Long‐Lasting Simultaneous Epidermal and Dermal Microneedle‐Enabled Drug Delivery

As the largest and most accessible organ in the body, with a surface area of 1.5–2 m 2 , the skin is an enticing target for drug delivery. Delivery of medication through the skin has expanded beyond the initial brief of topical delivery for local action to the transdermal application of drugs designed for systemic absorption and action. The principal obstacle to such transport is that of the stratum corneum, the outermost skin layer. To enable the delivery of a wider range of drug compounds and overcome the permeability barrier of the skin anatomy, microneedles (MNs) were born. MNs are a mechanical method of skin poration, first conceptualized in the 1970s [1]. Since manufacturing advances allowed the first practical realization in 1998 [2], MNs have demonstrated great promise as a novel drug delivery platform. MN arrays consist of a plurality of tiny projections on the micron scale arranged on a base plate. By bypassing the stratum corneum, its rate-controlling effect is nullified, allowing transdermal deliv ery of a much wider range of drug molecules than would be possible by passive diffusion, including macromolecules, such as biologics and vaccines. With a typical average length of 50–900 μm, MNs are long enough to penetrate to the dermis, but are short and narrow enough to avoid stimulation of dermal nerves or puncture of dermal blood vessels. Initially, MNs were typically prepared from silicon and metal. However, there is now great interest in the use of US FDA-approved polymeric materials for MN manufacture [3]. These materials are often inexpensive and widely available, amenable for MN manufacture without the use of harsh processing conditions, for example, elevated temperatures. Prepared from water-soluble polymers, dissolving MN arrays have the drug incorporated into the MN formulation and upon insertion, the MNs dissolve, releasing the drug in the viable skin layers. Such a strategy offers a number of advantages for the patient. As the MNs dissolve upon application, the dosage form is effectively self-disabling, meaning that not only is the reinsertion of the needles into another patient impossible, but there is also no risk of needle-stick injury to the healthcare professional, thereby reducing the overall risk of infection transmission. The question of disposal of MNs is also simplified, as with no sharp waste remaining, there is no need for safe disposal. Dissolving MN arrays have been used to deliver a range of compounds, from hydrophilic, low molecular weight drugs, to larger biopharmaceutical molecules, demonstrating the ability of such a platform to enhance transdermal delivery [4]. Indeed, the technology has progressed to human trials, with positive results recently published from a Phase 2a study for the delivery of human parathyroid hormone using a biodegradable MN technology called MicroCor ® , developed by Corium International, Inc. [5]. Another promising application for dissolving MNs is that of vaccination, capitalizing on the rich immune cell population in the skin,

Optical coherence tomography is a valuable tool in the study of the effects of microneedle geometry on skin penetration characteristics and in-skin dissolution

Quantification methods comparing in vitro and in vivo percutaneous permeation by microneedles and passive diffusion

Microneedle (MN) arrays bypass the skin's stratum corneum barrier to deliver drugs directly into the viable tissue. The skin disposition of three types of MNs-dissolvable, degradable and hydrogel-forming, fabricated using different polymers-have been evaluated post-treatment with examples of these MN arrays and then examined by confocal Raman spectroscopy and stimulated Raman scattering (SRS) microscopy. The presence of the polymers was assessed from their characteristic Raman signals. SRS image mosaics were acquired to survey and visualise larger areas of the skin surface. After MN insertion, the skin's spectrum was acquired using confocal Raman spectroscopy at the surface, and at nominal depths of 50µm, 100µm, and 150µm. For dissolvable and degradable MNs, Raman signals from the constituent polymers were detectable in the skin. However, the polymer used to form the hydrogel MNs was not detectable under the experimental conditions used. SRS confirmed that the MN arrays penetrated the skin in a reasonably uniform manner. In summary, polymeric MN insertion into the skin has been visualised using confocal Raman spectroscopy and SRS microscopy. Together, these techniques have the potential to shed light on the spatial and temporal skin disposition of the constituent MN polymers used.

Separable double-layered microneedle-based transdermal codelivery of DOX and LPS for synergistic immunochemotherapy of a subcutaneous glioma tumor

Continuous sampling of interstitial fluids from the human skin is a key technique for clinical bioassays using micro total analysis (TAS) technologies. Here, we present a porous microneedle (MN) array to be connected to a custom-designed microfluidic system for the minimally invasive access to the dermis. The pores and surface of the porous PDMS array are covered with hyaluronic acid to enhance mechanical strength and to achieve a fluidic path of water inside the MN bodies. The fabricated MN array is capable to penetrate an agarose gel phantom and extracts water contained in the gel, indicating the fluidic connection between the MN array and the microfluidic system.

Microneedles (MNs), with its numerous advantages over the traditional transdermal drug delivery approaches, represent a cutting-edge and idea-inspiring technology in the field of biomedical engineering. Over the past decades, great achievements have been made on the optimization of the MNs’ fabrication techniques, expending the various features of the MNs and generation of the MNs with multiple functions. MN is an innovative transdermal drug delivery strategy that overcome the limitations from invasive or inefficient conventional approaches. It create micropores on the skin in a non-invasive and painless manner to aid the efficient delivery of the therapeutics across the skin. Additionally, biomarker sampling and detection by accessing the skin interstitial fluid (ISF) is also achievable by swelling MNs with incorporated sensors. In this thesis, the application of MNs for Chinese herb herbal medicine extract delivery is proposed and demonstrated. Specifically, Chinese herb herbal medicine extract could be premixed with dissolvable polymers and made into MNs through micro-molding. The fabricated drug loaded MNs possess good mechanical strength for human skin penetration. The delivering of the Chinese herb herbal medicine extract via MN to hypertrophic scar fibroblast showed unaffected therapeutic efficiency and localized treatment effect. Additionally, a versatile drug coating methodology is proposed and discussed. In such methodology, drug solution is spray coated onto the frozen MNs and solidified upon contact with the cold MNs’ surface. Subsequent lyophilization could fix the solid drug on the surface of the MNs without affecting the properties of the MN core. As a proof of concept, insulin was coated onto swellable MNs for simultaneously diabetic treatment and glucose sampling. In a more advanced design, the MNs are made from bubble-generating materials which could help to deliver therapeutics deeper and more efficiently into the skin. Incorporating with ultrasound technology, the bubble-generating MNs show advances in delivering both small and big molecules that are frozen coated on the surface of MNs into the mice skin. Moreover, it is demonstrated that the delivering of photosensitizer into the tumor bearing-mouse through the skin by bubble-generating MNs and ultrasound synergistically enhance the penetration and subsequent therapeutic efficiency. Aside from maintaining the MN core properties, the efficiency of therapeutics, when coated onto the MN via the above-mentioned technology could be retained due to the fast fabrication process and low temperature condition that prevent the drug from being degraded or oxidized. Moreover, the therapeutics are in solid state after lyophilization, which further guaranteed their stability. Such property makes the frozen coating strategy a versatile strategy for incorporating various of therapeutics with various types of MNs depending on the application. In conclusion, a facile, versatile drug coating strategy to make functional MNs is introduced in this thesis. Such strategy has the potential for wide range of biomedical applications including controlled drug delivery, multiple drug delivery, biosensing and monitoring.

Microneedles for gene and drug delivery in skin cancer therapy

Micropore closure kinetics are delayed following microneedle insertion in elderly subjects

Microneedles (MNs) have been developed as minimally invasive tools for diagnostic and therapeutic applications. However, in recent years, there has been an increasing interest in developing smart multifunctional MN devices to provide automated and closed-loop systems for body fluid extraction, biosensing, and drug delivery in a stimuli-responsive manner. Although this technology is still in its infancy and far from being translated into the clinic, preclinical trials have shown some promise for the broad applications of multifunctional MN devices. The main challenge facing the fabrication of smart MN patches is the integration of multiple modules, such as drug carriers, highly sensitive biosensors, and data analyzers in one miniaturized MN device. Researchers have shown the feasibility of creating smart MNs by integrating stimuli-responsive biomaterials and advanced microscale technologies, such as microsensors and microfluidic systems, to precisely control the transportation of biofluids and drugs throughout the system. These multifunctional MN devices can be envisioned in two distinct strategies. The first type includes individual drug delivery and biosensing MN units with a microfluidic system and a digital analyzer responsible for fluid transportation and communication between these two modules. The second type relies on smart biomaterials that can function as drug deliverers and biosensors by releasing drugs in a stimuli-responsive manner. These smart biomaterials can undergo structural changes when exposed to external stimuli, such as pH and ionic changes, mimicking the biological systems. Studies have demonstrated a high potential of hydrogel-based MN devices for a wide variety of biomedical applications, such as drug and cell delivery, as well as interstitial fluid extraction. Biodegradable hydrogels have also been advantageous for fabricating multifunctional MNs due to their high loading capacity and biocompatibility with the drug of choice. Here, we first review a set of MN devices that can be employed either for biosensing or delivery of multiple target molecules and compare them to the conventional and more simple systems, which are mainly designed for single-molecule sensing or delivery. Subsequently, we expand our insight into advanced MN systems with multiple competencies, such as body fluid extraction, biosensing, and drug delivery at the point of care. The improvement of biomaterials knowledge and biofabrication techniques will allow us to efficiently tune the next generation of smart MNs and provide a realistic platform for more effective personalized therapeutics.

Modelling of dissolving microneedles for transdermal drug delivery: Theoretical and experimental aspects

Hollow microneedle (MN) arrays offer versatility and control to transdermal drug delivery systems where a variety of drugs and their continuous supply are concerned. They may be used as a standalone device or be integrated with the drug reservoir or micropump. An important aspect in this regard is the effective fluidic communication between the reservoir and the MNs on a robust substrate. In a novel attempt of its kind, we present the development hollow SU-8 MNs on a pre-etched silicon wafer having through holes. SU-8 MNs are fabricated by direct laser writing by aligning them on the silicon substrate with microfluidic ports pre-etched by wet chemical etching. Each process step was optimized after a parametric study. The optimized MNs (500–600 µm length, 100 µm outer diameter and 40 µm inner diameter) have an aspect ratio of 5. The MNs have been characterized for mechanical strength and biological insertion tests for their effectiveness in puncturing the skin without breaking. The maximum compressive force and bending forces for the MNs are 0.27 N and 0.022 N per needle, which are higher than the resistive skin penetrating forces. The microfluidic characterizations show the development of hollow MN lumen with a flowrate of around 0.93 µl s−1 at 2 KPa pressure difference at the inlet. The array of 10 × 10 MNs with 500 µm spacing was able to successfully penetrate mice and rat skin without any breakage.

This study describes the processing of microneedle (MN) arrays with three different heights of arrowhead (600 µm (A1), 800 µm (A2), and 1000 µm (A3)), pyramid (600 µm (P1), 800 µm (P2), and 1000 µm (P3)), and turret (600 µm (T1), 800 µm (T2), and 1000 µm (T3)) designs using a digital light processing (DLP)-based 3D printing method. The 3D-printed MNs were examined for their morphological characteristics and mechanical performance. Scanning electron microscopy (SEM) imaging confirmed that all of the MNs were fabricated without fracture or bending. Each design exhibited distinct structural characteristics: arrowhead MNs displayed a well-defined morphology with sharp tips, pyramid MNs showed slight layering, and turret MNs, characterized by a wider base and sharp tips, had a smoother surface compared to the other designs. Mechanical tests revealed that the arrowhead MNs carried less load and were more prone to bending, while the pyramid and turret designs provided higher mechanical stability and penetration capacity. The pyramid design (P3) showed the highest mechanical strength, while turret MNs offered a more stable performance despite lower penetration capacity. These findings highlight the critical role of geometric design in optimizing MN performance for effective transdermal drug delivery.

Local dermal delivery of cyclosporin A, a hydrophobic and high molecular weight drug, using dissolving microneedles

6 - Microneedles for drug delivery and monitoring