Institute of Biomaterials & Biomedical Engineering

Permanent URI for this collectionhttps://hdl.handle.net/1807/71651

The Institute of Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto is a unique, multidisciplinary research unit where investigators from engineering, medicine and dentistry collaborate to find innovative solutions for the world’s most pressing health-care challenges.

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Advancing tissue-engineered vascular grafts via their endothelialization and mechanical conditioning
(Edizioni Minerva Medica, 2020-10) Antonyshyn, Jeremy A.; D'Costa, Katya A.; Santerre, J. Paul
Tissue engineering has garnered significant attention for its potential to address the predominant modes of failure of small diameter vascular prostheses, namely mid-graft thrombosis and anastomotic intimal hyperplasia. In this review, we described two main features underpinning the promise of tissue-engineered vascular grafts: the incorporation of an antithrombogenic endothelium, and the generation of a structurally and biomechanically mimetic extracellular matrix. From the early attempts at the in-vitro endothelialization of vascular prostheses in the 1970s through to the ongoing clinical trials of fully tissue-engineered vascular grafts, the historical advancements and unresolved challenges that characterize the current state-of-the-art are summarized in a manner that establishes a guide for the development of an effective vascular prosthesis for small diameter arterial reconstruction. The importance of endothelial cell purity and their arterial specification for the prevention of both diffuse neointimal hyperplasia and the accelerated development of atherosclerotic lesions is delineated. Additionally, the need for an extracellular matrix that recapitulates both the composition and structure of native elastic arteries to facilitate the protracted stability and patency of an engineered vasoactive conduit is described. Finally, the capacity of alternative sources of cells and mechanical conditioning to overcome these technical barriers to the clinical translation of an effective small diameter vascular prosthesis is discussed. In conclusion, this review provides an overview of the historical development of tissue-engineered vascular grafts, highlighting specific areas warranting further research, and commentating on the outlook of a clinically feasible and therapeutically efficacious vascular prosthesis for small diameter arterial reconstruction.
Tracking the expression of therapeutic protein targets in rare cells by antibody-mediated nanoparticle labelling and magnetic sorting
(Nature Research, 2020-07-27) Labib, Mahmoud; Wang, Zongjie; Ahmed, Sharif U; Mohamadi, Reza M; Duong, Bill; Green, Brenda; Sargent, Edward H; Kelley, Shana O
Molecular-level features of tumours can be tracked using single-cell analyses of circulating tumour cells (CTCs). However, single-cell measurements of protein expression for rare CTCs are hampered by the presence of a large number of non-target cells. Here, we show that antibody-mediated labelling of intracellular proteins in the nucleus, mitochondria and cytoplasm of human cells with magnetic nanoparticles enables analysis of target proteins at the single-cell level by sorting the cells according to their nanoparticle content in a microfluidic device with cell-capture zones sandwiched between arrays of magnets. We used the magnetic labelling and cell-sorting approach to track the expression of therapeutic protein targets in CTCs isolated from blood samples of mice with orthotopic prostate xenografts and from patients with metastatic castration-resistant prostate cancer. We also show that mutated proteins that are drug targets or markers of therapeutic response can be directly identified in CTCs, analysed at the single-cell level and used to predict how mice with drug-susceptible and drug-resistant pancreatic tumour xenografts respond to therapy.
Unobtrusive Pain Monitoring in Older Adults with Dementia using Pairwise and Contrastive Training
(IEEE, 2020-12-18) Rezaei, Sia; Moturu, Abhishek; Zhao, Shun; Prkachin, K M; Hadjistavropoulos, Thomas; Taati, Babak
Although pain is frequent in old age, older adults are often undertreated for pain. This is especially the case for long-term care residents with moderate to severe dementia who cannot report their pain because of cognitive impairments that accompany dementia. Nursing staff acknowledge the challenges of effectively recognizing and managing pain in long-term care facilities due to lack of human resources and, sometimes, expertise to use validated pain assessment approaches on a regular basis. Vision-based ambient monitoring will allow for frequent automated assessments so care staff could be automatically notified when signs of pain are displayed. However, existing computer vision techniques for pain detection are not validated on faces of older adults or people with dementia, and this population is not represented in existing facial expression datasets of pain. We present the first fully automated vision-based technique validated on a dementia cohort. Our contributions are threefold. First, we develop a deep learning based computer vision system for detecting painful facial expressions on a video dataset that is collected unobtrusively from older adult participants with and without dementia. Second, we introduce a pairwise comparative inference method that calibrates to each person and is sensitive to changes in facial expression while using training data more efficiently than sequence models. Third, we introduce a fast contrastive training method that improves cross-dataset performance. Our pain estimation model outperforms baselines by a wide margin, especially when evaluated on faces of people with dementia. Pre-trained model and demo code available at https://github.com/TaatiTeam/pain_detection_demo.
Rapid high-resolution T(1) mapping by variable flip angles: accurate and precise measurements in the presence of radiofrequency field inhomogeneity
(Wiley, 2006-01-31) Cheng, Hai-Ling Margaret; Wright, Graham A
Rapid 3D mapping of T(1) relaxation times is valuable in diverse clinical applications. Recently, the variable flip angle (VFA) spoiled gradient recalled echo approach was shown to be a practical alternative to conventional methods, providing better precision and speed. However, the method is known to be sensitive to transmit field (B(1) (+)) inhomogeneity and can result in significant systematic errors in T(1) estimates, especially at high field strengths. The main challenge is to improve the accuracy of the VFA approach without sacrificing speed. In this article, the VFA method was optimized for both accuracy and precision by considering the influence of imperfect transmit fields, noise bias, and selection of flip angles. An analytic solution was developed for systematic B(1) (+)-induced T(1) errors and allows simple correction of T(1) measurements acquired with any imaging parameters. A noise threshold was also identified and provided a guideline for avoiding T(1) biases. Finally, it was shown that three flip angles were the most efficient for maintaining accuracy and high precision over large ranges of T(1). A rapid B(1) (+) mapping sequence was employed in all phantom experiments and high-field in vivo brain scans. Experimental results confirmed the theory and validated the accuracy of the proposed method.
Temporal resolution and SNR requirements for accurate DCE-MRI data analysis using the AATH model
(Wiley, 2010-08-16) Kershaw, Lucy E; Cheng, Hai-Ling Margaret
Dynamic contrast-enhanced MRI has been used in conjunction with tracer kinetics modeling in a wide range of tissues for treatment monitoring, oncology drug development, and investigation of disease processes. Accurate measurement of model parameters relies on acquiring data with high temporal resolution and low noise, particularly for models with large numbers of free parameters, such as the adiabatic approximation to the tissue homogeneity model for separate measurements of blood flow and vessel permeability. In this simulation study, accuracy of the adiabatic approximation to the tissue homogeneity model was investigated, examining the effects of temporal resolution, noise levels, and error in the measured arterial input function. A temporal resolution of 1.5 s and high SNR (noise sd = 0.05) were found to ensure minimal bias (<5%) in all four model parameters (extraction fraction, blood flow, mean transit time, and extravascular extracellular volume), and the sampling interval can be relaxed to 6 s, if the transit time need not be measured accurately (bias becomes >10%). A 10% error in the measured height of the arterial input function first pass peak resulted in an error of at most 10% in each model parameter.
MRI method for labeling and imaging decellularized extracellular matrix scaffolds for tissue engineering
(Wiley, 2019-11-14) Szulc, Daniel Andrzej; Ahmadipour, Mohammadali; Aoki, Fabio Gava; Waddell, Thomas K; Karoubi, Golnaz; Cheng, Hai-Ling Margaret
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, MnPNH , 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 a3T clinical scanner was performed to assess reductions in T and T 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 MnPNH and its long‐term retention in dECM were assessed on transmission electron microscopy and ultraviolet absorbance of eluted MnPNH 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 T 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% MnPNH 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 onMRI and has the potential for long‐term monitoring and optimization of dECM‐based organ tissue engineering.
Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane
(Springer Nature, 2019-08-30) Bayat Mokhtari, Reza; Baluch, Narges; Morgatskaya, Evgeniya; Kumar, Sushil; Sparaneo, Angelo; Muscarella, Lucia Anna; Zhao, Sheyun; Cheng, Hai-Ling; Das, Bikul; Yeger, Herman
Background: Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants,the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchialcarcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchialcarcinoid phenotype and behavior. Methods: Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factorsupplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansionof the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity inboth subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFNcombination were evaluated for targeting TIC in bronchial carcinoids. Results: Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drugresistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection andexpansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressedstemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derivedspheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumorformation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroidformation and in reducing tumor formation in immunocompromised mice. Conclusions: Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TICexhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that maytarget the TIC population of bronchial carcinoids.
Manganese-porphyrin-enhanced MRI for the detection of cancer cells: A quantitative in vitro investigation with multiple clinical subtypes of breast cancer
(Public Library of Science, 2018-05-24) Alhamami, Mosa; Cheng, Weiran; Lyu, Yuanyuan; Allen, Christine; Zhang, Xiao-An; Cheng, Hai-Ling
Magnetic resonance imaging (MRI) contrast agents (CAs) are chemical compounds that can enhance image contrast on T1- or T2- weighted MR image. We have previously demonstrated the potential of MnCl2, a manganese-based CA, in cellular imaging of breast cancer using T1-weighted MRI. In this work, we examined the potential of another class of manganese-based CAs, manganese porphyrins (MnPs), for sensitive cellular detection of multiple clinical subtypes of breast cancer using quantitative MRI. Using a clinical 3.0-T MRI scanner, the relaxivities of two MnPs, MnTPPS4 and MnTPPS3NH2, and conventional Gd-DTPA (control) were measured in ultrapure water and their T1 contrast enhancement patterns were characterized in multiple clinical subtypes of breast cancer. The toxicity of the three CAs was evaluated in vitro. Compared to Gd-DTPA, both MnTPPS3NH2 and MnTPPS4 enabled a more sensitive multi-subtype detection of four breast cell lines at doses that posed no cytotoxic effects, with MnTPPS3NH2 producing the greatest positive enhancement. The superior T1 enhancement capabilities of MnPs over Gd-DTPA are statistically significant and are likely due to their greater cellular uptake and relaxivities. The results demonstrate that multiple clinical subtypes of breast cancer can be imaged on a 3.0-T MRI scanner using MnPs as T1 cellular CAs.
A technique for rapid single-echo spin-echo T2 mapping
(Wiley, 2010-07-20) Sussman, Marshall S; Vidarsson, Logi; Pauly, John M; Cheng, Hai-Ling Margaret
A rapid technique for mapping of T(2) relaxation times is presented. The method is based on the conventional single-echo spin echo approach but uses a much shorter pulse repetition time to accelerate data acquisition. The premise of the new method is the use of a constant difference between the echo time and pulse repetition time, which removes the conventional and restrictive requirement of pulse repetition time > T(1). Theoretical and simulation investigations were performed to evaluate the criteria for accurate T(2) measurements. Measured T(2)s were shown to be within 1% error as long as the key criterion of pulse repetition time/T(2) > or =3 is met. Strictly, a second condition of echo time/T(1) < 1 is also required. However, violations of this condition were found to have minimal impact in most clinical scenarios. Validation was conducted in phantoms and in vivo T(2) mapping of healthy cartilage and brain. The proposed method offers all the advantages of single-echo spin echo imaging (e.g., immunity to stimulated echo effects, robustness to static field inhomogeneity, flexibility in the number and choice of echo times) in a considerably reduced amount of time and is readily implemented on any clinical scanner.
A manganese porphyrin-based T1 contrast agent for cellular MR imaging of human embryonic stem cells
(Nature Research, 2018-08-14) Venter, Andrei; Szulc, Daniel A; Loai, Sadi; Ganesh, Tameshwar; Haedicke, Inga E; Cheng, Hai-Ling Margaret
MRI for non-invasive cell tracking is recognized for enabling pre-clinical research on stem cell therapy. Yet, adoption of cellular imaging in stem cell research has been restricted to sites with experience in MR contrast agent synthesis and to small animal models that do not require scaled-up synthesis. In this study, we demonstrate the use of a gadolinium-free T1 contrast agent for tracking human embryonic stem cells. The agent, MnPNH2, is an easily synthesized manganese porphyrin that can be scaled for large cell numbers. MRI was performed on a 3 T clinical scanner. Cell pellets labeled at different MnPNH2 concentrations for 24 hours demonstrated a decrease in T1 relaxation time of nearly two-fold (P < 0.05), and cellular contrast was maintained for 24 hours (P < 0.05). Cell viability (Trypan blue) and differentiation (embryoid body formation) were unaffected. Cell uptake of Mn on inductively coupled plasma atomic emission spectroscopy corroborated MRI findings, and fluorescence microscopy revealed the agent localized mainly in cell-cell boundaries and cell nuclei. Labeled cells transplanted in rats demonstrated the superior sensitivity of MnPNH2 for in-vivo cell tracking.
Clinical Perspectives on 3D Bioprinting Paradigms for Regenerative Medicine
(Hapres, 2019-07-23) Loai, Sadi; Kingston, Benjamin R.; Wang, Zongjie; Philpott, David N.; Tao, Mingyang; Cheng, Hai-Ling Margaret
Three-dimensional (3D) bioprinting is an emerging manufacturing technology that layers living cells and biocompatible natural or synthetic materials to build complex, functional living tissue with the requisite 3D geometries. This technology holds tremendous promise across a plethora of applications as diverse as regenerative medicine, pathophysiological studies, and drug testing. Despite some success demonstrated in early attempts to recreate complex tissue structures, however, the field of bioprinting is very much in its infancy. There are a variety of challenges to building viable, functional, and lasting 3D structures, not the least of which is translation from a research to a clinical setting. In this review, the current translational status of 3D bioprinting is assessed for several major tissue types in the body (skin, bone/cartilage, cardiovascular, central/peripheral nervous systems, skeletal muscle, kidney, and liver), recent breakthroughs and current challenges are highlighted, and future prospects for this exciting research field are discussed. We begin with an overview of the technology itself, followed by a detailed discussion of the current approaches relevant for bioprinting different tissues for regenerative medicine.
A novel MRI analysis for assessment of microvascular vasomodulation in low-perfusion skeletal muscle
(Nature Research, 2020-03-13) Zakher, Eric; Ganesh, Tameshwar; Cheng, Hai-Ling Margaret
Compromised microvascular reactivity underlies many conditions and injuries, but its assessment remains difficult, particularly in low perfusion tissues. In this paper, we develop a new mathematical model for the assessment of vasomodulation in low perfusion settings. A first-order model was developed to approximate changes in T1 relaxation times as a result of vasomodulation. Healthy adult rats (N = 6) were imaged on a 3-Tesla clinical MRI scanner, and vasoactive response was probed on gadofosveset using hypercapnic gases at 20% and 5% CO2 to induce vasoconstriction and vasodilation, respectively. MRI included dynamic 3D T1 mapping and T1-weighted images during gas challenge; heart rate was continuously monitored. Laser Doppler perfusion measurements were performed to corroborate MRI findings. The model was able to identify hypercapnia-mediated vasoconstriction and vasodilation through the partial derivative [Formula: see text]. MRI on animals revealed gradual vasoconstriction in the skeletal muscle bed in response to 20% CO2 followed by gradual vasodilation on transitioning to 5% CO2. These trends were confirmed on laser Doppler perfusion measurements. Our new mathematical model has the potential for detecting microvascular dysfunction that manifests in the early stages across multiple metabolic and ischemic pathologies.
Synthesis of degradable-polar-hydrophobic-ionic co-polymeric microspheres by membrane emulsion photopolymerization: In vitro and in vivo studies
(Elsevier, 2019-03-07) Tawagi, Eric; Ganesh, Tameshwar; Cheng, Hai-Ling Margaret; Santerre, J Paul
The synthesis of microspheres for tissue regeneration requires good control over the particle size and size distribution. This is particularly important when considering the immune response that may be triggered by the presence of particles in tissue. This report outlines the design of an injectable microsphere system using a low-inflammatory, degradable-polar-hydrophobic-ionic polyurethane, termed D-PHI, and investigates the system's performance in vitro and in vivo. Crosslinked polyurethane microspheres were prepared via a rapid and controlled process based on membrane emulsion and subsequent photopolymerization. The fabrication process efficiently generated microspheres with a narrow size distribution (12 ± 2 μm, PDI = 0.03). The D-PHI microspheres exhibited a slow and controlled degradation and a high capacity for water uptake. Water within the particles existed primarily within the pores of the particles and to a lesser degree within the polymer matrix itself. D-PHI microspheres supported human endothelial and fibroblast cell growth, and they maintained human blood-derived monocytes in a low-inflammatory state. Sub-acute toxicity was assessed for the particles after being administered via intramuscular injection in the gastrocnemius muscle of rats. Cellular infiltration and vascularization into the tissue region where the particles were deposited were observed along with an absence of a fibrous capsule around the particles. The microspheres did not cause elevated human monocyte induced inflammatory character, and supported tissue integration without a prolonged inflammatory response in the rat muscle. These injectable, degradable and low-inflammatory microspheres provide an attractive system for potential drug delivery and tissue regeneration applications in future studies. STATEMENT OF SIGNIFICANCE: Biodegradable, synthetic polymers are attractive candidates for generating tailored drug delivery vehicles and tissue scaffolds owing to their diverse chemical and physical properties that can be customised for delivering defined macromolecules at specific sites in the body. The past two decades have yielded interesting work exploring the fabrication of polymer microspheres with a narrow size distribution. However, the markedly low number of synthetic polymer chemistries currently used for microsphere production exhibit elevated proinflammatory character, both acute and chronic. Furthermore, a limited number of studies have explored the biocompatibility and immune response of polymeric microspheres with human primary cells and in vivo. In the current study, a method was conceived for efficiently generating low-activating polyurethane microspheres with respect to in vitro monocytes and in vivo macrophages. The biodegradable polyurethane, which contained multiple chemistry function and which has previously demonstrated anti-inflammatory properties in film and mm scale scaffold form, was selected as the base material. In this work we undertook the use of a room temperature membrane emulsification photopolymerization approach to avoid the need for high temperature cures and the use of solvents. The response of immune cells to the microspheres was studied with human primary cells and in the rat gastrocnemius muscle. The present work reveals important progress in the design of microspheres, with well-characterized low monocyte-activating properties and the translational advantages of a synthetic polyurethane which could be investigated in future studies for potential macromolecule delivery and tissue regeneration applications.
One-Step Labeling of Collagen Hydrogels with Polydopamine and Manganese Porphyrin for Non-Invasive Scaffold Tracking on Magnetic Resonance Imaging
(Wiley, 2019-01-15) Szulc, Daniel Andrzej; Cheng, Hai-Ling Margaret
Biomaterial scaffolds are the cornerstone to supporting 3D tissue growth. Optimized scaffold design is critical to successful regeneration, and this optimization requires accurate knowledge of the scaffold's interaction with living tissue in the dynamic in vivo milieu. Unfortunately, non-invasive methods that can probe scaffolds in the intact living subject are largely underexplored, with imaging-based assessment relying on either imaging cells seeded on the scaffold or imaging scaffolds that have been chemically altered. In this work, the authors develop a broadly applicable magnetic resonance imaging (MRI) method to image scaffolds directly. A positive-contrast "bright" manganese porphyrin (MnP) agent for labeling scaffolds is used to achieve high sensitivity and specificity, and polydopamine, a biologically derived universal adhesive, is employed for adhering the MnP. The technique was optimized in vitro on a prototypic collagen gel, and in vivo assessment was performed in rats. The results demonstrate superior in vivo scaffold visualization and the potential for quantitative tracking of degradation over time. Designed with ease of synthesis in mind and general applicability for the continuing expansion of available biomaterials, the proposed method will allow tissue engineers to assess and fine-tune the in vivo behavior of their scaffolds for optimal regeneration.
Heart failure with preserved ejection fraction: the missing pieces in diagnostic imaging
(Springer Nature, 2019-07-31) Loai, Sadi; Cheng, Hai-Ling Margaret
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
(Wiley, 2018-10-09) Ganesh, Tameshwar; Zakher, Eric; Estrada, Marvin; Cheng, Hai-Ling Margaret
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
Liver iron overload assessment by T 2 magnetic resonance imaging in pediatric patients: an accuracy and reproducibility study
(Wiley, 2012-01-05) Cheng, Hai-Ling Margaret; Holowka, Stephanie; Moineddin, Rahim; Odame, Isaac
T2 magnetic resonance imaging (MRI) provides rapid quantiﬁcation of liver iron content (LIC). The reciprocal of T2 is directly proportional to iron and has been calibrated against LIC. There has, however, been few independent validation of the T2 method in a clinical setting. In 100 MRI studies on 75 pediatric patients being investigated for liver iron overload, we assess the accuracy and reproducibility of T2-measured LIC, using regulatory approved T2-based FerriScan1 for reference measurements. Results from independent analyses by two observers demonstrated robust inter- and intra-observer agreement (intraclass correlation coefﬁcient (ICC) 5 0.99 and 1.0, respectively). T2-measured and reference LIC were strongly correlated (r 5 0.94, P < 0.0001), with a regression slope of 0.97 over the range 0–25 mg Fe/g. The T2 technique is shown to be accurate and reproducible for rapid, non-invasive LIC quantiﬁcation.
The acellular matrix (ACM) for bladder tissue engineering: A quantitative magnetic resonance imaging study
(Wiley, 2010-07-20) Cheng, Hai-Ling Margaret; Loai, Yasir; Beaumont, Marine; Farhat, Walid A
Bladder acellular matrices (ACMs) derived from natural tissue are gaining increasing attention for their role in tissue engineering and regeneration. Unlike conventional scaffolds based on biodegradable polymers or gels, ACMs possess native biomechanical and many acquired biologic properties. Efforts to optimize ACM-based scaffolds are ongoing and would be greatly assisted by a noninvasive means to characterize scaffold properties and monitor interaction with cells. MRI is well suited to this role, but research with MRI for scaffold characterization has been limited. This study presents initial results from quantitative MRI measurements for bladder ACM characterization and investigates the effects of incorporating hyaluronic acid, a natural biomaterial useful in tissue-engineering and regeneration. Measured MR relaxation times (T(1), T(2)) and diffusion coefficient were consistent with increased water uptake and glycosaminoglycan content observed on biochemistry in hyaluronic acid ACMs. Multicomponent MRI provided greater specificity, with diffusion data showing an acellular environment and T(2) components distinguishing the separate effects of increased glycosaminoglycans and hydration. These results suggest that quantitative MRI may provide useful information on matrix composition and structure, which is valuable in guiding further development using bladder ACMs for organ regeneration and in strategies involving the use of hyaluronic acid.
Binding of a dimeric manganese porphyrin to serum albumin: towards a gadolinium-free blood-pool T1 MRI contrast agent
(Springer Verlag, 2014-01-10) Cheng, Weiran; Ganesh, Tameshwar; Martinez, Francisco; Lam, Jolie; Yoon, Hyung; Macgregor, Robert B; Scholl, Timothy J; Cheng, Hai-Ling Margaret; Zhang, Xiao-an
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.
Complementary strategies for developing Gd-free high-field T₁ MRI contrast agents based on Mn(III) porphyrins
(American Chemical Society, 2013-12-12) Cheng, Weiran; Haedicke, Inga E; Nofiele, Joris; Martinez, Francisco; Beera, Kiran; Scholl, Timothy J; Cheng, Hai-Ling Margaret; Zhang, Xiao-An
Mn(III) porphyrin (MnP) holds the promise of addressing the emerging challenges associated with Gd-based clinical MRI contrast agents (CAs), namely, Gd-related adverse effect and decreasing sensitivity at high clinical magnetic fields. Two complementary strategies for developing new MnPs as Gd-free CAs with optimized biocompatibility were established to improve relaxivity or clearance rate. MnPs with distinct and tunable pharmacokinetic properties can consequently be constructed for different in vivo applications at clinical field of 3 T.

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