A novel threaded acupuncture needle that combines penetration and drug sustained-release functions, comprising: a custom-made threaded titanium acupuncture needle, hesperidin purchased from Anhui Zesheng Technology Co., Ltd., and carboxymethyl-β-cyclodextrin, sodium β-cyclodextrin sulfate, sulfobutyl ether-β-cyclodextrin, or phosphate-β-cyclodextrin purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0013] To address the shortcomings of existing technologies, the purpose of this invention is to provide a drug-loadable acupuncture needle with high drug loading efficiency, good drug retention, and controllable release behavior.

[0014] Another objective of this invention is to provide a method for preparing the above-mentioned acupuncture needles, which is characterized by mature technology, mild conditions, and ease of large-scale production.

[0015] Another objective of this invention is to clarify the use of the above-mentioned acupuncture needles in the preparation of drugs or medical devices for treating tendinitis and related diseases.

[0016] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: Firstly, this invention provides a controlled-release drug-eluting medical device for treating tendinitis. This medical device is essentially a functionalized puncture needle, and its innovation lies in constructing a three-tiered synergistic system of "structure-interface-function": Primary structure: A needle-like carrier, at least a portion of its surface (particularly the needle tip portion intended for insertion into tissue) is provided with microstructures. These microstructures are not limited to threads, but can also be regular or irregular grooves, ravines, porous structures, etc. Their core function is to significantly increase the specific surface area of ​​this region (preferably by more than 50% compared to a smooth surface, more preferably 100%-500%), thereby providing more drug loading sites. Simultaneously, the microstructures (especially grooves) can form drug reservoirs; as the needle penetrates the tissue, some drug can be stored within the grooves, reducing loss due to scraping by the tissue along the way.

[0017] Secondary structure: A colloidal coating is applied to the surface of the needle-like carrier using physical and chemical methods. This functional layer is firmly bonded by chemical bonds (such as Si-OM bonds, where M represents the metal needle). This colloidal coating acts as a "molecular bridge" connecting the metal needle to the subsequent drug carrier, providing the foundation for drug loading.

[0018] Tertiary structure: A therapeutic composition loaded onto a colloidal coating via non-covalent interactions. The composition comprises two parts: a carrier material, preferably a cyclodextrin derivative; and a therapeutic agent carried or encapsulated by the carrier material, preferably a poorly water-soluble hydrophobic anti-inflammatory and repair-promoting agent.

[0019] Preferably, the needle-like carrier is made of a biocompatible metallic material, such as medical stainless steel, titanium, titanium alloy, nickel-titanium alloy, etc., preferably titanium or titanium alloy. The diameter and length of the needle can be adjusted according to the treatment site (such as superficial or deep tendons).

[0020] Preferably, the functional layer is formed by modification with a colloidal silica composition, wherein the silane coupling agent contained therein has a hydrolyzable alkoxy group at one end, which can react with the hydroxyl groups on the needle surface to form a strong Si-O-Si or Si-OM covalent bond. The most preferred silane coupling agent is trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride or (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride.

[0021] Preferably, the carrier material is a natural or synthetic macromolecule. Most preferably, it is a cyclodextrin derivative, such as carboxymethyl-β-cyclodextrin, sodium β-cyclodextrin sulfate, or phosphate ester-β-cyclodextrin. The hydrophobic cavity of cyclodextrin can effectively encapsulate hydrophobic drugs.

[0022] Preferably, the therapeutic agent is selected from hydrophobic compounds with clear anti-inflammatory and / or tendon repair promoting effects, including but not limited to: polymethoxyflavonoids (such as hesperidin, norihesperidin, sweet orange flavonoids, and tangerine flavonoids), curcumin derivatives (such as curcumin and tetrahydrocurcumin), and some nonsteroidal anti-inflammatory drugs (such as indomethacin and celecoxib). Hesperidin and norihesperidin are most preferred.

[0023] Secondly, this invention provides a method for preparing the aforementioned medical device. This method is logically clear and proceeds in steps: S1. Surface Pretreatment: Thoroughly clean the needle to remove grease and contaminants, then perform surface activation (e.g., hydroxylation) to introduce abundant active groups (-OH) to provide reaction sites for subsequent silanization. Hydroxylation can be achieved by treatment with a strong oxidizing solution (e.g., piranha solution, potassium persulfate solution, etc.).

[0024] S2. Preparation of modified colloidal silica coating: Deionized water was added to trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride or (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride, and the mixture was stirred until homogeneous. The pH was then adjusted to 4.0-4.5 with phosphoric acid, and the mixture was hydrolyzed at room temperature for 15-20 minutes to obtain a hydrolysate. The silane coupling agent hydrolysate and colloidal silica were added to an organic solvent, and the mixture was stirred under closed conditions at 60°C for 10 minutes to prepare a homogeneous modified colloidal silica composition. S3. Preparation of therapeutic agent complex: The carrier material and the therapeutic drug are mixed in a suitable solvent system, and a stable nano- or micron-sized complex is formed by methods such as host-guest inclusion, ion pair recombination or nano-coprecipitation.

[0025] S4. Loading: The needle with the functional surface layer is immersed in a solution containing a therapeutic agent complex. Through physical interaction, the complex is adsorbed onto the needle surface. After drying, the final product is obtained. The loading process can control the drug loading amount by adjusting the solution concentration, pH value, ionic strength, and time.

[0026] In some preferred embodiments, the preparation method of a novel spiral-shaped drug-loaded acupuncture needle loaded with cyclodextrin and hesperidin includes the following steps: (1) Surface treatment of threaded needles: Wash the newly manufactured titanium acupuncture needles three times in sequence with acetone, ethanol and pure water, and dry them; then soak them in concentrated sulfuric acid for 1 hour to wash away surface stains, and dry them for later use. Soak the treated titanium needles in piranha solution (concentrated sulfuric acid: hydrogen peroxide = 3:1) for 1 hour. After the surface hydroxylation is completed, wash and dry them. (2) Construction of functional coating for threaded needles: A small amount of water was added to trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride or (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride, and the pH was adjusted to 4.0-4.5 with phosphoric acid. The mixture was reacted for 15 minutes to obtain a hydrolysate. The hydrolysate of silane coupling agent and colloidal silica were added to an organic solvent and stirred in a closed container at 60°C for 10 minutes to prepare a homogeneous modified silica composition. The threaded needles after surface hydroxylation were immersed in the above modified silica composition solution overnight to obtain coated threaded needles. After washing and drying, they were ready for use.

[0027] (3) Synthesis of TAN@CDs system: Accurately weigh 277 mg of β-cyclodextrin sodium sulfate and dissolve it in 4 mL of water, and stir at 50 °C; then weigh 37.2 mg of hesperidin and dissolve it in 4 mL of anhydrous ethanol, and then slowly add the TAN solution to the CDs solution. React at 50 °C for 2 h. After the reaction is complete, evaporate the solvent to remove the ethanol; add 4 mL of water to redissolve, filter with a 450 μm filter membrane, and freeze-dry the filtrate to obtain the soluble TAN@CDs package system.

[0028] (4) Preparation of drug-loaded acupuncture needles: Prepare TAN@CDs solution, soak the above-treated spiral needles in it overnight, take them out and dry them to obtain drug-loaded acupuncture needles.

[0029] Thirdly, the present invention provides a drug delivery system incorporating the aforementioned medical device. This system includes not only the drug-loaded needle itself, but also crucial instructions for use, guiding the user on how to trigger drug release through specific operations. These operations aim to apply shear, friction, or vibration forces to the needle body to disrupt the relatively weak physical interaction between the functional layer on the needle surface and the therapeutic agent complex, thereby achieving "on-demand" drug release. Operation methods include rotation, lifting and thrusting, vibration, or combinations thereof.

[0030] Fourthly, the present invention provides the use of the above-described therapeutic composition (i.e., a carrier material encapsulating a hydrophobic drug) in the preparation of a surface-functionalized puncture needle for treating tendinitis. This protects the application of the core "drug-carrier" pairing of the present invention in novel medical device forms.

[0031] Fifthly, this invention provides a method for treating tendinitis. The method includes the following steps: locating the affected tendon; inserting the drug-loaded needle of this invention into the core area of ​​the lesion; performing a physical operation to trigger release within the lesion (such as rotating several times); retaining the needle for a certain period as needed to ensure drug diffusion; and finally removing the needle. This method combines the physical stimulation of acupuncture with the chemical therapy of drugs, is simple to operate, and conforms to clinical practice.

[0032] The in vivo animal experiment of this invention involves the application of the novel threaded drug-loaded acupuncture needle to the treatment of Achilles tendon injury (ATI). The specific experimental protocol is as follows: (1) Fifty SD rats were randomly divided into five groups. The sham group had only the skin at the Achilles tendon cut open. The model group, AC group, AC+CD group and AC+CD+TAN group had a rectangular full-thickness defect of about 5×1mm made in the center of the Achilles tendon with microscissors.

[0033] (2) The Sham and model groups received no further treatment; the other groups received treatment every 2 weeks post-surgery. The specific procedure involved inserting acupuncture needles into the Achilles tendon, holding them in place for 1-3 minutes, rotating them several times, and then removing the needles. The AC group, AC+CD group, and AC+CD+TAN group were respectively treated with acupuncture needles alone, acupuncture needles with cyclodextrin sulfate, and acupuncture needles with cyclodextrin sulfate and hesperidin. (3) Four and eight weeks after the operation, the rats were sacrificed and the Achilles tendon tissue was removed. The gross appearance was observed.

[0034] (4) After embedding rat Achilles tendon specimens, paraffin sections were prepared and then stained with hematoxylin and eosin (HE). The degree of Achilles tendon injury and the degree of inflammatory response among different groups were quantitatively evaluated using an existing Achilles tendon histological scoring system.

[0035] Sixthly, the present invention provides a reagent kit. This kit may contain pre-made drug-loaded acupuncture needles for convenient direct clinical use; alternatively, it may contain all individually packaged components for immediate preparation by medical institutions before use to maintain drug activity. Components typically include: a cleaning agent, an activator, a carrier material, a therapeutic drug, a dispensing solvent, as well as sterile gloves, disinfectant wipes, instructions for use, and a sharps container, etc.

[0036] Beneficial effects of the present invention The threaded and other microstructure designs in this invention physically increase the drug-carrying area and provide a "drug reservoir," while chemically providing a strong binding force. These two aspects work synergistically to significantly improve the drug loading capacity per needle and ensure a high drug retention rate during puncture and delivery.

[0037] In this invention, drug release is triggered by a doctor-controlled physical operation (such as rotation). The timing and extent of release can be partially controlled by the operator, and this operation itself is part of the acupuncture technique, making it easy to integrate into existing treatment procedures.

[0038] By utilizing cyclodextrin inclusion technology, poorly soluble drugs such as hesperidin have been successfully converted into soluble forms, greatly improving their bioavailability and therapeutic potential.

[0039] The surface functionalization modification and drug encapsulation technologies used are all mature processes with mild conditions, do not involve complex equipment, and are easy to convert and produce. Attached Figure Description

[0040] Figure 1 These are actual images and SEM images of the drug-loaded acupuncture needles of this invention.

[0041] Figure 2 This is a schematic diagram of drug administration in a rat Achilles tendonitis model.

[0042] Figure 3 Gross image of the tendon after treatment of tendinitis in SD rats with threaded drug-loaded acupuncture needles.

[0043] Figure 4 Hematoxylin-eosin stained sections of tendon tissue from SD rats after treatment with threaded drug-loaded acupuncture needles for tendinitis.

[0044] Figure 5 This is a section of cartilage tissue stained with stylosin after treatment of tendinitis in SD rats with threaded drug-loaded acupuncture needles.

[0045] Figure 6 Immunohistochemical sections of tendons from SD rats treated with threaded drug-loaded acupuncture needles.

[0046] Figure 7 Immunohistochemical fluorescence semi-quantitative analysis results and histological scores of tendons in SD rats treated with threaded drug-loaded acupuncture needles.

[0047] Figure 8 This is a curve showing the cumulative drug release of the drug-loaded needle (AC+CD+TAN group) of the present invention in simulated body fluid. Detailed Implementation

[0048] The present invention will be further illustrated below with reference to specific embodiments and comparative examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions in the art or as recommended by the manufacturer. Unless otherwise specified, all reagents and materials used are commercially available products.

[0049] Example 1: Preparation of hesperidin-loaded spiral acupuncture needles 1. Materials: Custom-made titanium alloy threaded acupuncture needles (5mm needle tip with grooved thread, 0.25mm diameter), acetone, anhydrous ethanol, concentrated sulfuric acid, 30% hydrogen peroxide, trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride (TMAPS, 50% in methanol), (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride (DMOAP, 40% in methanol), sodium β-cyclodextrin sulfate (degree of substitution ~7, CDs), hesperidin (TAN, purity >98%).

[0050] 2. Fabrication of functionalized threaded needles: Cleaning: Place the threaded needle in acetone, anhydrous ethanol and ultrapure water in sequence for ultrasonic cleaning for 15 minutes each, and then blow it dry with nitrogen.

[0051] Acid washing and hydroxylation: Immerse the cleaned needle in concentrated sulfuric acid for 1 hour, rinse with plenty of ultrapure water until neutral, and dry. Then immerse it in freshly prepared piranha solution (V concentrated sulfuric acid: V 30% hydrogen peroxide = 3:1) and react at room temperature for 1 hour. After removal, rinse thoroughly with ultrapure water and dry. At this point, the needle surface is rich in Ti-OH.

[0052] Coating preparation: Trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride was added to an equal volume of deionized water and stirred until homogeneous. The pH was then adjusted to 4.0-4.5 with phosphoric acid, and hydrolyzed at room temperature for 15-20 minutes to obtain a hydrolysate. The silane coupling agent hydrolysate and silica (the mass concentration of the silane coupling agent hydrolysate was 50%, and the mass ratio of the silane coupling agent hydrolysate to silica was 1:3) were added to methanol solvent and stirred under sealed conditions at 60°C for 10 minutes to prepare a homogeneous modified colloidal silica composition.

[0053] Surface modification: The hydroxylated needle was immersed in a modified silica composition solution and reacted at room temperature in the dark for 12 hours. After removal, it was ultrasonically cleaned with ethanol and ultrapure water for 5 minutes in sequence to remove physically adsorbed silane. It was then dried with nitrogen to obtain the modified threaded needle (denoted as Q-Needle). Figure 1 As shown, Figure 1 Image A shows a physical example of a titanium acupuncture needle, revealing the grooved structure at the tip. (SEM results) Figure 1 B) As shown, a distinct threaded groove structure can be seen, which greatly increases the surface area of ​​the needle, making it more conducive to drug adhesion and improving drug bioavailability.

[0054] 3. Preparation of hesperidin@cyclodextrin sulfate inclusion complex (TAN@CDs): Weigh 277 mg of sodium β-cyclodextrin sulfate (equivalent to 0.2 mmol, based on an average molecular weight of 1385) and dissolve it in 4 mL of preheated ultrapure water at 50 °C, stirring magnetically.

[0055] Weigh 37.2 mg of hesperidin (0.1 mmol) and dissolve it in 4 mL of anhydrous ethanol.

[0056] While stirring, the hesperidin ethanol solution was slowly added dropwise (approximately 1 mL / min) to the hot cyclodextrin aqueous solution. After the addition was complete, the reaction was continued to be stirred at 50°C for 2 hours.

[0057] The reaction solution was rotary evaporated at 40°C to remove ethanol. The remaining clear solution was filtered through a 0.45 μm aqueous filter membrane. The filtrate was freeze-dried to obtain a pale yellow, spongy solid, which was the TAN@CDs inclusion complex powder.

[0058] 4. Preparation of drug-loaded acupuncture needles: The above TAN@CDs inclusion complex powder was prepared into a homogeneous solution with ultrapure water at a concentration of 5 mg / mL.

[0059] Immerse the Q-Needle vertically into the solution, ensuring the threaded portion is completely submerged. Place in a 4°C refrigerator and allow to stand for 12 hours for adsorption.

[0060] Carefully remove the needle body, gently blow away surface droplets with nitrogen gas, and then place it in a desiccator to dry at room temperature overnight to obtain the final drug-loaded spiral acupuncture needle (denoted as TAN@CDs-Q-Needle). The amount of dissolved drug was determined by weighing (difference in needle weight before and after drug loading) and high-performance liquid chromatography (HPLC), and the average drug loading per needle was calculated to be approximately 45±5 μg.

[0061] Comparative Example 1: In step 2 of Example 1, the surface modification step was omitted. That is, the hydroxylated needle was immersed in silica gel overnight to obtain a coated threaded needle. After washing and drying, it was immersed in a hesperidin ethanol solution for the drug loading process described in step 4. The resulting needle had an extremely low drug loading, with a stable drug load almost undetectable by HPLC (<1 μg).

[0062] Comparative Example 2: Unmodified-Needle with Medicated Thread In step 2 of Example 1, the hydroxylated needle was immersed in a 15% (w / v) aqueous solution of trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride and reacted at room temperature in the dark for 12 hours. After removal, it was ultrasonically cleaned with ethanol and ultrapure water for 5 minutes in sequence to remove physically adsorbed silane, and dried with nitrogen to obtain a surface-quaternized threaded needle. Other steps were the same as in Example 1. The drug loading of the prepared needle was significantly reduced. The amount of dissolved drug was determined by weighing (difference in needle weight before and after drug loading) and high-performance liquid chromatography (HPLC), and the average drug loading per needle was calculated to be approximately 15 ± 2 μg.

[0063] Comparative Example 3: Physical-Coating-Needle The cyclodextrin inclusion step was not used. An equal volume of hesperidin (37.2 mg) was directly dissolved in a small amount of dimethyl sulfoxide (DMSO, 0.5 mL). The coated threaded needle (Q-Needle) from Example 1 was immersed in this solution, and after removal, the solvent was evaporated, allowing the hesperidin to adhere directly to the needle surface. This method resulted in uneven drug loading, and the hydrophobic hesperidin was easily detached in aqueous environments.

[0064] Example 2: In vivo treatment of Achilles tendinitis in rats 1. Animals and Grouping: Fifty healthy male SD rats, weighing 220-250g, were randomly divided into 5 groups (n=10): Sham surgery group: Only the skin of the right hind limb Achilles tendon area was cut open, the Achilles tendon was exposed and then sutured, without damaging the Achilles tendon.

[0065] Model: After exposing the Achilles tendon, a full-thickness rectangular defect of approximately 5 mm (length) × 1 mm (width) is created in the middle of the Achilles tendon using microsurgical scissors.

[0066] Simple acupuncture group (AC): After modeling, treatment was performed using untreated coated threaded needles (Q-Needle).

[0067] Carrier control group (AC+CD): After modeling, patients were treated with spiral needles loaded with sodium β-cyclodextrin sulfate (preparation method is the same as step 3 of Example 1, but without hesperidin) that do not contain hesperidin.

[0068] Drug-loaded treatment group (AC+CD+TAN, this invention): After modeling, the patient was treated with TAN@CDs-Q-Needle prepared in Example 1.

[0069] 2. Treatment protocol: The first treatment began on the 3rd day post-surgery, followed by treatment every two weeks for a total of 4 treatments (8 weeks). During treatment, the rats were immobilized and disinfected. Acupuncture needles corresponding to the group were inserted vertically into the center of the Achilles tendon defect area to a depth of approximately 3 mm. During needle retention, the needles were rotated uniformly 5-10 times, held for 1-3 minutes, and then withdrawn. The Sham and Model groups did not receive any acupuncture treatment. Acupuncture drug administration was as follows... Figure 2 The threaded structure forms a mechanical fit with the surrounding tissue, and the needle body does not shift or dislodge under muscle contraction or slight movement; the needle tip accurately reaches the target lesion area, achieving precise drug delivery deep into the lesion.

[0070] 3. Sample Collection and Evaluation: Five animals from each group were sacrificed at week 4 (after two treatments) and week 8 (after four treatments) postoperatively, and Achilles tendon tissue from the surgical side was collected for the following analysis: General observation ( Figure 3 After 4 weeks of treatment following modeling, a small amount of new tissue formed in the Achilles tendon defect area of ​​the AC+CD and AC+CD+TAN groups, and the defect began to heal, especially in the AC+CD+TAN group where the new tissue growth was more obvious; however, no significant new tissue growth was observed in the model group, and a large defect remained. After 8 weeks of treatment, the defect areas in the AC and AC+CD groups were still not completely healed, with defects remaining and a small amount of new tissue around them; the AC+CD+TAN group showed almost no defect, and the Achilles tendon was thicker than that in the AC+CD group, approaching normal Achilles tendon tissue, indicating effective repair of the Achilles tendon.

[0071] Histological analysis: After fixation, paraffin embedding, and sectioning, the tissue was subjected to the following procedures: H&E staining ( Figure 4 In the sham group, dense, neatly arranged, and orderly collagen fibers were observed, with uniform cell distribution, few nuclei, and no inflammatory cell infiltration. In the model group, tendon defects were observed, primarily consisting of scar tissue, with a more severe inflammatory response. Collagen fibers exhibited disordered morphology and were interspersed with numerous disordered inflammatory cells. There was no significant difference between the AC and AC+CD groups. Compared to the sham group, the AC+CD+TAN group showed disordered and disordered collagen fiber arrangement, discontinuous original fibers at the defect site, and inflammatory cell infiltration nearby. Compared to other treatment groups, the AC+CD+TAN group showed the most continuous collagen fiber reconstruction within the defect area, with relatively neat and orderly fiber course; simultaneously, the degree of inflammatory cell infiltration was significantly reduced, and the local inflammatory microenvironment was effectively alleviated.

[0072] Masson staining ( Figure 5Collagen fibers stained blue. In the sham group, dense, neatly arranged, and orderly collagen fibers were observed, with no inflammatory cell infiltration. In the model group, tendon defects, more scar tissue, and more severe inflammatory response were observed, with disordered collagen fiber arrangement and a large number of disordered inflammatory cells. There was no significant difference between the AC group and the AC+CD group; tendon defects were observed, and compared with the sham group, the collagen fibers were disordered, random, and mixed with a large number of disordered inflammatory cells. Compared with other treatment groups, the AC+CD+TAN group showed relatively neat and orderly collagen arrangement, a small number of continuous collagen fibers were reconstructed, and the number of inflammatory cells was significantly reduced. The AC+CD+TAN group had the largest blue area, showing the most continuous collagen fiber reconstruction and neat arrangement, indicating good collagen synthesis and remodeling.

[0073] Immunohistochemical staining: Figure 6 This study demonstrates the expression of key factors in tendon tissue at different postoperative time points, including... Figure 6 A represents the test results at 4 weeks of treatment. Figure 6 B represents the results at 8 weeks of treatment: the positive expression area ratio of the pro-inflammatory factor IL-1β:AC+CD+TAN group was significantly lower than that of all other experimental groups.

[0074] The positive expression area ratios of anti-inflammatory / repair factor IL-10, type I collagen (COL-1), tendon transcription factor SCX, and tendinogen TNMD in the AC+CD+TAN group were significantly higher than those in the Model, AC, and AC+CD groups.

[0075] At weeks 4 and 8, the positive staining rate of IL-1β in the AC+CD+TAN group was significantly lower than that in other groups; while the positive staining rates of IL-10, COL-1, SCX, and TNMD were significantly higher than those in other groups. This indicates that hesperidin promotes tendon cell differentiation and tendon-specific gene expression by regulating SCX expression. Furthermore, the high expression of TNMD, a downstream protein of SCX, further confirms the role of hesperidin in promoting tendon regeneration.

[0076] Figure 7 The F-historical scoring results showed that the tendon tissue structure, cell arrangement and collagen distribution of the AC+CD+TAN group were closest to those of the normal physiological group, suggesting that the drug-loaded needle of the present invention (AC+CD+TAN group) has a significant advantage in promoting tendon structural repair.

[0077] Conclusion: In vivo experiments confirmed that the drug-loaded spiral acupuncture needle (AC+CD+TAN) of this invention has a significant therapeutic effect on Achilles tendon defects in rats, and its efficacy is significantly better than that of simple physical stimulation (AC group) or drug carrier only (AC+CD group). Its mechanism of action is closely related to the precise delivery of hesperidin to the lesion by the needle, effectively inhibiting the inflammatory response (reducing IL-1β) and simultaneously upregulating the tendon repair process (increasing IL-10, COL-1, SCX, TNMD).

[0078] Figure 8 This invention demonstrates the cumulative release curve of a simulated drug from a cyclodextrin carrier in vitro using the TAN@CDs-Q-Needle drug delivery needle described in this invention. TAN@CDs were placed in a 500 Da dialysis bag, sealed, and immersed in PBS buffer solution (pH 7.4, 37°C). Samples were taken at preset time points, and the drug concentration at each time point was detected using high-performance liquid chromatography (HPLC) to plot the cumulative release curve.

[0079] Data fitting results indicate that the drug exhibits good sustained-release properties from the cyclodextrin carrier, with complete release occurring in approximately 2 hours. This release behavior conforms to a first-order kinetic model (R0). 2 >0.99), indicating that the cyclodextrin carrier effectively prolongs the drug's action time, meeting the local sustained-release drug delivery requirements for tendon repair.

[0080] Example 3: Different drugs with silane coupling agents 1. Alternative Drugs: Preparation of Curcumin-Loaded Needles and In Vitro Anti-inflammatory Effects Following the method of Example 1, hesperidin was replaced with an equimolar amount of curcumin to prepare curcumin@cyclodextrin sulfate inclusion complexes (Cur@CDs), which were then loaded onto coated threaded needles.

[0081] In vitro anti-inflammatory experiment: An inflammation model was established by stimulating mouse macrophages (RAW264.7) with lipopolysaccharide (LPS). Extracts from different groups of needles (unloaded Q-Needle, Cur@CDs-Q-Needle) were co-cultured with cells. The content of tumor necrosis factor-α (TNF-α) in the cell supernatant was detected.

[0082] Results: Compared with the unloaded needle group and the model control group, Cur@CDs-Q-Needle extract significantly inhibited LPS-induced TNF-α release (P<0.01), demonstrating that the needle loaded with curcumin also has anti-inflammatory potential.

[0083] 2. Replacement of silane coupling agents: Modification of needles with different silane coupling agents In step 2 of Example 1, TMAPS is replaced with DMOAP silane coupling agent, and steps 3 and 4 are continued.

[0084] This (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride modified threaded needle was used to load TAN@CDs.

[0085] Results: The prepared needles also had a considerable drug loading capacity (approximately 42±3 μg / needle), and their in vitro release behavior was similar to that of the TMAPS-modified needles.

[0086] The above embodiments and comparative examples fully illustrate the inventiveness, effectiveness, and universality of the technical solution of the present invention. Its core innovation lies in the creative combination of the threaded structure design of the needle body, the controllable coating modification of the surface, and the drug loading / release mechanism, forming a synergistic whole that solves the key problems of low drug loading, easy loss, and uncontrollable release in existing drug-loaded needles.

Claims

1. A drug-loadable spiral acupuncture needle for treating tendinitis, characterized in that, include: The needle body is a needle-shaped carrier with puncture function, and at least a portion of the surface of the needle-shaped carrier is provided with microstructures. A colloidal coating applied to the surface of the needle body; A pharmaceutical composition loaded on the colloidal coating, the pharmaceutical composition comprising an inclusion complex formed of a carrier and a hydrophobic anti-inflammatory drug.

2. The drug-loadable spiral acupuncture needle according to claim 1, characterized in that, The microstructure is a groove, a thread, a porous structure, or a combination thereof; The needle body is made of titanium or titanium alloy, and the thread structure is a grooved thread provided at the needle tip.

3. The drug-loadable spiral acupuncture needle according to claim 1, characterized in that, The colloidal coating is a composition of silica and silane coupling agent hydrolysate; the silane coupling agent is trimethyl[3-(trimethoxysilyl)propyl]ammonium chloride or (3-trimethoxysilylpropyl)dimethyloctadecylammonium chloride.

4. The drug-loadable spiral acupuncture needle according to claim 1, characterized in that, The carrier is a cyclodextrin derivative, specifically carboxymethyl-β-cyclodextrin, sodium β-cyclodextrin sulfate, sulfobutyl ether-β-cyclodextrin, or phosphate ester-β-cyclodextrin.

5. The drug-loadable spiral acupuncture needle according to claim 1 or 4, characterized in that, The hydrophobic anti-inflammatory drug is a polymethoxyflavonoid natural product, such as hesperidin, norihesperidin, sweet orange flavonoid, or tangerine flavonoid.

6. A method for preparing a drug-loadable spiral acupuncture needle according to any one of claims 1-5, characterized in that, Includes the following steps: S1. Needle body pretreatment: Clean the needle body and perform surface hydroxylation treatment; S2. Preparation of modified colloidal silica coating formulation: Add deionized water, stir evenly, then adjust the pH to 4.0~4.5 with phosphoric acid, hydrolyze for 15~20 minutes at room temperature to obtain hydrolysate, add silane coupling agent hydrolysate and colloidal silica to organic solvent, stir at 60-80℃ to obtain modified colloidal silica coating formulation; S3. Surface modification: The hydroxylated needle body is immersed in a modified colloidal silica coating formulation to form a modification layer on the surface of the needle body, thereby obtaining a coated threaded needle; S4. Preparation of drug inclusion complex: The carrier and the hydrophobic anti-inflammatory drug are mixed and reacted in a solvent to form an inclusion complex; S5. Drug loading: The coated threaded needle obtained in step S2 is immersed in the inclusion complex solution obtained in step S4 to load the drug, and then dried to obtain the final product.

7. The preparation method according to claim 6, characterized in that, In step S2, the mass concentration of the silane coupling agent solution is 30-50%.

8. The preparation method according to claim 6, characterized in that, In step S3, the molar ratio of the carrier to the hydrophobic anti-inflammatory drug is 1:5 to 1:

1.

9. The preparation method according to claim 6, characterized in that, In step S3, the mass concentration of the inclusion complex solution is 5-30 mg / mL.

10. The application of the drug-loaded spiral acupuncture needle for treating tendinitis according to any one of claims 1-5 in a medical device for treating tendinitis, characterized in that, The drug-loaded spiral acupuncture needle is inserted into the lesion site of the patient's tendon. By rotating or pulling the needle, the loaded drug inclusion complex is released from the needle surface into the lesion tissue.

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