Transdermal microneedle (MN) patches are a promising tool used to transport a wide variety of active compounds into the skin. To serve as a substitute for common hypodermic needles, MNs must pierce the human stratum corneum (~ 10 to 20 µm), without rupturing or bending during penetration. This ensures that the cargo is released at the predetermined place and time. Therefore, the ability of MN patches to sufficiently pierce the skin is a crucial requirement. In the current review, the pain signal and its management during application of MNs and typical hypodermic needles are presented and compared. This is followed by a discussion on mechanical analysis and skin models used for insertion tests before application to clinical practice. Factors that affect insertion (e.g., geometry, material composition and cross-linking of MNs), along with recent advancements in developed strategies (e.g., insertion responsive patches and 3D printed biomimetic MNs using two-photon lithography) to improve the skin penetration are highlighted to provide a backdrop for future research.

Nature contains abundant systems that can significantly alter their structures and properties to adapt to the surrounding environment. Through natural selection and unceasing evolution, hierarchical architectures and sophisticated strategies have been created by nature to achieve optimally adapted materials for biomedical applications. The development of microneedles has advanced to the next generation of bioinspired microneedles, with the goal of improving functions such as amelioration of mechanical properties and tissue adhesion. The biomimetic designs and structures of microneedles are highlighted in the present review. This is followed by an in-depth discussion of the fabrication approaches from molding techniques to 3D and 4D printing. The medical applications of bioinspired microneedles, including drug delivery, regenerative medicine, biopsy sampling and biosensing, are also discussed. Lastly, future opportunities and challenges with respect to clinical translation are also deliberated.

The success of protein, peptide and antibody based therapies is evident - the biopharmaceuticals market is predicted to reach $388 billion by 2024 [1], and more than half of the current top 20 blockbuster drugs are biopharmaceuticals. However, the intrinsic properties of biopharmaceuticals has restricted the routes available for successful drug delivery. While providing 100% bioavailability, the intravenous route is often associated with pain and needle phobia from a patient perspective, which may translate as a reluctance to receive necessary treatment. Several non-invasive strategies have since emerged to overcome these limitations. One such strategy involves the use of microneedles (MNs), which are able to painlessly penetrate the stratum corneum barrier to dramatically increase transdermal drug delivery of numerous drugs. This review reports the wealth of studies that aim to enhance transdermal delivery of biopharmaceutics using MNs. The true potential of MNs as a drug delivery device for biopharmaceuticals will not only rely on acceptance from prescribers, patients and the regulatory authorities, but the ability to upscale MN manufacture in a cost-effective manner and the long term safety of MN application. Thus, the current barriers to clinical translation of MNs, and how these barriers may be overcome are also discussed.

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trademark of the company Aprecia Pharmaceuticals, LLC., Ohio, USA. Recently, Triastek has received Investigational New Drug (IND) approval from the US FDA for T19, their first 3D printed drug product designed to treat rheumatoid arthritis. [13] As a result of this approval, research into 3D printing for drug delivery has continued to rapidly expand, with several commercially available 3D printers emerging. [14][15][16][17][18][19] More recently, 3D printing has shown its promising potential in the mass production of face masks and face shields in the middle of the 2020 global pandemic when these items were in high demand for protecting healthcare professionals in the fight against COVID-19. [20,21] Generally, the fabrication of complex structures by 3D printing involves the creation of a prototype in computer-aided design (CAD) software, which is subsequently exported as a standard tessellation language (STL) file and sent to the 3D printer. [16,22] The 3D printer's software divides the 3D model data into consecutive 2D slices to facilitate the fabrication of each structure in a layerby-layer manner. Additionally, 3D scanners can also be used to record objects or body parts in the form of digital 3D images. [23] Likewise, X-rays, magnetic resonance imaging (MRI) and computerized tomography (CT) scans produce 2D radiographic images that can be converted to digital 3D model files for the fabrication of personalized anatomical structures. [1,2,6,[24][25][26][27][28] In recent years, the use of 3D printing technology to produce tailor-shaped MNs has gained great attention. MNs are a noninvasive device consisting of multiple micron-sized needles on a single patch, ranging most commonly in height from 25 to 2000 µm. [29] Upon skin insertion, MNs create temporary microscopic channels in the epidermis to either deliver drug molecules via diffusion into the microcirculation or to collect interstitial fluid (ISF) for disease diagnosis and monitoring. [30][31][32][33] As a drug delivery platform, MNs combine the patient-friendly benefits of a transdermal patch with the potential delivery capabilities of a hypodermic injection. The unique attribute of MNs is that they are strong enough to penetrate the resilient skin barrier, the stratum corneum (SC), sufficiently to enable access to the skin's rich microcirculation, yet are short and narrow enough to avoid stimulation with nerve fibers or puncture blood vessels that primarily reside in the dermal layer. Painless application is thus considered the principal benefit of MNs. [34][35][36] Microneedles (MNs) are minimally invasive devices, which have gained extensive interest over the past decades in various fields including drug delivery, disease diagnosis, monitoring, and cosmetics. MN geometry and shape are key parameters that dictate performance and therapeutic efficacy, however, traditional fabrication methods, such as molding, may not be able to offer rapid design modifications. In this regard, the fabrication of MNs using 3D printing technology enables the rapid creation ...

For the first time, we have shown that molecular weight plays a role in permeation through a ‘super-swelling’ microneedle system.

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Purpose Whilst significant progress has been made to defeat HIV infection, the efficacy of antiretroviral (ARV) therapy in the paediatric population is often hindered by poor adherence. Currently, two long-acting (LA) intramuscular injectable nanosuspensions of rilpivirine (RPV) and cabotegravir (CAB) are in clinical development for paediatric populations. However, administration requires access to healthcare resources, is painful, and can result in needle-stick injuries to the end user. To overcome these barriers, this proof-of-concept study was developed to evaluate the intradermal delivery of RPV LA and CAB LA via self-disabling dissolving microarray patches (MAPs). Methods Dissolving MAPs of two conformations, a conventional pyramidal and a bilayer design, were formulated, with various nanosuspensions of RPV and CAB incorporated within the respective MAP matrix. MAPs were mechanically robust and were capable of penetrating ex vivo skin with intradermal ARV deposition. Results In a single-dose in vivo study in rats, all ARV MAPs demonstrated sustained release profiles, with therapeutically relevant plasma concentrations of RPV and CAB detected to at least 63 and 28 d, respectively. In a multi-dose in vivo study, repeated MAP applications at 14-d intervals maintained therapeutically relevant plasma concentrations throughout the duration of the study. Conclusions These results illustrate the potential of the platform to repeatedly maintain plasma concentrations for RPV and CAB. As such, these MAPs could represent a viable option to improve adherence in the paediatric population, one that is capable of being painlessly administered in the comfort of the patient’s own home on a biweekly or less frequent basis. Graphical abstract