| 1. |
- Gupta, Dhanu, et al.
(författare)
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Amelioration of systemic inflammation via the display of two different decoy protein receptors on extracellular vesicles
- 2021
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Ingår i: Nature Biomedical Engineering. - Stockholm : Karolinska Institutet, Dept of Laboratory Medicine. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Extracellular vesicles (EVs) can be functionalized to display specific protein receptors on their surface. However, surface-display technology typically labels only a small fraction of the EV population. Here, we show that the joint display of two different therapeutically relevant protein receptors on EVs can be optimized by systematically screening EV-loading protein moieties. We used cytokine-binding domains derived from tumour necrosis factor receptor 1 (TNFR1) and interleukin-6 signal transducer (IL-6ST), which can act as decoy receptors for the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-α) and IL-6, respectively. We found that the genetic engineering of EV-producing cells to express oligomerized exosomal sorting domains and the N-terminal fragment of syntenin (a cytosolic adaptor of the single transmembrane domain protein syndecan) increased the display efficiency and inhibitory activity of TNFR1 and IL-6ST and facilitated their joint display on EVs. In mouse models of systemic inflammation, neuroinflammation and intestinal inflammation, EVs displaying the cytokine decoys ameliorated the disease phenotypes with higher efficacy as compared with clinically approved biopharmaceutical agents targeting the TNF-α and IL-6 pathways.
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| 2. |
- Artursson, Per, et al.
(författare)
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A new opening for orally taken peptide drugs
- 2020
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 4:1, s. 12-13
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Negatively charged nanoparticles of about 50 nm in size permit the oral delivery of insulin and other peptide drugs by temporally enhancing the permeability of the intestinal wall.
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| 3. |
- Farina, D., et al.
(författare)
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Toward higher-performance bionic limbs for wider clinical use
- 2021
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 7:4, s. 473-85
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Tidskriftsartikel (refereegranskat)abstract
- Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged towards the creation of a new generation of high-performance bionic limbs. These technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs. This Perspective argues that technologies for the neural interfacing of robotic devices with the body that have been clinically tested in humans should be leveraged toward the creation of a new generation of high-performance bionic limbs.
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| 4. |
- He, B., et al.
(författare)
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Integrating spatial gene expression and breast tumour morphology via deep learning
- 2020
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Ingår i: Nature Biomedical Engineering. - : Nature Research. - 2157-846X. ; 4:8, s. 827-834
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Tidskriftsartikel (refereegranskat)abstract
- Spatial transcriptomics allows for the measurement of RNA abundance at a high spatial resolution, making it possible to systematically link the morphology of cellular neighbourhoods and spatially localized gene expression. Here, we report the development of a deep learning algorithm for the prediction of local gene expression from haematoxylin-and-eosin-stained histopathology images using a new dataset of 30,612 spatially resolved gene expression data matched to histopathology images from 23 patients with breast cancer. We identified over 100 genes, including known breast cancer biomarkers of intratumoral heterogeneity and the co-localization of tumour growth and immune activation, the expression of which can be predicted from the histopathology images at a resolution of 100 µm. We also show that the algorithm generalizes well to The Cancer Genome Atlas and to other breast cancer gene expression datasets without the need for re-training. Predicting the spatially resolved transcriptome of a tissue directly from tissue images may enable image-based screening for molecular biomarkers with spatial variation.
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| 5. |
- Herland, Anna, et al.
(författare)
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Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips
- 2020
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 4:4, s. 421-436
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Tidskriftsartikel (refereegranskat)abstract
- Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans—using computationally scaled data from multiple fluidically linked two-channel organ chips—predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.
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| 6. |
- Jin, Chuan, 1986-, et al.
(författare)
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CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers
- 2022
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Ingår i: Nature Biomedical Engineering. - : Springer Nature. - 2157-846X. ; 6:7, s. 830-841
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Tidskriftsartikel (refereegranskat)abstract
- Chimeric antigen receptor T cells (CAR T cells) are effective against haematologic malignancies. However, in solid tumours, their potency is hampered by local immunosuppression and by the heterogeneous expression of the antigen that the CAR targets. Here we show that CAR T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein (NAP) from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers. In mice with subcutaneous murine pancreatic ductal adenocarcinomas, neuroblastomas or colon carcinomas, CAR(NAP) T cells led to slower tumour growth and higher survival rates than conventional mouse CAR T cells, regardless of target antigen, tumour type and host haplotype. In tumours with heterogeneous antigen expression, NAP secretion induced the formation of an immunologically 'hot' microenvironment that supported dendritic cell maturation and bystander responses, as indicated by epitope spreading and infiltration of cytotoxic CD8(+) T cells targeting tumour-associated antigens other than the CAR-targeted antigen. CAR T cells armed with NAP neither increased off-tumour toxicity nor hampered the efficacy of CAR T cells, and hence may have advantageous translational potential. T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers.
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| 7. |
- Li, J., et al.
(författare)
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Dramatic enhancement of the detection limits of bioassays via ultrafast deposition of polydopamine
- 2017
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 1:6
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Louhivuori, L, et al.
(författare)
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Predicting a tumour's drug uptake
- 2018
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Ingår i: Nature biomedical engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 2:10, s. 717-718
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Nadeau, P., et al.
(författare)
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Prolonged energy harvesting for ingestible devices
- 2017
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Ingår i: Nature Biomedical Engineering. - : Nature Publishing Group. - 2157-846X. ; 1:3
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Tidskriftsartikel (refereegranskat)abstract
- Ingestible electronics have revolutionized the standard of care for a variety of health conditions. Extending the capacity and safety of these devices, and reducing the costs of powering them, could enable broad deployment of prolonged-monitoring systems for patients. Although previous biocompatible power-harvesting systems for in vivo use have demonstrated short (minute-long) bursts of power from the stomach, little is known about the potential for powering electronics in the longer term and throughout the gastrointestinal tract. Here, we report the design and operation of an energy-harvesting galvanic cell for continuous in vivo temperature sensing and wireless communication. The device delivered an average power of 0.23 μW mm -2 of electrode area for an average of 6.1 days of temperature measurements in the gastrointestinal tract of pigs. This power-harvesting cell could provide power to the next generation of ingestible electronic devices for prolonged periods of time inside the gastrointestinal tract.
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| 10. |
- Ni, Ruiqing, et al.
(författare)
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Multiscale optical and optoacoustic imaging of amyloid-beta deposits in mice
- 2022
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Ingår i: Nature Biomedical Engineering. - : NATURE PORTFOLIO. - 2157-846X. ; 6, s. 1031-1044
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Tidskriftsartikel (refereegranskat)abstract
- Large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess amyloid-beta deposits in transgenic mouse models of Alzheimers disease. Deposits of amyloid-beta (A beta) in the brains of rodents can be analysed by invasive intravital microscopy on a submillimetre scale, or via whole-brain images from modalities lacking the resolution or molecular specificity to accurately characterize A beta pathologies. Here we show that large-field multifocal illumination fluorescence microscopy and panoramic volumetric multispectral optoacoustic tomography can be combined to longitudinally assess A beta deposits in transgenic mouse models of Alzheimers disease. We used fluorescent A beta-targeted probes (the luminescent conjugated oligothiophene HS-169 and the oxazine-derivative AOI987) to transcranially detect A beta deposits in the cortex of APP/PS1 and arcA beta mice with single-plaque resolution (8 mu m) and across the whole brain (including the hippocampus and the thalamus, which are inaccessible by conventional intravital microscopy) at sub-150 mu m resolutions. Two-photon microscopy, light-sheet microscopy and immunohistochemistry of brain-tissue sections confirmed the specificity and regional distributions of the deposits. High-resolution multiscale optical and optoacoustic imaging of A beta deposits across the entire brain in rodents thus facilitates the in vivo study of A beta accumulation by brain region and by animal age and strain.
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| 11. |
- Novak, R., et al.
(författare)
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Robotic fluidic coupling and interrogation of multiple vascularized organ chips
- 2020
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Ingår i: Nature Biomedical Engineering. - : Nature Research. - 2157-846X.
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Tidskriftsartikel (refereegranskat)abstract
- Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an ‘interrogator’ that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood–brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.
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| 12. |
- Ols, S, et al.
(författare)
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Imaging the early fate of mRNA vaccines
- 2019
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Ingår i: Nature biomedical engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 3:5, s. 331-332
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Tidskriftsartikel (refereegranskat)
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| 13. |
- Ortiz Catalan, Max Jair, 1982
(författare)
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Neuroengineering: Deciphering neural drive
- 2017
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 1:2
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 14. |
- Ortiz Catalan, Max Jair, 1982
(författare)
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Ultrasound-powered tiny neural stimulators
- 2020
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 4:2, s. 144-145
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Tidskriftsartikel (refereegranskat)abstract
- Wireless and leadless millimetre-scale implantable pulse generators, powered and controlled by ultrasonic links, enable the electrical stimulation of neural pathways in anaesthetized rats.
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| 15. |
- Paulsen, B. S., et al.
(författare)
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Ectopic expression of RAD52 and dn53BP1 improves homology-directed repair during CRISPR-Cas9 genome editing
- 2017
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Ingår i: Nature Biomedical Engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 1:11, s. 878-888
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Tidskriftsartikel (refereegranskat)abstract
- Gene disruption by clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) is highly efficient and relies on the error-prone non-homologous end-joining pathway. Conversely, precise gene editing requires homology-directed repair (HDR), which occurs at a lower frequency than non-homologous end-joining in mammalian cells. Here, by testing whether manipulation of DNA repair factors improves HDR efficacy, we show that transient ectopic co-expression of RAD52 and a dominant-negative form of tumour protein p53-binding protein 1 (dn53BP1) synergize to enable efficient HDR using a single-stranded oligonucleotide DNA donor template at multiple loci in human cells, including patient-derived induced pluripotent stem cells. Co-expression of RAD52 and dn53BP1 improves multiplexed HDR-mediated editing, whereas expression of RAD52 alone enhances HDR with Cas9 nickase. Our data show that the frequency of non-homologous end-joining-mediated double-strand break repair in the presence of these two factors is not suppressed and suggest that dn53BP1 competitively antagonizes 53BP1 to augment HDR in combination with RAD52. Importantly, co-expression of RAD52 and dn53BP1 does not alter Cas9 off-target activity. These findings support the use of RAD52 and dn53BP1 co-expression to overcome bottlenecks that limit HDR in precision genome editing. © 2017 The Author(s).
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| 16. |
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| 17. |
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| 18. |
- Silverå Ejneby, Malin, et al.
(författare)
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Chronic electrical stimulation of peripheral nerves via deep-red light transduced by an implanted organic photocapacitor
- 2022
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Ingår i: Nature Biomedical Engineering. - : NATURE PORTFOLIO. - 2157-846X. ; 6:6, s. 741-753
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Tidskriftsartikel (refereegranskat)abstract
- Implantable devices for the wireless modulation of neural tissue need to be designed for reliability, safety and reduced invasiveness. Here we report chronic electrical stimulation of the sciatic nerve in rats by an implanted organic electrolytic photocapacitor that transduces deep-red light into electrical signals. The photocapacitor relies on commercially available semiconducting non-toxic pigments and is integrated in a conformable 0.1-mm(3) thin-film cuff. In freely moving rats, fixation of the cuff around the sciatic nerve, 10 mm below the surface of the skin, allowed stimulation (via 50-1,000-mu s pulses of deep-red light at wavelengths of 638 nm or 660 nm) of the nerve for over 100 days. The robustness, biocompatibility, low volume and high-performance characteristics of organic electrolytic photocapacitors may facilitate the wireless chronic stimulation of peripheral nerves. An organic electrolytic photocapacitor transducing deep-red light into electrical signals and implanted within a thin cuff around the sciatic nerve of rats allows for wireless electrical stimulation of the nerve for over 100 days.
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| 19. |
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| 20. |
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| 21. |
- Tanaka, Nobuyuki, et al.
(författare)
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Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity
- 2017
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Ingår i: Nature Biomedical Engineering. - : Nature Publishing Group. - 2157-846X. ; 1:10, s. 796-806
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Tidskriftsartikel (refereegranskat)abstract
- Intratumoral heterogeneity is a critical factor when diagnosing and treating patients with cancer. Marked differences in the genetic and epigenetic backgrounds of cancer cells have been revealed by advances in genome sequencing, yet little is known about the phenotypic landscape and the spatial distribution of intratumoral heterogeneity within solid tumours. Here, we show that three-dimensional light-sheet microscopy of cleared solid tumours can identify unique patterns of phenotypic heterogeneity, in the epithelial-to-mesenchymal transition and in angiogenesis, at single-cell resolution in whole formalin-fixed paraffin-embedded (FFPE) biopsy samples. We also show that cleared FFPE samples can be re-embedded in paraffin after examination for future use, and that our tumour-phenotyping pipeline can determine tumour stage and stratify patient prognosis from clinical samples with higher accuracy than current diagnostic methods, thus facilitating the design of more efficient cancer therapies.
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| 22. |
- van der Laak, Jeroen, et al.
(författare)
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No pixel-level annotations needed
- 2019
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Ingår i: Nature Biomedical Engineering. - : NATURE PUBLISHING GROUP. - 2157-846X. ; 3:11, s. 855-856
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A deep-learning model for cancer detection trained on a large number of scanned pathology slides and associated diagnosis labels enables model development without the need for pixel-level annotations.
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| 23. |
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| 24. |
- Zickler, AM, et al.
(författare)
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Functional extracellular vesicles aplenty
- 2020
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Ingår i: Nature biomedical engineering. - : Springer Science and Business Media LLC. - 2157-846X. ; 4:1, s. 9-11
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Tidskriftsartikel (refereegranskat)
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