Microneedles: An Emerging Vaccine Delivery Tool and a Prospective Solution to the Challenges of SARS-CoV-2 Mass Vaccination.

Vaccination is an effective measure to prevent infectious diseases. Protective immunity is induced when the immune system is exposed to a vaccine formulation with appropriate immunogenicity. However, traditional injection vaccination is always accompanied by fear and severe pain. As an emerging vaccine delivery tool, microneedles overcome the problems associated with routine needle vaccination, which can effectively deliver vaccines rich in antigen-presenting cells (APCs) to the epidermis and dermis painlessly, inducing a strong immune response. In addition, microneedles have the advantages of avoiding cold chain storage and have the flexibility of self-operation, which can solve the logistics and delivery obstacles of vaccines, covering the vaccination of the special population more easily and conveniently. Examples include people in rural areas with restricted vaccine storage facilities and medical professionals, elderly and disabled people with limited mobility, infants and young children afraid of pain. Currently, in the late stage of fighting against COVID-19, the main task is to increase the coverage of vaccines, especially for special populations. To address this challenge, microneedle-based vaccines have great potential to increase global vaccination rates and save many lives. This review describes the current progress of microneedles as a vaccine delivery system and its prospects in achieving mass vaccination against SARS-CoV-2.

Microneedle technology for potential SARS-CoV-2 vaccine delivery.

INTRODUCTION: Microneedle fabrication was conceptualized in the 1970s as devices for painless transdermal drug delivery. The last two decades have seen considerable research and financial investment in this area with SARS-CoV-2 and other vaccines catalyzing their application to in vivo intradermal vaccine delivery. Microneedle arrays have been fabricated in different shapes, geometries, formats, and out of different materials. AREAS COVERED: The recent pandemic has offered microneedle platforms the opportunity to be employed as a vehicle for SARS-CoV-2 vaccine administration. Various modes of vaccination delivery and the potential of microneedle array-based vaccines will be presented, with a specific focus placed on recent SARS-CoV-2 research. The advantages of microneedle-based vaccine administration, in addition to the major hurdles to their en masse implementation, will be examined. EXPERT OPINION: Considering the widely acknowledged disadvantages of current vaccine delivery, such as anxiety, pain, and the requirement for professional administration, a large shift in this research sphere is imminent. The SARS-CoV-2 pandemic has catalyzed the development of alternate vaccination platforms, working to avoid the requirement for mass vaccination centers. As microneedle vaccine patches are transitioning through clinical study phases, research will be required to prepare this technology for a more mass production environment.

Microneedles for Efficient and Precise Drug Delivery in Cancer Therapy.

Cancer is the leading cause of death, acting as a global burden, severely impacting the patients' quality of life and affecting the world economy despite the expansion of cumulative advances in oncology. The current conventional therapies for cancer which involve long treatment duration and systemic exposure of drugs leads to premature degradation of drugs, a massive amount of pain, side effects, as well as the recurrence of the condition. There is also an urgent demand for personalized and precision-based medicine, especially after the recent pandemic, to avoid future delays in diagnosis or treatments for cancer patients as they are very essential in reducing the global mortality rate. Recently, microneedles which consist of a patch with tiny, micron-sized needles attached to it have been quite a sensation as an emerging technology for transdermal application to diagnose or treat various illnesses. The application of microneedles in cancer therapies is also being extensively studied as they offer a myriad of benefits, especially since microneedle patches offer a better treatment approach through self administration, painless treatment, and being an economically and environmentally friendly approach in comparison with other conventional methods. The painless gains from microneedles significantly improves the survival rate of cancer patients. The emergence of versatile and innovative transdermal drug delivery systems presents a prime breakthrough opportunity for safer and more effective therapies, which could meet the demands of cancer diagnosis and treatment through different application scenarios. This review highlights the types of microneedles, fabrication methods and materials, along with the recent advances and opportunities. In addition, this review also addresses the challenges and limitations of microneedles in cancer therapy with solutions through current studies and future works to facilitate the clinical translation of microneedles in cancer therapies.

Recent Updates in Vaccine Delivery through Microneedles.

Recent coronavirus pandemic and its global socio-economic impact has re-emphasized the need for safe, fast, and efficient delivery of vaccines for humankind. With advent of technological advances, and to improve patient acquiescence, several techniques for fast, effective, and safe delivery of vaccines have been researched and published in the literature in last three decades. These delivery enhancement techniques include but are not limited to electroporation, microneedles (MN), ultrasound, iontophoresis, etc. This review aims at discussing the current research undergoing in vaccine delivery, specifically focusing on microneedles assisted, the historical background of microneedles and their introduction to drug delivery area, and a special focus on formulation challenges and stability in these systems. The review also sheds light on regulatory challenges one must keep in mind for bringing a successful microneedles-based vaccine delivery into market as well as a snapshot of current commercially available microneedles-based products in cosmetic and pharmaceutical industry.

Real-Time Monitoring and Early Warning of a Cytokine Storm In Vivo Using a Wearable Noninvasive Skin Microneedle Patch.

A cytokine storm may be the last attack of various diseases, such as sepsis, cancer, and coronavirus disease 2019, that can be life threatening. Real-time monitoring of cytokines in vivo is helpful for assessing the immune status of patients and providing an early warning of a cytokine storm. In this study, a functional carbon nanotube biointerface-based wearable microneedle patches for real-time monitoring of a cytokine storm in vivo via electrochemical analysis are reported. This wearable system has sensitivity with a detection limit of 0.54 pg mL-1 , high specificity, and 5 days of stability with a coefficient of variation of 4.0%. The system also has a quick response of several hours (1-4 h) to increasing cytokines. This wearable microneedle patch may offer a promising route for real-time biomolecule wearables construction. The patch is also the first reported integrated capture and monitoring system that is capable of real-time measurement of protein markers in interstitial fluid.

A Single-Administration Microneedle Skin Patch for Multi-Burst Release of Vaccine against SARS-CoV-2.

The necessity for multiple injections and cold-chain storage has contributed to suboptimal vaccine utilization, especially in pandemic situations. Thermally-stable and single-administration vaccines hold a great potential to revolutionize the global immunization process. Here, a new approach to thermally stabilize protein-based antigens is presented and a new high-throughput antigen-loading process is devised to create a single-administration, pulsatile-release microneedle (MN) patch which can deliver a recombinant SARS-CoV-2 S1-RBD protein-a model for the COVID-19 vaccine. Nearly 100% of the protein antigen could be stabilized at temperatures up to 100 °C for at least 1 h and at an average human body temperature (37 °C) for up to 4 months. Arrays of the stabilized S1-RBD formulations can be loaded into the MN shells via a single-alignment assembly step. The fabricated MNs are administered at a single time into the skin of rats and induce antibody response which could neutralize authentic SARS-CoV-2 viruses, providing similar immunogenic effect to that induced by multiple bolus injections of the same antigen stored in conventional cold-chain conditions. The MN system presented herein could offer the key solution to global immunization campaigns by avoiding low patient compliance, the requirement for cold-chain storage, and the need for multiple booster injections.

Dissolvable polymer microneedles for drug delivery and diagnostics.

Dissolvable transdermal microneedles (µND) are promising micro-devices used to transport a wide selection of active compounds into the skin. To provide an effective therapeutic outcome, µNDs must pierce the human stratum corneum (~10 to 20 µm), without rupturing or bending during penetration, then release their cargo at the predetermined area and time. The ability of dissolvable µND arrays/patches to sufficiently pierce the skin is a crucial requirement, which depends on the material composition, µND geometry and fabrication techniques. This comprehensive review not only provides contemporary knowledge on the µND design approaches, but also the materials science facilitating these delivery systems and the opportunities these advanced materials can provide to enhance clinical outcomes.

An Adjuvanted Inactivated SARS-CoV-2 Microparticulate Vaccine Delivered Using Microneedles Induces a Robust Immune Response in Vaccinated Mice.

SARS-CoV-2, the causal agent of COVID-19, is a contagious respiratory virus that frequently mutates, giving rise to variant strains and leading to reduced vaccine efficacy against the variants. Frequent vaccination against the emerging variants may be necessary; thus, an efficient vaccination system is needed. A microneedle (MN) vaccine delivery system is non-invasive, patient-friendly, and can be self-administered. Here, we tested the immune response produced by an adjuvanted inactivated SARS-CoV-2 microparticulate vaccine administered via the transdermal route using a dissolving MN. The inactivated SARS-CoV-2 vaccine antigen and adjuvants (Alhydrogel® and AddaVax™) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer matrices. The resulting MP were approximately 910 nm in size, with a high percentage yield and percent encapsulation efficiency of 90.4%. In vitro, the vaccine MP was non-cytotoxic and increased the immunostimulatory activity measured as nitric oxide release from dendritic cells. The adjuvant MP potentiated the immune response of the vaccine MP in vitro. In vivo, the adjuvanted SARS-CoV-2 MP vaccine induced high levels of IgM, IgG, IgA, IgG1, and IgG2a antibodies and CD4+ and CD8+ T-cell responses in immunized mice. In conclusion, the adjuvanted inactivated SARS-CoV-2 MP vaccine delivered using MN induced a robust immune response in vaccinated mice.

Microneedle Patch for Painless Intradermal Collection of Interstitial Fluid Enabling Multianalyte Measurement of Small Molecules, SARS-CoV-2 Antibodies, and Protein Profiling.

Blood sampling is a common practice to monitor health, but it entails a series of drawbacks for patients including pain and discomfort. Thus, there is a demand for more convenient ways to obtain samples. Modern analytical techniques enable monitoring of multiple bioanalytes in smaller samples, opening possibilities for new matrices, and microsampling technologies to be adopted. Interstitial fluid (ISF) is an attractive alternative matrix that shows good correlation with plasma concentration dynamics for several analytes and can be sampled in a minimally invasive and painless manner from the skin at the point-of-care. However, there is currently a lack of sampling devices compatible with clinical translation. Here, to tackle state-of-the-art limitations, a cost-effective and compact single-microneedle-based device designed to painlessly collect precisely 1.1 µL of dermal ISF within minutes is presented. The fluid is volume-metered, dried, and stably stored into analytical-grade paper within the microfluidic device. The obtained sample can be mailed to a laboratory, quantitatively analyzed, and provide molecular insights comparable to blood testing. In a human study, the possibility to monitor various classes of molecular analytes is demonstrated in ISF microsamples, including caffeine, hundreds of proteins, and SARS-CoV-2 antibodies, some being detected in ISF for the first time.

Newly Developed Microneedles Can Dissolve in The Skin to Deliver Drugs

Microneedles were first created for medication delivery many decades ago, but serious study on them did not commence until the mid-1990s. Microneedles, skin creams, and transdermal patches are the most extensive treatments for the transdermal administration of medications. Due to the stratum corneum layer of the skin, which acts as a barrier for the particles, multiple particles can appear at the site of action, limiting the effectiveness of the vast majority of supportive specialists. Microneedles are a further type of drug delivery device that aids in working on the transport of pharmaceuticals through this course and overcoming the numerous challenges associated with conventional nuances. The essential rule comprises interruption of the skin layer, so creating micron-sized routes that lead the drug plainly to the epidermis or higher dermis region, from which it can enter the central course straight without encountering a restriction. Copyright © 2022 Wolters Kluwer Medknow Publications. All rights reserved.

Subunit microparticulate vaccine delivery using microneedles trigger significant SARS-spike-specific humoral and cellular responses in a preclinical murine model.

The objective of this "proof-of-concept" study was to evaluate the synergistic effect of a subunit microparticulate vaccine and microneedles (MN) assisted vaccine delivery system against a human coronavirus. Here, we formulated PLGA polymeric microparticles (MPs) encapsulating spike glycoprotein (GP) of SARS-CoV as the model antigen. Similarly, we formulated adjuvant MPs encapsulating Alhydrogel® and AddaVax™. The antigen/adjuvant MPs were characterized and tested in vitro for immunogenicity. We found that the antigen/adjuvant MPs were non-cytotoxic in vitro. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs showed enhanced immunogenicity in vitro as confirmed through the release of nitrite, autophagy, and antigen presenting molecules with their co-stimulatory molecules. Next, we tested the in vivo efficacy of the spike GP MP vaccine with and without adjuvant MPs in mice vaccinated using MN. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs induced heightened spike GP-specific IgG, IgG1 and IgG2a antibodies in mice. Also, spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs enhanced expression of CD4+ and CD8+ T cells in secondary lymphoid organ like spleen. These results indicated spike GP-specific humoral immunity and cellular immunity in vivo. Thus, we employed the benefits of both the subunit vaccine MPs and dissolving MN to form a non-invasive and effective vaccination strategy against human coronaviruses.

Polymer-based microneedle composites for enhanced non-transdermal drug delivery

The applications of microneedles (MNs) are becoming popular with the promise of efficient and advanced drug delivery. MNs were developed to overcome the limitations of conventional drug delivery systems and bypass biological barriers. While most MN applications in the past decades focused on transdermal biomedical appli-cations, recent advancements in engineering and technology have enabled MNs to be used in a wide range of non-transdermal applications. Compared with the other types of MNs, polymer-based MN composites have attracted more attention for non-transdermal drug delivery because they exhibit excellent biological properties, including being nontoxic, biocompatible, and biodegradable, making them ideal biomaterials for drug delivery applications that overcome the metabolic constraints of drug delivery for macromolecular payloads across a variety of tissues and organs other than the skin. This review provides an overview of recent advancements in polymer-based MN composite carriers that aim to overcome the delivery challenges for non-transdermal drug delivery, specifically in the vascular, ocular, gastrointestinal tract, buccal transmucosal, periodontal, cardio-vascular, and vaginal tissue. Furthermore, this review will discuss future perspectives and challenges for poly-meric MN composites in non-transdermal drug delivery that must be resolved.

Microneedle Delivery of an Adjuvanted Microparticulate Vaccine Induces High Antibody Levels in Mice Vaccinated against Coronavirus.

This 'proof-of-concept' study aimed to test the microparticulate vaccine delivery system and a transdermal vaccine administration strategy using dissolving microneedles (MN). For this purpose, we formulated poly(lactic-co-glycolic) acid (PLGA) microparticles (MP) encapsulating the inactivated canine coronavirus (iCCoV), as a model antigen, along with adjuvant MP encapsulating Alhydrogel® and AddaVax. We characterized the vaccine MP for size, surface charge, morphology, and encapsulation efficiency. Further, we evaluated the in vitro immunogenicity, cytotoxicity, and antigen-presentation of vaccine/adjuvant MP in murine dendritic cells (DCs). Additionally, we tested the in vivo immunogenicity of the MP vaccine in mice through MN administration. We evaluated the serum IgG, IgA, IgG1, and IgG2a responses using an enzyme-linked immunosorbent assay. The results indicate that the particulate form of the vaccine is more immunogenic than the antigen suspension in vitro. We found the vaccine/adjuvant MP to be non-cytotoxic to DCs. The expression of antigen-presenting molecules, MHC I/II, and their costimulatory molecules, CD80/40, increased with the addition of the adjuvants. Moreover, the results suggest that the MP vaccine is cross presented by the DCs. In vivo, the adjuvanted MP vaccine induced increased antibody levels in mice following vaccination and will further be assessed for its cell-mediated responses.

Emerging technologies for combating pandemics.

INTRODUCTION: Covid-19, alongside previous pandemics, has highlighted the need for the continued development of technologies that are at our disposal. Emerging technologies are those that show true promise in achieving such a goal and have begun to form sturdy independent research areas. Technological advances in healthcare must continually develop to ensure that the world is prepared for any future diseases that may ensue. As such, a strategic review into 43 manuscripts since 2019 has been conducted to determine the prominence of emerging technologies since the beginning of the Covid-19 pandemic. AREAS COVERED: Relating to their use in a pandemic state, additive manufacturing (AM), biofabrication, microfluidics, biomedical microelectromechanical systems (BioMEMS), and artificial intelligence (AI) are described. Applications over the past 2-3 years, as well as future developments, are considered throughout. EXPERT OPINION: All the technologies mentioned in this review are sure to develop further, having shown their importance and value during the covid-19 pandemic. As research continues within the area, their efficacy will increase to the point where it likely will become gold standard for pandemic control. Combining certain technologies mentioned has also proved to have had great success in improving the final results obtained.

Potential of Microneedle Systems for COVID-19 Vaccination: Current Trends and Challenges.

To prevent the coronavirus disease 2019 (COVID-19) pandemic and aid restoration to prepandemic normality, global mass vaccination is urgently needed. Inducing herd immunity through mass vaccination has proven to be a highly effective strategy for preventing the spread of many infectious diseases, which protects the most vulnerable population groups that are unable to develop immunity, such as people with immunodeficiencies or weakened immune systems due to underlying medical or debilitating conditions. In achieving global outreach, the maintenance of the vaccine potency, transportation, and needle waste generation become major issues. Moreover, needle phobia and vaccine hesitancy act as hurdles to successful mass vaccination. The use of dissolvable microneedles for COVID-19 vaccination could act as a major paradigm shift in attaining the desired goal to vaccinate billions in the shortest time possible. In addressing these points, we discuss the potential of the use of dissolvable microneedles for COVID-19 vaccination based on the current literature.

Local Response and Barrier Recovery in Elderly Skin Following the Application of High-Density Microarray Patches.

The high-density microneedle array patch (HD-MAP) is a promising alternative vaccine delivery system device with broad application in disease, including SARS-CoV-2. Skin reactivity to HD-MAP applications has been extensively studied in young individuals, but not in the >65 years population, a risk group often requiring higher dose vaccines to produce protective immune responses. The primary aims of the present study were to characterise local inflammatory responses and barrier recovery to HD-MAPs in elderly skin. In twelve volunteers aged 69-84 years, HD-MAPs were applied to the forearm and deltoid regions. Measurements of transepidermal water loss (TEWL), dielectric permittivity and erythema were performed before and after HD-MAP application at t = 10 min, 30 min, 48 h, and 7 days. At all sites, TEWL (barrier damage), dielectric permittivity (superficial water);, and erythema measurements rapidly increased after HD-MAP application. After 7 days, the mean measures had recovered toward pre-application values. The fact that the degree and chronology of skin reactivity and recovery after HD-MAP was similar in elderly skin to that previously reported in younger adults suggests that the reactivity basis for physical immune enhancement observed in younger adults will also be achievable in the older population.

Microneedle patches integrated with lateral flow cassettes for blood-free chronic kidney disease point-of-care testing during a pandemic.

Chronic kidney disease (CKD) is the most neglected chronic disease affecting over 750 million persons in the world. Currently, many patients with cancers or other chronic diseases (i.e., CKD) struggle to receive clinical treatment or examination due to hospitals cancelling or delaying in the COVID-19 pandemic, which may increase the risk of death. Cystatin C (Cys C) has been proposed as a potential glomerular filtration rate (GFR) marker for the early detection of acute kidney injury and CKD. However, most traditional methods for Cys C detection are immunoassays using serum as a sample and are tedious to perform and economically burdensome. To diagnose the disease in the early stage and carry out daily management during the current pandemic, we developed an integration of hydrogel microneedle patch (HMNP) and lateral flow cassette (LFC) to rapidly detect Cys C in skin interstitial fluid (ISF) in 25 min for blood-free CKD management anytime and anywhere by the naked eye that can reduce the impact of an individual's quality of life and life expectancy. Conceivably, this strategy presents a wide scope in the application of numerous other diseases if corresponding analytes are available in skin ISF.

Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective.

The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA vaccines were developed and have been instrumental in preventing the disease by boosting the immune system against the pathogen, SARS-CoV-2. These vaccines have been built on decades of scientific research in drug delivery of mRNA, vaccines, and other biologicals. In this manuscript, several leading and emerging scientists in the field of drug delivery share their perspective on the role of drug delivery technologies in developing safe and efficacious vaccines, in a roundtable discussion. The authors also discussed their viewpoint on the current challenges, and the key research questions that should drive this important area of research.

A dual-delivery platform for vaccination using antigen-loaded nanoparticles in dissolving microneedles.

Effective vaccines delivered via painless methods would revolutionize the way people approach vaccinations. This study focused on the development of fast-dissolving microneedles (MNs) to deliver antigen-loaded sustained release polymeric nanoparticles (NPs), achieving a dual-delivery platform for vaccination through the skin. The platform utilizes dissolving MNs (dMNs), which penetrate to the epidermal layer of the skin and rapidly dissolve, releasing the antigen-loaded NPs. In this study, seven dissolving microneedle formulations were tested based on screening of various biocompatible and biodegradable polymers and sugars. The lead dMN formulation was selected based on optimal mechanical strength and dissolution of the needles and was loaded with poly(lactic-co-glycolic) acid (PLGA) NPs encapsulating a model influenza matrix 2 (M2) protein antigen. Antigen-loading efficiency in the needles was determined by centrifugation of the lead formulation containing various concentrations of antigen nanoparticles. Next, the reproducibility and translatability of ex vivo mechanical strength and dissolvability of the lead M2 PLGA NP-loaded dMN formulation was assessed by formulating and testing two different microneedle arrays on murine and porcine skin. Finally, the lead microneedle array was loaded with fluorescent dye NPs and evaluated for pore formation and closure in vivo in a murine model. This proof-of-concept study yielded an easy-to-formulate, well-characterized, translatable antigen NP-loaded dMN platform for transdermal vaccine administration.

Bioengineering Strategies for Developing Vaccines against Respiratory Viral Diseases.

Respiratory viral pathogens like influenza and coronaviruses such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have caused outbreaks leading to millions of deaths. Vaccinations are, to date, the best and most economical way to control such outbreaks and have been highly successful for several pathogens. Currently used vaccines for respiratory viral pathogens are primarily live attenuated or inactivated and can risk reversion to virulence or confer inadequate immunity. The recent trend of using potent biomolecules like DNA, RNA, and protein antigenic components to synthesize vaccines for diseases has shown promising results. Still, it remains challenging to translate due to their high susceptibility to degradation during storage and after delivery. Advances in bioengineering technology for vaccine design have made it possible to control the physicochemical properties of the vaccines for rapid synthesis, heightened antigen presentation, safer formulations, and more robust immunogenicity. Bioengineering techniques and materials have been used to synthesize several potent vaccines, approved or in trials, against coronavirus disease 2019 (COVID-19) and are being explored for influenza, SARS, and Middle East respiratory syndrome (MERS) vaccines as well. Here, we review bioengineering strategies such as the use of polymeric particles, liposomes, and virus-like particles in vaccine development against influenza and coronaviruses and the feasibility of adopting these technologies for clinical use.