Publications by authors named "Sean Weaver"

16 Publications

  • Page 1 of 1

Nanoscale Patterning of Neuronal Circuits.

ACS Nano 2022 Apr 11. Epub 2022 Apr 11.

Laboratory for Biosensors and Bioelectronics, ETH Zürich, 8092 Zürich, Switzerland.

Methods for patterning neurons have gradually improved and are used to investigate questions that are difficult to address or . Though these techniques guide axons between groups of neurons, multiscale control of neuronal connectivity, from circuits to synapses, is yet to be achieved As studying neuronal circuits with synaptic resolution poses significant challenges, we present an alternative to validate biophysical and computational models. In this work we use a combination of electron beam lithography and photolithography to create polydimethylsiloxane (PDMS) structures with features ranging from 150 nm to a few millimeters. Leveraging the difference between average axon and dendritic spine diameters, we restrict axon growth while allowing spines to pass through nanochannels to guide synapse formation between small groups of neurons (i.e., nodes). We show this technique can be used to generate large numbers of isolated feed-forward circuits where connections between nodes are restricted to regions connected by nanochannels. Using a genetically encoded calcium indicator in combination with fluorescently tagged postsynaptic protein, PSD-95, we demonstrate functional synapses can form in this region.
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http://dx.doi.org/10.1021/acsnano.1c10750DOI Listing
April 2022

Topologically controlled circuits of human iPSC-derived neurons for electrophysiology recordings.

Lab Chip 2022 03 29;22(7):1386-1403. Epub 2022 Mar 29.

Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, ETH Zurich, Gloriastrasse 35, 8092 Zurich, Switzerland.

Bottom-up neuroscience, which consists of building and studying controlled networks of neurons , is a promising method to investigate information processing at the neuronal level. However, studies tend to use cells of animal origin rather than human neurons, leading to conclusions that might not be generalizable to humans and limiting the possibilities for relevant studies on neurological disorders. Here we present a method to build arrays of topologically controlled circuits of human induced pluripotent stem cell (iPSC)-derived neurons. The circuits consist of 4 to 50 neurons with well-defined connections, confined by microfabricated polydimethylsiloxane (PDMS) membranes. Such circuits were characterized using optical imaging and microelectrode arrays (MEAs), suggesting the formation of functional connections between the neurons of a circuit. Electrophysiology recordings were performed on circuits of human iPSC-derived neurons for at least 4.5 months. We believe that the capacity to build small and controlled circuits of human iPSC-derived neurons holds great promise to better understand the fundamental principles of information processing and storing in the brain.
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http://dx.doi.org/10.1039/d1lc01110cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8963377PMC
March 2022

An experimental paradigm to investigate stimulation dependent activity in topologically constrained neuronal networks.

Biosens Bioelectron 2022 Apr 29;201:113896. Epub 2021 Dec 29.

Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, University and ETH Zurich, Gloriastrasse 35, 8092, Zurich, Switzerland. Electronic address:

We present a stimulate and record paradigm to examine the behavior of multiple neuronal networks with controlled topology in vitro. Our approach enabled us to electrically induce and record neuronal activity from 60 independent networks in parallel over multiple weeks. We investigated the network performance of neuronal networks of primary hippocampal neurons until 29 days in vitro. We introduced a systematic stimulate and record protocol during which well-defined 4-node neural networks were stimulated electrically 4 times per second (4Hz) and their response was recorded over many days. We found that the network response pattern to a stimulus remained fairly stable for at least 12 h. Moreover, continuous stimulation over multiple weeks did not cause a significant change in the stimulation-induced mean spiking frequency of a circuit. We investigated the effect of stimulation amplitude and stimulation timing on the detailed network response. Finally, we could show that our setup can apply complex stimulation protocols with 125 different stimulation patterns. We used these patterns to perform basic addition tasks with the network, revealing the highly non-linear nature of biological networks' responses to complex stimuli.
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http://dx.doi.org/10.1016/j.bios.2021.113896DOI Listing
April 2022

Systems-based investigation of patient safety incidents.

Future Healthc J 2021 Nov;8(3):e593-e597

Healthcare Safety Investigation Branch, Farnborough, UK.

Patient safety events are common in healthcare. We can learn from other safety-critical industries that further incidents are most likely to be prevented where lessons are learned at the system level rather than looking to attribute blame for errors to individuals. Progress has been made over the last 20 years and relies on a positive safety culture (or just culture) where staff trust organisations to investigate safety events for learning rather than blame. Systems-based investigation models, such as the Systems Engineering Initiative for Patient Safety (SEIPS), help investigators to consider the full range of contributory factors across a system and to identify important findings. Considering the hierarchy of controls, recommendations should be targeted at system changes which are more likely to produce sustained safety improvements, rather than at individual behaviours or training, which are less likely to influence future safety. Systems-based safety investigations can positively influence safety culture in organisations.
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http://dx.doi.org/10.7861/fhj.2021-0147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651333PMC
November 2021

Plurality of governance - plurality of systems.

J R Coll Physicians Edinb 2021 Dec;51(4):424-3427

Healthcare Safety Investigation Branch, Farnborough, UK.

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http://dx.doi.org/10.4997/JRCPE.2021.431DOI Listing
December 2021

Force-Controlled Formation of Dynamic Nanopores for Single-Biomolecule Sensing and Single-Cell Secretomics.

ACS Nano 2020 10 18;14(10):12993-13003. Epub 2020 Sep 18.

Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, ETH Zürich, 8092 Zürich, Switzerland.

Nanopore sensing of single nucleotides has emerged as a promising single-molecule technology for DNA sequencing and proteomics. Despite the conceptual simplicity of nanopores, adoption of this technology for practical applications has been limited by a lack of pore size adjustability and an inability to perform long-term recordings in complex solutions. Here we introduce a method for fast and precise on-demand formation of a nanopore with controllable size between 2 and 20 nm through force-controlled adjustment of the nanospace formed between the opening of a microfluidic device (made of silicon nitride) and a soft polymeric substrate. The introduced nanopore system enables stable measurements at arbitrary locations. By accurately positioning the nanopore in the proximity of single neurons and continuously recording single-molecule translations over several hours, we have demonstrated this is a powerful approach for single-cell proteomics and secretomics.
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http://dx.doi.org/10.1021/acsnano.0c04281DOI Listing
October 2020

Alginate Sulfate Substrates Control Growth Factor Binding and Growth of Primary Neurons: Toward Engineered 3D Neural Networks.

Adv Biosyst 2020 07 27;4(7):e2000047. Epub 2020 May 27.

Biomedical Engineering Program, Maroun Semaan Faculty of Engineering and Architecture, American University of Beirut, Beirut, 1107 2020, Lebanon.

Sulfated glycosaminoglycans (sGAGs) are vital molecules of the extracellular matrix (ECM) of the nervous system known to regulate proliferation, migration, and differentiation of neurons mainly through binding relevant growth factors. Alginate sulfate (AlgSulf) mimics sGAGs and binds growth factors such as basic fibroblast growth factor (FGF-2). Here, thin films of biotinylated AlgSulf (b-AlgSulf ) are engineered with sulfation degrees (DS = 0.0 and 2.7) and the effect of polysaccharide concentration on FGF-2 and nerve growth factor (β-NGF) binding and subsequent primary neural viability and neurite outgrowth is assessed. An increase in b-AlgSulf concentration results in higher FGF-2 and β-NGF binding as demonstrated by greater frequency and dissipation shifts measured with quartz crystal microbalance with dissipation monitoring (QCM-D). Primary neurons seeded on the 2D b-AlgSulf films maintain high viability comparable to positive controls grown on poly-d-lysine. Neurons grown in 3D AlgSulf hydrogels (DS = 0.8) exhibit a significantly higher viability, neurite numbers and mean branch length compared to neurons grown in nonsulfated controls. Finally, a first step is made toward constructing 3D neuronal networks by controllably patterning neurons encapsulated in AlgSulf into an alginate carrier. The substrates and neural networks developed in the current study can be used in basic and applied neural applications.
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http://dx.doi.org/10.1002/adbi.202000047DOI Listing
July 2020

Consensus standards of healthcare for adults and children with inflammatory bowel disease in the UK.

Frontline Gastroenterol 2020 24;11(3):178-187. Epub 2019 Jul 24.

Craigavon Area Hospital, Portadown, Armagh, UK.

Objective: Symptoms and clinical course during inflammatory bowel disease (IBD) vary among individuals. Personalised care is therefore essential to effective management, delivered by a strong patient-centred multidisciplinary team, working within a well-designed service. This study aimed to fully rewrite the UK Standards for the healthcare of adults and children with IBD, and to develop an IBD Service Benchmarking Tool to support current and future personalised care models.

Design: Led by IBD UK, a national multidisciplinary alliance of patients and nominated representatives from all major stakeholders in IBD care, Standards requirements were defined by survey data collated from 689 patients and 151 healthcare professionals. Standards were drafted and refined over three rounds of modified electronic-Delphi.

Results: Consensus was achieved for 59 Standards covering seven clinical domains; (1) design and delivery of the multidisciplinary IBD service; (2) prediagnostic referral pathways, protocols and timeframes; (3) holistic care of the newly diagnosed patient; (4) flare management to support patient empowerment, self-management and access to specialists where required; (5) surgery including appropriate expertise, preoperative information, psychological support and postoperative care; (6) inpatient medical care delivery (7) and ongoing long-term care in the outpatient department and primary care setting including shared care. Using these patient-centred Standards and informed by the IBD Quality Improvement Project (IBDQIP), this paper presents a national benchmarking framework.

Conclusions: The Standards and Benchmarking Tool provide a framework for healthcare providers and patients to rate the quality of their service. This will recognise excellent care, and promote quality improvement, audit and service development in IBD.
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http://dx.doi.org/10.1136/flgastro-2019-101260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223296PMC
July 2019

Modular microstructure design to build neuronal networks of defined functional connectivity.

Biosens Bioelectron 2018 Dec 8;122:75-87. Epub 2018 Sep 8.

Laboratory of Biosensors and Bioelectronics, Institute for Biomedical Engineering, ETH Zürich, Zürich, Switzerland. Electronic address:

Theoretical and in vivo neuroscience research suggests that functional information transfer within neuronal networks is influenced by circuit architecture. Due to the dynamic complexities of the brain, it remains a challenge to test the correlation between structure and function of a defined network. Engineering controlled neuronal networks in vitro offers a way to test structural motifs; however, no method has achieved small, multi-node networks with stable, unidirectional connections. Here, we screened ten different microchannel architectures within polydimethylsiloxane (PDMS) devices to test their potential for axonal guidance. The most successful design had a 92% probability of achieving strictly unidirectional connections between nodes. Networks built from this design were cultured on multielectrode arrays and recorded on days in vitro 9, 12, 15 and 18 to investigate spontaneous and evoked bursting activity. Transfer entropy between subsequent nodes showed up to 100 times more directional flow of information compared to the control. Additionally, directed networks produced a greater amount of information flow, reinforcing the importance of directional connections in the brain being critical for reliable communication. By controlling the parameters of network formation, we minimized response variability and achieved functional, directional networks. The technique provides us with a tool to probe the spatio-temporal effects of different network motifs.
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http://dx.doi.org/10.1016/j.bios.2018.08.075DOI Listing
December 2018

Evaluation of the Ability of a Novel Miconazole Formulation To Penetrate Nail by Using Three Nail Models.

Antimicrob Agents Chemother 2017 07 27;61(7). Epub 2017 Jun 27.

MedPharm Ltd., Surrey Research Park, Guildford, United Kingdom.

In an effort to increase the efficacy of topical medications for treating onychomycosis, several new nail penetration enhancers were recently developed. In this study, the ability of 10% (wt/wt) miconazole nitrate combined with a penetration enhancer formulation to permeate the nail is demonstrated by the use of a selection of nail penetration assays. These assays included the bovine hoof, TurChub zone of inhibition, and infected-nail models.
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http://dx.doi.org/10.1128/AAC.02554-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5487659PMC
July 2017

Defining Molecular Details of the Chemistry of Biofilm Formation by Raman Microspectroscopy.

Biochemistry 2017 05 19;56(17):2247-2250. Epub 2017 Apr 19.

Department of Biochemistry and ‡Department of Pharmacology, Case Western Reserve University , Cleveland, Ohio 44106, United States.

Two protocols that allow for the comparison of Raman spectra of planktonic cells and biofilm formed from these cells in their growth phase have been developed. Planktonic cells are washed and flash-frozen in <1 min to reduce the time for metabolic changes during processing, prior to freeze-drying. Biofilm is formed by standing cells in 50 μL indentations in aluminum foil in an atmosphere of saturated water vapor for 24-48 h. The results for Escherichia coli type K12 cells, which do not readily form biofilm, are compared to those for Staphylococcus epidermidis cells, which prolifically synthesize biofilm. For E. coli, the Raman spectra of the planktonic and biofilm samples are similar with the exception that the spectral signature of RNA, present in planktonic cells, could not be detected in biofilm. For S. epidermidis, major changes occur upon biofilm formation. In addition to the absence of the RNA features, new bands occur near 950 cm and between 1350 and 1420 cm that are associated with an increase in carbohydrate content. Unlike the case in E. coli biofilm, the intensity of G base ring modes is reduced in but A and T base ring signatures become more prominent. For S. epidermis in the biofilm's amide III region, there is evidence of an increase in the level of β-sheet structure accompanied by a decrease in α-helical content. The presence of biofilm is confirmed by microscope-aided photography and, separately, by staining with methyl violet.
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http://dx.doi.org/10.1021/acs.biochem.7b00116DOI Listing
May 2017

A Novel Vehicle for Enhanced Drug Delivery Across the Human Nail for the Treatment of Onychomycosis.

Int J Pharm Compd 2016 Jan-Feb;20(1):71-80

The aim of this study was to use in vitro nail models to investigate the potential of a novel base formulation (Recura) containing either fluconazole or miconazole for the treatment of onychomycosis in comparison to two commercial comparators (Jublia and a Penlac generic). Initially, a modified Franz cell was used, where sections of human nail served as the barrier through which drug penetrated into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes grew into human nail and adenosine triphosphate levels were used as biological marker for antimicrobial activity. The novel enhancing system Recura increased the permeation of both existing drugs through human nail sections mounted in a modified Franz cell. Furthermore, the infected nail model also confirmed that the system also enhanced the permeation through infected nail resulting in a decrease in adenosine triphosphate levels superior (P ≤ 0.05) to Penlac generic and equivalent (P > 0.05) to the commercial comparator Jublia. This study demonstrated that with the use of a novel permeation-enhancing formulation base, Recura enhances delivery of miconazole and fluconazole when applied ungually such that the efficacy was equivalent or superior to commercial comparators. Such a topically applied system has the possibility of overcoming the systemic side effects of antifungals when taken orally.
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May 2016

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

J Crohns Colitis 2016 02 29;10(2):149-58. Epub 2015 Nov 29.

Department of Gastroenterology, West Hertfordshire Hospitals NHS Trust, Watford General Hospital, Watford, UK.

Background And Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.

Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls.

Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1).

Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.
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http://dx.doi.org/10.1093/ecco-jcc/jjv219DOI Listing
February 2016

Low dose thiopurine and allopurinol co-therapy results in significant cost savings at a district general hospital.

Frontline Gastroenterol 2015 Oct 7;6(4):285-289. Epub 2014 Nov 7.

Department of Gastroenterology, The Royal Bournemouth Hospital, Bournemouth, UK.

Background: Thiopurines are widely used for maintenance of remission in Crohn's disease (CD). Published data report >50% of patients stop thiopurines due to therapeutic failure, hepatitis or side effects. In this situation, many UK clinicians start biologics in CD patients. This has significant cost implications. An alternative strategy is low dose thiopurine and allopurinol (LDTA) co-therapy. We report the annual cost savings from adopting this strategy at our centre.

Methods: Patients with CD treated with LDTA in preference to biological therapy were identified using a prospective local inflammatory bowel disease database. The annual drug cost of treatment with LDTA compared with biologic therapy was calculated. Cost of attending the day unit for an infusion was not included.

Results: 26 patients with CD who failed standard dose thiopurine and were treated with LDTA were identified over a 12-month period and followed up for 1 year. 12 patients failed LDTA and progressed to biological therapy. The remaining 14 patients entered sustained clinical remission on LDTA. The cost savings achieved using the LDTA strategy in this group of patients was £146 413 per year with an average saving of £10 458 per patient per year.

Conclusions: This study has identified a significant annual cost savings with this treatment strategy through the prevention of escalation to biologics. These cost savings are likely to be even more significant in the long term since a significant proportion of patients treated with biological therapy require dose escalation. We believe adopting this strategy more widely could lead to significant healthcare savings.
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http://dx.doi.org/10.1136/flgastro-2014-100504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5369596PMC
October 2015

Differential regulation of prostaglandin E biosynthesis by interferon-gamma in colonic epithelial cells.

Br J Pharmacol 2004 Apr 15;141(7):1091-7. Epub 2004 Mar 15.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY.

1. Cyclooxygenase (COX)-2 expression and activity in response to pro-inflammatory cytokines TNF alpha and IFN gamma was evaluated in the colonic epithelial cell line HT29 and the airway epithelial cell line A549. 2. TNF alpha induced concentration- and time-dependent upregulation of COX-2 mRNA, protein and prostaglandin (PG)E(2) synthesis. 3. Co-stimulation of TNF alpha with IFN gamma resulted in reduced COX-2 mRNA and protein expression. 4. IFN gamma had no effect on the stability of TNF alpha-induced COX-2 mRNA. 5. TNF alpha-induced PGE(2) biosynthesis was significantly enhanced by the simultaneous addition of IFN gamma and was COX-2 dependent. 6. The combination of IFN gamma and TNF alpha induced the microsomal prostaglandin E synthase (mPGES), comensurate with the enhanced PGE(2) synthesis. 7. These results suggest that, in terms of PGE(2) biosynthesis, IFN gamma plays a negative regulatory role at the level of COX-2 expression and a positive regulatory role at the level of mPGES expression. This may have important implications for the clinical use of IFN gamma in inflammatory diseases.
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http://dx.doi.org/10.1038/sj.bjp.0705719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574887PMC
April 2004
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