Impact of ovary-intact menopause in a mouse model of heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) afflicts over half of all patients with heart failure and is a debilitating and fatal syndrome affecting postmenopausal women more than any other demographic. This bias toward older females calls into question the significance of menopause in the development of HFpEF, but this question has not been probed in detail. In this study, we report the first investigation into the impact of ovary-intact menopause in the context of HFpEF. To replicate the human condition as faithfully as possible, vinylcyclohexene dioxide (VCD) was used to accelerate ovarian failure (AOF) in female mice while leaving the ovaries intact. HFpEF was established with a mouse model that involves two stressors typical in humans: a high-fat diet and hypertension induced from the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME). In young female mice, AOF or HFpEF-associated stressors independently induced abnormal myocardial strain indicative of early subclinical systolic and diastolic cardiac dysfunction. HFpEF but not AOF was associated with elevations in systolic blood pressure. Increased myocyte size and reduced myocardial microvascular density were not observed in any group. Also, a broad panel of measurements that included echocardiography, invasive pressure measurements, histology, and serum hormones revealed no interaction between AOF and HFpEF. Interestingly, AOF did evoke a higher density of infiltrating cardiac immune cells in both healthy and HFpEF mice, suggestive of proinflammatory effects. In contrast to young mice, middle-aged "old" mice did not exhibit cardiac dysfunction from estrogen deprivation alone or from HFpEF-related stressors.NEW & NOTEWORTHY This is the first preclinical study to examine the impact of ovary-intact menopause [accelerated ovarian failure (AOF)] on HFpEF. Echocardiography of young female mice revealed early evidence of diastolic and systolic cardiac dysfunction apparent only on strain imaging in HFpEF only, AOF only, or the combination. Surprisingly, AOF did not exacerbate the HFpEF phenotype. Results in middle-aged "old" females also showed no interaction between HFpEF and AOF and, importantly, no cardiovascular impact from HFpEF or AOF.

In Vivo MRI Tracking of Degradable Polyurethane Hydrogel Degradation In Situ Using a Manganese Porphyrin Contrast Agent.

BACKGROUND: A noninvasive method to track implanted biomaterials is desirable for real-time monitoring of material interactions with host tissues and assessment of efficacy and safety. PURPOSE: To explore quantitative in vivo tracking of polyurethane implants using a manganese porphyrin (MnP) contrast agent containing a covalent binding site for pairing to polymers. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Rodent model of dorsal subcutaneous implants (10 female Sprague Dawley rats). FIELD STRENGTH/SEQUENCE: A 3-T; two-dimensional (2D) T1-weighted spin-echo (SE), T2-weighted turbo SE, three-dimensional (3D) spoiled gradient-echo T1 mapping with variable flip angles. ASSESSMENT: A new MnP-vinyl contrast agent to covalently label polyurethane hydrogels was synthesized and chemically characterized. Stability of binding was assessed in vitro. MRI was performed in vitro on unlabeled hydrogels and hydrogels labeled at different concentrations, and in vivo on rats with unlabeled and labeled hydrogels implanted dorsally. In vivo MRI was performed at 1, 3, 5, and 7 weeks postimplantation. Implants were easily identified on T1-weighted SE, and fluid accumulation from inflammation was distinguished on T2-weighted turbo SE. Implants were segmented on contiguous T1-weighted SPGR slices using a threshold of 1.8 times the background muscle signal intensity; implant volume and mean T1 values were then calculated at each timepoint. Histopathology was performed on implants in the same plane as MRI and compared to imaging results. STATISTICAL TESTS: Unpaired t-tests and one-way analysis of variance (ANOVA) were used for comparisons. A P value <0.05 was considered to be statistically significant. RESULTS: Hydrogel labeling with MnP resulted in a significant T1 reduction in vitro (T1 = 517 ± 36 msec vs. 879 ± 147 msec unlabeled). Mean T1 values of labeled implants in rats increased significantly by 23% over time, from 1 to 7 weeks postimplantation (651 ± 49 msec to 801 ± 72 msec), indicating decreasing implant density. DATA CONCLUSION: Polymer-binding MnP enables in vivo tracking of vinyl-group coupling polymers. EVIDENCE LEVEL: 1. TECHNICAL EFFICACY: Stage 1.

A Manganese Porphyrin Platform for the Design and Synthesis of Molecular and Targeted MRI Contrast Agents.

Magnetic resonance imaging (MRI) contrast agents, in contrast to the plethora of fluorescent agents available to target disease biomarkers or exogenous implants, have remained predominantly non-specific. That is, they do not preferentially accumulate in specific locations in vivo because doing so necessitates longer contrast retention, which is contraindicated for current gadolinium (Gd) agents. This double-edge sword implies that Gd agents can offer either rapid elimination (but lack specificity) or targeted accumulation (but with toxicity risks). For this reason, MRI contrast agent innovation has been severely constrained. Gd-free alternatives based on manganese (Mn) chelates have been largely ineffective, as they are inherently unstable. In this study, we present a Mn(III) porphyrin (MnP) platform for bioconjugation, offering the highest stability and chemical versatility compared to any other T1 contrast agent. We exploit the inherent metal stability conferred by porphyrins and the absence of pendant bases (found in Gd or Mn chelates) that limit versatile functionalization. As proof-of-principle, we demonstrate labeling of human serum albumin, a model protein, and collagen hydrogels for applications in in-vivo targeted imaging and material tracking, respectively. In-vitro and in-vivo results confirm unprecedented metal stability, ease of functionalization, and high T1 relaxivity. This new platform opens the door to ex-vivo validation by fluorescent imaging and multipurpose molecular imaging in vivo.

Three-Dimensional Bioprinted MR-Trackable Regenerative Scaffold for Postimplantation Monitoring on T1-Weighted MRI.

BACKGROUND: A three-dimensional (3D) bioprinted tissue scaffold is a promising therapeutic that goes beyond providing physical support for tissue regeneration by enabling precise spatial control over scaffold geometry and integration of different materials/cells. Critically important is in vivo confirmation of correct scaffold placement and retention during the initial 24 hours postimplantation, to detect unwanted implant migration. PURPOSE: To incorporate a safe, efficient MR contrast agent into a bioprinting workflow, and to achieve bright-contrast scaffold monitoring in vivo postimplantation. STUDY TYPE: In vitro and animal in vivo longitudinal study. ANIMAL MODEL: Two female Sprague Dawley rats (~200 g) for labeled and unlabeled scaffold implantation in the subcutaneous dorsal space flanking the vertebral column. FIELD STRENGTH/SEQUENCE: A 7.0 T/T1 -weighted spin echo (SE) sequence and T1 mapping using turbo SE with variable repetition times (TRs). ASSESSMENT: Cell viability and proliferation were assessed over 2 weeks after labeling bioprinted gelatin/alginate scaffolds with MnPNH2 (0.5 mM, 24 hours). In vitro MRI was performed 0, 12, and 24 hours postlabeling in nine labeled and three unlabeled (control) scaffolds to monitor T1 evolution. In vivo MRI was performed immediately and 24 hours postimplantation to assess T1 . Acute inflammation near surgical site was monitored in one rat to 3 days. STATISTICAL TESTS: One-way analysis of variance with Tukey-Kramer post hoc analysis (P < 0.01). RESULTS: Cell viability was unaffected by bioprinting/labeling: viability exceeded 90% in all scaffolds after 1 week. In vitro T1 's were significantly lower in labeled scaffolds compared to control (207 msec vs. 2257 msec) immediately postlabeling and 24 hours later (1227 msec vs. 2257 msec). In vivo T1 's were significantly different (243.6 msec vs. 2414.6 msec) immediately postimplantation, and no differences emerged compared to respective in vitro control/labeled counterparts. The 24-hours imaging and gross pathology confirmed migration of scaffolds beyond the imaging field. DATA CONCLUSION: We report an MR-detectable, cell-compatible bioprinted scaffold, utilizing a T1 -weighting contrast agent for high-resolution, postimplantation scaffold tracking. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

MRI method for labeling and imaging decellularized extracellular matrix scaffolds for tissue engineering.

PURPOSE: To develop a facile method for labeling and imaging decellularized extracellular matrix (dECM) scaffolds intended for regenerating 3D tissues. METHODS: A small molecule manganese porphyrin, MnPNH2 , was synthesized and used to label dECM scaffolds made from porcine bladder and trachea and murine whole lungs. The labeling protocol was optimized on bladder dECM, and imaging on a 3T clinical scanner was performed to assess reductions in T1 and T2 relaxation times. In vivo MRI was performed on dECM injected in the rat dorsum to verify sensitivity of detection. Toxicity assays for cell viability, metabolism, and proliferation were performed on human umbilical vein endothelial cells. The incorporation of MnPNH2 and its long-term retention in dECM were assessed on transmission electron microscopy and ultraviolet absorbance of eluted MnPNH2 over time. RESULTS: All tissues, including thick whole 3D organs, were uniformly labeled and demonstrated high signal-to-noise on MRI. A nearly 10-fold reduction in T1 was consistently obtained at a labeling dose of 0.4 mM, and even 0.2 mM provided sufficient contrast in vivo and ex vivo. No toxicity was observed up to 0.4 mM, the maximum tested. Binding studies suggested nonspecific association, and retention studies in the labeled whole decellularized lungs revealed less than 20% MnPNH2 loss over 30 days, the majority occurring in the first 3 days after labeling. CONCLUSION: The proposed labeling method is the first report for visualizing dECM on MRI and has the potential for long-term monitoring and optimization of dECM-based organ tissue engineering.

Heart failure with preserved ejection fraction: the missing pieces in diagnostic imaging.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent phenotype affecting over half of today's heart failure patients. With no proven therapy and no universally accepted diagnostic guideline, many HFpEF patients continue to be misdiagnosed or underdiagnosed at the early stages until the disease has progressed much further along. It is extremely difficult to diagnose the HFpEF patient, because they have a normal ejection fraction and present with non-specific symptoms such as dyspnea or exercise intolerance. To provide greater specificity, the current diagnostic criteria mandate the presence of diastolic dysfunction, where myocardial relaxation is impaired and ventricular filling pressure is elevated as a result of a hypertrophic and stiff heart. Unfortunately, diastolic dysfunction reflects late-stage structural and functional changes and offers a very narrow window, if at all, for successful intervention. In this article, we review the imaging modalities used in the current diagnostic workflow for assessing HFpEF. We also describe the most up-to-date insight into its pathophysiological basis, which attributes systemic inflammation driven by comorbidities as the initiator of disease. With this extramyocardial perspective, we provide our recommendation on new imaging targets that extend beyond the heart to enable early, accurate diagnosis of HFpEF and allow an opportunity for treating this fatal condition.

Assessment of microvascular dysfunction in acute limb ischemia-reperfusion injury.

BACKGROUND: Ischemia-reperfusion (I/R) injury involves damage to the microvessel structure (eg, increased permeability) and function (blunted vasomodulation). While microstructural damage can be detected with dynamic contrast-enhanced (DCE) MRI, there is no diagnostic to detect deficits in microvascular function. PURPOSE: To apply a novel MRI method for evaluating dynamic vasomodulation to assess microvascular dysfunction in skeletal muscle following I/R injury. STUDY TYPE: Prospective, longitudinal. ANIMAL MODEL: Twenty-three healthy male adult Sprague-Dawley rats. FIELD STRENGTH/SEQUENCE: Dynamic T1 fast field echo imaging at 3.0T with preinjection T1 mapping. ASSESSMENT: Injury in the left hindlimb was induced using a 3-hour I/R procedure. Longitudinal MRI scanning was performed up to 74 days, with animals completing assessment at different intervals for histological and laser Doppler perfusion validation. Pharmacokinetic parameters Ktrans and ve were determined following i.v. injection of gadovist (0.1 mmol/kg). Vasomodulatory response was probed on gadofosveset (0.3 mmol/kg) using hypercapnic gases delivered through a controlled gas-mixing circuit to induce vasoconstriction and vasodilation in ventilated rats. Heart rate and blood oxygen saturation were monitored. STATISTICAL TESTS: Two-way analysis of variance with Tukey-Kramer post-hoc analysis was used to determine significant changes in vasomodulatory response, Ktrans , and ve . RESULTS: This new MRI technique revealed impaired vasomodulation in the injured hindlimb. Vasoconstriction was maintained, but vasodilation was blunted up to 21 days postinjury (P < 0.05). However, DCE-MRI measured Ktrans and ve were significantly (P < 0.05) different from baseline only during acute inflammation (Day 3), with severe inflammation noted on histology. DATA CONCLUSION: While conventional DCE-MRI shows normalization after the acute phase, our new approach reveals sustained functional impairment in muscle microvasculature following I/R injury, with compromised response in vasomotor tone present for at least 21 days. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:1174-1185.

Manganese-enhanced MRI of minimally gadolinium-enhancing breast tumors.

PURPOSE: To investigate the potential of manganese (Mn)-enhanced MRI for sensitive detection and delineation of tumors that demonstrate little enhancement on Gd-DTPA. MATERIALS AND METHODS: Eighteen nude rats bearing 1 to 2 cm in diameter orthotopic breast tumors (ZR75 and LM2) were imaged on a 3 Tesla (T) clinical scanner. Gd-DTPA was administered intravenously and MnCl2 subcutaneously, both at 0.05 mmol/kg. T1 -weighted imaging and T1 measurements were performed precontrast, 10 min post-Gd-DTPA, and 24 h post-MnCl2 . Tumors were excised and histologically assessed using H&E (composition and necrosis) and CD34 (vascularity). RESULTS: Most tumors (78%) demonstrated little enhancement (< 20% change in R1 ) on Gd-DTPA. MnCl2 administration achieved greater and more uniform enhancement throughout the tumor mass (i.e., not restricted to the tumor periphery), with R1 changing over 20% in 72% of tumors. MnCl2 -induced R1 changes compared with Gd-induced changes were significantly greater in both ZR75 (P < 0.01) and LM2 tumors (P < 0.05). Histology confirmed very low vascularity in both tumor models, and necrotic areas were well delineated only on Mn-enhanced MRI. CONCLUSION: Mn-enhanced MRI is a promising approach for detection of low-Gd-enhancing tumors.

Gadolinium-free extracellular MR contrast agent for tumor imaging.

PURPOSE: To evaluate a new formulation of manganese porphyrin as a potential gadolinium (Gd)-free extracellular magnetic resonance imaging (MRI) contrast agent for dynamic contrast-enhanced (DCE) MRI of tumors. MATERIALS AND METHODS: A previously reported new contrast agent, MnTCP, was evaluated in six female tumor-bearing nude rats. MRI was performed on a 3 T clinical scanner 3 to 4 weeks after inoculation of breast tumor cells in the mammary fat pads. Gd-DTPA was injected intravenously, followed by injection of MnTCP at least 2 hours later (both at 0.05 mmol/kg). T1 relaxation time measurements and DCE-MRI were performed. RESULTS: Enhancement and clearance patterns were visually similar between MnTCP and Gd-DTPA. However, relative R1 increases in all 11 tumors were larger for MnTCP over 60 minutes postcontrast, the difference being significant as late as 20 minutes (R1post /R1pre = 1.42 ± 0.15 for MnTCP vs. 1.20 ± 0.08 for Gd-DTPA, P < 0.05). R1 -related effects for MnTCP were largely reduced after 60 minutes (R1post /R1pre = 1.13 ± 0.07) and completely gone within 24 hours (R1post /R1pre = 0.97 ± 0.06). DCE-MRI revealed a consistently larger (1.5 to over 2-fold) peak enhancement and higher values of the steepest slope, time-to-peak, and AUC60 in all tumors with MnTCP (P < 0.01). CONCLUSION: MnTCP is an alternative to extracellular Gd agents for tumor imaging, offering sensitive detection and rapid renal clearance.

Noninvasive manganese-enhanced magnetic resonance imaging for early detection of breast cancer metastatic potential.

Cancer cells with a high metastatic potential will more likely escape and form distant tumors. Once the cancer has spread, a cure is rarely possible. Unfortunately, metastasis often proceeds unnoticed until a secondary tumor has formed. The culprit is that current imaging-based cancer screening and diagnosis are limited to assessing gross physical changes, not the earliest cellular changes that drive cancer progression. The purpose of this study is to develop a novel noninvasive magnetic resonance (MR) cellular imaging capability for characterizing the metastatic potential of breast cancer and enable early cancer detection. This MR method relies on imaging cell uptake of manganese, an endogenous calcium analogue and an MR contrast agent, to detect aggressive cancer cells. Studies on normal breast epithelial cells and three breast cancer cell lines, from nonmetastatic to highly metastatic, demonstrated that aggressive cancer cells appeared significantly brighter on MR as a result of altered cell uptake of manganese. In vivo results in nude rats showed that aggressive tumors that are otherwise unseen on conventional gadolinium-enhanced MR imaging are detected after manganese injection. This cellular MR imaging technology brings a critically needed, unique dimension to cancer imaging by enabling us to identify and characterize metastatic cancer cells at their earliest appearance.

Ultrashort echo time magnetic resonance imaging of the lung using a high-relaxivity t1 blood-pool contrast agent.

The lung remains one of the most challenging organs to image using magnetic resonance imaging (MRI) due to intrinsic rapid signal decay. However, unlike conventional modalities such as computed tomography, MRI does not involve radiation and can provide functional and morphologic information on a regional basis. Here we demonstrate proof of concept for a new MRI approach to achieve substantial gains in a signal to noise ratio (SNR) in the lung parenchyma: contrast-enhanced ultrashort echo time (UTE) imaging following intravenous injection of a high-relaxivity blood-pool manganese porphyrin T1 contrast agent. The new contrast agent increased relative enhancement of the lung parenchyma by over 10-fold compared to gadolinium diethylene triamine pentaacetic acid (Gd-DTPA), and the use of UTE boosted the SNR by a factor of 4 over conventional T1-weighted gradient echo acquisitions. The new agent also maintains steady enhancement over at least 60 minutes, thus providing a long time window for obtaining high-resolution, high-quality images and the ability to measure a number of physiologic parameters.

3D myocardial T1 mapping at 3T using variable flip angle method: pilot study.

PURPOSE: Myocardial T1 mapping is an emerging technique that could improve cardiovascular magnetic resonance diagnostic accuracy. In this study, a variable flip angle approach with B1 correction is proposed at 3T on the myocardium, employing standard 3D spoiled fast gradient echo and echo planar imaging sequences. METHODS: The method was tested on phantoms to determine the set of standard 3D spoiled fast gradient echo angles adapted to myocardial T1 measurements and was compared to the inversion-recovery spin-echo reference T1 method. Seven volunteers underwent magnetic imaging resonance to acquire myocardial T1 maps and T1 values of the human heart. RESULTS: This original method demonstrated good reproducibility in phantoms and a significant correlation between variable flip angle T1 values and reference inversion-recovery spin-echo T1 values. It yielded myocardial T1 values consistent with expected T1 and an increasing homogenization of myocardial segments owing to B1 correction. The mean myocardial T1 value was 1341 ± 42 ms. CONCLUSION: Myocardial 3D T1 mapping using the variable flip angle approach can potentially be useful for evaluating fibrosis on the entire myocardium using a standard clinical sequence.

Binding of a dimeric manganese porphyrin to serum albumin: towards a gadolinium-free blood-pool T1 MRI contrast agent.

As the first clinically approved gadolinium-based blood-pool MRI contrast agent, gadofosveset was designed to bind to human serum albumin (HSA) reversibly, extending the circulation time in the bloodstream. This valuable pharmacokinetic property required for vasculature imaging, however, raises the risk of release and accumulation of gadolinium in vivo. The binding of gadofosveset to HSA significantly increases the relaxivity at low field, which decreases drastically when the magnetic field increases, limiting the applications of gadofosveset at fields of 3 T and higher. To address those challenges, we evaluated a novel dimeric manganese(III) porphyrin (MnP2) in vitro and in vivo as a potential gadolinium-free blood-pool agent. Through multiple spectroscopic studies, we demonstrated that MnP2 binds to HSA tightly. MnP2 exhibits a moderate relaxivity decrease on HSA binding. Nevertheless, owing to the unique field-dependent relaxation behaviors and the dimeric construct (two Mn(III) ions per complex), MnP2-HSA has a molar relaxivity twice that of the gadofosveset-HSA complex at 3 T. Through intravenous injection in rats, MnP2 exhibits long retention and significant contrast enhancement in the vascular compartment, as tested in a 3-T high-field clinical MRI scanner. Taken together, these data demonstrate that MnP2 represents a new class of gadolinium-free blood-pool agents suitable for both regular and high-field applications.

Gadolinium-free T1 contrast agents for MRI: tunable pharmacokinetics of a new class of manganese porphyrins.

PURPOSE: To evaluate a new class of manganese porphyrins with tunable pharmacokinetics as potential gadolinium (Gd)-free T1 agents for contrast-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: Two new contrast agents, MnTCP and MnP2, were evaluated in four female rats. MRI was performed daily up to 3 days postinjection (0.05 mmol/kg) on a 3 T clinical scanner. T1 relaxation times and dynamic contrast-enhanced MRI were performed to assess contrast enhancement and clearance in blood, heart, liver, kidney, and muscle. RESULTS: Relative T1 decreases were similar for MnTCP and Gd-DTPA in all tissues but were significantly larger (P < 0.05) for MnP2 in blood, heart, kidney, and liver (2-6-fold larger). Clearance of MnTCP was similar to Gd-DTPA, with T1 returning to baseline by 40 minutes and complete elimination in 1 day. MnP2 was cleared from blood after 2 days and sustained a lowered T1 in other tissues for at least 1 hour (P < 0.05). The maximum enhancement, slope, and time-to-peak were similar between contrast agents. Only the parameter AUC60 differed, with MnP2 yielding the largest AUC60 values primarily through longer retention in tissue. CONCLUSION: MnTCP and MnP2 offer distinct applications as Gd-free T1 contrast agents. MnTCP behaves like a Gd-DTPA analog, while MnP2 provides significantly greater and longer positive signal enhancement.

Longitudinal Magnetic Resonance Imaging Tracking of Transplanted Neural Progenitor Cells in the Spinal Cord Utilizing the Bright-Ferritin Mechanism.

Human neural progenitor cells (hNPCs) hold promise for treating spinal cord injury. Studies to date have focused on improving their regenerative potential and therapeutic effect. Equally important is ensuring successful delivery and engraftment of hNPCs at the injury site. Unfortunately, no current imaging solution for cell tracking is compatible with long-term monitoring in vivo. The objective of this study was to apply a novel bright-ferritin magnetic resonance imaging (MRI) mechanism to track hNPC transplants longitudinally and on demand in the rat spinal cord. We genetically modified hNPCs to stably overexpress human ferritin. Ferritin-overexpressing (FT) hNPCs labeled with 0.2 mM manganese provided significant T1-induced bright contrast on in vitro MRI, with no adverse effect on cell viability, morphology, proliferation, and differentiation. In vivo, 2 M cells were injected into the cervical spinal cord of Rowett nude rats. MRI employed T1-weighted acquisitions and T1 mapping on a 3 T scanner. Conventional short-term cell tracking was performed using exogenous Mn labeling prior to cell transplantation, which displayed transient bright contrast on MRI 1 day after cell transplantation and disappeared after 1 week. In contrast, long-term cell tracking using bright-ferritin allowed on-demand signal recall upon Mn supplementation and precise visualization of the surviving hNPC graft. In fact, this new cell tracking technology identified 7 weeks post-transplantation as the timepoint by which substantial hNPC integration occurred. Spatial distribution of hNPCs on MRI matched that on histology. In summary, bright-ferritin provides the first demonstration of long-term, on-demand, high-resolution, and specific tracking of hNPCs in the rat spinal cord.

A primer on in vivo cell tracking using MRI.

Cell tracking by in vivo magnetic resonance imaging (MRI) offers a collection of multiple advantages over other imaging modalities, including high spatial resolution, unlimited depth penetration, 3D visualization, lack of ionizing radiation, and the potential for long-term cell monitoring. Three decades of innovation in both contrast agent chemistry and imaging physics have built an expansive array of probes and methods to track cells non-invasively across a diverse range of applications. In this review, we describe both established and emerging MRI cell tracking approaches and the variety of mechanisms available for contrast generation. Emphasis is given to the advantages, practical limitations, and persistent challenges of each approach, incorporating quantitative comparisons where possible. Toward the end of this review, we take a deeper dive into three key application areas - tracking cancer metastasis, immunotherapy for cancer, and stem cell regeneration - and discuss the cell tracking techniques most suitable to each.

Arrhenius-model-based degradable oligourethane hydrogels for controlled growth factor release.

Biodegradable hydrogels are growing in demand to enable the delivery of biomolecules (e.g. growth factors) for regenerative medicine. This research investigated the resorption of an oligourethane/polyacrylic acid hydrogel, a biodegradable hydrogel which supports tissue regeneration. The Arrhenius model was used to characterize the resorption of the polymeric gels in relevant in vitro conditions, and the Flory-Rehner equation was used to correlate the volumetric swelling ratio with the extent of degradation. The study found that the swelling rate of the hydrogel follows the Arrhenius model at elevated temperatures, estimating degradation time in saline solution at 37°C to be between 5 and 13 months, serving as a preliminary approximation of degradation in vivo. The degradation products had low cytotoxicity towards endothelial cells, and the hydrogel supported stromal cell proliferation. Additionally, the hydrogels were able to release growth factors and maintain the biomolecules' bioactivity towards cell proliferation. The study of the vascular endothelial growth factor (VEGF) release from the hydrogel used a diffusion process model, showing that the electrostatic attraction between VEGF and the anionic hydrogel allowed for controlled and sustained VEGF release over three weeks. In a rat subcutaneous implant model, a selected hydrogel with desired degradation rates exhibited minimal foreign body response and supported M2a macrophage phenotype, and vascularization. The low M1 and high M2a macrophage phenotypes within the implants were associated with tissue integration. This research supports the use of oligourethane/polyacrylic acid hydrogels as a promising material for delivering growth factors and supporting tissue regeneration. STATEMENT OF SIGNIFICANCE: There is a need for degradable elastomeric hydrogels that can support the formation of soft tissues and minimize long-term foreign body responses. An Arrhenius model was used to estimate the relative breakdown of hydrogels, in-vitro. The results demonstrate that hydrogels made from a combination of poly(acrylic acid) and oligo-urethane diacrylates can be designed to resorb over defined periods ranging from months to years depending on the chemical formulation prescribed by the model. The hydrogel formulations also provided for different release profiles of growth factors, relevant to tissue regeneration. In-vivo, these hydrogels had minimal inflammatory effects and showed evidence of integration into the surrounding tissue. The hydrogel approach can help the field design a broader range of biomaterials for tissue regeneration.

A predictive signal model for dynamic cardiac magnetic resonance imaging.

Robust dynamic cardiac magnetic resonance imaging (MRI) has been a long-standing endeavor-as real-time imaging can provide information on the temporal signatures of disease we currently cannot assess-with the past decade seeing remarkable advances in acceleration using compressed sensing (CS) and artificial intelligence (AI). However, substantial limitations to real-time imaging remain and reconstruction quality is not always guaranteed. To improve reconstruction fidelity in dynamic cardiac MRI, we propose a novel predictive signal model that uses a priori statistics to adaptively predict temporal cardiac dynamics. By using a small training set obtained from the same patient, the new signal model can achieve robust dynamic cardiac MRI in the presence of irregular cardiac rhythm. Evaluation on simulated irregular cardiac dynamics and prospectively undersampled clinical cardiac MRI data demonstrate improved reconstruction quality for two reconstruction frameworks: Kalman filter and CS. The predictive model also works with different undersampling patterns (cartesian, radial, spiral) and can serve as a versatile foundation for robust dynamic cardiac MRI.

Blood-pool MRI assessment of myocardial microvascular reactivity.

Purpose: The ability to non-invasively image myocardial microvascular dilation and constriction is essential to assessing intact function and dysfunction. Yet, conventional measurements based on blood oxygenation are not specific to changes in blood volume. The purpose of this study was to extend to the heart a blood-pool MRI approach for assessing vasomodulation in the presence of blood gas changes and investigate if sex-related differences exist. Methods: Animals [five male and five female healthy Sprague Dawley rats (200-500 g)] were intubated, ventilated, and cycled through room air (normoxia) and hypercapnia (10% CO2) in 10-minute cycles after i.v. injection of blood-pool agent Ablavar (0.3 mmol/kg). Pre-contrast T1 maps and T1-weighted 3D CINE were acquired on a 3 Tesla preclinical MRI scanner, followed by repeated 3D CINE every 5 min until the end of the gas regime. Invasive laser Doppler flowmetry of myocardial perfusion was performed to corroborate MRI results. Results: Myocardial microvascular dilation to hypercapnia and constriction to normoxia were readily visualized on T1 maps. Over 10 min of hypercapnia, female myocardial T1 reduced by 20% (vasodilation), while no significant change was observed in the male myocardium. After return to normoxia, myocardial T1 increased (vasoconstriction) in both sexes (18% in females and 16% in males). Laser Doppler perfusion measurements confirmed vasomodulatory responses observed on MRI. Conclusion: Blood-pool MRI is sensitive and specific to vasomodulation in the myocardial microcirculation. Sex-related differences exist in the healthy myocardium in response to mild hypercapnic stimuli.

Dual-domain accelerated MRI reconstruction using transformers with learning-based undersampling.

Acceleration in MRI has garnered much attention from the deep-learning community in recent years, particularly for imaging large anatomical volumes such as the abdomen or moving targets such as the heart. A variety of deep learning approaches have been investigated, with most existing works using convolutional neural network (CNN)-based architectures as the reconstruction backbone, paired with fixed, rather than learned, k-space undersampling patterns. In both image domain and k-space, CNN-based architectures may not be optimal for reconstruction due to its limited ability to capture long-range dependencies. Furthermore, fixed undersampling patterns, despite ease of implementation, may not lead to optimal reconstruction. Lastly, few deep learning models to date have leveraged temporal correlation across dynamic MRI data to improve reconstruction. To address these gaps, we present a dual-domain (image and k-space), transformer-based reconstruction network, paired with learning-based undersampling that accepts temporally correlated sequences of MRI images for dynamic reconstruction. We call our model DuDReTLU-net. We train the network end-to-end against fully sampled ground truth dataset. Human cardiac CINE images undersampled at different factors (5-100) were tested. Reconstructed images were assessed both visually and quantitatively via the structural similarity index, mean squared error, and peak signal-to-noise. Experimental results show superior performance of DuDReTLU-net over state-of-the-art methods (LOUPE, k-t SLR, BM3D-MRI) in accelerated MRI reconstruction; ablation studies show that transformer-based reconstruction outperformed CNN-based reconstruction in both image domain and k-space; dual-domain reconstruction architectures outperformed single-domain reconstruction architectures regardless of reconstruction backbone (CNN or transformer); and dynamic sequence input leads to more accurate reconstructions than single frame input. We expect our results to encourage further research in the use of dual-domain architectures, transformer-based architectures, and learning-based undersampling, in the setting of accelerated MRI reconstruction. The code for this project is made freely available at https://github.com/william2343/dual-domain-mri-recon-nets (Hong et al., 2022).