What is a Micro Needle Array Based on Nanomaterials?

Micro needle (MN) is a micro needle-shaped structure, the length of 100 ~ 1000μm, the bottom diameter of several hundred micrometers, the tip diameter is less than a few dozen micrometer, usually in the form of micro- needle array sticker, can penetrate the skin surface cortex to form micro-porous tubes, without touching the nerve endings within the cortex causing pain. At present, researchers generally use silicon, metal, polymers and other materials to prepare micro needles through traditional microelectronic mechanical systems (MEMS) processes and new processing technologies. Depending on the way of action, the micro needle can be divided into solid, coated, empty, soluble and hydrogel micro needles, widely used in the fields of skin beauty, disease diagnosis and treatment. However, there are some problems in the application, such as the mechanical performance of the soluble needle prepared with polymers as the main material is poor, and the load of drugs may also reduce the mechanic performance of micro needles, thereby reducing the drug delivery efficiency of the needle; for the extraction of the detected hydrogel needle mechanical properties are poor and easy to absorb moisture, resulting in insufficient depth, reduces the volume of the micro needle to extract the skin intermittent fluid; and for the bio-sensor needle lacks excellent electrochemical characteristics, catalysis activity and stability.

In recent years, with the rapid development of nanotechnology, research into using nanomaterials to improve micro needle-related performance has attracted widespread attention. Nanoparticles (NPs) refers to at least one-dimensional space size of 1 to 100 nm of solid particles, compared with conventional materials, nanoparticles have unique physical and chemical properties because of the size of smaller, larger surface area, higher than surface energy, with quantum size effect and macro quantum tunnel effect, for different application needs, you can choose different functional nanoparticle and micro-nucleus combination application. Nanoparticles can be divided into inorganic and organic nanoparticles by material type. Due to the different types of materials and shape structures, the properties of different nanoparticles will be different, and the way and effects that are combined with different kinds of microneedles will also be different. This article introduces a variety of nanoparticles and drug nanoparticle that bind to micro needles, and subsequently outlines the progress of research on the application of nano particles in microneedles.

The Role of Nanomaterials in Microneedles

As a new type of transdermal method, microneedle plays an important role in the diagnosis and treatment of diseases. Its performance is still the key to the application of microneedle. Nanoparticles can improve the related performance of microneedle. It is the trend of future of multifunctional microneedle design. At present, the common combination of nanoparticles and microneedles and the role of nanoparticles in microneedles are shown in the figure.

Enhanced Mechanical Properties of Polymer Microneedles

Inorganic nanoparticles have excellent mechanical properties, and as a reinforcing phase, they can enhance the mechanical properties of microneedles, increase the depth of microneedle penetration into the skin, and thereby improve the delivery efficiency of drugs. The researchers loaded insulin (INS) with calcium carbonate (CaCO3) nanoparticles, blended it with polyvinylpyrrolidone (PVP), and used a two-step centrifugation process to fabricate soluble microneedles, which can be used to treat diabetes. Compared with PVP-MN, the as-formed INS-CaCO3/PVP-MN has higher toughness and mechanical strength, and in static analysis, the tip of PVP-MN exhibits severe bending when a load of 500 g is applied for 1 min , while no obvious bending was observed in INS-CaCO3/PVP-MN; the mechanical strength of the microneedles was further characterized by dynamic analysis, and the stress-displacement curves showed that with the increase of the pressing displacement, the INS-CaCO3/PVP- MN bears a greater stress, up to 1.05 N at 600μm, which is much higher than that of PVP-MN (0.26 N). The results show that CaCO3, as insoluble rigid particles, can significantly improve the toughness and strength of microneedles. The mechanism may be that the load is transferred from the matrix to the reinforcement phase through interfacial shear, increasing the stress bearing of the nanoparticles, preventing the dislocation movement of the matrix material, and inhibiting the plastic deformation of the matrix, thereby improving the performance of the material. At the same time, the mechanical reinforcement effect of nanoparticles on microneedles is related to the type of nanoparticles. Different nanoparticles have different reinforcement effects on PVP, and may even lead to a decrease in the hardness of PVP. Therefore, suitable nanoparticles should be selected according to the matrix material used.

For hydrogel microneedles, the degree of cross-linking is an important factor affecting its mechanical properties. Studies have shown that hydrogel with high cross-linking degree has excellent mechanical properties, but its swelling rate is low, which reduces the volume of interstitial fluid extracted by microneedles; on the contrary, hydrogel microneedles with low cross-linking degree have high swelling rate, but its mechanical properties are poor. Therefore, it is difficult to achieve the balance of high mechanical properties and high extraction rate by adjusting the degree of crosslinking. In order to achieve this balance, some researchers added nanoparticles to make the microneedles maintain good mechanical properties and better swelling properties even at low cross-linking degrees.

Synergistically Improves Drug Release

Nanoparticle carriers have unique physicochemical and biological properties. Loading drugs by embedding, bonding, adsorption and other methods can reduce the toxic and side effects of drugs, improve stability, bioavailability and therapeutic effect, and modify the surface of particles to achieve slow, responsive and targeted release of drugs. Traditional transdermal drug delivery mainly penetrates the stratum corneum through passive diffusion, and the drug penetration rate is limited. The combination of nanoparticles and microneedles can greatly improve the transdermal penetration of nanoparticles.

Controlled Release

The combined application of nanoparticles and microneedles can produce a synergistic effect, improve the retention ability of drugs in the skin, and prolong the action time. Some researchers prepared cross-linked hyaluronic acid nanoparticle microneedles (X-linked HA-NP-MNs), compared with HA aqueous solution and cross-linked hyaluronic acid (X-linked HA) hydrogel, X-linked HA The nanoparticle solution has lower viscosity and better fluidity, which is conducive to filling the mold to prepare microneedles. Cross-linked hyaluronic acid nanoparticle microneedles and sodium hyaluronate microneedles containing isothiocyanate-labeled dextran were applied to the back skin of mice, and the relative fluorescence intensity in the back skin was measured over time, The results showed that RITC-dextran could be slowly released from X-linked HA-NP-MNs, and its relative fluorescence intensity lasted longer than that of HA-MNs, and the intensity at 48 h was about twice that of HA-MNs.

Responsive Release

Nanomaterials can produce changes in morphological structure, physical and chemical properties under the slight stimulation of their own physiological environment (pH value, temperature, glucose concentration, enzyme activity, etc.) or external environment (light, electricity, magnetic field, ultrasound, etc.), so as to realize Responsive release of drug for better therapeutic effect. In recent years, researchers have successively developed nanoparticles with pH-responsive, magnetic-responsive, and light-responsive properties, combined with microneedles to enhance the drug efficacy of transdermal drug delivery systems.

Targeted Release

Nanoparticles are small in size and have strong penetrability, and the loaded drugs can be directly delivered to different tissues and organs to achieve targeted drug therapy. Rhodamine B (RhB) was used as a model compound to make PLGA nanoparticles, combined with PVP-MN to study drug distribution in mice. Compared with pure RhB-MN, RhB loaded with PLGA nanoparticles accumulated in a large amount in lymph nodes. On the basis of previous work, the researchers further studied lymphatic targeted drug delivery, and combined solid lipid nanoparticles (SLN) with soluble microneedles for transdermal targeted delivery of doxycycline, diethylcarbazine and albendazole. For the treatment of lymphatic filariasis, the microneedles loaded with SLN have sufficient mechanical strength and puncture performance. The three drugs have larger areas under the curve and higher bioavailability in rat plasma. This system has the potential to treat lymphatic filariasis and is a promising intradermal lymphatic-targeted drug delivery system.

Immune Enhancement

A special subtype of dendritic cells, called Langerhans cells (LC), is distributed in the basal layer of the human skin epidermis, accounting for 3% to 8% of epidermal cells. LC can detect pathogens that penetrate the skin barrier, present antigens to CD8+ T and CD4+ T cells through the major histocompatibility complex (MHC I and MHC II), and cause the proliferation of effector T cells. LCs are the major antigen-presenting cells (APCs) in the skin and constitute the first line of defense against invading pathogens. The length of microneedles for transcutaneous immunization (TCI) is generally 100-1 000 μm, which is sufficient to break through the stratum corneum and deliver drugs to the basal layer. Studies have shown that the microneedles loaded with antigens on the needle tip can target the LC located in the basal layer of the epidermis. Vaccine-loaded microneedles conferred higher immune protection than subcutaneous injections.