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Journal articleKrzeczkowski L, Nteliopoulos G, Ali S, et al., 2026, , Lab Chip
Liquid biopsy requires the isolation of viable circulating tumour cells (CTCs) from whole blood at high purity and with sufficient quality for functional assays. These requirements are not readily met by either label-based methods or size-only low-pass filters. Antibody labels can be specific yet miss phenotypically diverse CTCs, while size-based approaches may capture more broadly but suffer from leukocyte contamination. Here, we introduce a microfluidic band-stop filter that implements a size-selective transfer function, replacing a single threshold with an engineered peaked size-capture response. This is achieved by coupling hydrodynamic filtering with hydrodynamic trapping in a high-density array. Small cells follow streamlines that pass through trap apertures, intermediate-sized cells are admitted but retained by downstream constrictions, whereas larger cells occupy streamlines displaced from the channel wall and are hydrodynamically transported past the traps. As a result, only cells with diameters within the band-stop window are retained, while both smaller and larger cells pass. Using rigid microspheres, the device exhibits a canonical band-stop profile. Using cultured cell lines, capture efficiency peaks for CTC-like diameters and is suppressed for leukocyte-sized cells. Critically, the behaviour is preserved in undiluted, full haematocrit whole blood, where no leukocyte retention is observed and target-sized cancer cells are selectively enriched without fouling at capture efficiencies comparable to commercial systems. Trapped cells tolerate buffer exchange and on-chip drug exposure, where responses were concordant with matched off-chip culture. Cells are released on demand and expanded off-chip, confirming post-processing viability.
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Journal articleCieslik J-P, Xia X, Salehi-Reyhani A, 2026, , Lab Chip
Automating the isolation of rare cells such as circulating tumour cells (CTCs) within crowded microfluidic environments remains a bottleneck in liquid biopsy workflows. Optical tweezers offer contact-free, selective manipulation but traditionally rely on expert operators. We present MaGIC-OT (machine-guided isolation of cells using optical tweezers), a platform that integrates classical path planning and deep reinforcement learning (DRL) to automate single-cell manipulation inside a microfluidic chip. We built a high-fidelity simulation to train and benchmark control policies and show that cooperative, human-in-the-loop training improves DRL performance. Trained agents outperform expert users in speed and isolation success in silico, and we demonstrate proof-of-concept isolation of a cancer cell from a spiked blood sample on-chip. MaGIC-OT provides a flexible framework for intelligent optical manipulation, aligning microfluidic device design with autonomous control strategies and offering a pathway toward high-purity, label-free single-cell workflows.
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Journal articleSherin PS, Wong Chap Lan M, Brooks NJ, et al., 2026, , J Mater Chem B, Vol: 14, Pages: 1882-1892
Epicuticular wax is the outermost layer of plant leaves, whose function is to protect the leaf, including preventing uncontrolled water loss. However, the resilience of this layer may present challenges in agriculture by preventing the ingress of pesticides and herbicides. Chemical formulations used in modern agrochemistry to enhance the efficiency of pesticides and herbicides often contain softening adjuvants that are expected to facilitate the permeability of waxes to chemicals. However, the mechanism of the adjuvants' action is relatively unexplored. Here, we report that an environmentally sensitive fluorophore, Nile Red (NR), can be used to directly visualise the penetration of adjuvants inside common plant waxes, such as Carnauba and Candelilla. In particular, we utilised Fluorescence Lifetime Imaging Microscopy (FLIM), which revealed that NR's emission is quenched by wax components. However, the penetration of adjuvants of different chemical structures significantly reduced the quenching, leading to an increase in NR's fluorescence intensity and lifetime. This effect allows the direct visualisation and kinetic monitoring of penetration of agrochemicals within the semicrystalline plant waxes using conventional fluorescent microscopes and opens a new area for the application of NR.
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Journal articleHay CD, Mahutanattan SM, Pilkington CP, et al., 2026, , Lab Chip, Vol: 26, Pages: 635-649
Lipid nanocarriers utilise the self-assembly of amphiphilic molecules to generate particle formulations capable of drug encapsulation and dynamic interactions with user-defined cell types, enabling applications within targeted therapeutic delivery. This offers increased bioavailability, stability, and reduced off-target effects, with the promise of application to numerous cell types and consequently, diseases. Here, we have developed a highly accessible, cleanroom-free method for the fabrication of poly(methyl methacrylate) millifluidic vertical flow focusing (VFF) devices via laser cutting, multilayered solvent and heat-assisted bonding. We demonstrate that these can be used for one-step production of targeted lipid nanocarriers via the production of cardiomyocyte-targeting vesicle nanoparticles loaded with the hydrophobic drug menadione. We characterise vesicle size using dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM), whilst also probing the membrane viscosity of vesicles produced via flow-focusing for the first time using molecular rotors. Finally, we apply cardiomyocyte-targeting, menadione-loaded vesicles to H9C2 tissue culture demonstrating significant inhibition of cell viability via targeted delivery, showcasing the potential of our device to produce formulations for therapeutic delivery. As a flow-based method, VFF can facilitate rapid formulation investigation and produce large sample volumes for cell-based validation studies, whilst avoiding inter-batch sample variation. Furthermore, the accessible nature of this VFF approach will help to democratise millifluidics, facilitating the wider adoption of flow-based production methods to develop nanomedical formulations.
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Journal articleAllen ME, Hindley JW, M眉ller MI, et al., 2026, , ACS Nano, Vol: 20, Pages: 1945-1961
Artificial cells assembled from materials such as hydrogels have emerged as platforms to replicate and understand biological functionalities, processes, and behaviors. However, hydrogels lack a lipid membrane, a vital property of cellular systems. Here we develop a process for the assembly of a fluid and stable lipid membrane which coats the hydrogel mesh network within the particle, through electostatically-mediated fusion of nanoscale lipid vesicles. This confers cell-mimetic and biotechnologically relevant properties upon microscale, cell sized, hydrogel artificial cells generated through microfluidics. We exploit the properties of the created membrane to augment existing hydrogel properties through permeability alteration and protection of the hydrogel from small molecule degraders. Furthermore, we show that the lipid membrane is compatible with organelle substructures within the hydrogels, which enables the exploitation of an enhanced material design space to build hydrogel artificial cells that increasingly mimic the organization of cells. This platform paves the way for producing next generation artificial cells and functional microdevices from interfaced hydrogel-lipid materials. Our technologies may underpin new opportunities for integrating membranes into hydrogel-based systems, inlcuding for drug delivery and tissue engineering.
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Journal articleFletcher M, Diggines B, Elani Y, 2026, , Nat Chem, Vol: 18, Pages: 14-22
Building synthetic versions of biological cells from the bottom up offers an unprecedented opportunity to understand the rules of life and harness cellular capabilities in biotechnology. Whereas substantial progress has been made in recapitulating elementary cell functions, we argue that accelerating the engineering of synthetic cells requires a shift in research practices. The dominant approach-rationally designing and integrating functional modules-becomes restrictive when dealing with the massively complex biochemical pathways associated with life, especially when design principles remain unclear. We advocate moving away from theoretical rational design towards a data-driven model that is centred on library generation. Inspired by a systems chemistry perspective, this strategy prioritizes the systematic creation and distribution of composition-function libraries. To enable this, experimental strategies must integrate high-throughput synthetic cell generation, automation and closed-feedback control of workflows. Broad adoption will also require greater emphasis on quantitative benchmarking, and the de-skilling of techniques, supporting effective laboratory-to-laboratory collaboration.
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Journal articleGrob A, Copeman T, Chen S, et al., 2025, , TRENDS IN BIOTECHNOLOGY, Vol: 43, Pages: 2566-2585, ISSN: 0167-7799
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- Citations: 1
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Journal articleFletcher M, Elani Y, Keyser UF, et al., 2025, , BIOPHYSICAL REVIEWS, ISSN: 1867-2450
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Journal articleChan CL, Malia D, Paez-Perez M, et al., 2025, , CHEMISTRY AND PHYSICS OF LIPIDS, Vol: 270, ISSN: 0009-3084
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- Citations: 1
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Journal articleShmool TA, Martin LK, Jirkas A, et al., 2025, , ACS Nano, Vol: 19, Pages: 24806-24816, ISSN: 1936-0851
Ionic liquid (IL) nanotechnology holds significant promise for designing nanoscale materials with tunable viscosity, polarity, and thermal stability for advanced therapeutic applications. However, the field currently lacks comprehensive guidelines for integrating ILs into complex therapeutic formulations. Herein, we propose the key design considerations for engineering immunoglobulin G (IgG) conjugated to gold nanoparticles (AuNPs) in the presence of choline-based ILs. By judicious IL cation and anion selection, we fine-tune the supramolecular assemblies and leverage the unique physicochemical properties of ILs to impart AuNPs with advantageous characteristics including enhanced structural, thermal, and thermodynamic stabilities, highly tunable morphologies, and markedly reduced aggregation propensities. Through systematic circular dichroism measurements, the thermodynamic parameters of the complex formulations were determined, offering insight into the IgG conformational changes and design parameters for systems of enhanced IgG conjugation to AuNP surfaces. In demonstrating the power of our design approach, the complex formulation of IgG-choline chloride-AuNPs, also including trehalose, histidine, and arginine, was delivered via focused ultrasound and microbubbles across the blood–brain barrier and showed a 7.6-fold increase in delivery in vivo compared to the traditional formulation. We demonstrate that IgG-IL-AuNPs can be easily and precisely manipulated at the nanometer scale, enabling the formation of versatile structural configurations. Holistically, we believe the rational design approach developed will advance the engineering of tailored IL-nanocarriers for targeted therapeutic delivery and broaden the scope of IL applications in biomedicine.
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Journal articleOToole N, Allen ME, Contini C, et al., 2025, , Chemical Communications, ISSN: 1359-7345
Bacterial biohybrids use bacterial and synthetic components for biotechnological applications. Here, we outline an adaptable and high-throughput microfluidic platform to create microscale biocontained bacterial biohybrids enclosed in a hydrogel with magnetotactic and biosensing properties. The biohybrids are capable of magnetically driven motility, biochemical sensing and controlled cargo release. This approach enables the scalable fabrication of biocontained multifunctional biohybrids for potential industrial and biomedical applications.
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Journal articleSigl M, Egger M, Knez D, et al., 2025, , MATERIALS ADVANCES, Vol: 6, Pages: 3985-3997
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Journal articleGispert I, Elani Y, 2025, , CHEMICAL COMMUNICATIONS, Vol: 61, Pages: 8359-8362, ISSN: 1359-7345
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Journal articleSeddon JM, 2025, , CELLS, Vol: 14
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Journal articleSleath H, Mognetti BM, Elani Y, et al., 2025, , LANGMUIR, Vol: 41, Pages: 11474-11485, ISSN: 0743-7463
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Journal articleFletcher M, Elani Y, 2025, , ACS NANO, Vol: 19, Pages: 13768-13778, ISSN: 1936-0851
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- Citations: 2
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Journal articleAllen ME, Hindley JW, Law RV, et al., 2025, , Small Science, Vol: 5, ISSN: 2688-4046
Artificial cells serve as promising micro-robotic platforms that replicate cellular features. One ubiquitous characteristic of living cells is compartmentalization of content in distinct and well-defined locations. Herein, a microfluidic strategy to mimic compartmentalization is developed through the production of micron-scale two and three compartment biomimetic microgels, where hydrogel compartment number, composition, size, and shape can be controlled. Our lab-on-chip system enables the incorporation of various synthetic organelles into spatially separated compartments within the microgels. This design concept allows for the introduction of a variety of individually triggered bioinspired behaviors, including protein capture, enzyme-mediated content release, and stimuli-triggered motility, each isolated in a distinct compartment enabling the use of the microgels as compartmentalized artificial cells. With this approach, the division of content and function seen in biological cells can be mirrored, which will underpin the generation of increasingly sophisticated and functional soft matter microdevices using bottom-up synthetic biology principles.
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Journal articleAllen ME, Sun Y, Chan CL, et al., 2025, , Small, ISSN: 1613-6810
Stimuli-responsive polymeric vesicles offer a versatile platform for mimicking dynamic cell-like behaviors for synthetic cell applications. In this study, thermally responsive polymeric droplets derived from poly(ethylene oxide)-poly(butylene oxide) (PEO-PBO) polymersomes, aiming to create synthetic cell models that mimic key biological functions are developed. Upon heating, the nanoscale vesicles undergo fusion, transforming into sponge-like microscale droplets enriched with membrane features. By modulating the temperature, these droplets display dynamic properties such as contractility, temperature-induced fusion, and cargo trapping, including small molecules and bacteria, thereby demonstrating their ability to dynamically interface with biological entities. The findings demonstrate the potential of our sponge-like droplets in synthetic cell applications, contributing to the understanding of PEO-PBO polymersomes’ unique characteristics, expanding the capabilities of synthetic cell structures, and representing an exciting possibility for advancing soft matter engineering to cell-like behaviors.
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Journal articleSeddon JM, Watts A, 2025, , EUROPEAN BIOPHYSICS JOURNAL, Vol: 54, Pages: 1-20, ISSN: 0175-7571
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Book chapterSeddon JM, Tyler AII, 2025, , Membrane Shape and Biological Function, Pages: 42-60
This chapter describes the self-assembly of membrane lipids into non-lamellar phases, whose structures are based upon curved fluid monolayers or bilayers. Such membrane curvature arises from a mismatch in the lateral packing between the lipid polar headgroups and the hydrocarbon chains. The relationship between lateral pressure profiles and membrane curvature elasticity is discussed, as well as the role of curvature and packing frustration in stabilizing curved membrane phases. Non-lamellar structures appear to play a role in a wide range of biological processes. For example, they are believed to be intimately involved in the mechanism of fat digestion in the gut. In any event, the localized dynamic shape changes that occur during biological processes such as membrane fusion and fission are geometrically and topologically closely related to the local structures of certain non-lamellar phases. Thus studies of the latter in model systems may yield valuable insights into the molecular rearrangements that occur during these complex dynamic biological processes. Non-lamellar phases also have a large number of existing or potential biomedical applications, such as in membrane protein crystallization, and drug/gene delivery to living cells. Self-assembled lipid nanoparticles with incorporated mRNA has led to the recent development of the highly-successful Covid-19 vaccine.
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Journal articleLi Z, Saurabh S, Hollowell P, et al., 2024, , ACS Applied Materials and Interfaces, Vol: 16, Pages: 70231-70241, ISSN: 1944-8244
Investigating the molecular conformations of monoclonal antibodies (mAbs) adsorbed at the solid/liquid interface is crucial for understanding mAb solution stability and advancing the development of mAb-based biosensors. This study examines the pH-dependent conformational plasticity of a human IgG1k mAb, COE-3, at the SiO2/water interface under varying pH conditions (pH 5.5 and 9). By integrating neutron reflectivity (NR) and molecular dynamics (MD) simulations, we reveal that the mAb irreversibly deposits onto the interface at pH 5.5, with surface density saturation reached at 20 ppm bulk concentration. At pH 5.5, the adsorbed mAb adopts a stable “flat-on” orientation, while at pH 9, it assumes a more flexible conformation and a “tilted” orientation. This pH-dependent orientation shift is reversible and influenced by the distinct surface charge properties of the Fab and Fc fragments, with the Fc fragment more prone to desorption at higher pH. The root-mean-square deviation (RMSD) analysis further shows that COE-3 maintains structural stability upon adsorption across both pH levels, showing minimal unfolding or denaturation. These findings highlight how pH-dependent electrostatic interactions between mAb fragments and the SiO2 interface drive conformational adjustments in the intact mAb, offering insights into adsorption-induced aggregation and suggesting pH modulation as a mechanism for controlling biosensor efficiency.
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Journal articleRafat AA, Barbara PV, Ullah A, et al., 2024, , CELLULOSE, ISSN: 0969-0239
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Journal articleCheng Y, Hay CD, Mahuttanatan SM, et al., 2024, , LAB ON A CHIP, Vol: 24, Pages: 4679-4716, ISSN: 1473-0197
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Journal articleMonck C, Elani Y, Ceroni F, 2024, , Nature Chemical Biology, Vol: 20, Pages: 1380-1386, ISSN: 1552-4450
Synthetic cells containing genetic programs and protein expression machinery are increasingly recognized as powerful counterparts to engineered living cells in the context of biotechnology, therapeutics and cellular modelling. So far, genetic regulation of synthetic cell activity has been largely confined to chemical stimuli; to unlock their potential in applied settings, engineering stimuli-responsive synthetic cells under genetic regulation is imperative. Here we report the development of temperature-sensitive synthetic cells that control protein production by exploiting heat-responsive mRNA elements. This is achieved by combining RNA thermometer technology, cell-free protein expression and vesicle-based synthetic cell design to create cell-sized capsules able to initiate synthesis of both soluble proteins and membrane proteins at defined temperatures. We show that the latter allows for temperature-controlled cargo release phenomena with potential implications for biomedicine. Platforms like the one presented here can pave the way for customizable, genetically programmed synthetic cells under thermal control to be used in biotechnology.
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Journal articleCeroni F, Elani Y, 2024, , Nature Chemical Biology, Vol: 20, Pages: 1258-1259, ISSN: 1552-4450
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Journal articlePilkington CP, Gispert I, Chui SY, et al., 2024, , Nature Chemistry, Vol: 16, Pages: 1612-1620, ISSN: 1755-4330
Soft-matter nanoscale assemblies such as liposomes and lipid nanoparticles have the potential to deliver and release multiple cargos in an externally stimulated and site-specific manner. Such assemblies are currently structurally simplistic, comprising spherical capsules or lipid clusters. Given that form and function are intertwined, this lack of architectural complexity restricts the development of more sophisticated properties. To address this, we have devised an engineering strategy combining microfluidics and conjugation chemistry to synthesize nanosized liposomes with two discrete compartments, one within another, which we term concentrisomes. We can control the composition of each bilayer and tune both particle size and the dimensions between inner and outer membranes. We can specify the identity of encapsulated cargo within each compartment, and the biophysical features of inner and outer bilayers, allowing us to imbue each bilayer with different stimuli-responsive properties. We use these particles for multi-stage release of two payloads at defined time points, and as attolitre reactors for triggered in situ biochemical synthesis.
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Journal articleIoannou IA, Monck C, Ceroni F, et al., 2024, , PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 121, ISSN: 0027-8424
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- Citations: 4
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Journal articleHuang J, Elani Y, Friddin M, 2024, , Sensors & Diagnostics, Vol: 3, Pages: 1461-1466, ISSN: 2635-0998
We report the rapid fabrication of a handheld laser cut platform that can support the assembly, functionalisation, size-control and electrical characterisation of lipid bilayers. We achieve this by building a modular DIY platform that can support the lowering of a Ag/AgCl electrode through a phase transfer column consisting of an upper oil phase containing lipids, and a lower aqueous phase containing buffer.
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Journal articleAllen ME, Kamilova E, Monck C, et al., 2024, , Advanced Science, Vol: 11, ISSN: 2198-3844
Dermal tattoo biosensors are promising platforms for real-time monitoring of biomarkers, with skin used as a diagnostic interface. Traditional tattoo sensors have utilized small molecules as biosensing elements. However, the rise of synthetic biology has enabled the potential employment of engineered bacteria as living analytical tools. Exploiting engineered bacterial sensors will allow for potentially more sensitive detection across a broad biomarker range, with advanced processing and sense/response functionalities using genetic circuits. Here, the interfacing of bacterial biosensors as living analytics in tattoos is shown. Engineered bacteria are encapsulated into micron-scale hydrogel beads prepared through scalable microfluidics. These biosensors can sense both biochemical cues (model biomarkers) and biophysical cues (temperature changes, using RNA thermometers), with fluorescent readouts. By tattooing beads into skin models and confirming sensor activity post-tattooing, our study establishes a foundation for integrating bacteria as living biosensing entities in tattoos.
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Journal articleSaurabh S, Lei L, Li Z, et al., 2024, , APL Bioengineering, Vol: 8, ISSN: 2473-2877
Monoclonal antibodies (mAbs) can undergo structural changes due to interaction with oil-water interfaces during storage. Such changes can lead to aggregation, resulting in a loss of therapeutic efficacy. Therefore, understanding the microscopic mechanism controlling mAb adsorption is crucial to developing strategies that can minimize the impact of interfaces on the therapeutic properties of mAbs. In this study, we used MARTINI coarse-grained molecular dynamics simulations to investigate the adsorption of the Fab and Fc domains of the monoclonal antibody COE3 at the oil-water interface. Our aim was to determine the regions on the protein surface that drive mAb adsorption. We also investigate the role of protein concentration on protein orientation and protrusion to the oil phase. While our structural analyses compare favorably with recent neutron reflectivity measurements, we observe some differences. Unlike the monolayer at the interface predicted by neutron reflectivity experiments, our simulations indicate the presence of a secondary diffused layer near the interface. We also find that under certain conditions, protein-oil interaction can lead to a considerable distortion in the protein structure, resulting in enhanced adsorption behavior.
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