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All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Neutron Radiography and Computed Tomography of Biological Systems at the Oak Ridge National Laboratory's High Flux Isotope Reactor

Neutrons have historically been used for a broad range of biological applications employing techniques such as small-angle neutron scattering, neutron spin echo, diffraction, and inelastic scattering. Unlike neutron scattering techniques that obtain information in reciprocal space, attenuation-based neutron imaging measures a signal in real space that is resolved on the order of tens of micrometers. The principle of neutron imaging follows the Beer-Lambert law and is based on the measurement of the bulk neutron attenuation through a sample. Greater attenuation is exhibited by some light elements (most notably, hydrogen), which are major components of biological samples. Contrast agents such as deuterium, gadolinium, or lithium compounds can be used to enhance contrast in a similar fashion as it is done in medical imaging, including techniques such as optical imaging, magnetic resonance imaging, X-ray, and positron emission tomography. For biological systems, neutron radiography and computed tomography have increasingly been used to investigate the complexity of the underground plant root network, its interaction with soils, and the dynamics of water flux in situ. Moreover, efforts to understand contrast details in animal samples, such as soft tissues and bones, have been explored. This manuscript focuses on the advances in neutron bioimaging such as sample preparation, instrumentation, data acquisition strategy, and data analysis using the High Flux Isotope Reactor CG-1D neutron imaging beamline. The aforementioned capabilities will be illustrated using a selection of examples in plant physiology (herbaceous plant/root/soil system) and biomedical applications (rat femur and mouse lung).

Bilheux, Hassina↗
DOE OSTI2023

A microCT-based platform to quantify drug targeting

Abstract Background Heterotopic ossification (HO) is a frequent and debilitating complication of traumatic musculoskeletal injuries and orthopedic procedures. Prophylactic dosing of botulinum toxin type A (BTxA) holds potential as a novel treatment option if accurately distributed throughout soft-tissue volumes where protection is clinically desired. We developed a high-resolution, microcomputed tomography (microCT)-based imaging strategy to assess drug distribution and validated this platform by quantifying distribution achieved via a prototype delivery system versus a single-bolus injection. Methods We injected an iodine-containing contrast agent (iodixanol 320 mg I/mL) into dissected rabbit musculature followed by microCT imaging and analysis. To contrast the performance of distributed versus bolus injections, a three-dimensional (3D) 64-cm 3 -printed soft-tissue holder was developed. A centered 2-cm 3 volume of interest (VOI) was targeted with a single-bolus injection or an equal volume distributed injection delivered via a 3D-printed prototype. VOI drug coverage was quantified as a percentage of the VOI volume that was < 1.0 mm from the injected fluid. Results The microCT-based approach enabled high-resolution quantification of injection distribution within soft tissue. The distributed dosing prototype provided significantly greater tissue coverage of the targeted VOI (72 ± 3%, mean ± standard deviation) when compared to an equal volume bolus dose (43 ± 5%, p = 0.031) while also enhancing the precision of injection targeting. Conclusions A microCT-based imaging technique precisely quantifies drug distribution within a soft-tissue VOI, providing a path to overcome a barrier for clinical translation of prophylactic inhibition of HO by BTxA. Relevance statement This platform will facilitate rapid optimization of injection parameters for clinical devices used to effectively and safely inhibit the formation of heterotopic ossification. Key points • MicroCT provides high-resolution quantification of soft-tissue drug distribution. • Distributed dosing is required to maximize soft-tissue drug coverage. • Imaging platform will enable rapid screening of 3D-printed drug distribution prototypes. Graphical Abstract

Ausk, Brandon J. (ORCID:0000000335338303)↗
DOE OSTI2022

Thermal and concentration effects on 1 H NMR relaxation of Gd 3+ -aqua using MD simulations and measurements

We report gadolinium-based contrast agents are key in clinical MRI for enhancing the longitudinal NMR relativity (r 1 ) of hydrogen nuclei ( 1 H) in water and improving the contrast among different tissues. The importance of MRI in clinical practice cannot be gainsaid, yet the interpretation of MRI relies on models with severe assumptions, reflecting a poor understanding of the molecular-scale relaxation processes. In a step towards building a clearer understanding of the relaxation processes, here we investigate thermal and concentration effects on r 1 of the Gd 3+ -aqua complex using both semi-classical molecular dynamics (MD) simulations and measurements. We follow the MD simulation approach recently introduced by [Singer et al., Phys. Chem. Chem. Phys., 2021, 23, 20974], in which no NMR relaxation model or free-parameter is assumed to predict r 1 , thereby bringing new insights into the physics of r 1 on a molecular scale. We expand the autocorrelation function G(t) in terms of molecular modes and determine the thermal activation energies of the two largest modes, both of which are consistent with the range of literature values for rotational diffusion. We also determine the activation energies for translational diffusion and low-field electron-spin relaxation, both of which are consistent with the literature. Furthermore, we validate the MD simulations at human body temperature and concentrations of the paramagnetic ion used in clinical MRI, and we quantify the uncertainties in both simulations and measurements.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Time-Resolved Neutron Imaging for Hydrogen Uptake in Subsurface Lithologies

Geologic hydrogen production and underground storage are increasingly important for meeting rising energy demands while providing clean-combustion advantages. However, hydrogen’s high diffusivity and propensity for leakage through porous media necessitate direct evaluation of its transport behavior in subsurface materials. Whereas X-ray microcomputed tomography (μCT) studies often employ contrast agents or surrogate gases, this study leverages neutron transmission radiography/CT to observe hydrogen migration in situ. This work represents the first demonstration of real-time neutron radiography of hydrogen migration in reservoir and caprock lithologies. Cylindrical cores of Indiana limestone, Amherst Gray sandstone, and Tumey shale were subjected to constant-pressure hydrogen charging and scanned in real time using high-resolution neutron radiography. Results indicate immediate hydrogen infiltration in sandstone and limestone, with homogeneous distribution detected throughout their pore structure. In contrast, hydrogen remained largely absent from fine-grained shale under the same pressure, except in an apparently localized fracture zone, where neutron signatures confirmed the presence of hydrogen. Subsequent neutron CT of the sandstone sample, using image subtraction against an uncharged reference, corroborated hydrogen distribution patterns. Even under lowpressure, single-phase conditions, distinct neutron imaging signatures of hydrogen were achieved. These preliminary findings underscore the potential of neutron imaging for advancing subsurface hydrogen migration research.

08 HYDROGEN↗
DOE OSTI2021

Alkali-silica reaction products and cracks: X-ray micro-tomography-based analysis of their spatial-temporal evolution at a mesoscale

In this study, we propose a laboratory-scale methodology, based on X-ray micro-tomography and caesium (Cs) as a contrast agent, to advance the understanding of cracking due to alkali-silica reaction (ASR) in concrete. The methodology allows achieving a completely non-destructive and time-lapse characterization of the spatial-temporal patterns of both the cracks and the ASR products. While Cs addition slightly accelerated the ASR kinetics, the crack patterns, with and without Cs addition, were statistically equivalent. Cracks with ASR products appeared first in the aggregates, close to the interface with the cement paste. They propagated afterwards towards the aggregates interior. Some products were then extruded for several mm into air voids and cracks in the cement paste. This process suggests that, in the early stage, the ASR products may be a low-viscosity gel that can flow away from the source aggregate and may settle later elsewhere as a rigid phase, upon calcium uptake.

36 MATERIALS SCIENCE↗
DOE OSTI2023

3D Visualization of Proteins within Metal–Organic Frameworks via Ferritin‐Enabled Electron Microscopy

Abstract Electron tomography holds great promise as a tool for investigating the 3D morphologies and internal structures of metal‐organic framework‐based protein biocomposites (protein@MOFs). Understanding the 3D spatial arrangement of proteins within protein@MOFs is paramount for developing synthetic methods to control their spatial localization and distribution patterns within the biocomposite crystals. In this study, the naturally occurring iron oxide mineral core of the protein horse spleen ferritin (Fn) is leveraged as a contrast agent to directly observe individual proteins once encapsulated into MOFs by electron microscopy techniques. This methodology couples scanning electron microscopy, transmission electron microscopy, and electron tomography to garner detailed 2D and 3D structural interpretations of where proteins spatially lie in Fn@MOF crystals, addressing the significant gaps in understanding how synthetic conditions relate to overall protein spatial localization and aggregation. These findings collectively reveal that adjusting the ligand‐to‐metal ratios, protein concentration, and the use of denaturing agents alters how proteins are arranged, localized, and aggregated within MOF crystals.

Chemistry↗
DOE OSTI2022

Structurally Defined Water‐Soluble Metallofullerene Derivatives towards Biomedical Applications

Abstract Endohedral metallofullerenes (EMFs) are excellent carriers of rare‐earth element (REE) ions in biomedical applications because they preclude the release of toxic metal ions. However, existing approaches to synthesize water‐soluble EMF derivatives yield mixtures that inhibit precise drug design. Here we report the synthesis of metallobuckytrio (MBT), a three‐buckyball system, as a modular platform to develop structurally defined water‐soluble EMF derivatives with ligands by choice. Demonstrated with PEG ligands, the resulting water‐soluble MBTs show superb biocompatibility. The Gd MBTs exhibit superior T 1 relaxivity than typical Gd complexes, potentially superseding current clinical MRI contrast agents in both safety and efficiency. The Lu MBTs generated reactive oxygen species upon light irradiation, showing promise as photosensitizers. With their modular nature to incorporate other ligands, we anticipate the MBT platform to open new paths towards bio‐specific REE drugs.

Li, Yanbang↗
DOE OSTI2024

Carbon‐13 Hyperpolarization of α‐Ketocarboxylates with Parahydrogen in Reversible Exchange

Abstract Signal Amplification by Reversible Exchange (SABRE) is a relatively simple and fast hyperpolarization technique that has been used to hyperpolarize the α‐ketocarboxylate pyruvate, a central metabolite and the leading hyperpolarized MRI contrast agent. In this work, we show that SABRE can readily be extended to hyperpolarize 13 C nuclei at natural abundance on many other α‐ketocarboxylates. Hyperpolarization is observed and optimized on pyruvate (P 13C =17 %) and 2‐oxobutyrate (P 13C =25 %) with alkyl chains in the R‐group, oxaloacetate (P 13C =11 %) and alpha‐ketoglutarate (P 13C =13 %) with carboxylate moieties in the R group, and phenylpyruvate (P 13C =2 %) and phenylglyoxylate (P 13C =2 %) with phenyl rings in the R‐group. New catalytically active SABRE binding motifs of the substrates to the hyperpolarization transfer catalyst – particularly for oxaloacetate – are observed. We experimentally explore the connection between temperature and exchange rates for all of these SABRE systems and develop a theoretical kinetic model, which is used to fit the hyperpolarization build‐up and decay during SABRE activity.

McBride, Stephen J. [Department of Chemistry North↗
DOE OSTI2023

Metal–Organic Framework as a New Type of Magnetothermally‐Triggered On‐Demand Release Carrier

The development of external stimuli‐controlled payload systems has been sought after with increasing interest toward magnetothermally‐triggered drug release (MTDR) carriers due to their non‐invasive features. However, current MTDR carriers present several limitations, such as poor heating efficiency caused by the aggregation of iron oxide nanoparticles (IONPs) or the presence of antiferromagnetic phases which affect their efficiency. Herein, a novel MTDR carrier is developed using a controlled encapsulation method that fully fixes and confines IONPs of various sizes within the metal–organic frameworks (MOFs). This novel carrier preserves the MOF's morphology, porosity, and IONP segregation, while enhances heating efficiency through the oxidation of antiferromagnetic phases in IONPs during encapsulation. It also features a magnetothermally‐responsive nanobrush that is stimulated by an alternating magnetic field to enable on‐demand drug release. The novel carrier shows improved heating, which has potential applications as contrast agents and for combined chemo and magnetic hyperthermia therapy. It holds a great promise for magneto‐thermally modulated drug dosing at tumor sites, making it an exciting avenue for cancer treatment.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Impacts of anthropogenic gadolinium on the activity of the ammonia oxidizing bacterium Nitrosomonas europaea

Widespread use of gadolinium-based contrast agents in medical imaging has resulted in increased Gd inputs to municipal wastewater treatment plants. Others have reported that typical wastewater treatment does not attenuate Gd, resulting in discharges to natural waters. However, whether elevated Gd impacts the performance of biological treatment has not been investigated. We examined whether gadolinium chloride or Gd chelated with diethylenetriaminepentaacetic acid (DTPA) affected the activity of the model nitrifying bacterium Nitrosomonas europaea. At nominal GdCl 3 additions ranging from 1 to 500 µM, no impact was observed compared to the control. Most (>98%) of the added Gd precipitated, and extracellular GdPO 4 nanoparticles were observed. When chelated with DTPA, Gd remained soluble, but no statistically significant impact on ammonia oxidation was observed until the highest concentrations tested. At 300 and 500 µM Gd-DTPA, a temporary reduction of nitrite production relative to the control (effect size 1.3 mg l -1 and 1.5 mg l -1 , respectively, at 24 h) was seen. By itself, DTPA was highly inhibitory. Modeling suggested that DTPA likely chelated other metals, but adjusting the concentrations of the most abundant metals in the medium, calcium and magnesium, indicated that lowering their free ion activities was probably not the cause of inhibition. Complexation of other essential metals was more likely. Furthermore, our studies indicate that while the low bioavailability of Gd may limit its ecosystem impacts, the role of synthetic ligands used with Gd and other rare earth elements should e considered as the production, use and disposal of these elements increases.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Susceptibility weighted MRI pinpoints spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats

Purpose: To find magnetic resonance imaging (MRI) precursors of spontaneous intracerebral hemorrhage in stroke-prone spontaneously hypertensive rats (SHRSP). Method: SHRSP rats were used with both a low/high salt (n = 18 or 11) Japanese diet and salty drinking water to generate spontaneous intracerebral hemorrhage (ICH). Various MRI sequences, and in particular, susceptibility weighted imaging (SWI), were used and combined with a gadolinium (Gd) contrast agent or oxygen gas to identify the rupture of the blood brain barrier (BBB) and the temporal ICH. Results: Most rats developed hypertensive ICH stroke in the high salt group during the 10–13 week period compared to only one third of rats in the low salt group during the 14–18 week period. The location of stroke for both the low/high-salt groups was highest in the striatum (58%/43%), followed by the cortex (21%/30%). The edematous enhancement on T2 weighted (T2W) imaging or Gd based T1 weighted (Gd-T1W) imaging due to the ruptured BBB preceded the striatal hemorrhages seen on SWI. The most recent bleeds were observed on temporal SWI or on oxygen-enhanced SWI. The mode of the volume of bleeds was 0.4 mm 3 . A positive correlation between susceptibility x volume and R2* x volume of the bleeds was observed. Conclusions: SHRSP rats with the high salt diet effectively generated a hypertensive hemorrhagic stroke which could be monitored by various MRI sequences. The venous dilation on SWI may precede any abnormality on T2W or Gd-T1W imaging. The edematous enhancement on T2W or Gd-T1W indicated a BBB breakdown that may precede striatal ICH by several days. This suggests the need for immediate treatment to improve outcome if this finding is observed. Here, the use of oxygen with SWI was able to help differentiate old bleeds from very recent bleeds.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Acoustics at the nanoscale (nanoacoustics): A comprehensive literature review. Part II: Nanoacoustics for biomedical imaging and therapy

We report in the past decade, acoustics at the nanoscale (i.e., nanoacoustics) has evolved rapidly with continuous and substantial expansion of capabilities and refinement of techniques. Motivated by research innovations in the last decade, for the first time, recent advancements of acoustics-associated nanomaterials/nanostructures and nanodevices for different applications are outlined in this comprehensive review, which is written in two parts. As part II of this two-part review, this paper concentrates on nanoacoustics in biomedical imaging and therapy applications, including molecular ultrasound imaging, photoacoustic imaging, ultrasound-mediated drug delivery and therapy, and photoacoustic drug delivery and therapy. Firstly, the recent developments of nanosized ultrasound and photoacoustic contrast agents as well as their various imaging applications are examined. Secondly, different types of nanomaterials/nanostructures as nanocarriers for ultrasound and photoacoustic therapies are discussed. Finally, a discussion of challenges and future research directions are provided for nanoacoustics in medical imaging and therapy.

47 OTHER INSTRUMENTATION↗
DOE OSTI2020

Bright Silicon Nanocrystals from a Liquid Precursor: Quasi-Direct Recombination with High Quantum Yield

Silicon nanocrystals (SiNCs) with bright bandgap photoluminescence (PL) are of current interest for a range of potential applications, from solar windows to biomedical contrast agents. Here, we use the liquid precursor cyclohexasilane (Si 6 H 12 ) for the plasma synthesis of colloidal SiNCs with exemplary core emission. Here, through size separation executed in an oxygen-shielded environment, we achieve PL quantum yields (QYs) approaching 70% while exposing intrinsic constraints on efficient core emission from smaller SiNCs. Time-resolved PL spectra of these fractions in response to femtosecond pulsed excitation reveal a zero-phonon radiative channel that anticorrelates with QY, which we model using advanced computational methods applied to a 2 nm SiNC. Our results offer additional insight into the photophysical interplay of the nanocrystal surface, quasi-direct recombination, and efficient SiNC core PL.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Delivering Robust Proton-Only Sensing of Hyperpolarized [1,2- 13 C 2 ]-Pyruvate Using Broad-Spectral-Range Nuclear Magnetic Resonance Pulse Sequences

Hyperpolarized [1- 13 C]pyruvate is the leading hyperpolarized injectable contrast agent and is currently under evaluation in clinical trials for molecular imaging of metabolic diseases, including cardiovascular disease and cancer. One aspect limiting broad scalability of the technique is that hyperpolarized 13 C MRI requires specialized 13 C hardware and software that are not generally available on clinical MRI scanners, which employ proton-only detection. Here, we present an approach that uses pulse sequences to transfer 13 C hyperpolarization to methyl protons for detection of the 13 C– 13 C pyruvate singlet, employing proton-only excitation and detection only. The new pulse sequences are robust to the B 1 and B 0 magnetic field inhomogeneities. The work focuses on singlet-to-magnetization (S2M) and rotor-synchronized (R) pulses, both relying on trains of hard pulses with broad spectral width coverage designed to effectively transform hyperpolarized 13 C 2 -singlet hyperpolarization to 1 H polarization on the CH 3 group of [1,2- 13 C 2 ]pyruvate. Finally, this approach may enable a broader adoption of hyperpolarized MRI as a molecular imaging technique.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Perivascular network segmentations derived from high-field MRI and their implications for perivascular and parenchymal mass transport in the rat brain

A custom segmentation workflow was applied to ex vivo high-field MR images of rat brains acquired following in vivo intraventricular contrast agent infusion to generate maps of the perivascular spaces (PVS). The resulting perivascular network segmentations enabled analysis of perivascular connections to the ventricles, parenchymal solute clearance, and dispersive solute transport within PVS. Numerous perivascular connections between the brain surface and the ventricles suggest the ventricles integrate into a PVS-mediated clearance system and raise the possibility of cerebrospinal fluid (CSF) return from the subarachnoid space to the ventricles via PVS. Assuming rapid solute exchange between the PVS and CSF spaces primarily by advection, the extensive perivascular network decreased the mean clearance distance from parenchyma to the nearest CSF compartment resulting in an over 21-fold reduction in the estimated diffusive clearance time scale, irrespective of solute diffusivity. This corresponds to an estimated diffusive clearance time scale under 10 min for amyloid-beta which suggests that the widespread distribution of PVS may render diffusion an effective parenchymal clearance mechanism. Additional analysis of oscillatory solute dispersion within PVS indicates that advection rather than dispersion is likely the primary transport mechanism for dissolved compounds greater than 66 kDa in the long (> 2 mm) perivascular segments identified here, although dispersion may be significant for smaller compounds in shorter perivascular segments.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Predicting 1 H NMR relaxation in Gd 3+ -aqua using molecular dynamics simulations

Atomistic molecular dynamics simulations are used to predict 1 H NMR T 1 relaxation of water from paramagnetic Gd 3+ ions in solution at 25 °C. Simulations of the T 1 relaxivity dispersion function r 1 computed from the Gd 3+ – 1 H dipole–dipole autocorrelation function agree within ≃8% of measurements in the range f 0 ≃ 5 ↔ 500 MHz, without any adjustable parameters in the interpretation of the simulations, and without any relaxation models. Here the simulation results are discussed in the context of the Solomon-Bloembergen-Morgan inner-sphere relaxation model, and the Hwang-Freed outer-sphere relaxation model. Below f 0 ≲ 5 MHz, the simulation overestimates r 1 compared to measurements, which is used to estimate the zero-field electron-spin relaxation time. The simulations show potential for predicting r 1 at high frequencies in chelated Gd 3+ contrast-agents used for clinical MRI.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Extended molecular eigenmodes treatment of dipole–dipole NMR relaxation in real fluids

Traditional models of NMR relaxation fail to account for the complex, multi-exponential behavior of the autocorrelation function in realistic systems characterized by soft-interactions and molecules that are chemically and physically complex. Here, in this study, we describe the relative diffusion of the spin dipoles by means of a Fokker–Planck equation that includes an interaction potential of mean force to account for the response of the physical/chemical environment around the dipoles. By numerically solving the Fokker–Planck equation for the diffusion propagator, we estimate dipole–dipole NMR relaxation for like- and unlike-spin systems via its eigenmode solution. We test the model against molecular simulations of diffusing dipoles with harmonic potentials and also validate using experimental longitudinal relaxation data from real systems, including Gd(III)–aqua and Gd(III)–DO3A–butrol complexes, the latter being an important MRI contrast agent. Using this novel approach, we predict both the inner- and outer-shell contributions to the relaxivity rates with excellent accuracy at frequencies relevant to MRI. We also show that, under the appropriate assumptions, our framework naturally recovers the Bloembergen–Purcell–Pound, the Solomon–Bloembergen–Morgan, and the Hwang–Freed models. Our implementation is general and publicly available for application to a broad range of systems.

Pinheiro dos Santos, Thiago J. [Rice Univ., Housto↗