Content uploaded by Alexander K Andrianov
Author content
All content in this area was uploaded by Alexander K Andrianov
Content may be subject to copyright.
A preview of the PDF is not available
Microneedle-Based Vaccines
Abstract and Figures
The threat of pandemic influenza and other public health needs motivate the development of better vaccine delivery systems. To address this need, microneedles have been developed as micron-scale needles fabricated using low-cost manufacturing methods that administer vaccine into the skin using a simple device that may be suitable for self-administration. Delivery using solid or hollow microneedles can be accomplished by (1) piercing the skin and then applying a vaccine formulation or patch onto the permeabilized skin, (2) coating or encapsulating vaccine onto or within microneedles for rapid, or delayed, dissolution and release in the skin, and (3) injection into the skin using a modified syringe or pump. Extensive clinical experience with smallpox, TB, and other vaccines has shown that vaccine delivery into the skin using conventional intradermal injection is generally safe and effective and often elicits the same immune responses at lower doses compared to intramuscular injection. Animal experiments using microneedles have shown similar benefits. Microneedles have been used to deliver whole, inactivated virus; trivalent split antigen vaccines; and DNA plasmids encoding the influenza hemagglutinin to rodents, and strong antibody responses were elicited. In addition, ChimeriVax-JE against yellow fever was administered to nonhuman primates by microneedles and generated protective levels of neutralizing antibodies that were more than seven times greater than those obtained with subcutaneous delivery; DNA plasmids encoding hepatitis B surface antigen were administered to mice and antibody and T cell responses at least as strong as hypodermic injections were generated; recombinant protective antigen of Bacillus anthracis was administered to rabbits and provided complete protection from lethal aerosol anthrax spore challenge at a lower dose than intramuscular injection; and DNA plasmids encoding four vaccinia virus genes administered to mice in combination with electroporation generated neutralizing antibodies that apparently included both Th1 and Th2 responses. Dose sparing with microneedles was specifically studied in mice with the model vaccine ovalbumin. At low dose (1 microg), specific antibody titers from microneedles were one order of magnitude greater than subcutaneous injection and two orders of magnitude greater than intramuscular injection. At higher doses, antibody responses increased for all delivery methods. At the highest levels (20-80 microg), the route of administration had no significant effect on the immune response. Concerning safety, no infections or other serious adverse events have been observed in well over 1,000 microneedle insertions in human and animal subjects. Bleeding generally does not occur for short microneedles (<1 mm). Highly localized, mild, and transient erythema is often observed. Microneedle pain has been reported as nonexistent to mild, and always much less than a hypodermic needle control. Overall, these studies suggest that microneedles may provide a safe and effective method of delivering vaccines with the possible added attributes of requiring lower vaccine doses, permitting low-cost manufacturing, and enabling simple distribution and administration.
Figures - uploaded by Alexander K Andrianov
Author content
All figure content in this area was uploaded by Alexander K Andrianov
Content may be subject to copyright.
... These immune cells can be targeted using microneedles (MN) vaccine delivery techniques to induce a robust immune response [38,39]. Additionally, MN is minimally invasive as they do not affect the nerve endings, leading to a painless delivery method [40,41]. This vaccine approach also allows the potential for self-administration, easing the burden on healthcare professionals. ...
... This vaccine approach also allows the potential for self-administration, easing the burden on healthcare professionals. Self-administration can accelerate mass immunization, especially during a global pandemic [40,42]. ...
... The MNs were also able to penetrate the excised mouse skin, forming micropores that were seen clearly with the help of methylene blue staining solution ( Figure 1). minimally invasive as they do not affect the nerve endings, leading to a painless delivery method [40,41]. This vaccine approach also allows the potential for self-administration, easing the burden on healthcare professionals. ...
COVID-19 continues to cause an increase in the number of cases and deaths worldwide. Due to the ever-mutating nature of the virus, frequent vaccination against COVID-19 is anticipated. Most of the approved SARS-CoV-2 vaccines are administered using the conventional intramuscular route, causing vaccine hesitancy. Thus, there is a need for an effective, non-invasive vaccination strategy against COVID-19. This study evaluated the synergistic effects of a subunit microparticulate vaccine delivered using microneedles. The microparticles encapsulated a highly immunogenic subunit protein of the SARS-CoV-2 virus, such as the spike protein’s receptor binding domain (RBD). Adjuvants were also incorporated to enhance the spike RBD-specific immune response. Our vaccination study reveals that a microneedle-based vaccine delivering these microparticles induced spike RBD-specific IgM, IgG, IgG1, IgG2a, and IgA antibodies. The vaccine also generated high levels of CD4+ and CD8a+ molecules in the secondary lymphoid organs. Overall, dissolving microneedles delivery spike RBD antigen in microparticulate form induced a robust immune response, paving the way for an alternative self-administrable, non-invasive vaccination strategy against COVID-19.
... Microneedles have shown great promise in facilitating the delivery of various types of drugs, including small molecules 23,24 , peptides 25 , nucleic acids 26,27 , and nano composites [28][29][30][31][32][33] . Furthermore, modulating the structural integration and chemical functionalization of MNs enables a broad range of release profiles. ...
Transdermal drug delivery is of vital importance for medical treatments. However, user adherence to long-term repetitive drug delivery poses a grand challenge. Furthermore, the dynamic and unpredictable disease progression demands a pharmaceutical treatment that can be actively controlled in real-time to ensure medical precision and personalization. Here, we report a spatiotemporal on-demand patch (SOP) that integrates drug-loaded microneedles with biocompatible metallic membranes to enable electrically triggered active control of drug release. Precise control of drug release to targeted locations (<1 mm²), rapid drug release response to electrical triggers (<30 s), and multi-modal operation involving both drug release and electrical stimulation highlight the novelty. Solution-based fabrication ensures high customizability and scalability to tailor the SOP for various pharmaceutical needs. The wireless-powered and digital-controlled SOP demonstrates great promise in achieving full automation of drug delivery, improving user adherence while ensuring medical precision. Based on these characteristics, we utilized SOPs in sleep studies. We revealed that programmed release of exogenous melatonin from SOPs improve sleep of mice, indicating potential values for basic research and clinical treatments.
... The immunological efficacy of microneedles has been verified through animal studies [5][6][7] and clinical trials [8][9][10][11]. Currently, studies are being undertaken to evaluate whether microneedles can be used to deliver various vaccines while improving storage stability [12]. An adjuvant is the main additive to vaccine microneedles [13]. ...
Purpose
For successful delivery of a solid vaccine formulation into the skin using microneedles, the solubility of an adjuvant should be considered because the decrease in the dissolution rate by the addition of adjuvant decreases the delivery efficiency of the vaccine.
Methods
In this study, cholera toxin A subunit 1 (CTA1) was examined as an adjuvant to Hepatitis B vaccine (HBV) microneedles because of its good water solubility, improved safety, and positive effect as shown in intramuscular administration of a liquid vaccine.
Results
All solid formulations with CTA 1 dissolved in in vivo mouse skin within 30 min, and they were successfully delivered into the skin. In experiments with mice, the addition of CTA1 led to improved IgG immune response compared to the use of an aluminum hydroxide–based formulation and intramuscular administration of HBV. In addition, CTA1 induced CD8 + T cell response as much as in which the aluminum hydroxide–based formulation induced.
Conclusions
CTA1 is an adjuvant that satisfies both the delivery efficiency and the immunological characteristics required for vaccine microneedles. CTA1 will be used as a potential adjuvant through vaccine microneedles.
... Different types of antigens including inactivated whole virus, live attenuated virus, virus-like particles, recombinant bacteria, protein subunits, and plasmid DNA have been investigated to demonstrate immune responses following MN delivery. Many promising examples of MN-based vaccine delivery have appeared in recent publications [160,161], a few of which have been highlighted in this section. Antigens can be introduced into the skin using different MN approaches, including intradermal injection (similar to the Mantoux method), stratum corneum disruption by solid MN abrasion, antigen-coated MN, and dissolvable MN insertion [162]. ...
Anti-SARS-CoV-2 vaccines have played a pivotal role in reducing the risk of developing severe illness from COVID-19, thus helping end the COVID-19 global public health emergency after more than three years. Intriguingly, as SARS-CoV-2 variants emerged, individuals who were fully vaccinated did get infected in high numbers, and viral loads in vaccinated individuals were as high as those in the unvaccinated. However, even with high viral loads, vaccinated individuals were significantly less likely to develop severe illness; this begs the question as to whether the main effect of anti-SARS-CoV-2 vaccines is to confer protection against severe illness or immunity against infection. The answer to this question is consequential, not only to the understanding of how anti-SARS-CoV-2 vaccines work, but also to public health efforts against existing and novel pathogens. In this review, we argue that immune system sensitization-desensitization rather than sterilizing immunity may explain vaccine-mediated protection against severe COVID-19 illness even when the SARS-CoV-2 viral load is high. Through the lessons learned from COVID-19, we make the case that in the disease’s aftermath, public health agencies must revisit healthcare policies, including redefining the term “vaccine effectiveness.”
Modulating the immune microenvironment to establish sustained positive feedback within immune pathways represents a promising avenue for the treatment of autoimmunity. However, the precise and efficient delivery of therapeutic systems to the subcutaneous basal layer to modulate immune disorders is a major challenge in the treatment of autoimmune psoriasis. In this project, we introduce a dual-functional microneedle (DF-MN) designed to combine MNs with multiple release kinetics and immunotherapy, the programmed treatment is achieved through segmented design of the MN structure, realizing the unification of rapid and long-lasting treatment of autoimmune psoriasis. In vivo imaging results showed that GelMA@M-CSF showed fluorescent signals after 5 days of delivery to subcutaneous tissues, whereas HA@IL-13 showed minimal fluorescent signals after 2 days. The multistage release behavior of MNs and the diffusion mechanism of drugs were explained at the molecular level, in combination with coarse-grained molecular dynamics. Additionally, DF-MN can successfully induce macrophage reprogramming in vitro and ameliorate overall symptoms in a psoriasis mice model, suggesting that it has the potential to be an effective strategy for the treatment of psoriasis and portends to be a transformative platform for the treatment of other autoimmune diseases.
Androgenetic alopecia (AGA), the most prevalent clinical hair loss, lacks safe and effective treatments due to downregulated angiogenic genes and insufficient vascularization in the perifollicular microenvironment of the bald scalp in AGA patients. In this study, a hyaluronic acid (HA) based hydrogel-formed microneedle (MN) was designed, referred to as V-R-MNs, which was simultaneously loaded with vascular endothelial growth factor (VEGF) and the novel hair loss drug Ritlecitinib, the latter is encapsulated in slowly biodegradable polyhydroxyalkanoates (PHAs) nanoparticles (R-PHA NPs) for minimally invasive AGA treatment. The integration of HA based hydrogel alongside PHA nanoparticles significantly bolstered the mechanical characteristics of microneedles and enhanced skin penetration efficiency. Due to the biosafety, mechanical strength, and controlled degradation properties of HA hydrogel formed microneedles, V-R-MNs can effectively penetrate the skin's stratum corneum, facilitating the direct delivery of VEGF and Ritlecitinib in a minimally invasive, painless and long-term sustained release manner. V-R-MNs not only promoted angiogenesis and improve the immune microenvironment around the hair follicle to promote the proliferation and development of hair follicle cells, but also the application of MNs to the skin to produce certain mechanical stimulation could also promote angiogenesis. In comparison to the clinical drug minoxidil for AGA treatment, the hair regeneration effect of V-R-MN in AGA model mice is characterized by a rapid onset of the anagen phase, improved hair quality, and greater coverage. This introduces a new, clinically safer, and more efficient strategy for AGA treatment, and serving as a reference for the treatment of other related diseases.
Microneedling, also known as percutaneous collagen induction, using microneedling devices and fabricated microneedle patches, has been widely employed in cosmetic applications for acne scar treatment, skin care, hair loss, melasma, skin rejuvenation, and skin cancer. The micro-channels formed by microneedling through the stratum corneum facilitate the delivery of cosmetic agents and stimulate collagen and elastin production by inducing the wound-healing cascade, keeping the skin shiny and wrinkle-free. Several cosmetic agents, such as ascorbic acid, hyaluronic acid, retinoids, niacinamide, and peptides, have been delivered by microneedling. This review aims to highlight the use of microneedling devices and fabricated microneedle patches in facilitating the delivery of cosmetic agents through the skin layers. Moreover, the differences between the microneedling devices, commonly used alone or in combinational treatments with topical formulations, are explored. Furthermore, the safety of microneedling in terms of skin irritation, pain sensation, skin or systemic infection, and chemical and biological materials used in the fabrication of microneedles is discussed.
Microneedles (MNs) have maintained their popularity in therapeutic and diagnostic medical applications throughout the past decade. MNs are originally designed to gently puncture the stratum corneum layer of the skin and have lately evolved into intelligent devices with functions including bodily fluid extraction, biosensing, and drug administration. MNs offer limited invasiveness, ease of application, and minimal discomfort. Initially manufactured solely from metals, MNs are now available in polymer‐based varieties. MNs can be used to create systems that deliver drugs and chemicals uniformly, collect bodily fluids, and are stimulus‐sensitive. Although these advancements are favorable in terms of biocompatibility and production costs, they are insufficient for the therapeutic use of MNs. This is the first comprehensive review that discusses individual MN functions toward the evolution and development of smart and multifunctional MNs for a variety of novel and impactful future applications. The study examines fabrication techniques, application purposes, and experimental details of MN constructs that perform multiple functions concurrently, including sensing, drug‐molecule release, sampling, and remote communication capabilities. It is highly likely that in the near future, MN‐based smart devices will be a useful and important component of standard medical practice for different applications.
The high-density microprojection array patch (HD-MAP) is a novel vaccine delivery system with potential for self-administered vaccination. HD-MAPs provide an alternative to needle and syringe (N&S) vaccination. Additional advantages could include reduced cold-chain requirements, reduced vaccine dose, reduced vaccine wastage, an alternative for needle phobic patients and elimination of needlestick injuries. The drivers and potential benefits of vaccination by self-administering HD-MAPs are high patient acceptance and preference, higher vaccination rates, speed of roll-out, cost-savings, and reduced sharps and environmental waste. The HD-MAP presents a unique approach in pandemic preparedness and routine vaccination of adults. It could alleviate strain on the healthcare workforce and allows vaccine administration by minimally-trained workers, guardian or subjects themselves. Self-vaccination using HD-MAPs could occur in vaccination hubs with supervision, at home after purchasing at the pharmacy, or direct distribution to in-home settings. As a result, it has the potential to increase vaccine coverage and expand the reach of vaccines, while also reducing labor costs associated with vaccination. Key challenges remain around shifting the paradigm from medical professionals administrating vaccines using N&S to a future of self-administration using HD-MAPs. Greater awareness of HD-MAP technology and improving our understanding of the implementation processes required for adopting this technology, are critical factors underpinning HD-MAP uptake by the public.
Conventional drug delivery using pills or injection is often not suitable for new protein, DNA, and other therapies.¹⁻³ An attractive alternative involves transdermal delivery from a patch, which avoids (i) degradation in the gastrointestinal tract and first-pass effects of the liver associated with oral delivery and (ii) the pain and inconvenience of intravenous injection.⁴⁻⁷ Delivery across skin also offers the possibility to continuously control the delivery rate, in contrast to conventional methods that deliver a large, discrete bolus. Despite these advantages, transdermal drug delivery is severely limited by the poor permeability of human skin; most drugs do not cross skin at therapeutic rates. Chemical,⁸ electrical,⁹ ultrasonic,¹⁰ and other methods have been developed to increase rates of transdermal transport, but have made only limited clinical impact to date.
The mechanical and transport-enhancing properties of microneedles were examined. Microneedle arrays were inserted into epidermis and transdermal transport of calcein or fluorescein-labeled BSA was determined by spectrofluorimetry. Following this, microneedles were examined to determine if any breakage occurred during insertion and removal. It was observed that the microneedles are mechanically strong, able to increase transdermal transport by more than four orders of magnitude in vitro, and do not cause pain in human subjects.
To overcome the skin's barrier properties that block transdermal delivery of most drugs, arrays of microscopic needles have been microfabricated primarily out of silicon or metal. This study addresses microneedles made of biocompatible and biodegradable polymers, which are expected to improve safety and manufacturability. To make biodegradable polymer microneedles with sharp tips, micro-electromechanical masking and etching were adapted to produce beveled- and chisel-tip microneedles and a new fabrication method was developed to produce tapered-cone microneedles using an in situ lens-based lithographic approach. To replicate microfabricated master structures, PDMS micromolds were generated and a novel vacuum-based method was developed to fill the molds with polylactic acid, polyglycolic acid, and their co-polymers. Mechanical testing of the resulting needles measured the force at which needles broke during axial loading and found that this failure force increased with Young's modulus of the material and needle base diameter and decreased with needle length. Failure forces were generally much larger than the forces needed to insert microneedles into skin, indicating that biodegradable polymers can have satisfactory mechanical properties for microneedles. Finally, arrays of polymer microneedles were shown to increase permeability of human cadaver skin to a low-molecular weight tracer, calcein, and a macromolecular protein, bovine serum albumin, by up to three orders of magnitude. Altogether, these results indicate that biodegradable polymer microneedles can be fabricated with an appropriate geometry and sufficient strength to insert into skin, and thereby dramatically increase transdermal transport of molecules.