Multi-Layered Microneedles Loaded with Microspheres.

Delivery of therapies into skin is attractive for medical indications including vaccination and treatment of dermatoses but is highly constrained by the stratum corneum barrier. Microneedle (MN) patches have emerged as a promising technology to enable non-invasive, intuitive, and low-cost skin delivery. When combined with biodegradable polymer formulations, MN patches can further enable controlled-release drug delivery without injection.

IOP Reduction in Nonhuman Primates by Microneedle Injection of Drug-Free Hydrogel to Expand the Suprachoroidal Space.

Purpose: Expansion of the suprachoroidal space (SCS) by a hydrogel injection has been shown to reduce intraocular pressure (IOP) in rabbits as a potential treatment for ocular hypertension in glaucoma. Here, we evaluate the safety and efficacy of this approach in hypertensive and normotensive eyes in nonhuman primates.

Methods: A microneedle was used to inject a hyaluronic acid-based hydrogel or saline solution (control) into the SCS of cynomolgus monkey eyes that were either normotensive (n = 7 experimental; n = 2 control eyes) or had induced ocular hypertension (n = 6 experimental; n = 3 control eyes).

Computational modelling of scleral photocrosslinking: from rat to minipig to human.

Selective scleral crosslinking has been proposed as a novel treatment to increase scleral stiffness to counteract biomechanical changes associated with glaucoma and high myopia. Scleral stiffening has been shown by transpupillary peripapillary scleral photocrosslinking in rats, where the photosensitizer, methylene blue (MB), was injected retrobulbarly and red light initiated crosslinking reactions with collagen. Here, we adapted a computational model previously developed to model this treatment in rat eyes to additionally model MB photocrosslinking in minipigs and humans.

Tolerability of a piezoelectric microneedle electroporator in human subjects.

Electroporation, or the use of electric pulses to facilitate the intracellular delivery of DNA, RNA, and other molecules, is a well-established technique, that has been demonstrated to significantly augment the immunogenicity of DNA/mRNA vaccines and therapeutics. However, the clinical translation of traditional electroporators has been limited due to high costs, large size, complex user operation, and poor tolerability in humans due to nerve stimulation. In prior work, we introduced ePatch: an ultra-low-cost, handheld, battery-free electroporator employing a piezoelectric pulser coupled with a microneedle electrode array that showed enhanced immunogenic responses to an intradermal SARS-CoV-2 DNA vaccine in mice.

Feasibility of engineered for use as a microbiome-based topical drug delivery platform.

Non-adherence to medication is a major challenge in healthcare that results in worsened treatment outcomes for patients. Reducing the frequency of required administrations could improve adherence but is challenging for topical drug delivery due to the generally short residence time of topical formulations on the skin. In this study, we sought to determine the feasibility of developing a microbiome-based, long-acting, topical delivery platform using for drug production and delivery on the skin, which was assessed using green fluorescent protein as a model heterologous protein for delivery.

A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

Background: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children.

Methods: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia.

Hybrid Lipid Nanocapsules: A Robust Platform for mRNA Delivery.

The success of the mRNA vaccine against COVID-19 has garnered significant interest in the development of mRNA therapeutics against other diseases, but there remains a strong need for a stable and versatile delivery platform for these therapeutics. In this study, we report on a family of robust hybrid lipid nanocapsules (hLNCs) for the delivery of mRNA. The hLNCs are composed of kolliphore HS15, labrafac lipophile WL1349, 1,2-dioleoyl--glycero-3-phosphoethanolamine (DOPE), and a conjugate of oleic acid (OA) and polyethylenimines of varying size (PEI─0.

Microneedle patch-based enzyme-linked immunosorbent assay to quantify protein biomarkers of tuberculosis.

There is a clinical need for differential diagnosis of the latent versus active stages of tuberculosis (TB) disease by a simple-to-administer test. Alpha-crystallin (Acr) and early secretory antigenic target-6 (ESAT-6) are protein biomarkers associated with the latent and active stages of TB, respectively, and could be used for differential diagnosis. We therefore developed a microneedle patch (MNP) designed for application to the skin to quantify Acr and ESAT-6 in dermal interstitial fluid by enzyme-linked immunosorbent assay (ELISA).

The promise of microneedle technologies for drug delivery.

Microneedle (MN) technologies offer the opportunity to improve patient access and target delivery of drugs and vaccines to specific tissues. When in the form of skin patches, MNs can be administered by personnel with minimal training, or could be self-administered by patients, which can improve access to medication, especially those usually requiring injection. Because MNs are small (usually sub-millimetre), they can be used for precise tissue targeting.

Modulation of hair growth by topical drug delivery enhanced by STAR particles.

Topical treatments to modulate hair growth are generally limited by low drug bioavailability due to poor skin permeability. Here, we studied the use of STAR particles, which are millimeter-sized ceramic particles with protruding microneedles, to form micropores in the skin to increase skin permeability to hair growth-modulating drugs. STAR particle design and fabrication were optimized, and the resulting STAR particles were shown to reduce lag time and increase skin permeability to minoxidil and acyclovir by more than three-fold compared to no treatment in pig skin ex vivo.

Assessing the risk of a clinically significant infection from a Microneedle Array Patch (MAP) product.

Microneedle Array Patches (MAPs) are an emerging dosage form that creates transient micron-sized disruptions in the outermost physical skin barrier, the stratum corneum, to facilitate delivery of active pharmaceutical ingredients to the underlying tissue. Numerous MAP products are proposed and there is significant clinical potential in priority areas such as vaccination. However, since their inception scientists have hypothesized about the risk of a clinically significant MAP-induced infection.

Sweat induction using Pilocarpine microneedle patches for sweat testing in healthy adults.

Background: The sweat test using pilocarpine iontophoresis remains the gold standard for diagnosing cystic fibrosis, but access and reliability are limited by specialized equipment and insufficient sweat volume collected from infants and young children. These shortcomings lead to delayed diagnosis, limited point-of-care applications, and inadequate monitoring capabilities.

Methods: We created a skin patch with dissolvable microneedles (MNs) containing pilocarpine that eliminates the equipment and complexity of iontophoresis.

Tolerability, acceptability, and reproducibility of topical STAR particles in human subjects.

Topical delivery to treat dermatological disease is constrained by low skin permeability to most drugs due to the stratum corneum barrier. STAR particles containing microneedle protrusions can be topically applied on the skin to create micropores that dramatically increase skin permeability, even to water-soluble compounds and macromolecules. This study addresses the tolerability, acceptability, and reproducibility of STAR particles rubbed on the skin at multiple pressures and after multiple applications to human subjects.

Hepatitis B vaccine delivered by microneedle patch: Immunogenicity in mice and rhesus macaques.

Vaccination against hepatitis B using a dissolving microneedle patch (dMNP) could increase access to the birth dose by reducing expertise needed for vaccine administration, refrigerated storage, and safe disposal of biohazardous sharps waste. In this study, we developed a dMNP to administer hepatitis B surface antigen (HBsAg) adjuvant-free monovalent vaccine (AFV) at doses of 5 µg, 10 µg, and 20 µg, and compared its immunogenicity to vaccination with 10 µg of standard monovalent HBsAg delivered by intramuscular (IM) injection either in an AFV format or as aluminum-adjuvanted vaccine (AAV). Vaccination was performed on a three dose schedule of 0, 3, and 9 weeks in mice and 0, 4, and 24 weeks in rhesus macaques.

Suprachoroidal Delivery in Rats and Guinea Pigs Using a High-Precision Microneedle Injector.

Purpose: Methods of injection into the suprachoroidal space (SCS) have been developed for larger animals and humans, but reliable administration to the SCS of rodents remains challenging given their substantially smaller eyes. Here, we developed microneedle (MN)-based injectors for SCS delivery in rats and guinea pigs.

Methods: We optimized key design features, including MN size and tip characteristics, MN hub design, and eye stabilization, to maximize injection reliability.

Interrogating Encapsulated Protein Structure within Metal-Organic Frameworks at Elevated Temperature.

Encapsulating biomacromolecules within metal-organic frameworks (MOFs) can confer thermostability to entrapped guests. It has been hypothesized that the confinement of guest molecules within a rigid MOF scaffold results in heightened stability of the guests, but no direct evidence of this mechanism has been shown. Here, we present a novel analytical method using small-angle X-ray scattering (SAXS) to solve the structure of bovine serum albumin (BSA) while encapsulated within two zeolitic imidazolate frameworks (ZIF-67 and ZIF-8).

Skin Vaccination with Ebola Virus Glycoprotein Using a Polyphosphazene-Based Microneedle Patch Protects Mice against Lethal Challenge.

Ebolavirus (EBOV) infection in humans is a severe and often fatal disease, which demands effective interventional strategies for its prevention and treatment. The available vaccines, which are authorized under exceptional circumstances, use viral vector platforms and have serious disadvantages, such as difficulties in adapting to new virus variants, reliance on cold chain supply networks, and administration by hypodermic injection. Microneedle (MN) patches, which are made of an array of micron-scale, solid needles that painlessly penetrate into the upper layers of the skin and dissolve to deliver vaccines intradermally, simplify vaccination and can thereby increase vaccine access, especially in resource-constrained or emergency settings.

Enhanced immune responses to vaccine antigens in the corneal stroma.

To examine the widely accepted dogma that the eye is an immune-privileged organ that can suppress antigen immunogenicity, we explored systemic immune responses to a model vaccine antigen (tetanus toxoid) delivered to six compartments of the rodent eye (ocular surface, corneal stroma, anterior chamber, subconjunctival space, suprachoroidal space, vitreous body). We discovered that antigens delivered to corneal stroma induced enhanced, rather than suppressed, antigen-specific immune responses, which were 18- to 30-fold greater than conventional intramuscular injection and comparable to intramuscular vaccination with alum adjuvant. Systemic immune responses to antigen delivered to the other ocular compartments were much weaker.

Microneedle Patches Loaded with Nanovesicles for Glucose Transporter-Mediated Insulin Delivery.

Glucose-responsive insulin delivery systems that mimic insulin secretion activity in the pancreas show great potential to improve clinical therapeutic outcomes for people with type 1 and advanced type 2 diabetes. Here, we report a glucose-responsive insulin delivery microneedle (MN) array patch that is loaded with red blood cell (RBC) vesicles or liposome nanoparticles containing glucose transporters (GLUTs) bound with glucosamine-modified insulin (Glu-Insulin). In hyperglycemic conditions, high concentrations of glucose in interstitial fluid can replace Glu-Insulin a competitive interaction with GLUT, leading to a quick release of Glu-Insulin and subsequent regulation of blood glucose (BG) levels .

Microneedle patch tattoos.

Medical tattoos provide medical information, guide radiotherapy, and improve cosmetic outcomes of medical interventions. These tattoos are administered by repeated needle injection that causes pain, bleeding, and risk of infection, which limit more widespread use. Here, we developed single-use microneedle (MN) patches to deposit tattoos in the skin in a simple, rapid, painless, and bloodless way without biohazardous sharps waste.

Six-month sustained delivery of anti-VEGF from in-situ forming hydrogel in the suprachoroidal space.

Patients with wet age-related macular degeneration (AMD) require intravitreal injections of bevacizumab (Bev) or other drugs, often on a monthly basis, which is a burden on the healthcare system. Here, we developed an in-situ forming hydrogel comprised of Bev and hyaluronic acid (HA) crosslinked with poly(ethylene glycol) diacrylate for slow release of Bev after injection into the suprachoroidal space (SCS) of the eye using a microneedle. Liquid Bev formulations were cleared from SCS within 5 days, even when formulated with high viscosity, unless Bev was conjugated to a high molecular-weight HA (2.