CN118903670A - Special-shaped channel double-structure microneedle device for repairing soft tissue defects - Google Patents

Abstract

The present invention discloses a special-shaped channel double-structure microneedle device for repairing soft tissue defects, comprising: an injectable extracellular matrix material, a tree-shaped special-shaped channel microneedle base matrix, a conical straight channel microneedle base matrix, and a microneedle isolation sheet. The needle tip of the base matrix is covered with four layers of material, which are a hemostatic antibacterial layer, a protective layer, a hemostatic ion layer, and a biological nutrition layer from the inside to the outside; the back of the base matrix is covered with a medical-grade isolation sheet. The heterogeneous microneedle base matrix sheets are divided into two types: the first type has long layered special-shaped channel microneedles, a circular bracket at the bottom, and an upper layer of tree-shaped layered needle bodies, and a tree-shaped heterogeneous channel is penetrated inside; the second type has a single-layer short microneedle, a cone-shaped needle body, and a cylindrical straight channel is penetrated inside. The present invention can effectively penetrate the soft tissue of the joint and use the special-shaped channel microneedle matrix at different angles to fit the joint parts of the human body, which can reduce the mass of the microneedle to the greatest extent, increase the delivery rate of the therapeutic liquid, and quickly repair the goal of tissue defects.

Description

A special-shaped channel double-structure microneedle device for repairing soft tissue defects

Technical Field

The invention relates to a medical device, in particular to a special-shaped channel double-structure microneedle device for repairing soft tissue defects.

Background Art

Microneedles have attracted extensive attention in the regeneration of various tissues, such as skin trauma, corneal injury, myocardial infarction, endometrial injury, and spinal cord injury, due to their unique composition and structure. Microneedles can effectively penetrate the barriers of necrotic tissue or biofilm and improve the bioavailability of therapeutic drugs. The use of microneedles to deliver bioactive molecules, cell repair drugs, and growth factors can achieve the healing and repair of defective tissues.

The layered structure of the microneedles is derived from the layered structure of insect tentacles. Through the physical interlocking of the layered microneedles with the skin tissue, the adhesion ability of the layered microneedles is not affected by harsh environments (such as massive blood loss and uneven wound surfaces), and is therefore suitable for bleeding areas in different locations.

The application of special-shaped channels in microneedles can greatly improve the efficiency of drug delivery. Special-shaped channels can be designed according to the needs of drug delivery, improve drug permeability and absorption rate, and improve treatment effects. In addition, the cavity formed by the special-shaped channel can reduce the weight of the microneedle to a certain extent, deform accordingly to fit the skin, and improve the connectivity between the microneedle device and damaged tissue. After the shape and size of the internal channel of the microneedle are optimized, the friction and irritation caused by the microneedle when penetrating the skin can also be reduced, reducing the patient's pain and discomfort and improving the comfort of treatment.

Microneedle patches are made by reducing injection needles to nanoscale. They can be made through van der Waals interactions alone to have great flexibility and high adhesion to irregular and complex topography. They can achieve rapid bleeding control and effective wound closure, preventing excessive blood leakage and external contamination at the wound site.

In recent years, many important studies have focused on tissue or organ regeneration issues, such as bone and cartilage, skin defects or wound healing, peripheral nerves and periodontal tissues. Extracellular matrix materials (ECM) with controllable manufacturing parameters have become auxiliary tools for researchers in the fields of biomechanics, drug screening, drug delivery and disease simulation due to their good simulation of physiological and pathological environments. ECM is widely present in organisms and is the place and microenvironment for all biological activities of tissue cells in the body. It is synthesized by body cells and secreted outside the cells, distributed on the cell surface and between cells. Its main components include collagen, fibronectin, laminin, proteoglycans, aminoglycans and growth factor components. These proteins and polysaccharide molecules play a key role in regulating cell responses, can induce and promote cell migration, proliferation, differentiation and angiogenesis, and are the basis of tissue repair. Extracellular matrix materials can be used as one of the ideal materials for tissue repair and have broad application prospects.

Injectable extracellular matrix materials (IECM) that provide a growth environment for soft tissue cells contain complex tissue components and simulate natural microenvironments, providing attractive biological activities and showing great advantages in cartilage tissue remodeling. Adding IECM to microneedle devices is a promising method for repairing soft tissue defects. Microneedle devices based on IECM have great advantages in cartilage regeneration; for example, regenerative cells or repair drugs can be evenly encapsulated into microneedles, and after entering the human body, they can form repair tissues to fill irregular tissue defects. The environment for the growth of soft tissue cells provided by IECM is conducive to the fusion of drugs and soft tissues, guiding the rapid repair of soft tissues, indicating their potential application value in cartilage regeneration.

Tissue repair or regeneration is one of the most complex biological processes, which refers to the restoration of damaged tissue to a normal state with complete functions. Although small injuries can be healed by the body's regulation, special regenerative treatments are usually required for pathological defects or large-area injuries that cannot heal themselves. In recent years, with the in-depth exploration of tissue repair mechanisms and the development of biomaterials, MNs for minimally invasive delivery of therapeutic agents have become an emerging technology to promote tissue repair and healing.

The commonly used soft tissue repair methods currently mainly include surgical suture, autologous tissue transplantation, allogeneic tissue transplantation, etc. These methods have certain applications clinically, but also have defects to varying degrees. Therefore, the present invention combines microneedles with injectable extracellular matrix materials for repairing soft tissues, utilizes the injectability and biocompatibility of IECM, delivers microneedles and drugs to the lesion site, and naturally merges with surrounding tissues outside the human body tissue, and can also be stabilized at the joint, realize drug delivery, seal the blood flowing out, and promote the rapid growth of tissue cells. This treatment method can avoid postoperative pain, wound infection, and the problems of long recovery time, and also provides more options for tissue repair treatment, and improves clinical treatment effect.

Summary of the invention

In view of this, the present invention provides a special-shaped channel double-structure microneedle device that can achieve effective adhesion on irregular tissue surfaces and penetrate the skin to quickly stop bleeding and repair soft tissue defects.

In order to achieve the above-mentioned object, one aspect of the present invention provides a special-shaped channel double-structure microneedle device for repairing soft tissue defects, comprising:

Injectable extracellular matrix materials, shaped channel layered microneedles, single-layer microneedles, microneedle base matrices and medical-grade isolation films are provided to provide a growth environment for soft tissue cells. The needles of the shaped channel double-structure microneedle device for repairing soft tissue defects are covered with multiple layers of materials, including dopamine (DA) and antimicrobial peptide (AMP, KRWWKWWRRC), polycaprolactone (PCL, Mw～80000) and polyvinyl alcohol (PVA, 30% w/v) from the inside to the outside, hemostatic gelatin mixed with 75 mg/ml GDP polymer and photoinitiator I2959 (1% w/v) and CaCl2 (200 mmol/l) (GDP@Ca ²⁺ ), and decellularized cartilage matrix material (DDC). The microneedle base matrix is wrapped by a medical-grade isolation film.

Preferably, the material of the special-shaped channel double-structure microneedle device for repairing soft tissue defects is an injectable cell matrix material (decellularized cartilage matrix material, DDC) with injectability, biocompatibility and support.

Preferably, based on the tissue structure characteristics of the joint area, the microneedles formed on the base of the special-shaped channel double-structure microneedle device for repairing soft tissue defects have different lengths, angles, shapes, diameters, and different shapes of internal liquid delivery channels. The microneedles at the articular cartilage are single-layer microneedles with a height range of 350-450μm, an angle of 90° with the base, a diameter of 150-200μm at the bottom of the needle body, a diameter of 5-60μm at the tip, an angle of 30° at the tip, and a cylindrical internal channel placed in the middle of the microneedle with a height range of 100-150μm; the total height of the special-shaped channel layered microneedles at the joint movement is 650-800μm, the angle between the central axis of the special-shaped channel layered microneedle and the base ranges from 70° to 80°, the diameter of the cylindrical structure at the bottom is 200-300μm, the diameter of the upper tree-like structure is 400-700μm, the diameter of the upper vertebral needle tip is 5-60μm, the top needle tip angle is 30°, the internal channel is tree-branch shaped, the channel height is 600-750μm, and the tree-branch channel is connected to the special-shaped channel layered microneedle.

Compared with existing soft tissue repair methods, the present invention has the following advantages:

(1) The material of the present invention is novel. The special-shaped channel double-structure microneedle device for repairing soft tissue defects adopts a decellularized cartilage matrix material (DDC) that provides a biological environment suitable for the growth of soft tissue cells as the biological nutrient layer of the microneedle device. As an injectable exomatrix with broad prospects as a biomimetic biomaterial for tissue engineering, DDC is applied to the repair of defects in joints. It can eliminate the rejection reaction of the human immune system during the process of tissue repair, guide the differentiation of defective tissue, and further improve the efficiency of tissue repair. The DDC contained in the microneedle has good biological tissue guidance and can enhance the hemostatic ability. After entering the human body, DDC guides the repair of connective tissue and subcutaneous tissue. DDC will not cause rejection reaction when entering the human body environment. During the repair process, DDC molecules can also become part of the damaged muscle tissue and fibrous tissue, thereby accelerating the repair of damaged joints.

(2) The present invention has a novel structure, and applies microneedle technology to repair soft tissue defects. In particular, a special-shaped channel double-structure microneedle device for repairing soft tissue defects is manufactured. After the device penetrates the damaged tissue, the cavity structure of the special-shaped channel layered microneedle undergoes lateral deformation under the action of external squeezing force and the pressure in the human body, thereby being stabilized near the joint. After stabilization, the special-shaped channel inside the special-shaped channel layered microneedle and the columnar channel inside the single-layer microneedle begin to rapidly transport the drug solution, thereby achieving hemostasis and repairing tissue defects.

(3) The present invention has sufficient flexibility and adhesion, and the PCL and PVA contained in the special-shaped channel dual-structure microneedle device for repairing soft tissue defects show high mechanical strength and environmental adaptability. The microneedle device can adapt to substrates with complex morphology and can adhere tightly to tissues under bleeding and humid conditions; the bursting pressure of the microneedle device can reach 6.8±0.55kPa, which is greater than blood pressure and meets the requirements of wound hemostasis and sealing. At the same time, under the conditions of tension, compression and torsion, the microneedle device shows an adhesion of more than 200% in a humid environment, and is firmly attached to tissue joints under bleeding conditions;

(4) The Ca ²⁺ ions, dopamine and antimicrobial peptide molecules released by the special-shaped channel dual-structure microneedle device for repairing soft tissue defects of the present invention have good hemostatic ability and can prevent microbial infection. After the microneedles loaded with Ca ²⁺ ions enter the joint tissue, the Ca ²⁺ ions are released to the target cells to promote hemostasis. Ca ²⁺ activates the coagulation cascade reaction by binding to platelets in the blood. When the Ca ²⁺ concentration is 200mmol/l, the coagulation time is about 6 minutes, shortening the coagulation time;

(5) The medical-grade isolation sheet used in the special-shaped channel dual-structure microneedle device for repairing soft tissue defects of the present invention can ensure the storage conditions of the special-shaped channel microneedles, isolate the contamination of microorganisms and other contamination sources, and achieve the purpose of taking them as needed;

(6) The multi-angle needle body used in the special-shaped channel dual-structure microneedle device for repairing soft tissue defects of the present invention can be highly fitted to the articular cartilage. When the drug delivery device is used, a high degree of fit between the damaged joint and the needle body can be achieved. The layered needle body can improve the connectivity with the joint, thereby achieving the purpose of precise drug delivery;

(7) The present invention is safe and effective, suitable for repairing soft tissue defects, and is easy to promote and use on a larger scale.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosure.

This application document provides an overview of various implementations or examples of the technology described in the present disclosure, and is not a comprehensive disclosure of the entire scope or all features of the disclosed technology.

BRIEF DESCRIPTION OF THE DRAWINGS

Figures 1 and 2 are schematic diagrams of the structure of a special-shaped channel double-structure microneedle device for repairing soft tissue defects.

Figures 3, 4, 5, and 6 are schematic diagrams of the internal and external structures of the shaped channel layered microneedles. Figures 7, 8, and 9 are schematic diagrams of the internal and external structures of the single-layer microneedles. Figure 10 is a schematic diagram of the structure of the medical-grade isolation sheet.

DETAILED DESCRIPTION

In order to make the purpose, technical solution and advantages of the embodiments of the present disclosure more clear, the technical solution of the embodiments of the present disclosure will be clearly and completely described below in conjunction with the drawings of the embodiments of the present disclosure.

As shown in Figures 1 and 2, the embodiment of the present invention provides a special-shaped channel dual-structure microneedle device for repairing soft tissue defects. Figures 3, 4, 5, and 6 show the internal and external structures of the special-shaped channel layered microneedles; Figures 7, 8, and 9 show the internal and external structures of the single-layer microneedles; and Figure 10 shows the structure of the medical-grade isolation sheet.

The shaped channel layered microneedles of the shaped channel double structure microneedle device for repairing soft tissue defects have two angles of microneedles, which are suitable for the repair of soft tissues at different joints, such as ankle joints and knee joints. Different angles of shaped channel layered microneedles can be selected according to different repair sites, and the scope of application is wider. The shaped channel and columnar channel inside the microneedle device can accelerate the delivery of repair drugs. The channel of the shaped channel microneedle will deform with the depth of penetration into the skin tissue, and physically interlock with the human tissue to stabilize the injured part. The needle tip of the shaped channel double structure microneedle device contains dopamine (DA) and antimicrobial peptide (AMP, KRWWKWWRRC), polycaprolactone (PCL) and polyvinyl alcohol (PVA), 75mg/ml GDP polymer mixed with photoinitiator I2959 (1% w/v) and CaCl2 (200mmol/l) (GDP@Ca2+) hemostatic gelatin, and injectable extracellular matrix material (using decellularized cartilage matrix material, DDC). The polycaprolactone and polyvinyl alcohol in the needle tip give the microneedle a high mechanical strength, continuous and effective adhesion to uneven wound surfaces during joint bleeding, and high platelet adhesion. The combination of metal ions and antimicrobial peptides can play an excellent antibacterial role in tissue repair, avoiding the entry of microorganisms and secondary infection during the repair of defective tissues. DDC is harmless to the human body and will not be attacked by the immune system after entering the human body. It provides a suitable growth environment for stem cells and platelets in the damaged tissue of the joint, successfully seals and heals wounds, and effectively controls bleeding. At the same time, DDC is a bioabsorbable material that adheres to the damaged area and gradually becomes part of the healthy tissue of the human body, completing the repair of defective soft tissues.

For the repair of knee joint tissue defects, according to the flexion and extension angle of the knee joint of 0-130°, the bottom bracket of the special-shaped channel layered microneedle adopts an angle of 80° with the microneedle base, and according to the thickness of the cartilage near the knee joint of 2-3mm, the total height of the special-shaped channel layered microneedle is 650-800μm, and the total height of the single-layer microneedle is 350-450μm. The special-shaped channel layered microneedle surface is inserted into the tissue near the knee joint, and the single-layer microneedle is fixed to the joint activity site. The Ca ²⁺ ions, dopamine, and antimicrobial peptide molecules released by the special-shaped channels of the special-shaped channel layered microneedle and the columnar channels of the single-layer microneedle can repair the defective connective tissue and cells while quickly stopping bleeding. The PVA and PCL molecules contained in the microneedle allow the microneedle to maintain excellent mechanical strength, and can also adhere closely to the defect when the human joint is active or under bleeding and moist conditions, so as to achieve rapid control of bleeding and effective closure of the wound.

For the repair of elbow joint tissue defects, according to the elbow flexion and extension angle of 0-145°, the bottom bracket of the special-shaped channel layered microneedle adopts an angle of 70° with the microneedle base, and according to the thickness of the cartilage near the elbow joint of 1-2mm, the total height of the special-shaped channel layered microneedle is 700-800μm, and the total height of the single-layer microneedle is 350-400μm. The special-shaped channel layered microneedle is inserted into the tissue near the elbow joint, and the single-layer microneedle penetrates the skin. The cavity structure adapts to the groove surface of the damaged tissue to deform and stabilize. The subsequently released DDC molecules, dopamine (DA) and antimicrobial peptides (AMP) and Ca ²⁺ inhibit the growth of microorganisms in the bleeding site, improve the ability of platelet hematopoiesis, provide the best biological environment for tissue repair, guide the cell growth of damaged tissue, promote cell differentiation, quickly complete the blood sealing, and achieve the best repair effect.

Obviously, the described embodiments are only part of the embodiments of the present disclosure, rather than all of the embodiments. Based on the described embodiments of the present disclosure, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present disclosure.

The above embodiments are only exemplary embodiments of the present invention and are not intended to limit the present invention. The protection scope of the present invention is defined by the claims. Those skilled in the art may make various modifications or equivalent substitutions to the present invention within the essence and protection scope of the present invention, and such modifications or equivalent substitutions shall also be deemed to fall within the protection scope of the present invention.

Claims (10)

1. The special-shaped channel double-structure microneedle device for repairing soft tissue defects is characterized by comprising a matrix substrate and special-shaped channel microneedles, wherein the special-shaped channel microneedles are arranged on the substrate and comprise special-shaped channel layered microneedles and single-layer microneedles, the single-layer microneedles are of cone structures, and a cylindrical straight channel penetrates through the inside of the single-layer microneedles; the bottom of the special-shaped channel layered microneedle is of a cylindrical structure, the top end of the cylindrical structure is of a singular tree-shaped structure formed by overlapping a plurality of layers of cones and cylinders, and a singular tree-shaped liquid channel communicated with the singular tree-shaped structure is penetrated in the special-shaped channel layered microneedle; covering the surface of the special-shaped channel microneedle with a layer of hemostatic and antibacterial molecules of dopamine and antibacterial peptide; the antibacterial molecules are covered with PCL/PVA molecules; PCL/PVA molecules wrap a layer of Ca ²⁺ ions; covering the acellular cartilage matrix material DDC molecules outside Ca ²⁺ ions; the outside of the DDC molecules is wrapped by a medical grade separation sheet; when the special-shaped channel double-structure microneedle device for repairing soft tissue defects is used for a damaged joint, a single-layer microneedle acts on a joint cartilage, a special-shaped channel layered microneedle acts on a joint movement part, a cavity structure of the special-shaped channel layered microneedle is transversely deformed and is stably positioned at the joint movement part under the action of external extrusion force and human body pressure, and meanwhile, special-shaped channels inside the special-shaped channel layered microneedle and cylindrical channels inside the single-layer microneedle start to convey tissue repair factors DDC, ca ²⁺ ions and dopamine, so that defect joint repair is completed.

2. The special-shaped channel double-structure microneedle device for soft tissue defect repair according to claim 1, wherein the special-shaped channel layered microneedle internally penetrates through a singular tree-shaped delivery channel, and the single-layer microneedle internally penetrates through a cylindrical straight-shaped delivery channel.

3. The shaped channel double-structure microneedle device for soft tissue defect repair according to claim 2, wherein the surface of the needle tip of the shaped channel microneedle is a hemostatic and antibacterial layer containing dopamine and antibacterial peptide.

4. A shaped channel double structure microneedle device for soft tissue defect repair according to claim 3, wherein the hemostatic antibacterial layer is covered with a high strength protective layer comprising polycaprolactone PCL and polyvinyl alcohol PVA.

5. The shaped channel double structure microneedle device for soft tissue defect repair of claim 4, wherein the high strength protective layer is provided with a hemostatic ion layer containing hemostatic Ca ²⁺.

6. The double-structured micro-needle device with special-shaped channels for repairing soft tissue defects according to claim 5, wherein the hemostatic ion layer is arranged outside the double-structured micro-needle device and comprises a biological nutrition layer of a decellularized cartilage matrix material DDC.

7. The shaped channel double structure microneedle device for soft tissue defect repair of claim 6, wherein the outside of the biological nutrition layer is an isolation layer comprising a medical grade isolation sheet.

8. The special-shaped channel double-structure microneedle device for repairing soft tissue defects according to claim 1, wherein the height range of the single-layer microneedle is 350-450 μm, the included angle between the single-layer microneedle and a substrate is 90 degrees, the diameter of the bottom end of a needle body is 150-200 μm, the diameter of a needle tip is 5-60 μm, the included angle between the needle tip is 30 degrees, the internal channel is cylindrical and is arranged in the middle of the single-layer microneedle, and the height range is 100-150 μm; the total height of the layering microneedle of the special-shaped channel is 650-800 mu m, the included angle range of the central axis of the layering microneedle and the substrate is 70-80 degrees, the diameter of a cylindrical structure at the bottom of the microneedle is 200-300 mu m, the diameter of a conical structure at the upper end is 400-700 mu m, the diameter of the tip of a cone at the upper end is 5-60 mu m, the included angle of the tip is 30 degrees, the internal channel is in a crotch shape, the height of the channel is 600-750 mu m, and the crotch channel is connected with the layering microneedle.

9. The special-shaped channel double-structure microneedle device for soft tissue defect repair according to claim 1, wherein the structure of the cavity inside the special-shaped channel microneedle reduces the weight of the needle, and the cavity formed by the special-shaped channels inside the special-shaped channel layered microneedle is transversely deformed and fixed when contacting with tissues.

10. The profiled channel double-structure microneedle device for soft tissue defect repair according to claim 1, wherein the preparation method of the microneedle comprises the following steps:

s1, drilling holes on the surface of a polydimethylsiloxane plate by adopting a laser micro-machining method to obtain two corresponding microneedle mould pieces, wherein one microneedle mould piece is a special-shaped channel layered microneedle mould piece, and the other microneedle mould piece is a single-layer microneedle mould piece;

s2, dripping an antibacterial peptide solution and a dopamine solution on the surface of the prepared polydimethylsiloxane microneedle mould sheet, placing the microneedle mould sheet in a vacuum oven, vacuumizing at room temperature, and then drying the surface of a needle point in air to obtain a hemostatic antibacterial layer of the special-shaped channel double-structure microneedle device;

S3, preparing a polyvinyl alcohol solution by using deionized water, dripping 1ml of the polyvinyl alcohol solution on the hemostatic antibacterial layer, drying the surface in air, preparing a polycaprolactone solution by using methylene dichloride, dripping the polycaprolactone solution on the dried hemostatic antibacterial layer, drying by nitrogen flow, and treating the polycaprolactone layer by using plasma to obtain a high-strength protective layer of the special-shaped channel double-structure microneedle device;

s4, mixing 75mg/ml of guanosine diphosphate polymer with a photoinitiator I2959 and CaCl ₂ to prepare a solution, dripping 1ml of the solution on the dried polycaprolactone layer, drying the solution through nitrogen flow, and then crosslinking the solution for 1 to 8 minutes under ultraviolet irradiation to obtain a hemostatic ion layer of the special-shaped channel double-structure microneedle device;

S5, finally covering the acellular cartilage matrix material on the dried hemostatic ion layer to form a layer of biological nutrition film, so as to obtain a biological nutrition layer of the special-shaped channel double-structure microneedle device, and demolding;

S6, drying the formed microneedle after demolding, punching by using a ultramicropore puncher, and punching by using crotch-shaped and cylindrical punching needles to respectively obtain a special-shaped channel layered microneedle substrate matrix sheet and a single-layer microneedle substrate matrix sheet, thereby obtaining a special-shaped channel double-structure microneedle sheet;

and S7, connecting the prepared special-shaped channel double-structure microneedle sheet with the single-layer microneedle substrate matrix sheet through biological glue and the medical grade separation sheet to obtain the complete special-shaped channel double-structure microneedle device for repairing soft tissue defects.