A microneedle vaccine printer for thermostable COVID-19 mRNA vaccines.

Decentralized manufacture of thermostable mRNA vaccines in a microneedle patch (MNP) format could enhance vaccine access in low-resource communities by eliminating the need for a cold chain and trained healthcare personnel. Here we describe an automated process for printing MNP Coronavirus Disease 2019 (COVID-19) mRNA vaccines in a standalone device. The vaccine ink is composed of lipid nanoparticles loaded with mRNA and a dissolvable polymer blend that was optimized for high bioactivity by screening formulations in vitro. We demonstrate that the resulting MNPs are shelf stable for at least 6 months at room temperature when assessed using a model mRNA construct. Vaccine loading efficiency and microneedle dissolution suggest that efficacious, microgram-scale doses of mRNA encapsulated in lipid nanoparticles could be delivered with a single patch. Immunizations in mice using manually produced MNPs with mRNA encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain stimulate long-term immune responses similar to those of intramuscular administration.

Hydrogels for RNA delivery.

RNA-based therapeutics have shown tremendous promise in disease intervention at the genetic level, and some have been approved for clinical use, including the recent COVID-19 messenger RNA vaccines. The clinical success of RNA therapy is largely dependent on the use of chemical modification, ligand conjugation or non-viral nanoparticles to improve RNA stability and facilitate intracellular delivery. Unlike molecular-level or nanoscale approaches, macroscopic hydrogels are soft, water-swollen three-dimensional structures that possess remarkable features such as biodegradability, tunable physiochemical properties and injectability, and recently they have attracted enormous attention for use in RNA therapy. Specifically, hydrogels can be engineered to exert precise spatiotemporal control over the release of RNA therapeutics, potentially minimizing systemic toxicity and enhancing in vivo efficacy. This Review provides a comprehensive overview of hydrogel loading of RNAs and hydrogel design for controlled release, highlights their biomedical applications and offers our perspectives on the opportunities and challenges in this exciting field of RNA delivery.

Emerging immunomodulatory strategies for cell therapeutics.

Cellular therapies are poised to transform the field of medicine by restoring dysfunctional tissues and treating various diseases in a dynamic manner not achievable by conventional pharmaceutics. Spanning various therapeutic areas inclusive of cancer, regenerative medicine, and immune disorders, cellular therapies comprise stem or non-stem cells derived from various sources. Despite numerous clinical approvals or trials underway, the host immune response presents a critical impediment to the widespread adoption and success of cellular therapies. Here, we review current research and clinical advances in immunomodulatory strategies to mitigate immune rejection or promote immune tolerance to cellular therapies. We discuss the potential of these immunomodulatory interventions to accelerate translation or maximize the prospects of improving therapeutic outcomes of cellular therapies for clinical success.

Magyarország helye Európa transzplantációs térképén.

INTRODUCTION: The incidence of organ transplantation between the Eastern and Western part of Europe is quite different. This has several reasons; the main cause may be the Great Schism (A. D. 1054) when the Byzantine Empire separated himself also religiously from Rome. Since then there has been a different historical development followable until our days. Later on, disintegration of four previous large empires into many smaller countries during the last 150 years, furthermore in the second half of the twentieth century the separation by the Iron Curtain in the middle of Europe led to different social-economic and infrastructural developments between the different parts of the continent. In the new millennium, all transplantations for the routinely performed 5 organs were available for the Hungarian patients, but the real era-changing happened in 2012/13 by joining Eurotransplant. OBJECTIVE: Our analysis is based on the transplantation numbers of the last pre-COVID pandemic year (2019). RESULTS: The abovementioned differences can be traced well by the transplantation numbers: 28 Western- and Middle-European countries have 22.2 cadaveric donors per million population versus 3.8 for 10 Eastern-European countries and another 7 do not have any. The numbers of transplanted organs are the following: 39.5 vs. 12.0 for kidney; 14.8 vs. 5.5 for liver; 5.4 vs. 0.8 for heart; 4.6 vs. 0.2 for lung. DISCUSSION: The statistics have also a rejoicing message because since the fall of the Iron Curtain, 10 Middle-European countries could reach the Western standards in organ transplantation. Their example is also good news for other Eastern European countries. CONCLUSION: Hungary was one of these countries who could benefit from the political changes and, by joining Eurotransplant, the quantity and quality of the transplanted organs was raised significantly: since then, there are by 40% more transplantations performed in our country. Orv Hetil. 2022; 163(30): 1181-1188.

The landscape of mRNA nanomedicine.

Messenger RNA (mRNA) is an emerging class of therapeutic agent for the prevention and treatment of a wide range of diseases. The recent success of the two highly efficacious mRNA vaccines produced by Moderna and Pfizer-BioNTech to protect against COVID-19 highlights the huge potential of mRNA technology for revolutionizing life science and medical research. Challenges related to mRNA stability and immunogenicity, as well as in vivo delivery and the ability to cross multiple biological barriers, have been largely addressed by recent progress in mRNA engineering and delivery. In this Review, we present the latest advances and innovations in the growing field of mRNA nanomedicine, in the context of ongoing clinical translation and future directions to improve clinical efficacy.

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.

Lipid nanoparticles for mRNA delivery.

Messenger RNA (mRNA) has emerged as a new category of therapeutic agent to prevent and treat various diseases. To function in vivo, mRNA requires safe, effective and stable delivery systems that protect the nucleic acid from degradation and that allow cellular uptake and mRNA release. Lipid nanoparticles have successfully entered the clinic for the delivery of mRNA; in particular, lipid nanoparticle-mRNA vaccines are now in clinical use against coronavirus disease 2019 (COVID-19), which marks a milestone for mRNA therapeutics. In this Review, we discuss the design of lipid nanoparticles for mRNA delivery and examine physiological barriers and possible administration routes for lipid nanoparticle-mRNA systems. We then consider key points for the clinical translation of lipid nanoparticle-mRNA formulations, including good manufacturing practice, stability, storage and safety, and highlight preclinical and clinical studies of lipid nanoparticle-mRNA therapeutics for infectious diseases, cancer and genetic disorders. Finally, we give an outlook to future possibilities and remaining challenges for this promising technology.

Facts and Figures on Materials Science and Nanotechnology Progress and Investment.

As the twenty-first century unfolds, nanotechnology is no longer just a buzzword in the field of materials science, but rather a tangible reality. This is evident from the surging number of commercial nanoproducts and their corresponding revenue generated in different industry sectors. However, it is important to recognize that sustainable growth of nanotechnology is heavily dependent on government funding and relevant national incentive programs. Consequently, proper analyses on publicly available nanotechnology data sets comprising information on the past two decades can be illuminating, facilitate development, and amend previous strategies as we move forward. Along these lines, classical statistics and machine learning (ML) allow processing large data sets to scrutinize patterns in materials science and nanotechnology research. Herein, we provide an analysis on nanotechnology progress and investment from an unbiased, computational vantage point and using orthogonal approaches. Our data reveal both well-established and surprising correlations in the nanotechnology field and its actors, including the interplay between the number of research institutes-industry, publications-patents, collaborative research, and top contributors to nanoproducts. Overall, data suggest that, supported by incentive programs set out by stakeholders (researchers, funding agencies, policy makers, and industry), nanotechnology could experience an exponential growth and become a centerpiece for economical welfare. Indeed, the recent success of COVID-19 vaccines is also likely to boost public trust in nanotechnology and its global impact over the coming years.

A New Natural Defense Against Airborne Pathogens.

We propose the nasal administration of calcium-enriched physiological salts as a new hygienic intervention with possible therapeutic application as a response to the rapid and tenacious spread of COVID-19. We test the effectiveness of these salts against viral and bacterial pathogens in animals and humans. We find that aerosol administration of these salts to the airways diminishes the exhalation of the small particles that face masks fail to filter and, in the case of an influenza swine model, completely block airborne transmission of disease. In a study of 10 human volunteers (5 less than 65 years and 5 older than 65 years), we show that delivery of a nasal saline comprising calcium and sodium salts quickly (within 15 min) and durably (up to at least 6 h) diminishes exhaled particles from the human airways. Being predominantly smaller than 1 µm, these particles are below the size effectively filtered by conventional masks. The suppression of exhaled droplets by the nasal delivery of calcium-rich saline with aerosol droplet size of around 10 µm suggests the upper airways as a primary source of bioaerosol generation. The suppression effect is especially pronounced (99%) among those who exhale large numbers of particles. In our study, we found this high-particle exhalation group to correlate with advanced age. We argue for a new hygienic practice of nasal cleansing by a calcium-rich saline aerosol, to complement the washing of hands with ordinary soap, use of a face mask, and social distancing.

Inverse Pneumatic Artificial Muscles for Application in Low-Cost Ventilators.

The procurement and maintenance cost of high-end ventilators preclude their stockpiles sufficient for the mass emergency situations. Therefore, there is a significant demand for mechanical ventilators in such situations. Herein, a low-cost, portable, yet high-performance design for a volume-controlled mechanical ventilator is proposed. Pneumatic artificial muscles, such as air cylinders, are used in the inverse mode of operation to achieve mechanical ventilation. With the current design, the two fundamental modes of operation (controlled mode and assisted mode) are demonstrated. Unlike most intensive care unit ventilators, the proposed device does not need a high-pressure air pipeline to operate. The device is capable of mechanical ventilation for respiration rate ranging from 10 to 30 b min-1 with a tidal volume (VT) range of 150-1000 mL and the I:E ratio of 1:1-1:5. A total cost of less than $400 USD is achieved to make one device. The cost to produce the device in larger volumes can be estimated to be less than $250 USD.

Exhaled aerosol increases with COVID-19 infection, age, and obesity.

COVID-19 transmits by droplets generated from surfaces of airway mucus during processes of respiration within hosts infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. We studied respiratory droplet generation and exhalation in human and nonhuman primate subjects with and without COVID-19 infection to explore whether SARS-CoV-2 infection, and other changes in physiological state, translate into observable evolution of numbers and sizes of exhaled respiratory droplets in healthy and diseased subjects. In our observational cohort study of the exhaled breath particles of 194 healthy human subjects, and in our experimental infection study of eight nonhuman primates infected, by aerosol, with SARS-CoV-2, we found that exhaled aerosol particles vary between subjects by three orders of magnitude, with exhaled respiratory droplet number increasing with degree of COVID-19 infection and elevated BMI-years. We observed that 18% of human subjects (35) accounted for 80% of the exhaled bioaerosol of the group (194), reflecting a superspreader distribution of bioaerosol analogous to a classical 20:80 superspreader of infection distribution. These findings suggest that quantitative assessment and control of exhaled aerosol may be critical to slowing the airborne spread of COVID-19 in the absence of an effective and widely disseminated vaccine.

A materials-science perspective on tackling COVID-19.

The ongoing SARS-CoV-2 pandemic highlights the importance of materials science in providing tools and technologies for antiviral research and treatment development. In this Review, we discuss previous efforts in materials science in developing imaging systems and microfluidic devices for the in-depth and real-time investigation of viral structures and transmission, as well as material platforms for the detection of viruses and the delivery of antiviral drugs and vaccines. We highlight the contribution of materials science to the manufacturing of personal protective equipment and to the design of simple, accurate and low-cost virus-detection devices. We then investigate future possibilities of materials science in antiviral research and treatment development, examining the role of materials in antiviral-drug design, including the importance of synthetic material platforms for organoids and organs-on-a-chip, in drug delivery and vaccination, and for the production of medical equipment. Materials-science-based technologies not only contribute to the ongoing SARS-CoV-2 research efforts but can also provide platforms and tools for the understanding, protection, detection and treatment of future viral diseases.

A rapidly deployable individualized system for augmenting ventilator capacity

Strategies to split ventilators to support multiple patients requiring ventilatory support have been proposed and used in emergency cases in which shortages of ventilators cannot otherwise be remedied by production or procurement strategies. However, the current approaches to ventilator sharing lack the ability to individualize ventilation to each patient, measure pulmonary mechanics, and accommodate rebalancing of the airflow when one patient improves or deteriorates, posing safety concerns to patients. Potential cross-contamination, lack of alarms, insufficient monitoring, and inability to adapt to sudden changes in patient status have prevented widespread acceptance of ventilator sharing. We have developed an individualized system for augmenting ventilator efficacy (iSAVE) as a rapidly deployable platform that uses a single ventilator to simultaneously and more safely support two individuals. The iSAVE enables individual-specific volume and pressure control and the rebalancing of ventilation in response to improvement or deterioration in an individual's respiratory status. The iSAVE incorporates mechanisms to measure pulmonary mechanics, mitigate cross-contamination and backflow, and accommodate sudden flow changes due to individual interdependencies within the respiratory circuit. We demonstrate these capacities through validation using closed- and open-circuit ventilators on linear test lungs. We show that the iSAVE can temporarily ventilate two pigs on one ventilator as efficaciously as each pig on its own ventilator. By leveraging off-the-shelf medical components, the iSAVE could rapidly expand the ventilation capacity of health care facilities during emergency situations such as pandemics.

From micro to nano: evolution and impact of drug delivery in treating disease.

Over the past 50 years, drug delivery breakthroughs have enabled the approval of several important medicines. Often, this path starts with innovation from academic collaborations amongst biologists, chemists, and engineers, followed by the formation of a start-up company driving clinical translation and approval. An early wave featured injectable (i.e., intramuscular, subcutaneous) biodegradable polymeric microspheres to control drug release profiles for peptides and small molecules (e.g., Lupron Depot®, Risperdal Consta®). With these early successes for microspheres, research shifted to exploring systemic delivery by intravenous injection, which required smaller particle sizes and modified surface properties (e.g., PEGylation) to enable long circulation times. These new innovations resulted in the nanoparticle medicines Doxil® and Abraxane®, designed to improve the therapeutic index of cytotoxic cancer agents by decreasing systemic exposure and delivering more drug to tumors. Very recently, the first siRNA lipid nanoparticle medicine, Patisiran (Onpattro®), was approved for treating hereditary transthyretin-mediated amyloidosis. In this inspirational note, we will highlight the technological evolution of drug delivery from micro- to nano-, citing some of the approved medicines demonstrating the significant impact of the drug delivery field in treating many diseases.