Decentralized on-patient medical record (OPMR) storage would enable medical staff to access patients' medical information on demand, especially in low-resource settings lacking centralized recordkeeping infrastructure. We incorporated near-infrared (NIR) microparticles into microneedle patches (MNPs) to invisibly encode medical information in the skin for OPMR using a specialized reader. NIR particles were co-encapsulated with inactivated polio vaccine in the same microneedles without loss of antigenicity. However, measles and rubella vaccines combined with NIR particles lost almost all potency. We therefore developed hybrid MNPs that spatially separated NIR particles in patterned microneedles in the central part of the patch and vaccines in separate microneedles around the periphery. This approach preserved vaccine potency. Ex vivo testing in pig skin demonstrated effective microneedle penetration and reliable OPMR signal readability. In vivo studies in rats and guinea pigs demonstrated OPMR signal retention for up to 21 months. Immunogenicity studies in cotton rats confirmed that neutralizing antibody titers were similar after measles vaccination by hybrid MNPs (containing NIR particles), conventional MNPs (without NIR particles) and subcutaneous injection. These findings suggest that hybrid MNPs enable co-administration of vaccines and NIR particles for OPMR or co-delivery of other materials requiring sequestration.

Medical interventions often require timed series of doses, thus necessitating accurate medical record-keeping. In many global settings, these records are unreliable or unavailable at the point of care, leading to less effective treatments or disease prevention. Here we present an invisible-to-the-naked-eye on-patient medical record-keeping technology that accurately stores medical information in the patient skin as part of microneedles that are used for intradermal therapeutics. We optimize the microneedle design for both a reliable delivery of messenger RNA (mRNA) therapeutics and the near-infrared fluorescent microparticles that encode the on-patient medical record-keeping. Deep learning-based image processing enables encoding and decoding of the information with excellent temporal and spatial robustness. Long-term studies in a swine model demonstrate the safety, efficacy and reliability of this approach for the co-delivery of on-patient medical record-keeping and the mRNA vaccine encoding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This technology could help healthcare workers make informed decisions in circumstances where reliable record-keeping is unavailable, thus contributing to global healthcare equity.

Vaccination remains a critical tool in preventing infectious diseases, yet its effectiveness is undermined by under-immunization, particularly for vaccines requiring multiple doses that patients fail to complete. To address this challenge, the development of single-injection platforms delivering self-boosting vaccines has gained significant attention. Despite some advances, translating these platforms into clinical applications has been limited. In this study, a novel polyanhydride-based polymeric delivery platform is introduced, designed for single-injection self-boosting vaccines, replacing multiple doses. Over 20 polyanhydride polymers are synthesized and screened, ultimately down selecting to 6 for in vitro studies, and 2 for in vivo studies. Using diphtheria toxoid (DT) as a model antigen, programmed pulsatile release with a narrow window is demonstrated, ideal for self-boosting immunization. The platform effectively protects the pH-sensitive antigen before release, achieving recovery rate of 39.7% to 89.7%. The system's tunability is further enhanced by machine learning algorithms, which accurately predict release profiles, confirmed through experimental validation. In vivo studies in a mouse model reveals that the platform induces DT-specific antibody responses comparable to those generated by traditional multi-dose regimens. Collectively, these findings highlight the potential of this platform to deliver various vaccines, offering a potentially promising solution to the global challenge of under-immunization.

Myocardial infarction (MI) is a major global health challenge. Surgical interventions address the acute phase but often fail to support long-term recovery. Sequential post-operative drug delivery offers promise but is constrained by release methods. Here, we developed TIMED (temporal intervention with microparticle encapsulation and delivery), a polymeric device enabling programmed sequential release through spatially patterned microparticles in a tough hydrogel matrix. TIMED demonstrated excellent mechanical performance and biocompatibility for long-term implantation and retained strong stability after storage. A sequential dosing regimen aligned with the innate post-MI response was first validated in hiPSC-derived cardiac tissues, where it enhanced cell viability and vascularization while reducing collagen deposition. In vivo, delivery via the TIMED improved survival, reduced injury markers and infarct size, and enhanced cardiac output, outperforming equivalent i.v. dosing. This work establishes a first-of-its-kind cardiac implantable polymeric platform with modular sequential release and provides a framework for programmed multi-dosing across diverse applications.

Microplastic pollution is a pressing global crisis caused by the extensive use of nondegradable microplastic materials in daily activities. One effective approach to mitigate this issue is to replace nondegradable plastics with degradable materials that have properties amendable for targeted applications. Here we present the development of a degradable microparticle (MP) platform based on a poly(β-amino ester) (PAE) that degrades into sugar and amino acid derivatives. This PAE MP platform showed functional replacement of nondegradable microplastics used in cleansing products and food fortification. In cleansing products, PAE MPs effectively enhanced the cleansing efficiency of a representative rinse-off product and showed effective removal of potentially toxic elements, as an alternative of traditional nondegradable microbeads. In food fortification, PAE MPs provided robust protection for multiple essential vitamins and minerals against extensive cooking and storage conditions with rapid nutrient release in a simulated human digestion system. Collectively, these PAE MPs present a potential platform to replace microplastic usage on a global scale in many applications. This study reports the preparation of degradable poly(β-amino ester) microparticles as a promising replacement for nondegradable microplastics in cleansing products and food fortification, demonstrating effective cleansing, toxic element removal and robust nutrient protection with efficient release.

Mucosal pathogens, as exemplified by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human immunodeficiency virus (HIV) and Mycobacterium tuberculosis , lead to substantial morbidity and mortality worldwide and pose serious threats to global health. Mucosal vaccination is crucial to combating mucosal pathogens because it enables the immune system to directly target and neutralize pathogens at their point of entry. Mucosal vaccines need to penetrate the mucus layer, reach the target tissue and activate robust immune responses in the mucosal tissues. Material-based strategies are necessary to meet these requirements. In this Review, we provide an overview of current mucosal vaccines, categorized by administration route, to highlight the importance of material design in overcoming the existing delivery challenges. We discuss the different classes of materials currently being used as vaccine carriers to induce antigen-specific mucosal immunity, including lipids, natural and synthetic polymers, inorganic materials and pathogen-inspired materials.

Accurate medical recordkeeping is important for personal and public health. Conventional forms of on-patient medical information, such as medical alert bracelets or finger-markings, may compromise patient privacy because they are readily visible to other people. Here, the development of an invisible, temporary, and easily deployable on-patient medical recordkeeping system is reported. Information is stored in unique patterns of spatially distributed near-infrared (NIR) fluorescent quantum dots (QDs), which are delivered to the skin using dissolvable microneedle arrays. The patterns are invisible to the naked eye but detectable with an infrared camera, which can extract information with >98% accuracy using automated pattern recognition software. By encapsulating NIR QDs in an FDA-approved biodegradable polymer, biodegradation rates can be tuned so that the encoded medical information can be conveyed in both a spatial and temporal manner, with some components fading within 100 days and others persisting for 6 months. This may be particularly useful for administering a series of vaccinations or treatments by indicating if enough time has passed for the patient to receive the next dose. Importantly, this system contains no personal information, does not require connection to a centralized database, and is not visible to the naked eye, ensuring patient privacy.

Multimodal cancer therapies are often required for progressive cancers due to the high persistence and mortality of the disease and the negative systemic side effects of traditional therapeutic methods. Thus, the development of less invasive modalities for recurring treatment cycles is of clinical 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 mu m size containing molybdenum disulfide (MoS2) nanosheets as the photothermal agent and hydrophilic doxorubicin or hydrophobic violacein, as model drugs. Upon irradiation, the nanosheets heat up to >= 50 degrees C leading to polymer softening and release of the drug. MoS2 nanosheets exhibit high photothermal conversion efficiency and require low-power laser irradiation. A machine learning algorithm was applied to acquire the optimal laser operation conditions. 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 effects. Our on-demand, pulsatile synergistic treatment resulted in increased median survival up to 39 days post start of treatment compared to untreated mice, with complete eradication of the tumors at the primary site. Such a system is therapeutically relevant for patients in need of recurring cycles of treatment on small tumors, since it provides precise localization and low invasiveness and is not cross-resistant with other treatments.

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. Automated fabrication of microneedle patch mRNA vaccines for COVID-19 may improve vaccine access.

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. GRAPHICAL ABSTRACT:

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.

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.

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.

Congestive heart failure (CHF) remains one of the most costly diseases in the industrialized world, both in terms of healthcare dollars and the loss of human life. Despite great strides made in the treatment of CHF using mechanical ventricular assist devices (VADs), several longstanding difficulties associated with pumping blood continue to limit their long-term use. Among the most troublesome have been the increased risk of infection associated with the use of percutaneous drivelines and the persistent risk of clot formation at the blood-device interface. Development of a completely self-contained, non-blood-contacting VAD for long-term use would therefore be an important advance in circulatory support technology. Toward that end, we have developed a muscle-powered co-pulsation VAD (Figure 1) that avoids both these problems by using an internal muscle energy converter (MEC) to drive a non-blood-contacting direct cardiac compression sleeve (DCCS) for long-term circulatory support.

While great strides continue to be made in the treatment of congestive heart failure using mechanical ventricular assist devices (VADs), several longstanding difficulties associated with pumping blood continue to limit their long-term use. Among the most troublesome has been the persistent risk of clot formation at the blood-device interface, which generally requires VAD recipients to undergo costly — and potentially dangerous — anticoagulation therapy for the duration of the implant. Another serious and persistent problem with long-term use of these pumps is the increased risk of infection associated with the use of percutaneous drivelines. To address these issues we are currently exploring a new approach to blood pump design that aims to solve both these problems by avoiding them altogether. Toward that end, we propose to harness the body’s own endogenous energy stores in order to eliminate the need to transmit energy across the skin. Further, we intend to transfer the energy from this internal power source to the circulation without contacting the blood to obviate the thrombogenic risks imposed by devices placed directly into the bloodstream. To power the implant we will employ a device developed previously by our group called a muscle energy converter (MEC), shown in Figure 1. The MEC is, in essence, an implantable hydraulic actuator powered by the latissimus dorsi (LD) muscle with the capacity to transmit up to 1.37 joules of contractile work per stroke [1]. By training the muscle to express fatigue-resistant oxidative fibers and stimulating the LD to contract in coordination with the cardiac cycle, the MEC captures and transmits this contractile energy as a high-pressure low-volume (5 cc) hydraulic pulse that can be used, in principle, to actuate an implanted pulsatile blood pump. The goal of this research is to use the low-volume output of the MEC to drive a polymer-based aortic compression device for long-term circulatory support. In this context it is important to note that the idea of applying a counterpulsation device around the ascending aorta is not new. Indeed, this approach has been validated by clinical trials recently completed by Sunshine Heart Inc. showing that displacing 20 cc of blood at the aortic root has significant therapeutic benefits [2]. Unfortunately, while the pneumatic ‘C-Pulse’ device solves the blood-contacting problem, it suffers from the same limitations as traditional VADs — i.e., driveline infections. The device described here achieves the same volumetric displacement as the SSH device via geometric amplification of MEC outputs. Thus, through this mechanism we believe the low-volume power output of the MEC can be used to support heart failure patients while addressing the major limitations associated with long-term VAD use.

Electrospinning is an efficient process for the fabrication of microvascular tissue engineering scaffolds. It has recently become evident that platelets can facilitate microvascular network growth by acting as a bridging cell between neighboring endothelial cells. However, if platelet thrombotic activities are enhanced through direct/indirect contact with the scaffolds, microvascular network growth is hindered. Thus, the objective of this work was to determine the effect of electrospun scaffold fiber alignment on platelet functions, to determine whether or not these scaffolds are suitable for accelerated microvascular tissue engineering applications. We hypothesized that these scaffolds would not elicit platelet responses. Electrospun scaffolds were fabricated from combinations of cellulose acetate, chitosan and/or poly-caprolactone, using traditional and rotating cylinder electrospinning. A time course for platelet activation, adhesion potential and aggregation was obtained for up to 4 hours after incubation with scaffolds. Imaging flow cytometry and optical platelet aggregometry, antagonized with the thrombin receptor antagonist or collagen, were used to analyze platelet functional changes. Our results show that in general, all of these scaffolds are compatible with platelets; they do not enhance platelet activation, adhesion or aggregation responses, as compared to platelet samples not exposed to scaffold. Scaffold alignment did not alter platelet functions, except for some formulations consisting of PCL. The duration of incubation with scaffolds also did not alter platelet responses. These data suggest that these novel aligned or random scaffolds can be used in microvascular tissue engineering applications. Thanks to the NIH.