A light-thermal driving microneedle system based on space-time coupling control and a preparation method thereof

Abstract

The present invention discloses a photothermal-driven microneedle system based on spatiotemporal coupling control and a preparation method thereof. The system includes a stacked photothermal conversion unit, a spatiotemporal coupling control layer, and a drug-loaded microneedle array unit. The photothermal conversion unit constructs a heterojunction by using AIE-based carbon quantum dots and graphene through a silica dielectric isolation layer, and achieves full-spectrum coverage of visible light → near infrared → mid-far infrared through three-level spectral relay, with an emissivity of ≥0.85 in the 8-14 μm band and an emissivity of ≥0.90 at 9.6 μm. The spatiotemporal coupling control layer expands at the first phase transition temperature T1 to generate a thrust force to assist the microneedle penetration, and the thermal conductivity increases to more than 1.5 times that before the phase transition. The drug-loaded microneedle contains thermosensitive liposomes and triggers drug release at the third phase transition temperature T3. Through the temperature gradient of T1 < T3 ≤ T2 and the difference ≥2 °C, the four-element temporal coordination of light, wound, drug, and heat is automatically realized. The pain threshold recovery rate is 91.7%, the drug release rate at 6 hours is 98.2%, and the material complies with the GB / T 16886 standard.

Description

Technical Field

[0001] This invention relates to the fields of transdermal drug delivery and traditional Chinese medicine moxibustion, and particularly to a photothermal driven microneedle system based on spatiotemporal coupling control and its preparation method. Background Technology

[0002] Moxibustion is one of the most important external treatment methods in Traditional Chinese Medicine (TCM). Its core efficacy stems from the synergistic effect of four therapeutic elements: near-infrared and mid-to-far-infrared light radiation generated by the burning of moxa (photodynamic effect), warm stimulation (thermal effect), transdermal penetration of volatile medicinal components (pharmacological effect), and the micro-trauma to the skin caused by direct moxibustion stimulating the body's "stress-repair" response (wound effect). Among these, the 8-14μm mid-to-far-infrared radiation released by the burning of moxa is the core physical mechanism of moxibustion's efficacy—this wavelength falls precisely within the "energy window" of molecular resonance absorption in human tissues, especially around 9.6μm, which corresponds to the comprehensive peak absorption wavelength of human tissues. However, traditional moxibustion has problems such as the risk of open flame, smoke pollution, uncontrollable temperature, and burns, infections, and scarring, which limit its application in modern medical and home settings.

[0003] Microneedle systems have been extensively studied in the field. Microneedles can penetrate the stratum corneum of the skin to form microchannels, enabling efficient transdermal drug delivery. However, when combining microneedle technology with photothermal therapy, two core problems remain unresolved: First, microneedles are usually made of soluble polymer materials, and heating causes the microneedle material to soften. The softened microneedles bend and deform during insertion, which increases the insertion resistance, creating the contradiction that "heating makes the microneedles softer and harder to insert." Second, while existing photothermal nanomaterials such as carbon quantum dots have excellent photothermal conversion performance in the visible-near-infrared band, they do not yet have the ability to directly emit 8-14μm mid-far-infrared radiation, and cannot independently reproduce the core infrared radiation characteristics of traditional moxibustion.

[0004] Furthermore, existing photothermal-microneedle combination systems typically employ a simple physical superposition method, lacking precise control over the timing of the activation of the four therapeutic effects: light, heat, drug, and wound. Studies have shown that the order initiation of therapeutic effects has a significant impact on the final efficacy, but there are currently no effective means of timing control in existing technologies.

[0005] Therefore, a new technical solution is needed that can not only resolve the contradiction that "heating causes microneedles to soften and become more difficult to insert," but also achieve full coverage of the 8-14μm mid-far infrared region (especially 9.6μm radiation focusing) through the spectral relay of carbon quantum dots and graphene carbon nanomaterials, and achieve precise temporal synergy of four therapeutic effects: light, heat, medicine, and wound, so as to fully reproduce the core efficacy of traditional direct moxibustion under the premise of smokelessness, safety, and controllability. Summary of the Invention

[0006] The object of the present invention is to overcome the disadvantages and deficiencies in the prior art, and provide a photothermal-driven microneedle system based on spatiotemporal coupling control and its preparation method, so as to solve the contradiction in the existing photothermal-microneedle combined system that "heating makes it more difficult for microneedles to penetrate due to softening", the defect that carbon quantum dots cannot individually cover the mid- and far-infrared treatment band, and the problem of lack of temporal control of the quaternary treatment effect.

[0007] In the first aspect of the embodiment of the present invention, a photothermal-driven microneedle system based on spatiotemporal coupling control is provided, which includes a photothermal conversion unit, a spatiotemporal coupling control layer, and a drug-loaded microneedle array unit that are sequentially stacked and functionally coupled;

[0008] The photothermal conversion unit is used to convert external light energy into heat energy and radiate mid- and far-infrared light. The photothermal conversion unit includes a first photothermal material that can absorb visible light and emit near-infrared fluorescence, and a second photothermal material that is bonded to the first photothermal material through a dielectric isolation layer and has broadband absorption ability and can radiate 8-14 μm mid- and far-infrared light after being heated; the first photothermal material, the dielectric isolation layer, and the second photothermal material together form a heterostructure. The normal spectral emissivity of the 8-14 μm band measured by Fourier transform infrared spectroscopy with an integrating sphere and a standard blackbody at the same temperature as a reference at the system working temperature T2 is ≥0.85;

[0009] The spatiotemporal coupling control layer is arranged above the photothermal conversion unit and is composed of a thermosensitive material. When the thermosensitive material reaches the first phase change temperature T1, it expands in volume and generates a directional thrust, and at the same time, the storage modulus drops to less than 40% of that before the phase change, so that the thermal conductivity of the spatiotemporal coupling control layer increases to more than 1.5 times that before the phase change;

[0010] The drug-loaded microneedle array unit is arranged above the spatiotemporal coupling control layer and includes a plurality of microneedles that can penetrate the skin. The microneedles are internally loaded with a temperature-sensitive drug carrier, and the temperature-sensitive drug carrier releases the drug when it reaches the third phase change temperature T3;

[0011] The first phase change temperature T1, the third phase change temperature T3, and the system working temperature T2 satisfy T1 < T3 < T2, and the temperature difference between T3 and T1 is ≥2 °C, and the temperature difference between T2 and T3 is ≥1 °C;

[0012] The temperature temporal control is realized between the photothermal conversion unit, the spatiotemporal coupling control layer, and the drug-loaded microneedle array unit through the difference in thermal parameters, so that the spatiotemporal coupling control layer reaches the phase change temperature before the temperature-sensitive drug carrier.

[0013] As an implementation, the temperature difference between T3 and T1 is 2-6 °C, and the temperature difference between T2 and T3 is 1-4 °C.

[0014] In one implementation, the temperature difference between T3 and T1 is 2.5-5℃, and the temperature difference between T2 and T3 is 1.5-3℃.

[0015] In one implementation, the temperature difference between T3 and T1 is 3-4℃, and the temperature difference between T2 and T3 is 2-3℃.

[0016] In one embodiment, the first photothermal material is nitrogen-sulfur co-doped carbon quantum dots with a nitrogen content of 4-6 at, a sulfur content of 1.0-2.5 at, an average particle size of 3-6 nm, a fluorescence quantum yield of 12-18%, a broad-spectrum absorption in the range of 400-700 nm, and a fluorescence emission peak in the range of 650-750 nm.

[0017] In one embodiment, the second photothermal material is graphene obtained by thermal reduction of graphene oxide at 200-300℃, with 3-8 layers and a carbon-oxygen atom ratio ≥8:1; the dielectric isolation layer is a silicon dioxide layer with a thickness of 1.5-5nm; this thickness is configured to simultaneously achieve: ① suppressing nonradiative energy transfer between the first and second photothermal materials; ② enabling near-field coupling between the out-of-plane phonon vibrations of the second photothermal material and the Si-O-Si antisymmetric stretching vibrations of silicon dioxide, thereby enhancing the emissivity in the 9.6±0.3μm band.

[0018] In one embodiment, the heterostructure has a spectral emissivity of ≥0.90 at 9.6±0.3μm.

[0019] In one embodiment, the photothermal conversion efficiency of the photothermal conversion unit is ≥35%.

[0020] In one implementation, the infrared radiation spectrum of the heterostructure at the system operating temperature shows that the radiation energy in the 9.0-10.2μm band accounts for ≥30% of the total radiation energy in the 8-14μm band.

[0021] In one embodiment, the photothermal conversion unit further includes an aerogel substrate, which is selected from one of the following: (a) an aniline cellulose aerogel substrate with a porosity of 85-95%, a thermal conductivity ≤0.035W / (m·K), and a specific surface area ≥200m² / g, wherein the heterojunction composite material is loaded on the pore wall surface of the aerogel substrate; or (b) an aniline carbon quantum dot / graphene / cellulose multi-level heterojunction aerogel substrate, which is formed by in-situ generation of three components—carbon quantum dots, graphene-like carbon nanosheets, and nanocellulose—from Artemisia argyi raw material through a one-step hydrothermal carbonization-self-assembly process and spontaneous assembly, with a porosity of 85-98%, a photothermal conversion efficiency ≥45%, and a far-infrared emissivity ≥0.90 in the 8-14μm band.

[0022] In one embodiment, the cellulose aerogel substrate is prepared by freeze-drying and thermal cross-linking of cellulose obtained from Artemisia argyi stem cellulose via TEMPO oxidation to obtain cellulose nanofibers, wherein the cellulose nanofibers have a diameter of 5-20 nm.

[0023] In one embodiment, the heat-sensitive material is a crosslinked polymer of poly(N-isopropylacrylamide) and polyethylene glycol diacrylate, with a mass ratio of 80-85:15-20.

[0024] In one embodiment, the volume expansion rate of the thermosensitive material is 10-30%, and the directional thrust generated is 0.18-0.28 N / cm².

[0025] As one implementation, the storage modulus of the thermosensitive material decreases by ≥60% when the first phase transition temperature T1 is reached. The storage modulus is measured using a rotational rheometer under oscillating shear mode, frequency 1Hz, and strain 1%.

[0026] In one implementation, the thickness of the spatiotemporal coupling control layer is 200-500 μm, and the latent heat of phase change is 120-150 J / g.

[0027] In one embodiment, the microneedles are made of a biosoluble polymer material selected from at least one of hyaluronic acid, iodine cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, chondroitin sulfate, or gelatin.

[0028] In one embodiment, the microneedles have a needle height of 300-600 μm, a needle tip diameter of 5-15 μm, an array density of 50-200 needles / cm², and a needle spacing of 400-600 μm.

[0029] As one implementation method, the complete dissolution time of the microneedles in physiological saline at 37°C is 30-120 minutes.

[0030] In one embodiment, the thermosensitive drug carrier is a thermosensitive liposome, with dipalmitoylphosphatidylcholine and 1-stearoyl-2-hydroxy-sn-glycerol-3-phosphocholine as membrane materials in a molar ratio of 8-10:1; the particle size of the thermosensitive liposome is 100-150 nm, and the encapsulation efficiency is ≥75%.

[0031] In one embodiment, the drug loaded in the thermosensitive drug carrier is a compound combination of Artemisia argyi extract, Artemisia argyi extract and ginger extract, with a mass ratio of 2.5-3.5:1:0.8-1.2.

[0032] In one embodiment, the eucalyptol content in the Artemisia argyi extract is ≥18%, and the borneol content is ≥6%; the L-borneol content in the Artemisia argyi extract is ≥90%; and the 6-gingerol content in the ginger extract is ≥12%, and the 6-shogaol content is ≥6%.

[0033] In one implementation, the thermal response time constant τ1 of the photothermal conversion unit is 45-60 seconds, the thermal response time constant τ2 of the spatiotemporal coupling control layer is 90-120 seconds, and the thermal response time constant τ3 of the drug-loaded microneedle array unit is 150-180 seconds, satisfying τ1<τ2<τ3.

[0034] In one implementation, the arrival time t1 of T1 is 110-130 seconds, the arrival time t3 of T3 is 180-220 seconds, and the arrival time t2 of T2 is 240-300 seconds; the duration of a single treatment session is 15-30 minutes.

[0035] As one implementation, the cumulative drug release rate of the system over 6 hours is ≥90%.

[0036] As one implementation, an intelligent control module is also included, which includes a temperature sensor, a microprocessor, and a light source driving circuit. The temperature sensor monitors the system temperature in real time, and the microprocessor adjusts the light source power of the light source driving circuit according to the temperature feedback to ensure that the temperature rises in the order of T1→T3→T2 and is maintained at T2.

[0037] After extensive experimental screening, the inventors discovered that when T3-T1 is 2.5-6℃ and T2-T3 is 1.5-4℃, a good balance is achieved between time sequence resolution and treatment efficiency. Furthermore, the optimal range is when T3-T1 is 3-5℃ and T2-T3 is 2-3℃. At this time, the activation time intervals of the "light → wound → drug → heat" quaternary effect are 30 seconds, 20 seconds, and 25 seconds, respectively, which is most conducive to exerting synergistic therapeutic effects. Moreover, the single treatment time is controlled within 30 minutes, which meets the requirements of clinical application convenience.

[0038] As one implementation, the intelligent control module is also equipped with a safety protection unit, which shuts down the light source driving circuit when the detected temperature exceeds 50°C.

[0039] In one implementation, the time it takes for the directional thrust generated by the spatiotemporal coupling control layer after T1 to drive the microneedle to complete the puncture is shorter than the time it takes for the temperature of the microneedle body to rise to T3; the microneedle maintains its mechanical integrity when the puncture is completed and does not undergo bending deformation due to thermal softening.

[0040] During system operation, the photothermal conversion unit heats up first, with heat conducted upwards. When the temperature of the spatiotemporal coupling control layer reaches T1, its volume expansion generates directional thrust, driving the microneedles above to pierce the skin, forming a micro-trauma channel—the "incision" effect is initiated. Because the thermal conductivity of the spatiotemporal coupling control layer significantly increases after the phase transition, heat is efficiently transferred to the microneedles. When the internal temperature of the microneedles reaches T3, the thermosensitive liposomes undergo a phase transition, releasing the drug—the "drug" effect is initiated. Once the overall system temperature reaches T2 and enters a steady state, continuous thermal stimulation continues—the "thermal" effect persists. The photodynamic effect (near-infrared fluorescence + mid- and far-infrared radiation) is initiated immediately upon the light source is turned on and accompanies the entire process.

[0041] Thus, the system automatically activates each therapeutic effect in the order of "light → wound → medicine → heat" without the need for external program control, achieving precise temporal synergy of the four therapeutic effects.

[0042] A second aspect of this invention provides a preparation method, comprising the following steps:

[0043] S1. Preparation of nitrogen-sulfur co-doped carbon quantum dots: Using Artemisia argyi processing by-products as carbon and heteroatom sources, hydrothermal reaction was carried out at 150-200℃ for 4-8 hours, and carbon quantum dot dispersion was obtained after dialysis purification.

[0044] S2. Preparation of graphene / silica composite material: Graphene oxide is dispersed in ethanol, tetraethyl orthosilicate is added, and a sol-gel reaction is carried out under the catalysis of ammonia water to obtain graphene coated with silica.

[0045] S3. Preparation of heterojunction composite material: The carbon quantum dot dispersion is bonded to the graphene / silica composite material through a coupling reaction to obtain the heterojunction composite material; the coupling reaction is selected from one of the following:

[0046] (i) Bonded via siloxane bonds under the action of silane coupling agents; or

[0047] (ii) Bonded via amide bonds under activation by carbodiimide / N-hydroxysuccinimide;

[0048] S4. Prepare the photothermal conversion unit, selected from one of the following methods:

[0049] (i) The heterojunction composite material is dispersed in an aqueous solution of polyvinyl alcohol, coated on a substrate, and dried at 60-80°C to form a film with a thickness of 20-50 μm;

[0050] Or (ii) the heterojunction composite material is impregnated and loaded onto an icy cellulose aerogel substrate, with a loading amount of 10-30 wt% of the dry weight of the aerogel;

[0051] Or (iii) use Artemisia argyi raw material to directly prepare multi-level heterojunction aerogel containing carbon quantum dots, graphene-like carbon nanosheets and nanocellulose through a one-step hydrothermal carbonization-self-assembly process, as a photothermal conversion unit;

[0052] S5. Preparation of the spatiotemporal coupling control layer: Poly(N-isopropylacrylamide), polyethylene glycol diacrylate and photoinitiator are formulated into a precursor solution, which is coated on the surface of the photothermal conversion unit with a thickness of 200-500 μm and cured by ultraviolet light irradiation under an inert atmosphere.

[0053] S6. Preparation of drug-loaded microneedle array unit: Prepare drug-loaded thermosensitive liposomes, mix the thermosensitive liposomes with a soluble polymer solution, pour them into a microneedle mold, degas under vacuum and dry at 35-45℃, and demold to obtain the drug-loaded microneedle array unit;

[0054] S7. System Integration: The drug-loaded microneedle array unit and the spatiotemporal coupling control layer are laminated together under a pressure of 0.15-0.25 MPa.

[0055] As one embodiment, the preparation method of the aniline cellulose aerogel substrate in step S4 includes: crushing the stems of Artemisia argyi and then alkali-cooking and delignifying to obtain aniline cellulose slurry; oxidizing with a TEMPO / NaBr / NaClO system to obtain a cellulose nanofiber dispersion with a concentration of 0.5-2.0 wt%; injecting the cellulose nanofiber dispersion into a mold, freezing at -40 to -80°C and then freeze-drying for 24-48 hours; and thermally crosslinking at 120-150°C for 2-4 hours.

[0056] In one implementation method, in step S1, dialysis is performed using a dialysis bag with a molecular weight cutoff of 1000 Da, for 48 hours, with the dialysate being replaced 6-8 times; the concentration of the obtained carbon quantum dots is adjusted to 5-10 mg / mL.

[0057] In one embodiment, in step S3, the silane coupling agent is γ-aminopropyltriethoxysilane, and the amount added is 2-3% of the mass of the carbon quantum dots. The bonding reaction is carried out at 50-60°C for 2-3 hours.

[0058] In one implementation method, when selecting method (ii) in step S3, the graphene / silica composite material is dispersed in MES buffer at pH 5.0-6.5, and EDC and NHS are added for activation. The molar ratio of EDC to carboxyl groups on the carbon quantum dot surface is 2-5:1, and the molar ratio of NHS to EDC is 1-2:1. The reaction is carried out at room temperature for 2-6 hours.

[0059] As an implementation manner, when the selection method (iii) is adopted in step S4, the one-step hydrothermal carbonization-self-assembly process includes: mixing wormwood raw materials and deionized water according to a mass ratio of 1:5 to 1:20, preparing a homogenate through high-speed shearing, adjusting the pH to 3-7, performing hydrothermal reaction at 180-250 °C for 2-12 hours, and freeze-drying for 24-72 hours.

[0060] As an implementation manner, in step S5, the photoinitiator is selected from one of 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylpropiophenone or 2,2-dimethoxy-2-phenylacetophenone, and the addition amount is 0.3-0.8% of the mass of poly-N-isopropylacrylamide; the ultraviolet light wavelength is 365 nm, the irradiation intensity is 8-15 mW / cm², and the irradiation time is 10-20 minutes.

[0061] As an implementation manner, in step S6, the thermosensitive liposomes are prepared by the thin film dispersion-ultrasonic method, the thickness of the lipid membrane is controlled at 0.5-1.0 mm, the ultrasonic power is 150-200 W, and the ultrasonic time is 8-12 minutes; the soluble polymer is an aqueous solution of hyaluronic acid with a mass concentration of 8-15%, and the volume ratio of the thermosensitive liposomes to the hyaluronic acid solution is 1:2-1:4.

[0062] As an implementation manner, in step S7, the surface of the space-time coupling control layer is subjected to plasma treatment before lamination, the treatment power is 40-60 W, and the treatment time is 20-40 seconds.

[0063] The beneficial effects of the present invention are as follows:

[0064] (1) It solves the contradiction of "heating makes the microneedles softer and more difficult to penetrate" in the prior art. The test of the control example shows that when there is no space-time coupling control layer, after heating to 42 °C, the microneedle penetration force increases by 25% (from 0.28 N to 0.35 N). The reason is that the microneedle material softens and undergoes bending deformation. Through the expansion thrust (0.18-0.28 N / cm²) of the space-time coupling control layer of the present invention, the microneedle penetration force after heating is reduced by 35% (from 0.28 N to 0.18 N), achieving the counterintuitive effect of "the hotter, the easier to penetrate".

[0065] (2) It realizes the precise timing coordination of the four-element treatment effect. Through the temperature gradient design of T1 < T3 ≤ T2 and T3 - T1 ≥ 2 °C and the thermal response time constant gradient of τ1 < τ2 < τ3, the system automatically starts each treatment effect in the order of "light → wound → drug → heat" without external program control.

[0066] (3) The drug release rate is significantly improved. The cumulative drug release rate of the system of the present invention reaches 98.2% after 6 hours, while that of the control system without the spatiotemporal coupling control layer is only 62.5%, which is 57.1% higher. The reason is that the thermal conductivity of the spatiotemporal coupling control layer increases to 2.08 times that before the phase transition after the phase transition, which efficiently transfers heat to the inside of the microneedle and ensures that the liposome reaches the phase transition temperature.

[0067] (4) Experimental data demonstrate the existence of the quaternary synergistic effect and the key role of temporal control. The key comparative experiment (group F vs. group E) showed that the two groups had the same material composition. The only difference was that group F had temporal control (spatiotemporal coupling layer), while group E did not (direct superposition). The pain threshold recovery rate of group F was 91.7±4.8%, and that of group E was 59.6±5.5%, with a difference of 32.1 percentage points (P<0.001), which proves that temporal control itself (rather than material composition) is the key factor in generating the synergistic effect.

[0068] Furthermore, to eliminate the potential influencing factor of "thermal conductivity matching," a control system X was specifically constructed—which uses a non-responsive hydrogel as the spacer layer. This hydrogel has similar thermal conductivity to the spatiotemporal coupling control layer of this invention before the phase transition but exhibits no phase transition or volume expansion characteristics. Four comparative tests were conducted under identical experimental conditions. The results showed that although group X had a higher drug release rate than group E due to improved interlayer thermal contact, its pain threshold recovery rate was still significantly lower than group F, with a statistically significant difference (P<0.01). The difference in efficacy between group F and group X purely reflects the technical contribution of the core inventive point of "spatiotemporal coupling timing control," constituting a non-obvious and unexpected technical effect.

[0069] (5) Excellent safety, meeting medical device standards. Cytotoxicity test (CCK-8 method): cell survival rate of all materials >95%; Skin irritation test (Draize method): irritation index <0.5; Thermal safety: automatic light source cut-off above 50℃; Minimally invasive healing: complete healing without scarring within 72 hours. All indicators meet the GB / T16886 series standards.

[0070] (6) Flexible application and clear industrialization prospects. The system of this invention supports two application modes: Mode 1 (independent application mode) - the system is used in combination with an external LED light source, suitable for home self-use; Mode 2 (equipment enhancement mode) - the system is installed as a replaceable medicine core in a dedicated intelligent moxibustion device to achieve precise temperature control and treatment program management, suitable for medical institutions and professional users. The two modes share the same medicine core (three-layer system), reducing research and development and manufacturing costs.

[0071] (7) Through the three-level spectral relay of carbon quantum dots and graphene, full coverage of the 8-14μm mid-far-infrared treatment window and 9.6μm radiation focusing are achieved. The heterojunction thin film photothermal conversion unit has an emissivity of 0.88 in the 8-14μm band and 0.93 at 9.6μm at the system operating temperature; the aerogel photothermal conversion unit further increases the energy ratio of 8-14μm to 62.8%, reaching or even exceeding the level of traditional moxa stick combustion. Carbon quantum dots are responsible for the near-infrared band, and graphene relays the coverage of the mid-far-infrared band. The two work together to make up for the technical shortcoming that carbon quantum dots alone cannot emit mid-far-infrared radiation. The core infrared radiation characteristics of traditional direct moxibustion are completely reproduced under smokeless and safe temperatures, making the system of this invention a truly biomimetic direct moxibustion system.

[0072] (8) The one-step hydrothermal carbonization-self-assembly process provided by this invention achieves stable preparation of multi-level heterogeneous aerogels by strictly limiting the quality control parameters of Artemisia argyi raw materials (cellulose content 38-42wt%, lignin content 15-18wt%, moisture content ≤8%) and process control parameters (D90<80μm, reaction pressure 2.2±0.1MPa, stirring speed 60rpm). Three batches of independent repeated experiments proved that the RSD of the porosity, photothermal conversion efficiency and 8-14μm emissivity of the product were all less than 5%, indicating that this process has excellent reproducibility and batch stability, meeting the requirements of industrial production. Compared with the multi-step synthesis route commonly used in the prior art (such as preparing carbon quantum dots, graphene and nanocellulose separately and then compositing them), this one-step process has fewer steps (3 steps), higher retention rate of active ingredients (≥70%), and the three components form an integrated heterostructure through in-situ covalent bonding, with better interfacial bonding strength than the post-loading scheme.

[0073] (9) The present invention has carried out multi-level refined design of the temperature difference between T3-T1 and T2-T3:

[0074] When T3-T1=2-6°C and T2-T3=1-4°C, the temporal resolution reaches a clinically acceptable level; the pain threshold recovery rate is ≥85%; and the cumulative drug release rate over 6 hours is ≥90%.

[0075] When T3-T1 = 2.5-5°C and T2-T3 = 1.5-3°C (optimal): temporal resolution is significantly improved; pain threshold recovery rate ≥ 88%; 6-hour cumulative drug release rate ≥ 94%.

[0076] When T3-T1 = 3-4°C and T2-T3 = 2-3°C (optimal), the four-element initiation intervals of "light → wound → drug → heat" are 30 seconds, 20 seconds, and 25 seconds, respectively; the pain threshold recovery rate reaches 91.7%; the cumulative drug release rate over 6 hours reaches 98.2%; and the single treatment time is controlled within 30 minutes.

[0077] In summary, the experimental data corresponding to different temperature difference ranges show a clear gradient correspondence.

[0078] (10) The critical values ​​of the temperature gradient parameters have been verified by the system (see Example 7 for details).

[0079] Seven comparative experiments were conducted, including a critical lower limit group (T3-T1=2.0°C, T2-T3=1.0°C), a critical upper limit group (T3-T1=6.0°C, T2-T3=4.0°C), an optimal interval group (T3-T1=3.5°C, T2-T3=2.5°C), a lower limit control group (T3-T1=1.5°C, T2-T3=0.8°C), and an upper limit control group (T3-T1=8.0°C, T2-T3=5.5°C). The results showed that:

[0080] When T3-T1<2°C or T2-T3<1°C (lower limit control group), the pain threshold recovery rate was only 71.2±6.5%, which was 14.1 percentage points lower than the critical lower limit group (P<0.01), indicating a serious lack of temporal resolution and a significant decrease in efficacy.

[0081] When T3-T1>6°C or T2-T3>4°C (exceeding the upper limit control group), the pain threshold recovery rate actually dropped to 79.5±5.8%. This is because the temperature difference was too large, resulting in an excessively high T2, which triggered tissue heat stress, and the treatment time was too long, affecting clinical acceptability.

[0082] Within the multi-level temperature difference range defined above, the therapeutic effect shows a clear gradient correspondence of "the more precise the temperature difference, the better the effect", with the pain threshold recovery rate increasing step by step from about 86% to about 89% to 91.7%.

[0083] The above-mentioned critical value experimental data fully support the multi-level range limitation of the temperature difference between T3-T1 and T2-T3 in this invention, proving that the temperature difference boundary is not arbitrarily chosen, but a critical parameter with sufficient experimental basis.

[0084] The multi-level temperature difference range defined in this invention ensures both therapeutic efficacy and clinical safety and ease of operation, constituting one of the non-obvious technical contributions of this invention.

[0085] To provide a clearer understanding of the present invention, the specific embodiments of the present invention will be described below in conjunction with the accompanying drawings. Attached Figure Description

[0086] Figure 1 This is a schematic diagram of the layered structure and timing coordination mechanism of the system of the present invention.

[0087] Figure 2 This is a schematic diagram of a three-temperature gradient design.

[0088] Figure 3 The graph shows the rheological performance of the spatiotemporal coupling control layer.

[0089] Figure 4 Images are obtained using SEM and fluorescence microscopy for the drug-loaded microneedle array.

[0090] Figure 5 Infrared thermal image of the system during operation.

[0091] Figure 6 This is a schematic diagram of a three-level spectral relay mechanism.

[0092] Figure 7 The image shows the mid- and far-infrared radiation spectrum and system transmittance of the photothermal conversion unit. Detailed Implementation

[0093] To make the objectives, technical solutions, and advantages of the present invention clearer, the embodiments of the present invention will be described in further detail below with reference to the accompanying drawings.

[0094] It should be understood that the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0095] In the following description, when referring to the accompanying drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. In the description of this invention, it should be understood that the terms "first," "second," "third," etc., are used only to distinguish similar objects and are not necessarily used to describe a specific order or sequence, nor should they be construed as indicating or implying relative importance. Those skilled in the art will understand the specific meaning of the above terms in this invention according to the specific circumstances. The singular forms "a," "described," and "the" used in this invention and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. The word "if" as used herein can be interpreted as "when," "when," or "in response to a determination."

[0096] Furthermore, in the description of this invention, unless otherwise stated, "multiple" means two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. The character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0097] Please see Figure 1-7, in the first aspect of the embodiments of the present invention, a photothermal-driven microneedle system based on spatiotemporal coupling control is provided. As Figure 1 shown, it includes a photothermal conversion unit, a spatiotemporal coupling control layer, and a drug-loaded microneedle array unit that are stacked in sequence and functionally coupled;

[0098] The photothermal conversion unit is used to convert external light energy into heat energy and radiate mid- and far-infrared light. The photothermal conversion unit includes a first photothermal material that can absorb visible light and emit near-infrared fluorescence, and a second photothermal material that is bonded to the first photothermal material through a dielectric isolation layer and has broadband absorption ability and can radiate 8-14 μm mid- and far-infrared light after being heated. The first photothermal material, the dielectric isolation layer, and the second photothermal material together form a heterostructure. The heterostructure has a normal spectral emissivity of ≥0.85 in the 8-14 μm band measured by Fourier transform infrared spectroscopy with an integrating sphere and a standard blackbody at the same temperature as a reference at the system working temperature T2;

[0099] The spatiotemporal coupling control layer is arranged above the photothermal conversion unit and is composed of a thermosensitive material. The thermosensitive material undergoes volume expansion and generates a directional thrust when reaching the first phase change temperature T1, and at the same time, the storage modulus drops to less than 40% of that before the phase change, causing the thermal conductivity of the spatiotemporal coupling control layer to increase to more than 1.5 times that before the phase change;

[0100] The drug-loaded microneedle array unit is arranged above the spatiotemporal coupling control layer and includes a plurality of microneedles that can penetrate the skin. The microneedles are internally loaded with a temperature-sensitive drug carrier, and the temperature-sensitive drug carrier releases the drug when reaching the third phase change temperature T3;

[0101] The first phase change temperature T1, the third phase change temperature T3, and the system working temperature T2 satisfy T1 < T3 < T2, and the temperature difference between T3 and T1 is ≥2 °C, and the temperature difference between T2 and T3 is ≥1 °C;

[0102] The temperature sequential control is achieved through the difference in thermal parameters between the photothermal conversion unit, the spatiotemporal coupling control layer, and the drug-loaded microneedle array unit, so that the spatiotemporal coupling control layer reaches the phase change temperature before the temperature-sensitive drug carrier.

[0103] In a feasible embodiment, the temperature difference between T3 and T1 is 2-6 °C, and the temperature difference between T2 and T3 is 1-4 °C.

[0104] In a feasible embodiment, the temperature difference between T3 and T1 is 2.5-5 °C, and the temperature difference between T2 and T3 is 1.5-3 °C.

[0105] In a feasible embodiment, the temperature difference between T3 and T1 is 3-4 °C, and the temperature difference between T2 and T3 is 2-3 °C.

[0106] For example, such as Figure 2 As shown, the temperature range of T1 is 38-40℃, the temperature range of T3 is 41-43℃, and the temperature range of T2 is 44-46℃.

[0107] In one feasible embodiment, the first photothermal material is nitrogen-sulfur co-doped carbon quantum dots with a nitrogen content of 4-6 at, a sulfur content of 1.0-2.5 at, an average particle size of 3-6 nm, a fluorescence quantum yield of 12-18%, a broad-spectrum absorption in the range of 400-700 nm, and a fluorescence emission peak in the range of 650-750 nm.

[0108] In one feasible embodiment, the second photothermal material is graphene obtained by thermal reduction of graphene oxide at 200-300℃, with 3-8 layers and a carbon-oxygen atom ratio ≥8:1; the dielectric isolation layer is a silicon dioxide layer with a thickness of 1.5-5nm; this thickness is configured to simultaneously achieve: ① suppressing nonradiative energy transfer between the first and second photothermal materials; ② enabling near-field coupling between the out-of-plane phonon vibrations of the second photothermal material and the Si-O-Si antisymmetric stretching vibrations of silicon dioxide, thereby enhancing the emissivity in the 9.6±0.3μm band.

[0109] In a feasible embodiment, the Si-O-Si antisymmetric stretching vibration mode of the dielectric isolation layer resonates with the out-of-plane phonon vibration mode of the second photothermal material in the 9.4-9.8 μm band, so that the spectral emissivity of the heterostructure at 9.6±0.3 μm is ≥0.90.

[0110] In one feasible embodiment, the photothermal conversion efficiency of the photothermal conversion unit is ≥35%.

[0111] In a feasible embodiment, the infrared radiation energy of the heterostructure in the 9.0-10.2μm band accounts for ≥30% of the total radiation energy in the 8-14μm band at the system operating temperature.

[0112] In one feasible embodiment, the photothermal conversion unit further includes an aerogel substrate, the aerogel substrate being selected from one of the following: (a) an aniline cellulose aerogel substrate with a porosity of 85-95%, a thermal conductivity ≤0.035W / (m·K), and a specific surface area ≥200m² / g, wherein the heterojunction composite material is loaded on the pore wall surface of the aerogel substrate; or (b) an aniline carbon quantum dot / graphene / cellulose multi-level heterojunction aerogel substrate, which is formed by in-situ generation of three components—carbon quantum dots, graphene-like carbon nanosheets, and nanocellulose—from Artemisia argyi raw material through a one-step hydrothermal carbonization-self-assembly process and spontaneous assembly, with a porosity of 85-98%, a photothermal conversion efficiency ≥45%, and a far-infrared emissivity ≥0.90 in the 8-14μm band.

[0113] In one feasible embodiment, the cellulose aerogel substrate is prepared by freeze-drying and thermal cross-linking of cellulose obtained from Artemisia argyi stem cellulose via TEMPO oxidation to obtain cellulose nanofibers, wherein the cellulose nanofibers have a diameter of 5-20 nm.

[0114] In one feasible embodiment, the thermosensitive material is a crosslinked polymer of poly(N-isopropylacrylamide) and polyethylene glycol diacrylate in a mass ratio of 80-85:15-20.

[0115] In one feasible embodiment, the volume expansion rate of the thermosensitive material is 10-30%, and the resulting directional thrust is 0.18-0.28 N / cm².

[0116] In one feasible embodiment, the storage modulus of the thermosensitive material decreases by ≥60% when the first phase transition temperature T1 is reached. The storage modulus is measured using a rotational rheometer under oscillating shear mode, frequency 1Hz, and strain 1%.

[0117] In one feasible embodiment, the thickness of the spatiotemporal coupling control layer is 200-500 μm, and the latent heat of phase change is 120-150 J / g.

[0118] In one feasible embodiment, the microneedles are made of a biosoluble polymer material selected from at least one of hyaluronic acid, iodine, sodium carboxymethyl cellulose, polyvinylpyrrolidone, chondroitin sulfate, or gelatin.

[0119] In one feasible embodiment, the microneedles have a needle height of 300-600 μm, a needle tip diameter of 5-15 μm, an array density of 50-200 needles / cm², and a needle spacing of 400-600 μm.

[0120] In one feasible embodiment, the complete dissolution time of the microneedles in physiological saline at 37°C is 30-120 minutes.

[0121] In one feasible embodiment, the thermosensitive drug carrier is a thermosensitive liposome, with dipalmitoylphosphatidylcholine and 1-stearoyl-2-hydroxy-sn-glycerol-3-phosphocholine as membrane materials in a molar ratio of 8-10:1; the thermosensitive liposome has a particle size of 100-150 nm and an encapsulation efficiency of ≥75%.

[0122] In one feasible embodiment, the drug loaded in the thermosensitive drug carrier is a compound combination of Artemisia argyi extract, Artemisia argyi extract and ginger extract, with a mass ratio of 2.5-3.5:1:0.8-1.2.

[0123] In one feasible embodiment, the eucalyptol content in the Artemisia argyi extract is ≥18%, and the borneol content is ≥6%; the L-borneol content in the Artemisia argyi extract is ≥90%; and the 6-gingerol content in the ginger extract is ≥12%, and the 6-shogaol content is ≥6%.

[0124] In a feasible embodiment, the thermal response time constant τ1 of the photothermal conversion unit is 45-60 seconds, the thermal response time constant τ2 of the spatiotemporal coupling control layer is 90-120 seconds, and the thermal response time constant τ3 of the drug-loaded microneedle array unit is 150-180 seconds, satisfying τ1<τ2<τ3.

[0125] In a feasible embodiment, the arrival time t1 of T1 is 110-130 seconds, the arrival time t3 of T3 is 180-220 seconds, and the arrival time t2 of T2 is 240-300 seconds; the single treatment time is 15-30 minutes.

[0126] In one feasible embodiment, the cumulative drug release rate of the system over 6 hours is ≥90%.

[0127] In one feasible embodiment, the system further includes an intelligent control module, which includes a temperature sensor, a microprocessor, and a light source driving circuit. The temperature sensor monitors the system temperature in real time, and the microprocessor adjusts the light source power of the light source driving circuit according to the temperature feedback to ensure that the temperature rises in the order of T1→T3→T2 and is maintained at T2.

[0128] In one feasible embodiment, the intelligent control module is further provided with a safety protection unit, which shuts down the light source driving circuit when the detected temperature exceeds 50°C.

[0129] In a feasible embodiment, the time it takes for the directional thrust generated by the spatiotemporal coupling control layer after T1 to drive the microneedle to complete the puncture is shorter than the time it takes for the temperature of the microneedle body to rise to T3; the microneedle maintains its mechanical integrity when the puncture is completed and does not undergo bending deformation due to thermal softening.

[0130] A second aspect of this invention provides a preparation method, comprising the following steps:

[0131] S1. Preparation of nitrogen-sulfur co-doped carbon quantum dots: Using Artemisia argyi processing by-products as carbon and heteroatom sources, hydrothermal reaction was carried out at 150-200℃ for 4-8 hours, and carbon quantum dot dispersion was obtained after dialysis purification.

[0132] S2. Preparation of graphene / silica composite material: Graphene oxide is dispersed in ethanol, tetraethyl orthosilicate is added, and a sol-gel reaction is carried out under the catalysis of ammonia water to obtain graphene coated with silica.

[0133] S3. Preparation of heterojunction composite material: The carbon quantum dot dispersion is bonded to the graphene / silica composite material through a coupling reaction to obtain the heterojunction composite material; the coupling reaction is selected from one of the following:

[0134] (i) Bonded via siloxane bonds under the action of silane coupling agents; or

[0135] (ii) Bonded via amide bonds under activation by carbodiimide / N-hydroxysuccinimide;

[0136] S4. Prepare the photothermal conversion unit, selected from one of the following methods:

[0137] (i) The heterojunction composite material is dispersed in an aqueous solution of polyvinyl alcohol, coated on a substrate, and dried at 60-80°C to form a film with a thickness of 20-50 μm;

[0138] Or (ii) the heterojunction composite material is impregnated and loaded onto an icy cellulose aerogel substrate, with a loading amount of 10-30 wt% of the dry weight of the aerogel;

[0139] Or (iii) use Artemisia argyi raw material to directly prepare multi-level heterojunction aerogel containing carbon quantum dots, graphene-like carbon nanosheets and nanocellulose through a one-step hydrothermal carbonization-self-assembly process, as a photothermal conversion unit;

[0140] S5. Preparation of the spatiotemporal coupling control layer: Poly(N-isopropylacrylamide), polyethylene glycol diacrylate and photoinitiator are formulated into a precursor solution, which is coated on the surface of the photothermal conversion unit with a thickness of 200-500 μm and cured by ultraviolet light irradiation under an inert atmosphere.

[0141] S6. Preparation of drug-loaded microneedle array unit: Prepare drug-loaded thermosensitive liposomes, mix the thermosensitive liposomes with a soluble polymer solution, pour them into a microneedle mold, degas under vacuum and dry at 35-45℃, and demold to obtain the drug-loaded microneedle array unit;

[0142] S7. System Integration: The drug-loaded microneedle array unit and the spatiotemporal coupling control layer are laminated together under a pressure of 0.15-0.25 MPa.

[0143] In a feasible embodiment, the preparation method of the aniline cellulose aerogel substrate in step S4 includes: crushing Artemisia argyi stems and then alkali-cooking and delignifying to obtain aniline cellulose slurry; oxidizing with a TEMPO / NaBr / NaClO system to obtain a cellulose nanofiber dispersion with a concentration of 0.5-2.0 wt%; injecting the cellulose nanofiber dispersion into a mold, freezing at -40 to -80°C and then freeze-drying for 24-48 hours; and thermally crosslinking at 120-150°C for 2-4 hours.

[0144] In one feasible embodiment, in step S1, dialysis is performed using a dialysis bag with a molecular weight cutoff of 1000 Da, for 48 hours, with the dialysate being changed 6-8 times; the concentration of the obtained carbon quantum dots is adjusted to 5-10 mg / mL.

[0145] In a feasible embodiment, in step S3, the silane coupling agent is γ-aminopropyltriethoxysilane, and the amount added is 2-3% of the mass of the carbon quantum dots. The bonding reaction is carried out at 50-60°C for 2-3 hours.

[0146] In a feasible embodiment, when selecting mode (ii) in step S3, the graphene / silica composite material is dispersed in MES buffer at pH 5.0-6.5, and EDC and NHS are added for activation. The molar ratio of EDC to carboxyl groups on the carbon quantum dot surface is 2-5:1, and the molar ratio of NHS to EDC is 1-2:1. The reaction is carried out at room temperature for 2-6 hours.

[0147] In a feasible embodiment, when mode (iii) is selected in step S4, the one-step hydrothermal carbonization-self-assembly process includes: mixing Artemisia argyi raw material with deionized water at a mass ratio of 1:5 to 1:20, preparing a homogenate by high-speed shearing, adjusting the pH to 3-7, hydrothermally reacting at 180-250℃ for 2-12 hours, and freeze-drying for 24-72 hours.

[0148] In a feasible embodiment, in step S5, the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone or 2,2-dimethoxy-2-phenylacetophenone, and the amount added is 0.3-0.8% of the mass of poly(N-isopropylacrylamide); the ultraviolet light wavelength is 365 nm, the irradiation intensity is 8-15 mW / cm², and the irradiation time is 10-20 minutes.

[0149] In a feasible embodiment, in step S6, the thermosensitive liposomes are prepared by thin-film dispersion-ultrasound method, the lipid film thickness is controlled at 0.5-1.0 mm, the ultrasonic power is 150-200 W, and the ultrasonic time is 8-12 minutes; the soluble polymer is an aqueous solution of hyaluronic acid with a mass concentration of 8-15%, and the volume ratio of the thermosensitive liposomes to the hyaluronic acid solution is 1:2-1:4.

[0150] In a feasible embodiment, in step S7, the surface of the spatiotemporal coupling control layer is subjected to plasma treatment before lamination, with a treatment power of 40-60W and a treatment time of 20-40 seconds.

[0151] The technical solution of the present invention will be further described below with reference to several embodiments:

[0152] The main detection methods and instruments involved in the embodiments of this invention are as follows:

[0153] (1) Rheological performance test: A TA Instruments AR2000 rotational rheometer was used with a flat plate fixture (diameter 25mm), a gap of 500μm, oscillation mode, frequency 1Hz, strain 1%, temperature scan range 25-50℃, and heating rate 1℃ / min.

[0154] (2) Expansion test: A laser displacement sensor (Keyence LK-G30, resolution 0.01μm) was used to record the thickness change of the spatiotemporal coupling control layer during the heating process in real time.

[0155] (3) Thrust test: The pressure generated by the spatiotemporal coupling control layer on the microneedle substrate during the phase transition was measured using a TA Instruments Q800 dynamic mechanical analyzer in compression mode.

[0156] (4) Microneedle penetration force test: Stable MicroSystems TA.XTplus texture analyzer, P / 2 probe (diameter 2mm), test speed 0.5mm / s, test distance 1mm, trigger force 0.05N. The simulated skin was Parafilm M sealing film (8 layers stacked, about 1mm thick).

[0157] (5) Drug release test: A Franz diffusion cell (effective diffusion area 1.77 cm²) was used, the receiving solution was pH 7.4 PBS, the temperature was 37-45℃ (controlled by constant temperature water bath), 0.5 mL of sample was taken at preset time points (and an equal amount of fresh receiving solution was added at the same time), and the drug content was determined by high performance liquid chromatography (HPLC) and the cumulative release rate was calculated.

[0158] (6) Scanning electron microscopy (SEM) observation: Hitachi SU8010 field emission scanning electron microscope was used with an accelerating voltage of 5kV and the sample was sputtered with gold.

[0159] (7) Infrared thermal imaging test: FLIRE60 infrared thermal imager was used, with a temperature range of -20 to 650℃, accuracy of ±2℃, thermal sensitivity of <0.05℃, and acquisition frequency of 1Hz.

[0160] (8) Photothermal conversion efficiency test: The incident light power and transmitted light power were measured using a power meter (ThorlabsPM100D), and the temperature rise curve was recorded using a thermocouple. The photothermal conversion efficiency was calculated according to η=mc_pΔT / (P·t).

[0161] (9) Thermal conductivity test: The thermal conductivity of each layer of material before and after phase transition was measured using a HotDisk TPS2500S thermal constant analyzer and the transient plane heat source method.

[0162] (10) Mid- and far-infrared emissivity test: Fourier transform infrared spectrometer (Bruker VERTEX 70v, equipped with DTGS detector and integrating sphere accessory), reflectance mode, test band 2-25μm (4000-400cm) was used. -1 ), resolution 4cm -1 Sample heating was performed using a precision temperature-controlled heating stage (Linkam HFS600) with a temperature accuracy of ±0.1℃. Using a standard blackbody radiation source (emissivity 0.99) as a reference, the spectral emissivity at each wavelength was calculated as ε(λ) = I_sample(λ) / I_blackbody(λ).

[0163] Example 1: Fabrication and Characterization of the Spatiotemporal Coupling Control Layer

[0164] 1.1 Raw materials

[0165] Poly(N-isopropylacrylamide) (PNIPAM, Mn≈40000, Sigma-Aldrich); Polyethylene glycol diacrylate (PEGDA, Mn≈700, Sigma-Aldrich); Photoinitiator 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone (Irgacure2959, BASF).

[0166] 1.2 Preparation method

[0167] (1) Dissolve PNIPAM and PEGDA in deionized water at a mass ratio of 82:18, with a total solid content of 15wt%.

[0168] (2) Add photoinitiator Irgacure2959 at a rate of 0.5 wt% of PNIPAM mass.

[0169] (3) The precursor liquid is coated on the surface of the photothermal conversion unit, and the thickness is controlled by a scraper to 350 μm.

[0170] (4) The film was cured by irradiation with 365nm ultraviolet light in a nitrogen atmosphere (irradiation intensity 10mW / cm², irradiation time 15 minutes).

[0171] 1.3 Characterization Results

[0172] (1) Rheological properties: The storage modulus G' is 45.2 kPa at 25℃ and drops to 7.05 kPa at 42℃, a decrease of 84.4%. The loss tangent tanδ shows an abrupt peak at 38.5℃, confirming the phase transition temperature T1=38.5℃.

[0173] (2) Expansion and thrust (see) Figure 3The laser displacement sensor recorded that the spatiotemporal coupling control layer began to expand at T1=38.5℃, and the expansion rate reached 18.5% at 45℃. The directional thrust measured by DMA was 0.22 N / cm².

[0174] (3) Thermal conductivity: HotDisk measurements show that the thermal conductivity before the phase change (25℃) is 0.25W / (m·K) and after the phase change (42℃) is 0.52W / (m·K), which is 2.08 times that before the phase change.

[0175] (4) Latent heat of phase change: DSC measurement showed that the latent heat of phase change was 135 J / g.

[0176] Example 2: Preparation and Characterization of Drug-Loaded Microneedle Array Units

[0177] 2.1 Preparation of thermosensitive liposomes

[0178] (1) Weigh DPPC and MSPC (molar ratio 9:1) and dissolve them in a chloroform-methanol (2:1, v / v) mixed solvent.

[0179] (2) Rotary evaporation (45℃, 120rpm, -0.09MPa) removes organic solvents and forms a uniform lipid film with a thickness of about 0.8mm.

[0180] (3) Add pH 7.4 PBS buffer containing the drug (the drug is a compound combination of Artemisia argyi extract, Artemisia argyi extract and ginger extract, with a mass ratio of 3:1:1), hydration temperature 50℃, hydration time 30 minutes.

[0181] (4) Ultrasonic treatment (power 180W, time 10 minutes) to obtain a uniform liposome suspension.

[0182] (5) Extruded through 400nm and 200nm polycarbonate films in sequence, 5 times each.

[0183] Characterization results: Particle size 128±15 nm (DLS determination), PDI 0.18, encapsulation efficiency 82.3%. DSC confirmed phase transition temperature T3 = 42.0℃. The mass ratio of thermosensitive liposomes to drug was 10:1.

[0184] 2.2 Preparation of drug-loaded microneedle arrays

[0185] (1) Prepare a 12wt% hyaluronic acid (HA, Mn≈200kDa) aqueous solution.

[0186] (2) Mix the thermosensitive liposome suspension and HA solution at a volume ratio of 1:3 and stir gently until homogeneous.

[0187] (3) Pour the mixture into a PDMS microneedle mold (mold parameters: needle height 500μm, needle tip diameter 10μm, array density 100 needles / cm², needle spacing 500μm).

[0188] (4) Vacuum degassing (-0.08MPa, 10 minutes) to ensure that the mixture completely fills the needle cavity.

[0189] (5) Dry at 40℃ for 12 hours, and demold to obtain drug-loaded microneedle array units.

[0190] Characterization results: SEM observation showed that the microneedles had intact morphology (see...). Figure 4 (a)), needle height 485±12μm, needle tip diameter 8±2μm. Observed under a fluorescence microscope (excitation wavelength 450nm, see [reference]). Figure 4 (b) shows a uniform fluorescence signal inside the microneedles, confirming that carbon quantum dots and liposomes are uniformly distributed in the microneedle matrix. The substrate thickness of the microneedle array is 150 μm.

[0191] Microneedle dissolution time test: The microneedle array was immersed in PBS at 37℃ and pH 7.4, and observed every 15 minutes. The results showed that the microneedles completely dissolved at 45 minutes and the substrate completely dissolved at 90 minutes.

[0192] Example 3: Fabrication and Characterization of Photothermal Conversion Unit

[0193] 3.1 Preparation of carbon quantum dots (step S1)

[0194] (1) Take 5g of Artemisia argyi processing by-product (sifted stem powder), add 50mL of deionized water, and ultrasonically disperse for 30 minutes.

[0195] (2) Transfer to a 100mL polytetrafluoroethylene-lined hydrothermal reactor and react at 180℃ for 6 hours.

[0196] (3) Allow to cool naturally to room temperature, then centrifuge (10,000 rpm, 15 minutes) to remove large precipitate particles.

[0197] (4) The supernatant was transferred into a dialysis bag with a molecular weight cutoff of 1000 Da and dialyzed in deionized water for 48 hours, with the dialysate being changed every 8 hours (a total of 6 changes).

[0198] (5) The dialysate was concentrated by rotary evaporation and the carbon quantum dot concentration was adjusted to 8 mg / mL.

[0199] Characterization results: TEM showed an average carbon quantum dot size of 4.2 ± 0.8 nm. XPS analysis showed a nitrogen content of 5.1 at% (in the range of 4-6 at%) and a sulfur content of 1.8 at% (in the range of 1.0-2.5 at%). Fluorescence spectroscopy showed an emission peak at 695 nm (in the range of 650-750 nm) under 450 nm excitation, with a fluorescence quantum yield of 15.2% (in the range of 12-18%). UV-Vis spectroscopy showed continuous broad absorption in the range of 400-700 nm.

[0200] Mid- and far-infrared emissivity test (carbon quantum dots alone): At 45℃, the average emissivity of the carbon quantum dot PVA film in the 8-14μm band was only 0.52, and the emissivity at 9.6μm was only 0.55. This confirms that carbon quantum dots alone do not possess effective mid- and far-infrared radiation capabilities and require the supplementation of graphene.

[0201] 3.2 Preparation of graphene / silica composite material (step S2)

[0202] (1) Graphene oxide (GO, monolayer rate >90%) was dispersed in ethanol at a concentration of 2 mg / mL.

[0203] (2) Add tetraethyl orthosilicate (TEOS), with a mass ratio of GO to TEOS of 1:0.5.

[0204] (3) Add ammonia (28wt%) dropwise until pH 10, and stir at room temperature for 12 hours.

[0205] (4) Centrifuge and wash 3 times (alternating between ethanol and water), and vacuum dry at 60°C.

[0206] (5) Graphene / SiO2 composite material was obtained by thermal reduction at 250°C for 2 hours under nitrogen atmosphere.

[0207] Characterization results: Raman spectroscopy showed a D / G peak intensity ratio of 0.95, confirming partial reduction of graphene. TEM showed a SiO2 layer thickness of approximately 2.5 nm. XPS analysis showed a carbon-to-oxygen atomic ratio of 8.5:1. AFM indicated approximately 5 layers.

[0208] 3.3 Preparation of heterojunction composite materials (step S3)

[0209] (1) Take 10 mL of carbon quantum dot dispersion (8 mg / mL) and add 50 mg of graphene / SiO2 composite material.

[0210] (2) Add γ-aminopropyltriethoxysilane (APTES) at a rate of 2.5% of the mass of carbon quantum dots (i.e., 2 mg).

[0211] (3) Stir the reaction at 55℃ for 2.5 hours.

[0212] (4) Centrifuge and wash 3 times, then redisperse in deionized water.

[0213] 3.4 Fabrication of thin-film photothermal conversion unit (Step S4, Scheme 1)

[0214] (1) The heterojunction composite material was dispersed in a 5wt% polyvinyl alcohol (PVA) aqueous solution, and the heterojunction content was 15wt% of the dry weight of PVA.

[0215] (2) Coated onto a PET substrate, with a doctor blade controlling the wet film thickness.

[0216] (3) Dry at 70℃ for 2 hours to obtain a photothermal conversion unit film with a dry film thickness of 35μm.

[0217] Characterization results:

[0218] Photothermal conversion efficiency test: The photothermal conversion unit was irradiated with a 450nm LED light source (power density 100mW / cm²), and the temperature rise curve was recorded by thermocouples. The temperature rose from 25℃ to 42.8℃ within 5 minutes, and the photothermal conversion efficiency η was calculated to be 38.5%.

[0219] Thermal response time constant: τ1 = 52 seconds, fitted from the temperature rise curve of the infrared thermogram.

[0220] Example 4: System Integration and Thermal Performance Characterization

[0221] 4.1 System Integration (Steps S5-S7)

[0222] (1) A spatiotemporal coupling control layer is prepared on the surface of the photothermal conversion unit prepared in Example 3 according to the method of Example 1 (step S5).

[0223] (2) Plasma treatment is performed on the surface of the spatiotemporal coupling control layer.

[0224] (3) The drug-loaded microneedle array unit prepared in Example 2 was laminated with the spatiotemporal coupling control layer under a pressure of 0.20 MPa (step S7) for 60 seconds.

[0225] 4.2 Thermal performance characterization

[0226] (1) Thermal response time constant test: The bottom of the system was irradiated with a 450nm LED light source (power density 100mW / cm²), and the FLIRE60 infrared thermal imager recorded the temperature changes of each layer in real time from the side.

[0227] Results: Photothermal conversion unit τ1 = 52 seconds; spatiotemporal coupling control layer τ2 = 108 seconds (within the range of 90-120 seconds); drug-loaded microneedle array unit τ3 = 165 seconds (within the range of 150-180 seconds).

[0228] (2) Timing arrival time test: T1 arrival time t1=118 seconds (within the range of 110-130 seconds); T3 arrival time t3=198 seconds (within the range of 180-220 seconds); T2 arrival time t2=268 seconds (within the range of 240-300 seconds).

[0229] (3) Direct measurement of thermal conductivity and verification of thermal resistance:

[0230] HotDisk measured thermal conductivity of each layer: k1 (photothermal conversion unit) = 0.48 W / (m·K); k2 (spatiotemporal coupling control layer, before phase transition) = 0.25 W / (m·K); k3 (drug-loaded microneedle array) = 0.18 W / (m·K).

[0231] The heat capacity C of each layer is calculated from the material density ρ, specific heat capacity c_p, and thickness L (per unit area):

[0232] C1 = 1.3 × 1.5 × 35 × 10 -6 =6.8×10 -5 J / (cm²·K)

[0233] C2 = 1.1 × 3.8 × 350 × 10 -6 =1.46×10 -3 J / (cm²·K)

[0234] C3 = 1.2 × 2.5 × 650 × 10 -6 =1.95×10 -3 J / (cm²·K)

[0235] The gradient design of the thermal parameters in the three-layer structure results in a progressively increasing thermal capacity delay as heat is transferred from the bottom to the top layer. Combined with the different thermal conductivities of each layer, this achieves a time-sequence control effect of τ1 < τ2 < τ3 (t1 = 118 s). <t3=198s<t2=268s)。

[0236] (4) Infrared thermal image recording (see Figure 5 ):

[0237] Figure 5Before the display system starts (t = 0 s), the temperatures of all three layers are at the ambient temperature of 25 °C. At t = 120 s (when T1 is reached), the temperature of the photothermal conversion unit rises to 42.0 °C, and the space-time coupling control layer just reaches T1 = 38.5 °C and starts to undergo phase change expansion. At this time, the temperature of the drug-loaded microneedle array is only 32.8 °C, much lower than T3 = 42 °C, ensuring that the microneedles complete puncture in the state where the main body is not softened. At t = 300 s (steady state of T2), the system stabilizes at T2 = 44.5 °C, and the drug-loaded microneedles reach T3 = 42.3 °C to achieve liposome phase change drug release, and the temperature distribution of the three layers shows a stable gradient of T2 > middle layer > T3.

[0238] The infrared thermogram visually verifies the successful operation of the four-element time-sequential coordination mechanism of "photothermal conversion → space-time coupling control → drug-loaded microneedles" of the present invention.

[0239] 4.3 Drug release test

[0240] The Franz diffusion cell test system was used to test the drug release behavior of the system. The bottom of the system was irradiated with a 450 nm LED light source, and the system temperature was maintained within the range of 44 - 46 °C. Samples were taken at 0.5, 1, 2, 3, 4, 5, and 6 hours, and the content of eucalyptol was determined by HPLC.

[0241] Results: The cumulative release rate at 6 hours was 98.2 ± 6.8%. The release curve showed a typical S shape: the release rate was <5% (liposomes did not undergo phase change) within 0 - 3 minutes (t < t3); the release rate increased sharply to 78% within 3 - 30 minutes (liposomes underwent phase change drug release); and it slowly released to 98.2% within 30 minutes - 6 hours (the microneedle matrix dissolved to release the remaining drug).

[0242] Example 5: Microneedle penetration force test

[0243] 5.1 Test method

[0244] A StableMicroSystems TA.XTplus texture analyzer with a P / 2 probe was used, the test speed was 0.5 mm / s, and Parafilm M sealing film (8 layers stacked) was used to simulate the skin.

[0245] 5.2 Test groups

[0246] Group A: The drug-loaded microneedle array unit was used alone at room temperature (25 °C) and manually pressed.

[0247] Group B: The drug-loaded microneedle array unit was used alone, heated to 42 °C, and manually pressed.

[0248] Group C: The complete system (including the space-time coupling control layer) was irradiated with a light source to 42 °C.

[0249] 5.3 Test results

[0250] Group A (room temperature) 0.28±0.05 418±22 95% Group B (Heating without coupling layer) 0.35±0.06 415±20 88% Group C (Complete System) 0.18±0.04 462±18 100%

[0251] Compared to group A, group B showed a 25% increase in insertion force, confirming the contradiction that "heating softens the microneedle, making it more difficult to insert." Compared to group A, group C showed a 35% decrease in insertion force, a 10.5% increase in insertion depth, and a 100% success rate. This confirms that the expansion thrust of the spatiotemporal coupling control layer effectively resolved the aforementioned contradiction.

[0252] To further elucidate the mechanism by which "heating makes it easier to insert," a high-speed camera system (PhotronFASTCAM Mini UX100, 10000fps) was used in conjunction with a microforce sensor (Futek LSB200, ±0.01N) to observe the dynamic behavior of the microneedles in the complete system (Group C) during the heating process.

[0253] Test method:

[0254] The complete system was applied to the surface of transparent Parafilm M simulated skin. An LED light source (450nm, 100mW / cm²) was used to illuminate the surface from the bottom. A high-speed camera recorded the displacement changes of the microneedle array from the side, and a microforce sensor was placed under the simulated skin to record the changes in the insertion force.

[0255] Observation results:

[0256] (1) t=0-100s: The system temperature rises from 25℃ to 37℃ (lower than T1), the spatiotemporal coupling control layer does not deform significantly, the microneedles remain in their initial position, and the insertion force is 0N (not in contact with the skin).

[0257] (2) t=118s (T1 arrives): The temperature of the spatiotemporal coupling control layer reaches 38.5℃, and the volume expansion is completed within 0.5 seconds (the expansion rate jumps from 0% to 18.5%), generating a directional thrust of 0.22N / cm² on the microneedle substrate.

[0258] (3) t=118.2-118.8s: The microneedle base gains an instantaneous displacement of about 65μm under the thrust, and the needle tip completes the penetration of the simulated skin surface (about 20μm thick) within 0.6 seconds. The peak penetration force recorded by the microforce sensor is 0.18±0.04N, which is consistent with the data of group C in Table 5.3.

[0259] (4) After t=119s: the microneedle is inserted and maintains a stable position. At this time, the temperature of the microneedle body is only about 39.5℃ (measured by infrared thermal imager), which is far below the softening temperature of hyaluronic acid (about 43℃). The microneedle maintains its mechanical integrity and does not bend or deform.

[0260] (5) t=198s (T3 reached): The internal temperature of the microneedle reaches 42℃, and the liposome phase change drug release begins. At this time, the microneedle has completed the establishment of a deep drug delivery channel, and the insertion depth is stable at 462±18μm.

[0261] Mechanism interpretation:

[0262] The above-described kinetic process demonstrates that the microneedle puncture action of the system of this invention occurs before the "temperature-sensitive window" (i.e., before the microneedle softens). The critical time window is: T1 reaches (t=118s) → microneedle completes puncture (t=119s) → microneedle heats up to softening temperature (t≈180s), with a time difference of approximately 60 seconds. This time difference ensures that the microneedle completes puncture while maintaining its mechanical strength, fundamentally resolving the technical contradiction that "heating and softening makes puncture more difficult."

[0263] Example 6: Verification of the quaternary synergistic effect (animal experiment)

[0264] 6.1 Laboratory Animals and Ethics

[0265] Male SD rats, weighing 220-250g, SPF grade. The animal experimental protocol was approved by the Laboratory Animal Ethics Committee (Approval No.: [Actual No.]). All procedures complied with the "Regulations on the Management of Laboratory Animals".

[0266] 6.2 Pain Model Establishment

[0267] A chronic inflammatory pain model induced by complete Freund's adjuvant (CFA) was established. 0.1 mL of CFA was subcutaneously injected into the left hind paw of rats, and treatment began on day 3 post-modeling.

[0268] 6.3 Experimental Grouping (n=8 per group)

[0269] Group A (blank control) No action taken none Group B (Light + Heat Only) Photothermal conversion unit + LED light source, no microneedles, no drugs Light + Heat Group C (Created Only) Blank microneedles (without medication), manually press and insert. Creation Group D (Medication Only) Drug-loaded microneedles are inserted manually with pressure, without heating. Drug + Injury Group E (quaternion without timing) Photothermal conversion unit + drug-loaded microneedles directly stacked (without spatiotemporal coupling layer), irradiated by LED light source. Light + Heat + Medicine + Wound (without time control) Group F (Complete System) Complete three-layer system + LED light source illumination Light + Heat + Medicine + Wound (with sometimes sequential control)

[0270] Treat once a day for 30 minutes each time, for 7 consecutive days.

[0271] 6.4 Pain Threshold Measurement

[0272] Mechanical pain threshold was determined using the von Frey fiber method. Measurement time points: before modeling (baseline), day 3 after modeling (before treatment), and days 1, 3, 5, and 7 of treatment. Pain threshold recovery rate (%) = (Pain threshold after treatment - Pain threshold before treatment) / (Baseline pain threshold - Pain threshold before treatment) × 100%.

[0273] 6.5 Experimental Results

[0274] Pain threshold recovery rate in each group on day 7 of treatment:

[0275] Group A (blank control) 12.3±3.2 — Group B (Light + Heat Only) 35.8±6.1 <0.001 Group C (Created Only) 22.5±4.7 <0.05 Group D (Medication Only) 41.2±5.3 <0.001 Group E (quaternary unordered) 59.6±5.5 <0.001 Group F (Complete System) 91.7±4.8 <0.001

[0276] Key Comparison: Group F vs. Group E – The two groups have identical substance compositions; the only difference is that Group F has temporal control, while Group E does not. Group F (91.7%) was significantly higher than Group E (59.6%), a difference of 32.1 percentage points (P<0.001). This demonstrates that temporal control itself is a key factor in generating a synergistic effect.

[0277] 6.6 Histological observation

[0278] After treatment, skin tissue from the treated area of ​​rats was collected and observed by HE staining. Skin tissue from group F showed minute epidermal repair traces at the microneedle insertion points, with an intact dermal structure and no scar formation. A small number of newly formed capillaries and fibroblasts were observed around the insertion points, suggesting that the microtrauma triggered a local tissue repair response. The microtrauma healed completely after 72 hours.

[0279] Example 7: Critical value verification experiment of temperature gradient parameter

[0280] 7.1 Experimental Objective

[0281] Verify the technical rationality of the critical values ​​and optimal ranges of the defined temperature difference parameter ranges (T3-T1 and T2-T3), and isolate the independent contribution of the temperature difference parameter to the synergistic effect.

[0282] 7.2 Experimental Grouping

[0283] By adjusting the power of the photothermal conversion unit, the thickness of the spatiotemporal coupling control layer, and the molar ratio of the liposome membrane material, seven systems with different T3-T1 and T2-T3 temperature differences were prepared:

[0284] Group G1 (critical lower limit): T3-T1=2.0°C, T2-T3=1.0°C;

[0285] Group G2: T3-T1=6.0°C, T2-T3=4.0°C;

[0286] Group G3: T3-T1=2.5°C, T2-T3=1.5°C;

[0287] Group G4: T3-T1=5.0°C, T2-T3=3.0°C;

[0288] Group G5 (Optimal Interval): T3-T1=3.5°C, T2-T3=2.5°C;

[0289] Group G6 (lower limit control): T3-T1=1.5°C, T2-T3=0.8°C;

[0290] Group G7 (Exceeding Upper Limit Control): T3-T1=8.0°C, T2-T3=5.5°C;

[0291] 7.3 Test Methods

[0292] The method for determining the pain threshold recovery rate is the same as in Example 6, and the method for determining the drug release rate is the same as in Example 4.

[0293] 7.4 Experimental Results (Table 7-1)

[0294] Table 7-1 Comparison of treatment effects under different temperature gradient parameters (n=8)

[0295] G1 (Critical Lower Limit) 2.0 1.0 85.3±5.1 90.6±3.2 G2 (weight 3 cap) 6.0 4.0 86.1±4.8 91.5±3.5 G3 (Weight 4 lower limit) 2.5 1.5 88.5±4.5 94.2±2.8 G4 (Weight 4 cap) 5.0 3.0 89.2±4.6 95.1±3.0 G5 (Optimal Interval) 3.5 2.5 91.7±4.8 98.2±2.5 G6 (Below Limit Comparison) 1.5 0.8 71.2±6.5 78.4±4.6 G7 (Exceeding the upper limit comparison) 8.0 5.5 79.5±5.8 83.6±4.2

[0296] 7.5 Data Interpretation

[0297] Data Interpretation of Example 7: Criticality Demonstration of Temperature Gradient Parameters

[0298] (1) Lower limit criticality verification:

[0299] The pain threshold recovery rate in group G6 (T3-T1=1.5°C) was only 71.2%, significantly lower than the 85.3% in group G1 (T3-T1=2.0°C) (difference 14.1 percentage points, P<0.01). This demonstrates that T3-T1≥2°C is the minimum temperature difference required to produce effective temporal synergy, constituting the lower limit critical value.

[0300] (2) Verification of the reasonableness of the upper limit:

[0301] The pain threshold recovery rate in group G7 (T3-T1=8°C) was only 79.5%, which was significantly lower than the 86.1% in group G2 (T3-T1=6°C) (P<0.01). This is because an excessive temperature difference can lead to an excessively high T2 (>46°C), causing tissue thermal damage; at the same time, it prolongs the treatment time and affects clinical acceptability.

[0302] (3) The gradient correspondence is clear:

[0303] As the temperature difference range narrowed step by step from (2-6°C) to (2.5-5°C) to (3-4°C), the pain threshold recovery rate increased step by step from 86% to 89% to 91.7%, showing a clear "gradient → effect" correspondence.

[0304] Example 8: Security Assessment

[0305] 8.1 Cytotoxicity test

[0306] The CCK-8 assay was used, with L929 mouse fibroblasts as a model. Extracts from each layer of material (prepared according to GB / T16886.12) were co-cultured with the cells for 24 hours.

[0307] Results: The cell viability of the photothermal conversion unit extract group was 97.2±2.1%; the cell viability of the spatiotemporal coupling control layer extract group was 96.8±1.8%; and the cell viability of the drug-loaded microneedle array extract group was 95.5±2.3%. The cell viability of all groups was >95%, and the cytotoxicity grade was 0-1, which met the GB / T16886.5 standard.

[0308] 8.2 Skin irritation test

[0309] Using the Draize method, three New Zealand white rabbits were used. The complete system was applied to the hair-removing area on the rabbit's back, and the area was irradiated with an LED light source for 30 minutes. Erythema and edema reactions were observed at 1, 24, 48, and 72 hours.

[0310] Results: Erythema score ≤0.5, edema score 0, and irritation index <0.5 at all time points, which is considered "non-irritating" and meets the GB / T16886.10 standard.

[0311] 8.3 Thermal safety test

[0312] Under the control of the intelligent control module, the ambient temperature is artificially raised to simulate extreme conditions. When the system temperature reaches 50℃, the safety protection unit shuts off the light source drive circuit within 0.5 seconds, and the system temperature drops back to below 45℃ within 30 seconds.

[0313] Example 9: Intelligent Moxibustion Therapy Device (Device Enhancement Mode)

[0314] This embodiment provides an intelligent moxibustion device for use in conjunction with the three-layer system of the present invention.

[0315] 9.1 Equipment Composition

[0316] (1) Microneedle core slot: used to install the three-layer system of the present invention, with a treatment area of ​​4cm², for single use.

[0317] (2) LED light source array: wavelength 450-650nm, total power 350mW, power is adjusted by microprocessor through PID algorithm.

[0318] (3) Temperature sensor: flexible thermocouple, accuracy ±0.1℃, real-time monitoring of system temperature.

[0319] (4) Microprocessor: STM32 ultra-low power microcontroller, running PID temperature control algorithm to ensure that the temperature rises in the order of T1→T3→T2 and is maintained at T2.

[0320] (5) Safety protection unit: When the detected temperature exceeds 50℃, the light source will be turned off within 0.5 seconds.

[0321] (6) BLE communication module: transmits temperature data to mobile APP in real time for treatment records and remote monitoring.

[0322] (7) Rechargeable lithium battery: 200mAh capacity, which can support 3-5 treatments on a single charge.

[0323] 9.2 Workflow

[0324] The user installs the microneedle core into the device slot → applies the device to the acupoints → clicks "Start Treatment" on the mobile app → the LED light source is activated → the photothermal conversion unit heats up → the spatiotemporal coupling control layer undergoes a phase change at T1 (expansion thrust drives microneedle insertion) → heat is conducted to the inside of the microneedle → the T3 liposome phase change releases the drug → the system stabilizes at T2 for continuous thermal stimulation → the temperature sensor provides real-time feedback → the PID adjusts the LED power → the device automatically shuts off after 30 minutes → the app records the treatment data.

[0325] Example 10: Characterization of the mid- and far-infrared radiation performance of the photothermal conversion unit

[0326] This embodiment is one of the core characterization embodiments of the present invention, used to verify the effectiveness of the three-level spectral relay mechanism of carbon quantum dots and graphene, as well as the coverage ability of the heterostructure on the 8-14μm mid-far-infrared treatment window and the radiation focusing effect on 9.6μm.

[0327] 10.1 Test Method

[0328] The spectral emissivity of the photothermal conversion unit at different temperatures was measured using a Fourier transform infrared spectrometer (Bruker VERTEX 70v, equipped with a DTGS detector and integrating sphere accessory) in reflectance mode. Test wavelength range: 2-25 μm (4000-400 cm⁻¹). -1 ), resolution 4cm -1 Sample heating was performed using a precision temperature-controlled heating stage (Linkam HFS600) with a temperature accuracy of ±0.1℃. Using a standard blackbody radiation source (emissivity 0.99) as a reference, the spectral emissivity at each wavelength was calculated as ε(λ) = I_sample(λ) / I_blackbody(λ).

[0329] 10.2 Test Samples

[0330] Sample I: Heterojunction thin-film photothermal conversion unit prepared in Example 3 (CQDs / SiO2 / rGO heterojunction dispersed on PVA substrate, film thickness 35μm) - carbon quantum dots and graphene are bonded to form a heterojunction through a SiO2 dielectric isolation layer.

[0331] Sample II: PVA film containing only carbon quantum dots (no graphene, film thickness 35 μm) – used to verify the mid- and far-infrared radiation capabilities of carbon quantum dots alone.

[0332] Sample III: PVA film containing only graphene (no carbon quantum dots, film thickness 35 μm) – used to verify the mid- and far-infrared radiation capabilities of graphene alone.

[0333] Sample IV: A PVA film of a physical mixture of carbon quantum dots and graphene (without SiO2 dielectric isolation layer, film thickness 35 μm) – used to verify the enhancement effect of heterojunction interface effect on 9.6 μm focusing.

[0334] Sample V: Heterogeneous composite material loaded on icy cellulose aerogel substrate (loading 20wt%, aerogel thickness 500μm, porosity 91%) – used to verify the enhancement effect of aerogel substrate on mid- and far-infrared radiation.

[0335] 10.3 Test Results

[0336] (1) Emissivity in the 8-14μm band (45℃):

[0337] Sample II (CQDs only) 0.52 0.55 21.2% Sample III (rGO only) 0.78 0.80 26.8% Sample IV (physical mixing) 0.81 0.82 27.5% Sample I (heterojunction thin film) 0.88 0.93 33.5% Sample V (aerogel type) 0.92 0.96 36.2%

[0338] (2) Key findings and verification of the spectral relay mechanism:

[0339] a) Shortcomings of carbon quantum dots in the mid-to-far infrared range: The average emissivity of sample II (CQDs only) at 8-14 μm is only 0.52, and the emissivity at 9.6 μm is only 0.55. This confirms that carbon quantum dots, limited by quantum confinement effects and surface state emission mechanisms, currently lack the ability to effectively emit mid-to-far infrared radiation in the 8-14 μm range. The core contribution of carbon quantum dots lies in visible light absorption and near-infrared fluorescence emission (400-750 nm), making them the "first link" in the spectral relay.

[0340] b) Graphene's Mid-to-Far Infrared Relay: Sample III (rGO only) achieved an average emissivity of 0.78 at 8-14 μm and 0.80 at 9.6 μm. Graphene, with its excellent phonon vibration characteristics (out-of-plane acoustic ZA mode frequencies corresponding to the 8-14 μm band), can efficiently emit mid-to-far infrared radiation after heating, successfully completing the mid-to-far infrared band that carbon quantum dots cannot cover, serving as the "second leg" in the spectral relay.

[0341] c) Focused enhancement at the 9.6 μm heterojunction interface: Sample I (heterojunction) vs. Sample IV (physical mixture) – the average emissivity at 8-14 μm increased from 0.81 to 0.88 (an increase of 8.6%), the emissivity at 9.6 μm increased from 0.82 to 0.93 (an increase of 13.4%), and the energy percentage at 9.0-10.2 μm increased from 27.5% to 33.5% (an increase of 21.8%). This significant difference demonstrates that the Si-O-Si antisymmetric stretching vibration mode (approximately 9.7 μm) of the SiO2 dielectric insulating layer resonates with the out-of-plane phonon mode of graphene, producing an emissivity enhancement peak at 9.6 ± 0.3 μm. This is the "third leg" of the spectral relay – interface enhancement.

[0342] d) Enhanced radiation of the aerogel substrate: Sample V (aerogel type) vs. Sample I (film type) – the average emissivity at 8-14 μm increased from 0.88 to 0.92, the emissivity at 9.6 μm increased from 0.93 to 0.96, and the energy percentage at 9.0-10.2 μm increased from 33.5% to 36.2%. The high specific surface area (285 m² / g) of the aerogel substrate significantly increases the effective radiation area, while the ultra-low thermal conductivity (0.028 W / (m·K)) reduces ineffective heat loss away from the skin. These two effects together enhance the mid- and far-infrared radiation power density.

[0343] (3) Temperature dependence:

[0344] Within the range of 25-50℃, the average emissivity of sample I at 8-14μm monotonically increases from 0.85 (25℃) to 0.89 (50℃), and is 0.88-0.89 within the system operating temperature range of 44-46℃.

[0345] (4) Comparison with the infrared radiation of traditional moxibustion:

[0346] 8-14μm energy percentage 61.4% 58.2% 62.8% Radiation intensity at 9.6 μm (normalized) 1.00 0.91 1.05 Radiant temperature Approximately 600℃ (open flame) 44-46℃ (Safe) 44-46℃ (Safe) smoke have none none Burn risk high none none

[0347] Sample V (aerogel type) exhibits an energy percentage (62.8%) at 8-14 μm and a radiation intensity (normalized to 1.05) at 9.6 μm that meets or exceeds the levels of traditional moxa stick combustion, while operating at only 44-46℃ with no smoke or risk of burns. This demonstrates that the system of this invention, through the spectral relay of carbon quantum dots and graphene, completely reproduces the core infrared radiation characteristics of traditional direct moxibustion at a safe temperature.

[0348] 10.4 Verification of the far-infrared radiation transmittance of the complete system

[0349] Please see Figure 7To verify whether the spatiotemporal coupling control layer and the drug-loaded microneedle array unit would block the mid- and far-infrared radiation emitted by the photothermal conversion unit from reaching the skin, the far-infrared transmittance of the complete three-layer system was tested.

[0350] Test method: The complete three-layer system (photothermal conversion unit + spatiotemporal coupling control layer + drug-loaded microneedle array unit) was placed in the transmission optical path of the FTIR spectrometer and heated with a 45℃ heating stage to measure the transmittance in the 8-14μm band.

[0351] Test results:

[0352] Spatiotemporal coupling control layer (single layer) 82.5% 80.8% Drug-loaded microneedle array (single layer) 78.3% 76.5% Complete three-tier system 65.2% 62.8%

[0353] Analysis: After the phase transition (42℃), the water content of the spatiotemporal coupling control layer decreases, and the absorption of mid- and far-infrared radiation by water molecules weakens, resulting in a high transmittance (82.5%). The hyaluronic acid matrix of the drug-loaded microneedle array exhibits some absorption in the 8-14μm wavelength range, but the transmittance still reaches 78.3%. The overall transmittance of the complete system is 65.2%, meaning that approximately two-thirds of the mid- and far-infrared radiation emitted by the photothermal conversion unit can penetrate the two layers above to reach the skin surface.

[0354] Considering the emissivity of the photothermal conversion unit (sample I) at 8-14 μm is 0.88, the overall equivalent far-infrared radiation efficiency of the system is 0.88 × 0.652 = 0.574, meaning approximately 57.4% of the incident light energy ultimately reaches the skin in the form of mid-to-far-infrared radiation. For the aerogel type (sample V, emissivity 0.92), the equivalent efficiency is...

[0355] 0.92 × 0.652 = 0.600, which is 60.0%.

[0356] This value is comparable to the far-infrared energy utilization efficiency of traditional moxibustion (reported in the literature as about 40-60%, due to the scattering of moxa smoke and loss from air convection), further proving that the system of the present invention can be equivalent to traditional moxibustion in terms of far-infrared radiation efficiency.

[0357] Example 11: Preparation and Characterization of Icy Cellulose Aerogel Substrates

[0358] 11.1 Raw Materials

[0359] Artemisia argyi stems (derived from a byproduct of Artemisia argyi processing, pulverized to 40 mesh); TEMPO (2,2,6,6-tetramethylpiperidine-1-oxygen radical, Sigma-Aldrich); NaBr (analytical grade); NaClO (available chlorine content 10%); NaOH (analytical grade).

[0360] 11.2 Preparation method

[0361] (1) Alkali boiling delignification: Take 50g of Artemisia argyi stem powder, add 1000mL of 2wt% NaOH solution, stir and boil at 90℃ for 2 hours, filter and wash until neutral to obtain Artemisia argyi cellulose slurry (cellulose content ≥85%).

[0362] (2) TEMPO oxidation: Take 5g of cellulose slurry (dry weight), disperse it in 500mL of deionized water, and add 80mg of TEMPO and 500mg of NaBr. Add NaClO solution (available chlorine 25mmol / g cellulose) dropwise while stirring, maintain pH 10.0 with 0.5M NaOH, and react at room temperature for 4 hours. Terminate the reaction by adding ethanol, centrifuge and wash 3 times to obtain cellulose nanofiber (CNF) dispersion.

[0363] (3) Concentration adjustment: The CNF dispersion was concentrated to 1.0 wt%. TEM observation showed that the fiber diameter was 8 ± 3 nm and the length was 500 nm - 2 μm.

[0364] (4) Freeze-drying: Inject CNF dispersion into a circular mold (30 mm in diameter and 5 mm in depth), freeze at -60°C for 12 hours, and then dry in a freeze dryer for 36 hours (-50°C, <10 Pa).

[0365] (5) Thermal crosslinking: The freeze-dried sample was thermally crosslinked in an oven at 130°C for 3 hours to obtain acetylsaccharide aerogel substrate.

[0366] 11.3 Characterization Results

[0367] (1) Porosity: 91.2%. Calculation method: Porosity = (1 - ρ_bulk / ρ_cellulose) × 100%, where ρ_bulk = 0.138 g / cm³. 3 ρ_cellulose = 1.56 g / cm³ 3 .

[0368] (2) Thermal conductivity: 0.028 W / (m·K) (measured by HotDisk).

[0369] (3) Specific surface area: 285 m² / g (BET method, N2 adsorption-desorption, ≥200 m² / g).

[0370] (4) Mechanical properties: compression modulus 12.5 kPa (50% strain), can withstand the 0.20 MPa pressure required for system lamination without collapsing.

[0371] (5) Heterogeneous junction loading: The heterogeneous junction composite material dispersion (concentration 5 mg / mL) prepared in Example 3 was impregnated into the aerogel substrate, vacuum-assisted permeation was performed for 30 minutes, and then dried at 60°C. The loading amount was 20 wt% of the dry weight of the aerogel. SEM observation showed that the heterogeneous junction nanoparticles were uniformly distributed on the surface of the aerogel pore walls.

[0372] Comparison Example 1: A control system without a spatiotemporal coupling control layer

[0373] Preparation method: The photothermal conversion unit of Example 3 and the drug-loaded microneedle array unit of Example 2 were directly laminated together (the spatiotemporal coupling control layer was omitted), and the other conditions were exactly the same as those of Example 4.

[0374] Penetration force test (method as in Example 5):

[0375] At room temperature (25℃): Penetration force 0.28±0.05N, penetration depth 418±22μm;

[0376] Heating unit (42℃): Penetration force 0.35±0.06N, penetration depth 415±20μm.

[0377] The insertion force of the heated group increased by (0.35-0.28) / 0.28×100%=25%, proving the contradiction that "heating softens the microneedle material, making it more difficult to insert."

[0378] Drug release test (method as in Example 4): The cumulative release rate after 6 hours was 62.5±5.2%, significantly lower than the 98.2±6.8% of the system of the present invention. Reason for the decrease in release rate: The control system lacks the thermal conduction effect of the spatiotemporal coupling layer. The measured internal temperature of the microneedle was only about 38°C, which is lower than the liposome phase transition temperature T3 (42°C). Most of the liposomes did not undergo phase transition, resulting in incomplete drug release.

[0379] Example 12: One-step aerogel photothermal conversion unit

[0380] 12.1 Preparation method

[0381] (1) Take 20g of dried Artemisia argyi leaves (dried, produced in Nanyang, Henan Province, harvested around the Dragon Boat Festival, with a cellulose content of 38-42wt%, lignin content of 15-18wt%, and moisture content ≤8%), add 200mL of deionized water (mass ratio 1:10), process with a high-speed shearing machine (IKA T25, speed 15000rpm) for 5 minutes, and monitor in real time with a laser particle size analyzer until the D90 particle size of the solids in the homogenate is less than 80μm, and obtain a uniform homogenate.

[0382] (2) Add 2g of urea and 1g of thiourea as N / S doping sources and stir until homogeneous.

[0383] (3) Transfer the homogenate to a 500mL polytetrafluoroethylene-lined hydrothermal reactor and add citric acid to adjust the pH to 5.0.

[0384] (4) Programmed temperature rise hydrothermal reaction: First stage: rise to 100℃ at 3℃ / min and hold for 45 minutes; Second stage: rise to 160℃ at 2℃ / min and hold for 90 minutes; Third stage: rise to 220℃ at 1.5℃ / min and hold for 180 minutes. Stirring was carried out continuously at a rate of 60 rpm throughout the process, and the pressure inside the reactor was monitored and maintained at 2.2±0.1 MPa in real time during the 220℃ holding stage.

[0385] (5) Allow the hydrogel to cool naturally to room temperature and remove it.

[0386] (6) Pre-freeze at -60℃ for 12 hours and freeze-dry for 48 hours to obtain a one-step Agi multi-level heterojunction aerogel.

[0387] Process reproducibility verification

[0388] Using the same raw material specifications and process control parameters, three independent replicate experiments were conducted on different dates by different operators. The relative standard deviations (RSDs) of the porosity (93.5%±1.8%), photothermal conversion efficiency (56.2%±2.1%), and 8-14μm emissivity (0.93±0.01) of the three batches of products were all less than 5%, demonstrating that this one-step process has good reproducibility and reliability under strict quality control.

[0389] 12.2 Characterization Results

[0390] (1) Porosity: 93.5%. (2) Photothermal conversion efficiency: 56.2%. (3) Far-infrared emissivity in the 8-14μm band: 0.93. (4) Emissivity at 9.6μm: 0.95. (5) Energy percentage in the 9.0-10.2μm range: 34.8%. (6) Retention rate of active ingredients of Artemisia argyi: 76% (18.5% eucalyptol, 7.2% borneol). (7) Specific surface area: 310 m² / g.

[0391] 12.3 System Integration

[0392] The one-step aerogel was cut into 4cm² circular pieces (500μm thick), and a spatiotemporal coupling control layer and a drug-loaded microneedle array were prepared on top of them according to the method in Example 4 to complete the system integration.

[0393] System performance: T1 arrival time t1=125 seconds, T3 arrival time t3=205 seconds, T2 arrival time t2=275 seconds, timing control is normal. Cumulative drug release rate over 6 hours is 96.8%.

[0394] 12.4 Comparison with Thin Film and Loaded Types

[0395] Preparation steps S1-S4 (4 steps) S1-S4+ aerogel (5 steps) One-step hydrothermal treatment + drying (2 steps) 8-14μm emissivity 0.88 0.92 0.93 9.6μm emissivity 0.93 0.96 0.95 Photothermal conversion efficiency 38.5% 40.2% 56.2% Retention of active ingredients none none 76% Preparation cycle 3 days 5 days 2 days

[0396] One-step aerogel has significant advantages in photothermal conversion efficiency (56.2% vs 38.5%) and ease of preparation (2 steps vs 4-5 steps), and additionally retains the active ingredients of Artemisia argyi, which can form a dual drug source with microneedle drug delivery.

[0397] Example 13: Preparation of heterojunctions by amide bond coupling of EDC / NHS

[0398] 13.1 Preparation method

[0399] (1) Take 50 mg of the graphene / SiO2 composite material prepared in step 3.2 of Example 3 and disperse it in 10 mL of pH 5.5 MES buffer (0.1 M).

[0400] (2) Add 20mg of EDC and 12mg of NHS, and stir at room temperature for 30 minutes to activate.

[0401] (3) Add 10 mL of the carbon quantum dot dispersion (8 mg / mL) prepared in step 3.1 of Example 3, and stir at room temperature for 4 hours.

[0402] (4) Centrifuge and wash 3 times (with deionized water) and redisperse.

[0403] 13.2 Characterization Results

[0404] FTIR spectrum at 1640 cm⁻¹ -1 An absorption peak for amide I appears at 1540 cm⁻¹. -1 The presence of an absorption peak in amide II confirms the formation of the amide bond.

[0405] Photothermal conversion efficiency: 37.8%. Emissivity in the 8-14μm band: 0.87.

[0406] Emissivity at 9.6 μm: 0.91.

[0407] Compared with the APTES method (Example 3): there was no significant difference in photothermal performance and far-infrared radiation performance between the two bonding methods (P>0.05), proving that both coupling methods can effectively achieve chemical bonding between carbon quantum dots and graphene.

[0408] Control Example 2: Drug-only control (no photothermal, no time-series control)

[0409] Preparation method: The drug-loaded microneedle array unit prepared in Example 2 is used independently without being integrated with the photothermal conversion unit and the spatiotemporal coupling control layer.

[0410] Instructions for use: Manually press the drug-loaded microneedle array onto the surface of Parafilm M simulated skin and place it in a constant temperature environment of 37°C for 6 hours.

[0411] Drug release test results: The cumulative release rate over 6 hours was 28.5 ± 4.1%. The release mechanism was that the microneedle matrix slowly dissolved and released the drug at 37°C. The liposomes did not undergo a phase transition at 37°C (T3 = 42°C), and the encapsulated drug was not triggered for release.

[0412] This comparative example demonstrates that, under conditions without photothermal drive, relying solely on passive release through the dissolution of the microneedle matrix, the drug release rate is extremely low (28.5%), far lower than that of the complete system of this invention (98.2%) and Comparative Example 1 without a spatiotemporal coupling layer (62.5%).

[0413] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention should be included within the scope of protection of the present invention. Special Note:

[0414] 1. The material of the spatiotemporal coupling control layer is not limited to the poly(N-isopropylacrylamide) / polyethylene glycol diacrylate system. Any hydrogel material with similar thermally induced phase change properties (phase change temperature 38-42℃, modulus decrease ≥50% during phase change, volume expansion rate 10-30%) can be used.

[0415] 2. Microneedle materials are not limited to hyaluronic acid; biosoluble materials such as cellulose acetate, sodium carboxymethyl cellulose, polyvinylpyrrolidone, chondroitin sulfate, and gelatin can also be used.

[0416] 3. Traditional Chinese medicine compound prescriptions are not limited to the combination of "Artemisia argyi-Ayana-Ginger". Other traditional Chinese medicine combinations with the effects of warming the meridians and dispelling cold, promoting blood circulation and removing blood stasis can also be used.

[0417] 4. The heterojunction of the photothermal conversion unit is not limited to the carbon quantum dot / SiO2 / graphene system. Other nanocomposite materials with similar spectral conversion, photothermal conversion and mid- and far-infrared radiation functions can be used, but should meet the basic requirement of emissivity ≥0.85 in the 8-14μm band.

[0418] 5. The aerogel substrate is not limited to icy cellulose aerogel; other biomass aerogels with similar porosity (85-95%) and low thermal conductivity (≤0.035W / (m·K)) can also be used.

[0419] Please see Figure 6 This invention achieves full coverage of 8-14μm through the following three-level spectral relay mechanism:

[0420] The first stage of "light-to-light" conversion involves carbon quantum dots absorbing visible light (400-700nm) and emitting 650-750nm near-infrared fluorescence through radiative relaxation. This fluorescence directly acts on skin tissue to activate mitochondrial cytochrome c oxidase, promoting ATP synthesis. Simultaneously, it generates heat through non-radiative relaxation.

[0421] The second stage of "photothermolysis" involves graphene absorbing near-infrared fluorescence and residual visible light emitted by carbon quantum dots, generating heat through phonon relaxation, and emitting mid-to-far-infrared light in the 8-14 μm range as thermal radiation at operating temperatures. The frequency of graphene's out-of-plane acoustic (ZA) phonon mode precisely corresponds to the infrared radiation in the 8-14 μm band, making it an ideal mid-to-far-infrared radiator.

[0422] The third level of “interface enhancement” is the interfacial phonon coupling effect of the carbon quantum dot / silica / graphene heterostructure. This causes the Si-O-Si antisymmetric stretching vibration mode (approximately 9.7 μm) of the silica layer to resonate with the out-of-plane phonon mode of graphene, generating an emissivity enhancement peak at 9.6 ± 0.3 μm, thus achieving radiation focusing on the peak absorption wavelength of human tissue.

[0423] Through this three-stage spectral relay, carbon quantum dots handle the first leg of the spectrum from visible light to near-infrared, graphene completes the second leg from near-infrared to heat to mid- and far-infrared, and the heterojunction interface effect completes the third leg of the spectrum from 9.6μm focusing enhancement. The synergy of these three elements compensates for the inability of carbon quantum dots alone to cover the mid- and far-infrared bands, thus fully reproducing the core infrared radiation characteristics of traditional moxibustion under flameless conditions.

[0424] Optionally, the photothermal conversion unit can also use icy cellulose aerogel as a substrate. The ultra-high porosity (85-95%) and ultra-low thermal conductivity (≤0.035W / (m·K)) of the aerogel give it two major advantages: thermal insulation effect reduces ineffective heat loss away from the skin and improves the efficiency of thermal radiation towards the skin; the high specific surface area effect allows the heterojunction material loaded on the surface of the aerogel pore walls to have an effective radiation area much larger than that of a planar thin film, significantly enhancing the radiation power density in the 8-14μm band.

[0425] The photothermal conversion unit of this invention supports three fabrication methods:

[0426] Option 1 (Heterojunction Thin Film): The carbon quantum dot / SiO2 / graphene heterojunction composite material prepared in steps is dispersed in a PVA solution and coated to form a film. This option has a mature preparation process, and the film thickness can be precisely controlled, making it suitable for precision lamination integration with a spatiotemporal coupling control layer.

[0427] Option 2 (Heterogeneous Junction Aerogel Type): The heterojunction composite material prepared in steps is impregnated and loaded onto an icy cellulose aerogel substrate prepared by the TEMPO method. This option utilizes the high specific surface area of ​​the aerogel to enhance the far-infrared radiation power density, while utilizing the ultra-low thermal conductivity to reduce ineffective heat loss.

[0428] Option 3 (One-Step Aerogel): Using Artemisia argyi as a single raw material, a multi-level heterojunction aerogel containing carbon quantum dots, graphene-like carbon nanosheets, and nanocellulose is directly prepared through a one-step hydrothermal carbonization-self-assembly process, which can be used directly as a photothermal conversion unit. This option has the simplest process (3 steps), the highest retention rate of active ingredients (≥70%), and the three components form an integrated heterostructure through in-situ self-assembly via covalent bonds, with better interfacial bonding strength than the post-loading option.

[0429] All three schemes can achieve the core functional requirements of emissivity ≥0.85 in the 8-14μm band and radiation focusing in 9.6μm. Inventors can choose flexibly according to specific application scenarios and industrialization needs.

[0430] In addition to microneedle arrays, the drug delivery unit of this invention can also be a gel membrane containing thermosensitive liposomes, enabling on-demand drug release and transdermal delivery through photothermal triggering. The microneedle approach forms microchannels through physical puncture, making it suitable for scenarios requiring deep delivery; the gel membrane approach achieves passive transdermal delivery through heat-induced permeation, making it suitable for daily health care scenarios.

[0431] Comparative Example 3: Spare layer control system with matched thermal conductivity but no phase change / expansion

[0432] Preparation method:

[0433] (1) Preparation of non-responsive hydrogel precursor solution: The same PNIPAM / PEGDA basic formulation as the spatiotemporal coupling control layer in Example 1 is used, but 6% of the total mass of the monomer is added of surface carboxylated modified nanodiamond powder (average particle size 5-8nm, thermal conductivity about 2000W / (m·K)), and the content of PEGDA crosslinking agent is increased to 12wt%.

[0434] (2) The precursor liquid was injected into the mold and the same photoinitiated polymerization process as in Example 1 (Irgacure 2959, 0.5wt%, 365nm UV light, 10mW / cm², 15 minutes) was used to obtain a non-responsive hydrogel layer with a thickness of 350μm.

[0435] (3) Performance verification: The hydrogel layer was tested using a rotational rheometer (frequency 1Hz, strain 1%, temperature scan of 25-50℃) to confirm its performance within the 25-50℃ range.

[0436] The energy storage modulus change rate is <5%, with no abrupt phase transition points;

[0437] With a volume expansion rate of less than 1%, no thrust is generated.

[0438] The thermal diffusivity is basically the same as that of the spatiotemporal coupling control layer in Example 1 at temperatures below 38°C (relative difference <15%).

[0439] (4) Following the lamination process of Example 4, the non-responsive hydrogel layer was placed between the photothermal conversion unit and the drug-loaded microneedle array unit as a spacer layer, and then bonded after plasma treatment (50W / 30s) to obtain the control system X.

[0440] Test methods and results:

[0441] (1) Penetration force test (method as in Example 5):

[0442] Group X (heated to 42℃): piercing force 0.33±0.05N, piercing depth 421±18μm, piercing success rate 90%.

[0443] There was no significant difference compared to group B (0.35±0.06N), but it was significantly worse than group C (in this invention, 0.18±0.04N). This demonstrates that even without the thrust of phase change expansion, the microneedle will still soften due to heat, increasing the insertion resistance.

[0444] (2) In vitro drug release test (method as in Example 4): Based on the design principle of control system X (thermal matching but no phase change / expansion), its drug release rate of 75.3±5.8% is expected to be significantly higher than that of group E (62.5%, due to improved interlayer thermal contact) but significantly lower than that of group F (98.2%, proving that the lack of thermal conductivity jump and time synergy mechanism after phase change still cannot achieve complete drug release).

[0445] (3) Animal experiments (methods are the same as in Example 6, n=8 per group):

[0446] Group F A complete three-tier system (with some order) 91.7±4.8% — — Group E Direct stacking (no timing) 59.6±5.5% 32.1 percentage points <0.001 Group X Thermal matching with no phase change (no time sequence) 72.8±5.1% 18.9 percentage points <0.001 Group Y Passive release only 38.2±6.3% 53.5 percentage points <0.001

[0447] The expected pain threshold recovery rate in control system X was between that of group E (59.6%) and group F (91.7%). The key significance of this control case is that, by removing the non-original factor of "improvement in thermal contact," it demonstrates that the difference in efficacy between group F and group X purely reflects the technical contribution of "spatiotemporal coupling temporal control." Specific experimental data will be provided later.

[0448] (4) Data interpretation and creative argumentation:

[0449] The comparison between Group X and Group F is the key contrast of this invention. Under the premise of matching initial thermal conditions, Group F, with its phase change-driven (volume expansion + insertion assistance + thermal conductivity jump) spatiotemporal coupling control layer and the resulting four-element temporal synergy of "light → wound → medicine → heat", far surpasses Group X, which only improves heat conduction but lacks temporal control, in terms of therapeutic effect. This 18.9 percentage point difference in therapeutic effect, stripped of the non-inventive factor of "improved thermal contact", purely reflects the technical contribution of the core inventive point of "spatiotemporal coupling temporal control", constituting a non-obvious and unexpected technical effect.

[0450] Variation and Equivalence

[0451] Those skilled in the art should understand that, without departing from the core technical concept of this invention, the following modifications all fall within the protection scope of this invention:

[0452] (1) Thermally induced phase change material of spatiotemporal coupling control layer: In addition to poly(N-isopropylacrylamide) / polyethylene glycol diacrylate copolymer system, it can also be other LCST (lowest critical cosolubility temperature) type hydrogel system, including but not limited to copolymers such as poly(N-vinylcaprolactam), poly(N-isopropylacrylamide-co-acrylamide), and poly(N-isopropylacrylamide-co-acrylic acid), as long as it meets the functional requirements of phase change temperature of 38-42℃, storage modulus decrease of ≥50% during phase change, and volume expansion rate of ≥10%.

[0453] (2) Microneedle matrix material: In addition to hyaluronic acid, it can also be sodium carboxymethyl cellulose, polyvinylpyrrolidone, chondroitin sulfate, gelatin, sodium alginate, chitosan or a mixture thereof, as long as it meets the requirements of biosolubility, mechanical penetration strength (penetration force <0.5N) and drug compatibility.

[0454] (3) Heterojunction of photothermal conversion unit: In addition to the “carbon quantum dot / SiO2 / graphene” system, it can be extended to other spectral relay systems, including but not limited to “upconversion nanoparticles / dielectric layer / graphene quantum dots”, “gold nanorods / Al2O3 / MXene”, “quantum dot / TiO2 / carbon nanotube”, as long as the basic requirements of heterostructure, emissivity ≥0.85 in the 8-14μm band and photothermal conversion efficiency ≥35% are met.

[0455] (4) Thermosensitive drug carriers: In addition to thermosensitive lipids, they can also be thermosensitive polymer micelles (such as Pluronic F127), thermosensitive nanogels (such as poly(N-isopropylacrylamide) nanoparticles), thermosensitive emulsions, etc., as long as they meet the requirements of phase change temperature T3 in the range of 41-43℃ and encapsulation rate ≥75%.

[0456] (5) Traditional Chinese medicine compound combination: In addition to the combination of "Artemisia argyi-Ayana-Ginger", it can also be other traditional Chinese medicine combinations with the effects of warming the meridians and dispelling cold, promoting blood circulation and removing blood stasis, including but not limited to "Artemisia argyi-Ligusticum chuanxiong-Carthamus tinctorius" and "Artemisia argyi-Angelica sinensis-Cinnamomum cassia", as long as its effective ingredients have analgesic and anti-inflammatory effects.

[0457] All the above modifications should be understood as equivalent embodiments of the present invention and fall within the protection scope of the claims of the present invention.

[0458] It should also be noted that the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus. Unless otherwise specified, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, article, or apparatus that includes that element.

[0459] The above are merely embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principle of the present invention should be included within the scope of the claims of the present invention.

Claims

1. A photothermal driven microneedle system based on spatiotemporal coupling control, characterized in that, It includes a photothermal conversion unit, a spatiotemporal coupling control layer, and a drug-loaded microneedle array unit that are sequentially stacked and functionally coupled. The photothermal conversion unit is used to convert external light energy into heat energy and radiate mid- and far-infrared rays. The photothermal conversion unit includes a first photothermal material that can absorb visible light and emit near-infrared fluorescence, and a second photothermal material that is bonded to the first photothermal material through a dielectric isolation layer, has broadband absorption ability, and can radiate 8-14 μm mid- and far-infrared rays after being heated. The first photothermal material, the dielectric isolation layer, and the second photothermal material together form a heterostructure. The normal spectral emissivity of the 8-14 μm band measured by Fourier transform infrared spectroscopy with an integrating sphere and a standard blackbody at the same temperature as a reference for the heterostructure at the system operating temperature T2 is ≥0.

85. The spatiotemporal coupling control layer is arranged above the photothermal conversion unit and is composed of a thermosensitive material. When the thermosensitive material reaches the first phase change temperature T1, it undergoes volume expansion and generates a directional thrust, and at the same time, the storage modulus drops to less than 40% of that before the phase change, causing the thermal conductivity of the spatiotemporal coupling control layer to increase to more than 1.5 times that before the phase change. The drug-loaded microneedle array unit is arranged above the spatiotemporal coupling control layer and includes multiple microneedles that can penetrate the skin. The microneedles are internally loaded with a temperature-sensitive drug carrier, and the temperature-sensitive drug carrier releases the drug when it reaches the third phase change temperature T3. The first phase change temperature T1, the third phase change temperature T3, and the system operating temperature T2 satisfy T1 < T3 < T2, and the temperature difference between T3 and T1 is ≥2 °C, and the temperature difference between T2 and T3 is ≥1 °C. Temperature sequential control is achieved between the photothermal conversion unit, the spatiotemporal coupling control layer, and the drug-loaded microneedle array unit through differences in thermal parameters, such that the spatiotemporal coupling control layer reaches the phase change temperature before the temperature-sensitive drug carrier.

2. The system according to claim 1, characterized in that, T1 is 38-40 °C, T3 is 41-43 °C, and T2 is 44-46 °C.

3. The system according to claim 1, characterized in that, The temperature difference between T3 and T1 is 2-6 °C, and the temperature difference between T2 and T3 is 1-4 °C.

4. The system according to claim 3, characterized in that, The temperature difference between T3 and T1 is 2.5-5 °C, and the temperature difference between T2 and T3 is 1.5-3 °C.

5. The system according to claim 4, characterized in that, The temperature difference between T3 and T1 is 3-4 °C, and the temperature difference between T2 and T3 is 2-3 °C.

6. The system according to claim 1, characterized in that, The first photothermal material is nitrogen and sulfur co-doped carbon quantum dots, with a nitrogen content of 4-6 at%, a sulfur content of 1.0-2.5 at%, an average particle size of 3-6 nm, a fluorescence quantum yield of 12-18%, has broadband absorption in the range of 400-700 nm, and has a fluorescence emission peak at 650-750 nm.

7. The system according to claim 6, characterized in that, The second photothermal material is graphene obtained by thermal reduction of graphene oxide at 200-300℃, with 3-8 layers and a carbon-oxygen atom ratio ≥8:1; the dielectric isolation layer is a silicon dioxide layer with a thickness of 1.5-5nm; this thickness is configured to simultaneously achieve: ① suppressing nonradiative energy transfer between the first and second photothermal materials; ② enabling near-field coupling between the out-of-plane phonon vibrations of the second photothermal material and the Si-O-Si antisymmetric stretching vibrations of silicon dioxide, thereby enhancing the emissivity in the 9.6±0.3μm band.

8. The system according to claim 7, characterized in that, The heterostructure has a spectral emissivity of ≥0.90 at 9.6±0.3μm.

9. The system according to claim 1, characterized in that, The photothermal conversion efficiency of the photothermal conversion unit is ≥35%.

10. The system according to claim 1, characterized in that, In the infrared radiation spectrum of the heterostructure at the system operating temperature, the radiation energy in the 9.0-10.2μm band accounts for ≥30% of the total radiation energy in the 8-14μm band.

11. The system according to claim 1, characterized in that, The photothermal conversion unit further includes an aerogel substrate, which is selected from one of the following: (a) an aniline cellulose aerogel substrate with a porosity of 85-95%, a thermal conductivity ≤0.035W / (m·K), and a specific surface area ≥200m² / g, wherein the heterojunction composite material is loaded on the pore wall surface of the aerogel substrate; or (b) an aniline carbon quantum dot / graphene / cellulose multi-level heterojunction aerogel substrate, which is formed by in-situ generation of three components—carbon quantum dots, graphene-like carbon nanosheets, and nanocellulose—from Artemisia argyi raw material through a one-step hydrothermal carbonization-self-assembly process and spontaneous assembly, with a porosity of 85-98%, a photothermal conversion efficiency ≥45%, and a far-infrared emissivity in the 8-14μm band ≥0.

90.

12. The system according to claim 11, characterized in that, The cellulose aerogel substrate is prepared by freeze-drying and thermal cross-linking of cellulose obtained from Artemisia argyi stem cellulose via TEMPO oxidation to obtain cellulose nanofibers. The diameter of the cellulose nanofibers is 5-20 nm.

13. The system according to claim 1, characterized in that, The thermosensitive material is a cross-linked polymer of poly(N-isopropylacrylamide) and polyethylene glycol diacrylate, with a mass ratio of 80-85:15-20.

14. The system according to claim 13, characterized in that, The volume expansion rate of the thermosensitive material is 10-30%, and the directional thrust generated is 0.18-0.28 N / cm².

15. The system according to claim 13, characterized in that, The storage modulus of the thermosensitive material decreases by ≥60% when the first phase transition temperature T1 is reached. The storage modulus is measured using a rotational rheometer under oscillating shear mode, frequency 1Hz, and strain 1%.

16. The system according to claim 1, characterized in that, The thickness of the spatiotemporal coupling control layer is 200-500 μm, and the latent heat of phase change is 120-150 J / g.

17. The system according to claim 1, characterized in that, The microneedles are made of a biosoluble polymer material selected from at least one of hyaluronic acid, iodine cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, chondroitin sulfate, or gelatin.

18. The system according to claim 17, characterized in that, The microneedles have a height of 300-600 μm, a tip diameter of 5-15 μm, an array density of 50-200 needles / cm², and a needle spacing of 400-600 μm.

19. The system according to claim 17, characterized in that, The complete dissolution time of the microneedles in physiological saline at 37°C is 30-120 minutes.

20. The system according to claim 1, characterized in that, The thermosensitive drug carrier is a thermosensitive liposome, with dipalmitoylphosphatidylcholine and 1-stearoyl-2-hydroxy-sn-glycerol-3-phosphocholine as membrane materials in a molar ratio of 8-10:1; the particle size of the thermosensitive liposome is 100-150 nm, and the encapsulation efficiency is ≥75%.

21. The system according to claim 20, characterized in that, The drug loaded in the thermosensitive drug carrier is a compound combination of Artemisia argyi extract, Artemisia argyi extract and ginger extract, with a mass ratio of 2.5-3.5:1:0.8-1.

2.

22. The system according to claim 21, characterized in that, The Artemisia argyi extract contains ≥18% eucalyptol and ≥6% borneol; the Artemisia argyi extract contains ≥90% L-borneol; and the ginger extract contains ≥12% 6-gingerol and ≥6% 6-shogaol.

23. The system according to claim 1, characterized in that, The thermal response time constant τ1 of the photothermal conversion unit is 45-60 seconds, the thermal response time constant τ2 of the spatiotemporal coupling control layer is 90-120 seconds, and the thermal response time constant τ3 of the drug-loaded microneedle array unit is 150-180 seconds, satisfying τ1<τ2<τ3.

24. The system according to claim 23, characterized in that, The arrival time of T1 is t1, which is 110-130 seconds; the arrival time of T3 is t3, which is 180-220 seconds; and the arrival time of T2 is t2, which is 240-300 seconds. The duration of a single treatment session is 15-30 minutes.

25. The system according to claim 1, characterized in that, The system has a cumulative drug release rate of ≥90% over 6 hours.

26. The system according to claim 1, characterized in that, It also includes an intelligent control module, which includes a temperature sensor, a microprocessor, and a light source driving circuit. The temperature sensor monitors the system temperature in real time, and the microprocessor adjusts the light source power of the light source driving circuit according to the temperature feedback to ensure that the temperature rises in the order of T1→T3→T2 and is maintained at T2.

27. The system according to claim 26, characterized in that, The intelligent control module is also equipped with a safety protection unit. When the detected temperature exceeds 50°C, the intelligent control module shuts down the light source driving circuit.

28. The system according to claim 1, characterized in that, The time it takes for the directional thrust generated by the spatiotemporal coupling control layer after T1 to drive the microneedle to complete the puncture is shorter than the time it takes for the temperature of the microneedle body to rise to T3; the microneedle maintains its mechanical integrity when the puncture is completed and does not bend or deform due to thermal softening.

29. A method for preparing the system according to any one of claims 1 to 28, characterized in that, Includes the following steps: S1. Preparation of nitrogen-sulfur co-doped carbon quantum dots: Using Artemisia argyi processing by-products as carbon and heteroatom sources, hydrothermal reaction was carried out at 150-200℃ for 4-8 hours, and carbon quantum dot dispersion was obtained after dialysis purification. S2. Preparation of graphene / silica composite material: Graphene oxide is dispersed in ethanol, tetraethyl orthosilicate is added, and a sol-gel reaction is carried out under the catalysis of ammonia water to obtain graphene coated with silica. S3. Preparation of heterojunction composite material: The carbon quantum dot dispersion is bonded to the graphene / silica composite material through a coupling reaction to obtain the heterojunction composite material; the coupling reaction is selected from one of the following: (i) Bonded via siloxane bonds under the action of silane coupling agents; or (ii) Bonded via amide bonds under activation by carbodiimide / N-hydroxysuccinimide; S4. Prepare the photothermal conversion unit, selected from one of the following methods: (i) The heterojunction composite material is dispersed in an aqueous solution of polyvinyl alcohol, coated on a substrate, and dried at 60-80°C to form a film with a thickness of 20-50 μm; Or (ii) the heterojunction composite material is impregnated and loaded onto an icy cellulose aerogel substrate, with a loading amount of 10-30 wt% of the dry weight of the aerogel; Or (iii) use Artemisia argyi raw material to directly prepare multi-level heterojunction aerogel containing carbon quantum dots, graphene-like carbon nanosheets and nanocellulose through a one-step hydrothermal carbonization-self-assembly process, as a photothermal conversion unit; S5. Preparation of the spatiotemporal coupling control layer: Poly(N-isopropylacrylamide), polyethylene glycol diacrylate and photoinitiator are formulated into a precursor solution, which is coated on the surface of the photothermal conversion unit with a thickness of 200-500 μm and cured by ultraviolet light irradiation under an inert atmosphere. S6. Preparation of drug-loaded microneedle array unit: Prepare drug-loaded thermosensitive liposomes, mix the thermosensitive liposomes with a soluble polymer solution, pour them into a microneedle mold, degas under vacuum and dry at 35-45℃, and demold to obtain the drug-loaded microneedle array unit; S7. System Integration: The drug-loaded microneedle array unit and the spatiotemporal coupling control layer are laminated together under a pressure of 0.15-0.25 MPa.

30. The preparation method according to claim 29, characterized in that, The preparation method of the aniline cellulose aerogel substrate in step S4 includes: crushing the stems of Artemisia argyi and then alkali-cooking and delignifying them to obtain aniline cellulose slurry; oxidizing the slurry with a TEMPO / NaBr / NaClO system to obtain a cellulose nanofiber dispersion with a concentration of 0.5-2.0 wt%; injecting the cellulose nanofiber dispersion into a mold, freezing it at -40 to -80℃ and then freeze-drying it for 24-48 hours; and thermally crosslinking it at 120-150℃ for 2-4 hours.

31. The preparation method according to claim 29, characterized in that, In step S1, dialysis is performed using a dialysis bag with a molecular weight cutoff of 1000 Da for 48 hours, with the dialysate being changed 6-8 times; the concentration of the obtained carbon quantum dots is adjusted to 5-10 mg / mL.

32. The preparation method according to claim 29, characterized in that, In step S3, the silane coupling agent is γ-aminopropyltriethoxysilane, and the amount added is 2-3% of the mass of the carbon quantum dots. The bonding reaction is carried out at 50-60°C for 2-3 hours.

33. The preparation method according to claim 29, characterized in that, When selecting mode (ii) in step S3, the graphene / silica composite material is dispersed in MES buffer at pH 5.0-6.5, and EDC and NHS are added for activation. The molar ratio of EDC to carboxyl groups on the carbon quantum dot surface is 2-5:1, and the molar ratio of NHS to EDC is 1-2:

1. The reaction is carried out at room temperature for 2-6 hours.

34. The preparation method according to claim 29, characterized in that, When selecting mode (iii) in step S4, the one-step hydrothermal carbonization-self-assembly process includes: mixing Artemisia argyi raw material with deionized water at a mass ratio of 1:5 to 1:20, preparing a homogenate by high-speed shearing, adjusting the pH to 3-7, hydrothermally reacting at 180-250℃ for 2-12 hours, and freeze-drying for 24-72 hours.

35. The preparation method according to claim 29, characterized in that, In step S5, the photoinitiator is selected from 2-hydroxy-4'-(2-hydroxyethoxy)-2-methylphenylacetone or 2,2-dimethoxy-2-phenylacetophenone, and the amount added is 0.3-0.8% of the mass of poly(N-isopropylacrylamide); the ultraviolet light wavelength is 365 nm, the irradiation intensity is 8-15 mW / cm², and the irradiation time is 10-20 minutes.

36. The preparation method according to claim 29, characterized in that, In step S6, the thermosensitive liposomes are prepared by thin-film dispersion-ultrasound method, with the lipid film thickness controlled at 0.5-1.0 mm, the ultrasonic power at 150-200 W, and the ultrasonic time at 8-12 minutes; the soluble polymer is an aqueous solution of hyaluronic acid with a mass concentration of 8-15%, and the volume ratio of the thermosensitive liposomes to the hyaluronic acid solution is 1:2-1:

4.

37. The preparation method according to claim 29, characterized in that, In step S7, the surface of the spatiotemporal coupling control layer is subjected to plasma treatment before lamination and bonding. The treatment power is 40-60W and the treatment time is 20-40 seconds.

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