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A functional tacrolimus-releasing nerve wrap for enhancing nerve regeneration following surgical nerve repair

Neural Regeneration Research 2025年第1期20卷 291-304页

作者： Simeon C.Daeschler Katelyn J.W.So Konstantin Feinberg Marina Manoraj Jenny Cheung Jennifer Zhang Kaveh Mirmoeini JPaul Santerre Tessa Gordon Gregory HBorschel SickKids Research Institute Neuroscience and Mental Health ProgramTorontoONCanada Institute of Biomaterials and Biomedical Engineering University of TorontoTorontoONCanada Indiana University School of Medicine IndianapolisINUSA Division of Plastic and Reconstructive Surgery the Hospital for Sick ChildrenTorontoONCanada Translational Biology and Engineering Program Ted Rogers Centre for Heart ResearchInstitute of Biomedical EngineeringFaculty of DentistryUniversity of TorontoTorontoONCanada

Axonal regeneration following surgical nerve repair is slow and often incomplete,resulting in poor functional recovery which sometimes contributes to lifelong ***,there are no FDA-approved therapies available to promote nerve *** accelerates axonal regeneration,but systemic side effects presently outweigh its potential benefits for peripheral nerve *** authors describe herein a biodegradable polyurethane-based drug delivery system for the sustained local release of tacrolimus at the nerve repair site,with suitable properties for scalable production and clinical application,aiming to promote nerve regeneration and functional recovery with minimal systemic drug *** is encapsulated into co-axially electrospun polycarbonate-urethane nanofibers to generate an implantable nerve wrap that releases therapeutic doses of bioactive tacrolimus over 31 *** and drug loading are adjustable for applications in small and large caliber nerves,and the wrap degrades within 120 days into biocompatible *** released from the nerve wrap promotes axon elongation in vitro and accelerates nerve regeneration and functional recovery in preclinical nerve repair models while off-target systemic drug exposure is reduced by 80%compared with systemic *** its surgical suitability and preclinical efficacy and safety,this system may provide a readily translatable approach to support axonal regeneration and recovery in patients undergoing nerve surgery.

关键词： biodegradable local drug delivery nerve injury nerve regeneration nerve wrap tacrolimus

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Human induced pluripotent stem cell derived nanovesicles for cardiomyocyte protection and proliferation

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Bioactive Materials 2025年 50卷 585-602页

作者： Wei, Yuhua Geng, Xiaoxiao You, Qing Zhang, Yu Cao, Fangfang Narayanan, Gunaseelan Nguyen, Thanh Chen, Xiaoyuan Zhang, Jianyi Ye, Lei Department of Diagnostic Radiology Yong Loo Lin School of Medicine National University of Singapore 1190742 United States Department of Chemical and Biomolecular Engineering College of Design and Engineering National University of Singapore 1175753 Singapore Department of Biomedical Engineering College of Design and Engineering National University of Singapore 1175754 Singapore Department of Pharmacy and Pharmaceutical Sciences Faculty of Science National University of Singapore 1175445 Singapore Clinical Imaging Research Centre Centre for Translational Medicine Yong Loo Lin School of Medicine National University of Singapore 1175996 Singapore Nanomedicine Translational Research Program Yong Loo Lin School of Medicine National University of Singapore 1175977 Singapore Theranostics Center of Excellence (TCE) Yong Loo Lin School of Medicine National University of Singapore 1386678 Singapore Institute of Molecular and Cell Biology Agency for Science Technology and Research (A∗STAR) 138673 United States

It remains a significant challenge to reactivate the cell cycle activity of adult mammalian cardiomyocytes (CMs). This study created a hypo-immunogenic human induced pluripotent stem cell (hiPSC) line using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 gene editing to knockout β2-microglobulin in hiPSCs (^B2MKOhiPSCs) for manufacturing nanovesicles (^B2MKOhiPSC-NVs). Approximately 9500 ^B2MKOhiPSC-NVs were produced from a single ^B2MKOhiPSC. Proteomic analyses indicated that, compared to ^B2MKOhiPSCs, the cargos of ^B2MKOhiPSC-NVs were enriched in spindle and chromosomal proteins, as well as proteins that regulate the cell cycle and scavenge reactive oxygen species (ROS). When administrated to hiPSCs derived CMs (hiPSC-CMs), ^B2MKOhiPSC-NVs reduced lactate dehydrogenase leakage and apoptosis in hypoxia-cultured hiPSC-CMs through activating the AKT pathway, protected hiPSC-CMs from H₂O₂-induced damage by ROS scavengers in the NV cargo, increased hiPSC-CM proliferation via the YAP pathway, and were hypoimmunogenic when co-cultured with human CD8⁺ T cells or delivered to mice. Furthermore, when ^B2MKOhiPSC-NVs or 0.9 % NaCl were intramyocardially injected into mice after cardiac ischemia/reperfusion injury, cardiac function and infarct size, assessed 4 weeks later, were significantly improved in the ^B2MKOhiPSC-NV group, with increased mouse CM survival and cell cycle activity. Thus, the proteins in the ^B2MKOhiPSC-NV cargos convergently activated the AKT pathway, scavenged ROS to protect CMs, and upregulated YAP signaling to induce CM cell cycle activity. Thus, ^B2MKOhiPSC-NVs hold great potential for cardiac protection and regeneration. © 2025 The Authors

关键词： Cell cycle Myocardial protection Nanovesicles Pluripotent stem cells Regeneration

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Amplifying X-ray-Induced Charge Transfer Facilitates Direct Sensitization of Photosensitizers in Radiotherapy

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ACS Nano 2025年第17期19卷 16775-16793页

作者： Zhang, Da Chen, Qingjing Zhang, Junrong Xing, Xiaohua Zhou, Yang Ou, Xiangyu Dai, Shuheng Chen, Qiushui Liu, Xiaolong Chen, Xiaoyuan Zeng, Yongyi The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province Mengchao Hepatobiliary Hospital of Fujian Medical University Fuzhou350025 China Departments of Diagnostic Radiology Surgery Chemical and Biomolecular Engineering and Biomedical Engineering Yong Loo Lin School of Medicine Faculty of Engineering National University of Singapore Singapore119074 Singapore Clinical Imaging Research Centre Centre for Translational Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore138667 Singapore Nanomedicine Translational Research Program NUS Center for Nanomedicine Yong Loo Lin School of Medicine National University of Singapore Singapore138667 Singapore CAS Key Laboratory of Design and Assembly of Functional Nanostructures Fujian Institute of Research on the Structure of Matter Chinese Academy of Sciences Fuzhou350002 China Linköping University LinköpingSE-58183 Sweden MOE Key Laboratory for Analytical Science of Food Safety and Biology Fuzhou University Fuzhou350108 China Department of General Surgery Fujian Medical University Union Hospital Fuzhou350001 China Mengchao Med-X Center Fuzhou University Fuzhou350116 China Liver Disease Center The First Affiliated Hospital of Fujian Medical University Fuzhou350005 China

X-ray-induced photodynamic therapy offers substantial promise for treating deep-seated tumors, but it is still limited by highly inefficient energy transfer processes and the stringent requirements for scintillators with high luminescence quantum yield and significant singlet-triplet intersystem crossing ratios. Herein, we describe X-ray-induced electron-dynamic therapy (X-eDT), which obviates the need for intersystem crossing by exposing nonluminescent hafnium-silica nanoparticles to X-rays, to generate high-energy electrons that can sensitize lower-lying triplet states of various photosensitizers. Our approach strongly induced the production of singlet oxygen (6.18-fold) in vitro even at lower X-ray doses, and in mice it strongly inhibited the growth of xenografts derived from liver, breast, or colon cancer cell lines (CDX), and growth of patient-derived xenografts (PDX) of hepatocellular carcinoma. In these CDX preclinical systems, X-eDT was not only effective against the irradiated xenograft but also against untreated xenografts in the same animal, and these abscopal effects involved enhanced tumor infiltration by CD4+T cells, CD8+T cells, and IFN-γ-polarized M1 macrophages within the tumor microenvironment. X-eDT even stimulated the production of memory T cells that inhibited rechallenges after treatment. These findings suggest that X-eDT can be effective against primary and metastatic tumors as well as tumor recurrence, which makes it much more powerful than conventional X-PDT. © 2025 American Chemical Society.

关键词： Animal cell culture

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Artificial Intelligence in Cancer Immunotherapy: Navigating Challenges and Unlocking Opportunities

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engineering 2025年第1期44卷 12-16页

作者： Xiang, Wei Yu, Lu Chen, Xiaoyuan Herold, Marco J. Australian Centre for Artificial Intelligence in Medical Innovation La Trobe University MelbourneVIC3086 Australia School of Computing Engineering and Mathematical Sciences La Trobe University MelbourneVIC3086 Australia Department of Diagnostic Radiology Yong Loo Lin School of Medicine National University of Singapore Singapore119074 Singapore Department of Chemical and Biomolecular Engineering College of Design and Engineering National University of Singapore Singapore117575 Singapore Department of Biomedical Engineering College of Design and Engineering National University of Singapore Singapore117575 Singapore Department of Pharmacy and Pharmaceutical Sciences Faculty of Science National University of Singapore Singapore117544 Singapore Clinical Imaging Research Centre Centre for Translational Medicine Yong Loo Lin School of Medicine National University of Singapore Singapore117599 Singapore Nanomedicine Translational Research Program Yong Loo Lin School of Medicine National University of Singapore Singapore117597 Singapore Yong Loo Lin School of Medicine National University of Singapore Singapore138667 Singapore Singapore138673 Singapore Olivia Newton-John Cancer Research Institute HeidelbergVIC3084 Australia School of Cancer Medicine La Trobe University MelbourneVIC3086 Australia The Walter and Eliza Hall Institute of Medical Research ParkvilleVIC3052 Australia Department of Medical Biology University of Melbourne ParkvilleVIC3010 Australia

Cancer continues to be a major cause of global mortality rates, with conventional treatments such as chemotherapy and radiotherapy exhibiting inconsistent efficacy, high costs, and considerable side effects. Over the past decade, a promising alternative has emerged: cancer immunotherapy, which leverages the body’s immune system to identify and eradicate cancer cells. Significant progress has been made in several novel immunotherapies, including immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapies, and personalized therapeutic cancer vaccines. However, the heterogeneity and complexity of cancer types still pose enormous challenges. The efficient use of large numbers of medical datasets is essential for overcoming these obstacles. Without artificial intelligence (AI), linking translational and clinical data to derive meaningful insights would remain an insurmountable task. Recently, single-cell RNA sequencing cell typing (scGPT), a pretrained generative model utilizing a database of more than 33 million cells, is developed to accurately extract important biological insights concerning cellular biology. A personalized learning workflow is also proposed as a simple and effective pipeline to discover neoantigens for cancer immunotherapy.

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Mechanical Characterization of Biostable Dental Restoratives and Adhesives

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Dental Materials 2025年 41卷 e36-e36页

作者： Gouveia, Z Finer, Y Santerre, P Faculty of Dentistry University of Toronto Toronto Canada Institute of Biomedical Engineering University of Toronto Toronto Canada Translational Biology and Engineering Program University of Toronto Toronto Canada Department of Chemical Engineering and Applied Chemistry University of Toronto Toronto Canada

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Combination of antimicrobial peptide and clinical antibiotic shows enhanced potency toward Acinetobacter baumannii infection

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European Journal of Pharmacology 2025年 999卷

作者： Yeh, Jih-Chao Yang, Chin-Hao Hazam, Prakash Kishore Selvaraj, Sanjay Prasad Lin, You-Ying Hsieh, Chu-Yi Liou, Je-Wen Chen, Jyh-Yih Marine Research Station Institute of Cellular and Organismic Biology Academia Sinica 23-10 Dawen Rd. Jiaushi Ilan 262 Taiwan Department of Biomedical Sciences and Engineering College of Medicine Tzu Chi University Hualien 970 Taiwan Molecular and Biological Agricultural Science Program Taiwan International Graduate Program Academia Sinica Taipei 11529 Taiwan Graduate Institute of Biotechnology National Chung Hsing University Taichung 402 Taiwan The IEGG and Animal Biotechnology Center and the Rong Hsing Research Center for Translational Medicine National Chung Hsing University Taichung 402 Taiwan

The continued development of novel antimicrobial treatment strategies is crucial for maintaining an effective therapeutic arsenal, and antimicrobial peptides (AMPs) exhibit promising activities against a wide range of pathogens. In this study, we tested the combined effects of an AMP, TP4-3, and meropenem on Acinetobacter baumannii, which is responsible for many severe infections and is associated with high rates of overall mortality and morbidity. This study aimed to develop an effective combination therapy for microbial infections. TP4-3 and meropenem were found to act synergistically toward Acinetobacter baumannii and exhibit an activity profile better than those of the individual compounds. TP4-3 is an antimicrobial peptide with proven activity, low toxicity and extended stability. This AMP was combined with meropenem and tested for efficacy against A. baumannii using a panel of in vitro and in vivo tests. The combination of TP4-3 and meropenem exhibited robust activity against Acinetobacter baumannii pathogens. In particular, the combined treatment demonstrated significant antibiofilm properties and a lower degree of induced resistance than meropenem alone. Additionally, the combination showed an excellent activity profile in in vivo studies. Thus, the combination of TP4-3 and meropenem appears to be an effective strategy to mitigate the detrimental consequences of infections caused by this clinically relevant pathogen. Since the combination of TP4-3 and meropenem displayed better activity than the individual compounds, this strategy of combining AMPs with clinical antibiotics may be suitable for development of clinical treatments targeting various microbial infections. © 2025 Elsevier B.V.

关键词： Acinetobacter baumannii Antimicrobial peptide Gram-negative bacteria In vivo antimicrobial activity Stapled peptide Synergism

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High-resolution dynamic imaging of chromatin DNA communication using Oligo-LiveFISH

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Cell 2025年

作者： Zhu, Yanyu Balaji, Ashwin Han, Mengting Andronov, Leonid Roy, Anish R. Wei, Zheng Chen, Crystal Miles, Leanne Cai, Sa Gu, Zhengxi Tse, Ariana Yu, Betty Chentzu Uenaka, Takeshi Lin, Xueqiu Spakowitz, Andrew J. Moerner, W.E. Qi, Lei S. Department of Bioengineering Stanford University Stanford 94305 CA United States Department of Chemistry Stanford University Stanford 94305 CA United States Biophysics PhD Program Stanford University Stanford 94305 CA United States Computational Biology Program Public Health Sciences Division and Translational Data Science IRC Fred Hutchinson Cancer Center Seattle 98109 WA United States Department of Chemical Engineering Stanford University Stanford 94305 CA United States Department of Materials Science and Engineering Stanford University Stanford 94305 CA United States Institute for Stem Cell Biology & Regenerative Medicine and Department of Pathology Stanford University School of Medicine Stanford 94305 CA United States Sarafan ChEM-H Stanford University Stanford 94305 CA United States Chan Zuckerberg Biohub San Francisco 94080 CA United States

Three-dimensional (3D) genome dynamics are crucial for cellular functions and disease. However, real-time, live-cell DNA visualization remains challenging, as existing methods are often confined to repetitive regions, suffer from low resolution, or require complex genome engineering. Here, we present Oligo-LiveFISH, a high-resolution, reagent-based platform for dynamically tracking non-repetitive genomic loci in diverse cell types, including primary cells. Oligo-LiveFISH utilizes fluorescent guide RNA (gRNA) oligo pools generated by computational design, in vitro transcription, and chemical labeling, delivered as ribonucleoproteins. Utilizing machine learning, we characterized the impact of gRNA design and chromatin features on imaging efficiency. Multi-color Oligo-LiveFISH achieved 20-nm spatial resolution and 50-ms temporal resolution in 3D, capturing real-time enhancer and promoter dynamics. Our measurements and dynamic modeling revealed two distinct modes of chromatin communication, and active transcription slows enhancer-promoter dynamics at endogenous genes like FOS. Oligo-LiveFISH offers a versatile platform for studying 3D genome dynamics and their links to cellular processes and disease. © 2025 Elsevier Inc.

关键词： CRISPR imaging DNA communication dynamic tracking enhancer-promoter interaction high-resolution imaging live DNA imaging non-repetitive genome imaging Oligo-LiveFISH polymer modeling primary cell

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Microfluidic method for the electrochemical determination of endothelial permeability 20

Microfluidic method for the electrochemical determination of...

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20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016

作者： Wong, J.F. Young, E.W.K. Simmons, C.A. University of Toronto Toronto Canada Translational Biology and Engineering Program Ted Rogers Centre for Heart Research Toronto Canada

ISBN: (纸本)9780979806490

Solute permeability across the endothelium is an important metric of vascular barrier function that is most commonly studied in vitro using bulky and complex fluorescent detection instrumentation. This work presents a novel microfluidic method to electrochemically determine endothelial permeability under physiological flow-induced shear stress in a bilayer microfluidic device. The method was characterized and successfully validated using a layer of known permeability. The use of electrochemical detection significantly reduced the cost, complexity and footprint of the device instrumentation.

关键词： Shear stress

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Abnormal skeletal muscle and myocardial vasoreactivity manifests prior to heart failure in a diabetic cardiomyopathy rat model

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Discover medicine 2025年第1期2卷 2页

作者： Sadi Loai Hai-Ling Margaret Cheng Institute of Biomedical Engineering University of Toronto Toronto ON Canada. Translational Biology & Engineering Program Ted Rogers Centre for Heart Research 661 University Avenue Room 1433 Toronto ON M5G 1M1 Canada. The Edward S. Rogers Sr. Department of Electrical and Computer Engineering University of Toronto Toronto ON Canada.

Background:Microvascular dysfunction (MVD) is a recognized sign of disease in heart failure progression. Intact blood vessels exhibit abnormal vasoreactivity in early stage, subsequently deteriorating to rarefaction and reduced perfusion. In managing heart failure with preserved ejection fraction (HFpEF), earlier diagnosis is key to improving management. In this study, we applied a steady-state blood-pool magnetic resonance imaging (MRI) method to investigate if it can sensitively detect abnormal leg muscle vasoreactivity, a sign of MVD, posited to manifest before structural and functional cardiac changes emerge in a diabetes model of HFpEF. Methods:Male and female Sprague-Dawley rats were maintained on either a high-fat, high-sugar diet or a control diet for 6 months after the induction of diabetes ( = 5 per group). Beginning at month 1 or 2 post-diabetes and every 2 months thereafter, rats underwent steady-state blood-pool MRI to assess vasoreactivity in the heart or skeletal muscle, respectively. A T1-reducing blood-pool agent was administered and the T1 relaxation time dynamically measured as animals breathed in elevated CO levels to modulate vessels. Results:In male rats, the normally unresponsive heart to 10% CO revealed a pro-vasoconstriction response beginning at 5 months post-diabetes. Abnormal leg skeletal muscle vasoreactivity appeared even earlier, at 2 months: the usual vasodilatory response to 5% CO was interrupted with periods of vasoconstriction in diseased rats. In female rats, differences were observed between healthy and diseased animals only in the first 2 months post-diabetes and not later. In the heart, vasodilation to 10% CO seen in healthy females was abolished in diabetic females. In skeletal muscle, 5% CO was suboptimal in inducing reproducible vasoreactivity, but young diabetic females responded by vasodilation only. Conclusions:Abnormal vasoreactivity presented earlier than overt functional changes in both heart and skeletal muscle in dia

关键词： Blood-pool T1 imaging Diabetes Gadofosveset Heart Hypercapnia Microvascular dysfunction Skeletal muscle Vasoreactivity

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A microfluidic electrochemical assay for the on-chip measurement of endothelial permeability 22

A microfluidic electrochemical assay for the on-chip measure...

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22nd International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2018

作者： Wong, Jeremy Simmons, Craig A. Institute of Biomaterials & Biomedical Engineering University of Toronto Canada Department of Mechanical and Industrial Engineering University of Toronto Canada Translational Biology and Engineering Program Ted Rogers Centre for Heart Research Canada

ISBN: (纸本)9781510897571

In this work, thin film electrodes were integrated into a bilayer microfluidic device in order to electrochemically measure the permeability of an endothelial cell monolayer. Unlike currently existing fluorescence-based methods, the electrochemical assay enables measurements to easily be performed directly on-chip without the need for manual sampling or large, bulky and costly instrumentation. The method was successfully validated against a computational model of mass transport in the device, and was further applied to measuring the permeability of an endothelial cell monolayer. These results confirm that, as expected, the electrochemical assay functions as the charge-based analog to the existing fluorescence-based methods. Copyright © (2018) by Chemical and Biological Microsystems Society. All rights reserved.

关键词： Endothelial cells

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