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.
Ingenuity across field boundaries Nat. Biomed. Eng. Pub Date : 2017-09-12
Ingenuity across field boundariesNature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0138-1Interdisciplinarity yields brilliant scientific innovations.
Making bone via nanoscale kicks Nat. Biomed. Eng. Pub Date : 2017-09-12 Jeroen Eyckmans, Christopher S. Chen
Making bone via nanoscale kicksNature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0133-6Causing 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 dendrimersNature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0136-3A 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 biomarkersNature Biomedical Engineering, Published online: 12 September 2017; doi:10.1038/s41551-017-0134-5Laser 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.
Making vessels more permeable Nat. Biomed. Eng. Pub Date : 2017-08-09 Abdullah Muhammad Syed, Shrey Sindhwani, Warren C. W. Chan
Making vessels more permeable Nature Biomedical Engineering, Published online: 9 August 2017; doi:10.1038/s41551-017-0123-8 Depletion of tumour-associated platelets improves the delivery of anticancer drugs.
Author correction: Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours Nat. Biomed. Eng. Pub Date : 2017-08-02 Suping Li, Yinlong Zhang, Jing Wang, Ying Zhao, Tianjiao Ji, Xiao Zhao, Yanping Ding, Xiaozheng Zhao, Ruifang Zhao, Feng Li, Xiao Yang, Shaoli Liu, Zhaofei Liu, Jianhao Lai, Andrew K. Whittaker, Gregory J. Anderson, Jingyan Wei, Guangjun Nie
Author correction: Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours Nature Biomedical Engineering, Published online: 2 August 2017; doi:10.1038/s41551-017-0125-6
Iron oxide nanoclusters for T 1 magnetic resonance imaging of non-human primates Nat. Biomed. Eng. Pub Date : 2017-07-31 Yang Lu, Yun-Jun Xu, Guo-bing Zhang, Daishun Ling, Ming-quan Wang, Yong Zhou, Ya-Dong Wu, Tao Wu, Michael J. Hackett, Byung Hyo Kim, Hogeun Chang, Jonghoon Kim, Xin-Tian Hu, Liang Dong, Nohyun Lee, Fangyuan Li, Jia-Cai He, Li Zhang, Hui-Qin Wen, Bo Yang, Seung Hong Choi, Taeghwan Hyeon, Duo-Hong Zou
Iron-oxide-based contrast agents for magnetic resonance imaging (MRI) had been clinically approved in the United States and Europe, yet most of these nanoparticle products were discontinued owing to failures to meet rigorous clinical requirements. Significant advances have been made in the synthesis of magnetic nanoparticles and their biomedical applications, but several major challenges remain for their clinical translation, in particular large-scale and reproducible synthesis, systematic toxicity assessment, and their preclinical evaluation in MRI of large animals. Here, we report the results of a toxicity study of iron oxide nanoclusters of uniform size in large animal models, including beagle dogs and the more clinically relevant macaques. We also show that iron oxide nanoclusters can be used as T1 MRI contrast agents for high-resolution magnetic resonance angiography in beagle dogs and macaques, and that dynamic MRI enables the detection of cerebral ischaemia in these large animals. Iron oxide nanoclusters show clinical potential as next-generation MRI contrast agents.
Nanoparticle-mediated local depletion of tumour-associated platelets disrupts vascular barriers and augments drug accumulation in tumours Nat. Biomed. Eng. Pub Date : 2017-07-24 Suping Li, Yinlong Zhang, Jing Wang, Ying Zhao, Tianjiao Ji, Xiao Zhao, Yanping Ding, Xiaozheng Zhao, Ruifang Zhao, Feng Li, Xiao Yang, Shaoli Liu, Zhaofei Liu, Jianhao Lai, Andrew K. Whittaker, Gregory J. Anderson, Jingyan Wei, Guangjun Nie
Limited intratumoural perfusion and nanoparticle retention remain major bottlenecks for the delivery of nanoparticle therapeutics into tumours. Here, we show that polymer–lipid–peptide nanoparticles delivering the antiplatelet antibody R300 and the chemotherapeutic agent doxorubicin can locally deplete tumour-associated platelets, thereby enhancing vascular permeability and augmenting the accumulation of the nanoparticles in tumours. R300 is specifically released in the tumour on cleavage of the lipid–peptide shell of the nanoparticles by matrix metalloprotease 2, which is commonly overexpressed in tumour vascular endothelia and stroma, thus facilitating vascular breaches that enhance tumour permeability. We also show that this strategy leads to substantial tumour regression and metastasis inhibition in mice.
Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion Nat. Biomed. Eng. Pub Date : 2017-07-11 Eric H. Nguyen, William T. Daly, Ngoc Nhi T. Le, Mitra Farnoodian, David G. Belair, Michael P. Schwartz, Connie S. Lebakken, Gene E. Ananiev, Mohammad Ali Saghiri, Thomas B. Knudsen, Nader Sheibani, William L. Murphy
The physiological relevance of Matrigel as a cell-culture substrate and in angiogenesis assays is often called into question. Here, we describe an array-based method for the identification of synthetic hydrogels that promote the formation of robust in vitro vascular networks for the detection of putative vascular disruptors and that support human embryonic stem cell expansion and pluripotency. We identified hydrogel substrates that promote endothelial-network formation by primary human umbilical vein endothelial cells and by endothelial cells derived from human-induced pluripotent stem cells, and used the hydrogels with endothelial networks to identify angiogenesis inhibitors. The synthetic hydrogels showed superior sensitivity and reproducibility over Matrigel when known inhibitors were evaluated, as well as in a blinded screen of a subset of 38 chemicals, selected according to predicted vascular disruption potential, from the Toxicity ForeCaster library of the United States Environmental Protection Agency. We propose that the identified synthetic hydrogels are suitable alternatives to Matrigel for common cell-culture applications.
Ageing: Biomarkers get physical Nat. Biomed. Eng. Pub Date : 2017-07-11 Xiao Dong, Jan Vijg
Ageing: Biomarkers get physical Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0102 Cellular biophysical features are identified as predictive biomarkers of ageing.
Genetic engineering: Lassoing genomic libraries Nat. Biomed. Eng. Pub Date : 2017-07-11 Nathan B. Lubock, Sriram Kosuri
Genetic engineering: Lassoing genomic libraries Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0098 Long single-stranded DNA probes enable the capture and multiplexed cloning of DNA at the megabase scale.
Intraoperative histology: Lightning 3D histopathology Nat. Biomed. Eng. Pub Date : 2017-07-11 Rory M. Power, Jan Huisken
Intraoperative histology: Lightning 3D histopathology Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0101 A light-sheet microscope offers fast three-dimensional imaging of intact clinical tissue samples over large fields of view.
Synthetic biology: A probiotic probe for inflammation Nat. Biomed. Eng. Pub Date : 2017-07-11 Ferdinand Sedlmayer, Martin Fussenegger
Synthetic biology: A probiotic probe for inflammation Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0097 Genetically modified bacteria provide a long-lasting record of intestinal inflammation in mice.
Cell migration: Arraying neutrophils in swarms Nat. Biomed. Eng. Pub Date : 2017-07-11 Tim Lämmermann
Cell migration: Arraying neutrophils in swarms Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0100 Microscale arrays of protein–polysaccharide clusters enable the functional characterization of human-neutrophil migration.
Biophysical and biomolecular determination of cellular age in humans Nat. Biomed. Eng. Pub Date : 2017-07-11 Jude M. Phillip, Pei-Hsun Wu, Daniele M. Gilkes, Wadsworth Williams, Shaun McGovern, Jena Daya, Jonathan Chen, Ivie Aifuwa, Jerry S. H. Lee, Rong Fan, Jeremy Walston, Denis Wirtz
Ageing research has focused either on assessing organ- and tissue-based changes, such as lung capacity and cardiac function, or on changes at the molecular scale such as gene expression, epigenetic modifications and metabolism. Here, by using a cohort of 32 samples of primary dermal fibroblasts collected from individuals between 2 and 96 years of age, we show that the degradation of functional cellular biophysical features—including cell mechanics, traction strength, morphology and migratory potential—and associated descriptors of cellular heterogeneity predict cellular age with higher accuracy than conventional biomolecular markers. We also demonstrate the use of high-throughput single-cell technologies, together with a deterministic model based on cellular features, to compute the cellular age of apparently healthy males and females, and to explore these relationships in cells from individuals with Werner syndrome and Hutchinson–Gilford progeria syndrome, two rare genetic conditions that result in phenotypes that show aspects of premature ageing. Our findings suggest that the quantification of cellular age may be used to stratify individuals on the basis of cellular phenotypes and serve as a biological proxy of healthspan.
Challenge the impact factor Nat. Biomed. Eng. Pub Date : 2017-07-11
Challenge the impact factor Nature Biomedical Engineering, Published online: 11 July 2017; doi:10.1038/s41551-017-0103 When comparing journals using citation-based metrics, the percentage of highly cited papers is more informative than the average number of citations.
Microscale arrays for the profiling of start and stop signals coordinating human-neutrophil swarming Nat. Biomed. Eng. Pub Date : 2017-06-30 Eduardo Reátegui, Fatemeh Jalali, Aimal H. Khankhel, Elisabeth Wong, Hansang Cho, Jarone Lee, Charles N. Serhan, Jesmond Dalli, Hunter Elliott, Daniel Irimia
Neutrophil swarms protect healthy tissues by sealing off sites of infection. In the absence of swarming, microbial invasion of surrounding tissues can result in severe infections. Recent observations in animal models have shown that swarming requires rapid neutrophil responses and well-choreographed neutrophil migration patterns. However, in animal models, physical access to the molecular signals coordinating neutrophil activities during swarming is limited. Here, we report the development and validation of large microscale arrays of zymosan particle clusters for the study of human neutrophils during swarming ex vivo. We characterized the synchronized swarming of human neutrophils under the guidance of neutrophil-released chemokines, and measured the mediators released at different phases of human-neutrophil swarming against targets simulating infections. We found that the network of mediators coordinating human-neutrophil swarming includes start and stop signals, proteolytic enzymes and enzyme inhibitors, as well as modulators of activation of other immune and non-immune cells. We also show that the swarming behaviour of neutrophils from patients following major trauma is deficient and gives rise to smaller swarms than those of neutrophils from healthy individuals.
Light-sheet microscopy for slide-free non-destructive pathology of large clinical specimens Nat. Biomed. Eng. Pub Date : 2017-06-26 Adam K. Glaser, Nicholas P. Reder, Ye Chen, Erin F. McCarty, Chengbo Yin, Linpeng Wei, Yu Wang, Lawrence D. True, Jonathan T. C. Liu
For the 1.7 million patients per year in the US who receive a new cancer diagnosis, treatment decisions are largely based on histopathological specimen examinations. Unfortunately, the gold standard of slide-based microscopic pathology suffers from high inter-observer variability and limited prognostic value due to sampling limitations and the inability to visualize tissue structures and molecular targets in their native 3D context. Here, we show that an open-top light-sheet microscope optimized for non-destructive slide-free pathology of clinical specimens enables the rapid imaging of intact tissues at high resolution over large 2D and 3D fields of view, with the same level of detail as traditional pathology. We demonstrate the utility of this technology for various applications: wide-area surface microscopy to triage surgical specimens (with ~200 μm surface irregularities), rapid intraoperative assessment of tumour-margin surfaces (12.5 s cm−2), and volumetric assessment of optically cleared core-needle biopsies (1 mm in diameter, 2 cm in length). Light-sheet microscopy can be a versatile tool for both rapid surface microscopy and deep volumetric microscopy of human specimens.
Long-adapter single-strand oligonucleotide probes for the massively multiplexed cloning of kilobase genome regions Nat. Biomed. Eng. Pub Date : 2017-06-26 Lorenzo Tosi, Viswanadham Sridhara, Yunlong Yang, Dongli Guan, Polina Shpilker, Nicola Segata, H. Benjamin Larman, Biju Parekkadan
As the catalogue of sequenced genomes and metagenomes continues to grow, massively parallel approaches for the comprehensive and functional analysis of gene products and regulatory elements are becoming increasingly valuable. Current strategies to synthesize or clone complex libraries of DNA sequences are limited by the length of the DNA targets, throughput and cost. Here, we show that long-adapter single-strand oligonucleotide (LASSO) probes can capture and clone thousands of kilobase DNA fragments in a single reaction. As proof of principle, we simultaneously cloned over 3,000 bacterial open reading frames (ORFs) from Escherichia coli genomic DNA (spanning 400- to 5,000-bp targets). Targets were enriched up to a median of around 60-fold compared with non-targeted genomic regions. At a cutoff of three times the median non-target reads per kilobase of genetic element per million reads, around 75% of the targeted ORFs were successfully captured. We also show that LASSO probes can clone human ORFs from complementary DNA, and an ORF library from a human-microbiome sample. LASSO probes could be used for the preparation of long-read sequencing libraries and for massively multiplexed cloning.
Erratum: Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks Nat. Biomed. Eng. Pub Date : 2017-06-26 Ruei-Zeng Lin, Chin Nien Lee, Rafael Moreno-Luna, Joseph Neumeyer, Breanna Piekarski, Pingzhu Zhou, Marsha A. Moses, Monisha Sachdev, William T. Pu, Sitaram Emani, Juan M. Melero-Martin
Erratum: Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks Nature Biomedical Engineering, Published online: 26 June 2017; doi:10.1038/s41551-017-0099
Joint implants: An elution solution Nat. Biomed. Eng. Pub Date : 2017-06-13 Noreen J. Hickok
Joint implants: An elution solution Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0087 An optimized drug-eluting polymer for the surface of articulating artificial joints may make them infection-free.
Engineering the pre-metastatic niche Nat. Biomed. Eng. Pub Date : 2017-06-13 Brian A. Aguado, Grace G. Bushnell, Shreyas S. Rao, Jacqueline S. Jeruss, Lonnie D. Shea
The pre-metastatic niche — the accumulation of aberrant immune cells and extracellular-matrix proteins in target organs — primes the initially healthy organ microenvironment and renders it amenable for subsequent colonization by metastatic cancer cells. By attracting metastatic cells, mimics of the pre-metastatic niche offer both diagnostic and therapeutic potential. However, deconstructing the complexity of the niche by identifying the interactions between cell populations as well as the mediatory roles of the immune system, soluble factors, extracellular-matrix proteins and stromal cells has proved challenging. Experimental models are needed to recapitulate niche-population biology in situ and to mediate in vivo tumour-cell homing, colonization and proliferation. In this Review, we outline the biology of the pre-metastatic niche and discuss advances in the engineering of niche-mimicking biomaterials that regulate the behaviour of tumour cells at an implant site. Such ‘oncomaterials’ offer strategies for the early detection of metastatic events, the inhibition of the formation of the pre-metastatic niche and the attenuation of metastatic progression.
Biosensing: CRISPR-powered diagnostics Nat. Biomed. Eng. Pub Date : 2017-06-13 Xiaolei Zuo, Chunhai Fan, Hong-Yuan Chen
Biosensing: CRISPR-powered diagnostics Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0091 A CRISPR-associated nuclease that can promiscuously cleave RNAs enables a rapid and cheap test for the single-molecule detection and single-base discrimination of nucleic acids.
Host non-inflammatory neutrophils mediate the engraftment of bioengineered vascular networks Nat. Biomed. Eng. Pub Date : 2017-06-13 Ruei-Zeng Lin, Chin Nien Lee, Rafael Moreno-Luna, Joseph Neumeyer, Breanna Piekarski, Pingzhu Zhou, Marsha A. Moses, Monisha Sachdev, William T. Pu, Sitaram Emani, Juan M. Melero-Martin
Notwithstanding the remarkable progress in vascular network engineering, implanted bioengineered microvessels mostly fail to form anastomoses with the host vasculature. Here we demonstrate that implants containing assembled human vascular networks (A-grafts) fail to engraft owing to their inability to engage non-inflammatory host neutrophils upon implantation into mice. By contrast, unassembled vascular cells (U-grafts) readily engage alternatively polarized neutrophils, which in turn serve as indispensable mediators of vascular assembly and anastomosis. The depletion of host neutrophils abrogated vascularization in U-grafts, whereas an adoptive transfer of neutrophils fully restored vascularization in myeloid-depleted mice. Neutrophil engagement was regulated by secreted factors and was progressively silenced as the vasculature matured. Exogenous addition of factors from U-grafts re-engaged neutrophils and enhanced revascularization in A-grafts, a process that was recapitulated by blocking Notch signalling. Our data suggest that the pro-vascularization potential of neutrophils can be harnessed to improve the engraftment of bioengineered tissues.
Bioassays: Universal sensitivity booster Nat. Biomed. Eng. Pub Date : 2017-06-13 Shana O. Kelley
Bioassays: Universal sensitivity booster Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0088 A universal ‘add-on’ method based on the ultrafast and localized deposition of polydopamine amplifies the sensitivity of a variety of bioassays for clinical diagnostics.
Long-lived biomaterials Nat. Biomed. Eng. Pub Date : 2017-06-13
Long-lived biomaterials Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0095 The design of implantable biomaterials with lasting function is rooted in biomolecular and cellular principles.
Immunoengineering: Valet parking for CAR genes Nat. Biomed. Eng. Pub Date : 2017-06-13 Marcela V. Maus
Immunoengineering: Valet parking for CAR genes Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0085 T-cell-binding nanoparticles bypass the complexities of in vitro gene transfer to deliver genes to T cells within the host.
Implanted scaffolds: Pre-ordered vessels halt ischaemia Nat. Biomed. Eng. Pub Date : 2017-06-13 Shahar Ben-Shaul, Shira Landau, Shulamit Levenberg
Implanted scaffolds: Pre-ordered vessels halt ischaemia Nature Biomedical Engineering, Published online: 13 June 2017; doi:10.1038/s41551-017-0089 Implanted scaffolds bearing 3D-printed parallel endothelialized channels restore blood perfusion in ischaemic hind limbs and infarcted hearts in rodents.
One-week glucose control via zero-order release kinetics from an injectable depot of glucagon-like peptide-1 fused to a thermosensitive biopolymer Nat. Biomed. Eng. Pub Date : 2017-06-05 Kelli M. Luginbuhl, Jeffrey L. Schaal, Bret Umstead, Eric M. Mastria, Xinghai Li, Samagya Banskota, Susan Arnold, Mark Feinglos, David D’Alessio, Ashutosh Chilkoti
Stimulation of the glucagon-like peptide-1 (GLP1) receptor is a useful treatment strategy for type 2 diabetes due to pleiotropic effects, such as the regulation of islet hormones and the induction of satiety. However, the native ligand for the GLP1 receptor has a short half-life owing to enzymatic inactivation and rapid clearance. Here, we show that a subcutaneous depot formed after a single injection of GLP1 recombinantly fused to a thermosensitive elastin-like polypeptide results in zero-order release kinetics and circulation times of up to 10 days in mice and 17 days in monkeys. The optimized pharmacokinetics lead to 10 days of glycaemic control in three different mouse models of diabetes, as well as the reduction of glycosylated haemoglobin levels and weight gain in ob/ob mice treated once weekly for 8 weeks. Our results suggest that the optimized GLP1 formulation could enhance therapeutic outcomes by eliminating peak-and-valley pharmacokinetics and improving overall safety and tolerability. The design principles that we established should be broadly applicable for improving the pharmacological performance of other peptide and protein therapeutics.
Dramatic enhancement of the detection limits of bioassays via ultrafast deposition of polydopamine Nat. Biomed. Eng. Pub Date : 2017-06-05 Junwei Li, Madison A. Baird, Michael A. Davis, Wanyi Tai, Larry S. Zweifel, Kristina M. Adams Waldorf, Michael Gale Jr, Lakshmi Rajagopal, Robert H. Pierce, Xiaohu Gao
The ability to detect biomarkers with ultrahigh sensitivity radically transformed biology and disease diagnosis. However, owing to incompatibilities with infrastructure in current biological and medical laboratories, recent innovations in analytical technology have not yet been adopted broadly. Here, we report a simple, universal ‘add-on’ technology (dubbed EASE) that converts the ordinary sensitivities of common bioassays to extraordinary ones, and that can be directly plugged into the routine practices of current research and clinical laboratories. The assay relies on the bioconjugation capabilities and ultrafast and localized deposition of polydopamine at the target site, which permit a large number of reporter molecules to be captured and lead to detection-sensitivity enhancements exceeding three orders of magnitude. The application of EASE in the ELISA-based detection of the HIV antigen in blood from patients leads to a sensitivity lower than 3 fg ml−1. We also show that EASE allows for the direct visualization, in tissues, of the Zika virus and of low-abundance biomarkers related to neurological diseases and cancer immunotherapy.
Engineering CRISPR–Cpf1 crRNAs and mRNAs to maximize genome editing efficiency Nat. Biomed. Eng. Pub Date : 2017-05-10 Bin Li, Weiyu Zhao, Xiao Luo, Xinfu Zhang, Chenglong Li, Chunxi Zeng, Yizhou Dong
Cpf1, a type-V CRISPR–Cas effector endonuclease, exhibits gene-editing activity in human cells through a single RNA-guided approach. Here, we report the design and assessment of an array of 42 types of engineered Acidaminococcus sp. Cpf1 (AsCpf1) CRISPR RNA (crRNA) and 5 types of AsCpf1 mRNA in human cell lines. We show that the top-performing modified crRNA (cr3′5F, containing five 2′-fluoro ribose at the 3′ terminus) and AsCpf1 mRNA (full ψ-modification) improved gene-cutting efficiency by, respectively, 127% and 177%, with respect to unmodified crRNA and plasmid-encoding AsCpf1. We also show that the combination of cr3′5F and ψ-modified AsCpf1 or Lachnospiraceae bacterium Cpf1 (LbCpf1) mRNA augmented gene-cutting efficiency by over 300% with respect to the same control, and discovered that 11 out of 16 crRNAs from Cpf1 orthologues enabled genome editing in the presence of AsCpf1. Engineered CRISPR–Cpf1 systems should facilitate a broad range of genome editing applications.
Neuroprosthetics: Restoring multi-joint motor control Nat. Biomed. Eng. Pub Date : 2017-05-10 Silvestro Micera
Neuroprosthetics: Restoring multi-joint motor control Nature Biomedical Engineering, Published online: 10 May 2017; doi:10.1038/s41551-017-0073 An intracortical brain–computer interface combined with functional electrical stimulation allows an individual with traumatic spinal cord injury to perform coordinated reaching and grasping movements.
Closed-loop control of circulating drug levels in live animals Nat. Biomed. Eng. Pub Date : 2017-05-10 P. L. Mage, B. S. Ferguson, D. Maliniak, K. L Ploense, T. E. Kippin, H. T. Soh
Current methods of drug dosing rely on physical parameters (such as sex, age and weight) that do not account for genetic and physiological differences among individual patients. These differences can greatly affect how drugs are processed in the body and can result in ineffective underdosing or toxic overdosing. Here, we describe a generalizable closed-loop system consisting of a biosensor, controller and infusion pump, and a model of drug pharmacokinetics that continuously monitors and adjusts the concentration of a given drug in the body. As proof of concept, we demonstrate that the system can maintain the concentration of doxorubicin—a widely used chemotherapy drug—in live rabbits and rats at any desired set point and in real time, while automatically compensating for large pharmacokinetic differences among individual animals and stabilizing dramatic perturbations arising from acute drug–drug interactions. The feedback-loop system opens up the possibility of tightly controlled, patient-specific dosing of chemotherapeutics and other drugs within narrow therapeutic windows.
Organs-on-chips: Filtration enabled by differentiation Nat. Biomed. Eng. Pub Date : 2017-05-10 Eliza Li Shan Fong, Hanry Yu
Organs-on-chips: Filtration enabled by differentiation Nature Biomedical Engineering, Published online: 10 May 2017; doi:10.1038/s41551-017-0074 The efficient generation of mature podocytes from induced pluripotent stem cells makes possible the recapitulation of renal blood filtration on a chip.
Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution Nat. Biomed. Eng. Pub Date : 2017-05-10 Lei Li, Liren Zhu, Cheng Ma, Li Lin, Junjie Yao, Lidai Wang, Konstantin Maslov, Ruiying Zhang, Wanyi Chen, Junhui Shi, Lihong V. Wang
Imaging of small animals has played an indispensable role in preclinical research by providing high-dimensional physiological, pathological and phenotypic insights with clinical relevance. Yet, pure optical imaging suffers from either shallow penetration (up to ~1–2 mm) or a poor depth-to-resolution ratio (~3), and non-optical techniques for whole-body imaging of small animals lack either spatiotemporal resolution or functional contrast. Here, we demonstrate that stand-alone single-impulse panoramic photoacoustic computed tomography (SIP-PACT) mitigates these limitations by combining high spatiotemporal resolution (125 μm in-plane resolution, 50 μs per frame data acquisition and 50 Hz frame rate), deep penetration (48 mm cross-sectional width in vivo), anatomical, dynamical and functional contrasts, and full-view fidelity. Using SIP-PACT, we imaged in vivo whole-body dynamics of small animals in real time and obtained clear sub-organ anatomical and functional details. We tracked unlabelled circulating melanoma cells and imaged the vasculature and functional connectivity of whole rat brains. SIP-PACT holds great potential for both preclinical imaging and clinical translation.
Precision assessment of label-free psoriasis biomarkers with ultra-broadband optoacoustic mesoscopy Nat. Biomed. Eng. Pub Date : 2017-05-10 Juan Aguirre, Mathias Schwarz, Natalie Garzorz, Murad Omar, Andreas Buehler, Kilian Eyerich, Vasilis Ntziachristos
Imaging plays a critical role in the diagnosis and assessment of dermatological conditions. However, optical or optoacoustic microscopy techniques are limited to visualizing superficial skin features owing to strong photon scattering, whereas ultrasound methods, which can probe deeper-seated tissue, lack the contrast to image pathophysiological mechanisms in detail. Here, we demonstrate that raster-scan optoacoustic mesoscopy (RSOM) implemented in ultra-broadband (10–180 MHz) detection mode bridges the depth capabilities of ultrasound and the resolution range and high contrast of optical methods in clinical dermatology. Using tomographic reconstruction and frequency equalization to represent low and high spatial-frequency components, we visualize skin morphology and vascular patterns in the dermis and sub-dermis of psoriasis patients, enabling quantification of inflammation and other biomarkers of psoriasis without the need for contrast agents. Implemented in a handheld device, we showcase how label-free biomarkers detected by RSOM correlate with clinical score. The method can also be extended to assess a larger spectrum of dermatological conditions.
Photoacoustic tomography: Breathtaking whole-body imaging Nat. Biomed. Eng. Pub Date : 2017-05-10 Orly Liba, Adam de la Zerda
Photoacoustic tomography: Breathtaking whole-body imaging Nature Biomedical Engineering, Published online: 10 May 2017; doi:10.1038/s41551-017-0075 High-frame-rate, high-resolution photoacoustic computed tomography reveals, for small live animals, the brain's functional connectivity and the dynamics of breathing, blood oxygenation and circulating melanoma cells.
Drug delivery: Closed-loop dynamic dosing Nat. Biomed. Eng. Pub Date : 2017-05-10 Rohit Karnik
Drug delivery: Closed-loop dynamic dosing Nature Biomedical Engineering, Published online: 10 May 2017; doi:10.1038/s41551-017-0072 A system consisting of an aptamer-based microfluidic biosensor and a simple feedback-control algorithm adjusts therapeutic dosing in near real time in small animals.
Drug delivery: Closed-loop dynamic dosing Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@87cc1ea[name=Rohit Karnik,email=some(firstname.lastname@example.org)]
A system consisting of an aptamer-based microfluidic biosensor and a simple feedback-control algorithm adjusts therapeutic dosing in near real time in small animals.
Photoacoustic tomography: Breathtaking whole-body imaging Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@6616cc20[name=Orly Liba,email=none()], com.springer.oscar.shared.search.Author@12a2596b[name=Adam de la Zerda,email=some(email@example.com)]
High-frame-rate, high-resolution photoacoustic computed tomography reveals, for small live animals, the brain's functional connectivity and the dynamics of breathing, blood oxygenation and circulating melanoma cells.
Precision assessment of label-free psoriasis biomarkers with ultra-broadband optoacoustic mesoscopy Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@687b8a57[name=Juan Aguirre,email=none()], com.springer.oscar.shared.search.Author@6667523[name=Mathias Schwarz,email=none()], com.springer.oscar.shared.search.Author@56c1de03[name=Natalie Garzorz,email=none()], com.springer.oscar.shared.search.Author@56a8bcb1[name=Murad Omar,email=none()], com.springer.oscar.shared.search.Author@62b5ad01[name=Andreas Buehler,email=none()], com.springer.oscar.shared.search.Author@57cf0319[name=Kilian Eyerich,email=none()], com.springer.oscar.shared.search.Author@fa6ee25[name=Vasilis Ntziachristos,email=some(firstname.lastname@example.org)]
Ultra-broadband optoacoustic mesoscopy implemented in a handheld device enables the visualization of vascular patterns in the dermis and sub-dermis of psoriasis patients, and the quantification of inflammatory biomarkers of psoriasis.
Single-impulse panoramic photoacoustic computed tomography of small-animal whole-body dynamics at high spatiotemporal resolution Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@1cf88654[name=Lei Li,email=none()], com.springer.oscar.shared.search.Author@53eaed6f[name=Liren Zhu,email=none()], com.springer.oscar.shared.search.Author@7c92fbc0[name=Cheng Ma,email=none()], com.springer.oscar.shared.search.Author@44fdf5b1[name=Li Lin,email=none()], com.springer.oscar.shared.search.Author@1c6f115c[name=Junjie Yao,email=none()], com.springer.oscar.shared.search.Author@18ea062b[name=Lidai Wang,email=none()], com.springer.oscar.shared.search.Author@73cdb20d[name=Konstantin Maslov,email=none()], com.springer.oscar.shared.search.Author@583691b8[name=Ruiying Zhang,email=none()], com.springer.oscar.shared.search.Author@3cb79e13[name=Wanyi Chen,email=none()], com.springer.oscar.shared.search.Author@74240cf0[name=Junhui Shi,email=none()], com.springer.oscar.shared.search.Author@6a6795a3[name=Lihong V. Wang,email=some(LVW@Caltech.edu)]
Single-impulse photoacoustic computed tomography can, at deep penetration and high resolution and contrast, image the whole-body dynamics of small animals in real time, and track injected cancer cells and image the vasculature of whole rat brains.
Organs-on-chips: Filtration enabled by differentiation Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@6b06206[name=Eliza Li Shan Fong,email=none()], com.springer.oscar.shared.search.Author@6f733c5[name=Hanry Yu,email=some(email@example.com)]
The efficient generation of mature podocytes from induced pluripotent stem cells makes possible the recapitulation of renal blood filtration on a chip.
Closed-loop control of circulating drug levels in live animals Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@5260ec67[name=P. L. Mage,email=none()], com.springer.oscar.shared.search.Author@47ca105[name=B. S. Ferguson,email=none()], com.springer.oscar.shared.search.Author@1d943de[name=D. Maliniak,email=none()], com.springer.oscar.shared.search.Author@3e8f213b[name=K. L Ploense,email=none()], com.springer.oscar.shared.search.Author@6bd9e159[name=T. E. Kippin,email=none()], com.springer.oscar.shared.search.Author@acc01ae[name=H. T. Soh,email=some(firstname.lastname@example.org)]
A closed-loop control system measures and adjusts the concentration of a chemotherapeutic in real time and maintains it within a predefined therapeutic window in both rabbits and rats.
Neuroprosthetics: Restoring multi-joint motor control Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@4140649a[name=Silvestro Micera,email=some(Silvestro.email@example.com)]
An intracortical brain–computer interface combined with functional electrical stimulation allows an individual with traumatic spinal cord injury to perform coordinated reaching and grasping movements.
Engineering CRISPR–Cpf1 crRNAs and mRNAs to maximize genome editing efficiency Nat. Biomed. Eng. Pub Date : 2017-05-10 com.springer.oscar.shared.search.Author@6010370[name=Bin Li,email=none()], com.springer.oscar.shared.search.Author@22f6f9c0[name=Weiyu Zhao,email=none()], com.springer.oscar.shared.search.Author@48dd4d41[name=Xiao Luo,email=none()], com.springer.oscar.shared.search.Author@a7b8474[name=Xinfu Zhang,email=none()], com.springer.oscar.shared.search.Author@46f1cc8[name=Chenglong Li,email=none()], com.springer.oscar.shared.search.Author@11c2dd7c[name=Chunxi Zeng,email=none()], com.springer.oscar.shared.search.Author@33573d40[name=Yizhou Dong,email=some(firstname.lastname@example.org)]
An array of chemically engineered CRISPR RNAs and AsCpf1 messenger RNAs leads to improvements in gene-cutting efficiency up to about 300% with respect to unmodified CRISPR RNA and plasmid-encoding AsCpf1.
A carbon nanotube reporter of microRNA hybridization events in vivo Nat. Biomed. Eng. Pub Date : 2017-03-13 Jackson D. Harvey, Prakrit V. Jena, Hanan A. Baker, Gül H. Zerze, Ryan M. Williams, Thomas V. Galassi, Daniel Roxbury, Jeetain Mittal, Daniel A. Heller
A carbon nanotube sensor enables real-time optical quantification of hybridization events of microRNA and other oligonucleotides in vivo and in whole urine and serum.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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