488 results found
Moore AC, Hennessy MG, Nogueira LP, et al., 2023, Fiber reinforced hydrated networks recapitulate the poroelastic mechanics of articular cartilage, Acta Biomaterialia, Vol: 167, Pages: 69-82, ISSN: 1742-7061
The role of poroelasticity on the functional performance of articular cartilage has been established in the scientific literature since the 1960s. Despite the extensive knowledge on this topic there remain few attempts to design for poroelasticity and to our knowledge no demonstration of an engineered poroelastic material that approaches the physiological performance. In this paper, we report on the development of an engineered material that begins to approach physiological poroelasticity. We quantify poroelasticity using the fluid load fraction, apply mixture theory to model the material system, and determine cytocompatibility using primary human mesenchymal stem cells. The design approach is based on a fiber reinforced hydrated network and uses routine fabrication methods (electrohydrodynamic deposition) and materials (poly[ɛ-caprolactone] and gelatin) to develop the engineered poroelastic material. This composite material achieved a mean peak fluid load fraction of 68%, displayed consistency with mixture theory, and demonstrated cytocompatibility. This work creates a foundation for designing poroelastic cartilage implants and developing scaffold systems to study chondrocyte mechanobiology and tissue engineering. STATEMENT OF SIGNIFICANCE: Poroelasticity drives the functional mechanics of articular cartilage (load bearing and lubrication). In this work we develop the design rationale and approach to produce a poroelastic material, known as a fiber reinforced hydrated network (FiHy™), that begins to approach the native performance of articular cartilage. This is the first engineered material system capable of exceeding isotropic linear poroelastic theory. The framework developed here enables fundamental studies of poroelasticity and the development of translational materials for cartilage repair.
Ritzau-Reid K, Callens S, Xie R, et al., 2023, Microfibrous scaffolds guide stem cell lumenogenesis and brain organoid engineering, Advanced Materials, ISSN: 0935-9648
Najer A, Rifaie Graham O, Yeow J, et al., 2023, Differences in human plasma protein interactions between various polymersomes and stealth liposomes as observed by fluorescence correlation spectroscopy, Macromolecular Bioscience, Vol: 23, 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.
Saunders C, Foote J, Wojciechowski J, et al., 2023, Revealing population heterogeneity in vesicle-based nanomedicines using automated, single particle Raman analysis, ACS Nano, Vol: 17, Pages: 11713-11728, ISSN: 1936-0851
The intrinsic heterogeneity of many nanoformulations is currently challenging to characterise on boththe single particle and population level. Therefore there is great opportunity to develop newtechniques to describe and understand nanomedicine heterogeneity, which will aid translation to theclinic by informing manufacturing quality control, characterisation for regulatory bodies, andconnecting nanoformulation properties to clinical outcomes to enable rational design. Here, wepresent an analytical technique to provide such information, whilst measuring the nanocarrier andcargo simultaneously with label-free, non-destructive single particle automated Raman trappinganalysis (SPARTA). We first synthesised a library of model compounds covering a range ofhydrophilicities and providing distinct Raman signals. These compounds were then loaded into modelnanovesicles (polymersomes) that can load both hydrophobic and hydrophilic cargo into themembrane or core regions respectively. Using our analytical framework, we characterised theheterogeneity of the population by correlating the per particle membrane and cargo signals. We foundthat core and membrane loading can be distinguished, and we detected sub-populations of highlyloaded particlesin certain cases. We then confirmed suitability of our technique in liposomes, anotherPeer reviewed version of the manuscript published in final form in ACS Nano (2023)2nanovesicle class, including the commercial formulation Doxil. Our label-free analytical techniqueprecisely determines cargo location alongside loading and release heterogeneity in nanomedicines,which could be instrumental for future quality control, regulatory body protocols and development ofstructure-function relationships, to bring more nanomedicines to the clinic
Sych T, Schlegel J, Barriga HMG, et al., 2023, High-throughput measurement of the content and properties of nano-sized bioparticles with single-particle profiler., Nat Biotechnol
We introduce a method, single-particle profiler, that provides single-particle information on the content and biophysical properties of thousands of particles in the size range 5-200 nm. We use our single-particle profiler to measure the messenger RNA encapsulation efficiency of lipid nanoparticles, the viral binding efficiencies of different nanobodies, and the biophysical heterogeneity of liposomes, lipoproteins, exosomes and viruses.
Øvrebø Ø, Ojansivu M, Kartasalo K, et al., 2023, RegiSTORM: channel registration for multi-color stochastic optical reconstruction microscopy, BMC Bioinformatics, Vol: 24, Pages: 1-18, ISSN: 1471-2105
Background: Stochastic optical reconstruction microscopy (STORM), a super-resolution microscopy technique based on single-molecule localizations, has become popular to characterize sub-diffraction limit targets. However, due to lengthy image acquisition, STORM recordings are prone to sample drift. Existing cross-correlation or fiducial marker-based algorithms allow correcting the drift within each channel, but misalignment between channels remains due to interchannel drift accumulating during sequential channel acquisition. This is a major drawback in multi-color STORM, a technique of utmost importance for the characterization of various biological interactions. Results: We developed RegiSTORM, a software for reducing channel misalignment by accurately registering STORM channels utilizing fiducial markers in the sample. RegiSTORM identifies fiducials from the STORM localization data based on their non-blinking nature and uses them as landmarks for channel registration. We first demonstrated accurate registration on recordings of fiducials only, as evidenced by significantly reduced target registration error (TRE) with all the tested channel combinations. Next, we validated the performance in a more practically relevant setup on cells multi-stained for tubulin. Finally, we showed that RegiSTORM successfully registers two-color STORM recordings of cargo-loaded lipid nanoparticles without fiducials, demonstrating the broader applicability of this software. Conclusions: The developed RegiSTORM software was demonstrated to be able to accurately register multiple STORM channels and is freely available as open-source (MIT license) at https://github.com/oystein676/RegiSTORM.git and DOI:10.5281/zenodo.5509861 (archived), and runs as a standalone executable (Windows) or via Python (Mac OS, Linux).
Geng H, Lupton EJ, Ma Y, et al., 2023, Hybrid polypyrrole and polydopamine nanosheets for precise Raman/photoacoustic imaging and photothermal therapy, Advanced Healthcare Materials, Pages: 1-21, ISSN: 2192-2640
The development of near-infrared light (NIR)-responsive conductive polymers provides a useful theranostic platform for malignant tumours by maximizing spatial resolution with deep tissue penetration for diagnosis and photothermal therapy. Herein, we demonstrated the self-assembly of ultrathin two-dimensional (2D) polypyrrole nanosheets utilizing dopamine as a capping agent and a monolayer of octadecylamine as a template. The 2D polypyrrole-polydopamine nanostructure (DPPy) had tunable size distribution which showed strong absorption in the first and second near-infrared windows, enabling photoacoustic imaging and photothermal therapy. The hybrid double-layer was demonstrated to increase Raman intensity for 3D Raman imaging (up to two orders of magnitude enhancement and spatial resolution up to 1 μm). The acidic environment drove reversible doping of polypyrrole, which could be detected by Raman spectroscopy. The combined properties of the nanosheets could substantially enhance performance in dual-mode Raman and photoacoustic guided photothermal therapy, as shown by the 69% light to heat conversion efficiency and higher cytotoxicity against cancer spheroids. These pH-responsive features highlight the potential of 2D conductive polymers for applications in accurate, highly efficient theranostics.
Shamsabadi A, Haghighi T, Carvalho S, et al., 2023, The nanozyme revolution: enhancing the performance of medical biosensing platforms, Advanced Materials, Pages: 1-15, ISSN: 0935-9648
Nanozymes represent a class of nanosized materials that exhibit innate catalytic properties similar to biological enzymes. The unique features of these materials have positioned them as promising candidates for applications in clinical sensing devices, specifically those employed at the point-of-care. They notably have found use as a means to amplify signals in nanosensor-based platforms and thereby improve sensor detection limits. Recent developments in the understanding of the fundamental chemistries underpinning these materials have enabled the development of highly effective nanozymes capable of sensing clinically relevant biomarkers at detection limits that compete with “gold-standard” techniques. However, there remain considerable hurdles that need to be overcome before these nanozyme-based sensors can be utilized in a platform ready for clinical use. An overview of the current understandings of nanozymes for disease diagnostics and biosensing applications and the unmet challenges that must be considered prior to their translation in clinical diagnostic tests is provided.
Lalone V, Aizenshtadt A, Goertz J, et al., 2023, Quantitative chemometric phenotyping of three-dimensional liver organoids by Raman spectral imaging, Cell Reports: Methods, Vol: 3, Pages: 1-21, ISSN: 2667-2375
Confocal Raman spectral imaging (RSI) enables high-content, label-free visualization of a wide range of molecules in biological specimens without sample preparation. However, reliable quantification of the deconvoluted spectra is needed. Here we develop an integrated bioanalytical methodology, qRamanomics, to qualify RSI as a tissue phantom calibrated tool for quantitative spatial chemotyping of major classes of biomolecules. Next, we apply qRamanomics to fixed 3D liver organoids generated from stem-cell-derived or primary hepatocytes to assess specimen variation and maturity. We then demonstrate the utility of qRamanomics for identifying biomolecular response signatures from a panel of liver-altering drugs, probing drug-induced compositional changes in 3D organoids followed by in situ monitoring of drug metabolism and accumulation. Quantitative chemometric phenotyping constitutes an important step in developing quantitative label-free interrogation of 3D biological specimens.
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, Pages: 1-14, ISSN: 0935-9648
Semiconducting polymer nanoparticles (SPNs) are explored for applications in cancer theranostics because of their high absorption coefficients, photostability, and biocompatibility. However, SPNs are susceptible to aggregation and protein fouling in physiological conditions, which can be detrimental for in vivo applications. Here, a method for achieving colloidally stable and low-fouling SPNs is described by grafting poly(ethylene glycol) (PEG) onto the backbone of the fluorescent semiconducting polymer, poly(9,9′-dioctylfluorene-5-fluoro-2,1,3-benzothiadiazole), in a simple one-step substitution reaction, postpolymerization. Further, by utilizing azide-functionalized PEG, anti-human epidermal growth factor receptor 2 (HER2) antibodies, antibody fragments, or affibodies are site-specifically “clicked” onto the SPN surface, which allows the functionalized SPNs to specifically target HER2-positive cancer cells. In vivo, the PEGylated SPNs are found to have excellent circulation efficiencies in zebrafish embryos for up to seven days postinjection. SPNs functionalized with affibodies are then shown to be able to target HER2 expressing cancer cells in a zebrafish xenograft model. The covalent PEGylated SPN system described herein shows great potential for cancer theranostics.
Solanki A, Autefage H, Rodriguez A, et al., 2023, Cobalt containing glass fibres and their synergistic effect on the HIF-1 pathway for wound healing applications, Frontiers in Bioengineering and Biotechnology, Vol: 11, Pages: 1-15, ISSN: 2296-4185
Introduction and Methods: Chronic wounds are a major healthcare problem, but their healing may be improved by developing biomaterials which can stimulate angiogenesis, e.g. by activating the Hypoxia Inducible Factor (HIF) pathway. Here, novel glass fibres were produced by laser spinning. The hypothesis was that silicate glass fibres that deliver cobalt ions will activate the HIF pathway and promote the expression of angiogenic genes. The glass composition was designed to biodegrade and release ions, but not form a hydroxyapatite layer in body fluid.Results and Discussion: Dissolution studies demonstrated that hydroxyapatite did not form. When keratinocyte cells were exposed to conditioned media from the cobalt-containing glass fibres, significantly higher amounts of HIF-1α and Vascular Endothelial Growth Factor (VEGF) were measured compared to when the cells were exposed to media with equivalent amounts of cobalt chloride. This was attributed to a synergistic effect of the combination of cobalt and other therapeutic ions released from the glass. The effect was also much greater than the sum of HIF-1α and VEGF expression when the cells were cultured with cobalt ions and with dissolution products from the Co-free glass, and was proven to not be due to a rise in pH. The ability of the glass fibres to activate the HIF-1 pathway and promote VEGF expression shows the potential for their use in chronic wound dressings.
Callens SJP, Fan D, van Hengel IAJ, et al., 2023, Emergent collective organization of bone cells in complex curvature fields, Nature Communications, Vol: 14, Pages: 1-19, ISSN: 2041-1723
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.
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, Vol: 35, Pages: 1-14, 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.
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.
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, Pages: 1-16, ISSN: 2667-2375
In this study, we report static and perfused models of human myocardial-microvascular interaction. In static culture, we observe distinct regulation of electrophysiology of human induced pluripotent stem cell derived-cardiomyocytes (hiPSC-CMs) in co-culture with human cardiac microvascular endothelial cells (hCMVECs) and human left ventricular fibroblasts (hLVFBs), including modification of beating rate, action potential, calcium handling, and pro-arrhythmic substrate. Within a heart-on-a-chip model, we subject this three-dimensional (3D) co-culture to microfluidic perfusion and vasculogenic growth factors to induce spontaneous assembly of perfusable myocardial microvasculature. Live imaging of red blood cells within myocardial microvasculature reveals pulsatile flow generated by beating hiPSC-CMs. This study therefore demonstrates a functionally vascularized in vitro model of human myocardium with widespread potential applications in basic and translational research.
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