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We present an integrated, open-source device for parahydrogen-based hyperpolarization processes in the microtesla field regime with a cost of components of less than $7000. The device is designed to produce a batch of 13C and 15N hyperpolarized (HP) compounds via hydrogenative or non-hydrogenative parahydrogen-induced polarization methods that employ microtesla magnetic fields for efficient polarization transfer of parahydrogen-derived spin order to X-nuclei (e.g., 13C and 15N). The apparatus employs a layered structure (reminiscent of a Russian doll "Matryoshka") that includes a nonmagnetic variable-temperature sample chamber, a microtesla magnetic field coil (operating in the range of 0.02-75 microtesla), a three-layered mu-metal shield (to attenuate the ambient magnetic field), and a magnetic shield degaussing coil placed in the overall device enclosure. The gas-handling manifold allows for parahydrogen-gas flow and pressure control (up to 9.2 bar of total parahydrogen pressure). The sample temperature can be varied either using a water bath or a PID-controlled heat exchanger in the range from -12 to 80 °C. This benchtop device measures 62 cm (length) × 47 cm (width) × 47 cm (height), weighs 30 kg, and requires only connections to a high-pressure parahydrogen gas supply and a single 110/220 VAC power source. The utility of the device has been demonstrated using an example of parahydrogen pairwise addition to form HP ethyl [1-13C]acetate (P13C = 7%, [c] = 1 M). Moreover, the Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) technique was employed to demonstrate efficient hyperpolarization of 13C and 15N spins in a wide range of biologically relevant molecules, including [1-13C]pyruvate (P13C = 14%, [c] = 27 mM), [1-13C]-α-ketoglutarate (P13C = 17%), [1-13C]ketoisocaproate (P13C = 18%), [15N3]metronidazole (P15N = 13%, [c] = 20 mM), and others. While the vast majority of the utility studies have been performed in standard 5 mm NMR tubes, the sample chamber of the device can accommodate a wide range of sample container sizes and geometries of up to 1 L sample volume. The device establishes an integrated, simple, inexpensive, and versatile equipment gateway needed to facilitate parahydrogen-based hyperpolarization experiments ranging from basic science to preclinical applications; indeed, detailed technical drawings and a bill of materials are provided to support the ready translation of this design to other laboratories.
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PURPOSE: To demonstrate the feasibility of 3D echo-planar spectroscopic imaging (EPSI) technique with rapid volumetric radial k-space sampling for hyperpolarized (HP) 13C magnetic resonance spectroscopic imaging (MRSI) in vivo. METHODS: A radial EPSI (rEPSI) was implemented on a 3 T clinical PET/MR system. To enable volumetric coverage, the sinusoidal shaped readout gradients per k-t-spoke were rotated along the three spatial dimensions in a golden-angle like manner. A distance-weighted, density-compensated gridding reconstruction was used, also in cases with undersampling of spokes in k-space. Measurements without and with HP 13C-labeled substances were performed in phantoms and rats using a double-resonant 13C/1H volume resonator with 72 mm inner diameter. RESULTS: Phantom measurements demonstrated the feasibility of the implemented rEPSI sequence, as well as the robustness to undersampling in k-space up to a factor of 5 without advanced reconstruction techniques. Applied to measurements with HP [1-13C]pyruvate in a tumor-bearing rat, we obtained well-resolved MRSI datasets with a large matrix size of 123 voxels covering the whole imaging FOV of (180 mm)3 within 6.3 s, enabling to observe metabolism in dynamic acquisitions. CONCLUSION: After further optimization, the proposed rEPSI method may be useful in applications of HP 13C-tracers where unknown or varying metabolite resonances are expected, and the acquisition of dynamic, volumetric MRSI datasets with an adequate temporal resolution is a challenge.
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It has recently been shown that a bolus of hyperpolarized nuclear spins can yield stimulated emission signals similar in nature to maser signals, potentially enabling new ways of sensing hyperpolarized contrast media, including most notably [1-13C]pyruvate that is under evaluation in over 50â clinical trials for metabolic imaging of cancer. The stimulated NMR signal emissions lasting for minutes do not require radio-frequency excitation, offering unprecedented advantages compared to conventional MR sensing. However, creating nuclear spin maser emission is challenging in practice due to stringent fundamental requirements, making practical in vivo applications hardly possible using conventional passive MR detectors. Here, we demonstrate the utility of a wireless NMR maser detector, the quality factor of which was enhanced 22-fold (to 1,670) via parametric pumping. This active-feedback technique breaks the intrinsic fundamental limit of NMR detector circuit quality factor. We show the use of parametric pumping to reduce the threshold requirement for inducing nuclear spin masing at 300â MHz resonance frequency in a preclinical MRI scanner. Indeed, stimulated emission from hyperpolarized protons was obtained under highly unfavorable conditions of low magnetic field homogeneity (T2* of 3â ms). Greater gains of the quality factor of the MR detector (up to 1â million) were also demonstrated.
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Espectroscopia de Ressonância Magnética , Imageamento por Ressonância Magnética/métodos , Tecnologia sem Fio , Ácido Pirúvico/químicaRESUMO
Conventional nuclear magnetic resonance (NMR) enables detection of chemicals and their transformations by exciting nuclear spin ensembles with a radio-frequency pulse followed by detection of the precessing spins at their characteristic frequencies. The detected frequencies report on chemical reactions in real time and the signal amplitudes scale with concentrations of products and reactants. Here, we employ Radiofrequency Amplification by Stimulated Emission of Radiation (RASER), a quantum phenomenon producing coherent emission of 13C signals, to detect chemical transformations. The 13C signals are emitted by the negatively hyperpolarized biomolecules without external radio frequency pulses and without any background signal from other, nonhyperpolarized spins in the ensemble. Here, we studied the hydrolysis of hyperpolarized ethyl-[1-13C]acetate to hyperpolarized [1-13C]acetate, which was analyzed as a model system by conventional NMR and 13C RASER. The chemical transformation of 13C RASER-active species leads to complete and abrupt disappearance of reactant signals and delayed, abrupt reappearance of a frequency-shifted RASER signal without destroying 13C polarization. The experimentally observed "quantum" RASER threshold is supported by simulations.
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BACKGROUND: Three-dimensional (3D) multiecho balanced steady-state free precession (ME-bSSFP) has previously been demonstrated in preclinical hyperpolarized (HP) 13 C-MRI in vivo experiments, and it may be suitable for clinical metabolic imaging of prostate cancer (PCa). PURPOSE: To validate a signal simulation framework for the use of sequence parameter optimization. To demonstrate the feasibility of ME-bSSFP for HP 13 C-MRI in patients. To evaluate the metabolism in PCa measured by ME-bSSFP. STUDY TYPE: Retrospective single-center cohort study. PHANTOMS/POPULATION: Phantoms containing aqueous solutions of [1-13 C] lactate (2.3 M) and [13 C] urea (8 M). Eight patients (mean age 67 ± 6 years) with biopsy-confirmed Gleason 3 + 4 (n = 7) and 4 + 3 (n = 1) PCa. FIELD STRENGTH/SEQUENCES: 1 H MRI at 3 T with T2 -weighted turbo spin-echo sequence used for spatial localization and spoiled dual gradient-echo sequence used for B0 -field measurement. ME-bSSFP sequence for 13 C MR spectroscopic imaging with retrospective multipoint IDEAL metabolite separation. ASSESSMENT: The primary endpoint was the analysis of pyruvate-to-lactate conversion in PCa and healthy prostate regions of interest (ROIs) using model-free area under the curve (AUC) ratios and a one-directional kinetic model (kP ). The secondary objectives were to investigate the correlation between simulated and experimental ME-bSSFP metabolite signals for HP 13 C-MRI parameter optimization. STATISTICAL TESTS: Pearson correlation coefficients with 95% confidence intervals and paired t-tests. The level of statistical significance was set at P < 0.05. RESULTS: Strong correlations between simulated and empirical ME-bSSFP signals were found (r > 0.96). Therefore, the simulation framework was used for sequence optimization. Whole prostate metabolic HP 13 C-MRI, observing the conversion of pyruvate into lactate, with a temporal resolution of 6 seconds was demonstrated using ME-bSSFP. Both assessed metrics resulted in significant differences between PCa (mean ± SD) (AUC = 0.33 ± 012, kP = 0.038 ± 0.014) and healthy (AUC = 0.15 ± 0.10, kP = 0.011 ± 0.007) ROIs. DATA CONCLUSION: Metabolic HP 13 C-MRI in the prostate using ME-bSSFP allows for differentiation between aggressive PCa and healthy tissue. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.
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Neoplasias da Próstata , Ácido Pirúvico , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Ácido Pirúvico/química , Ácido Pirúvico/metabolismo , Estudos Retrospectivos , Estudos de Coortes , Neoplasias da Próstata/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Ácido LácticoRESUMO
The metabolism of malignant cells differs significantly from that of healthy cells and thus, it is possible to perform metabolic imaging to reveal not only the exact location of a tumor, but also intratumoral areas of high metabolic activity. Herein, we demonstrate the feasibility of metabolic tumor imaging using signal-enhanced 1-13 C-pyruvate-d3 , which is rapidly enhanced via para-hydrogen, and thus, the signal is amplified by several orders of magnitudes in less than a minute. Using as a model, human melanoma xenografts injected with signal-enhanced 1-13 C-pyruvate-d3, we show that the conversion of pyruvate into lactate can be monitored along with its kinetics, which could pave the way for rapidly detecting and monitoring changes in tumor metabolism.
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Neoplasias , Ácido Pirúvico , Humanos , Ácido Pirúvico/metabolismo , Hidrogênio , Imageamento por Ressonância Magnética/métodos , Isótopos de CarbonoRESUMO
The feasibility of Carbon-13 Radiofrequency (RF) Amplification by Stimulated Emission of Radiation (C-13 RASER) is demonstrated on a bolus of liquid hyperpolarized ethyl [1-13 C]acetate. Hyperpolarized ethyl [1-13 C]acetate was prepared via pairwise addition of parahydrogen to vinyl [1-13 C]acetate and polarization transfer from nascent parahydrogen-derived protons to the carbon-13 nucleus via magnetic field cycling yielding C-13 nuclear spin polarization of approximately 6 %. RASER signals were detected from samples with concentration ranging from 0.12 to 1â M concentration using a non-cryogenic 1.4Tâ NMR spectrometer equipped with a radio-frequency detection coil with a quality factor (Q) of 32 without any modifications. C-13 RASER signals were observed for several minutes on a single bolus of hyperpolarized substrate to achieve 21â mHz NMR linewidths. The feasibility of creating long-lasting C-13 RASER on biomolecular carriers opens a wide range of new opportunities for the rapidly expanding field of C-13 magnetic resonance hyperpolarization.
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Hidrogênio , Prótons , Hidrogênio/química , Espectroscopia de Ressonância Magnética , Acetatos/químicaRESUMO
Metabolic magnetic resonance imaging (MRI) using hyperpolarized (HP) pyruvate is becoming a non-invasive technique for diagnosing, staging, and monitoring response to treatment in cancer and other diseases. The clinically established method for producing HP pyruvate, dissolution dynamic nuclear polarization, however, is rather complex and slow. Signal Amplification By Reversible Exchange (SABRE) is an ultra-fast and low-cost method based on fast chemical exchange. Here, for the first time, we demonstrate not only in vivo utility, but also metabolic MRI with SABRE. We present a novel routine to produce aqueous HP [1-13 C]pyruvate-d3 for injection in 6â minutes. The injected solution was sterile, non-toxic, pH neutral and contained ≈30â mM [1-13 C]pyruvate-d3 polarized to ≈11 % (residual 250â mM methanol and 20â µM catalyst). It was obtained by rapid solvent evaporation and metal filtering, which we detail in this manuscript. This achievement makes HP pyruvate MRI available to a wide biomedical community for fast metabolic imaging of living organisms.
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Imageamento por Ressonância Magnética , Ácido Pirúvico , Imageamento por Ressonância Magnética/métodos , Solventes/química , Metanol , Água/químicaRESUMO
We present a selectively pulsed (SP) generation of sequences to transfer the spin order of parahydrogen (pH2 ) to heteronuclei in weakly coupled spin systems. We analyze and discuss the mechanism and efficiency of SP spin order transfer (SOT) and derive sequence parameters. These new sequences are most promising for the hyperpolarization of molecules at high magnetic fields. SP-SOT is effective and robust despite the symmetry of the 1 H-13 C J-couplings even when precursor molecules are not completely labeled with deuterium. As only one broadband 1 H pulse is needed per sequence, which can be replaced for instance by a frequency-modulated pulse, lower radiofrequency (RF) power is required. This development will be useful to hyperpolarize (new) agents and to perform the hyperpolarization within the bore of an MRI system, where the limited RF power has been a persistent problem.
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Hidrogênio , Imageamento por Ressonância Magnética , Hidrogênio/química , Campos MagnéticosRESUMO
MR is a prominent technology to investigate diseases, with millions of clinical procedures performed every year. Metabolic dysfunction is one common aspect associated with many diseases. Thus, understanding and monitoring metabolic changes is essential to develop cures for many illnesses, including for example cancer and neurodegeneration. MR methodologies are especially suited to study endogenous metabolites and processes within an organism in vivo, which has led to many insights about physiological functions. Advancing metabolic MR techniques is therefore key to further understand physiological processes. Here, we introduce an approach based on nuclear spin singlet states to specifically filter metabolic signals and particularly show that singlet-filtered glutamate can be observed distinctly in the hippocampus of a living mouse in vivo. This development opens opportunities to make use of the singlet spin phenomenon in vivo and besides its use as a filter to provide scope for new contrast agents.
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Espectroscopia de Ressonância Magnética , Animais , Simulação por Computador , Imageamento por Ressonância Magnética , Masculino , Metaboloma , Camundongos Endogâmicos C57BLRESUMO
The signal enhancement provided by the hyperpolarization of nuclear spins of metabolites is a promising technique for diagnostic magnetic resonance imaging (MRI). To date, most 13C-contrast agents are hyperpolarized utilizing a complex or cost-intensive polarizer. Recently, the in situ parahydrogen-induced 13C hyperpolarization was demonstrated. Hydrogenation, spin order transfer (SOT) by a pulsed NMR sequence, in vivo administration, and detection was achieved within the magnet bore of a 7 Tesla MRI system. So far, the hyperpolarization of the xenobiotic molecule 1-13C-hydroxyethylpropionate (HEP) and the biomolecule 1-13C-succinate (SUC) through the PH-INEPT+ sequence and a SOT scheme proposed by Goldman et al., respectively, was shown. Here, we investigate further the hyperpolarization of SUC at 7 Tesla and study the performance of two additional SOT sequences. Moreover, we present first results of the hyperpolarization at high magnetic field of 1-13C-phospholactate (PLAC), a derivate to obtain the metabolite lactate, employing the PH-INEPT+ sequence. For SUC and PLAC, 13C polarizations of about 1-2% were achieved within seconds and with minimal equipment. Effects that potentially may explain loss of 13C polarization have been identified, i.e. low hydrogenation yield, fast T1/T2 relaxation and the rarely considered 13C isotope labeling effect.
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We describe a new method for pulsed spin order transfer of parahydrogen-induced polarization (PHIP) that enables high polarization in incompletely 2H-labeled molecules by exciting only the desired protons in a frequency-selective manner. This way, the effect of selected J-couplings is suspended. Experimentally 1.25% 13C polarization were obtained for 1-13C-ethyl pyruvate and 50% pH2 at 9.4 Tesla.
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Among the hyperpolarization techniques geared toward in vivo magnetic resonance imaging, parahydrogen-induced polarization (PHIP) shows promise due to its low cost and fast speed of contrast agent preparation. The synthesis of 13C-labeled, unsaturated precursors to perform PHIP by side arm hydrogenation has recently opened new possibilities for metabolic imaging owing to the biological compatibility of the reaction products, although the polarization transfer between the parahydrogen-derived protons and the 13C heteronucleus must yet be better understood, characterized, and eventually optimized. In this realm, a new experimental strategy incorporating pulse-programmable magnetic field sweeping and in situ detection has been developed. The approach is evaluated by measuring the 13C polarization of ethyl acetate-1-13C, i.e., the product of pairwise addition of parahydrogen to vinyl acetate-1-13C, resulting from zero-crossing magnetic field ramps of various durations, amplitudes, and step sizes. The results demonstrate (i) the profound effect these parameters have on the 1H to 13C polarization transfer efficiency and (ii) the high reproducibility of the technique.
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Acetatos/química , Hidrogênio/química , Isótopos de Carbono , Hidrogenação , Campos Magnéticos , Imageamento por Ressonância Magnética , Estrutura MolecularRESUMO
Molecular hydrogen has unique nuclear spin properties. Its nuclear spin isomer, parahydrogen (pH2 ), was instrumental in the early days of quantum mechanics and allows to boost the NMR signal by several orders of magnitude. pH2- induced polarization (PHIP) is based on the survival of pH2 spin order in solution, yet its lifetime has not been investigated in aqueous or biological media required for inâ vivo applications. Herein, we report longitudinal relaxation times (T1 ) and lifetimes of pH2 ( τPOC ) in methanol and water, with or without O2 , NaCl, rhodium-catalyst or human blood. Furthermore, we present a relaxation model that uses T1 and τPOC for more precise theoretical predictions of the H2 spin state in PHIP experiments. All measured T1 values were in the range of 1.4-2â s and τPOC values were of the order of 10-300 minutes. These relatively long lifetimes hold great promise for emerging inâ vivo implementations and applications of PHIP.
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Hidrogênio/sangue , Hidrogênio/química , Humanos , Hidrogênio/análise , Soluções , Água/químicaRESUMO
13C hyperpolarized pyruvate is an emerging MRI contrast agent for sensing molecular events in cancer and other diseases with aberrant metabolic pathways. This metabolic contrast agent can be produced via several hyperpolarization techniques. Despite remarkable success in research settings, widespread clinical adoption faces substantial roadblocks because the current sensing technology utilized to sense this contrast agent requires the excitation of 13C nuclear spins that also need to be synchronized with MRI field gradient pulses. Here, we demonstrate sensing of hyperpolarized allyl [1-13C]pyruvate via the stimulated emission of radiation that mitigates the requirements currently blocking broader adoption. Specifically, 13C Radiofrequency Amplification by Stimulated Emission of Radiation (13C RASER) was obtained after pairwise addition of parahydrogen to a pyruvate precursor, detected in a commercial inductive detector with a quality factor (Q) of 32 for sample concentrations as low as 0.125 M with 13C polarization of 4%. Moreover, parahydrogen-induced polarization allowed for the preparation of a mixture of ketone and hemiketal forms of hyperpolarized allyl [1-13C]pyruvate, which are separated by 10 ppm in 13C NMR spectra. This is a good model system to study the simultaneous 13C RASER signals of multiple 13C species. This system models the metabolic production of hyperpolarized [1-13C]lactate from hyperpolarized [1-13C]pyruvate, which has a similar chemical shift difference. Our results show that 13C RASER signals can be obtained from both species simultaneously when the emission threshold is exceeded for both species. On the other hand, when the emission threshold is exceeded only for one of the hyperpolarized species, 13C stimulated emission is confined to this species only, therefore enabling the background-free detection of individual hyperpolarized 13C signals. The reported results pave the way to novel sensing approaches of 13C hyperpolarized pyruvate, potentially unlocking hyperpolarized 13C MRI on virtually any MRI systemâan attractive vision for the future molecular imaging and diagnostics.
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Isótopos de Carbono , Meios de Contraste , Ácido Pirúvico , Ácido Pirúvico/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Ácido LácticoRESUMO
Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.
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Imageamento por Ressonância Magnética , Oncologia , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodosRESUMO
Nanomaterials play an important role in the development and application of hyperpolarized materials for magnetic resonance imaging (MRI). In this context they can not only act as hyperpolarized materials which are directly imaged but also play a role as carriers for hyperpolarized gases and catalysts for para-hydrogen induced polarization (PHIP) to generate hyperpolarized substrates for metabolic imaging. Those three application possibilities are discussed, focusing on carbon-based materials for the directly imaged particles. An overview over recent developments in all three fields is given, including the early developments in each field as well as important steps towards applications in MRI, such as making the initially developed methods more biocompatible and first imaging experiments with spatial resolution in either phantoms or in vivo studies. Focusing on the important features nanomaterials need to display to be applicable in the MRI context, a wide range of different approaches to that extent is covered, giving the reader a general idea of different possibilities as well as recent developments in those different fields of hyperpolarized magnetic resonance. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.
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Hidrogênio , Imageamento por Ressonância Magnética , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Carbono , Descoberta de DrogasRESUMO
Carbon-13 hyperpolarized pyruvate is about to become the next-generation contrast agent for molecular magnetic resonance imaging of cancer and other diseases. Here, efficient and rapid pyruvate hyperpolarization is achieved via signal amplification by reversible exchange (SABRE) with parahydrogen through synergistic use of substrate deuteration, alternating, and static microtesla magnetic fields. Up to 22 and 6% long-lasting 13C polarization (T1 = 3.7 ± 0.25 and 1.7 ± 0.1 min) is demonstrated for the C1 and C2 nuclear sites, respectively. The remarkable polarization levels become possible as a result of favorable relaxation dynamics at the microtesla fields. The ultralong polarization lifetimes will be conducive to yielding high polarization after purification, quality assurance, and injection of the hyperpolarized molecular imaging probes. These results pave the way to future in vivo translation of carbon-13 hyperpolarized molecular imaging probes prepared by this approach.
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Imageamento por Ressonância Magnética , Ácido Pirúvico , Espectroscopia de Ressonância Magnética/métodos , Isótopos de CarbonoRESUMO
Noma victims suffer from a three-dimensional facial soft-tissue loss. Some may also develop complex viscerocranial defects, due to acute osteitis, chronic exposure, or arrested skeletal growth. Reconstruction has mainly focused on soft tissue so far, whereas skeletal restoration was mostly avoided. After successful microvascular soft tissue free flap reconstruction, we now included skeletal restoration and mandibular ankylosis release into the initial step of complex noma surgery. One free rib graft and parascapular flap, one microvascular osteomyocutaneous flap from the subscapular system, and two sequential chimeric free flaps including vascularized bone were used as the initial steps for facial reconstruction. Ankylosis release could spare the temporomandibular joint. Complex noma reconstruction should include skeletal restoration. Avascular bone is acceptable in cases with complete vascularized graft coverage. Microsurgical chimeric flaps are preferable as they can reduce the number and complexity of secondary operations and provide viable, infection-resistant bone supporting facial growth.