Botulinum toxin A dissolving microneedles for hyperhidrosis treatment: design, formulation and in vivo evaluation.

Multiple periodic injections of botulinum toxin A (BTX-A) are the standard treatment of hyperhidrosis which causes excessive sweating. However, BTX-A injections can create problems, including incorrect and painful injections, the risk of drug entry into the bloodstream, the need for medical expertise, and waste disposal problems. New drug delivery systems can substantially reduce these problems. Transdermal delivery is an effective alternative to conventional BTX-A injections. However, BTX-A's large molecular size and susceptibility to degradation complicate transdermal delivery. Dissolving microneedle patches (DMNPs) encapsulated with BTX-A (BTX-A/DMNPs) are a promising solution that can penetrate the dermis painlessly and provide localized translocation of BTX-A. In this study, using high-precision 3D laser lithography and subsequent molding, DMNPs were prepared based on a combination of biocompatible polyvinylpyrrolidone and hyaluronic acid polymers to deliver BTX-A with ultra-sharp needle tips of 1.5 ± 0.5 µm. Mechanical, morphological and histological assessments of the prepared DMNPs were performed to optimize their physicochemical properties. Furthermore, the BTX-A release and diffusion kinetics across the skin layers were investigated. A COMSOL simulation was conducted to study the diffusion process. The primary stability analysis reported significant stability for three months. Finally, the functionality of the BTX-A/DMNPs for the suppression of sweat glands was confirmed on the hyperhidrosis mouse footpad, which drastically reduced sweat gland activity. The results demonstrate that these engineered DMNPs can be an effective, painless, inexpensive alternative to hypodermic injections when treating hyperhidrosis.

The role of microneedles in the healing of chronic wounds.

Chronic wounds occur for several reasons, such as trauma, accidents, and diseases. Diabetes has been one of the primary causes of non-healing wounds, and the number of people with diabetes is increasing in most countries. Wounds in diabetic people have a complex and prolonged treatment process, with high treatment costs to both healthcare providers and patients. They often have severe consequences, such as pain, wound infection, tissue necrosis, and even limb amputation. Various methods have been used to treat chronic wounds, but clinical success has been limited due to inefficient delivery to the wound bed. Microneedles (MNs), as new platforms, can offer an effective treatment, easy to use and non-invasive with less tissue damage, capable of delivering a wide range of drugs to accelerate the wound healing process. Different methods and materials can be used for this technique, and there are different geometric parameters such as needle length, tip angle, shape and radius, together with needle array density to optimize for the most effective treatment. This review paper will investigate the role of MNs in healing chronic wounds and discuss the most recent development in MN-based devices in the field and their effectiveness. The manuscript will also discuss the various types of MNs and their potential applications for delivering therapeutic agents. Finally, the challenges associated with using MNs to heal chronic wounds and future directions in this field are discussed.

Recent progress in PLGA-based microneedle-mediated transdermal drug and vaccine delivery.

Microneedles (MNs) have recently been found to have applications in drug, vitamin, protein and vaccine delivery. Polymeric MN arrays continue to attract increasing attention due to their capability to bypass the skin's stratum corneum (SC) barrier with minimal invasiveness. These carriers can achieve the targeted intradermal delivery of drugs and vaccines and improve their transdermal delivery level. As a nontoxic FDA-approved copolymer, polylactic glycolic acid (PLGA) has good biocompatibility and biodegradability. Currently, PLGA-based MNs have a noticeable tendency to be utilized as a delivery system. This study focuses on the most recent advances in PLGA-based MNs. Both PLGA nanoparticle-based MNs and PLGA matrix-based MNs, created for the delivery of vaccines, drugs, proteins and other therapeutic agents, are discussed. The paper also discusses the various types of MNs and their potential applications. Finally, the prospects and challenges of PLGA-based MNs are reviewed.

Carbon-based nanostructures for cancer therapy and drug delivery applications.

Synthesis, design, characterization, and application of carbon-based nanostructures (CBNSs) as drug carriers have attracted a great deal of interest over the past half of the century because of their promising chemical, thermal, physical, optical, mechanical, and electrical properties and their structural diversity. CBNSs are well-known in drug delivery applications due to their unique features such as easy cellular uptake, high drug loading ability, and thermal ablation. CBNSs, including carbon nanotubes, fullerenes, nanodiamond, graphene, and carbon quantum dots have been quite broadly examined for drug delivery systems. This review not only summarizes the most recent studies on developing carbon-based nanostructures for drug delivery (e.g. delivery carrier, cancer therapy and bioimaging), but also tries to deal with the challenges and opportunities resulting from the expansion in use of these materials in the realm of drug delivery. This class of nanomaterials requires advanced techniques for synthesis and surface modifications, yet a lot of critical questions such as their toxicity, biodistribution, pharmacokinetics, and fate of CBNSs in biological systems must be answered.

Fabrication and testing of polymer microneedles for transdermal drug delivery.

Microneedle (MN) patches have considerable potential for medical applications such as transdermal drug delivery, point-of-care diagnostics, and vaccination. These miniature microdevices should successfully pierce the skin tissues while having enough stiffness to withstand the forces imposed by penetration. Developing low-cost and simple manufacturing processes for MNs is of considerable interest. This study reports a simple fabrication process for thermoplastic MNs from cycloolefin polymers (COP) using hot embossing on polydimethylsiloxane (PDMS) soft molds. COP has gained interest due to its high molding performance and low cost. The resin master MN arrays (9 × 9) were fabricated using two-photon polymerization (TPP). A previous gap in the detailed characterization of the embossing process was investigated, showing an average of 4.99 ± 0.35% longitudinal shrinkage and 2.15 ± 0.96% lateral enlargement in the molded MN replicas. The effects of bending, buckling, and tip blunting were then examined using compression tests and also theoretically. MN array insertion performance was studied in vitro on porcine back skin using both a prototype custom-made applicator and a commercial device. An adjustable skin stretcher mechanism was designed and manufactured to address current limitations for mimicking skin in vivo conditions. Finite element analysis (FEA) was developed to simulate single MN insertion into a multilayered skin model and validated experimentally using a commercial Pen Needle as a model for the thermoplastic MNs. Margins of safety for the current MN design demonstrated its potential for transdermal drug delivery and fluid sampling. Experimental results indicated significant penetration improvements using the prototype applicator, which produced array penetration efficiencies as high as >92%, depending on the impact velocity setting.

An overview of microneedle applications, materials, and fabrication methods.

Microneedle-based microdevices promise to expand the scope for delivery of vaccines and therapeutic agents through the skin and withdrawing biofluids for point-of-care diagnostics - so-called theranostics. Unskilled and painless applications of microneedle patches for blood collection or drug delivery are two of the advantages of microneedle arrays over hypodermic needles. Developing the necessary microneedle fabrication processes has the potential to dramatically impact the health care delivery system by changing the landscape of fluid sampling and subcutaneous drug delivery. Microneedle designs which range from sub-micron to millimetre feature sizes are fabricated using the tools of the microelectronics industry from metals, silicon, and polymers. Various types of subtractive and additive manufacturing processes have been used to manufacture microneedles, but the development of microneedle-based systems using conventional subtractive methods has been constrained by the limitations and high cost of microfabrication technology. Additive manufacturing processes such as 3D printing and two-photon polymerization fabrication are promising transformative technologies developed in recent years. The present article provides an overview of microneedle systems applications, designs, material selection, and manufacturing methods.

High-resolution two-photon polymerization: the most versatile technique for the fabrication of microneedle arrays.

Microneedle patches have received much interest in the last two decades as drug/vaccine delivery or fluid sampling systems for diagnostic and monitoring purposes. Microneedles are manufactured using a variety of additive and subtractive micromanufacturing techniques. In the last decade, much attention has been paid to using additive manufacturing techniques in both research and industry, such as 3D printing, fused deposition modeling, inkjet printing, and two-photon polymerization (2PP), with 2PP being the most flexible method for the fabrication of microneedle arrays. 2PP is one of the most versatile and precise additive manufacturing processes, which enables the fabrication of arbitrary three-dimensional (3D) prototypes directly from computer-aided-design (CAD) models with a resolution down to 100 nm. Due to its unprecedented flexibility and high spatial resolution, the use of this technology has been widespread for the fabrication of bio-microdevices and bio-nanodevices such as microneedles and microfluidic devices. This is a pioneering transformative technology that facilitates the fabrication of complex miniaturized structures that cannot be fabricated with established multistep manufacturing methods such as injection molding, photolithography, and etching. Thus, microstructures are designed according to structural and fluid dynamics considerations rather than the manufacturing constraints imposed by methods such as machining or etching processes. This article presents the fundamentals of 2PP and the recent development of microneedle array fabrication through 2PP as a precise and unique method for the manufacture of microstructures, which may overcome the shortcomings of conventional manufacturing processes.

High-fidelity replication of thermoplastic microneedles with open microfluidic channels.

Development of microneedles for unskilled and painless collection of blood or drug delivery addresses the quality of healthcare through early intervention at point-of-care. Microneedles with submicron to millimeter features have been fabricated from materials such as metals, silicon, and polymers by subtractive machining or etching. However, to date, large-scale manufacture of hollow microneedles has been limited by the cost and complexity of microfabrication techniques. This paper reports a novel manufacturing method that may overcome the complexity of hollow microneedle fabrication. Prototype microneedles with open microfluidic channels are fabricated by laser stereolithography. Thermoplastic replicas are manufactured from these templates by soft-embossing with high fidelity at submicron resolution. The manufacturing advantages are (a) direct printing from computer-aided design (CAD) drawing without the constraints imposed by subtractive machining or etching processes, (b) high-fidelity replication of prototype geometries with multiple reuses of elastomeric molds, (c) shorter manufacturing time compared to three-dimensional stereolithography, and (d) integration of microneedles with open-channel microfluidics. Future work will address development of open-channel microfluidics for drug delivery, fluid sampling and analysis.