A wound treatment microneedle patch with mechanical sensing function

Abstract

The present application relates to the field of biomedical technology, and in particular to a wound treatment microneedle patch with mechanical sensing function. The microneedle patch comprises: a flexible substrate; a microneedle array arranged on the flexible substrate, the microneedle array comprising a plurality of microneedles; at least one of the microneedles is provided with a cavity, and the cavity is filled with liquid metal. Since the microneedle is provided with a cavity and the cavity is filled with liquid metal, when the microneedle is inserted into the skin, the change in skin tissue tension causes the cavity to deform, resulting in a change in the cross-sectional area of the liquid metal, so that the mechanical characteristics can be analyzed by measuring the resistance change signal of the liquid metal.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of biomedical technology, in particular to a wound treatment microneedle patch with mechanical sensing function. BACKGROUND

[0002] As a new transdermal drug delivery technology, microneedle can deliver drugs efficiently by penetrating the stratum corneum with micron-sized needles, and has the advantages of minimally invasive and painless, and is widely used in wound healing. The existing technology mainly focuses on drug loading and controlled release function, such as using hydrogel matrix to load growth factors, antibacterial drugs or bioactive materials to promote angiogenesis, inhibit infection or accelerate collagen deposition.

[0003] However, the dynamic mechanical changes of skin tissue during wound healing (such as 3kPa-5kPa tension in the inflammation period and 1kPa-2kPa stress in the granulation tissue formation period) are key indicators for evaluating the repair process, and the existing microneedle system generally lacks real-time monitoring capability for such mechanical parameters. SUMMARY

[0004] Therefore, the present application provides a wound treatment microneedle patch with mechanical sensing function, which at least solves one problem in the prior art.

[0005] In a first aspect, the present application provides a wound treatment microneedle patch with mechanical sensing function, which comprises:

[0006] a flexible substrate;

[0007] a microneedle array disposed on the flexible substrate, the microneedle array comprising a plurality of microneedles;

[0008] At least one of the microneedles is provided with a cavity, and the cavity is filled with a liquid metal.

[0009] In a second aspect, the present application provides a preparation method of the wound treatment microneedle patch with mechanical sensing function, which comprises the following steps:

[0010] preparing a mixture comprising methacrylated gelatin, hyaluronic acid and a photoinitiator;

[0011] using 3D printing technology to print the mixture into a flexible substrate and a microneedle array, wherein a cavity is reserved on at least one of the microneedles;

[0012] curing the flexible substrate and the microneedle array by ultraviolet light;

[0013] immersing the cured flexible substrate and microneedle array in a liquid metal, so that the liquid metal enters the cavity.

[0014] With the above technical scheme, the embodiments of the present application have at least the following beneficial effects:

[0015] (1) Breaking through the functional limitation of the prior art which only focuses on the "single treatment" of drug delivery, realizing real-time sensing of the mechanical parameters of the wound microenvironment, enabling medical staff to dynamically adjust the treatment plan according to the mechanical changes of the tissue, effectively avoiding complications such as excessive growth of scars and delayed healing caused by the absence of mechanical environment monitoring, and laying a technical foundation for personalized precision treatment of complex wounds (such as diabetic ulcers and infected wounds);

[0016] (2) Taking advantage of the molding advantage of 3D printing technology, the flow channel cavity is constructed synchronously in the microneedle body, and the sensing unit is formed by filling liquid metal under negative pressure. This structural design fundamentally solves the problem of complex assembly process and poor compatibility of the sensor and the microneedle, realizes the organic integration of the sensing function and the microneedle treatment structure, and provides an innovative technical path with minimally invasive and real-time monitoring capability for the precision and personalized treatment of wound healing. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 It is a front view of the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0018] Figure 2 It is a back view of the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0019] Figure 3 It is a physical photo of the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0020] Figure 4 It is an enlarged view of the liquid metal injection hole on the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0021] Figure 5 It is an enlarged view of the serpentine flow channel cavity section on the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0022] Figure 6 It is a pressure-resistance characteristic curve diagram of the liquid metal sensing unit on the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application.

[0023] Figure 7 It is a resistance change curve diagram of the liquid metal sensing unit on the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application under the action of cyclic force.

[0024] Figure 8 It is a responsiveness curve diagram of the liquid metal sensing unit on the wound treatment microneedle patch with mechanical sensing function in the embodiments of the present application. DETAILED DESCRIPTION

[0025] The following is a clear and complete description of the concept of the present invention and the technical effects produced, so as to fully explain the purpose, scheme and effects of the present invention.

[0026] Current microneedle technology lacks integrated stress-sensing units, making it incapable of capturing dynamic mechanical signals from the wound microenvironment. Typical microneedle treatments rely on pre-defined drug release profiles, making them incapable of responding to the localized pressure increases (up to 5 kPa) caused by scar hyperplasia. Furthermore, they are unable to identify stress fluctuations during the early (1 kPa-3 kPa) and mid-healing stages (3 kPa-5 kPa), making it impossible to assess collagen deposition and angiogenesis through mechanical changes. This functional deficiency deprives treatment strategies of critical data support.

[0027] Due to the lack of a mechanical feedback mechanism, existing technologies struggle to adapt to the personalized needs of complex wounds (such as diabetic ulcers and infected wounds). Clinical treatments cannot adjust intervention strategies based on real-time pressure data (such as enhanced drug release for scar hyperplasia), relying solely on empirical medications, which can easily lead to complications such as delayed healing and excessive scar growth.

[0028] To this end, in a first aspect, the present invention provides a wound treatment microneedle patch with mechanical sensing function. Figure 1 and Figure 2 As shown, it includes:

[0029] Flexible substrate 1;

[0030] A microneedle array 2 is provided on the flexible substrate 1, wherein the microneedle array 2 comprises a plurality of microneedles;

[0031] At least one of the microneedles is provided with a cavity, and the cavity is filled with liquid metal 3 .

[0032] Since the microneedle has a cavity filled with liquid metal, when the microneedle is inserted into the skin, the change in skin tissue tension causes the cavity to deform, resulting in a change in the cross-sectional area of ​​the liquid metal. This allows the mechanical characteristics to be analyzed by measuring the resistance change signal of the liquid metal. According to the resistance formula R= p · L / S ( p is the resistivity, L is the length, S is the cross-sectional area), the cross-sectional area of ​​the liquid metal S The change causes resistance change, and the mechanical characteristics of the wound healing stage are analyzed through the resistance change signal (such as 3kPa-5kPa in the inflammation stage and 1kPa-2kPa in the granulation stage), providing data basis for drug release. The cavity structure design can ensure the liquid metal length when the microneedle swells. LThe resistance change is mainly caused by the cross-sectional area of the liquid metal S The sensing accuracy is improved by the influence of the tissue pressure.

[0033] In some optional embodiments, the cavity is a flow channel cavity. It can be understood that the flow channel cavity refers to a cavity in which the fluid can flow along the flow channel after entering.

[0034] In some optional embodiments, the cross section of the flow channel cavity is elliptical. The elliptical flow channel cavity is beneficial to deformation, thereby improving the mechanical sensing accuracy.

[0035] In some optional embodiments, the flow channel cavity is located in the microneedle body at a distance of 1 / 3 to 2 / 3 of the height of the microneedle from the bottom of the microneedle, and the two ends of the flow channel cavity extend from the microneedle body to the flexible substrate 1, forming a liquid metal injection hole 4 on the flexible substrate 1. The flow channel cavity at 1 / 3 to 2 / 3 of the height of the microneedle can better sense the skin tissue tension. The two ends of the flow channel cavity extend to the flexible substrate in order to inject the liquid metal and connect the electrodes. The liquid metal in the flow channel cavity is connected to the electrodes at both ends, respectively, in order to measure the resistance change.

[0036] In some optional embodiments, the microneedle array 2 includes 100 microneedles arranged in a 10 row x 10 column array, and cavities are provided in 4 microneedles in a 2 row x 2 column area. The height of the microneedle can be 800-1500 μm, the bottom diameter can be 500-1000 μm, and the center distance between adjacent microneedles can be 800-1200 μm.

[0037] In some optional embodiments, the flexible substrate 1 and the microneedle array 2 are both made of methyl methacrylated gelatin / hyaluronic acid composite hydrogel. For example, a composite hydrogel formed by mixing 10w / v%-15w / v% methyl methacrylated gelatin (GelMA), 5w / v%-8w / v% hyaluronic acid (HA), and a wound healing drug, wherein the wound healing drug can be selected from 5wt%-10wt% recombinant human epidermal growth factor (rhEGF) or 0.1wt%-0.5wt% silver ion antibacterial agent.

[0038] In some optional embodiments, the liquid metal 3 is a gallium-indium-tin alloy. For example, the liquid metal is a gallium-indium-tin alloy with a mass ratio of gallium, indium, and tin of 68.5%:21.5%:10%.

[0039] In a second aspect, the present application provides a preparation method of the above-mentioned wound treatment microneedle patch with mechanical sensing function, which comprises the following steps:

[0040] A mixture comprising methyl methacrylated gelatin, hyaluronic acid, and a photoinitiator is prepared;

[0041] Printing the mixture above into a flexible substrate and microneedle array using 3D printing technology, wherein a cavity is reserved on at least one of the microneedles above;

[0042] Curing the flexible substrate and microneedle array above by ultraviolet light;

[0043] Immersion of the cured flexible substrate and microneedle array above into liquid metal, so that the liquid metal enters the cavity above.

[0044] In some optional embodiments, the photoinitiator above is (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide.

[0045] In some optional embodiments, the liquid metal enters the cavity above by using atmospheric pressure through vacuum extraction.

[0046] A typical embodiment is described below.

[0047] Embodiment 1

[0048] Prepare a wound treatment microneedle patch with mechanical sensing function according to the following steps:

[0049] (1) Synthesis of methacrylated gelatin (GelMA):

[0050] Dissolve 10 g of gelatin in 100 mL of deionized water, stir at 55°C until completely dissolved, slowly add 8 mL of methacrylic anhydride (MA), and stir at 45°C for 3 h; after the reaction is completed, use a 12 kDa dialysis bag to dialyze in deionized water for 7 days to remove unreacted MA, and freeze-dry to obtain white porous GelMA powder.

[0051] (2) Preparation of photocuring precursor solution:

[0052] Dissolve 12 g of GelMA, 6 g of hyaluronic acid (HA) in 100 mL of PBS, add 0.5 g of (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide (TPO), add 0.1 g of transparent pigment lemon yellow as a light absorber, add 1 g of glycerol as a humectant, and then add recombinant human epidermal growth factor (rhEGF) powder (concentration 5 wt%), mix and stir at 50°C until completely dissolved, pass through a 0.45 μm filter membrane to remove impurities, and vacuum degas for 10 min to obtain a photocuring precursor solution.

[0053] (3) Printing of flexible substrate and microneedle array:

[0054] An Anycubic Photon M3 Premium printer (resolution 28.9 μm) was used to print 50 layers at a thickness of 20 μm per layer. Each layer was exposed to ultraviolet light (UV light wavelength 405 nm) for 15 s to form a 1000 μm-thick flexible substrate. The substrate surface was pre-set with microneedle array positioning grooves (10×10 array, with a center-to-center distance of 1000 μm between adjacent positioning grooves). The microneedles were solidified layer by layer in the substrate positioning grooves. The parameters of a single needle were: height 1000 μm, bottom diameter 600 μm. A serpentine flow channel cavity was simultaneously printed (at 2 / 3 the height from the needle bottom, with an elliptical cross-section with a major axis of 100 μm and a minor axis of 60 μm, surrounding the microneedle). Lead-out holes with a diameter of 100 μm were reserved at both ends of the flow channel cavity to the surface of the flexible substrate.

[0055] (4) Post-curing treatment:

[0056] After the flexible substrate and microneedle array were printed, they were washed with deionized water three times and post-cured under a 405nm UV lamp for 10 minutes to enhance the cross-linking degree of the hydrogel.

[0057] (5) Integrated liquid metal sensing unit

[0058] The serpentine cavity was ultrasonically cleaned with deionized water (30W, 5 minutes) and oven-dried at 60°C for 30 minutes to ensure that no moisture remained on the inner wall of the serpentine cavity. The flexible substrate and microneedle array were immersed in liquid metal (a gallium-indium-tin alloy with a mass ratio of 68.5% gallium, 21.5% indium, and 10% tin). The vacuum was evacuated to -0.1 MPa using a vacuum pump and maintained for 20 minutes to expel bubbles. The vacuum chamber valve was then opened, and atmospheric pressure was used to press the liquid metal into the serpentine cavity to construct a sensing unit. Platinum electrode leads were then connected to both ends of the sensing unit, and the printed material was cured and sealed (irradiated with 405 nm ultraviolet light for 5 minutes), resulting in a wound therapy microneedle patch with mechanical sensing capabilities.

[0059] The wound treatment microneedle patch with mechanical sensing function prepared in Example 1 is as follows Figure 3 As shown, it can be seen that the four liquid metal sensing units are confined in the serpentine flow channel cavity on the microneedle. Figure 4 This is an enlarged view of the liquid metal injection hole (i.e., the outlet hole at one end of the flow channel cavity) on the microneedle patch. Figure 5 This is an enlarged view of the cross-section of the serpentine flow channel cavity on the microneedle patch.

[0060] The sensing function of the wound treatment microneedle patch with mechanical sensing function prepared in Example 1 was verified by the following steps:

[0061] (1) Preparation of bionic skin model:

[0062] 3% agarose gel (Sigma-Aldrich, product number A9539, elastic modulus 5 kPa) was used to simulate inflammatory tissue, and 1.5% agarose gel (elastic modulus 2 kPa) was used to simulate granulation tissue. The gels were cast into cylindrical models with a diameter of 50 mm and a thickness of 10 mm. A 10 mm × 10 mm deep wound depression was machined on the surface.

[0063] (2) Mechanical loading and signal acquisition:

[0064] A PY-888B single-column tensile and compressive testing machine was used to apply a vertical pressure of 0-10 kPa to the bionic skin model at a rate of 0.1 mm / min using a 10 mm diameter indenter. The microneedle patch was fixed to the center of the wound surface, and the platinum electrode was connected to a Keysight 34460A digital source meter to acquire and output resistance signals.

[0065] (3) Drawing of pressure-resistance curve:

[0066] Pressure was applied to the bionic skin model in a 0.5 kPa gradient (0 → 0.5 → 1 → … → 10 kPa). Each pressure point was maintained for 30 seconds to ensure signal stability. The resistance values ​​of the four sensing units were collected in real time using a Keysight 34460A digital source meter, and the average value was taken as the test result under this pressure. The load-unload cycle was repeated three times, and the standard deviation was calculated to verify data repeatability.

[0067] Figure 6 The pressure-resistance curve is drawn based on the test data. The results show that in the pressure range of 0-10kPa, the relative change rate of liquid metal resistance (Δ R / R 0 ) has a good linear relationship with pressure, and the linear equation is Δ R / R 0 =0.2 P , with a sensitivity of 0.2 / kPa. The specific characteristic range is as follows: the simulated pressure during the inflammation period (3-5kPa) corresponds to Δ R / R 0=0.6-1.0, granulation stage simulated pressure (1-2kPa) corresponds to Δ R / R 0=0.2-0.4, which matches the mechanical characteristics of different stages of wound healing, verifying the ability of the liquid metal sensing unit to distinguish changes in tissue tension.

[0068] The resistance stability of the liquid metal sensor unit under cyclic force was tested simultaneously. The results are as follows Figure 7 As shown in the figure, when the loads are alternately cycled at 1 kPa, 3 kPa, 5 kPa and 10 kPa, the resistance change amplitude deviation is less than 5%, indicating the signal stability of the serpentine flow channel structure under repeated deformation.

[0069] Figure 8 The liquid metal sensing unit response test result of the application shows that the response time of the resistance reaching a stable value is 0.3s, and the recovery time when unloading is 0.4s, which meets the real-time monitoring requirement.

[0070] The above only describes the preferred embodiments of the application, and the application is not limited to the above-described embodiments, as long as the same or equivalent means achieve the technical effects of the application, which should belong to the protection scope of the application. Within the protection scope of the application, the technical solutions and / or embodiments can have various modifications and changes.

Claims

1. A wound treatment microneedle patch with mechanical sensing function, characterized in that, The application relates to a flexible substrate and a microneedle array arranged on the flexible substrate, wherein the microneedle array comprises a plurality of microneedles, and at least one of the microneedles is provided with a cavity filled with liquid metal. The cavity is a flow channel cavity. The flow channel cavity has an elliptical cross section. The flow channel cavity is located in the microneedle body at a distance of 1 / 3 to 2 / 3 of the height of the microneedle from the bottom of the microneedle, and the two ends of the flow channel cavity extend from the microneedle body to the flexible substrate to form liquid metal injection holes on the flexible substrate.

2. The microneedle patch for wound therapy with mechanical sensing function according to claim 1, characterized in that, The microneedle array comprises 100 microneedles arranged in a 10-row-by-10-column array, and cavities are arranged in four microneedles in a 2-row-by-2-column area.

3. The microneedle patch for wound therapy with mechanical sensing function according to claim 2, characterized in that, The flexible substrate and the microneedle array are made of methylacrylated gelatin / hyaluronic acid composite hydrogel.

4. The microneedle patch for wound therapy with mechanical sensing function according to claim 2, characterized in that, The liquid metal is a gallium-indium-tin alloy.

5. The microneedle patch for wound therapy with mechanical sensing function according to claim 1, characterized in that, The application further relates to a preparation method of the flexible substrate and the microneedle array.

6. The microneedle patch for wound therapy with mechanical sensing function according to claim 1, characterized in that, The method comprises the following steps: preparing a mixture comprising methylacrylated gelatin, hyaluronic acid and a photoinitiator; printing the mixture into the flexible substrate and the microneedle array by using a 3D printing technology, wherein a cavity is reserved in at least one of the microneedles; curing the flexible substrate and the microneedle array by using ultraviolet light; and immersing the cured flexible substrate and microneedle array in liquid metal so that the liquid metal enters the cavity.

7. The microneedle patch for wound therapy with mechanical sensing function according to claim 1, characterized in that, The photoinitiator is (2,4,6-trimethylbenzoyl) diphenyl phosphine oxide.

8. The method for preparing the wound therapy microneedle patch with mechanical sensing function according to claim 1, characterized in that, The liquid metal enters the cavity by using atmospheric pressure through vacuum extraction. ​ ​ ​ ​ 9. The method for preparing a wound treatment microneedle patch with mechanical sensing function according to claim 8, characterized in that: ​ 10. The method for preparing a wound treatment microneedle patch with mechanical sensing function according to claim 8, characterized in that: ​

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