基于MEMS微针技术的研究现状与展望

基于MEMS的微针技术研究是当前药物传输领域中的热点。随着微细加工技术的发展,微针技术及其应用得到了快速发展,除了向生物体内传输药物和向细胞内传输DNA外,还可以用来监测和反馈药物对生物体的影响及外源DNA在受体内的表达形式,同时在植入式器械方面也有所发展。本文综述了基于MEMS微针技术及应用的发展状况。     

Composite Dissolving Microneedles for Coordinated Control of Antigen and Adjuvant Delivery Kinetics in Transcutaneous Vaccination

Transcutaneous administration has the potential to improve therapeutics delivery, providing an approach that is safer and more convenient than traditional alternatives, while offering the opportunity for improved therapeutic efficacy through sustained/controlled drug release. To this end, a microneedle materials platform is demonstrated for rapid implantation of controlled‐release polymer depots into the cutaneous tissue. Arrays of microneedles composed of drug‐loaded poly(lactide‐co‐glycolide) (PLGA) microparticles or solid PLGA tips are prepared with a supporting and rapidly water‐soluble poly(acrylic acid) (PAA) matrix. Upon application of microneedle patches to the skin of mice, the microneedles perforate the stratum corneum and epidermis. Penetration of the outer skin layers is followed by rapid dissolution of the PAA binder on contact with the interstitial fluid of the epidermis, implanting the microparticles or solid polymer microneedles in the tissue, which are retained following patch removal. These polymer depots remain in the skin for weeks following application and sustain the release of encapsulated cargos for systemic delivery. To show the utility of this approach the ability of these composite microneedle arrays to deliver a subunit vaccine formulation is demonstrated. In comparison to traditional needle‐based vaccination, microneedle delivery gives improved cellular immunity and equivalent generation of serum antibodies, suggesting the potential of this approach for vaccine delivery. However, the flexibility of this system should allow for improved therapeutic delivery in a variety of diverse contexts.     

Tapered conical polymer microneedles fabricated using an integrated lens technique for transdermal drug delivery

Administration of protein and DNA biotherapeutics is limited by the need for hypodermic injection. Use of micron-scale needles to deliver drugs in a minimally invasive manner provides an attractive alternative, but application of this approach is limited by the need for suitable microneedle designs and fabrication methods. To address this need, this paper presents a conical polymer microneedle design that is fabricated using a novel integrated lens technique and analyzed for its ability to insert into the skin without mechanical failure. Microneedle master structures were fabricated using microlenses etched into a glass substrate that focused light through SU-8 negative epoxy resist to produce sharply tapered structures. Microneedle replicates were fabricated out of biodegradable polymers by micromolding. Because microneedle mechanical properties are critical to their insertion into the skin, we theoretically modeled two failure modes (axial mode and transverse mode), and analytical models were compared with measured data showing general agreement. Guided by this analysis, polymer microneedles were designed and demonstrated to insert to different depths into porcine skin in vitro. "Long" polymer microneedles were also demonstrated in human subjects to insert deeply without failure.     

Hydrogel‐Forming Microneedle Arrays for Enhanced Transdermal Drug Delivery

Unique microneedle arrays prepared from crosslinked polymers, which contain no drug themselves, are described. They rapidly take up skin interstitial fluid upon skin insertion to form continuous, unblockable, hydrogel conduits from attached patch‐type drug reservoirs to the dermal microcirculation. Importantly, such microneedles, which can be fabricated in a wide range of patch sizes and microneedle geometries, can be easily sterilized, resist hole closure while in place, and are removed completely intact from the skin. Delivery of macromolecules is no longer limited to what can be loaded into the microneedles themselves and transdermal drug delivery is now controlled by the crosslink density of the hydrogel system rather than the stratum corneum, while electrically modulated delivery is also a unique feature. This technology has the potential to overcome the limitations of conventional microneedle designs and greatly increase the range of the type of drug that is deliverable transdermally, with ensuing benefits for industry, healthcare providers and, ultimately, patients.     

用于药物释放系统的柔性微针研制

提出了一种基于MEMS技术在柔性基底上制造微针的工艺技术,这是一种高效、安全和无痛的全新给药方式-微针阵列.该微针阵列能够适用于平面或非平面物体表面,对大分子药剂、蛋白质或者疫苗合成药剂也能够使用.     

4D Printing of a Bioinspired Microneedle Array with Backward‐Facing Barbs for Enhanced Tissue Adhesion

Microneedle (MN), a miniaturized needle with a length‐scale of hundreds of micrometers, has received a great deal of attention because of its minimally invasive, pain‐free, and easy‐to‐use nature. However, a major challenge for controlled long‐term drug delivery or biosensing using MN is its low tissue adhesion. Although microscopic structures with high tissue adhesion are found from living creatures in nature (e.g., microhooks of parasites, barbed stingers of honeybees, quills of porcupines), creating MNs with such complex microscopic features is still challenging with traditional fabrication methods. Here, a MN with bioinspired backward‐facing curved barbs for enhanced tissue adhesion, manufactured by a digital light processing 3D printing technique, is presented. Backward‐facing barbs on a MN are created by desolvation‐induced deformation utilizing cross‐linking density gradient in a photocurable polymer. Barb thickness and bending curvature are controlled by printing parameters and material composition. It is demonstrated that tissue adhesion of a backward‐facing barbed MN is 18 times stronger than that of barbless MN. Also demonstrated is sustained drug release with barbed MNs in tissue. Improved tissue adhesion of the bioinspired MN allows for more stable and robust performance for drug delivery, biofluid collection, and biosensing.     

Fabrication of Silk Microneedles for Controlled‐Release Drug Delivery

Microneedles are emerging as a minimally invasive drug delivery alternative to hypodermic needles. Current material systems utilized in microneedles impose constraints hindering the further development of this technology. In particular, it is difficult to preserve sensitive biochemical compounds (such as pharmaceuticals) during processing in a single microneedle system and subsequently achieve their controlled release. A possible solution involves fabricating microneedles systems from the biomaterial silk fibroin. Silk fibroin combines excellent mechanical properties, biocompatibility, biodegradability, benign processing conditions, and the ability to preserve and maintain the activity of biological compounds entrained in its material matrix. The degradation rate of silk fibroin and the diffusion rate of the entrained molecules can be controlled simply by adjusting post‐processing conditions. This combination of properties makes silk an ideal choice to improve on existing issues associated with other microneedle‐based drug delivery system. In this study, a fabrication method to produce silk biopolymer microstructures with the high aspect ratios and mechanical properties required to manufacture microneedle systems is reported. Room temperature and aqueous‐based micromolding allows for the bulk loading of these microneedles with labile drugs. The drug release rate is decreased 5.6‐fold by adjusting the post‐processing conditions of the microneedles, mainly by controlling the silk protein secondary structure. The release kinetics are quantified in an in vitro collagen hydrogel model, which allows tracking of the model drug. Antibiotic loaded silk microneedles are manufactured and used to demonstrate a 10‐fold reduction of bacterial density after their application. The processing strategies developed in this study can be expanded to other silk‐based structural formats for drug delivery and biologicals storage applications.     

Hollow metal microneedles for insulin delivery to diabetic rats

The goal of this study was to design, fabricate, and test arrays of hollow microneedles for minimally invasive and continuous delivery of insulin in vivo. As a simple, robust fabrication method suitable for inexpensive mass production, we developed a modified-LIGA process to micromachine molds out of polyethylene terephthalate using an ultraviolet laser, coated those molds with nickel by electrodepostion onto a sputter-deposited seed layer, and released the resulting metal microneedle arrays by selectively etching the polymer mold. Mechanical testing showed that these microneedles were sufficiently strong to pierce living skin without breaking. Arrays containing 16 microneedles measuring 500 microm in length with a 75 microm tip diameter were then inserted into the skin of anesthetized, diabetic, hairless rats. Insulin delivery through microneedles caused blood glucose levels to drop steadily to 47% of pretreatment values over a 4-h insulin delivery period and were then approximately constant over a 4-h postdelivery monitoring period. Direct measurement of plasma insulin levels showed a peak value of 0.43 ng/ml. Together, these data suggest that microneedles can be fabricated and used for in vivo insulin delivery.     

一种聚合物实心微针的制作方法

为实现制作微针加工工艺简单、加工周期短及成本低的目的,提出了一种制作聚合物微针的新方法,这种聚合物微针的制作过程主要包括三个部分:微针原始模具的制作、聚合物微针模具的制作和浇铸工艺复制微针。通过KOH腐蚀液刻蚀晶面为{100}的Si片和紫外线对准光刻SU8胶得到由Si-SU8胶构成的原始模具,再在该模具上注入聚二甲基硅氧烷(PDMS)进行转模,固化脱模后在PDMS微针二级模具表面溅射一层Cu/Cr金属薄膜,然后再注入PDMS,得到最终的聚合物微针模具,对该模具进行浇铸工艺,便可批量制作微针。通过浇注PDMS获得微针初始结构,使针尖和针体合为一体,提高了脱模的可靠性;通过改变设计,能得到不同截面尺寸和长度的微针,因此这种方法具有很高的灵活性。     

MEMS微针的最新研究进展

介绍了MEMS微针技术在微针制备工艺、力学和流体性能模拟以及透皮给药方面研究的近况。描述了硅、金属和聚合物材料的微针制备工艺,分析了这些材料在MEMS微针应用上的优缺点。比如硅微针制备工艺成熟但是硅的质地太脆;金属微针机械强度高却不易载药;聚合物微针易于批量化复制但是机械强度差。进一步阐述了微针研究取得的进展,总结了微针技术发展需要解决的关键问题。微针制备工艺已经日趋成熟,微针将朝着可复制化、批量化方向发展,微针经皮给药将逐渐从动物实验转移到人体实验,以实现微针研究的最终目的——临床给药。     

A Patch of Detachable Hybrid Microneedle Depot for Localized Delivery of Mesenchymal Stem Cells in Regeneration Therapy

Mesenchymal stem cells (MSCs) have been widely used for regenerative therapy. In most current clinical applications, MSCs are delivered by injection but face significant issues with cell viability and penetration into the target tissue due to a limited migration capacity. Some therapies have attempted to improve MSC stability by their encapsulation within biomaterials; however, these treatments still require an enormous number of cells to achieve therapeutic efficacy due to low efficiency. Additionally, while local injection allows for targeted delivery, injections with conventional syringes are highly invasive. Due to the challenges associated with stem cell delivery, a local and minimally invasive approach with high efficiency and improved cell viability is highly desired. In this study, a detachable hybrid microneedle depot (d‐HMND) for cell delivery is presented. The system consists of an array of microneedles with an outer poly(lactic‐co‐glycolic) acid shell and an internal gelatin methacryloyl (GelMA)‐MSC mixture (GMM). The GMM is characterized and optimized for cell viability and mechanical strength of the d‐HMND required to penetrate mouse skin tissue is also determined. MSC viability and function within the d‐HMND is characterized in vitro and the regenerative efficacy of the d‐HMND is demonstrated in vivo using a mouse skin wound model.     

Reprintable Polymers for Digital Light Processing 3D Printing

3D printing is becoming a disruptive technology and shows great potential for various practical applications. Specially, digital light processing (DLP) 3D printing demonstrates advantages in high resolution and high efficiency. However, extensive production of infusible and insoluble thermosets in DLP printing causes serious resource waste and environmental problems after its disposal. Herein, a reprintable linear polymer is reported for repeatable DLP printing. Taking advantage of the dissolution of linear polymer in its monomer, printed objects can be recycled into liquid resin and reprinted via the same DLP. Polymerization kinetics and printing resolution of recycled resins and mechanical properties of reprinted polymers retain identical as the original. The thermoplastic nature of linear polymer endows 3D objects with welding and reshaping property. Recyclable composites are also successfully fabricated, and sustainable usage of high-value fillers comes true. This strategy helps to address environmental issues arising from unprocessable thermosets and may contribute to an efficient materials recycling.     

A Review of 3D Printing Technologies for Soft Polymer Materials

Soft polymer materials, which are similar to human tissues, have played critical roles in modern interdisciplinary research. Compared with conventional methods, 3D printing allows rapid prototyping and mass customization and is ideal for processing soft polymer materials. However, 3D printing of soft polymer materials is still in the early stages of development and is facing many challenges including limited printable materials, low printing resolution and speed, and poor functionalities. The present review aims to summarize the ideas to address these challenges. It focuses on three points: 1) how to develop printable materials and make unprintable materials printable, 2) how to choose suitable methods and improve printing resolution, and 3) how to directly construct functional structures/systems with 3D printing. After a brief introduction on this topic, the mainstream 3D printing technologies for printing soft polymer materials are reviewed, with an emphasis on improving printing resolution and speed, choosing suitable printing techniques, developing printable materials, and printing multiple materials. Moreover, the state‐of‐the‐art advancements in multimaterial 3D printing of soft polymer materials are summarized. Furthermore, the revolutions brought about by 3D printing of soft polymer materials for applications similar to biology are highlighted. Finally, viewpoints and future perspectives for this emerging field are discussed.     

Electro‐Drawn Drug‐Loaded Biodegradable Polymer Microneedles as a Viable Route to Hypodermic Injection

Hypodermic needle injection is still the most common method of drug delivery despite its numerous limitations and drawbacks, such as pain, one‐shot administration, and risk of infection. Seeking a viable, safe, and pain‐free alternative to the over 16 billion injections per year has therefore become a top priority for our modern technological society. Here, a system that uses a pyroelectric cartridge in lieu of the syringe piston as a potential solution is discussed. Upon stimulation, the cartridge electro‐draws, at room temperature, an array of drug‐encapsulated, biodegradable polymer microneedles, able to deliver into hypodermic tissue both hydrophobic and hydrophilic bioactive agents, according to a predefined chrono‐programme. This mould‐free and contact‐free method permits the fabrication of biodegradable polymer microneedles into a ready‐to‐use configuration. In fact, they are formed on a flexible substrate/holder by drawing them directly from drop reservoirs, using a controlled electro‐hydrodynamic force. Tests of insertion are performed and discussed in order to demonstrate the possibility to prepare microneedles with suitable geometric and mechanical properties using this method.     

Efficient Drug Delivery into Skin Using a Biphasic Dissolvable Microneedle Patch with Water-Insoluble Backing

Dissolvable microneedle patches (MNPs) enable simplified delivery of therapeutics via the skin. However, most dissolvable MNPs do not deliver their full drug loading to the skin because only some of the drug is localized in the microneedles (MNs), and the rest remains adhered to the patch backing after removal from the skin. In this work, biphasic dissolvable MNPs are developed by mounting water-soluble MNs on a water-insoluble backing layer. These MNPs enable the drug to be contained in the MNs without migrating into the patch backing due to the inability of the drugs to partition into the hydrophobic backing materials during MNP fabrication. In addition, the insoluble backing is poorly wetted upon MN dissolution in the skin, which significantly reduces drug residue on the MNP backing surface after application. These effects enable a drug delivery efficiency of >90% from the MNPs into the skin 5 min after application. This study shows that the biphasic dissolvable MNPs can facilitate efficient drug delivery to the skin, which can improve the accuracy of drug dosing and reduce drug wastage.     

Inherent Photodegradability of Polymethacrylate Hydrogels: Straightforward Access to Biocompatible Soft Microstructures

Hydrogels are important functional materials useful for 3D cell culture, tissue engineering, 3D printing, drug delivery, sensors, or soft robotics. The ability to shape hydrogels into defined 3D structures, patterns, or particles is crucial for biomedical applications. Here, the rapid photodegradability of commonly used polymethacrylate hydrogels is demonstrated without the need to incorporate additional photolabile functionalities. Hydrogel degradation depths are quantified with respect to the irradiation time, light intensity, and chemical composition. It can be shown that these parameters can be utilized to control the photodegradation behavior of polymethacrylate hydrogels. The photodegradation kinetics, the change in mechanical properties of polymethacrylate hydrogels upon UV irradiation, as well as the photodegradation products are investigated. This approach is then exploited for microstructuring and patterning of hydrogels including hydrogel gradients as well as for the formation of hydrogel particles and hydrogel arrays of well‐defined shapes. Cell repellent but biocompatible hydrogel microwells are fabricated using this method and used to form arrays of cell spheroids. As this method is based on readily available and commonly used methacrylates and can be conducted using cheap UV light sources, it has vast potential to be applied by laboratories with various backgrounds and for diverse applications.     

MXene‐Reinforced Cellulose Nanofibril Inks for 3D‐Printed Smart Fibres and Textiles

Fibre‐based materials have received tremendous attention due to their flexibility and wearability. Although great efforts have been devoted to achieve high‐performance fibres over the past several years, it is still challenging for multifunctional macroscopic fibres to satisfy versatile applications. 2D transition metal carbides/nitrides (MXenes) with intriguing physical/chemical properties have been explored in broad application, and may be able to reinforce synthetic fibres. Inspired by natural materials, for the first time, flexible smart fibres and textiles are fabricated using a 3D printing process with hybrid inks of TEMPO (2,2,6,6‐tetramethylpiperidine‐1‐oxylradi‐cal)‐mediated oxidized cellulose nanofibrils (TOCNFs) and Ti₃C₂ MXene. The hybrid inks display good rheological properties, which allow them to achieve accurate structures and be rapidly printed. TOCNFs/Ti₃C₂ in hybrid inks self‐assemble to fibres with an aligned structure in ethanol, mimicking the features of the natural structures of plant fibres. In contrast to conventional synthetic fibres with limited functions, smart TOCNFs/Ti₃C₂ fibres and textiles exhibit significant responsiveness to multiple external stimuli (electrical/photonic/mechanical). TOCNFs/Ti₃C₂ textiles with electromechanical performance can be processed into sensitive strain sensors. Such multifunctional smart fibres and textiles will be promising in diverse applications, including wearable heating textiles, human health monitoring, and human–machine interfaces.     

Bioengineered Biomimetic and Bioinspired Noninvasive Drug Delivery Systems

The main purpose herein is to provide an up-to-date review on noninvasive biomimetic, bioinspired, and bioengineered drug delivery system (DDS). Noninvasive DDS is an ever-growing field critical for the applicability of drugs. It offers noninvasive administration routes with improved controlled, targeted, and triggered drug delivery. Noninvasive DDS employ many approaches and strategies, such as, nano- and microparticles, lipid-based systems, sonophoresis, electrophoresis and iontophoresis, penetration enhancers, microneedles, and gels. The last decade seen a surge in research papers employing the paradigms of biomimicry, bioinspiration, and bioengineering. However, since the use of these terms in noninvasive DDS field is often inconsistent and unclear, some generalized perspectives are provided on the possible usage of these terms in future publications. Additionally, a critical discussion on the novelty and origins of these paradigms is provided. The advantages and disadvantages of each of the noninvasive routes and their current main limitations are summarized. The main aspects of indicated fields are discussed: The unique physiology of the related tissues, the main hurdles for mass transport, the various DDS tested, and materials selection. Finally, the basic concepts and therapeutic effects of these DDS are discussed and future venues for noninvasive biomimetic, bioinspired, and bioengineered DDS research are proposed.     

Microsystems for drug and gene delivery

Microneedles and other structures have been developed for introducing therapeutic agents into tissues and cells. Microstructures for transdermal delivery hold the promise of pain-free drug injection. Electrodes integrated with microneedles can sense and monitor the effects of injected materials on tissues. Microprobes have been shown to be effective in transfecting cells through the delivery of DNA in experiments with both plants and animals. Microfabricated delivery devices have great potential for local delivery of drugs and genes where systemic administration presents serious safety concerns. In this paper, we review recent progress in microdevices for delivering therapeutic agents, including microneedles, DNA transfection schemes, and intravascular drug and gene delivery systems.     

Tailoring Hyaluronic Acid Hydrogels for Biomedical Applications

Hyaluronic acid (HA) is an attractive anionic polysaccharide polymer with inherent pharmacological properties and versatile chemical groups for modification. Due to their water retention ability, biocompatibility, biodegradation, cluster of differentiation-44 targeting, and highly designable capacity, HA hydrogels have been an emerging biomaterial, showing tailoring performance in terms of chemical modifications and hydrogel forms. Various preparation technologies have been developed for the fabrication of the tailoring HA hydrogels with unique structures and functions. They have been utilized in diverse biomedical applications like drug delivery and tissue engineering scaffolds. Herein, this review comprehensively summarizes the HA derivatives with different molecule weights and functional modifications. Then the various fabrication methods to obtain tailoring hydrogels in the forms of nanogel, nanofiber, microparticle, microneedle patch, injectable hydrogel, and scaffold are reviewed as well. The emphasis is focused on the shining biomedical applications of these tailoring HA hydrogels in anti-bacteria, anti-inflammation, wound healing, cancer treatment, regenerative medicine, psoriasis treatment, diagnosis, etc. The potentials and prospects are subsequently given to inspire further investigation, aiming at accelerating product translation from research to clinic.