Showing papers in "Nature Biomedical Engineering in 2019"

Biodegradable and flexible arterial-pulse sensor for the wireless monitoring of blood flow

Abstract: The ability to monitor blood flow is critical to patient recovery and patient outcomes after complex reconstructive surgeries. Clinically available wired implantable monitoring technology requires careful fixation for accurate detection and needs to be removed after use. Here, we report the design of a pressure sensor, made entirely of biodegradable materials and based on fringe-field capacitor technology, for measuring arterial blood flow in both contact and non-contact modes. The sensor is operated wirelessly through inductive coupling, has minimal hysteresis, fast response times, excellent cycling stability, is highly robust, allows for easy mounting and eliminates the need for removal, thus reducing the risk of vessel trauma. We demonstrate the operation of the sensor with a custom-made artificial artery model and in vivo in rats. This technology may be advantageous in real-time post-operative monitoring of blood flow after reconstructive surgery.

A Complex Human-Gut Microbiome Cultured in an Anaerobic Intestine-on-a-Chip

Abstract: The diverse bacterial populations that comprise the commensal microbiome of the human intestine play a central role in health and disease. A method that sustains complex microbial communities in direct contact with living human intestinal cells and their overlying mucus layer in vitro would thus enable the investigation of host-microbiome interactions. Here, we show the extended coculture of living human intestinal epithelium with stable communities of aerobic and anaerobic human gut microbiota, using a microfluidic intestine-on-a-chip that permits the control and real-time assessment of physiologically relevant oxygen gradients. When compared to aerobic coculture conditions, the establishment of a transluminal hypoxia gradient in the chip increased intestinal barrier function and sustained a physiologically relevant level of microbial diversity, consisting of over 200 unique operational taxonomic units from 11 different genera and an abundance of obligate anaerobic bacteria, with ratios of Firmicutes and Bacteroidetes similar to those observed in human faeces. The intestine-on-a-chip may serve as a discovery tool for the development of microbiome-related therapeutics, probiotics and nutraceuticals.

Soft and elastic hydrogel-based microelectronics for localized low-voltage neuromodulation

Abstract: Narrowing the mechanical mismatch between tissue and implantable microelectronics is essential for reducing immune responses and for accommodating body movement. However, the design of implantable soft electronics (on the order of 10 kPa in modulus) remains a challenge because of the limited availability of suitable electronic materials. Here, we report electrically conductive hydrogel-based elastic microelectronics with Young’s modulus values in the kilopascal range. The system consists of a highly conductive soft hydrogel as a conductor and an elastic fluorinated photoresist as the passivation insulation layer. Owing to the high volumetric capacitance and the passivation layer of the hydrogel, electrode arrays of the thin-film hydrogel ‘elastronics’, 20 μm in feature size, show a significantly reduced interfacial impedance with tissue, a current-injection density that is ~30 times higher than that of platinum electrodes, and stable electrical performance under strain. We demonstrate the use of the soft elastronic arrays for localized low-voltage electrical stimulation of the sciatic nerve in live mice. Conductive and elastic hydrogel-based microelectronic arrays with high current-injection density and low interfacial impedance with tissue enable the localized low-voltage electrical stimulation of the sciatic nerve in live mice.

Detection of unamplified target genes via CRISPR–Cas9 immobilized on a graphene field-effect transistor

Abstract: Most methods for the detection of nucleic acids require many reagents and expensive and bulky instrumentation. Here, we report the development and testing of a graphene-based field-effect transistor that uses clustered regularly interspaced short palindromic repeats (CRISPR) technology to enable the digital detection of a target sequence within intact genomic material. Termed CRISPR–Chip, the biosensor uses the gene-targeting capacity of catalytically deactivated CRISPR-associated protein 9 (Cas9) complexed with a specific single-guide RNA and immobilized on the transistor to yield a label-free nucleic-acid-testing device whose output signal can be measured with a simple handheld reader. We used CRISPR–Chip to analyse DNA samples collected from HEK293T cell lines expressing blue fluorescent protein, and clinical samples of DNA with two distinct mutations at exons commonly deleted in individuals with Duchenne muscular dystrophy. In the presence of genomic DNA containing the target gene, CRISPR–Chip generates, within 15 min, with a sensitivity of 1.7 fM and without the need for amplification, a significant enhancement in output signal relative to samples lacking the target sequence. CRISPR–Chip expands the applications of CRISPR–Cas9 technology to the on-chip electrical detection of nucleic acids. An electrical biosensor combining CRISPR–Cas9 and a graphene field-effect transistor detects target genes in purified genomic samples at high sensitivity, within 15 minutes, and without the need for amplification.

Virtual histological staining of unlabelled tissue-autofluorescence images via deep learning.

Abstract: The histological analysis of tissue samples, widely used for disease diagnosis, involves lengthy and laborious tissue preparation. Here, we show that a convolutional neural network trained using a generative adversarial-network model can transform wide-field autofluorescence images of unlabelled tissue sections into images that are equivalent to the bright-field images of histologically stained versions of the same samples. A blind comparison, by board-certified pathologists, of this virtual staining method and standard histological staining using microscopic images of human tissue sections of the salivary gland, thyroid, kidney, liver and lung, and involving different types of stain, showed no major discordances. The virtual-staining method bypasses the typically labour-intensive and costly histological staining procedures, and could be used as a blueprint for the virtual staining of tissue images acquired with other label-free imaging modalities. Deep learning can be used to virtually stain autofluorescence images of unlabelled tissue sections, generating images that are equivalent to the histologically stained versions.

A bioprinted human-glioblastoma-on-a-chip for the identification of patient-specific responses to chemoradiotherapy

Abstract: Patient-specific ex vivo models of human tumours that recapitulate the pathological characteristics and complex ecology of native tumours could help determine the most appropriate cancer treatment for individual patients. Here, we show that bioprinted reconstituted glioblastoma tumours consisting of patient-derived tumour cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue in a compartmentalized cancer–stroma concentric-ring structure that sustains a radial oxygen gradient, recapitulate the structural, biochemical and biophysical properties of the native tumours. We also show that the glioblastoma-on-a-chip reproduces clinically observed patient-specific resistances to treatment with concurrent chemoradiation and temozolomide, and that the model can be used to determine drug combinations associated with superior tumour killing. The patient-specific tumour-on-a-chip model might be useful for the identification of effective treatments for glioblastoma patients resistant to the standard first-line treatment. A tumour-on-a-chip model featuring patient-derived glioblastoma cells, vascular endothelial cells and decellularized extracellular matrix from brain tissue can be used to identify patient-specific resistance to standard chemoradiotherapy.

Ultrasensitive detection of circulating exosomes with a 3D-nanopatterned microfluidic chip.

Abstract: The performance of current microfluidic methods for exosome detection is constrained by boundary conditions, as well as fundamental limits to microscale mass transfer and interfacial exosome binding. Here, we show that a microfluidic chip designed with self-assembled three-dimensional herringbone nanopatterns can detect low levels of tumour-associated exosomes in plasma (10 exosomes μl−1, or approximately 200 vesicles per 20 μl of spiked sample) that would otherwise be undetectable by standard microfluidic systems for biosensing. The nanopatterns promote microscale mass transfer, increase surface area and probe density to enhance the efficiency and speed of exosome binding, and permit drainage of the boundary fluid to reduce near-surface hydrodynamic resistance, thus promoting particle–surface interactions for exosome binding. We used the device for the detection—in 2 μl plasma samples from 20 ovarian cancer patients and 10 age-matched controls—of exosome subpopulations expressing CD24, epithelial cell adhesion molecule and folate receptor alpha proteins, and suggest exosomal folate receptor alpha as a potential biomarker for early detection and progression monitoring of ovarian cancer. The nanolithography-free nanopatterned device should facilitate the use of liquid biopsies for cancer diagnosis. A microfluidic chip with self-assembled 3D herringbone nanopatterns detects, with high sensitivity and specificity, tumour-associated exosomes in few-microlitre plasma samples from patients.

An explainable deep-learning algorithm for the detection of acute intracranial haemorrhage from small datasets

Abstract: Owing to improvements in image recognition via deep learning, machine-learning algorithms could eventually be applied to automated medical diagnoses that can guide clinical decision-making. However, these algorithms remain a 'black box' in terms of how they generate the predictions from the input data. Also, high-performance deep learning requires large, high-quality training datasets. Here, we report the development of an understandable deep-learning system that detects acute intracranial haemorrhage (ICH) and classifies five ICH subtypes from unenhanced head computed-tomography scans. By using a dataset of only 904 cases for algorithm training, the system achieved a performance similar to that of expert radiologists in two independent test datasets containing 200 cases (sensitivity of 98% and specificity of 95%) and 196 cases (sensitivity of 92% and specificity of 95%). The system includes an attention map and a prediction basis retrieved from training data to enhance explainability, and an iterative process that mimics the workflow of radiologists. Our approach to algorithm development can facilitate the development of deep-learning systems for a variety of clinical applications and accelerate their adoption into clinical practice.

Rapidly separable microneedle patch for the sustained release of a contraceptive

Abstract: Women often have limited access to contraception, and barrier methods have low acceptance and a high failure rate, mostly due to incorrect use, which can result in unplanned pregnancies. Sustained-release formulations of contraceptive hormones are available, yet typically require their administration by trained personnel. Here, we report the design of a microneedle patch with rapidly separable biodegradable polylactic acid and polylactic-co-glycolic acid needles, and its application for the continuous release of levonorgestrel—a contraceptive hormone. Bubble structures between each microneedle and the patch backing allow the microneedles to efficiently penetrate skin under compression, and to snap off under shear within five seconds after patch administration. In rats, the microneedle patch was well tolerated, leaving little visible evidence of use, and maintained plasma concentrations of the hormone above the human therapeutic level for one month. Further development of the rapidly separable microneedle patch for self-administered, long-acting contraception could enable women to better control their fertility. A microneedle skin patch with rapidly separable, biodegradable polymer needles continuously releases the contraceptive levonorgestrel for over one month in rats.

Low-cost thermophoretic profiling of extracellular-vesicle surface proteins for the early detection and classification of cancers.

Abstract: Non-invasive assays for early cancer screening are hampered by challenges in the isolation and profiling of circulating biomarkers. Here, we show that surface proteins from serum extracellular vesicles labelled with a panel of seven fluorescent aptamers can be profiled, via thermophoretic enrichment and linear discriminant analysis, for cancer detection and classification. In a cohort of 102 patients, including 6 cancer types at stages I–IV, the assay detected stage I cancers with 95% sensitivity (95% confidence interval (CI): 74–100%) and 100% specificity (95% CI: 80–100%), and classified the cancer type with an overall accuracy of 68% (95% CI: 59–77%). For patients who underwent prostate biopsies, the assay was superior to the analysis of prostate-specific antigen levels (area under the curve: 0.94 versus 0.68; 33 patients) for the discrimination of prostate cancer and benign prostate enlargement, and also in the assessment of biochemical cancer recurrence after radical prostatectomy. The assay is inexpensive, fast, and requires small serum volumes (<1 µl), and if validated in larger cohorts may facilitate cancer screening, classification and monitoring. An assay that thermophoretically profiles surface proteins from serum extracellular vesicles labelled with a panel of fluorescent aptamers detects and classifies patients according to cancer type and cancer stage.

Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours.

Abstract: Checkpoint blockade therapy targeting the programmed-death ligand 1 (PD-L1) and its receptor programmed cell death 1 promotes T-cell-mediated immunosurveillance against tumours, and has been associated with marked clinical benefit in cancer patients. Antibodies against PD-L1 function by blocking PD-L1 on the cell surface, but intracellular storage of PD-L1 and its active redistribution to the cell membrane can minimize the therapeutic benefits, which highlights the importance of targeting PD-L1 throughout the whole cell. Here, we show that PD-L1 is palmitoylated in its cytoplasmic domain, and that this lipid modification stabilizes PD-L1 by blocking its ubiquitination, consequently suppressing PD-L1 degradation by lysosomes. We identified palmitoyltransferase ZDHHC3 (DHHC3) as the main acetyltransferase required for the palmitoylation of PD-L1, and show that the inhibition of PD-L1 palmitoylation via 2-bromopalmitate, or the silencing of DHHC3, activates antitumour immunity in vitro and in mice bearing MC38 tumour cells. We also designed a competitive inhibitor of PD-L1 palmitoylation that decreases PD-L1 expression in tumour cells to enhance T-cell immunity against the tumours. These findings suggest new strategies for overcoming PD-L1-mediated immune evasion in cancer.

Large-area MRI-compatible epidermal electronic interfaces for prosthetic control and cognitive monitoring.

Abstract: Skin-interfaced medical devices are critically important for diagnosing disease, monitoring physiological health and establishing control interfaces with prosthetics, computer systems and wearable robotic devices. Skin-like epidermal electronic technologies can support these use cases in soft and ultrathin materials that conformally interface with the skin in a manner that is mechanically and thermally imperceptible. Nevertheless, schemes so far have limited the overall sizes of these devices to less than a few square centimetres. Here, we present materials, device structures, handling and mounting methods, and manufacturing approaches that enable epidermal electronic interfaces that are orders of magnitude larger than previously realized. As a proof-of-concept, we demonstrate devices for electrophysiological recordings that enable coverage of the full scalp and the full circumference of the forearm. Filamentary conductive architectures in open-network designs minimize radio frequency-induced eddy currents, forming the basis for structural and functional compatibility with magnetic resonance imaging. We demonstrate the use of the large-area interfaces for the multifunctional control of a transhumeral prosthesis by patients who have undergone targeted muscle-reinnervation surgery, in long-term electroencephalography, and in simultaneous electroencephalography and structural and functional magnetic resonance imaging.

Manufacturing of primed mesenchymal stromal cells for therapy.

Abstract: Mesenchymal stromal cells (MSCs) for basic research and clinical applications are manufactured and developed as unique cell products by many different manufacturers and laboratories, often under different conditions. The lack of standardization of MSC identity has limited consensus around which MSC properties are relevant for specific outcomes. In this Review, we examine how the choice of media, cell source, culture environment and storage affects the phenotype and clinical utility of MSC-based products, and discuss the techniques better suited to prime MSCs with specific phenotypes of interest and the need for the continued development of standardized assays that provide quality assurance for clinical-grade MSCs. Bioequivalence between cell products and batches must be investigated rather than assumed, so that the diversity of phenotypes between differing MSC products can be accounted for to identify products with the highest therapeutic potential and to preserve their safety in clinical treatments.

Phage-guided modulation of the gut microbiota of mouse models of colorectal cancer augments their responses to chemotherapy.

Abstract: The microbiota in the human gut is strongly correlated with the progression of colorectal cancer (CRC) and with therapeutic responses to CRC. Here, by leveraging the higher concentration of the pro-tumoural Fusobacterium nucleatum and the absence of antineoplastic butyrate-producing bacteria in the faecal microbiota of patients with CRC, we show that—in mice with orthotopic colorectal tumours or with spontaneously formed colorectal tumours—oral or intravenous administration of irinotecan-loaded dextran nanoparticles covalently linked to azide-modified phages that inhibit the growth of F. nucleatum significantly augments the efficiency of first-line chemotherapy treatments of CRC. We also show that oral administration of the phage-guided irinotecan-loaded nanoparticles in piglets led to negligible changes in haemocyte counts, immunoglobulin and histamine levels, and liver and renal functions. Phage-guided nanotechnology for the modulation of the gut microbiota might inspire new approaches for the treatment of CRC. Dextran nanoparticles loaded with a chemotherapeutic agent and bound to phages that eliminate a pro-tumoural gut bacterium and promote the growth of anticancer-compound-producing bacteria boost chemotherapy responses in mouse models of colorectal cancer.

Patient-specific reconstruction of volumetric computed tomography images from a single projection view via deep learning

Abstract: Tomographic imaging using penetrating waves generates cross-sectional views of the internal anatomy of a living subject. For artefact-free volumetric imaging, projection views from a large number of angular positions are required. Here we show that a deep-learning model trained to map projection radiographs of a patient to the corresponding 3D anatomy can subsequently generate volumetric tomographic X-ray images of the patient from a single projection view. We demonstrate the feasibility of the approach with upper-abdomen, lung, and head-and-neck computed tomography scans from three patients. Volumetric reconstruction via deep learning could be useful in image-guided interventional procedures such as radiation therapy and needle biopsy, and might help simplify the hardware of tomographic imaging systems.

A wireless and artefact-free 128-channel neuromodulation device for closed-loop stimulation and recording in non-human primates

Abstract: Closed-loop neuromodulation systems aim to treat a variety of neurological conditions by delivering and adjusting therapeutic electrical stimulation in response to a patient's neural state, recorded in real time. Existing systems are limited by low channel counts, lack of algorithmic flexibility, and the distortion of recorded signals by large and persistent stimulation artefacts. Here, we describe an artefact-free wireless neuromodulation device that enables research applications requiring high-throughput data streaming, low-latency biosignal processing, and simultaneous sensing and stimulation. The device is a miniaturized neural interface capable of closed-loop recording and stimulation on 128 channels, with on-board processing to fully cancel stimulation artefacts. In addition, it can detect neural biomarkers and automatically adjust stimulation parameters in closed-loop mode. In a behaving non-human primate, the device enabled long-term recordings of local field potentials and the real-time cancellation of stimulation artefacts, as well as closed-loop stimulation to disrupt movement preparatory activity during a delayed-reach task. The neuromodulation device may help advance neuroscientific discovery and preclinical investigations of stimulation-based therapeutic interventions.

Bioresorbable pressure sensors protected with thermally grown silicon dioxide for the monitoring of chronic diseases and healing processes

Abstract: Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use

Rapid volumetric optoacoustic imaging of neural dynamics across the mouse brain.

Abstract: Efforts to scale neuroimaging towards the direct visualization of mammalian brain-wide neuronal activity have faced major challenges. Although high-resolution optical imaging of the whole brain in small animals has been achieved ex vivo, the real-time and direct monitoring of large-scale neuronal activity remains difficult, owing to the performance gap between localized, largely invasive, optical microscopy of rapid, cellular-resolved neuronal activity and whole-brain macroscopy of slow haemodynamics and metabolism. Here, we demonstrate both ex vivo and non-invasive in vivo functional optoacoustic (OA) neuroimaging of mice expressing the genetically encoded calcium indicator GCaMP6f. The approach offers rapid, high-resolution three-dimensional snapshots of whole-brain neuronal activity maps using single OA excitations, and of stimulus-evoked slow haemodynamics and fast calcium activity in the presence of strong haemoglobin background absorption. By providing direct neuroimaging at depths and spatiotemporal resolutions superior to optical fluorescence imaging, functional OA neuroimaging bridges the gap between functional microscopy and whole-brain macroscopy.

Computationally guided personalized targeted ablation of persistent atrial fibrillation.

Abstract: Atrial fibrillation (AF)-the most common arrhythmia-significantly increases the risk of stroke and heart failure. Although catheter ablation can restore normal heart rhythms, patients with persistent AF who develop atrial fibrosis often undergo multiple failed ablations, and thus increased procedural risks. Here, we present personalized computational modelling for the reliable predetermination of ablation targets, which are then used to guide the ablation procedure in patients with persistent AF and atrial fibrosis. First, we show that a computational model of the atria of patients identifies fibrotic tissue that, if ablated, will not sustain AF. Then, we report the results of integrating the target ablation sites in a clinical mapping system and testing its feasibility in ten patients with persistent AF. The computational prediction of ablation targets avoids lengthy electrical mapping and could improve the accuracy and efficacy of targeted AF ablation in patients while eliminating the need for repeat procedures.

Optoacoustic mesoscopy for biomedicine

Abstract: Fuelled by innovation, optical microscopy plays a critical role in the life sciences and medicine, from basic discovery to clinical diagnostics. However, optical microscopy is limited by typical penetration depths of a few hundred micrometres for in vivo interrogations in the visible spectrum. Optoacoustic microscopy complements optical microscopy by imaging the absorption of light, but it is similarly limited by penetration depth. In this Review, we summarize progress in the development and applicability of optoacoustic mesoscopy (OPAM); that is, optoacoustic imaging with acoustic resolution and wide-bandwidth ultrasound detection. OPAM extends the capabilities of optical imaging beyond the depths accessible to optical and optoacoustic microscopy, and thus enables new applications. We explain the operational principles of OPAM, its placement as a bridge between optoacoustic microscopy and optoacoustic macroscopy, and its performance in the label-free visualization of tissue pathophysiology, such as inflammation, oxygenation, vascularization and angiogenesis. We also review emerging applications of OPAM in clinical and biological imaging.

Tissue-adhesive wirelessly powered optoelectronic device for metronomic photodynamic cancer therapy

Abstract: Metronomic (that is, low-dose and long-term) photodynamic therapy (mPDT) for treating internal lesions requires the stable fixation of optical devices to internal tissue surfaces to enable continuous, local light delivery. Surgical suturing—the standard choice for device fixation—can be unsuitable in the presence of surrounding major nerves and blood vessels, as well as for organs or tissues that are fragile, change their shape or actively move. Here, we show that an implantable and wirelessly powered mPDT device consisting of near-field-communication-based light-emitting-diode chips and bioadhesive and stretchable polydopamine-modified poly(dimethylsiloxane) nanosheets can be stably fixed onto the inner surface of animal tissue. When implanted subcutaneously in mice with intradermally transplanted tumours, the device led to significant antitumour effects by irradiating for 10 d at approximately 1,000-fold lower intensity than conventional PDT approaches. The mPDT device might facilitate treatment strategies for hard-to-detect microtumours and deeply located lesions that are hard to reach with standard phototherapy.

Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier.

Abstract: Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.

A viscoelastic adhesive epicardial patch for treating myocardial infarction.

Abstract: Acellular epicardial patches that treat myocardial infarction by increasing the mechanical integrity of damaged left ventricular tissues exhibit widely scattered therapeutic efficacy. Here, we introduce a viscoelastic adhesive patch, made of an ionically crosslinked transparent hydrogel, that accommodates the cyclic deformation of the myocardium and outperforms most existing acellular epicardial patches in reversing left ventricular remodelling and restoring heart function after both acute and subacute myocardial infarction in rats. The superior performance of the patch results from its relatively low dynamic modulus, designed at the so-called 'gel point' via finite-element simulations of left ventricular remodelling so as to balance the fluid and solid properties of the material.

The softness of tumour-cell-derived microparticles regulates their drug-delivery efficiency.

Abstract: Extracellular microparticles (MPs) can function as drug-delivery vehicles for anticancer drugs. Here, we show that the softness of MPs derived from tumour-repopulating cells (TRCs) isolated from three-dimensional fibrin gels enhances the MPs' drug-delivery efficiency. We found that, compared with MPs derived from tumour cells cultured in conventional tissue-culture plastic, TRC-derived MPs intravenously injected in tumour-xenograft-bearing mice showed enhanced accumulation in tumour tissues, enhanced blood-vessel crossing and penetration into tumour parenchyma, and preferential uptake by highly tumorigenic TRCs. We also show that the cytoskeleton-related protein cytospin-A plays a critical role in the regulation of TRC-derived MP softness. The modulation of the mechanical properties of TRC-derived MPs could aid the efficiency of delivery of anticancer drugs.

Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility.

Abstract: In breast cancer, the increased stiffness of the extracellular matrix is a key driver of malignancy. Yet little is known about the epigenomic changes that underlie the tumorigenic impact of extracellular matrix mechanics. Here, we show in a three-dimensional culture model of breast cancer that stiff extracellular matrix induces a tumorigenic phenotype through changes in chromatin state. We found that increased stiffness yielded cells with more wrinkled nuclei and with increased lamina-associated chromatin, that cells cultured in stiff matrices displayed more accessible chromatin sites, which exhibited footprints of Sp1 binding, and that this transcription factor acts along with the histone deacetylases 3 and 8 to regulate the induction of stiffness-mediated tumorigenicity. Just as cell culture on soft environments or in them rather than on tissue-culture plastic better recapitulates the acinar morphology observed in mammary epithelium in vivo, mammary epithelial cells cultured on soft microenvironments or in them also more closely replicate the in vivo chromatin state. Our results emphasize the importance of culture conditions for epigenomic studies, and reveal that chromatin state is a critical mediator of mechanotransduction. In a 3D model of breast cancer, a stiff extracellular matrix promotes a tumorigenic phenotype through broad changes in chromatin accessibility and in the activity of histone deacetylases and the transcription factor Sp1.

Hyperphysiological compression of articular cartilage induces an osteoarthritic phenotype in a cartilage-on-a-chip model

Abstract: Owing to population aging, the social impact of osteoarthritis (OA)-the most common musculoskeletal disease-is expected to increase dramatically. Yet, therapy is still limited to palliative treatments or surgical intervention, and disease-modifying OA (DMOA) drugs are scarce, mainly because of the absence of relevant preclinical OA models. Therefore, in vitro models that can reliably predict the efficacy of DMOA drugs are needed. Here, we show, using a newly developed microphysiological cartilage-on-a-chip model that enables the application of strain-controlled compression to three-dimensional articular cartilage microtissue, that a 30% confined compression recapitulates the mechanical factors involved in OA pathogenesis and is sufficient to induce OA traits. Such hyperphysiological compression triggers a shift in cartilage homeostasis towards catabolism and inflammation, hypertrophy, and the acquisition of a gene expression profile akin to those seen in clinical osteoarthritic tissue. The cartilage on-a-chip model may enable the screening of DMOA candidates.

Engineering patient-specific cancer immunotherapies.

Abstract: Research into the immunological processes implicated in cancer has yielded a basis for the range of immunotherapies that are now considered the fourth pillar of cancer treatment (alongside surgery, radiotherapy and chemotherapy). For some aggressive cancers, such as advanced non-small-cell lung carcinoma, combination immunotherapies have resulted in unprecedented treatment efficacy for responding patients, and have become frontline therapies. Individualized immunotherapy, enabled by the identification of patient-specific mutations, neoantigens and biomarkers, and facilitated by advances in genomics and proteomics, promises to broaden the responder patient population. In this Perspective, we give an overview of immunotherapies leveraging engineering approaches, including the design of biomaterials, delivery strategies and nanotechnology solutions, for the realization of individualized cancer treatments such as nanoparticle vaccines customized with neoantigens, cell therapies based on patient-derived dendritic cells and T cells, and combinations of theranostic strategies. Developments in precision cancer immunotherapy will increasingly rely on the adoption of engineering principles.

Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium

Abstract: The compression of brain tissue by a tumour mass is believed to be a major cause of the clinical symptoms seen in patients with brain cancer. However, the biological consequences of these physical stresses on brain tissue are unknown. Here, via imaging studies in patients and by using mouse models of human brain tumours, we show that a subgroup of primary and metastatic brain tumours, classified as nodular on the basis of their growth pattern, exert solid stress on the surrounding brain tissue, causing a decrease in local vascular perfusion as well as neuronal death and impaired function. We demonstrate a causal link between solid stress and neurological dysfunction by applying and removing cerebral compression, which respectively mimic the mechanics of tumour growth and of surgical resection. We also show that, in mice, treatment with lithium reduces solid-stress-induced neuronal death and improves motor coordination. Our findings indicate that brain-tumour-generated solid stress impairs neurological function in patients, and that lithium as a therapeutic intervention could counter these effects.

Spatial control of in vivo CRISPR–Cas9 genome editing via nanomagnets

Abstract: The potential of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein 9 (Cas9)-based therapeutic genome editing is hampered by difficulties in the control of the in vivo activity of CRISPR-Cas9. To minimize any genotoxicity, precise activation of CRISPR-Cas9 in the target tissue is desirable. Here, we show that, by complexing magnetic nanoparticles with recombinant baculoviral vectors (MNP-BVs), CRISPR-Cas9-mediated genome editing can be activated locally in vivo via a magnetic field. The baculoviral vector was chosen for in vivo gene delivery because of its large loading capacity and ability to locally overcome systemic inactivation by the complement system. We demonstrate that a locally applied magnetic field can enhance the cellular entry of MNP-BVs, thereby avoiding baculoviral vector inactivation and causing a transient transgene expression in the target tissue. Because baculoviral vectors are inactivated elsewhere, gene delivery and in vivo genome editing via MNP-BVs are tissue specific.

Structural, geometric and genetic factors predict interregional brain connectivity patterns probed by electrocorticography.

Abstract: Electrocorticography (ECoG) data can be used to estimate brain-wide connectivity patterns. Yet, the invasiveness of ECoG, incomplete cortical coverage, and variability in electrode placement across individuals make the network analysis of ECoG data challenging. Here, we show that the architecture of whole-brain ECoG networks and the factors that shape it can be studied by analysing whole-brain, interregional and band-limited ECoG networks from a large cohort-in this case, of individuals with medication-resistant epilepsy. Using tools from network science, we characterized the basic organization of ECoG networks, including frequency-specific architecture, segregated modules and the dependence of connection weights on interregional Euclidean distance. We then used linear models to explain variabilities in the connection strengths between pairs of brain regions, and to highlight the joint role, in shaping the brain-wide organization of ECoG networks, of communication along white matter pathways, interregional Euclidean distance and correlated gene expression. Moreover, we extended these models to predict out-of-sample, single-subject data. Our predictive models may have future clinical utility; for example, by anticipating the effect of cortical resection on interregional communication.