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

Stevens MM, Parmar P, St-Pierre J, Chow L, Puetzer J, Stoichevska V, Peng Y, Werkmeister J, Ramshaw Jet al., 2016, Harnessing the versatility of bacterial collagen to improve the chondrogenic potential of porous collagen scaffolds, Advanced Healthcare Materials, Vol: 5, Pages: 1656-1666, ISSN: 2192-2640

Collagen type I foams have been used extensively in the clinic as scaffolds to promote articular cartilage repair by providing a bioactive environment for cells with chondrogenic potential. However, collagen type I as a base material does not allow for precise control over the bioactive regions interfaced with cells. On the other hand, recombinant bacterial collagens can be used as ‘blank slate’ collagen molecules to offer a versatile platform for controllable incorporation of selected bioactive sequences and fabricated into three–dimensional scaffolds. Here, we demonstrate the potential of Streptococcal collagen–like 2 (Scl2) protein foams modified with peptide sequences designed to specifically and non–covalently bind hyaluronic acid and chondroitin sulfate to significantly improve chondrogenesis of human mesenchymal stem cells (hMSCs), when compared to collagen type I foams. Specific compositions of the functionalized Scl2 proteins led to improved chondrogenesis compared to both non–functionalized Scl2 and collagen type I foams as indicated by differences in gene expression, extracellular matrix accumulation, and compression moduli. Furthermore, hMSCs cultured in functionalized Scl2 foams exhibited decreased collagen types I and X gene and protein expression, suggesting a major advantage over collagen type I foams in promoting an articular chondrocyte phenotype. These highly modular foams can be further modified to improve specific aspects of the chondrogenic response through careful selection of additional biological moieties. As such, these scaffolds also have the potential to be tailored for other regenerative medicine applications.

Journal article

Stevens MM, Gliddon H, Howes P, Kaforou M, Levin Met al., 2016, A nucleic acid strand displacement system for the multiplexed detection of tuberculosis-specific mRNA using quantum dots, Nanoscale, Vol: 8, Pages: 10087-10095, ISSN: 2040-3372

The development of rapid, robust and high performance point-of-care diagnostics relies on the advancement and combination of various areas of research. We have developed an assay for the detection of multiple mRNA molecules that combines DNA nanotechnology with fluorescent nanomaterials. The core switching mechanism is toehold-mediated strand displacement. We have used fluorescent quantum dots (QDs) as signal transducers in this assay, as they bring many benefits including bright fluorescence and multiplexing abilities. The resulting assay is capable of multiplexed detection of long RNA targets against a high concentration background of non-target RNAs, with high sensitivity and specificity and limits of detection in the nanomolar range using only a standard laboratory plate reader. We demonstrate the utility of our QD-based system for the detection of two genes selected from a microarray-derived tuberculosis-specific gene expression signature. Levels of up- and downregulated gene transcripts comprising this signature can be combined to give a disease risk score, making the signature more amenable for use as a diagnostic marker. Our QD-based approach to detect these transcripts could pave the way for novel diagnostic assays for tuberculosis.

Journal article

Paresh P, Skaalure S, Chow L, St-Pierre JP, Stoichevska V, Peng YY, Werkmeister JAM, Stevens MMet al., 2016, Temporally degradable collagen–mimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells, Biomaterials, Vol: 99, Pages: 56-71, ISSN: 1878-5905

Tissue engineering strategies for repairing and regenerating articular cartilage face critical challenges to recapitulate the dynamic and complex biochemical microenvironment of native tissues. One approach to mimic the biochemical complexity of articular cartilage is through the use of recombinant bacterial collagens as they provide a well–defined biological ‘blank template’ that can be modified to incorporate bioactive and biodegradable peptide sequences within a precisely defined three–dimensional system. We customized the backbone of a Streptococcal collagen–like 2 (Scl2) protein with heparin–binding, integrin–binding, and hyaluronic acid–binding peptide sequences previously shown to modulate chondrogenesis and then cross–linked the recombinant Scl2 protein with a combination of matrix metalloproteinase 7 (MMP7)– and aggrecanase (ADAMTS4)–cleavable peptides at varying ratios to form biodegradable hydrogels with degradation characteristics matching the temporal expression pattern of these enzymes in human mesenchymal stem cells (hMSCs) during chondrogenesis. hMSCs encapsulated within the hydrogels cross–linked with both degradable peptides exhibited enhanced chondrogenic characteristics as demonstrated by gene expression and extracellular matrix deposition compared to the hydrogels cross–linked with a single peptide. Additionally, these combined peptide hydrogels displayed increased MMP7 and ADAMTS4 activities and yet increased compression moduli after 6 weeks, suggesting a positive correlation between the degradation of the hydrogels and the accumulation of matrix by hMSCs undergoing chondrogenesis. Our results suggest that including dual degradation motifs designed to respond to enzymatic activity of hMSCs going through chondrogenic differentiation led to improvements in chondrogenesis. Our hydrogel system demonstrates a bimodal enzymatically degradable biological platform that can mi

Journal article

He M, Callanan A, Lagaras K, Steele JA, Stevens MMet al., 2016, Optimization of SDS exposure on preservation of ECM characteristics in whole organ decellularization of rat kidneys., Journal of Biomedical Materials Research Part B: Applied Biomaterials, Vol: 105, Pages: 1352-1360, ISSN: 1552-4973

Renal transplantation is well established as the optimal form of renal replacement therapy but is restricted by the limited pool of organs available for transplantation. The whole organ decellularisation approach is leading the way for a regenerative medicine solution towards bioengineered organ replacements. However, systematic preoptimization of both decellularization and recellularization parameters is essential prior to any potential clinical application and should be the next stage in the evolution of whole organ decellularization as a potential strategy for bioengineered organ replacements. Here we have systematically assessed two fundamental parameters (concentration and duration of perfusion) with regards to the effects of differing exposure to the most commonly used single decellularizing agent (sodium dodecyl sulphate/SDS) in the perfusion decellularization process for whole rat kidney ECM bioscaffolds, with findings showing improved preservation of both structural and functional components of the whole kidney ECM bioscaffold. Whole kidney bioscaffolds based on our enhanced protocol were successfully recellularized with rat primary renal cells and mesenchymal stromal cells. These findings should be widely applicable to decellularized whole organ bioscaffolds and their optimization in the development of regenerated organ replacements for transplantation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2016.

Journal article

Fiocco L, Li S, Bernardo E, Stevens MM, Jones JRet al., 2016, Highly porous polymer-derived wollastonite–hydroxycarbonate apatite ceramics for bone regeneration, Biomedical Materials, Vol: 11, ISSN: 1748-605X

Journal article

Chapman R, Gormley AJ, Stenzel MH, Stevens MMet al., 2016, Combinatorial low-volume synthesis of well-defined polymers by enzyme degassing, Angewandte Chemie-International Edition, Vol: 55, Pages: 4500-4503, ISSN: 1521-3773

The synthesis of well-defined polymers in a low-volume, combinatorial fashion has long been a goal in polymer chemistry. Here, we report the preparation of a wide range of highly controlled homo and block co-polymers by Enz-RAFT (enzyme-assisted reversible addition–fragmentation chain transfer) polymerization in microtiter plates in the open atmosphere. The addition of 1 μm glucose oxidase (GOx) to water/solvent mixtures enables polymerization reactions to proceed in extremely low volumes (40 μL) and low radical concentrations. This procedure provides excellent control and high conversions across a range of monomer families and molecular weights, thus avoiding the need to purify for screening applications. This simple technique enables combinatorial polymer synthesis in microtiter plates on the benchtop without the need of highly specialized synthesizers and at much lower volumes than is currently possible by any other technique.

Journal article

Amit I, Baker D, Barker R, Berger B, Bertozzi C, Bhatia S, Biffi A, Demichelis F, Doudna J, Dowdy SF, Endy D, Helmstaedter M, Junca H, June C, Kamb S, Khvorova A, Kim D-H, Kim J-S, Krishnan Y, Lakadamyali M, Lappalainen T, Lewin S, Liao J, Loman N, Lundberg E, Lynd L, Martin C, Mellman I, Miyawaki A, Mummery C, Nelson K, Paz J, Peralta-Yahya P, Picotti P, Polyak K, Prather K, Qin J, Quake S, Regev A, Rogers JA, Shetty R, Sommer M, Stevens M, Stolovitzky G, Takahashi M, Tang F, Teichmann S, Torres-Padilla M-E, Tripathi L, Vemula P, Verdine G, Vollmer F, Wang J, Ying JY, Zhang F, Zhang Tet al., 2016, Voices of biotech, Publisher: NATURE PUBLISHING GROUP

Other

Liu NJ, Chapman R, Lin Y, Mmesi J, Bentham A, Tyreman M, Abraham S, Stevens MMet al., 2016, Point of care testing of phospholipase A2 group IIA for serological diagnosis of rheumatoid arthritis., Nanoscale, Vol: 8, Pages: 4482-4485, ISSN: 2040-3372

Secretory phospholipase A2 group IIA (sPLA2-IIA) was examined as a point of care marker for determining disease activity in rheumatoid (RA) and psoriatic (PsA) arthritis. Serum concentration and activity of sPLA2-IIA were measured using in-house antibodies and a novel point of care lateral flow device assay in patients diagnosed with varying severities of RA (n = 30) and PsA (n = 25) and found to correlate strongly with C-reactive protein (CRP). Levels of all markers were elevated in patients with active RA over those with inactive RA as well as both active and inactive PsA, indicating that sPLA2-IIA can be used as an analogue to CRP for RA diagnosis at point of care.

Journal article

Stevens MM, Amdursky N, Wang X, Meredith P, Bradley DDCet al., 2016, Long-Range Proton Conduction Across Free-Standing Serum Albumin, Advanced Materials, Vol: 28, Pages: 2692-2698, ISSN: 1521-4095

Free-standing serum-albumin mats can transport protons over millimetre length-scales. The results of photoinduced proton transfer and voltage-driven proton conductivity measurements, together with temperature dependent and isotope effect studies, suggest that oxo-amino-acids of the protein serum albumin play a major role in the translocation of protons via an “over-the-barrier” hopping mechanism. The use of proton-conducting protein mats opens new possibilities for bioelectronic interfaces.

Journal article

Hedegaard MAB, Bergholt MS, Stevens MM, 2016, Quantitative multi-image analysis for biomedical Raman spectroscopic imaging, Journal of Biophotonics, Vol: 9, Pages: 542-550, ISSN: 1864-0648

Imaging by Raman spectroscopy enables unparalleled label-free insights into cell and tissue composition at the molecular level. With established approaches limited to single image analysis, there are currently no general guidelines or consensus on how to quantify biochemical components across multiple Raman images. Here, we describe a broadly applicable methodology for the combination of multiple Raman images into a single image for analysis. This is achieved by removing image specific background interference, unfolding the series of Raman images into a single dataset, and normalisation of each Raman spectrum to render comparable Raman images. Multivariate image analysis is finally applied to derive the contributing ‘pure’ biochemical spectra for relative quantification. We present our methodology using four independently measured Raman images of control cells and four images of cells treated with strontium ions from substituted bioactive glass. We show that the relative biochemical distribution per area of the cells can be quantified. In addition, using k-means clustering, we are able to discriminate between the two cell types over multiple Raman images. This study shows a streamlined quantitative multi-image analysis tool for improving cell/tissue characterisation and opens new avenues in biomedical Raman spectroscopic imaging.

Journal article

Poh PSP, Hutmacher DW, Holzapfel BM, Solanki AK, Stevens MM, Woodruff MAet al., 2016, In vitro and in vivo bone formation potential of surface calcium phosphate-coated polycaprolactone and polycaprolactone/bioactive glass composite scaffolds, ACTA BIOMATERIALIA, Vol: 30, Pages: 319-333, ISSN: 1742-7061

Journal article

Crowder SW, Leonardo V, Whitaker T, Papathanasiou P, Stevens MMet al., 2016, Material Cues as Potent Regulators of Epigenetics and Stem Cell Function, Cell Stem Cell, Vol: 18, Pages: 39-52, ISSN: 1934-5909

Biophysical signals act as potent regulators of stem cell function, lineage commitment, and epigenetic status. In recent years, synthetic biomaterials have been used to study a wide range of outside-in signaling events, and it is now well appreciated that material cues modulate the epigenome. Here, we review the role of extracellular signals in guiding stem cell behavior via epigenetic regulation, and we stress the role of physicochemical material properties as an often-overlooked modulator of intracellular signaling. We also highlight promising new research tools for ongoing interrogation of the stem cell-material interface.

Journal article

Striolo A, Sicard F, Liz-Marzan L, Murphy C, Roig A, Mueller A, Reguera J, Zhou Y, Brust M, Scarabelli L, Tadiello L, Thill A, Yarovsky I, Mayer M, Lopez-Quintela MA, Kuttner C, Solveyra EG, Wolf H, Kay E, Pasquato L, Buceta D, Portehault D, Mattoussi H, Gonzalez G, Faller R, French D, Abecassis B, Stevens M, Xia Y, Jones R, Grzelczak M, Penna M, Drummond Cet al., 2016, Applications: general discussion, Publisher: ROYAL SOC CHEMISTRY

Other

Chan WWC, Glotzer S, Gogotsi Y, Hafner JH, Hammond PT, Hersam MC, Javey A, Kagan CR, Khademhosseini A, Kotov NA, Lee ST, Möhwald H, Mulvaney PA, Nel AE, Nordlander PJ, Parak WJ, Penner RM, Rogach AL, Schaak RE, Stevens MM, Wee ATS, Willson CG, Tierney HL, Weiss PSet al., 2015, Grand Plans for Nano

Other

Gothard D, Smith EL, Kanczler JM, Black CR, Wells JA, Roberts CA, White LJ, Qutachi O, Peto H, Rashidi H, Rojo L, Stevens MM, El Haj AJ, Rose FRAJ, Shakesheff KM, Oreffo ROCet al., 2015, In Vivo Assessment of Bone Regeneration in Alginate/Bone ECM Hydrogels with Incorporated Skeletal Stem Cells and Single Growth Factors, PLOS One, Vol: 10, ISSN: 1932-6203

The current study has investigated the use of decellularised, demineralised bone extracellularmatrix (ECM) hydrogel constructs for in vivo tissue mineralisation and bone formation.Stro-1-enriched human bone marrow stromal cells were incorporated together with selectgrowth factors including VEGF, TGF-β3, BMP-2, PTHrP and VitD3, to augment bone formation,and mixed with alginate for structural support. Growth factors were delivered throughfast (non-osteogenic factors) and slow (osteogenic factors) release PLGA microparticles.Constructs of 5 mm length were implanted in vivo for 28 days within mice. Dense tissueassessed by micro-CT correlated with histologically assessed mineralised bone formationin all constructs. Exogenous growth factor addition did not enhance bone formation furthercompared to alginate/bone ECM (ALG/ECM) hydrogels alone. UV irradiation reduced boneformation through degradation of intrinsic growth factors within the bone ECM componentand possibly also ECM cross-linking. BMP-2 and VitD3 rescued osteogenic induction. ALG/ECM hydrogels appeared highly osteoinductive and delivery of angiogenic or chondrogenicgrowth factors led to altered bone formation. All constructs demonstrated extensive host tissueinvasion and vascularisation aiding integration and implant longevity. The proposedhydrogel system functioned without the need for growth factor incorporation or an exogenousinducible cell source. Optimal growth factor concentrations and spatiotemporal release profiles require further assessment, as the bone ECM component may suffer batchvariability between donor materials. In summary, ALG/ECM hydrogels provide a versatilebiomaterial scaffold for utilisation within regenerative medicine which may be tailored, ultimately,to form the tissue of choice through incorporation of select growth factors.

Journal article

Bell RV, Parkins CC, Young RA, Preuss CM, Stevens MM, Bon SAFet al., 2015, Assembly of emulsion droplets into fibers by microfluidic wet spinning, Journal of Materials Chemistry A, Vol: 4, Pages: 813-818, ISSN: 2050-7496

We show that emulsion droplets stabilized by branched copolymers and Laponite clay discs can be assembled into supracolloidal fibers with control of the fiber composition and length. Upon drying they transform into a light-weight highly porous nanocomposite material. We demonstrate that the fibers made from emulsion droplets can be used to release volatile compounds in a time-controlled manner.

Journal article

Blaeser A, Campos DFD, Puster U, Richtering W, Stevens MM, Fischer Het al., 2015, Controlling shear stress in 3D bioprinting is a key factor to balance printing resolution and stem cell integrity, Advanced Healthcare Materials, Vol: 5, Pages: 326-333, ISSN: 2192-2640

A microvalve‐based bioprinting system for the manufacturing of high‐resolution, multimaterial 3D‐structures is reported. Applying a straightforward fluid‐dynamics model, the shear stress at the nozzle site can precisely be controlled. Using this system, a broad study on how cell viability and proliferation potential are affected by different levels of shear stress is conducted. Complex, multimaterial 3D structures are printed with high resolution. This work pioneers the investigation of shear stress‐induced cell damage in 3D bioprinting and might help to comprehend and improve the outcome of cell‐printing studies in the future.

Journal article

Maçon AL, Page SJ, Chung JJ, Amdursky N, Stevens MM, Weaver JV, Hanna JV, Jones JRet al., 2015, A structural and physical study of sol-gel methacrylate-silica hybrids: intermolecular spacing dictates the mechanical properties, Physical Chemistry Chemical Physics, Vol: 17, Pages: 29124-29133, ISSN: 1463-9084

Sol-gel hybrids are inorganic/organic co-networks with nanoscale interactions between the components leading to unique synergistic mechanical properties, which can be tailored, via a selection of the organic moiety. Methacrylate based polymers present several benefits for class II hybrids (which exhibit formal covalent bonding between the networks) as they introduce great versatility and can be designed with a variety of chemical side-groups, structures and morphologies. In this study, the effect of high cross-linking density polymers on the structure-property relationships of hybrids generated using poly(3-trimethoxysilylpropyl methacrylate) (pTMSPMA) and tetraethyl orthosilicate (TEOS) was investigated. The complexity and fine scale of the co-network interactions requires the development of new analytical methods to understand how network evolution dictates the wide-ranging mechanical properties. Within this work we developed data manipulation techniques of acoustic-AFM and solid state NMR output that provide new approaches to understand the influence of the network structure on the macroscopic elasticity. The concentration of pTMSPMA in the silica sol affected the gelation time, ranging from 2 h for a hybrid made with 75 wt% inorganic with pTMSPMA at 2.5 kDa, to 1 minute for pTMSPMA with molecular weight of 30 kDa without any TEOS. A new mechanism of gelation was proposed based on the different morphologies derived by AC-AFM observations. We established that the volumetric density of bridging oxygen bonds is an important parameter in structure/property relationships in SiO2 hybrids and developed a method for determining it from solid state NMR data. The variation in the elasticity of pTMSPMA/SiO2 hybrids originated from pTMSPMA acting as a molecular spacer, thus decreasing the volumetric density of bridging oxygen bonds as the inorganic to organic ratio decreased.

Journal article

Almeida CS, Herrmann IK, Howes PD, Stevens MMet al., 2015, Tailoring Cellular Uptake of Conjugated Polymer Nanoparticles Using Modular Amphiphilic Peptide Capping Ligands, Chemistry of Materials, Vol: 27, Pages: 6879-6889, ISSN: 1520-5002

Conjugated polymers possess excellent qualities as fluorescent probes for biomedical applications, because of their extremely high brightness, extinction coefficients, and photostability. Encapsulating these hydrophobic polymers in nanoparticulate form allows transfer to aqueous environments and construction of high-performance fluorescent nanoparticle constructs, and several surface capping strategies have been demonstrated to date. Here, we describe the development of a new class of multifunctional capping ligands for conjugated polymer nanoparticles based on custom-designed amphiphilic peptides. These versatile peptide ligands provide a protective hydrophilic capping layer, chemical handles for further conjugation, and directed biological activity tuned by altering the specific amino acid sequence. We show that (i) cellular uptake can be regulated as a function of peptide composition, and (ii) the nanoparticles show no signs of toxicity under the conditions used, which is a vital health and environmental issue when developing these technologies for clinical use. Finally, we demonstrate that this one-pot method can be applied can be applied to three classes of conjugated polymers and demonstrate potential for multicolor imaging.

Journal article

Herpoldt K-L, Artzy-Schnirman A, Yarovsky I, Christofferson AJ, Makarucha AJ, de la Rica R, Stevens MMet al., 2015, Designing fluorescent peptide sensors with dual specificity for the detection of HIV-1 protease, Chemistry of Materials, Vol: 27, Pages: 7187-7195, ISSN: 1520-5002

HIV-1 protease is a key enzyme in the life cycle of HIV/AIDS, as it is responsible for the formation of the mature virus particle. We demonstrate here that phage-display peptides raised against this enzyme can be used as peptide sensors for the detection of HIV-1 protease in a simple, one-pot assay. The presence of the enzyme is detected through an energy transfer between two peptide sensors when simultaneously complexed with the target protein. The multivalent nature of this assay increases the specificity of the detection by requiring all molecules to be interacting in order for there to be a FRET signal. We also perform molecular dynamics simulations to explore the interaction between the protease and the peptides in order to guide the design of these peptide sensors and to understand the mechanisms which cause these simultaneous binding events. This approach aims to facilitate the development of new assays for enzymes that are not dependent on the cleavage of a substrate and do not require multiple washing steps.

Journal article

Chiappini C, De Rosa E, Martinez JO, Campagnolo P, Almeida C, Tasciotti E, Stevens Met al., 2015, Porous silicon nanoneedles by metal assisted chemical etch for intracellular sensing and delivery, ECS Transactions, Vol: 69, Pages: 63-68, ISSN: 1938-5862

Metal assisted chemical etch has recently come to prominence as aversatile strategy for the realization of silicon nanostructures withtailored porosity. By exploiting metal assisted chemical etch, werecently developed porous silicon nanoneedles capable ofinterfacing with cells for delivery to and sensing of the intracellularmilieu. Here we review our recently published studies on thefabrication of such nanostructures. Further we review their use asvectors for the localized delivery nucleic acids capable of inducingneovasculature formation in a mouse model. Finally we provide anoverview of our findings on the use of porous silicon nanoneedlesas intracellular sensors for detection of enzymatic activity withhigh resolution across excised human tissue samples.

Journal article

Harrison RH, Steele JAM, Chapman R, Gormley A, Chow L, Mahat M, Podhorska L, Palgrave R, Payne D, Hettiaratchy S, Dunlop IE, Stevens Met al., 2015, Modular and versatile spatial functionalization of tissue engineering scaffolds through fiber-initiated controlled radical polymerization, Advanced Functional Materials, Vol: 25, Pages: 5748-5757, ISSN: 1616-301X

Journal article

Rojo L, Fernandez-Gutierrez M, Deb S, Stevens MM, San Roman Jet al., 2015, Designing dapsone polymer conjugates for controlled drug delivery, Acta Biomaterialia, Vol: 27, Pages: 32-41, ISSN: 1878-7568

Polymer-drug conjugates have significantly influenced polymer therapeutics over the last decade via controlled pharmacokinetics. Dapsone (4,4'-diamino diphenylsulphone) is not only widely used in the treatment of leprosy but forms an essential component in the treatment of autoimmune inflammatory diseases and malaria. However, its low bioavailability and non-specific distribution in the body leads to absorption throughout organs including skin, liver, and kidneys that can cause serious side effects. Thus, in this study we report the synthesis of polymer-drug conjugates of dapsone covalently bonded to macromolecular chains towards the development of new bioactive polymeric formulations with anti-inflammatory properties. Dapsone was functionalised with an acrylic moiety in which the acrylamide residue was directly bonded to one of the aromatic rings of dapsone. This functionalisation yielded an unsymmetrical dapsone methacrylamide (DapMA) structure, which on free radical polymerisation and co-polymerisation with HEMA yielded polymers of hydrocarbon macromolecules with pendant dapsone units. Thermal and size-exclusion chromatographic analysis revealed an increase in thermal stabilisation of the homopolymer (p(DapMA)) in comparison to the copolymer (p(Dap-co-HEMA)) with relatively high average molecular weight. The polymer conjugates exhibited high stability with low dapsone release from the polymeric backbone due to hydrolysis. However, a significant anti-inflammatory activity in a nitric oxide inhibition assay confirmed that this property was the consequence of only the macromolecular composition and not related to the release of low molecular weight compounds. Thus, the conjugation of dapsone to macromolecular systems provides a synthetic route to incorporate this drug into polymeric systems, facilitating their development into new anti-inflammatory therapies. Statement of Significance: The dapsone-conjugated methacrylic monomer and polymer derivatives with anti-infl

Journal article

Gormley AJ, Chandrawati R, Christofferson AJ, Loynachan C, Jumeaux C, Artzy-Schnirman A, Aili D, Yarovsky I, Stevens MMet al., 2015, Layer-by-layer self-assembly of polymer films and capsules through coiled-coil peptides, Chemistry of Materials, Vol: 27, Pages: 5820-5824, ISSN: 1520-5002

The layer-by-layer (LbL) technique is a simple and robust process for fabricating functional multilayer thin films. Here, we report the use of de novo designed polypeptides that self-assemble into coiled-coil structures (four-helix bundles) as a driving force for specific multilayer assembly. These pH- (sensitive between pH 4 and 7) and enzyme-responsive polypeptides were conjugated to polymers, and the LbL assembly of the polymer–peptide conjugates allowed the deposition of up to four polymer–peptide layers on planar surfaces and colloidal substrates. Stable hollow capsules were obtained, and by taking advantage of the peptide’s susceptibility to specific enzymatic cleavage, release of encapsulated cargo within the carriers can be triggered within 2 h in the presence of matrix metalloproteinase-7. The enormous diversity of materials that can form highly controllable and programmable coiled-coil interactions creates new opportunities and allows further exploration of the multilayer assembly and the formation of carrier capsules with unique functional properties.

Journal article

Santos L, Fuhrmann G, Juenet M, Amdursky N, Horejs C-M, Campagnolo P, Stevens MMet al., 2015, Extracellular stiffness modulates the expression of functional proteins and growth factors in endothelial cells, Advanced Healthcare Materials, Vol: 4, Pages: 2056-2063, ISSN: 2192-2640

Angiogenesis, the formation of blood vessels from pre-existing ones, is of vital importance during the early stages of bone healing. Extracellular stiffness plays an important role in regulating endothelial cell behavior and angiogenesis, but how this mechanical cue affects proliferation kinetics, gene regulation, and the expression of proteins implicated in angiogenesis and bone regeneration remains unclear. Using collagen-coated polyacrylamide (PAAm) hydrogels, human umbilical vein endothelial cells (HUVECs) are exposed to an environment that mimics the elastic properties of collagenous bone, and cellular proliferation and gene and protein expressions are assessed. The proliferation and gene expression of HUVECs are not differentially affected by culture on 3 or 30 kPa PAAm hydrogels, henceforth referred to as low and high stiffness gels, respectively. Although the proliferation and gene transcript levels remain unchanged, significant differences are found in the expressions of functional proteins and growth factors implicated both in the angiogenic and osteogenic processes. The down-regulation of the vascular endothelial growth factor receptor-2 protein with concomitant over-expression of caveolin-1, wingless-type 2, bone morphogenic protein 2, and basic fibroblast growth factor on the high stiffness PAAm hydrogel suggests that rigidity has a pro-angiogenic effect with inherent benefits for bone regeneration.

Journal article

Amdursky N, Stevens MM, 2015, Circular Dichroism of Amino Acids: Following the Structural Formation of Phenylalanine., Chemphyschem, Vol: 16, Pages: 2768-2774, ISSN: 1439-7641

Circular dichroism (CD) is frequently used to assess the secondary structure of peptides and proteins, whereas less attention has been given to their building blocks, that is, single amino acids, as they do not possess a secondary structure. Here, we follow the CD signal of amino acids and reveal that several acids exhibit a unique CD pattern as a function of their concentration. Accordingly, we propose an eight-level classification of the CD signal of the various amino acids. Special focus is given to the CD pattern of phenylalanine (Phe), for which we observe the formation of an ultra-narrow CD peak (full width at high maximum of only 5 nm). This CD peak can be attributed to the formation of Phe-based chiral structural features. Further support for the formation of an ordered structure is given by using NMR, and the additional self-assembly process of Phe to tubular structures.

Journal article

Morez CY, Noseda M, Abreu Paiva M, Belian E, Schneider MD, Stevens MMet al., 2015, Enhanced efficiency of genetic programming toward cardiomyocyte creation through topographical cues, Biomaterials, Vol: 70, Pages: 94-104, ISSN: 1878-5905

Generation of de novo cardiomyocytes through viral over-expression of key transcription factors represents a highly promising strategy for cardiac muscle tissue regeneration. Although the feasibility of cell reprogramming has proven possible both in vitro and in vivo, the efficiency of the process remains extremely low. Here, we report a chemical-free technique in which topographical cues, more specifically parallel microgrooves, enhance the trans-differentiation of cardiac progenitors into cardiomyocyte-like cells. Using a lentivirus-mediated direct reprogramming strategy for expression of Myocardin, Tbx5, and Mef2c, we showed that the microgrooved substrate provokes an increase in histone H3 acetylation (AcH3), known to be a permissive environment for reprogramming by “stemness” factors, as well as stimulation of myocardin sumoylation, a post-translational modification essential to the transcriptional function of this key co-activator. These biochemical effects mimicked those of a pharmacological histone deacetylase inhibitor, valproic acid (VPA), and like VPA markedly augmented the expression of cardiomyocyte-specific proteins by the genetically engineered cells. No instructive effect was seen in cells unresponsive to VPA. In addition, the anisotropy resulting from parallel microgrooves induced cellular alignment, mimicking the native ventricular myocardium and augmenting sarcomere organization.

Journal article

Chiappini C, Campagnolo P, Almeida CS, Abbassi-Ghadi N, Chow LW, Hanna GB, Stevens MMet al., 2015, Mapping Local Cytosolic Enzymatic Activity in Human Esophageal Mucosa with Porous Silicon Nanoneedles, Advanced Materials, Vol: 27, Pages: 5147-5152, ISSN: 1521-4095

Porous silicon nanoneedles can map Cathepsin B activity across normal and tumor human esophageal mucosa. Assembling a peptide-based Cathepsin B cleavable sensor over a large array of nano­needles allows the discrimination of cancer cells from healthy ones in mixed culture. The same sensor applied to tissue can map Cathepsin B activity with high resolution across the tumor margin area of esophageal adenocarcinoma.

Journal article

Soh JH, Lin Y, Rana S, Ying JY, Stevens MMet al., 2015, Colorimetric detection of small molecules in complex matrixes via target-mediated growth of aptamer-functionalized gold nanoparticles., Analytical Chemistry, Vol: 87, Pages: 7644-7652, ISSN: 0003-2700

A versatile and sensitive colorimetric assay that allows the rapid detection of small-molecule targets using the naked eye is demonstrated. The working principle of the assay integrates aptamer-target recognition and the aptamer-controlled growth of gold nanoparticles (Au NPs). Aptamer-target interactions modulate the amount of aptamer strands adsorbed on the surface of aptamer-functionalized Au NPs via desorption of the aptamer strands when target molecules bind with the aptamer. Depending on the resulting aptamer coverage, Au NPs grow into morphologically varied nanostructures, which give rise to different colored solutions. Au NPs with low aptamer coverage grow into spherical NPs, which produce red-colored solutions, whereas Au NPs with high aptamer coverage grow into branched NPs, which produce blue-colored solutions. We achieved visible colorimetric response and nanomolar detection limits for the detection of ochratoxin A (1 nM) in red wine samples, as well as cocaine (1 nM) and 17β-estradiol (0.2 nM) in spiked synthetic urine and saliva, respectively. The detection limits were well within clinically and physiologically relevant ranges, and below the maximum food safety limits. The assay is highly sensitive, specific, and able to detect an array of analytes rapidly without requiring sophisticated equipment, making it relevant for many applications, such as high-throughput drug and clinical screening, food sampling, and diagnostics. Furthermore, the assay is easily adapted as a chip-based platform for rapid and portable target detection.

Journal article

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