Perfusion microvessel microneedle and preparation method thereof

Abstract

The invention relates to a pourable microvessel microneedle and a preparation method thereof. The pourable microvessel microneedle comprises a microvessel network and a plurality of microneedles, the microvessel network is connected with a plurality of array microneedles; and barbs are arranged at the needle tips of the microneedles. The technical problem that in an existing microneedle technology, material exchange with tissue and long-term drug release cannot be comprehensively achieved is solved, and meanwhile the minimally invasive requirements of being stably attached to the tissue and in the operation process are met.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and particularly relates to a perfusable microvascular microneedle and a preparation method thereof. Background Art

[0002] In recent years, the microneedle-based transdermal drug delivery system has shown unique advantages in the field of tissue repair. Its characteristics such as painless penetration of the stratum corneum, precise drug delivery, and minimally invasive operation provide a new paradigm for the treatment of ischemic diseases. Especially in the regeneration and repair of metabolically active tissues such as the heart and skin, continuous and controllable drug release and the construction of a functional microenvironment have become key factors determining the curative effect. However, there are two common technical bottlenecks in the existing microneedle technology: First, although traditional microneedles can achieve drug delivery, they lack the ability to continuously and actively repair damaged tissues; Second, the interfacial adhesion stability in the dynamic physiological environment is insufficient, resulting in device displacement and affecting the continuous curative effect.

[0003] Research has shown that the regeneration of functional vascular networks is the core link of tissue repair. The multi-level microchannel biomimetic vascular network constructed by Lei et al. (LEI D, YANG Y, LIU Z, et al. 3D printing of biomimetic vasculature for tissue regeneration[J]. Materials Horizons, 2019, 6(6): 1197.) has confirmed that the biomimetic design of topological structure can significantly promote host angiogenesis and establish functional circulation, which provides a new idea for breaking through the problem of ischemic tissue regeneration. Shixing Huang et al. (HUANG S, LEI D, YANG Q, et al. A perfusable, multifunctional epicardial device improves cardiac function and tissue repair[J]. Nature Medicine, 2021, 27(3): 480.) has made progress in the adhesion of the microvascular network [3], using an additional metal claw puncture device and tissue, but it causes large trauma and poor stability, and there is an urgent need to develop a minimally invasive and effective method.

[0004] The iterative upgrades of current microneedle systems mainly focus on the optimization of single functions. For example, the double-layer adhesive microneedles developed by the Soomee Lim team (LIM S, PARK T Y, JEON E Y, et al. Double-layered adhesive microneedle bandage based on biofunctionalized mussel protein for cardiac tissue regeneration[J]. Biomaterials, 2021, 278.) enhance the interfacial binding force through surface modification, and the barbed microneedle structure disclosed in Chinese Patent CN113907915B strengthens mechanical anchoring. However, these solutions do not integrate the vascularization functional module. Traditional vascularization strategies (such as pre-vascularized stent implantation) often require open surgery, which is essentially in conflict with the minimally invasive characteristics of microneedle systems. This fragmentation of functional modules makes it difficult for existing technologies to simultaneously meet the coordinated requirements of "vascularized microenvironment construction - long-acting drug controlled release". The existing barbed microneedles cannot achieve long-acting and perfusable drug delivery, and there is no microvascular network to promote tissue repair. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a perfusable microvascular microneedle and its preparation method to achieve precise drug release while constructing a microenvironment for material exchange and ensuring firm attachment to the dynamic organ surface.

[0006] The present invention provides a perfusable microvascular microneedle, including a microvascular network and a plurality of microneedles; the microvascular network is connected to a plurality of arrayed microneedles; the tip of the microneedle has barbs.

[0007] Preferably, the microvascular network includes one or more layers of stacked hollow vessels.

[0008] Preferably, the wall of the hollow vessel has a plurality of micropores.

[0009] Preferably, the cross-sectional shape of the barb includes one or several of a circle, a triangle, a square, an ellipse, a wedge, or an octagon.

[0010] Preferably, the microneedle includes one or more layers of barbs stacked in a stepped manner along the axis of the needle body.

[0011] Preferably, the materials of the microvascular network and the microneedle include one or more of polyurethane, polycaprolactone, or polylactic acid.

[0012] The present invention also provides a preparation method of a perfusable microvascular microneedle, including the following steps:

[0013] S1. Construct a microvascular network

[0014] Prepare a caramel sacrificial template by 3D printing;

[0015] Dissolve the polymer raw material for forming the microvascular microneedles in a solvent to obtain a polymer solution;

[0016] Immerse the caramel sacrificial template in the polymer solution. After the solvent volatilizes, immerse the template with the polymer-coated surface in deionized water, wash, and freeze-dry to obtain a microvascular network;

[0017] S2. Prepare barbed microneedles with a microvascular network

[0018] Fill the polymer solution into a polydimethylsiloxane template in the shape of a barbed needle tip by solution perfusion method, and obtain barbed needle tips after drying;

[0019] Assemble the microvascular network and the barbed needle tips together to obtain perfusion-enabled microvascular microneedles.

[0020] Preferably, the specific process of preparing the caramel sacrificial template by 3D printing in step S1 is as follows: First, use AutoCAD 2014 software to construct a bionic structure model simulating the microchannels of blood vessels, and simulate the movement path of the 3D printer nozzle; then add sucrose into the heating chamber of the 3D printer, set the temperature of the heating chamber to 100 - 180 °C, and obtain a stable printable caramel ink after heating for 50 - 70 min. Subsequently, set the temperatures of the heating chamber and the nozzle to 90 - 150 °C, and print the caramel sacrificial template; the layer height is set to 0.3 - 0.6 mm, and the ink extrusion speed is 0.001 - 0.01 mm / s.

[0021] Preferably, the mass-volume ratio of the polymer to the solvent in the polymer solution in step S1 is 1 g : 4 - 30 ml.

[0022] Preferably, the mass-volume ratio of the polymer to the solvent in the polymer solution in step S2 is 1 g : 10 - 100 ml.

[0023] Preferably, the solvent includes but is not limited to any one of acetone, ethanol, tetrahydrofuran, hexafluoroisopropanol, and trifluoroethanol.

[0024] Beneficial effects

[0025] (1) In the present invention, the barbed microneedles with a tip-expanded shape can firmly adhere to the tissue surface. The microvascular network has a hollow vascular structure, and its tube wall is porous for material exchange. Continuous perfusion of drugs through the microvascular network on the back plate achieves the effect of continuous treatment.

[0026] (2) The present invention solves the technical problem in the prior art that it is impossible to comprehensively achieve material exchange with tissues and long-term drug release, and at the same time meets the requirements of firm attachment to tissues and minimally invasive needs during surgical procedures. Brief Description of the Drawings

[0027] Figure 1 It is a schematic diagram of the device of the (A) perfusable microvascular microneedle and (B) a schematic diagram for tissue repair in the embodiment of the present invention.

[0028] Figure 2 It is the SEM characterization of the microvascular network of the perfusable microvascular microneedle in the embodiment of the present invention at different magnifications (A) 1mm, (B) 400μm, (C) 50μm, (D) 10μm.

[0029] Figure 3 It is the SEM characterization of the barbed microneedle of the perfusable microvascular microneedle in the embodiment of the present invention at different magnifications (A) 2mm, (B) 1μm, (C) 500μm, (D) the bottom of the microneedle at 500μm magnification.

[0030] Brief Description of the Drawings: 101 - microvascular network, 102 - micropores, 201 - microneedle, 202 - barbs. Detailed Description of the Invention

[0031] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. In addition, it should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0032] Embodiment

[0033] This embodiment provides a perfusable microvascular microneedle, which includes a microvascular network 101 and a plurality of microneedles 201; the microvascular network 101 is connected to a plurality of array microneedles 201; the tip of the microneedle 201 has barbs 202; the microvascular network includes one or more layers of stacked hollow blood vessels, and its tube wall has a plurality of micropores 102. Its structure is as Figure 1 shown in A, Figure 1 B is a schematic diagram for tissue repair of the present invention.

[0034] The preparation method of the above-mentioned perfusable microvascular microneedle includes the following steps:

[0035] S1. Construct a microvascular network

[0036] First, use AutoCAD 2014 software to construct a bionic structure model simulating the microvascular channels, and simulate the movement path of the 3D printer nozzle; add an appropriate amount of sucrose into the heating chamber of the 3D printer, set the heating chamber temperature to 150 °C and heat for 60 min to obtain a stable printable caramel ink, set the heating chamber and nozzle temperatures to 135 °C, print the caramel sacrificial template, set the layer height to 0.5 mm, and the ink extrusion speed to 0.001 mm / s;

[0037] Dissolve the polymer raw materials for making the microvascular network and microneedles in tetrahydrofuran, and immerse the sacrificial template completely in the polymer solution (the mass-volume ratio of the polymer to the solvent is 1 g: 4 - 30 ml). After the solvent has completely evaporated, immerse the caramel sacrificial template coated with the polymer in deionized water, wash it three times repeatedly, and then freeze-dry to obtain PHMs. From Figure 2 In SEM photos at different magnification multiples (A. 1 mm, B. 400 μm, C. 50 μm, D. 10 μm), the formation of the porous microvascular network structure can be seen, enabling mass exchange;

[0038] S2. Preparation of barbed microneedles with a microvascular network

[0039] Use a polydimethylsiloxane template with a personalized customized barbed tip shape;

[0040] Weigh a certain mass of the polymer and dissolve it in a solvent. The mass-volume ratio of the polymer to the solvent is 1 g: 10 - 100 ml, and the solvent used is any one of acetone, ethanol, tetrahydrofuran, hexafluoroisopropanol, and trifluoroethanol;

[0041] Fill the polydimethylsiloxane template with a barbed tip shape by perfusion of the polymer solution through the solution method, and obtain polymer barbed tips after vacuum drying. From Figure 3 In SEM photos at different magnification multiples (A. 2 mm, B. 1 μm, C. 500 μm, D. the bottom of the microneedle at 500 μm magnification), the successful preparation of the barbed microneedle structure can be seen, where the barbs are distributed in a stepped and stacked manner along the needle body axis, with a swollen tip, enabling stable adhesion to the tissue surface;

[0042] Assemble the microvascular network and the barbed tips together to obtain a perfusable microvascular microneedle.

Claims

1. A perfusable microvascular microneedle, characterized in that, It includes a microvascular network and several microneedles; the microvascular network is connected to several array microneedles; the tips of the microneedles have barbs.

2. The perfusable microvascular microneedle according to claim 1, characterized in that, The microvascular network includes one or more layers of stacked hollow vessels.

3. The perfusable microvascular microneedle according to claim 2, wherein The wall of the hollow vessel has a plurality of micropores.

4. The perfusable microvascular microneedle according to claim 1, wherein The cross-sectional shape of the barb includes one or several of circular, triangular, square, oval, wedge-shaped or octagonal.

5. The perfusable microvascular microneedle according to claim 1, wherein The microneedle includes one or more layers of barbs that are stacked stepwise along the axis of the needle body.

6. A preparation method of a perfusable microvascular microneedle, comprising the following steps: S1. Construct a microvascular network Prepare a caramel sacrificial template by 3D printing; Dissolve the polymer raw material for forming the microvascular microneedle in a solvent to obtain a polymer solution; Immerse the caramel sacrificial template in the polymer solution, and after the solvent volatilizes, immerse the template with a polymer coating on its surface in deionized water, wash and freeze-dry to obtain a microvascular network; S2. Prepare barbed microneedles with a microvascular network Fill the polymer solution into a polydimethylsiloxane template in the shape of a barbed tip by solution perfusion, and obtain a barbed tip after drying; Assemble the microvascular network and the barbed tip together to obtain a perfusable microvascular microneedle.

7. The preparation method of the perfusable microvascular microneedle according to claim 6, wherein In the polymer solution in step S1, the mass-volume ratio of the polymer to the solvent is 1 g: 4-30 ml.

8. The preparation method of the perfusable microvascular microneedle according to claim 6, wherein In the polymer solution in step S2, the mass-volume ratio of the polymer to the solvent is 1 g: 10-100 ml.

9. The preparation method of the perfusable microvascular microneedle according to any one of claims 7 or 8, characterized in that, The solvent includes any one of acetone, ethanol, tetrahydrofuran, hexafluoroisopropanol, and trifluoroethanol.

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