Impact beyond citations Nat. Biomed. Eng. Pub Date : 2018-01-10
Impact beyond citationsImpact beyond citations, Published online: 10 January 2018; doi:10.1038/s41551-018-0189-yThe translational achievements, commercialization prospects and eventual clinical and societal impacts of biomedical work accrue over a long time. They should be better captured and publicized.
Towards a cancer-chemopreventive diet Nat. Biomed. Eng. Pub Date : 2018-01-10 David A. Drew, Andrew T. Chan
Towards a cancer-chemopreventive dietTowards a cancer-chemopreventive diet, Published online: 10 January 2018; doi:10.1038/s41551-017-0186-6Commensal microbes engineered to convert natural compounds found in cruciferous vegetables into molecules with anticancer properties prevent carcinogenesis and cause the regression of colorectal cancer in mice fed with a vegetable diet.
Personalized occluders for the left atrial appendage Nat. Biomed. Eng. Pub Date : 2018-01-10 Carola Gianni, Andrea Natale
Personalized occluders for the left atrial appendagePersonalized occluders for the left atrial appendage, Published online: 10 January 2018; doi:10.1038/s41551-017-0184-8Occluders for the left atrial appendage that are patient-specific, thus ensuring better fitting and potentially less complications, can be made by 3D-printing inflatable polymer devices on the basis of data derived from computed tomography scans.
Engineered commensal microbes for diet-mediated colorectal-cancer chemoprevention Nat. Biomed. Eng. Pub Date : 2018-01-10 Chun Loong Ho, Hui Qing Tan, Koon Jiew Chua, Aram Kang, Kiat Hon Lim, Khoon Lin Ling, Wen Shan Yew, Yung Seng Lee, Jean Paul Thiery, Matthew Wook Chang
Chemoprevention—the use of medication to prevent cancer—can be augmented by the consumption of produce enriched with natural metabolites. However, chemopreventive metabolites are typically inactive and have low bioavailability and poor host absorption. Here, we show that engineered commensal microbes can prevent carcinogenesis and promote the regression of colorectal cancer through a cruciferous vegetable diet. The engineered commensal Escherichia coli bound specifically to the heparan sulphate proteoglycan on colorectal cancer cells and secreted the enzyme myrosinase to transform host-ingested glucosinolates—natural components of cruciferous vegetables—to sulphoraphane, an organic small molecule with known anticancer activity. The engineered microbes coupled with glucosinolates resulted in >95% proliferation inhibition of murine, human and colorectal adenocarcinoma cell lines in vitro. We also show that murine models of colorectal carcinoma fed with the engineered microbes and the cruciferous vegetable diet displayed significant tumour regression and reduced tumour occurrence.
Prediction of off-target activities for the end-to-end design of CRISPR guide RNAs Nat. Biomed. Eng. Pub Date : 2018-01-10 Jennifer Listgarten, Michael Weinstein, Benjamin P. Kleinstiver, Alexander A. Sousa, J. Keith Joung, Jake Crawford, Kevin Gao, Luong Hoang, Melih Elibol, John G. Doench, Nicolo Fusi
Off-target effects of the CRISPR–Cas9 system can lead to suboptimal gene-editing outcomes and are a bottleneck in its development. Here, we introduce two interdependent machine-learning models for the prediction of off-target effects of CRISPR–Cas9. The approach, which we named Elevation, scores individual guide–target pairs, and also aggregates them into a single, overall summary guide score. We demonstrate that Elevation consistently outperforms competing approaches on both tasks. We also introduce an evaluation method that balances errors between active and inactive guides, thereby encapsulating a range of practical use cases. Because of the large-scale and computational demands of the prediction of off-target activities, we have developed a fast cloud-based service (https://crispr.ml) for end-to-end guide-RNA design. The service makes use of pre-computed on-target and off-target activity prediction for every genic region in the human genome.
Platelet vesicles help cardiac stem cells engraft Nat. Biomed. Eng. Pub Date : 2018-01-10 Philippe Menasché
Platelet vesicles help cardiac stem cells engraftPlatelet vesicles help cardiac stem cells engraft, Published online: 10 January 2018; doi:10.1038/s41551-017-0185-7Grafting platelet-derived nanovesicles onto the surface of cardiosphere-derived cardiac stem cells enables the cells to better engraft in infarcted tissue following systemic injection in rats and pigs.
Targeted repair of heart injury by stem cells fused with platelet nanovesicles Nat. Biomed. Eng. Pub Date : 2018-01-10 Junnan Tang, Teng Su, Ke Huang, Phuong-Uyen Dinh, Zegen Wang, Adam Vandergriff, Michael T. Hensley, Jhon Cores, Tyler Allen, Taosheng Li, Erin Sproul, Emily Mihalko, Leonard J. Lobo, Laura Ruterbories, Alex Lynch, Ashley Brown, Thomas G. Caranasos, Deliang Shen, George A. Stouffer, Zhen Gu, Jinying Zhang, Ke Cheng
Stem cell transplantation, as used clinically, suffers from low retention and engraftment of the transplanted cells. Inspired by the ability of platelets to recruit stem cells to sites of injury on blood vessels, we hypothesized that platelets might enhance the vascular delivery of cardiac stem cells (CSCs) to sites of myocardial infarction injury. Here, we show that CSCs with platelet nanovesicles fused onto their surface membranes express platelet surface markers that are associated with platelet adhesion to injury sites. We also find that the modified CSCs selectively bind collagen-coated surfaces and endothelium-denuded rat aortas, and that in rat and porcine models of acute myocardial infarction the modified CSCs increase retention in the heart and reduce infarct size. Platelet-nanovesicle-fused CSCs thus possess the natural targeting and repairing ability of their parental cell types. This stem cell manipulation approach is fast, straightforward and safe, does not require genetic alteration of the cells, and should be generalizable to multiple cell types.
Publisher Correction: An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding Nat. Biomed. Eng. Pub Date : 2018-01-02 Ilias Matis, Dafni Chrysanthi Delivoria, Barbara Mavroidi, Nikoletta Papaevgeniou, Stefania Panoutsou, Stamatia Bellou, Konstantinos D. Papavasileiou, Zacharoula I. Linardaki, Alexandra V. Stavropoulou, Kostas Vekrellis, Nikos Boukos, Fragiskos N. Kolisis, Efstathios S. Gonos, Marigoula Margarity, Manthos G. Papadopoulos, Spiros Efthimiopoulos, Maria Pelecanou, Niki Chondrogianni, Georgios Skretas
Publisher Correction: An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding Publisher Correction: An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding, Published online: 02 January 2018; doi:10.1038/s41551-017-0164-z Publisher Correction: An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding
Publisher Correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity Nat. Biomed. Eng. Pub Date : 2018-01-02 Nobuyuki Tanaka, Shigeaki Kanatani, Raju Tomer, Cecilia Sahlgren, Pauliina Kronqvist, Dagmara Kaczynska, Lauri Louhivuori, Lorand Kis, Claes Lindh, Przemysław Mitura, Andrzej Stepulak, Sara Corvigno, Johan Hartman, Patrick Micke, Artur Mezheyeuski, Carina Strell, Joseph W. Carlson, Carlos Fernández Moro, Hanna Dahlstrand, Arne Östman, Kazuhiro Matsumoto, Peter Wiklund, Mototsugu Oya, Ayako Miyakawa, Karl Deisseroth, Per Uhlén
Publisher Correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity Publisher Correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity, Published online: 02 January 2018; doi:10.1038/s41551-017-0162-1 Publisher Correction: Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity
Publisher Correction: Stem cells: The reprogramming method matters Nat. Biomed. Eng. Pub Date : 2018-01-02 Thomas F. Allison, William E. Lowry
Publisher Correction: Stem cells: The reprogramming method matters Publisher Correction: Stem cells: The reprogramming method matters, Published online: 02 January 2018; doi:10.1038/s41551-017-0170-1 Publisher Correction: Stem cells: The reprogramming method matters
Publisher Correction: Determining T-cell specificity to understand and treat disease Nat. Biomed. Eng. Pub Date : 2018-01-02 Sine Reker Hadrup, Evan W. Newell
Publisher Correction: Determining T-cell specificity to understand and treat disease Publisher Correction: Determining T-cell specificity to understand and treat disease, Published online: 02 January 2018; doi:10.1038/s41551-017-0176-8 Publisher Correction: Determining T-cell specificity to understand and treat disease
Patient-specific design of a soft occluder for the left atrial appendage Nat. Biomed. Eng. Pub Date : 2018-01-01 Sanlin S. Robinson, Seyedhamidreza Alaie, Hannah Sidoti, Jordyn Auge, Lohendran Baskaran, Kenneth Avilés-Fernández, Samantha D. Hollenberg, Robert F. Shepherd, James K. Min, Simon N. Dunham, Bobak Mosadegh
3D printing has been used to create a wide variety of anatomical models and tools for procedural planning and training. Yet, the printing of permanent, soft endocardial implants remains challenging because of the need for haemocompatibility and durability of the printed materials. Here, we describe an approach for the rapid prototyping of patient-specific cardiovascular occluders via 3D printing and static moulding of inflatable silicone/polyurethane balloons derived from volume-rendered computed tomography scans. We demonstrate the use of the approach, which provides custom-made implants made of high-quality, durable and haemocompatible elastomeric materials, in the fabrication of devices for occlusion of the left atrial appendage—a structure known to be highly variable in geometry and the primary source of stroke for patients with atrial fibrillation. We describe the design workflow, fabrication and deployment of patient-specific left atrial appendage occluders and, as a proof-of-concept, show their efficacy using 3D-printed anatomical models, in vitro flow loops and an in vivo large animal model.
Surveillance nanotechnology for multi-organ cancer metastases Nat. Biomed. Eng. Pub Date : 2017-12-12 Harini Kantamneni, Margot Zevon, Michael J. Donzanti, Xinyu Zhao, Yang Sheng, Shravani R. Barkund, Lucas H. McCabe, Whitney Banach-Petrosky, Laura M. Higgins, Shridar Ganesan, Richard E. Riman, Charles M. Roth, Mei-Chee Tan, Mark C. Pierce, Vidya Ganapathy, Prabhas V. Moghe
The identification and molecular profiling of early metastases remains a major challenge in cancer diagnostics and therapy. Most in vivo imaging methods fail to detect small cancerous lesions, a problem that is compounded by the distinct physical and biological barriers associated with different metastatic niches. Here, we show that intravenously injected rare-earth-doped albumin-encapsulated nanoparticles emitting short-wave infrared light (SWIR) can detect targeted metastatic lesions in vivo, allowing for the longitudinal tracking of multi-organ metastases. In a murine model of human breast cancer, the nanoprobes enabled whole-body SWIR detection of adrenal-gland microlesions and bone lesions that were undetectable via contrast-enhanced magnetic resonance imaging as early as three and five weeks post-inoculation, respectively. Whole-body SWIR imaging of nanoprobes functionalized to differentially target distinct metastatic sites and administered to a biomimetic murine model of human breast cancer resolved multi-organ metastases that showed varied molecular profiles in the lungs, adrenal glands and bones. Real-time surveillance of lesions in multiple organs should facilitate pre- and post-therapy monitoring in preclinical settings.
Convergence of microengineering and cellular self-organization towards functional tissue manufacturing Nat. Biomed. Eng. Pub Date : 2017-12-12 Jérémie Laurent, Guillaume Blin, Francois Chatelain, Valérie Vanneaux, Alexandra Fuchs, Jérôme Larghero, Manuel Théry
Technical progress in materials science and bioprinting has for the past few decades fostered considerable advances in medicine. More recently, the understanding of the processes of self-organization of cells into three-dimensional multicellular structures and the study of organoids have opened new perspectives for tissue engineering. Here, we review microengineering approaches for building functional tissues, and discuss recent progress in the understanding of morphogenetic processes and in the ability to steer them in vitro. On the basis of biological and technical considerations, we emphasize the achievements and remaining challenges of bringing together microengineering and morphogenesis. Our viewpoint underlines the importance of cellular self-organization for the success of tissue engineering in therapeutic applications. We reason that directed self-organization, at the convergence of microengineering and cellular self-organization, is a promising direction for the manufacturing of complex functional tissues.
Early detection of multi-organ metastases Nat. Biomed. Eng. Pub Date : 2017-12-12 Miqin Zhang
Early detection of multi-organ metastases Early detection of multi-organ metastases, Published online: 12 December 2017; doi:10.1038/s41551-017-0173-y Rare-earth-doped nanoprobes emitting short-wavelength infrared light enable the detection of metastatic lesions in multiple organs.
A dextran-based probe for the targeted magnetic resonance imaging of tumours expressing prostate-specific membrane antigen Nat. Biomed. Eng. Pub Date : 2017-12-12 Guanshu Liu, Sangeeta Ray Banerjee, Xing Yang, Nirbhay Yadav, Ala Lisok, Anna Jablonska, Jiadi Xu, Yuguo Li, Martin G. Pomper, Peter van Zijl
Safe imaging agents that are able to render the expression and distribution of cancer receptors, enzymes or other biomarkers would facilitate clinical screening of the disease. Here, we show that diamagnetic dextran particles that are coordinated to a urea-based targeting ligand for prostate-specific membrane antigen (PSMA) enable targeted magnetic resonance imaging (MRI) of the PSMA receptor. In a xenograft model of prostate cancer, micromolar concentrations of the dextran–ligand probe provided sufficient signal to specifically detect PSMA-expressing tumours via chemical exchange saturation transfer MRI. The dextran-based probe could be detected via the contrast that originated from dextran hydroxyl protons, thereby avoiding the need of chemical substitution for radioactive or metallic labelling. Because dextrans are currently used clinically, dextran-based contrast agents may help to extend receptor-targeted imaging to clinical MRI.
Cryptographic decoding of movement Nat. Biomed. Eng. Pub Date : 2017-12-12 Vikash Gilja
Cryptographic decoding of movement Cryptographic decoding of movement, Published online: 12 December 2017; doi:10.1038/s41551-017-0175-9 A method inspired by cryptography maps neural activity to limb movement without requiring the simultaneous collection of neural activity in the motor cortex and of the corresponding physical actions.
Towards safe therapy for immunodeficiency Nat. Biomed. Eng. Pub Date : 2017-12-12 Shengdar Q. Tsai
Towards safe therapy for immunodeficiency Towards safe therapy for immunodeficiency, Published online: 12 December 2017; doi:10.1038/s41551-017-0174-x A humanized mouse model of X-linked severe combined immunodeficiency suggests that the safety of correcting the human IL2RG gene in haematopoietic stem cells depends on both gene-correction frequency and the conditioning regimen used before cell transplantation.
A cryptography-based approach for movement decoding Nat. Biomed. Eng. Pub Date : 2017-12-12 Eva L. Dyer, Mohammad Gheshlaghi Azar, Matthew G. Perich, Hugo L. Fernandes, Stephanie Naufel, Lee E. Miller, Konrad P. Körding
Brain decoders use neural recordings to infer the activity or intent of a user. To train a decoder, one generally needs to infer the measured variables of interest (covariates) from simultaneously measured neural activity. However, there are cases for which obtaining supervised data is difficult or impossible. Here, we describe an approach for movement decoding that does not require access to simultaneously measured neural activity and motor outputs. We use the statistics of movement—much like cryptographers use the statistics of language—to find a mapping between neural activity and motor variables, and then align the distribution of decoder outputs with the typical distribution of motor outputs by minimizing their Kullback–Leibler divergence. By using datasets collected from the motor cortex of three non-human primates performing either a reaching task or an isometric force-production task, we show that the performance of such a distribution-alignment decoding algorithm is comparable to the performance of supervised approaches. Distribution-alignment decoding promises to broaden the set of potential applications of brain decoding.
Histopathology is ripe for automation Nat. Biomed. Eng. Pub Date : 2017-12-12
Histopathology is ripe for automation Histopathology is ripe for automation, Published online: 12 December 2017; doi:10.1038/s41551-017-0179-5 Advances in microscopy and the application of machine learning to histology will modernize the examination of tissues in the clinical laboratory and in the operating room.
Publisher Correction: Glial responses to implanted electrodes in the brain Nat. Biomed. Eng. Pub Date : 2017-12-07 Joseph W. Salatino, Kip A. Ludwig, Takashi D. Y. Kozai, Erin K. Purcell
Publisher Correction: Glial responses to implanted electrodes in the brain Publisher Correction: Glial responses to implanted electrodes in the brain, Published online: 07 December 2017; doi:10.1038/s41551-017-0177-7 Publisher Correction: Glial responses to implanted electrodes in the brain
Microscopy with ultraviolet surface excitation for rapid slide-free histology Nat. Biomed. Eng. Pub Date : 2017-12-04 Farzad Fereidouni, Zachary T. Harmany, Miao Tian, Austin Todd, John A. Kintner, John D. McPherson, Alexander D. Borowsky, John Bishop, Mirna Lechpammer, Stavros G. Demos, Richard Levenson
Histological examination of tissues is central to the diagnosis and management of neoplasms and many other diseases and is a foundational technique for preclinical and basic research. However, commonly used bright-field microscopy requires prior preparation of micrometre-thick tissue sections mounted on glass slides—a process that can require hours or days, contributes to cost and delays access to critical information. Here, we introduce a simple, non-destructive slide-free technique that, within minutes, provides high-resolution diagnostic histological images resembling those obtained from conventional haematoxylin and eosin histology. The approach, which we named microscopy with ultraviolet surface excitation (MUSE), can also generate shape and colour-contrast information. MUSE relies on ~280 nm ultraviolet light to restrict the excitation of conventional fluorescent stains to tissue surfaces and it has no significant effects on downstream molecular assays (including fluorescence in situ hybridization and RNA sequencing). MUSE promises to improve the speed and efficiency of patient care in both state-of-the-art and low-resource settings and to provide opportunities for rapid histology in research.
Fast and slide-free imaging Nat. Biomed. Eng. Pub Date : 2017-12-04 Daniel A. Orringer, Sandra Camelo-Piragua
Fast and slide-free imaging Fast and slide-free imaging, Published online: 04 December 2017; doi:10.1038/s41551-017-0172-z Optical imaging of fluorescently labelled tissue illuminated by ultraviolet light does not require microscope slides and makes for a rapid alternative to conventional histology.
Sustained miRNA release regenerates the heart Nat. Biomed. Eng. Pub Date : 2017-11-27 Charles E. Murry, Katie A. Mitzelfelt
Sustained miRNA release regenerates the heart Sustained miRNA release regenerates the heart, Published online: 27 November 2017; doi:10.1038/s41551-017-0171-0 Prolonged local delivery, via an injectable hydrogel, of a miRNA known to induce cardiomyocyte proliferation stimulates the recovery of mice from myocardial infarction.
Sustained miRNA delivery from an injectable hydrogel promotes cardiomyocyte proliferation and functional regeneration after ischaemic injury Nat. Biomed. Eng. Pub Date : 2017-11-27 Ann C. Gaffey, Christina A. Cavanaugh, Edward E. Morrisey, Jason A. Burdick, Jennifer J. Chung, Leo L. Wang, Minmin Lu, Pavan Atluri, Rahul Kanade, Su Zhou, Tao Wang, Ying Liu
MicroRNA-based therapies that target cardiomyocyte proliferation have great potential for the treatment of myocardial infarction. In previous work, we showed that the miR-302/367 cluster regulates cardiomyocyte proliferation in the prenatal and postnatal heart. Here, we describe the development and application of an injectable hyaluronic acid hydrogel for the local and sustained delivery of miR-302 mimics to the heart. We show that the miR-302 mimics released in vitro promoted cardiomyocyte proliferation over one week, and that a single injection of the hydrogel in the mouse heart led to local and sustained cardiomyocyte proliferation for two weeks. After myocardial infarction, gel–miR-302 injection caused local clonal proliferation and increased cardiomyocyte numbers in the border zone of a Confetti mouse model. Gel–miR-302 further decreased cardiac end-diastolic (39%) and end-systolic (50%) volumes, and improved ejection fraction (32%) and fractional shortening (64%) four weeks after myocardial infarction and injection, compared with controls. Our findings suggest that biomaterial-based miRNA delivery systems can lead to improved outcomes via cardiac regeneration after myocardial infarction.
Publisher Correction: Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor Nat. Biomed. Eng. Pub Date : 2017-11-22 Adam S. G. Curtis, Catalina Vallejo-Giraldo, Cristina González-García, Dilip Thomas, Gabriel D. Pemberton, Gavin Blackburn, Jingli Yang, Karl Burgess, Manuel Salmerón-Sánchez, Manus J. P. Biggs, Matthew J. Dalby, Penelope M. Tsimbouri, Peter G. Childs, Stuart Reid, Vineetha Jayawarna, Wich Orapiriyakul
Publisher Correction: Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor Publisher Correction: Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor, Published online: 22 November 2017; doi:10.1038/s41551-017-0155-0 Publisher Correction: Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor
Publisher Correction: Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification Nat. Biomed. Eng. Pub Date : 2017-11-22 Abhijit A. Patel, David Yu Zhang, Lucia R. Wu, Sherry X. Chen, Yalei Wu
Publisher Correction: Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification Publisher Correction: Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification, Published online: 22 November 2017; doi:10.1038/s41551-017-0156-z Publisher Correction: Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification
Enhanced precision and efficiency Nat. Biomed. Eng. Pub Date : 2017-11-10 Sanum Bashir, Ralf Kühn
Enhanced precision and efficiency Enhanced precision and efficiency, Published online: 10 November 2017; doi:10.1038/s41551-017-0159-9 NatureArticleSnippet(type=standfirst, markup= The expression of two DNA repair factors improves the recombination of single-stranded oligodeoxynucleotides with Cas9-induced double-strand breaks, facilitating precise and efficient gene editing. , isJats=true)
Nanoparticles for CRISPR–Cas9 delivery Nat. Biomed. Eng. Pub Date : 2017-11-10 Zachary Glass, Yamin Li, Qiaobing Xu
Nanoparticles for CRISPR–Cas9 delivery Nanoparticles for CRISPR–Cas9 delivery, Published online: 10 November 2017; doi:10.1038/s41551-017-0158-x NatureArticleSnippet(type=standfirst, markup= The DNA mutation that causes Duchenne muscular dystrophy in mice can be corrected, with minimal off-target effects, by gold nanoparticles carrying the CRISPR components. , isJats=true)
The expanding toolbox for genome engineering Nat. Biomed. Eng. Pub Date : 2017-11-10
The expanding toolbox for genome engineering The expanding toolbox for genome engineering, Published online: 10 November 2017; doi:10.1038/s41551-017-0163-0 NatureArticleSnippet(type=standfirst, markup= The optimization and diversification of methods for manipulating the genome will enable new therapeutic solutions. , isJats=true)
Glial responses to implanted electrodes in the brain Nat. Biomed. Eng. Pub Date : 2017-11-10 Joseph W. Salatino, Kip A. Ludwig, Takashi D. Y. Kozai, Erin K. Purcell
The use of implants that can electrically stimulate or record electrophysiological or neurochemical activity in nervous tissue is rapidly expanding. Despite remarkable results in clinical studies and increasing market approvals, the mechanisms underlying the therapeutic effects of neuroprosthetic and neuromodulation devices, as well as their side effects and reasons for their failure, remain poorly understood. A major assumption has been that the signal-generating neurons are the only important target cells of neural-interface technologies. However, recent evidence indicates that the supporting glial cells remodel the structure and function of neuronal networks and are an effector of stimulation-based therapy. Here, we reframe the traditional view of glia as a passive barrier, and discuss their role as an active determinant of the outcomes of device implantation. We also discuss the implications that this has on the development of bioelectronic medical devices.
Repacking chromatin for therapy Nat. Biomed. Eng. Pub Date : 2017-11-10 Alexandra Zidovska
Repacking chromatin for therapy Repacking chromatin for therapy, Published online: 10 November 2017; doi:10.1038/s41551-017-0161-2 NatureArticleSnippet(type=standfirst, markup= A theoretical model of chromatin packing heterogeneity predicts patterns in gene expression and can be used to screen for effective chemotherapeutic adjuvants. , isJats=true)
Early detection of valvular calcification Nat. Biomed. Eng. Pub Date : 2017-11-10 Jack P. M. Andrews, Marc R. Dweck
Early detection of valvular calcification Early detection of valvular calcification, Published online: 10 November 2017; doi:10.1038/s41551-017-0160-3 NatureArticleSnippet(type=standfirst, markup= The early stages of the formation of calcific nodules in the aortic valve can be detected by two-photon excited fluorescence microscopy. , isJats=true)
Non-destructive two-photon excited fluorescence imaging identifies early nodules in calcific aortic-valve disease Nat. Biomed. Eng. Pub Date : 2017-11-06 Lauren M. Baugh, Zhiyi Liu, Kyle P. Quinn, Sam Osseiran, Conor L. Evans, Gordon S. Huggins, Philip W. Hinds, Lauren D. Black, Irene Georgakoudi
Calcifications occur during the development of healthy bone and at the onset of calcific aortic-valve disease (CAVD) and many other pathologies. Although the mechanisms regulating early calcium deposition are not fully understood, they may provide targets for new treatments and early interventions. Here, we show that two-photon excited fluorescence (TPEF) can provide quantitative and sensitive readouts of calcific nodule formation, in particular in the context of CAVD. Specifically, by means of the decomposition of TPEF spectral images from excised human CAVD valves and rat bone before and after demineralization, as well as from calcific nodules formed within engineered gels, we identified an endogenous fluorophore that correlates with the level of mineralization in the samples. We then developed a ratiometric imaging approach that provides a quantitative readout of the presence of mineral deposits in early calcifications. TPEF should enable non-destructive, high-resolution imaging of three-dimensional tissue specimens for the assessment of the presence of calcification.
Macrogenomic engineering via modulation of the scaling of chromatin packing density Nat. Biomed. Eng. Pub Date : 2017-11-06 Luay M. Almassalha, Greta M. Bauer, Wenli Wu, Lusik Cherkezyan, Di Zhang, Alexis Kendra, Scott Gladstein, John E. Chandler, David VanDerway, Brandon-Luke L. Seagle, Andrey Ugolkov, Daniel D. Billadeau, Thomas V. O’Halloran, Andrew P. Mazar, Hemant K. Roy, Igal Szleifer, Shohreh Shahabi, Vadim Backman
Many human diseases result from the dysregulation of the complex interactions between tens to thousands of genes. However, approaches for the transcriptional modulation of many genes simultaneously in a predictive manner are lacking. Here, through the combination of simulations, systems modelling and in vitro experiments, we provide a physical regulatory framework based on chromatin packing-density heterogeneity for modulating the genomic information space. Because transcriptional interactions are essentially chemical reactions, they depend largely on the local physical nanoenvironment. We show that the regulation of the chromatin nanoenvironment allows for the predictable modulation of global patterns in gene expression. In particular, we show that the rational modulation of chromatin density fluctuations can lead to a decrease in global transcriptional activity and intercellular transcriptional heterogeneity in cancer cells during chemotherapeutic responses to achieve near-complete cancer cell killing in vitro. Our findings represent a ‘macrogenomic engineering’ approach to modulating the physical structure of chromatin for whole-scale transcriptional modulation.
Flexible piezoelectric devices for gastrointestinal motility sensing Nat. Biomed. Eng. Pub Date : 2017-10-10 Canan Dagdeviren, Farhad Javid, Pauline Joe, Thomas von Erlach, Taylor Bensel, Zijun Wei, Sarah Saxton, Cody Cleveland, Lucas Booth, Shane McDonnell, Joy Collins, Alison Hayward, Robert Langer, Giovanni Traverso
Improvements in ingestible electronics with the capacity to sense physiological and pathophysiological states have transformed the standard of care for patients. Yet, despite advances in device development, significant risks associated with solid, non-flexible gastrointestinal transiting systems remain. Here, we report the design and use of an ingestible, flexible piezoelectric device that senses mechanical deformation within the gastric cavity. We demonstrate the capabilities of the sensor in both in vitro and ex vivo simulated gastric models, quantify its key behaviours in the gastrointestinal tract using computational modelling and validate its functionality in awake and ambulating swine. Our proof-of-concept device may lead to the development of ingestible piezoelectric devices that might safely sense mechanical variations and harvest mechanical energy inside the gastrointestinal tract for the diagnosis and treatment of motility disorders, as well as for monitoring ingestion in bariatric applications.
Determining T-cell specificity to understand and treat disease Nat. Biomed. Eng. Pub Date : 2017-10-10 Sine Reker Hadrup, Evan W. Newell
Adaptive immune responses and immunopathogeneses are based on the ability of T cells to respond to specific antigens. Consequently, understanding T-cell recognition patterns in health and disease involves studying the complexity and genetic heterogeneity of the antigen recognition pathway, which includes both T-cell receptors and the antigen-presentation machinery. In this Perspective, we overview the development and use of technologies for assessing T-cell recognition in a clinical context, and discuss how knowledge of T-cell recognition pathways can be critical before, during and after disease treatment. The ability to assess T-cell-mediated immunity in individual patients during disease progression might enable the identification of patient-specific biomarkers that predict therapeutic efficacy and response. Effective strategies for the complex analysis of T-cell specificity in clinical settings are highly desirable and could complement current approaches for the monitoring of therapy responses.
The reprogramming method matters Nat. Biomed. Eng. Pub Date : 2017-10-10 Thomas F. Allison, William E. Lowry
The reprogramming method matters Nature Biomedical Engineering, Published online: 10 October 2017; doi:10.1038/s41551-017-0148-z The genetic, epigenetic and transcriptomic profiles of human-induced pluripotent stem cells are shaped by the reprogramming route.
Seeing whole-tumour heterogeneity Nat. Biomed. Eng. Pub Date : 2017-10-10 Boyan K. Garvalov, Ali Ertürk
Seeing whole-tumour heterogeneity Nature Biomedical Engineering, Published online: 10 October 2017; doi:10.1038/s41551-017-0150-5 Light-sheet microscopy reveals 3D tumour heterogeneity in optically cleared paraffin-embedded tumour samples.
Sensing gastrointestinal motility Nat. Biomed. Eng. Pub Date : 2017-10-10 Ghazaleh Haghiashtiani, Michael C. McAlpine
Sensing gastrointestinal motility Nature Biomedical Engineering, Published online: 10 October 2017; doi:10.1038/s41551-017-0146-1 Flexible piezoelectric sensors can detect mechanical deformations in the gastrointestinal tract of ambulating pigs and simultaneously harvest energy from it.
An integrated bacterial system for the discovery of chemical rescuers of disease-associated protein misfolding Nat. Biomed. Eng. Pub Date : 2017-10-10 Ilias Matis, Dafni Chrysanthi Delivoria, Barbara Mavroidi, Nikoletta Papaevgeniou, Stefania Panoutsou, Stamatia Bellou, Konstantinos D. Papavasileiou, Zacharoula I. Linardaki, Alexandra V. Stavropoulou, Kostas Vekrellis, Nikos Boukos, Fragiskos N. Kolisis, Efstathios S. Gonos, Marigoula Margarity, Manthos G. Papadopoulos, Spiros Efthimiopoulos, Maria Pelecanou, Niki Chondrogianni, Georgios Skretas
Protein misfolding and aggregation are common pathological features of several human diseases, including Alzheimer’s disease and type 2 diabetes. Here, we report an integrated and generalizable bacterial system for the facile discovery of chemical rescuers of disease-associated protein misfolding. In this system, large combinatorial libraries of macrocyclic molecules are biosynthesized in Escherichia coli cells and simultaneously screened for their ability to rescue pathogenic protein misfolding and aggregation using a flow cytometric assay. We demonstrate the effectiveness of this approach by identifying drug-like, head-to-tail cyclic peptides that modulate the aggregation of the Alzheimer’s disease-associated amyloid β peptide. Biochemical, biophysical and biological assays using isolated amyloid β peptide, primary neurons and various established Alzheimer’s disease nematode models showed that the selected macrocycles potently inhibit the formation of neurotoxic amyloid β peptide aggregates. We also applied the system to the identification of misfolding rescuers of mutant Cu/Zn superoxide dismutase—an enzyme linked with inherited forms of amyotrophic lateral sclerosis. Overall, the system enables the identification of molecules with therapeutic potential for rescuing the misfolding of disease-associated polypeptides.
Identifying rescuers of misfolding Nat. Biomed. Eng. Pub Date : 2017-10-10 Tobias Langenberg, Joost Schymkowitz, Frederic Rousseau
Identifying rescuers of misfolding Nature Biomedical Engineering, Published online: 10 October 2017; doi:10.1038/s41551-017-0149-y High-throughput screening of large libraries of cyclic peptides expressed in bacteria yields rescuers of the pathogenic misfolding of proteins associated with neurodegenerative diseases.
A non-cytotoxic dendrimer with innate and potent anticancer and anti-metastatic activities Nat. Biomed. Eng. Pub Date : 2017-09-12 Shiqun Shao, Quan Zhou, Jingxing Si, Jianbin Tang, Xiangrui Liu, Meng Wang, Jianqing Gao, Kai Wang, Rongzhen Xu, Youqing Shen
The structural perfection and multivalency of dendrimers have made them useful for biodelivery and bioactivity via peripheral functionalization and the modulation of core-forming structures and dendrimer generations. Yet only few dendrimers have shown inherent therapeutic activity arising from their inner repeating units. Here, we report the synthesis and characterization of a polyacylthiourea dendrimer with inherent potent anticancer activity and the absence of cytotoxicity in mice. The poly(ethylene glycol)-functionalized fourth generation of the dendrimer, which can be efficiently synthesized from sequential click reactions of orthogonal monomers, displays low in vivo acute and subacute toxicities yet potently inhibits tumour growth and metastasis. The dendrimer’s in vivo anticancer activity arises from the depletion of bioavailable copper and the subsequent inhibition of angiogenesis and cellular proliferation. When compared with some clinically used cytotoxin drugs, the dendrimer exerts inherent anticancer activity via non-cytotoxic pathways and leads to higher therapeutic efficacy, yet without cytotoxin-induced side effects.
Making bone via nanoscale kicks Nat. Biomed. Eng. Pub Date : 2017-09-12 Jeroen Eyckmans, Christopher S. Chen
Making bone via nanoscale kicks Nature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0133-6 Causing nanoscale vibrations in bone-marrow stromal cells embedded in a soft collagen gel induces the cells to undergo osteogenic differentiation and mineralization via mechanosensitive signalling pathways.
Localization of microscale devices in vivo using addressable transmitters operated as magnetic spins Nat. Biomed. Eng. Pub Date : 2017-09-12 Manuel Monge, Audrey Lee-Gosselin, Mikhail G. Shapiro, Azita Emami
The function of miniature wireless medical devices, such as capsule endoscopes, biosensors and drug-delivery systems, depends critically on their location inside the body. However, existing electromagnetic, acoustic and imaging-based methods for localizing and communicating with such devices suffer from limitations arising from physical tissue properties or from the performance of the imaging modality. Here, we embody the principles of nuclear magnetic resonance in a silicon integrated-circuit approach for microscale device localization. Analogous to the behaviour of nuclear spins, the engineered miniaturized radio frequency transmitters encode their location in space by shifting their output frequency in proportion to the local magnetic field; applied field gradients thus allow each device to be located precisely from its signal’s frequency. The devices are integrated in circuits smaller than 0.7 mm3 and manufactured through a standard complementary-metal-oxide-semiconductor process, and are capable of sub-millimetre localization in vitro and in vivo. The technology is inherently robust to tissue properties, scalable to multiple devices, and suitable for the development of microscale devices to monitor and treat disease.
Potent drugless dendrimers Nat. Biomed. Eng. Pub Date : 2017-09-12 Zhenbin Lyu, Ling Peng
Potent drugless dendrimers Nature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0136-3 A dendrimer that depletes bioavailable copper as a result of its internal make-up displays powerful anticancer activity in mice, and no observable adverse effects.
Multiplexed imaging for diagnosis and therapy Nat. Biomed. Eng. Pub Date : 2017-09-12 Kathrin Heinzmann, Lukas M. Carter, Jason S. Lewis, Eric O. Aboagye
Complex molecular and metabolic phenotypes depict cancers as a constellation of different diseases with common themes. Precision imaging of such phenotypes requires flexible and tunable modalities capable of identifying phenotypic fingerprints by using a restricted number of parameters while ensuring sensitivity to dynamic biological regulation. Common phenotypes can be detected by in vivo imaging technologies, and effectively define the emerging standards for disease classification and patient stratification in radiology. However, for the imaging data to accurately represent a complex fingerprint, the individual imaging parameters need to be measured and analysed in relation to their wider spatial and molecular context. In this respect, targeted palettes of molecular imaging probes facilitate the detection of heterogeneity in oncogene-driven alterations and their response to treatment, and lead to the expansion of rational-design elements for the combination of imaging experiments. In this Review, we evaluate criteria for conducting multiplexed imaging, and discuss its opportunities for improving patient diagnosis and the monitoring of therapy.
Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor Nat. Biomed. Eng. Pub Date : 2017-09-12 Penelope M. Tsimbouri, Peter G. Childs, Gabriel D. Pemberton, Jingli Yang, Vineetha Jayawarna, Wich Orapiriyakul, Karl Burgess, Cristina González-García, Gavin Blackburn, Dilip Thomas, Catalina Vallejo-Giraldo, Manus J. P Biggs, Adam S. G. Curtis, Manuel Salmerón-Sánchez, Stuart Reid, Matthew J. Dalby
Bone grafts are one of the most commonly transplanted tissues. However, autologous grafts are in short supply, and can be associated with pain and donor-site morbidity. The creation of tissue-engineered bone grafts could help to fulfil clinical demand and provide a crucial resource for drug screening. Here, we show that vibrations of nanoscale amplitude provided by a newly developed bioreactor can differentiate a potential autologous cell source, mesenchymal stem cells (MSCs), into mineralized tissue in 3D. We demonstrate that nanoscale mechanotransduction can stimulate osteogenesis independently of other environmental factors, such as matrix rigidity. We show this by generating mineralized matrix from MSCs seeded in collagen gels with stiffness an order of magnitude below the stiffness of gels needed to induce bone formation in vitro. Our approach is scalable and can be compatible with 3D scaffolds.
Lasing cancer biomarkers Nat. Biomed. Eng. Pub Date : 2017-09-12 Matjaž Humar
Lasing cancer biomarkers Nature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0134-5 Laser light emitted by fluorescently stained human tissue inside a laser cavity can be used to diagnose cancer.
Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification Nat. Biomed. Eng. Pub Date : 2017-09-04 Lucia R. Wu, Sherry X. Chen, Yalei Wu, Abhijit A. Patel, David Yu Zhang
Rare DNA-sequence variants hold important clinical and biological information, but existing detection techniques are expensive, complex, allele-specific, or don’t allow for significant multiplexing. Here, we report a temperature-robust polymerase-chain-reaction method, which we term blocker displacement amplification (BDA), that selectively amplifies all sequence variants, including single-nucleotide variants (SNVs), within a roughly 20-nucleotide window by 1,000-fold over wild-type sequences. This allows for easy detection and quantitation of hundreds of potential variants originally at ≤0.1% in allele frequency. BDA is compatible with inexpensive thermocycler instrumentation and employs a rationally designed competitive hybridization reaction to achieve comparable enrichment performance across annealing temperatures ranging from 56 °C to 64 °C. To show the sequence generality of BDA, we demonstrate enrichment of 156 SNVs and the reliable detection of single-digit copies. We also show that the BDA detection of rare driver mutations in cell-free DNA samples extracted from the blood plasma of lung-cancer patients is highly consistent with deep sequencing using molecular lineage tags, with a receiver operator characteristic accuracy of 95%.
Laser-emission imaging of nuclear biomarkers for high-contrast cancer screening and immunodiagnosis Nat. Biomed. Eng. Pub Date : 2017-09-04 Yu-Cheng Chen, Xiaotian Tan, Qihan Sun, Qiushu Chen, Wenjie Wang, Xudong Fan
Detection of nuclear biomarkers, such as nucleic acids and nuclear proteins, is critical for early-stage cancer diagnosis and prognosis. Conventional methods relying on morphological assessment of cell nuclei in histopathology slides may be subjective, whereas colorimetric immunohistochemical and fluorescence-based imaging are limited by strong light absorption, broad emission bands and low contrast. Here, we describe the development and use of a scanning laser-emission-based microscope that maps lasing emissions from nuclear biomarkers in human tissues. Forty-one tissue samples from 35 patients labelled with site-specific and biomarker-specific antibody-conjugated dyes were sandwiched in a Fabry–Pérot microcavity while an excitation laser beam built a laser-emission image. We observed multiple subcellular lasing emissions from cancer cell nuclei, with a threshold of tens of μJ mm−2, submicrometre resolution (<700 nm), and a lasing band in the few-nanometre range. Different lasing thresholds of nuclei in cancer and normal tissues enabled the identification and multiplexed detection of nuclear proteomic biomarkers, with high sensitivity for early-stage cancer diagnosis. Laser-emission-based cancer screening and immunodiagnosis might find use in precision medicine and facilitate research in cell biology.
Tumour-bound RNA-laden exosomes Nat. Biomed. Eng. Pub Date : 2017-08-09 Sander A. A. Kooijmans, Pieter Vader, Raymond M. Schiffelers
Tumour-bound RNA-laden exosomes Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0119-4 Exosomes expressing CD47 and loaded with interfering RNA dodge phagocytosis and accumulate in pancreatic tumours to silence the expression of the oncogene Kras in mice, with remarkable therapeutic efficacy.
No implant needed Nat. Biomed. Eng. Pub Date : 2017-08-09 Alexander Opitz, William J. Tyler
No implant needed Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0120-y High-frequency transcranial electric-field oscillations stimulate neural circuits in the deep brain.
Ultrasound-triggered local anaesthesia Nat. Biomed. Eng. Pub Date : 2017-08-09 Alina Y. Rwei, Juan L. Paris, Bruce Wang, Weiping Wang, Christopher D. Axon, María Vallet-Regí, Robert Langer, Daniel S. Kohane
On-demand relief of local pain would allow patients to control the timing, intensity and duration of nerve blocks in a safe and non-invasive manner. Ultrasound would be a suitable trigger for such a system, as it is in common clinical use and can penetrate deeply into the body. Here, we demonstrate that ultrasound-triggered delivery of an anaesthetic from liposomes allows the timing, intensity and duration of nerve blocks to be controlled by ultrasound parameters. On insonation, the encapsulated sonosensitizer protoporphyrin IX produced reactive oxygen species that reacted with the liposomal membrane, leading to the release of the potent local anaesthetic tetrodotoxin. Repeatable ultrasound-triggered nerve blocks were achieved in vivo, with the nerve-block duration depending on the extent and intensity of insonation. There was no detectable systemic toxicity and tissue reaction was benign in all groups. On-demand, personalized local anaesthesia could be beneficial for the management of relatively localized pain states and could potentially minimize opioid use.
Contrastingly small iron oxides Nat. Biomed. Eng. Pub Date : 2017-08-09 Ali Yilmaz
Contrastingly small iron oxides Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0124-7 Uniform iron oxide nanoparticles with a hydrodynamic diameter of about 12 nm offer high biocompatibility and diagnostic yield as contrast agents for the magnetic resonance imaging of large animals.
Real-time drug pharmacokinetics Nat. Biomed. Eng. Pub Date : 2017-08-09 Chunyan Li, Raj K. Narayan
Real-time drug pharmacokinetics Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0122-9 A new microsensor can simultaneously track drug pharmacokinetics and pharmacodynamics and the resulting electrophysiological activity in live animals.
Ultrasound-triggered pain relief Nat. Biomed. Eng. Pub Date : 2017-08-09 Patrick Couvreur
Ultrasound-triggered pain relief Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0121-x The ability to release an anaesthetic from liposomes by applying ultrasound opens up the possibility of managing localized pain on-demand.
A microsensing system for the in vivo real-time detection of local drug kinetics Nat. Biomed. Eng. Pub Date : 2017-08-09 Genki Ogata, Yuya Ishii, Kai Asai, Yamato Sano, Fumiaki Nin, Takamasa Yoshida, Taiga Higuchi, Seishiro Sawamura, Takeru Ota, Karin Hori, Kazuya Maeda, Shizuo Komune, Katsumi Doi, Madoka Takai, Ian Findlay, Hiroyuki Kusuhara, Yasuaki Einaga, Hiroshi Hibino
Real-time recording of the kinetics of systemically administered drugs in in vivo microenvironments may accelerate the development of effective medical therapies. However, conventional methods require considerable analyte quantities, have low sampling rates and do not address how drug kinetics correlate with target function over time. Here, we describe the development and application of a drug-sensing system consisting of a glass microelectrode and a microsensor composed of boron-doped diamond with a tip of around 40 μm in diameter. We show that, in the guinea pig cochlea, the system can measure—simultaneously and in real time—changes in the concentration of bumetanide (a diuretic that is ototoxic but applicable to epilepsy treatment) and the endocochlear potential underlying hearing. In the rat brain, we tracked the kinetics of the drug and the local field potentials representing neuronal activity. We also show that the actions of the antiepileptic drug lamotrigine and the anticancer reagent doxorubicin can be monitored in vivo. Our microsensing system offers the potential to detect pharmacological and physiological responses that might otherwise remain undetected.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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