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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 361 records · Page 20
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

The novel Mechanical Ventilator Milano for the COVID-19 pandemic

This paper presents the Mechanical Ventilator Milano (MVM), a novel intensive therapy mechanical ventilator designed for rapid, large-scale, low-cost production for the COVID-19 pandemic. Free of moving mechanical parts and requiring only a source of compressed oxygen and medical air to operate, the MVM is designed to support the long-term invasive ventilation often required for COVID-19 patients and operates in pressure-regulated ventilation modes, which minimize the risk of furthering lung trauma. The MVM was extensively tested against ISO standards in the laboratory using a breathing simulator, with good agreement between input and measured breathing parameters and performing correctly in response to fault conditions and stability tests. The MVM has obtained Emergency Use Authorization by U.S. Food and Drug Administration (FDA) for use in healthcare settings during the COVID-19 pandemic and Health Canada Medical Device Authorization for Importation or Sale, under Interim Order for Use in Relation to COVID-19. Furthermore, following these certifications, mass production is ongoing and distribution is under way in several countries. The MVM was designed, tested, prepared for certification, and mass produced in the space of a few months by a unique collaboration of respiratory healthcare professionals and experimental physicists, working with industrial partners, and is an excellent ventilator candidate for this pandemic anywhere in the world

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M pro ) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC 50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for M pro -ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M pro . Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.

99 GENERAL AND MISCELLANEOUS↗
DOE OSTI2021

CarcSeq Measurement of Rat Mammary Cancer Driver Mutations and Relation to Spontaneous Mammary Neoplasia

Abstract The ability to deduce carcinogenic potential from subchronic, repeat dose rodent studies would constitute a major advance in chemical safety assessment and drug development. This study investigated an error-corrected NGS method (CarcSeq) for quantifying cancer driver mutations (CDMs) and deriving a metric of clonal expansion predictive of future neoplastic potential. CarcSeq was designed to interrogate subsets of amplicons encompassing hotspot CDMs applicable to a variety of cancers. Previously, normal human breast DNA was analyzed by CarcSeq and metrics based on mammary-specific CDMs were correlated with tissue donor age, a surrogate of breast cancer risk. Here we report development of parallel methodologies for rat. The utility of the rat CarcSeq method for predicting neoplastic potential was investigated by analyzing mammary tissue of 16-week-old untreated rats with known differences in spontaneous mammary neoplasia (Fischer 344, Wistar Han, and Sprague Dawley). Hundreds of mutants with mutant fractions ≥ 10−4 were quantified in each strain, most were recurrent mutations, and 42.5% of the nonsynonymous mutations have human homologs. Mutants in the mammary-specific target of the most tumor-sensitive strain (Sprague Dawley) showed the greatest nonsynonymous/synonymous mutation ratio, indicative of positive selection consistent with clonal expansion. For the mammary-specific target (Hras, Pik3ca, and Tp53 amplicons), median absolute deviation correlated with percentages of rats that develop spontaneous mammary neoplasia at 104 weeks (Pearson r = 1.0000, 1-tailed p = .0010). Therefore, this study produced evidence CarcSeq analysis of spontaneously occurring CDMs can be used to derive an early metric of clonal expansion relatable to long-term neoplastic outcome.

McKim, Karen L.↗
DOE OSTI2023

Investigation of microorganisms in cannabis after heating in a commercial vaporizer

There are concerns about microorganisms present on cannabis materials used in clinical settings by individuals whose health status is already compromised and are likely more susceptible to opportunistic infections from microbial populations present on the materials. Most concerning is administration by inhalation where cannabis plant material is heated in a vaporizer, aerosolized, and inhaled to receive the bioactive ingredients. Heating to high temperatures is known to kill microorganisms including bacteria and fungi; however, microbial death is dependent upon exposure time and temperature. It is unknown whether the heating of cannabis at temperatures and times designated by a commercial vaporizer utilized in clinical settings will significantly decrease the microbial loads in cannabis plant material. To assess this question, bulk cannabis plant material supplied by National Institute on Drug Abuse (NIDA) was used to assess the impact of heating by a commercial vaporizer. Initial method development studies using a cannabis placebo spiked with Escherichia coli were performed to optimize culture and recovery parameters. Subsequent studies were carried out using the cannabis placebo, low delta-9 tetrahydrocannabinol (THC) potency and high THC potency cannabis materials exposed to either no heat or heating for 30 or 70 seconds at 190°C. Phosphate-buffered saline was added to the samples and the samples agitated to suspend the microorganism. Microbial growth after no heat or heating was evaluated by plating on growth media and determining the total aerobic microbial counts and total yeast and mold counts. Overall, while there were trends of reductions in microbial counts with heating, these reductions were not statistically significant, indicating that heating using standard vaporization parameters of 70 seconds at 190°C may not eliminate the existing microbial bioburden, including any opportunistic pathogens. When cultured organisms were identified by DNA sequence analyses, several fungal and bacterial taxa were detected in the different products that have been associated with opportunistic infections or allergic reactions including Enterobacteriaceae, Staphylococcus, Pseudomonas, and Aspergillus.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1998

Prognostic significance of electrical alternans versus signal averaged electrocardiography in predicting the outcome of electrophysiological testing and arrhythmia-free survival

OBJECTIVE: To investigate the accuracy of signal averaged electrocardiography (SAECG) and measurement of microvolt level T wave alternans as predictors of susceptibility to ventricular arrhythmias. DESIGN: Analysis of new data from a previously published prospective investigation. SETTING: Electrophysiology laboratory of a major referral hospital. PATIENTS AND INTERVENTIONS: 43 patients, not on class I or class III antiarrhythmic drug treatment, undergoing invasive electrophysiological testing had SAECG and T wave alternans measurements. The SAECG was considered positive in the presence of one (SAECG-I) or two (SAECG-II) of three standard criteria. T wave alternans was considered positive if the alternans ratio exceeded 3.0. MAIN OUTCOME MEASURES: Inducibility of sustained ventricular tachycardia or fibrillation during electrophysiological testing, and 20 month arrhythmia-free survival. RESULTS: The accuracy of T wave alternans in predicting the outcome of electrophysiological testing was 84% (p < 0.0001). Neither SAECG-I (accuracy 60%; p < 0.29) nor SAECG-II (accuracy 71%; p < 0.10) was a statistically significant predictor of electrophysiological testing. SAECG, T wave alternans, electrophysiological testing, and follow up data were available in 36 patients while not on class I or III antiarrhythmic agents. The accuracy of T wave alternans in predicting the outcome of arrhythmia-free survival was 86% (p < 0.030). Neither SAECG-I (accuracy 65%; p < 0.21) nor SAECG-II (accuracy 71%; p < 0.48) was a statistically significant predictor of arrhythmia-free survival. CONCLUSIONS: T wave alternans was a highly significant predictor of the outcome of electrophysiological testing and arrhythmia-free survival, while SAECG was not a statistically significant predictor. Although these results need to be confirmed in prospective clinical studies, they suggest that T wave alternans may serve as a non-invasive probe for screening high risk populations for malignant ventricular arrhythmias.

Non-NASA Center↗
DOE OSTI2021

Selective Photoswitchable Allosteric Agonist of a G Protein-Coupled Receptor

G protein-coupled receptors (GPCRs) are the most common targets of drug discovery. However, the similarity between related GPCRs combined with the complex spatiotemporal dynamics of receptor activation in vivo has hindered drug development. Photopharmacology offers the possibility of using light to control the location and timing of drug action by incorporating a photoisomerizable azobenzene into a GPCR ligand, enabling rapid and reversible switching between an inactive and active configuration. Recent advances in this area include (i) photoagonists and photoantagonists that directly control receptor activity but are nonselective because they bind conserved sites, and (ii) photoallosteric modulators that bind selectively to nonconserved sites but indirectly control receptor activity by modulating the response to endogenous ligand. In this study, we designed a photoswitchable allosteric agonist that targets a nonconserved allosteric site for selectivity and activates the receptor on its own to provide direct control. This work culminated in the development of aBINA, a photoswitchable allosteric agonist that selectively activates the G i/o -coupled metabotropic glutamate receptor 2 (mGluR2). aBINA is the first example of a new class of precision drugs for GPCRs and other clinically important signaling proteins.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS2007

The Use of Heavy Ion Radiation as an Analog for Space Radiation Environment and Its Effects on Drug Stability

While it is common knowledge that electromagnetic radiation such as x-rays and gamma rays affect physical-chemical characteristics (PC) of compounds in addition to their toxic and mutagenic effects on biological systems, there are no reports on the effects of cosmic radiation encountered during space missions on stability of pharmaceuticals. Alterations in PC of drug formulations can adversely affect treatment with medications in space. Preliminary evaluation of stability and shelf-life of select pharmaceuticals (12) flown on space missions revealed that 37% and 40% of the formulations failed to meet USP requirements after shuttle and ISS flights, respectively. Based on these results, the current investigation is designed to examine the effect of proton (P) and heavy ion (Fe) radiation on 20 pharmaceutical preparations flown aboard the shuttle and ISS. The objectives of this project are: 1) Examine susceptibility of pharmaceuticals to short acute bouts of high intensity ionizing radiation species encountered during space flights; 2) Estimate extent of degradation of susceptible formulations as a function of intensity of each beam (P & Fe); and 3) compare and contrast the effects of single beam irradiation to that of a combined beam (P + Fe) that simulates space craft environment on drug stability. Irradiations were conducted at the Brookhaven National Laboratories (BNL) with beam strengths of 10 cGy, 10 or 50Gy of P and Fe beams separately. Preliminary evaluation of results revealed a reduction in the chemical content of label claim ranging 12-55 % for Augmentin, 7% for promethzine tablets and 9% for ciprofloxacin ointment. These results are in agreement, although less in magnitude than those observed during space flight and after gamma irradiation.

Vaksman, Z.↗
NASA NTRS2017

The Pathway to a Safe and Effective Medication Formulary for Exploration Spaceflight

PURPOSE: Exploration space missions pose several challenges to providing a comprehensive medication formulary designed to accommodate the size and space limitations of the spacecraft; while addressing the individual medications needs and preferences of the Crew; the negative outcome of a degrading inventory over time, the inability to resupply before expiration dates; and the need to properly forecast the best possible medication candidates to treat conditions that will occur in the future. METHODS: The Pharmacotherapeutics Discipline has partnered with the Exploration Medical Capabilities (ExMC) Element to develop and propose a research pathway that is comprehensively focused on evidence-based models and theories, as well as on new diagnostic tools and treatments or preventive measures aimed at closure of the Med02 “Pharmacy” Gap; defined in the Human Research Program’s (HRP) risk-based research strategy. The Med02 Gap promotes the challenge to identify a strategy to ensure that medications used to treat medical conditions during exploration space missions are available, safe, and effective. It is abundantly clear that pharmaceutical intervention is an essential component of risk management planning for astronaut healthcare during exploration space. However, the quandary still remains of how to assemble a formulary that is comprehensive enough to prevent or treat anticipated medical events; and is also chemically stable, safe, and robust enough to have sufficient potency to last for the duration of an exploration space mission. In cases where that is not possible, addressing this Gap requires exploration of novel drug development techniques, dosage forms, and dosage delivery platforms that enhance chemical stability as well as therapeutic effectiveness. RESULTS: The proposed research pathway outlines the steps, processes, procedures, and a research portfolio aimed at identifying a capability that will provide a safe and effective pharmacy for any specific exploration Design Reference Mission (DRM). The proposed approach to building this research portfolio is to seek research projects that concentrate on four major focus areas; (1) Formulary selection, (2) Formulary potency and shelf life, (3) Formulary safety and toxicity, and (4) Novel technology and innovation such as portable real-time chemical analysis innovative drug therapies and dosage and delivery platforms. CONCLUSION: The research pathway has been completed and presented to the HRP. In spring 2017, it is scheduled to be reviewed by a panel of pharmaceutical and clinical experts that will evaluate the scientific merit and operational feasibility of the research pathway, as well as make suggestions for any warranted additions or improvements. Once finalized, the ExMC Element will proceed with the execution of this research pathway with the goal of gathering as much data, and learning as much as possible, to provide a safe and effective pharmaceutical formulary for use during exploration missions.

Daniels, V. R.↗
DOE OSTI2021

Detection of significant antiviral drug effects on COVID-19 with reasonable sample sizes in randomized controlled trials: A modeling study

Development of an effective antiviral drug for Coronavirus Disease 2019 (COVID-19) is a global health priority. Although several candidate drugs have been identified through in vitro and in vivo models, consistent and compelling evidence from clinical studies is limited. The lack of evidence from clinical trials may stem in part from the imperfect design of the trials. We investigated how clinical trials for antivirals need to be designed, especially focusing on the sample size in randomized controlled trials. A modeling study was conducted to help understand the reasons behind inconsistent clinical trial findings and to design better clinical trials. We first analyzed longitudinal viral load data for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) without antiviral treatment by use of a within-host virus dynamics model. The fitted viral load was categorized into 3 different groups by a clustering approach. Comparison of the estimated parameters showed that the 3 distinct groups were characterized by different virus decay rates (p-value < 0.001). The mean decay rates were 1.17 d -1 (95% CI: 1.06 to 1.27 d -1 ), 0.777 d -1 (0.716 to 0.838 d -1 ), and 0.450 d -1 (0.378 to 0.522 d -1 ) for the 3 groups, respectively. Such heterogeneity in virus dynamics could be a confounding variable if it is associated with treatment allocation in compassionate use programs (i.e., observational studies). Subsequently, we mimicked randomized controlled trials of antivirals by simulation. An antiviral effect causing a 95% to 99% reduction in viral replication was added to the model. To be realistic, we assumed that randomization and treatment are initiated with some time lag after symptom onset. Using the duration of virus shedding as an outcome, the sample size to detect a statistically significant mean difference between the treatment and placebo groups (1:1 allocation) was 13,603 and 11,670 (when the antiviral effect was 95% and 99%, respectively) per group if all patients are enrolled regardless of timing of randomization. The sample size was reduced to 584 and 458 (when the antiviral effect was 95% and 99%, respectively) if only patients who are treated within 1 day of symptom onset are enrolled. We confirmed the sample size was similarly reduced when using cumulative viral load in log scale as an outcome. We used a conventional virus dynamics model, which may not fully reflect the detailed mechanisms of viral dynamics of SARS-CoV-2. The model needs to be calibrated in terms of both parameter settings and model structure, which would yield more reliable sample size calculation. In this study, we found that estimated association in observational studies can be biased due to large heterogeneity in viral dynamics among infected individuals, and statistically significant effect in randomized controlled trials may be difficult to be detected due to small sample size. The sample size can be dramatically reduced by recruiting patients immediately after developing symptoms. We believe this is the first study investigated the study design of clinical trials for antiviral treatment using the viral dynamics model.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

A Review of Polymeric Nanoparticle Design, Synthesis, and Biomedical Applications

Polymeric nanoparticles (PNPs) are solid particles that contain macromolecular polymers ranging in size from 1-1000 nm. They have a wide variety of structures that are determined by their identity as either natural biopolymers, synthetic polymers or a combination of both. In the design of PNPs, the polymeric system, size, internal structure, additional molecules, and synthetic pathway can be engineered, allowing for a multitude of properties including differing responses to physiological environments and the incorporation of a drug. The easily accessible fine tuning of PNPs allows for a multitude of applications in medicine. PNPs allow for increased pharmacokinetics, efficacy, safety, and targeting strength when utilized as carriers for drugs. Currently there are a wide range of PNPs approved by the Food and Drug Administration for use in clinical settings and many more being investigated in clinical studies. There is also research that is being conducted for the usage of PNPs in controlled drug delivery systems and as carriers through the blood brain barrier to aid in treating neurological diseases.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1998

Taxane recovery from cells of Taxus in micro- and hypergravity

Cell suspension cultures of Taxus cuspidata produce taxanes that are released from the outer surface of cells into the culture medium as free and bound alkaloids. Paclitaxel (Taxol (TM)), is an anti-cancer drug in short supply. It has a taxane ring derived from baccatin III and a C-13 phenylisoserine side-chain. This drug is produced over a wide range of gravitational forces. Monoclonal and polyclonal antibodies to paclitaxel, baccatin III, and the C-13 phenylisoserine side chain were combined in multiple-labeling studies to localize taxanes and paclitaxel on cell surfaces or on particles released into the culture medium. Bioreactor vessel design altered the composition of taxanes recovered from cells in simulated microgravity. At 10(-2) and 2x10(-4)g, taxane recovery was reduced but biomass growth and percent paclitaxel was significantly increased. At 1 to 24g, growth was reduced with a significant recovery of total taxanes with low percent paclitaxel. Bound paclitaxel was also localized in endonuclease-rich fragmenting nuclei of individual apoptotic cells. A model is presented comprising TCH (touch) genes encoding enzymes that modify taxane-bearing xylan residues in cell walls, the calcium-sensing of gravitational forces by the cytoplasm, and the predisposition of nuclei to apoptosis. This integrates the adaptive physiological and biochemical responses of drug-producing genomes with gravitational forces.

Plants, Medicinal/chemistry/cytology↗
DOE OSTI2026

A Prodrug Strategy to Conditionally Trap Therapeutic Payloads for Improved Tumor Retention

Altered extracellular proteolysis has been exploited to selectively activate therapeutics in diseases such as cancer; however, once activated, extracellular drugs can diffuse away, limiting efficacy. We address this challenge by coupling proteolytic activation with membrane tethering to retain drugs within diseased tissue. To accomplish this, we developed “restricted interaction peptides” (RIPs), a delivery platform that leverages elevated proteolytic activity to activate membrane-interacting peptides, localizing cargos near the site of proteolysis. We demonstrate that RIPs can deliver diverse therapeutic cargos, including cytotoxins and radioisotopes. As proof of concept, we engineered “FRIP,” a RIP designed for cleavage by fibroblast activation protein (FAP), an endoprotease upregulated in solid tumors and fibrosis. Efficient P4–P4’ substrate sequences were identified and incorporated into FRIPs. Cell-based studies showed that, upon activation, the peptide adhered to membranes rapidly internalized and successfully delivered therapeutic cargos. Consistent with this, FRIPs delivering MMAE inhibited proliferation in an FAP-dependent manner. Imaging studies confirmed tumor targeting with minimal uptake in normal tissues. Finally, FRIPs delivering MMAE or Cu-67 exhibited potent antitumor effects. These findings establish membrane tethering as a strategy to enhance drug retention.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Computational Prediction of Coiled–Coil Protein Gelation Dynamics and Structure

Protein hydrogels represent an important and growing biomaterial for a multitude of applications, including diagnostics and drug delivery. We have previously explored the ability to engineer the thermoresponsive supramolecular assembly of coiled–coil proteins into hydrogels with varying gelation properties, where we have defined important parameters in the coiled–coil hydrogel design. Using Rosetta energy scores and Poisson–Boltzmann electrostatic energies, we iterate a computational design strategy to predict the gelation of coiled–coil proteins while simultaneously exploring five new coiled–coil protein hydrogel sequences. Provided this library, we explore the impact of in silico energies on structure and gelation kinetics, where we also reveal a range of blue autofluorescence that enables hydrogel disassembly and recovery. As a result of this library, we identify the new coiled–coil hydrogel sequence, Q5, capable of gelation within 24 h at 4 °C, a more than 2-fold increase over that of our previous iteration Q2. The fast gelation time of Q5 enables the assessment of structural transition in real time using small-angle X-ray scattering (SAXS) that is correlated to coarse-grained and atomistic molecular dynamics simulations revealing the supramolecular assembling behavior of coiled–coils toward nanofiber assembly and gelation. This work represents the first system of hydrogels with predictable self-assembly, autofluorescent capability, and a molecular model of coiled–coil fiber formation.

36 MATERIALS SCIENCE↗
DOE OSTI2025

Knowledge graph-aided Bayesian active learning for top- K genetic interaction discovery

In silico methods for predicting the effects of multi-gene perturbations hold great promise for advancing functional genomics, computational drug discovery, and disease modeling. However, the development of these predictive algorithms for mammalian systems has been hampered by limited datasets and high experimental costs. In this study, we present a Bayesian active learning framework designed to discover pairwise host gene knockdowns that effectively inhibit viral proliferation in an in vitro HIV-1 infection model. Our method leverages a biological knowledge graph as side information and employs a computationally efficient batch diversification approach. We evaluated this framework using a dataset of viral load measurements obtained from multi-day dual-gene depletion experiments, encompassing all possible pairwise knockdowns of over 350 host genes associated with HIV infection. We demonstrate that our framework rapidly identifies the most effective gene knockdown pairs for reducing viral load. Furthermore, we show that incorporating side information enhances performance during the early stages of active learning (low data regime), while our batch diversification strategy significantly boosts performance in later stages (high data regime). This framework is general and can be adapted to explore gene interactions in other contexts, such as synthetic lethality prediction and mapping epistatic effects across quantitative trait loci.

Computational biology and bioinformatics↗
NASA NTRS1997

Development of an Antimicrobial Susceptibility Testing Method Suitable for Performing During Space Flight

Very little is known regarding the affects of the microgravity environment of space flight upon the action of antimicrobial agents on bacterial pathogens. This study was undertaken to develop a simple method for conducting antibacterial susceptibility tests during a Space Shuttle mission. Specially prepared susceptibility test research cards (bioMerieux Vitek, Hazelwood, MO) were designed to include 6-11 serial two-fold dilutions of 14 antimicrobial agents, including penicillins, cephalosporins, a Beta-lactamase inhibitor, vancomycin, erythromycin, tetracycline, gentamicin, ciprofloxacin, and trimethoprim/sulfamethoxazole. Minimal inhibitory concentrations (MICS) of the drugs were determined by visual reading of color endpoints in the Vitek research cards made possible by incorporation of a colorimetric growth indicator (alamarBlue(Trademark), Accumed International, Westlake, OH). This study has demonstrated reproducible susceptibility results when testing isolates of Staphylococcus aurezis, Group A Streptococcus, Enterococcusfaecalis, Escherichia coli (beta-lactamase positive and negative strains), Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomoiias aeruginosa. In some instances, the MICs were comparable to those determined using a standard broth microdilution method, while in some cases the unique test media and format yielded slightly different values, that were themselves reproducible. The proposed in-flight experiment will include inoculation of the Vitek cards on the ground prior to launch of the Space Shuttle, storage of inoculated cards at refrigeration temperature aboard the Space Shuttle until experiment initiation, then incubation of the cards for 18-48 h prior to visual interpretation of MICs by the mission's astronauts. Ground-based studies have shown reproducible MICs following storage of inoculated cards for 7 days at 4-8 C to accommodate the mission's time schedule and the astronauts' activities. For comparison, ground-based control (normal gravity) MIC values will be generated by simultaneous inoculation and incubation of a second set of test cards in a laboratory at the launch site. This procedure can provide a safe and compact experiment that should yield new information on the affects of microgravity on the biological activities of various classes of antibiotics.

Jorgensen, James H.↗
NASA NTRS2004

Structural Evaluation of Radially Expandable Cardiovascular Stents Encased in a Polyurethane Film

A method of encasing cardiovascular stents with an expandable polyurethane coating has been developed to provide a smooth homogeneous inner wall allowing for a confluent growth of endothelial cells. In this design, the metal wire stent structure is completely covered by the polyurethane film minimizing biocorrosion of the metal (stainless steel or nitinol), and providing a homogeneous surface for surface treatment and incorporation of various eluting drugs to prevent platelet aggregation while supporting endothelialization. The polyurethane surface was treated with a helium plasma for sterilization and promotes growth of cells. The paper details the performance of the coated film to expand with the metal stent up to 225 % during deployment. We present stress/strain behavior of polyurethane films, and subsequent plasma treatment of the surface and the adhesion of the coating to the stent structure upon expansion. A film of less than 25 tm was found to be sufficient for corrosion resistance and flexibility without producing any excess stress on the stent structure. Straining the film to 225 % and plasma modification did not affect the mechanical and surface properties while allowing for improved biocompatibility as determined by the critical surface tension, surface chemistry, and roughness.

Trigwell, Steve↗
DOE OSTI2020

A Systematic Assessment of US Food and Drug Administration Dosing Recommendations For Drug Development Programs Amenable to Response‐Guided Titration

A key goal in drug development is optimized dosing for patients. Interactions between drug developers and regulatory scientists throughout development are important for the optimization of dosing and serve as a forum to discuss approaches for optimal dosing, such as precision or individualized dosing. To date, there has not been a systematic assessment of the advice provided by the US Food and Drug Administration (FDA) to drug developers from an individualized dosing perspective. Here, we reviewed FDA recommendations on dose selection for efficacy trials at end‐of‐phase meetings between the FDA and drug developers for 76 new molecular entities approved between 2013 and 2017 that are considered amenable for an individualized dosing method, response‐guided titration. Forty FDA dosing recommendations were identified as specific to dose selection and design of the respective efficacy trials and subsequently: (i) characterized based on if they were supportive of individualized dosing and (ii) compared with dosing regimens used in efficacy trials and labeling at approval to evaluate if FDA recommendations were implemented. Of these 40 recommendations for efficacy trials, 35 (88%) were considered supportive of individualized dosing. Eighteen of these 40 recommendations (45%) were incorporated into efficacy trials and 11 (28%) were incorporated into labeling. This research suggests that early FDA‐sponsor interactions can support the study of doses in efficacy trials that may lead to individualized dosing strategies in labeling.

Wang, Lingshan↗