Publications
478 results found
Fernandez-Galiana A, Bibikova O, Pedersen S, et al., 2023, Fundamentals and applications of Raman-based techniques for the design and development of active biomedical materials, Advanced Materials, ISSN: 0935-9648
Creamer A, Lo Fiego A, Agliano A, et al., 2023, Modular synthesis of semiconducting graft co-polymers to achieve ‘clickable’ fluorescent nanoparticles with long circulation and specific cancer targeting, Advanced Materials, ISSN: 0935-9648
Lalone V, Aizenshtadt A, Goertz J, et al., 2023, Quantitative chemometric phenotyping of three dimensional liver organoids by Raman spectral imaging (qRamanomics), Cell Reports Methods
Callens SJP, Fan D, van Hengel IAJ, et al., 2023, Emergent collective organization of bone cells in complex curvature fields., Nat Commun, Vol: 14
Individual cells and multicellular systems respond to cell-scale curvatures in their environments, guiding migration, orientation, and tissue formation. However, it remains largely unclear how cells collectively explore and pattern complex landscapes with curvature gradients across the Euclidean and non-Euclidean spectra. Here, we show that mathematically designed substrates with controlled curvature variations induce multicellular spatiotemporal organization of preosteoblasts. We quantify curvature-induced patterning and find that cells generally prefer regions with at least one negative principal curvature. However, we also show that the developing tissue can eventually cover unfavorably curved territories, can bridge large portions of the substrates, and is often characterized by collectively aligned stress fibers. We demonstrate that this is partly regulated by cellular contractility and extracellular matrix development, underscoring the mechanical nature of curvature guidance. Our findings offer a geometric perspective on cell-environment interactions that could be harnessed in tissue engineering and regenerative medicine applications.
Shamsabadi A, Haghighi T, Carvalho S, et al., 2023, The Nanozyme Revolution: Enhancing the Performance of Medical Biosensing Platforms, Advanced Materials, ISSN: 0935-9648
Lee J, Mulay P, Tamasi MJ, et al., 2023, A fully automated platform for photoinitiated RAFT polymerization, Digital Discovery, Vol: 2, Pages: 219-233, ISSN: 2635-098X
Oxygen tolerant polymerizations including Photoinduced Electron/Energy Transfer-Reversible Addition–Fragmentation Chain-Transfer (PET-RAFT) polymerization allow for high-throughput synthesis of diverse polymer architectures on the benchtop in parallel. Recent developments have further increased throughput using liquid handling robotics to automate reagent handling and dispensing into well plates thus enabling the combinatorial synthesis of large polymer libraries. Although liquid handling robotics can enable automated polymer reagent dispensing in well plates, photoinitiation and reaction monitoring require automation to provide a platform that enables the reliable and robust synthesis of various polymer compositions in high-throughput where polymers with desired molecular weights and low dispersity are obtained. Here, we describe the development of a robotic platform to fully automate PET-RAFT polymerizations and provide individual control of reactions performed in well plates. On our platform, reagents are automatically dispensed in well plates, photoinitiated in individual wells with a custom-designed lightbox until the polymerizations are complete, and monitored online in real-time by tracking fluorescence intensities on a fluorescence plate reader, with well plate transfers between instruments occurring via a robotic arm. We found that this platform enabled robust parallel polymer synthesis of both acrylate and acrylamide homopolymers and copolymers, with high monomer conversions and low dispersity. The successful polymerizations obtained on this platform make it an efficient tool for combinatorial polymer chemistry. In addition, with the inclusion of machine learning protocols to help navigate the polymer space towards specific properties of interest, this robotic platform can ultimately become a self-driving lab that can dispense, synthesize, and monitor large polymer libraries.
Tan WS, Moore AC, Stevens M, 2023, Minimum design requirements for a poroelastic mimic of articular cartilage, Journal of The Mechanical Behavior of Biomedical Materials, Vol: 137, ISSN: 1751-6161
The exceptional functional performance of articular cartilage (load-bearing and lubrication) is attributed to its poroelastic structure and resulting interstitial fluid pressure. Despite this, there remains no engineered cartilage repair material capable of achieving physiologically relevant poroelasticity. In this work we develop in silico models to guide the design approach for poroelastic mimics of articular cartilage. We implement the constitutive models in FEBio, a PDE solver for multiphasic mechanics problems in biological and soft materials. We investigate the influence of strain rate, boundary conditions at the contact interface, and fiber modulus on the reaction force and load sharing between the solid and fluid phases. The results agree with the existing literature that when fibers are incorporated the fraction of load supported by fluid pressure is greatly amplified and increases with the fiber modulus. This result demonstrates that a stiff fibrous phase is a primary design requirement for poroelastic mimics of articular cartilage. The poroelastic model is fit to experimental stress-relaxation data from bovine and porcine cartilage to determine if sufficient design constraints have been identified. In addition, we fit experimental data from FiHy™, an engineered material which is claimed to be poroelastic. The fiber-reinforced poroelastic model was able to capture the primary physics of these materials and demonstrates that FiHy™ is beginning to approach a cartilage-like poroelastic response. We also develop a fiber-reinforced poroelastic model with a bonded interface (rigid contact) to fit stress relaxation data from an osteochondral explant and FiHy™ + bone substitute. The model fit quality is similar for both the chondral and osteochondral configurations and clearly captures the first order physics. Based on this, we propose that physiological poroelastic mimics of articular cartilage should be developed under a fiber-reinforced poroel
Armstrong JP, Pchelintseva E, Treumuth S, et al., 2022, Tissue engineering cartilage with deep zone cytoarchitecture by high-resolution acoustic cell patterning, Advanced Healthcare Materials, Vol: 11, ISSN: 2192-2640
The ultimate objective of tissue engineering is to fabricate artificial living constructs with a structural organization and function that faithfully resembles their native tissue counterparts. For example, the deep zone of articular cartilage possesses a distinctive anisotropic architecture with chondrocytes organized in aligned arrays ≈1–2 cells wide, features that are oriented parallel to surrounding extracellular matrix fibers and orthogonal to the underlying subchondral bone. Although there are major advances in fabricating custom tissue architectures, it remains a significant technical challenge to precisely recreate such fine cellular features in vitro. Here, it is shown that ultrasound standing waves can be used to remotely organize living chondrocytes into high-resolution anisotropic arrays, distributed throughout the full volume of agarose hydrogels. It is demonstrated that this cytoarchitecture is maintained throughout a five-week course of in vitro tissue engineering, producing hyaline cartilage with cellular and extracellular matrix organization analogous to the deep zone of native articular cartilage. It is anticipated that this acoustic cell patterning method will provide unprecedented opportunities to interrogate in vitro the contribution of chondrocyte organization to the development of aligned extracellular matrix fibers, and ultimately, the design of new mechanically anisotropic tissue grafts for articular cartilage regeneration.
Sun R, Song X, Zhou K, et al., 2022, Assembly of fillable microrobotic systems by microfluidic loading with dip sealing, Advanced Materials, ISSN: 0935-9648
Microrobots can provide spatiotemporally well-controlled cargo delivery that can improve therapeutic efficiency compared to conventional drug delivery strategies. Robust microfabrication methods to expand the variety of materials or cargoes that can be incorporated into microrobots can greatly broaden the scope of their functions. However, current surface coating or direct blending techniques used for cargo loading result in inefficient loading and poor cargo protection during transportation, which leads to cargo waste, degradation and non-specific release. Herein, a versatile platform to fabricate fillable microrobots using microfluidic loading and dip sealing (MLDS) is presented. MLDS enables the encapsulation of different types of cargoes within hollow microrobots and protection of cargo integrity. The technique is supported by high-resolution 3D printing with an integrated microfluidic loading system, which realizes a highly precise loading process and improves cargo loading capacity. A corresponding dip sealing strategy is developed to encase and protect the loaded cargo whilst maintaining the geometric and structural integrity of the loaded microrobots. This dip sealing technique is suitable for different materials, including thermal and light-responsive materials. The MLDS platform provides new opportunities for microrobotic systems in targeted drug delivery, environmental sensing, and chemically powered micromotor applications.
Najer A, Rifaie Graham O, Yeow J, et al., 2022, Differences in human plasma protein interactions between various polymersomes and stealth liposomes as observed by fluorescence correlation spectroscopy, Macromolecular Bioscience, ISSN: 1616-5187
A significant factor hindering the clinical translation of polymersomes as vesicular nanocarriers is the limited availability of comparative studies detailing their interaction with blood plasma proteins compared to liposomes. Here, polymersomes are self-assembled via film rehydration, solvent exchange, and polymerization-induced self-assembly using five different block copolymers. The hydrophilic blocks are composed of anti-fouling polymers, poly(ethylene glycol) (PEG) or poly(2-methyl-2-oxazoline) (PMOXA), and all the data is benchmarked to PEGylated “stealth” liposomes. High colloidal stability in human plasma (HP) is confirmed for all but two tested nanovesicles. In situ fluorescence correlation spectroscopy measurements are then performed after incubating unlabeled nanovesicles with fluorescently labeled HP or the specific labeled plasma proteins, human serum albumin, and clusterin (apolipoprotein J). The binding of HP to PMOXA-polymersomes could explain their relatively short circulation times found previously. In contrast, PEGylated liposomes also interact with HP but accumulate high levels of clusterin, providing them with their known prolonged circulation time. The absence of significant protein binding for most PEG-polymersomes indicates mechanistic differences in protein interactions and associated downstream effects, such as cell uptake and circulation time, compared to PEGylated liposomes. These are key observations for bringing polymersomes closer to clinical translation and highlighting the importance of such comparative studies.
Hu T, Brinker CJ, Chan WCW, et al., 2022, Publishing Translational Research of Nanomedicine in ACS Nano, Publisher: AMER CHEMICAL SOC
Budd J, Miller BS, Weckman NE, et al., 2022, Lateral flow test engineering and lessons learned from COVID-19, Nature Reviews Bioengineering, ISSN: 2731-6092
The acceptability and feasibility of large-scale testing with lateral flow tests (LFTs) for clinical and public health purposes has been demonstrated in the COVID-19 pandemic. LFTs can detect analytes in a variety of samples, providing a rapid read-out, which allows self-testing and decentralised diagnosis. In this Review, we examine the changing LFT landscape with a focus on lessons learned from COVID- 9. We discuss implications of LFTs for decentralised testing of infectious diseases, including diseases of epidemic potential, the ‘silent pandemic’ of antimicrobial resistance, and other acute and chronic infections. Bioengineering approaches will play a key role in increasing the sensitivity and specificity of LFTs, improving sample preparation, incorporating nucleic acid amplification and detection, andenabling multiplexing, digital connection and green manufacturing, with the aim to create the next generation of highly-accurate, easy-to-use, affordable and digitally-connected LFTs. We conclude with recommendations, including the building of a global network of LFT research and development hubs tofacilitate and strengthen future diagnostic resilience.
Rifaie Graham O, Yeow J, Najer A, et al., 2022, Photoswitchable gating of non-equilibrium enzymatic feedback in chemically communicating polymersome nanoreactors, Nature Chemistry, Vol: 15, Pages: 110-118, ISSN: 1755-4330
The circadian rhythm generates out-of-equilibrium metabolite oscillations controlled by feedbackloops under light/dark cycles. Here we describe a non-equilibrium nanosystem comprising a binarypopulation of enzyme-containing polymersomes capable of light-gated chemical communication,controllable feedback and coupling to macroscopic oscillations. The populations consist of esterase-containing polymersomes functionalised with photo-responsive Donor-Acceptor Stenhouse Adducts(DASA) and light-insensitive semi-permeable urease-loaded polymersomes. The DASA-polymersomemembrane becomes permeable under green light, switching on esterase activity and decreasing thepH, which in turn initiates production of alkali in the urease-containing population. A pH-sensitivepigment that absorbs green light when protonated provides a negative feedback loop for deactivatingthe DASA-polymersomes. Simultaneously, increased alkali production deprotonates the pigment, re-activating esterase activity by opening the membrane gate. We utilise light-mediated fluctuations ofpH to perform non-equilibrium communication between the nanoreactors and use the feedback loopsto induce work as chemomechanical swelling/deswelling oscillations in a crosslinked hydrogel. Weenvision possible applications in artificial organelles, protocells, and soft robotics.
Speidel AT, Chivers PRA, Wood CS, et al., 2022, Tailored biocompatible polyurethane-poly(ethylene glycol) hydrogels as a versatile nonfouling biomaterial, Advanced Healthcare Materials, Vol: 11, Pages: 1-13, ISSN: 2192-2640
Polyurethane-based hydrogels are relatively inexpensive and mechanically robust biomaterials with ideal properties for various applications, including drug delivery, prosthetics, implant coatings, soft robotics, and tissue engineering. In this report, a simple method is presented for synthesizing and casting biocompatible polyurethane-poly(ethylene glycol) (PU-PEG) hydrogels with tunable mechanical properties, nonfouling characteristics, and sustained tolerability as an implantable material or coating. The hydrogels are synthesized via a simple one-pot method using commercially available precursors and low toxicity solvents and reagents, yielding a consistent and biocompatible gel platform primed for long-term biomaterial applications. The mechanical and physical properties of the gels are easily controlled by varying the curing concentration, producing networks with complex shear moduli of 0.82–190 kPa, similar to a range of human soft tissues. When evaluated against a mechanically matched poly(dimethylsiloxane) (PDMS) formulation, the PU-PEG hydrogels demonstrated favorable nonfouling characteristics, including comparable adsorption of plasma proteins (albumin and fibrinogen) and significantly reduced cellular adhesion. Moreover, preliminary murine implant studies reveal a mild foreign body response after 41 days. Due to the tunable mechanical properties, excellent biocompatibility, and sustained in vivo tolerability of these hydrogels, it is proposed that this method offers a simplified platform for fabricating soft PU-based biomaterials for a variety of applications.
Song X, Sun R, Wang R, et al., 2022, Puffball-inspired microrobotic systems with robust payload, strong protection, and targeted locomotion for on-demand drug delivery, Advanced Materials, Vol: 34, Pages: 1-14, ISSN: 0935-9648
Microrobots have been recognized as transformative solutions for drug delivery systems (DDSs) because they can navigate through the body to specific locations and enable targeted drug release. However, their realization is substantially limited by insufficient payload capacity, unavoidable drug leakage/deactivation, and strict modification/stability criteria for drugs. Natural puffballs possess fascinating features that are highly desirable for DDSs, including a large fruitbody for storing spores, a flexible protective cap, and environmentally-triggered release mechanisms. This report presents a puffball-inspired microrobotic system which incorporates: an internal chamber for loading large drug quantities and spatial drug separation; and a near-infrared-responsive top-sealing layer offering strong drug protection and on-demand release. These puffball-inspired microrobots (PIMs) display tunable loading capacities up to high concentrations and enhanced drug protection with minimal drug leakage.Upon near-infrared laser irradiation, on-demand drug delivery with rapid release efficiency is achieved. The PIMs also demonstrate translational motion velocities, switchable motion modes, and precise locomotion under a rotating magnetic field. This work provides strong proof-of-concept for a DDS that combines the superior locomotion capability of microrobots with theunique characteristics of puffballs, thereby illustrating a versatile avenue for development of a new generation of microrobots for targeted drug delivery.
Pentinmikko N, Lozano R, Scharaw S, et al., 2022, Cellular shape reinforces niche to stem cell signaling in the small intestine., Science Advances, Vol: 8, Pages: 1-13, ISSN: 2375-2548
Niche-derived factors regulate tissue stem cells, but apart from the mechanosensory pathways, the effect of niche geometry is not well understood. We used organoids and bioengineered tissue culture platforms to demonstrate that the conical shape of Lgr5+ small intestinal stem cells (ISCs) facilitate their self-renewal and function. Inhibition of non-muscle myosin II (NM II)-driven apical constriction altered ISC shape and reduced niche curvature and stem cell capacity. Niche curvature is decreased in aged mice, suggesting that suboptimal interactions between old ISCs and their niche develop with age. We show that activation of NM IIC or physical restriction to young topology improves in vitro regeneration by old epithelium. We propose that the increase in lateral surface area of ISCs induced by apical constriction promotes interactions between neighboring cells, and the curved topology of the intestinal niche has evolved to maximize signaling between ISCs and neighboring cells.
Khodabukus A, Guyer T, Moore AC, et al., 2022, Translating musculoskeletal bioengineering into tissue regeneration therapies., Science Translational Medicine, Vol: 14, Pages: 1-17, ISSN: 1946-6234
Musculoskeletal injuries and disorders are the leading cause of physical disability worldwide and a considerable socioeconomic burden. The lack of effective therapies has driven the development of novel bioengineering approaches that have recently started to gain clinical approvals. In this review, we first discuss the self-repair capacity of the musculoskeletal tissues and describe causes of musculoskeletal dysfunction. We then review the development of novel biomaterial, immunomodulatory, cellular, and gene therapies to treat musculoskeletal disorders. Last, we consider the recent regulatory changes and future areas of technological progress that can accelerate translation of these therapies to clinical practice.
Mathew R, Stevensson B, Pujari-Palmer M, et al., 2022, Nuclear magnetic resonance and metadynamics simulations reveal the atomistic binding of L-serine and O-phospho-L-serine at disordered calcium phosphate surfaces of biocements, Chemistry of Materials, Vol: 34, Pages: 8815-8830, ISSN: 0897-4756
Interactions between biomolecules and structurally disordered calcium phosphate (CaP) surfaces are crucial for the regulation of bone mineralization by noncollagenous proteins, the organization of complexes of casein and amorphous calcium phosphate (ACP) in milk, as well as for structure–function relationships of hybrid organic/inorganic interfaces in biomaterials. By a combination of advanced solid-state NMR experiments and metadynamics simulations, we examine the detailed binding of O-phospho-l-serine (Pser) and l-serine (Ser) with ACP in bone-adhesive CaP cements, whose capacity of gluing fractured bone together stems from the close integration of the organic molecules with ACP over a subnanometer scale. The proximity of each carboxy, aliphatic, and amino group of Pser/Ser to the Ca2+ and phosphate species of ACP observed from the metadynamics-derived models agreed well with results from heteronuclear solid-state NMR experiments that are sensitive to the 13C–31P and 15N–31P distances. The inorganic/organic contacts in Pser-doped cements are also contrasted with experimental and modeled data on the Pser binding at nanocrystalline HA particles grown from a Pser-bearing aqueous solution. The molecular adsorption is driven mainly by electrostatic interactions between the negatively charged carboxy/phosphate groups and Ca2+ cations of ACP, along with H bonds to either protonated or nonprotonated inorganic phosphate groups. The Pser and Ser molecules anchor at their phosphate/amino and carboxy/amino moieties, respectively, leading to an extended molecular conformation across the surface, as opposed to an “upright standing” molecule that would result from the binding of one sole functional group.
Broto M, Kaminski MM, Adrianus C, et al., 2022, Nanozyme-catalysed CRISPR assay for preamplification-free detection of non-coding RNAs, Nature Nanotechnology, Vol: 17, Pages: 1120-1126, ISSN: 1748-3387
CRISPR-based diagnostics enable specific sensing of DNA and RNA biomarkers associated withhuman diseases. This is achieved through the binding of guide RNAs to a complementarysequence which activates Cas enzymes to cleave reporter molecules. Currently, most CRISPRbased diagnostics rely on target preamplification to reach sufficient sensitivity for clinicalapplications. This limits quantification capability and adds complexity to the reaction chemistry.Here, we show the combination of a CRISPR/Cas-based reaction with a Nanozyme-LinkedImmunoSorbent Assay which allows for the quantitative and colorimetric readout of Cas13-mediated RNA detection through catalytic metallic nanoparticles at room temperature(CrisprZyme). We demonstrate CrisprZyme is easily adaptable to a lateral-flow-based readoutand different Cas enzymes, and enables the sensing of non-coding RNAs including microRNAs,long non-coding RNAs and circular RNAs. We utilise this platform to identify patients with acutemyocardial infarction and to monitor cellular differentiation in vitro and in tissue biopsies fromprostate cancer patients. We anticipate that CrisprZyme has significant potential as a universallyapplicable signal catalyst for CRISPR-based diagnostics which will expand the spectrum oftargets for preamplification-free, quantitative detection.
Najer A, Blight J, Ducker CB, et al., 2022, Potent virustatic polymer-lipid nanomimics block viral entry and inhibit malaria parasites in vivo, ACS Central Science, Vol: 8, Pages: 1238-1257, ISSN: 2374-7943
Infectious diseases continue to pose a substantial burden on global populations, requiring innovative broad-spectrum prophylactic and treatment alternatives. Here, we have designed modular synthetic polymer nanoparticles that mimic functional components of host cell membranes, yielding multivalent nanomimics that act by directly binding to varied pathogens. Nanomimic blood circulation time was prolonged by reformulating polymer–lipid hybrids. Femtomolar concentrations of the polymer nanomimics were sufficient to inhibit herpes simplex virus type 2 (HSV-2) entry into epithelial cells, while higher doses were needed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given their observed virustatic mode of action, the nanomimics were also tested with malaria parasite blood-stage merozoites, which lose their invasive capacity after a few minutes. Efficient inhibition of merozoite invasion of red blood cells was demonstrated both in vitro and in vivo using a preclinical rodent malaria model. We envision these nanomimics forming an adaptable platform for developing pathogen entry inhibitors and as immunomodulators, wherein nanomimic-inhibited pathogens can be secondarily targeted to sites of immune recognition.
Liz-Marzan LM, Nel AE, Brinker CJ, et al., 2022, What Do We Mean When We Say Nanomedicine?, Publisher: AMER CHEMICAL SOC
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Kim H, Yeow J, Najer A, et al., 2022, Microliter scale synthesis of luciferase-encapsulated polymersomes as artificial organelles for optogenetic modulation of cardiomyocyte beating, Advanced Science, Vol: 9, Pages: 1-12, ISSN: 2198-3844
Constructing artificial systems that effectively replace or supplement natural biological machinery within cells is one of the fundamental challenges underpinning bioengineering. At the sub-cellular scale, artificial organelles (AOs) have significant potential as long-acting biomedical implants, mimicking native organelles by conducting intracellularly compartmentalized enzymatic actions. The potency of these AOs can be heightened when judiciously combined with genetic engineering, producing highly tailorable biohybrid cellular systems. Here, the authors present a cost-effective, microliter scale (10 µL) polymersome (PSome) synthesis based on polymerization-induced self-assembly for the in situ encapsulation of Gaussia luciferase (GLuc), as a model luminescent enzyme. These GLuc-loaded PSomes present ideal features of AOs including enhanced enzymatic resistance to thermal, proteolytic, and intracellular stresses. To demonstrate their biomodulation potential, the intracellular luminescence of GLuc-loaded PSomes is coupled to optogenetically engineered cardiomyocytes, allowing modulation of cardiac beating frequency through treatment with coelenterazine (CTZ) as the substrate for GLuc. The long-term intracellular stability of the luminescent AOs allows this cardiostimulatory phenomenon to be reinitiated with fresh CTZ even after 7 days in culture. This synergistic combination of organelle-mimicking synthetic materials with genetic engineering is therefore envisioned as a highly universal strategy for the generation of new biohybrid cellular systems displaying unique triggerable properties.
King O, Cruz-Moreira D, Sayed A, et al., 2022, Functional microvascularization of human myocardium in vitro, CELL REPORTS METHODS, Vol: 2, ISSN: 2667-2375
Hachim D, Zhao J, Bhankharia J, et al., 2022, Polysaccharide-polyplex nanofilm coatings enhance nanoneedle-based gene delivery and transfection efficiency, Small, Vol: 18, ISSN: 1613-6810
Non-viral vectors represent versatile and immunologically safer alternatives for nucleic acid delivery. Nanoneedles and high-aspect ratio nanostructures are unconventional but interesting delivery systems, in which delivery is mediated by surface interactions. Herein, nanoneedles are synergistically combined with polysaccharide-polyplex nanofilms and enhanced transfection efficiency is observed, compared to polyplexes in suspension. Different polyplex-polyelectrolyte nanofilm combinations are assessed and it is found that transfection efficiency is enhanced when using polysaccharide-based polyanions, rather than being only specific for hyaluronic acid, as suggested in earlier studies. Moreover, results show that enhanced transfection is not mediated by interactions with the CD44 receptor, previously hypothesized as a major mechanism mediating enhancement via hyaluronate. In cardiac tissue, nanoneedles are shown to increase the transfection efficiency of nanofilms compared to flat substrates; while in vitro, high transfection efficiencies are observed in nanostructures where cells present large interfacing areas with the substrate. The results of this study demonstrate that surface-mediated transfection using this system is efficient and safe, requiring amounts of nucleic acid with an order of magnitude lower than standard culture transfection. These findings expand the spectrum of possible polyelectrolyte combinations that can be used for the development of suitable non-viral vectors for exploration in further clinical trials.
Speidel A, Grigsby C, Stevens M, 2022, Ascendancy of semi-synthetic biomaterials from design towards democratization, Nature Materials, Vol: 21, ISSN: 1476-1122
Semi-synthetic “goldilocks” material design integrates the advantageous tunable characteristics of synthetic materials and the refined complexity of natural components, and has opened doors for the progress of biomaterials across length scales. Through this multi-modal approach, accelerated translational success may be possible for more personalized and accessible products.
Sri-Ranjan K, Sanchez-Alonso JL, Swiatlowska P, et al., 2022, Intrinsic cell rheology drives junction maturation, Nature Communications, Vol: 13, ISSN: 2041-1723
A fundamental property of higher eukaryotes that underpins their evolutionary success is stable cell-cell cohesion. Yet, how intrinsic cell rheology and stiffness contributes to junction stabilization and maturation is poorly understood. We demonstrate that localized modulation of cell rheology governs the transition of a slack, undulated cell-cell contact (weak adhesion) to a mature, straight junction (optimal adhesion). Cell pairs confined on different geometries have heterogeneous elasticity maps and control their own intrinsic rheology co-ordinately. More compliant cell pairs grown on circles have slack contacts, while stiffer triangular cell pairs favour straight junctions with flanking contractile thin bundles. Counter-intuitively, straighter cell-cell contacts have reduced receptor density and less dynamic junctional actin, suggesting an unusual adaptive mechano-response to stabilize cell-cell adhesion. Our modelling informs that slack junctions arise from failure of circular cell pairs to increase their own intrinsic stiffness and resist the pressures from the neighbouring cell. The inability to form a straight junction can be reversed by increasing mechanical stress artificially on stiffer substrates. Our data inform on the minimal intrinsic rheology to generate a mature junction and provide a springboard towards understanding elements governing tissue-level mechanics.
Ren Y, Autefage H, Jones JR, et al., 2022, Developing atom probe tomography to characterize Sr-loaded bioactive glass for bone scaffolding, Microscopy and Microanalysis, Vol: 28, Pages: 1310-1320, ISSN: 1431-9276
In this study, atom probe tomography (APT) was used to investigate strontium-containing bioactive glass particles (BG-Sr10) and strontium-releasing bioactive glass-based scaffolds (pSrBG), both of which are attractive biomaterials with applications in critical bone damage repair. We outline the challenges and corresponding countermeasures of this nonconductive biomaterial for APT sample preparation and experiments, such as avoiding direct contact between focussed ion beam micromanipulators and the extracted cantilever to reduce damage during liftout. Using a low imaging voltage (≤3 kV) and current (≤500 pA) in the scanning electron microscope and a low acceleration voltage (≤2 kV) and current (≤200 pA) in the focussed ion beam prevents tip bending in the final stages of annular milling. To optimize the atom probe experiment, we considered five factors: total detected hits, multiple hits, the background level, the charge-state ratio, and the accuracy of the measured compositions, to explore the optimal laser pulse for BG-Sr10 bioactive glass. We show that a stage temperature of 30 K, 200–250 pJ laser pulse energy, 0.3% detection rate, and 200 kHz pulse rate are optimized experimental parameters for bioactive glass. The use of improved experimental preparation methods and optimized parameters resulted in a 90% successful yield of pSrBG samples by APT.
Hsu CC, Serio A, Gopal S, et al., 2022, Biophysical regulations of epigenetic state and notch signalling in neural development using microgroove substrates, ACS Applied Materials and Interfaces, Vol: 14, ISSN: 1944-8244
A number of studies have recently shown how surface topography can alter behaviour and differentiation patterns of different types of stem cells. Although the exact mechanisms and molecular pathways involved remain unclear, a consistent portion of the literature points to epigenetic changes induced by nuclear remodelling. In this study, we investigate the behaviour of clinically relevant neural populations derived from human pluripotent stem cells when cultured on polydimethylsiloxane microgrooves (3 μm- and 10 μm-depth grooves), to investigate what mechanisms are responsible for their differentiation capacity and functional behaviour. Our results show that microgrooves enhance cell alignment, modify nuclear geometry and significantly increase cellular stiffness, which we were able to measure at high resolution with a combination of light and electron microscopy, scanning ion conductance microscopy (SICM) and atomic force microscopy (AFM) coupled with quantitative image analysis. The microgrooves promoted significant changes in the epigenetic landscape, as revealed by the expression of key histone modification markers. The main behavioural change of neural stem cells on microgrooves was an increase of neuronal differentiation under basal conditions on the microgrooves. Through measurements of cleaved Notch1 levels, we found that microgrooves downregulate Notch signalling. We in fact propose that microgroovetopography affects the differentiation potential of neural stem cells by indirectly altering Notch signalling through geometric segregation and that this mechanism in parallel with topography-dependent epigenetic modulations acts in concert to enhance stem cell neuronal differentiation.
Najer A, Belessiotis Richards A, Kim H, et al., 2022, Block length-dependent protein fouling on Poly(2-oxazoline)-based polymersomes: influence on macrophage association and circulation behavior, Small, Vol: 18, ISSN: 1613-6810
Polymersomes are vesicular structures self-assembled from amphiphilic block copolymers and are considered an alternative to liposomes for applications in drug delivery, immunotherapy, biosensing, and as nanoreactors and artificial organelles. However, the limited availability of systematic stability, protein fouling (protein corona formation), and blood circulation studies hampers their clinical translation. Poly(2-oxazoline)s (POx) are valuable antifouling hydrophilic polymers that can replace the current gold-standard, poly(ethylene glycol) (PEG), yet investigations of POx functionality on nanoparticles are relatively sparse. Herein, a systematic study is reported of the structural, dynamic and antifouling properties of polymersomes made of poly(2-methyl-2-oxazoline)-block-poly(dimethylsiloxane)-block-poly(2-methyl-2-oxazoline) (PMOXA-b-PDMS-b-PMOXA). The study relates in vitro antifouling performance of the polymersomes to atomistic molecular dynamics simulations of polymersome membrane hydration behavior. These observations support the experimentally demonstrated benefit of maximizing the length of PMOXA (degree of polymerization (DP) > 6) while keeping PDMS at a minimal length that still provides sufficient membrane stability (DP > 19). In vitro macrophage association and in vivo blood circulation evaluation of polymersomes in zebrafish embryos corroborate these findings. They further suggest that single copolymer presentation on polymersomes is outperformed by blends of varied copolymer lengths. This study helps to rationalize design rules for stable and low-fouling polymersomes for future medical applications.
Miller BS, Thomas MR, Banner M, et al., 2022, Sub-picomolar lateral flow antigen detection with two-wavelength imaging of composite nanoparticles, Biosensors and Bioelectronics, Vol: 207, Pages: 1-10, ISSN: 0956-5663
Lateral flow tests, commonly based on metal plasmonic nanoparticles, are rapid, robust, and low-cost. However, improvements in analytical sensitivity are required to allow detection of low-abundance biomarkers, for example detection of low antigen concentrations for earlier or asymptomatic diagnosis of infectious diseases. Efforts to improve sensitivity often require changes to the assay. Here, we developed optical methods to improve the sensitivity of absorption-based lateral flow tests, requiring no assay modifications to existing tests. We experimentally compared five different lock-in and subtraction-based methods, exploiting the narrow plasmonic peak of gold nanoparticles for background removal by imaging at different light wavelengths. A statistical framework and three fitting models were used to compare limits of detection, giving a 2.0–5.4-fold improvement. We then demonstrated the broad applicability of the method to an ultrasensitive assay, designing 530 nm composite nanoparticles to increase the particle volume, and therefore light absorption per particle, whilst retaining the plasmonic peak to allow background removal and without adding any assay steps. This multifaceted, modular approach gave a combined 58-fold improvement in the fundamental limit of detection using a biotin-avidin model over 50 nm gold nanoparticles with single-wavelength imaging. Applying to a sandwich assay for the detection of HIV capsid protein gave a limit of detection of 170 fM. Additionally, we developed an open-source software tool for performing the detection limit analysis used in this work.
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