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.

A Machine Learning-optimized system for on demand, pulsatile, photo- and chemo-therapeutic treatment using near-infrared responsive MoS 2 -based microparticles in a breast cancer model.

Cancer therapy research is of high interest because of the persistence and mortality of the disease and the side effects of traditional therapeutic methods, while often multimodal treatments are necessary based on the patient's needs. The development of less invasive modalities for recurring treatment cycles is thus of critical significance. Herein, a light-activatable microparticle system was developed for localized, pulsatile delivery of anticancer drugs with simultaneous thermal ablation, by applying controlled ON-OFF thermal cycles using near-infrared laser irradiation. The system is composed of poly(caprolactone) microparticles of 200 µm size with incorporated molybdenum disulfide (MoS 2 ) nanosheets as the photothermal agent and hydrophilic doxorubicin or hydrophobic violacein, as model drugs. Upon irradiation the nanosheets heat up to ≥50 °C leading to polymer matrix melting and release of the drug. MoS 2 nanosheets exhibit high photothermal conversion efficiency and allow for application of low power laser irradiation for the system activation. A Machine Learning algorithm was applied to acquire optimal laser operation conditions; 0.4 W/cm 2 laser power at 808 nm, 3-cycle irradiation, for 3 cumulative minutes. In a mouse subcutaneous model of 4T1 triple-negative breast cancer, 25 microparticles were intratumorally administered and after 3-cycle laser treatment the system conferred synergistic phototherapeutic and chemotherapeutic effect. Our on-demand, pulsatile synergistic treatment resulted in increased median survival up to 40 days post start of treatment compared to untreated mice, with complete eradication of the tumors at the primary site. Such a system could have potential for patients in need of recurring cycles of treatment on subcutaneous tumors.

Muscle-Powered Counterpulsation for Untethered, Non-Blood-Contacting Cardiac Support: A Path to Destination Therapy.

Conventional long-term ventricular assist devices continue to be extremely problematic due to infections caused by percutaneous drivelines and thrombotic events associated with the use of blood-contacting surfaces. Here we describe a muscle-powered cardiac assist device that avoids both these problems by using an internal muscle energy converter to drive a non-blood-contacting extra-aortic balloon pump. The technology was developed previously in this lab and operates by converting the contractile energy of the latissimus dorsi muscle into hydraulic power that can be used, in principle, to drive any blood pump amenable to pulsatile actuation. The two main advantages of this implantable power source are that it 1) significantly reduces infection risk by avoiding a constant skin wound, and 2) improves patient quality-of-life by eliminating all external hardware components. The counterpulsatile balloon pumps, which compress the external surface of the ascending aorta during the diastolic phase of the cardiac cycle, offer another critical advantage in the setting of long-term circulatory support in that they increase cardiac output and improve coronary perfusion without touching the blood. The goal of this work is to combine these two technologies into a single circulatory support system that eliminates driveline complications and avoids surface-mediated thromboembolic events, thereby providing a safe, tether-free means to support the failing heart over extended - or even indefinite - periods of time.

Ventricle-specific epicardial pressures as a means to optimize direct cardiac compression for circulatory support: A pilot study.

Direct cardiac compression (DCC) holds enormous potential as a safe and effective means to treat heart failure patients who require long-term, or even permanent, biventricular support. However, devices developed to date are not tuned to meet the individual compression requirements of the left and right ventricles, which can differ substantially. In this paper, a systematic study examining the relationship, range, and effect of independent pressures on the left and right epicardial surfaces of a passive human heart model was performed as a means to optimize cardiac output via DCC support. Hemodynamic and tissue deformation effects produced by varying epicardial compressions were examined using finite element analysis. Results indicate that 1) designing a direct cardiac compression pump that applies separate pressures to the left and right ventricles is critical to maintain equivalent stroke volume for both ventricles, and 2) left and right ventricular epicardial pressures of 340 mmHg and 44 mmHg, respectively, are required to induce normal ejection fractions in a passive heart. This pilot study provides fundamental insights and guidance towards the design of improved direct cardiac compression devices for long-term circulatory support.

Cardiac Assist Devices: Early Concepts, Current Technologies, and Future Innovations.

Congestive heart failure (CHF) is a debilitating condition that afflicts tens of millions of people worldwide and is responsible for more deaths each year than all cancers combined. Because donor hearts for transplantation are in short supply, a safe and durable means of mechanical circulatory support could extend the lives and reduce the suffering of millions. But while the profusion of blood pumps available to clinicians in 2019 tend to work extremely well in the short term (hours to weeks/months), every long-term cardiac assist device on the market today is limited by the same two problems: infections caused by percutaneous drivelines and thrombotic events associated with the use of blood-contacting surfaces. A fundamental change in device design is needed to address both these problems and ultimately make a device that can support the heart indefinitely. Toward that end, several groups are currently developing devices without blood-contacting surfaces and/or extracorporeal power sources with the aim of providing a safe, tether-free means to support the failing heart over extended periods of time.