This proposal seeks to address Focus Area #1 of the Request for Project Proposals MTEC-19-10-MID-PIP by processing and characterizing a point-of-care microneedle device to detect the presence of microbial infection. are painless as well as easy to attach to the skin. Three multiplexed lateral flow assays, which will be used to detect four biomarkers each, will be connected to three microneedles for real-time monitoring of an individual������������������s physiological status. The microneedle device will assess ����������������active microbial infection��������������� status by examining levels of interleukin-6, procalcitonin, C-reactive protein. Streptococcus pneumoniae, group A Streptococcus, Campylobacter, Escherichia coli, Candida albicans enolase, influenza A, influenza B, norovirus, and respiratory syncytial virus in the interstitial fluid. Lateral flow assays benefit from requiring no power source and exhibit stability for extended periods of time at ambient temperatures. The multiplexed lateral flow assays will provide results between 5 minutes and 30 minutes. Information obtained from the device would be used to determine the status of medical readiness of deployable and/or deployed warfighters.

Overview: Since the turn of this century, the inclusion of biological materials such as drugs, cells, cell aggregates, growth factors, and peptides into the feedstock materials for 3D printing has grown; this approach is known as bioprinting. Bioprinting is a multidisciplinary field that is faced with unique technical challenges. One challenge is that the bioprinting process must not damage the drugs, cells, and/or biological components in the "bioink" between placement of the bioink in the bioprinter and patterning of the bioink on the surface. Another challenge is that the patterning rates of conventional bioprinting technologies are too slow to create large three-dimensional cell-containing structures. Using 3D printing for small-scale manufacturing changes (e.g., process optimization) will make relatively small improvements to the functionality of medical products. On the other hand, radical 3D printing innovation will make large contributions to the functionality of medical products as well as significant improvements to the quality of life of those who require medical interventions. International collaborations through an IRES program are needed to drive radical innovation in 3D printing and bioprinting for medical applications. This IRES program contains three years of interrelated and multidisciplinary project activities, which take advantage of the unique facilities and expertise at the Pohang University of Science and Technology (POSTECH). A total of twenty undergraduate students and/or graduate students will spend 45 days in 2021 (Year 1), 2022 (Year 2), or 2023 (Year 3) under the research guidance of mentors at POSTECH. Each IRES student will be assigned a well-defined and independent research activity while at POSTECH. Each project is associated with two or more research project mentors; overall program coordination will be undertaken by the PI, who is based at NC State University, and Prof. Jinah Jang, who is based at POSTECH. POSTECH is an appropriate site for a program on 3D printing for medical applications since it offers students well-defined projects at the forefront of 3D printing; moreover, the participating university is distinguished by modern lab equipment and highly motivated research project mentors. The mentors in this program are leading convergent research efforts that involve biology, materials science, and physics to drive radical 3D printing innovation. The involvement of US undergraduate and graduate students in radical 3D printing innovation activities at POSTECH will provide added value to the projects as well as unique training and professional development opportunities for the US students. Intellectual Merit: The IRES program hopes to build collaborations between US students and the burgeoning South Korean medical 3D printing community. The IRES program will contribute to the development of a globally competitive scientific workforce by training undergraduate students and graduate students in practical skills that are relevant for interaction with the global medical device industry. We envision several positive outcomes from this program, including (1) the development of international as well as local career opportunities for the participating students and (2) the recruitment of students from underrepresented groups. The training provided by the IRES program will enable the participants to continue research collaborations with POSTECH researchers or develop independent research activities after returning to their home institutions. Broader Impacts: Slides and videos containing research results from the IRES program will be prepared by the IRES students at the conclusion of their activities at POSTECH. Data from the IRES program will be made available to the general public through publications in traditional peer-reviewed scientific journals. Efforts by the PI, Prof. Desai, and the POSTECH researchers to develop the IRES program will be described in manuscripts that will be submitted to Advances in Engineering Education as well as other relevant peer-reviewed engineering e

Conventional leishmaniasis treatments (e.g., administration of sodium stibogluconate or amphotericin B) are associated with several shortcomings, such as repeated dosing, long treatment times, and toxicity. Other shortcomings include unpredictable therapeutic responses, high cost, poor compliance, and pain. Previous efforts involving fiber optic microneedles have not considered (a) modulation of microneedle height and microneedle spacing or (b) combining light therapy and pharmacotherapy in a single multimodal microdevice. Novel low cost anti-leishmanial treatments are needed to overcome these shortcomings. We propose the use of microscale needle-shaped devices, which will be referred to as microneedles, for transdermal treatment of cutaneous leishmaniasis. These devices will be used to generate pores in the topmost 15 ���������m-thick stratum corneum layer of the skin. By physically disrupting the stratum corneum layer and bringing light in proximity to infectious organisms, a fiber optic-enabled microneedle device can provide light therapy for cutaneous leishmaniasis; this approach can be used in concert with pharmacotherapy to achieve a more effective ����������������multimodal��������������� treatment of cutaneous leishmaniasis.

The goals of this project include: (a) markedly reducing the processing time without altering the structural features of the active molecular species viral particles in the vaccine or the long-term stability of the vaccine , (b) demonstrating room temperature stability of the vaccine for one year, (c) demonstrating feasibility for low-cost filling production of injection devices with the dry vaccine, and (c) retaining the Critical Quality Attributes in the dry vaccine. If the project is successful, then the vaccine manufacturing industry will have a new processing approach that is suitable for creating vaccine dry product, which may be useful for processing production of many vaccines. The matrix assisted pulsed laser evaporation approach would be transformative for vaccine manufacturers in developing countries since the matrix assisted pulsed laser evaporation process instantly creates the dry product vaccine. The data obtained in this project will provide a new body of knowledge on the relationships between the matrix assisted pulsed laser evaporation processing parameters and the Critical Quality Attributes for a commonly used vaccine.

The development of new additive manufacturing/3D printing technologies has significantly impacted the medical device industry and substantial growth is predicted in this area. SmarTech Publishing estimated that the size of the global market for medical additive manufacturing was $3.0 billion at the end of 2018 and predicts strong growth in this industry over the next ten years, resulting in a total market size of $9.6 billion by 2027 [1,2]. 3D printing technologies allow ceramic devices to be prepared with more complex macroscale and microscale geometries than conventional methods. According to Smartech, the size of the ceramic 3D printing market will grow from $165 million in 2019 to $3.678 billion in 2028 [3]. Several companies, including Lithoz, 3D Ceram Sinto, 3D Systems, Admatec, ExOne, HP, Kwambio, Nanoe, Prodways, Tethon 3D, voxeljet, and Xjet, are distributing printers and materials that have potential use for photopolymerization-, extrusion-, or binder jetting-based 3D printing of ceramic medical devices. Over the past year, the PI has partnered with Lithoz and its Troy, NY-based subsidiary, Lithoz America, to understand the chemical, mechanical, and biological properties of 3D printed alumina, zirconia, and calcium phosphate parts. In order to more fully realize the promise of 3D printed ceramics in medicine and to aid CDRH in regulatory decision-making for devices manufactured using these novel technologies, we need to understand the effects of manufacturing on materials performance and biocompatibility. The overall goal of this project is to address additive manufacturing of ceramic medical devices with regards to the effects of the material properties on biological responses. Specifically, we will evaluate ceramic devices made with both inert and bioactive ceramics (e.g., zirconia/calcium phosphate composite) as well as devices made with controlled micro/nano porosity. In the proposed Scholar-in-Residence program, we will perform physico-chemical, mechanical, and vitro biological characterization of zirconia, calcium phosphate, and zirconia/calcium phosphate composites with controlled micro/nano porosity. These studies will allow us to understand the relationship between feedstock particle size, physico-chemical properties (e.g., porosity, composite adhesion), mechanical properties (e.g., fracture resistance), and biological responses of 3D printed ceramics. This program will involve a combination of graduate student and PI research activities at CDRH over a one-year period. The data obtained in this program will be relevant to the development of 3D printed ceramic medical devices and to the improvement of international consensus standards to assist in regulatory decision-making of these devices.

This proposal seeks to minimize the release of leachables from several classes of materials, including (a) polyvinylchloride bags (including dialysis bags and low volume parenteral bags), (b) cyclic olefin polymer syringes, and (c) nickel-titanium shape memory alloy (used in cardiovascular stents for vessel patency) by depositing hydrogenated diamond-like carbon coatings on the interior surfaces of these materials. Diamond-like carbon is an amorphous material that contains both sp2- and sp3- hybridized carbon atoms. The effect of hydrophilic amine and hydrophobic fluorine modification.

The research objective of the proposed GOALI program is to apply nanomanufacturing technologies based at NCSU (e.g., matrix assisted pulsed laser evaporation of water-insoluble drug coatings), manufacturing expertise based at Lynntech, and conventional drug delivery materials (e.g., itraconazole) to overcome limitations associated with transdermal itraconazole delivery for treatment of basal cell carcinoma. We will create proof of concept itraconazole-loaded microneedle arrays with appropriate chemical, biological, mechanical, and functional properties for transdermal treatment of basal cell carcinoma. We will collaborate with Lynntech to optimize the NCSU-based manufacturing technologies for commercialscale microneedle array production. The research plan contains three overlapping eight month phases, which will be conducted over a two year period.

COVID-19 in the US in the summer of 2020 represents a slowly-evolving national health emergency of a non- contained viral outbreak. Much energy is dedicated toward vaccine development. However, we have to realize that a highly effective vaccine will be unlikely anytime soon. Partially-effective vaccines will be more likely and they will have to be supported by other effective therapies such as antivirals. A promising antiviral, remdesivir, has to be injected, thus making it impractical to apply it to large numbers of early-infected COVID-19 patients who need to be home-sheltered to minimize/eliminate contact with others, especially medical personnel/infrastructure. Moreover, we have argued for early-onset lung barrier protection because alveolar lung edema is a powerful lethality factor in COVID-19, also for general endothelial barrier protection because SARS- CoV-2 directly infects and inflames vascular endothelia, an under-appreciated pathologic hallmark of COVID-19. To accomplish the goal of barrier protection, we advocate for inhibition of calcium-permeable TRPV4 ion channels, plus activation of barrier-regulating Tie2. Barrier protection together with inhibition of viral replication is a compelling preventive approach. A major obstacle to prevent clinical worsening is difficulty delivering the respective agents consistently, reliably and without jeopardizing the health of health care professionals. Remdesivir injections by healthcare providers of large numbers of early COVID-19 patients are not feasible, neither is self-injection by patients. For treatment with barrier-protective Tie2-activating compound AKB-9778, which went through phase-II clinical trials, this has to be injected 2x/d so that similar reservations apply as for remdesivir. The TRPV4-inhibiting GSK2798745 has been found safe in a limited number of patients with cardiogenic lung edema, and is available as tablet. However, it will be advantageous to co-inject it as part of an injection regimen that relies on more than one compound. Treatment with more than one compound has recently been found effective in more severely ill COVID-19 patients. We propose to combat COVID-19 and future coronavirus pandemics not with one transformative medicine (currently not-available), but with a multi-scale approach of add-on effectiveness, namely by using an antiviral and lung barrier- and endothelial barrier-protective agents. As we have argued, this approach has a chance to amplify effectiveness of a moderately helpful vaccine which will be easier to develop than an ����������������all- sweep��������������� vaccine. To deliver the preventive compounds that the newly-diagnosed COVID-19 patient can do by her/himself while home-sheltered, we propose to fabricate dermal-insertion patches centered around hollow microneedle-based delivery systems so that compounds can be injected directly into patients������������������ skin for systemic delivery. Compounds to be delivered, over an intended 30-day period, will be remdesivir (750mg/total), AKB-9778 (150mg/total), and GSK2798745 (120mg/total). Here we propose to -fabricate acrylate-based hollow microneedles for delivery of a triple drug combination to prevent COVID-19 deterioration -test their biomechanical, pharmacokinetic and pharmacotoxic properties in rat, pigs and artificial human skin Continuous infusion from the microneedle-patch system to skin, intended for daily use and daily renewed application, will be accomplished by engineering hollow microneedle-arrays connected to a membrane-based actuator for controlled fluid release.

One of the current goals at the National Aeronautics and Space Administration is to return astronauts to the moon by the year 2020. An extended human presence on the moon will be needed in order to harvest helium-3 and mine mineral resources. The moon will also be used as a launching pad for missions to Mars and other planets. Estimates of ionizing radiation exposure to astronauts during these extended missions will exceed the limits that have been previously set for low earth orbit missions. Two sources of ionizing radiation risk are galactic cosmic rays and solar particle events. Solar particle events are brief; however, galactic cosmic rays are prevalent and are of particular concern for space missions of greater than three months in length. Shielding materials may be used to protect crew members while they are within spacecraft; however, it is difficult to incorporate shielding into suits used by astronauts who are performing extravehicle activities. Reactive oxygen species, including hydrogen peroxide, hydroxyl radicals, and superoxide anions, may be generated during exposure to ionizing radiation. We hypothesize that hermetically sealing 3D printed polymers with ceramic coatings will improve the biocompatibility of these materials. In this program, we will subject the ceramic-coated and uncoated 3D printed polymers to gamma irradiation. The uncoated and coated samples will be subjected to the chemical, physical, mechanical, and in vitro biological characterization; comparisons between the results from the uncoated and coated samples will be made.

Services for the rapid and reliable testing of TissueFab��������� Conductive bioink, Vis/405 nm and TissueFab��������� Facile curable bioink.