Imperial College London

Professor Molly Stevens FREng

Faculty of EngineeringDepartment of Materials

Prof of Biomedical Materials&Regenerative Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6804m.stevens

 
 
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Location

 

208Royal School of MinesSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

353 results found

Wang S-T, Lin Y, NIelsen MH, Song CY, Thomas MT, Spicer C, Kroger R, Ercius P, Aloni S, Stevens Met al., Shape-controlled synthesis and in situ characterisation of anisotropic AU nanomaterials using liquid cell transmission electron microscopy, Nanoscale, ISSN: 2040-3364

Understanding the mechanisms behind crystal nucleation and growth is afundamental requirement for the design and production of bespoke nanomaterials withcontrolled sizes and morphologies. Herein, we select gold (Au) nanoparticles as themodel system for our study due to their representative applications in biology,electronics and optoelectronics. We investigate the radiation-induced in situ growth ofgold (Au) particles using liquid cell transmission electron microscopy (LCTEM) andstudy the growth kinetics of non-spherical Au structures. Under controlled electronfluence, liquid flow rate and Au3+ ion supply, we show the favoured diffusion-limitedgrowth of multi-twinned nascent Au seed particles into branched structures when usingthin liquid cells (100 nm and 250 nm) in LCTEM, whereas faceted structures (e.g.,spheres, rods, and prisms) formed when using a 1 µm thick liquid cell. In addition, weobserved that anisotropic Au growth could be modulated by Au-binding amyloid fibrils,which we ascribe to their capability of regulating Au3+ ion diffusion and mass transfer in solution. We anticipate that this study will provide new perspectives on the shapecontrolled synthesis of anisotropic metallic nanomaterials using LCTEM.

Journal article

Lin Y, Charchar P, Christofferson AJ, Thomas MR, Todorova N, Mazo MM, Chen Q, Doutch J, Richardson R, Yarovsky I, Stevens Met al., 2018, Surface dynamics and ligand-core interactions of quantum sized photoluminescent gold nanoclusters, Journal of the American Chemical Society, Vol: 140, Pages: 18217-18226, ISSN: 1520-5126

Quantum-sized metallic clusters protected by biological ligands represent a new class of luminescent materials; yet the understanding of structural information and photoluminescence origin of these ultrasmall clusters remains a challenge. Herein we systematically study the surface ligand dynamics and ligand–metal core interactions of peptide-protected gold nanoclusters (AuNCs) with combined experimental characterizations and theoretical molecular simulations. We show that the peptide sequence plays an important role in determining the surface peptide structuring, interfacial water dynamics and ligand–Au core interaction, which can be tailored by controlling peptide acetylation, constituent amino acid electron donating/withdrawing capacity, aromaticity/hydrophobicity and by adjusting environmental pH. Specifically, emission enhancement is achieved through increasing the electron density of surface ligands in proximity to the Au core, discouraging photoinduced quenching, and by reducing the amount of surface-bound water molecules. These findings provide key design principles for understanding the surface dynamics of peptide-protected nanoparticles and maximizing the photoluminescence of metallic clusters through the exploitation of biologically relevant ligand properties.

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Pujari-Palmer M, Guo H, Wenner D, Autefage H, Spicer CD, Stevens MM, Omar O, Thomsen P, Eden M, Insley G, Procter P, Engqvist Het al., 2018, A novel class of injectable bioceramics that glue tissues and biomaterials, Materials, Vol: 11, ISSN: 1996-1944

Calcium phosphate cements (CPCs) are clinically effective void fillers that are capable of bridging calcified tissue defects and facilitating regeneration. However, CPCs are completely synthetic/inorganic, unlike the calcium phosphate that is found in calcified tissues, and they lack an architectural organization, controlled assembly mechanisms, and have moderate biomechanical strength, which limits their clinical effectiveness. Herein, we describe a new class of bioinspired CPCs that can glue tissues together and bond tissues to metallic and polymeric biomaterials. Surprisingly, alpha tricalcium phosphate cements that are modified with simple phosphorylated amino acid monomers of phosphoserine (PM-CPCs) bond tissues up to 40-fold stronger (2.5–4 MPa) than commercial cyanoacrylates (0.1 MPa), and 100-fold stronger than surgical fibrin glue (0.04 MPa), when cured in wet-field conditions. In addition to adhesion, phosphoserine creates other novel properties in bioceramics, including a nanoscale organic/inorganic composite microstructure, and templating of nanoscale amorphous calcium phosphate nucleation. PM-CPCs are made of the biocompatible precursors calcium, phosphate, and amino acid, and these represent the first amorphous nano-ceramic composites that are stable in liquids.

Journal article

Armstrong J, Puetzer JL, Serio A, Guex AG, Kapnisi K, Breant A, Zong Y, Assal V, Skaalure S, King O, Murty T, Meinert C, Franklin AC, Bassindale PG, Nichols MK, Terracciano C, Hutmacher DW, Drinkwater BW, Klein TJ, Perriman AW, Stevens MMet al., 2018, Engineering anisotropic muscle tissue using acoustic cell patterning, Advanced Materials, Vol: 30, ISSN: 0935-9648

Tissue engineering has offered unique opportunities for disease modeling and regenerative medicine; however, the success of these strategies is dependent on faithful reproduction of native cellular organization. Here, it is reported that ultrasound standing waves can be used to organize myoblast populations in material systems for the engineering of aligned muscle tissue constructs. Patterned muscle engineered using type I collagen hydrogels exhibits significant anisotropy in tensile strength, and under mechanical constraint, produced microscale alignment on a cell and fiber level. Moreover, acoustic patterning of myoblasts in gelatin methacryloyl hydrogels significantly enhances myofibrillogenesis and promotes the formation of muscle fibers containing aligned bundles of myotubes, with a width of 120–150 µm and a spacing of 180–220 µm. The ability to remotely pattern fibers of aligned myotubes without any material cues or complex fabrication procedures represents a significant advance in the field of muscle tissue engineering. In general, these results are the first instance of engineered cell fibers formed from the differentiation of acoustically patterned cells. It is anticipated that this versatile methodology can be applied to many complex tissue morphologies, with broader relevance for spatially organized cell cultures, organoid development, and bioelectronics.

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Penders J, Pence I, Horgan C, Bergholt M, Wood C, Najer A, Kauscher U, Nagelkerke A, Stevens MMet al., 2018, Single Particle Automated Raman Trapping Analysis, Nature Communications, Vol: 9, ISSN: 2041-1723

Enabling concurrent, high throughput analysis of single nanoparticles would greatly increase the capacity to study size, composition and inter and intra particle population variance with applications in a wide range of fields from polymer science to drug delivery. Here, we present a comprehensive platform for Single Particle Automated Raman Trapping Analysis (SPARTA) able to integrally analyse nanoparticles ranging from synthetic polymer particles to liposomes without any modification. With the developed highly controlled automated trapping process, single nanoparticles are analysed with high throughput and sensitivity to resolve particle mixtures, obtain detailed compositional spectra of complex particles, track sequential functionalisations, derive particle sizes and monitor the dynamics of click reactions occurring on the nanoparticle surface. The SPARTA platform opens up a wide range of new avenues for nanoparticle research through label-free integral high-throughput single particle analysis, overcoming key limitations in sensitivity and specificity of existing bulk analysis methods.

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Gray ER, Bain R, Varsaneux O, Peeling RW, Stevens MM, Mckendry RAet al., 2018, p24 revisited: a landscape review of antigen detection for early HIV diagnosis, AIDS, Vol: 32, Pages: 2089-2102, ISSN: 0269-9370

Despite major advances in HIV testing, early detection of infection at the point of care (PoC) remains a key challenge. While rapid antibody PoC and laboratory-based nucleic acid amplification tests dominate the diagnostics market, the viral capsid protein p24 is recognized as an alternative early virological biomarker of infection. However, the detection of ultra-low levels of p24 at the PoC has proven challenging. Here we review the landscape of p24-diagnostics to identify knowledge gaps and barriers and help shape future research agendas. 574 research papers to May 2018 that propose or evaluate diagnostic assays for p24 were identified and reviewed. We give a brief history of diagnostic development, and the utility of p24 as a biomarker in different populations such as infants, the newly infected, those on pre-exposure prophylaxis and self-testers. We review the performance of commercial p24 assays and consider elements such as immune complex disruption, resource-poor settings, prevalence, and assay antibodies. Emerging and ultrasensitive assays are reviewed and show a number of promising approaches but further translation has been limited. We summarize studies on the health economic benefits of using antigen testing. Finally, we speculate on the future uses of high performance p24 assays, particularly if available in self-test format.

Journal article

Amdursky N, Mazo M, Thomas MR, Humphrey E, Puetzer J, St-Pierre J, Skaalure S, Richardson RM, Terracciano C, Stevens MMet al., 2018, Elastic serum-albumin based hydrogels: mechanism of formation and application in cardiac tissue engineering, Journal of Materials Chemistry B, Vol: 6, Pages: 5604-5612, ISSN: 2050-750X

Hydrogels are promising materials for mimicking the extra-cellular environment. Here, we present a simple methodology for the formation of a free-standing viscoelastic hydrogel from the abundant and low cost protein serum albumin. We show that the mechanical properties of the hydrogel exhibit a complicated behaviour as a function of the weight fraction of the protein component. We further use X-ray scattering to shed light on the mechanism of gelation from the formation of a fibrillary network at low weight fractions to interconnected aggregates at higher fractions. Given the match between our hydrogel elasticity and that of the myocardium, we investigated its potential for supporting cardiac cells in vitro. Interestingly, the sehydrogels support the formation of several layers of myocytes and significantly promote the maintenance of a native-likegene expression profile compared to those cultured on glass. When confronted with a multicellular ventricular cell preparation, the hydrogels can support macroscopically contracting cardiac-like tissues with a distinct cell arrangement, and form mm-long vascular-like structures. We envisage that our simple approach for the formation of an elastic substrate from an abundant protein makes the hydrogel a compelling biomedical material candidate for a wide range of cell types.

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Faria M, Björnmalm M, Thurecht KJ, Kent SJ, Parton RG, Kavallaris M, Johnston APR, Gooding JJ, Corrie SR, Boyd BJ, Thordarson P, Whittaker AK, Stevens MM, Prestidge CA, Porter CJH, Parak WJ, Davis TP, Crampin EJ, Caruso Fet al., 2018, Minimum information reporting on bio-nano experimental literature, Nature Nanotechnology, Vol: 13, Pages: 777-785, ISSN: 1748-3387

Studying the interactions between nanoengineered materials and biological systems plays a vital role in the development of biological applications of nanotechnology and the improvement of our fundamental understanding of the bio–nano interface. A significant barrier to progress in this multidisciplinary area is the variability of published literature with regards to characterizations performed and experimental details reported. Here, we suggest a ‘minimum information standard’ for experimental literature investigating bio–nano interactions. This standard consists of specific components to be reported, divided into three categories: material characterization, biological characterization and details of experimental protocols. Our intention is for these proposed standards to improve reproducibility, increase quantitative comparisons of bio–nano materials, and facilitate meta analyses and in silico modelling.

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Li C, Armstrong J, Pence I, Kit-Anan W, Puetzer J, Correia Carreira S, Stevens MMet al., 2018, Glycosylated superparamagnetic nanoparticle gradients for osteochondral tissue engineering, Biomaterials, Vol: 176, Pages: 24-33, ISSN: 0142-9612

In developmental biology, gradients of bioactive signals direct the formation of structural transitions in tissue that are key to physiological function. Failure to reproduce these native features in an in vitro setting can severely limit the success of bioengineered tissue constructs. In this report, we introduce a facile and rapid platform that uses magnetic field alignment of glycosylated superparamagnetic iron oxide nanoparticles, pre-loaded with growth factors, to pattern biochemical gradients into a range of biomaterial systems. Gradients of bone morphogenetic protein 2 in agarose hydrogels were used to spatially direct the osteogenesis of human mesenchymal stem cells and generate robust osteochondral tissue constructs exhibiting a clear mineral transition from bone to cartilage. Interestingly, the smooth gradients in growth factor concentration gave rise to biologically-relevant, emergent structural features, including a tidemark transition demarcating mineralized and non-mineralized tissue and an osteochondral interface rich in hypertrophic chondrocytes. This platform technology offers great versatility and provides an exciting new opportunity for overcoming a range of interfacial tissue engineering challenges.

Journal article

Tallia F, Russo L, Li S, Orrin A, Shi X, Chen S, Steele J, Meille S, Chevalier J, Lee P, Stevens M, Cipolla L, Jones JRet al., 2018, Bouncing and 3D printable hybrids with self-healing properties, Materials Horizons, Vol: 5, Pages: 849-860, ISSN: 2051-6355

Conventional composites often do not represent true synergy of their constituent materials. This is particularly evident in biomaterial applications where devices must interact with cells, resist cyclic loads and biodegrade safely. Here we propose a new hybrid system, with co-networks of organic and inorganic components, resulting in unprecedented mechanical properties, including “bouncy” elasticity and intrinsic ability to self-heal autonomously. They are also developed as new ‘inks’ that can be directly 3D printed. A hybrid is different from a nanocomposite because the components are indistinguishable from each other at the nanoscale and above. The properties are generated by a novel methodology that combines in situ cationic ring-opening polymerisation with sol–gel, creating silica/poly(tetrahydrofuran)/poly(ε-caprolactone) hybrids with molecular scale interactions and covalent links. Cartilage is notoriously difficult to repair and synthetic biomaterials have yet to mimic it closely. We show that 3D printed hybrid scaffolds with pore channels of ∼200 μm mimic the compressive behaviour of cartilage and provoke chondrocytes to produce markers integral to articular cartilage-like matrix. The synthesis method can be applied to different organic sources, leading to a new class of hybrid materials.

Journal article

Sigmundsson K, Ojala JRM, Öhman MK, Österholm A-M, Moreno-Moral A, Domogatskaya A, Chong LY, Sun Y, Chai X, Steele JAM, George B, Patarroyo M, Nilsson A-S, Rodin S, Ghosh S, Stevens MM, Petretto E, Tryggvason Ket al., 2018, Culturing functional pancreatic islets on α5-laminins and curative transplantation to diabetic mice, Matrix Biology, Vol: 70, Pages: 5-19, ISSN: 0945-053X

The efficacy of islet transplantation for diabetes treatment suffers from lack of cadaver-derived islets, islet necrosis and long transfer times prior to transplantation. Here, we developed a method for culturing mouse and human islets in vitro on α5-laminins, which are natural components of islet basement membranes. Adhering islets spread to form layers of 1-3 cells in thickness and remained normoxic and functional for at least 7 days in culture. In contrast, spherical islets kept in suspension developed hypoxia and central necrosis within 16 h. Transplantation of 110-150 mouse islets cultured on α5-laminin-coated polydimethylsiloxane membranes for 3-7 days normalized blood glucose already within 3 days in mice with streptozotocin-induced diabetes. RNA-sequencing of isolated and cultured mouse islets provided further evidence for the adhesion and spreading achieved with α5-laminin. Our results suggest that use of such in vitro expanded islets may significantly enhance the efficacy of islet transplantation treatment for diabetes.

Journal article

Wang Y, Howes P, Kim E, Spicer C, Thomas M, Lin Y, Crowder S, Pence I, Stevens MMet al., 2018, Duplex specific nuclease-amplified detection of microRNA using compact quantum dot-DNA conjugates, ACS Applied Materials and Interfaces, Vol: 10, Pages: 28290-28300, ISSN: 1944-8244

Advances in nanotechnology have provided new opportunities for the design of next-generation nucleic acid biosensors and diagnostics. Indeed, combining advances in functional nanoparticles, DNA nanotechnology, and nuclease-enzyme-based amplification can give rise to new assays with advantageous properties. In this work, we developed a microRNA (miRNA) assay using bright fluorescent quantum dots (QDs), simple DNA probes, and the enzyme duplex-specific nuclease. We employed an isothermal target-recycling mechanism, where a single miRNA target triggers the cleavage of many DNA signal probes. The incorporation of DNA-functionalized QDs enabled a quantitative fluorescent readout, mediated by Förster resonance energy transfer (FRET)-based interaction with the DNA signal probes. Our approach splits the reaction in two, performing the enzyme-mediated amplification and QD-based detection steps separately such that each reaction could be optimized for performance of the active components. Target recycling gave ca. 3 orders of magnitude amplification, yielding highly sensitive detection with a limit of 42 fM (or 1.2 amol) of miR-148, with excellent selectivity versus mismatched sequences and other miRNAs. Furthermore, we used an alternative target (miR-21) and FRET pair for direct and absolute quantification of miR-21 in RNA extracts from human cancer and normal cell lines.

Journal article

Holme MN, Rana S, Barriga H, Kauscher U, Brooks NJ, Stevens MMet al., 2018, A robust liposomal platform for direct colorimetric detection of sphingomyelinase enzyme and inhibitors, ACS Nano, Vol: 12, Pages: 8197-8207, ISSN: 1936-0851

The enzyme sphingomyelinase (SMase) is an important biomarker for several diseases such as Niemann Pick’s, atherosclerosis, multiple sclerosis, and HIV. We present a two-component colorimetric SMase activity assay that is more sensitive and much faster than currently available commercial assays. Herein, SMase-triggered release of cysteine from a sphingomyelin (SM)-based liposome formulation with 60 mol % cholesterol causes gold nanoparticle (AuNP) aggregation, enabling colorimetric detection of SMase activities as low as 0.02 mU/mL, corresponding to 1.4 pM concentration. While the lipid composition offers a stable, nonleaky liposome platform with minimal background signal, high specificity toward SMase avoids cross-reactivity of other similar phospholipases. Notably, use of an SM-based liposome formulation accurately mimics the natural in vivo substrate: the cell membrane. We studied the physical rearrangement process of the lipid membrane during SMase-mediated hydrolysis of SM to ceramide using small- and wide-angle X-ray scattering. A change in lipid phase from a liquid to gel state bilayer with increasing concentration of ceramide accounts for the observed increase in membrane permeability and consequent release of encapsulated cysteine. We further demonstrated the effectiveness of the sensor in colorimetric screening of small-molecule drug candidates, paving the way for the identification of novel SMase inhibitors in minutes. Taken together, the simplicity, speed, sensitivity, and naked-eye readout of this assay offer huge potential in point-of-care diagnostics and high-throughput drug screening.

Journal article

Holme MN, Rashid MH, Thomas MR, Barriga HMG, Herpoldt KL, Heenan RK, Dreiss CA, Banuelos JL, Xie HN, Yarovsky I, Stevens MMet al., 2018, Fate of liposomes in presence of phospholipase C and D: from atomic to supramolecular lipid arrangement, ACS Central Science, Vol: 4, Pages: 1023-1030, ISSN: 2374-7943

Understanding the origins of lipid membrane bilayer rearrangement in response to external stimuli is an essential component of cell biology and the bottom-up design of liposomes for biomedical applications. The enzymes phospholipase C and D (PLC and PLD) both cleave the phosphorus–oxygen bonds of phosphate esters in phosphatidylcholine (PC) lipids. The atomic position of this hydrolysis reaction has huge implications for the stability of PC-containing self-assembled structures, such as the cell wall and lipid-based vesicle drug delivery vectors. While PLC converts PC to diacylglycerol (DAG), the interaction of PC with PLD produces phosphatidic acid (PA). Here we present a combination of small-angle scattering data and all-atom molecular dynamics simulations, providing insights into the effects of atomic-scale reorganization on the supramolecular assembly of PC membrane bilayers upon enzyme-mediated incorporation of DAG or PA. We observed that PC liposomes completely disintegrate in the presence of PLC, as conversion of PC to DAG progresses. At lower concentrations, DAG molecules within fluid PC bilayers form hydrogen bonds with backbone carbonyl oxygens in neighboring PC molecules and burrow into the hydrophobic region. This leads initially to membrane thinning followed by a swelling of the lamellar phase with increased DAG. At higher DAG concentrations, localized membrane tension causes a change in lipid phase from lamellar to the hexagonal and micellar cubic phases. Molecular dynamics simulations show that this destabilization is also caused in part by the decreased ability of DAG-containing PC membranes to coordinate sodium ions. Conversely, PLD-treated PC liposomes remain stable up to extremely high conversions to PA. Here, the negatively charged PA headgroup attracts significant amounts of sodium ions from the bulk solution to the membrane surface, leading to a swelling of the coordinated water layer. These findings are a vital step toward a fundamental u

Journal article

Heeney MJ, Creamer A, Wood C, Howes P, Casey A, Cong S, Marsh A, Godin R, Panidi J, Anthopoulos T, Burgess C, Wu T, Fei Z, McLachlan M, Stevens Met al., 2018, Post-polymerisation functionalisation of conjugated polymer backbones and its application in multi-functional emissive nanoparticles, Nature Communications, Vol: 9, ISSN: 2041-1723

Backbone functionalisation of conjugated polymers is crucial to their performance in many applications, from electronic displays to nanoparticle biosensors, yet there are limited approaches to introduce functionality. To address this challenge we have developed a method for the direct modification of the aromatic backbone of a conjugated polymer, post-polymerisation. This is achieved via a quantitative nucleophilic aromatic substitution (SNAr) reaction on a range of fluorinated electron deficient comonomers. The method allows for facile tuning of the physical and optoelectronic properties within a batch of consistent molecular weight and dispersity. It also enables the introduction of multiple different functional groups onto the polymer backbone in a controlled manner. To demonstrate the versatility of this reaction, we designed and synthesised a range of emissive poly(9,9-dioctylfluorene-alt-benzothiadiazole) (F8BT) based polymers for the creation of mono and multifunctional semiconducting polymer nanoparticles (SPNs) capable of two orthogonal bioconjugation reactions on the same surface.

Journal article

Spicer C, Pashuck E, Stevens MM, 2018, Achieving controlled biomolecule-biomaterial conjugation, Chemical Reviews, Vol: 118, Pages: 7702-7743, ISSN: 1520-6890

The conjugation of biomolecules can impart materials with the bioactivity necessary to modulate specific cell behaviors. While the biological roles of particular polypeptide, oligonucleotide, and glycan structures have been extensively reviewed, along with the influence of attachment on material structure and function, the key role played by the conjugation strategy in determining activity is often overlooked. In this review, we focus on the chemistry of biomolecule conjugation and provide a comprehensive overview of the key strategies for achieving controlled biomaterial functionalization. No universal method exists to provide optimal attachment, and here we will discuss both the relative advantages and disadvantages of each technique. In doing so, we highlight the importance of carefully considering the impact and suitability of a particular technique during biomaterial design.

Journal article

Armstrong JP, Stevens MM, 2018, Strategic design of extracellular vesicle drug delivery systems, Advanced Drug Delivery Reviews, Vol: 130, Pages: 12-16, ISSN: 0169-409X

Extracellular vesicles (EVs), sub-micron vectors used in intercellular communication, have demonstrated great promise as natural drug delivery systems. Recent reports have detailed impressive in vivo results from the administration of EVs pre-loaded with therapeutic cargo, including small molecules, nanoparticles, proteins and oligonucleotides. These results have sparked intensive research interest across a huge range of disease models. There are, however, enduring limitations that have restricted widespread clinical and pharmaceutical adoption. In this perspective, we discuss these practical and biological concerns, critically compare the relative merit of EVs and synthetic drug delivery systems, and highlight the need for a more comprehensive understanding of in vivo transport and delivery. Within this framework, we seek to establish key areas in which EVs can gain a competitive advantage in order to provide the tangible added value required for widespread translation.

Journal article

Sang T, Li S, Ting HK, Stevens MM, Becer CR, Jones JRet al., 2018, Hybrids of silica/poly (caprolactone co-glycidoxypropyl trimethoxysilane) as biomaterials, Chemistry of Materials, Vol: 30, Pages: 3743-3751, ISSN: 0897-4756

Bioactive glasses stimulate bone regeneration but are brittle. Biomaterials are needed that share load with bone, promote bone regeneration and biodegrade at controlled rates. Sol-gel hybrids can achieve this through their intimate inorganic and organic co-networks, depending on the organic polymer used. Polycaprolactone degrades slowly but lacks functional groups for the critical step of covalent coupling to the silica co-network. Here, we synthesised a novel copolymer of caprolactone and glycidoxypropyl trimethoxysilane through one-pot ring opening polymerization (ROP). Hybrids with different organic content were fabricated using such a copolymer for the first time. The copolymer can directly bond to a silica network due its trimethoxysilane groups, which can hydrolyse, leaving silanol groups that undergo polycondensation with silanol groups of the silica network. Number of repeating units of caprolactone and glycidoxypropyl trimethoxysilane functional groups were controlled via ROP. The mechanical properties of the hybrids were tuned by weight percent and the number of repeating units of caprolactone independently, producing a homogeneous material with high strength (64 MPa) and strain to failure (20%) that deformed in a unique linear elastic manner until failure. MC3T3-E1 pre-osteoblast cells adhered to the hybrids. Introducing such a copolymer created a new way to fabricate covalently bonded polycaprolactone/silica hybrids for future bone repair.

Journal article

Elsharkawy S, Al-Jawad M, Pantano MF, Tejeda-Montes E, Mehta K, Jamal H, Agarwal S, Shuturminska K, Rice A, Tarakina NV, Wilson RM, Bushby AJ, Alonso M, Rodriguez-Cabello JC, Barbieri E, Del Rio Hernandez A, Stevens MM, Pugno NM, Anderson P, Mata Aet al., 2018, Protein disorder-order interplay to guide the growth of hierarchical mineralized structures, Nature Communications, Vol: 9, ISSN: 2041-1723

Journal article

Kapnisi M, Mansfield C, Marijon C, Guex AG, Perbellini F, Bardi I, Humphrey EJ, Puetzer J, Mawad D, Koutsogeorgis DC, Stuckey DJ, Terracciano CM, Harding SE, Stevens MMet al., 2018, Auxetic cardiac patches with tunable mechanical and conductive properties toward treating myocardial infarction, Advanced Functional Materials, Vol: 28, ISSN: 1616-301X

An auxetic conductive cardiac patch (AuxCP) for the treatment of myocardial infarction (MI) is introduced. The auxetic design gives the patch a negative Poisson's ratio, providing it with the ability to conform to the demanding mechanics of the heart. The conductivity allows the patch to interface with electroresponsive tissues such as the heart. Excimer laser microablation is used to micropattern a re‐entrant honeycomb (bow‐tie) design into a chitosan‐polyaniline composite. It is shown that the bow‐tie design can produce patches with a wide range in mechanical strength and anisotropy, which can be tuned to match native heart tissue. Further, the auxetic patches are conductive and cytocompatible with murine neonatal cardiomyocytes in vitro. Ex vivo studies demonstrate that the auxetic patches have no detrimental effect on the electrophysiology of both healthy and MI rat hearts and conform better to native heart movements than unpatterned patches of the same material. Finally, the AuxCP applied in a rat MI model results in no detrimental effect on cardiac function and negligible fibrotic response after two weeks in vivo. This approach represents a versatile and robust platform for cardiac biomaterial design and could therefore lead to a promising treatment for MI.

Journal article

Reznikov N, Matthew B, Leonardo L, Stevens MM, Kroger Ret al., 2018, Fractal-like hierarchical organization of bone begins at the nanoscale, Science, Vol: 360, ISSN: 0036-8075

INTRODUCTIONThe components of bone assemble hierarchically to provide stiffness and toughness. Deciphering the specific organization and relationship between bone’s principal components—mineral and collagen—requires answers to three main questions: whether the association of the mineral phase with collagen follows an intrafibrillar or extrafibrillar pattern, whether the morphology of the mineral building blocks is needle- or platelet-shaped, and how the mineral phase maintains continuity across an extensive network of cross-linked collagen fibrils. To address these questions, a nanoscale level of three-dimensional (3D) structural characterization is essential and has now been performed.RATIONALEBecause bone has multiple levels of 3D structural hierarchy, 2D imaging methods that do not detail the structural context of a sample are prone to interpretation bias. Site-specific focused ion beam preparation of lamellar bone with known orientation of the analyzed sample regions allowed us to obtain imaging data by 2D high-resolution transmission electron microscopy (HRTEM) and to identify individual crystal orientations. We studied higher-level bone mineral organization within the extracellular matrix by means of scanning TEM (STEM) tomography imaging and 3D reconstruction, as well as electron diffraction to determine crystal morphology and orientation patterns. Tomographic data allowed 3D visualization of the mineral phase as individual crystallites and/or aggregates that were correlated with atomic-resolution TEM images and corresponding diffraction patterns. Integration of STEM tomography with HRTEM and crystallographic data resulted in a model of 3D mineral morphology and its association with the organic matrix.RESULTSTo visualize and characterize the crystallites within the extracellular matrix, we recorded imaging data of the bone mineral in two orthogonal projections with respect to the arrays of mineralized collagen fibrils. Three motifs of minera

Journal article

Keane TJ, Horejs C, Stevens MM, 2018, Scarring vs. functional repair: matrix-based strategies to regulate tissue healing, Advanced Drug Delivery Reviews, Vol: 129, Pages: 407-419, ISSN: 0169-409X

All vertebrates possess mechanisms to restore damaged tissues with outcomes ranging from regeneration to scarring. Unfortunately, the mammalian response to tissue injury most often culminates in scar formation. Accounting for nearly 45% of deaths in the developed world, fibrosis is a process that stands diametrically opposed to functional tissue regeneration. Strategies to improve wound healing outcomes therefore require methods to limit fibrosis. Wound healing is guided by precise spatiotemporal deposition and remodelling of the extracellular matrix (ECM). The ECM, comprising the non-cellular component of tissues, is a signalling depot that is differentially regulated in scarring and regenerative healing. This Review focuses on the importance of the native matrix components during mammalian wound healing alongside a comparison to scar-free healing and then presents an overview of matrix-based strategies that attempt to exploit the role of the ECM to improve wound healing outcomes.

Journal article

Winther AK, Fejerskov B, ter Meer M, Jensen NBS, Dillion R, Schaffer JE, Chandrawati R, Schultze Kool LJ, Stevens MM, Simonsen U, Zelikin ANet al., 2018, Enzyme prodrug therapy achieves site-specific, personalized physiological responses to the locally produced nitric oxide, ACS Applied Materials and Interfaces, Vol: 10, Pages: 10741-10751, ISSN: 1944-8244

Nitric oxide (NO) is a highly potent but short-lived endogenous radical with a wide spectrum of physiological activities. In this work, we developed an enzymatic approach to the site-specific synthesis of NO mediated by biocatalytic surface coatings. Multilayered polyelectrolyte films were optimized as host compartments for the immobilized β-galactosidase (β-Gal) enzyme through a screen of eight polycations and eight polyanions. The lead composition was used to achieve localized production of NO through the addition of β-Gal–NONOate, a prodrug that releases NO following enzymatic bioconversion. The resulting coatings afforded physiologically relevant flux of NO matching that of the healthy human endothelium. The antiproliferative effect due to the synthesized NO in cell culture was site-specific: within a multiwell dish with freely shared media and nutrients, a 10-fold inhibition of cell growth was achieved on top of the biocatalytic coatings compared to the immediately adjacent enzyme-free microwells. The physiological effect of NO produced via the enzyme prodrug therapy was validated ex vivo in isolated arteries through the measurement of vasodilation. Biocatalytic coatings were deposited on wires produced using alloys used in clinical practice and successfully mediated a NONOate concentration-dependent vasodilation in the small arteries of rats. The results of this study present an exciting opportunity to manufacture implantable biomaterials with physiological responses controlled to the desired level for personalized treatment.

Journal article

Spicer C, Jumeaux C, Gupta B, Stevens MMet al., 2018, Peptide and protein nanoparticle conjugates: versatile platforms for biomedical applications, Chemical Society Reviews, Vol: 47, Pages: 3574-3620, ISSN: 1460-4744

Peptide– and protein–nanoparticle conjugates have emerged as powerful tools for biomedical applications, enabling the treatment, diagnosis, and prevention of disease. In this review, we focus on the key roles played by peptides and proteins in improving, controlling, and defining the performance of nanotechnologies. Within this framework, we provide a comprehensive overview of the key sequences and structures utilised to provide biological and physical stability to nano-constructs, direct particles to their target and influence their cellular and tissue distribution, induce and control biological responses, and form polypeptide self-assembled nanoparticles. In doing so, we highlight the great advances made by the field, as well as the challenges still faced in achieving the clinical translation of peptide- and protein-functionalised nano-drug delivery vehicles, imaging species, and active therapeutics.

Journal article

Fuhrmann G, Chandrawati R, Parmar P, Keane TJ, Maynard SA, Bertazzo S, Stevens MMet al., 2018, Engineering extracellular vesicles with the tools of enzyme prodrug therapy, Advanced Materials, Vol: 30, ISSN: 0935-9648

Extracellular vesicles (EVs) have been exploited as drug delivery vehicles but their therapeutic use may be limited due to off-target effects. To harness EVs’inherent properties and to couple them with site-specific drug delivery functions, EVs are incorporated into hydrogels and engineered with the tools of enzyme-prodrug therapy. Local sustained release of anti-inflammatory drugs is demonstrated in macrophage cell models.

Journal article

von Erlach T, Bertazzo S, Wozniak MA, Horejs C, Maynard SA, Attwood S, Robinson BK, Autefage H, Kallepitis C, Del Rio Hernandez A, Chen CS, Goldoni S, Stevens MMet al., 2018, Cell geometry dependent changes in plasma membrane order direct stem cell signalling and fate, Nature Materials, Vol: 17, Pages: 237-242, ISSN: 1476-1122

Cell size and shape affect cellular processes such as cell survival, growth and differentiation1,2,3,4, thus establishing cell geometry as a fundamental regulator of cell physiology. The contributions of the cytoskeleton, specifically actomyosin tension, to these effects have been described, but the exact biophysical mechanisms that translate changes in cell geometry to changes in cell behaviour remain mostly unresolved. Using a variety of innovative materials techniques, we demonstrate that the nanostructure and lipid assembly within the cell plasma membrane are regulated by cell geometry in a ligand-independent manner. These biophysical changes trigger signalling events involving the serine/threonine kinase Akt/protein kinase B (PKB) that direct cell-geometry-dependent mesenchymal stem cell differentiation. Our study defines a central regulatory role by plasma membrane ordered lipid raft microdomains in modulating stem cell differentiation with potential translational applications.

Journal article

Albro M, Bergholt M, St-Pierre JP, Vinals Guitart A, Zlotnick HM, Evita EG, Stevens MMet al., 2018, Raman Spectroscopic Imaging for Quantification of Depth-Dependent and Local Heterogeneities in Native and Engineered Cartilage, npj Regenerative Medicine, Vol: 3, ISSN: 2057-3995

Articular cartilage possesses a remarkable, mechanically-robust extracellular matrix (ECM) that is organized and distributed throughout the tissue to resist physiologic strains and provide low friction during articulation. The ability to characterize the make-up and distribution of the cartilage ECM is critical to both understand the process by which articular cartilage undergoes disease-related degeneration and to develop novel tissue repair strategies to restore tissue functionality. However, the ability to quantitatively measure the spatial distribution of cartilage ECM constituents throughout the tissue has remained a major challenge. In this experimental investigation, we assessed the analytical ability of Raman micro-spectroscopic imaging to semi-quantitatively measure the distribution of the major ECM constituents in cartilage tissues. Raman spectroscopic images were acquired of two distinct cartilage tissue types that possess large spatial ECM gradients throughout their depth: native articular cartilage explants and large engineered cartilage tissue constructs. Spectral acquisitions were processed via multivariate curve resolution to decompose the “fingerprint” range spectra (800–1800 cm−1) to the component spectra of GAG, collagen, and water, giving rise to the depth dependent concentration profile of each constituent throughout the tissues. These Raman spectroscopic acquired-profiles exhibited strong agreement with profiles independently acquired via direct biochemical assaying of spatial tissue sections. Further, we harness this spectroscopic technique to evaluate local heterogeneities through the depth of cartilage. This work represents a powerful analytical validation of the accuracy of Raman spectroscopic imaging measurements of the spatial distribution of biochemical components in a biological tissue and shows that it can be used as a valuable tool for quantitatively measuring the distribution and organization of ECM con

Journal article

Hsu C-C, Serio A, Amdursky N, Besnard C, Stevens MMet al., 2018, Fabrication of Hemin-Doped Serum Albumin-Based Fibrous Scaffolds for Neural Tissue Engineering Applications, ACS Applied Materials and Interfaces, Vol: 10, Pages: 5305-5317, ISSN: 1944-8244

Neural tissue engineering (TE) represents a promising new avenue of therapy to support nerve recovery and regeneration. To recreate the complex environment in which neurons develop and mature, the ideal biomaterials for neural TE require a number of properties and capabilities including the appropriate biochemical and physical cues to adsorb and release specific growth factors. Here, we present neural TE constructs based on electrospun serum albumin (SA) fibrous scaffolds. We doped our SA scaffolds with an iron-containing porphyrin, hemin, to confer conductivity, and then functionalized them with different recombinant proteins and growth factors to ensure cell attachment and proliferation. We demonstrated the potential for these constructs combining topographical, biochemical, and electrical stimuli by testing them with clinically relevant neural populations derived from human induced pluripotent stem cells (hiPSCs). Our scaffolds could support the attachment, proliferation, and neuronal differentiation of hiPSC-derived neural stem cells (NSCs), and were also able to incorporate active growth factors and release them over time, which modified the behavior of cultured cells and substituted the need for growth factor supplementation by media change. Electrical stimulation on the doped SA scaffold positively influenced the maturation of neuronal populations, with neurons exhibiting more branched neurites compared to controls. Through promotion of cell proliferation, differentiation, and neurite branching of hiPSC-derived NSCs, these conductive SA fibrous scaffolds are of broad application in nerve regeneration strategies.

Journal article

Jumeaux C, Wahlsten O, Block S, Kim E, Chandrawati R, Howes PD, Hook P, Stevens MMet al., 2018, MicroRNA detection by DNA-mediated liposome fusion, ChemBioChem, Vol: 19, Pages: 434-438, ISSN: 1439-4227

Membrane fusion is a process of fundamental importance in biological systems that involves highly selective recognition mechanisms for the trafficking of molecular and ionic cargos. Mimicking natural membrane fusion mechanisms for the purpose of biosensor development holds great potential for amplified detection because relatively few highly discriminating targets lead to fusion and an accompanied engagement of a large payload of signal-generating molecules. In this work, sequence-specific DNA-mediated liposome fusion is used for the highly selective detection of microRNA. The detection of miR-29a, a known flu biomarker, is demonstrated down to 18 nm within 30 min with high specificity by using a standard laboratory microplate reader. Furthermore, one order of magnitude improvement in the limit of detection is demonstrated by using a novel imaging technique combined with an intensity fluctuation analysis, which is coined two-color fluorescence correlation microscopy.

Journal article

Rizzo R, Alvaro M, Danz N, Napione L, Descrovi E, Schmieder S, Sinibaldi A, Rana S, Chandrawati R, Munzert P, Schubert T, Maillart E, Anopchenko A, Rivolo P, Mascioletti A, Förster E, Sonntag F, Stevens MM, Bussolino F, Michelotti Fet al., 2018, Bloch surface wave enhanced biosensor for the direct detection of angiopoietin-2 tumor biomarker in human plasma, Biomedical Optics Express, Vol: 9, Pages: 529-542, ISSN: 2156-7085

Quantitative detection of angiogenic biomarkers provides a powerful tool to diagnose cancers in early stages and to follow its progression during therapy. Conventional tests require trained personnel, dedicated laboratory equipment and are generally time-consuming. Herein, we propose our developed biosensing platform as a useful tool for a rapid determination of Angiopoietin-2 biomarker directly from patient plasma within 30 minutes, without any sample preparation or dilution. Bloch surface waves supported by one dimensional photonic crystal are exploited to enhance and redirect the fluorescence arising from a sandwich immunoassay that involves Angiopoietin-2. The sensing units consist of disposable and low-cost plastic biochips coated with the photonic crystal. The biosensing platform is demonstrated to detect Angiopoietin-2 in plasma samples at the clinically relevant concentration of 6 ng/mL, with an estimated limit of detection of approximately 1 ng/mL. This is the first Bloch surface wave based assay capable of detecting relevant concentrations of an angiogenic factor in plasma samples. The results obtained by the developed biosensing platform are in close agreement with enzyme-linked immunosorbent assays, demonstrating a good accuracy, and their repeatability showed acceptable relative variations.

Journal article

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