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

251 results found

Littmann E, Autefage H, Solanki AN, Kallepitis C, Jones JR, Alini M, Peroglio M, Stevens MMet al., Cobalt-containing bioactive glasses reduce humanmesenchymal stem cell chondrogenic differentiation despiteHIF-1α stabilisation, Journal of the European Ceramic Society, ISSN: 1873-619X

JOURNAL ARTICLE

Soh JH, Lin Y, Thomas MR, Todorova N, Kallepitis C, Ying JY, Yarovsky I, Stevens MMet al., Distinct bimodal roles of aromatic molecules in controlling gold nanorod growth for biosensing, Advanced Functional Materials, ISSN: 1616-3028

New aromatic molecule–seed particle interactions are examined and exploited to control and guide seed-mediated gold nanorod (Au NR) growth. This new approach enables better understanding of how small molecules impact the synthesis of metallic nanostructures, catalysing their use in various biomedical applications, such as plasmonic biosensing. We perform experimental studies and theoretical molecular simulations using a library of aromatic molecules where we take advantage of the chemical versatility of the molecules with varied spatial arrangements of electron donating/withdrawing groups, charge, and Au-binding propensity. Au NR growth is regulated by two principal mechanisms, producing either a red or blue shift in the longitudinal localized surface plasmon resonance (LLSPR) peaks. Aromatic molecules with high redox potentials produced an increase in NR aspect ratio and red shift of LLSPR peaks. In contrast, molecules that strongly bind gold surfaces resulted in blue shifts, demonstrating a strong correlation between their binding energy and blue shifts produced. Through enzymatic conversion of selected molecules, 4-aminophenylphosphate to 4-aminophenol, we obtained opposing growth mechanisms at opposite extremes of target concentration, and established a chemical pathway for performing plasmonic ELISA. This unlocks new strategies for tailoring substrate design and enzymatic mechanisms for controlling plasmonic response to target detection in biosensing applications.

JOURNAL ARTICLE

Amdursky N, Rashid MH, Stevens MM, Yarovsky I, Amdursky N, Rashid MH, Stevens MM, Yarovsky I, Amdursky N, Rashid MH, Stevens MM, Yarovsky Iet al., 2017, Exploring the binding sites and proton diffusion on insulin amyloid fibril surfaces by naphthol-based photoacid fluorescence and molecular simulations., Sci Rep, Vol: 7, ISSN: 2045-2322

The diffusion of protons along biological surfaces and the interaction of biological structures with water are fundamental areas of interest in biology and chemistry. Here, we examine the surface of insulin amyloid fibrils and follow the binding of small molecules (photoacids) that differ according to the number and location of their sulfonic groups. We use transient fluorescence combined with a spherically-symmetric diffusion theory to show that the binding mode of different photoacids determines the efficiency of proton dissociation from the photoacid and the dimensionality of the proton's diffusion. We use molecular dynamics simulations to examine the binding mode and mechanism of the photoacids and its influence on the unique kinetic rates and diffusion properties of the photoacid's dissociated proton, where we also suggest a proton transfer process between one of the photoacids to proximal histidine residues. We show that the photoacids can be used as fluorescent markers for following the progression of amyloidogenic processes. The detailed characterisation of different binding modes to the surface of amyloid fibrils paves the way for better understanding of the binding mechanism of small molecules to amyloid fibrils.

JOURNAL ARTICLE

Amdursky N, Wang X, Meredith P, Riley DJ, Payne DJ, Bradley DDC, Stevens MM, Amdursky N, Wang X, Meredith P, Riley DJ, Payne DJ, Bradley DDC, Stevens MM, Amdursky N, Wang X, Meredith P, Riley DJ, Payne DJ, Bradley DDC, Stevens MM, Amdursky N, Wang X, Meredith P, Riley DJ, Payne DJ, Bradley DDC, Stevens MM, Amdursky N, Wang X, Meredith P, Riley DJ, Payne DJ, Bradley D, Stevens MMet al., 2017, Electron Hopping Across Hemin-Doped Serum Albumin Mats on Centimeter-Length Scales, ADVANCED MATERIALS, Vol: 29, Pages: 1700810-1700810, ISSN: 0935-9648

Exploring long-range electron transport across protein assemblies is a central interest in both the fundamental research of biological processes and the emerging field of bioelectronics. This work examines the use of serum-albumin-based freestanding mats as macroscopic electron mediators in bioelectronic devices. In particular, this study focuses on how doping the protein mat with hemin improves charge-transport. It is demonstrated that doping can increase conductivity 40-fold via electron hopping between adjacent hemin molecules, resulting in the highest measured conductance for a protein-based material yet reported, and transport over centimeter length scales. The use of distance-dependent AC impedance and DC current-voltage measurements allows the contribution from electron hopping between adjacent hemin molecules to be isolated. Because the hemin-doped serum albumin mats have both biocompatibility and fabrication simplicity, they should be applicable to a range of bioelectronic devices of varying sizes, configurations, and applications.

JOURNAL ARTICLE

Armstrong JPK, Holme MN, Stevens MM, Armstrong JPK, Holme MN, Stevens MM, Armstrong JPK, Holme MN, Stevens MM, Armstrong JPK, Holme MN, Stevens MM, Armstrong JPK, Holme MN, Stevens MM, Armstrong JPK, Holme MN, Stevens MMet al., 2017, Re-Engineering Extracellular Vesicles as Smart Nanoscale Therapeutics, ACS NANO, Vol: 11, Pages: 69-83, ISSN: 1936-0851

In the past decade, extracellular vesicles (EVs) have emerged as a key cell-free strategy for the treatment of a range of pathologies, including cancer, myocardial infarction, and inflammatory diseases. Indeed, the field is rapidly transitioning from promising in vitro reports toward in vivo animal models and early clinical studies. These investigations exploit the high physicochemical stability and biocompatibility of EVs as well as their innate capacity to communicate with cells via signal transduction and membrane fusion. This review focuses on methods in which EVs can be chemically or biologically modified to broaden, alter, or enhance their therapeutic capability. We examine two broad strategies, which have been used to introduce a wide range of nanoparticles, reporter systems, targeting peptides, pharmaceutics, and functional RNA molecules. First, we explore how EVs can be modified by manipulating their parent cells, either through genetic or metabolic engineering or by introducing exogenous material that is subsequently incorporated into secreted EVs. Second, we consider how EVs can be directly functionalized using strategies such as hydrophobic insertion, covalent surface chemistry, and membrane permeabilization. We discuss the historical context of each specific technology, present prominent examples, and evaluate the complexities, potential pitfalls, and opportunities presented by different re-engineering strategies.

JOURNAL ARTICLE

Bergholt MS, Albro MB, Stevens MM, Bergholt MS, Albro MB, Stevens MM, Bergholt MS, Albro MB, Stevens MM, Bergholt MS, Albro MB, Stevens MM, Bergholt M, Albro M, Stevens MMet al., 2017, Online quantitative monitoring of live cell engineered cartilage growth using diffuse fiber-optic Raman spectroscopy, BIOMATERIALS, Vol: 140, Pages: 128-137, ISSN: 0142-9612

Tissue engineering (TE) has the potential to improve the outcome for patients with osteoarthritis (OA). The successful clinical translation of this technique as part of a therapy requires the ability to measure extracellular matrix (ECM) production of engineered tissues in vitro, in order to ensure quality control and improve the likelihood of tissue survival upon implantation. Conventional techniques for assessing the ECM content of engineered cartilage, such as biochemical assays and histological staining are inherently destructive. Raman spectroscopy, on the other hand, represents a non-invasive technique for in situ biochemical characterization. Here, we outline current roadblocks in translational Raman spectroscopy in TE and introduce a comprehensive workflow designed to non-destructively monitor and quantify ECM biomolecules in large (>3 mm), live cell TE constructs online. Diffuse near-infrared fiber-optic Raman spectra were measured from live cell cartilaginous TE constructs over a 56-day culturing period. We developed a multivariate curve resolution model that enabled quantitative biochemical analysis of the TE constructs. Raman spectroscopy was able to non-invasively quantify the ECM components and showed an excellent correlation with biochemical assays for measurement of collagen (R(2) = 0.84) and glycosaminoglycans (GAGs) (R(2) = 0.86). We further demonstrated the robustness of this technique for online prospective analysis of live cell TE constructs. The fiber-optic Raman spectroscopy strategy developed in this work offers the ability to non-destructively monitor construct growth online and can be adapted to a broad range of TE applications in regenerative medicine toward controlled clinical translation.

JOURNAL ARTICLE

Chandrawati R, Chang JYH, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MM, Chandrawati R, Chang JYH, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MM, Chandrawati R, Chang JYH, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MM, Chandrawati R, Chang JYH, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MM, Chandrawati R, Chang JYH, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MM, Chandrawati R, Chang J, Reina-Torres E, Jumeaux C, Sherwood JM, Stamer WD, Zelikin AN, Overby DR, Stevens MMet al., 2017, Localized and Controlled Delivery of Nitric Oxide to the Conventional Outflow Pathway via Enzyme Biocatalysis: Toward Therapy for Glaucoma, ADVANCED MATERIALS, Vol: 29, Pages: 1604932-1604932, ISSN: 0935-9648

Nitric oxide (NO) is able to lower intraocular pressure (IOP); however, its therapeutic effects on outflow physiology are location- and dose-dependent. A NO delivery platform that directly targets the resistance-generating region of the conventional outflow pathway and locally liberates a controlled dose of NO is reported. An increase in outflow facility (decrease in IOP) is demonstrated in a mouse model.

JOURNAL ARTICLE

Chandrawati R, Olesen MTJ, Marini TCC, Bisra G, Guex AG, de Oliveira MG, Zelikin AN, Stevens MM, Chandrawati R, Olesen MTJ, Marini TCC, Bisra G, Guex AG, de Oliveira MG, Zelikin AN, Stevens MM, Chandrawati R, Olesen MTJ, Marini TCC, Bisra G, Guex AG, de Oliveira MG, Zelikin AN, Stevens MM, Chandrawati R, Olesen MTJ, Marini TCC, Bisra G, Guex AG, De Oliveira MG, Zelikin AN, Stevens MMet al., 2017, Enzyme Prodrug Therapy Engineered into Electrospun Fibers with Embedded Liposomes for Controlled, Localized Synthesis of Therapeutics., Adv Healthc Mater, Pages: 1700385-1700385, ISSN: 2192-2640

Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the envisioned therapeutic application. β-glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β-glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks. It is further shown that liposomes provide the highly beneficial stabilization of the enzyme when incubated in cell culture media. The assembled biocatalytic materials successfully produce antiproliferative drugs (SN-38) using externally administered prodrugs (SN-38-glucuronide) and effectively suppress cell proliferation, with envisioned utility in the design of cardiovascular grafts.

JOURNAL ARTICLE

Chang JYH, Chow LW, Dismuke WM, Ethier CR, Stevens MM, Stamer WD, Overby DR, Chang JYH, Chow LW, Dismuke WM, Ethier CR, Stevens MM, Stamer WD, Overby DR, Chang JYH, Chow LW, Dismuke WM, Ethier CR, Stevens MM, Stamer WD, Overby DR, Chang JYH, Chow LW, Dismuke WM, Ethier CR, Stevens MM, Stamer WD, Overby Det al., 2017, Peptide-Functionalized Fluorescent Particles for In Situ Detection of Nitric Oxide via Peroxynitrite-Mediated Nitration., Adv Healthc Mater, Pages: 1700383-1700383, ISSN: 2192-2640

Nitric oxide (NO) is a free radical signaling molecule that plays a crucial role in modulating physiological homeostasis across multiple biological systems. NO dysregulation is linked to the pathogenesis of multiple diseases; therefore, its quantification is important for understanding pathophysiological processes. The detection of NO is challenging, typically limited by its reactive nature and short half-life. Additionally, the presence of interfering analytes and accessibility to biological fluids in the native tissues make the measurement technically challenging and often unreliable. Here, a bio-inspired peptide-based NO sensor is developed, which detects NO-derived oxidants, predominately peroxynitrite-mediated nitration of tyrosine residues. It is demonstrated that these peptide-based NO sensors can detect peroxynitrite-mediated nitration in response to physiological shear stress by endothelial cells in vitro. Using the peptide-conjugated fluorescent particle immunoassay, peroxynitrite-mediated nitration activity with a detection limit of ≈100 × 10(-9) m is detected. This study envisions that the NO detection platform can be applied to a multitude of applications including monitoring of NO activity in healthy and diseased tissues, localized detection of NO production of specific cells, and cell-based/therapeutic screening of peroxynitrite levels to monitor pronitroxidative stress in biological samples.

JOURNAL ARTICLE

Chung JJ, Fujita Y, Li S, Stevens MM, Kasuga T, Georgiou TK, Jones JR, Chung JJ, Fujita Y, Li S, Stevens MM, Kasuga T, Georgiou TK, Jones JR, Chung JJ, Fujita Y, Li S, Stevens MM, Kasuga T, Georgiou TK, Jones JR, Chung JJ, Fujita Y, Li S, Stevens MM, Kasuga T, Georgiou TK, Jones JR, Chung JJ, Fujita Y, Li S, Stevens MM, Kasuga T, Georgiou TK, Jones JR, Chung JJ, Fujita Y, Li S, Stevens M, Kasuga T, Georgiou T, Jones JRet al., 2017, Biodegradable inorganic-organic hybrids of methacrylate star polymers for bone regeneration, ACTA BIOMATERIALIA, Vol: 54, Pages: 411-418, ISSN: 1742-7061

Hybrids that are molecular scale co-networks of organic and inorganic components are promising biomaterials, improving the brittleness of bioactive glass and the strength of polymers. Methacrylate polymers have high potential as the organic source for hybrids since they can be produced, through controlled polymerization, with sophisticated polymer architectures that can bond to silicate networks. Previous studies showed the mechanical properties of hybrids can be modified by polymer architecture and molar mass (MM). However, biodegradability is critical if hybrids are to be used as tissue engineering scaffolds, since the templates must be remodelled by host tissue. Degradation by-products have to either completely biodegrade or be excreted by the kidneys. Enzyme, or bio-degradation is preferred to hydrolysis by water uptake as it is expected to give a more controlled degradation rate. Here, branched and star shaped poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate) (poly(MMA-co-TMSPMA)) were synthesized with disulphide based dimethacrylate (DSDMA) as a biodegradable branching agent. Biodegradability was confirmed by exposing the copolymers to glutathione, a tripeptide which is known to cleave disulphide bonds. Cleaved parts of the star polymer from the hybrid system were detected after 2weeks of immersion in glutathione solution, and MM was under threshold of kidney filtration. The presence of the branching agent did not reduce the mechanical properties of the hybrids and bone progenitor cells attached on the hybrids in vitro. Incorporation of the DSDMA branching agent has opened more possibilities to design biodegradable methacrylate polymer based hybrids for regenerative medicine. STATEMENT OF SIGNIFICANCE: Bioactive glasses can regenerate bone but are brittle. Hybrids can overcome this problem as intimate interactions between glass and polymer creates synergetic properties. Implants have previously been made with synthetic polymers that degrade b

JOURNAL ARTICLE

Chung JJ, Sum BST, Li S, Stevens MM, Georgiou TK, Jones JR, Chung JJ, Sum BST, Li S, Stevens MM, Georgiou TK, Jones JR, Chung JJ, Sum BST, Li S, Stevens MM, Georgiou TK, Jones JR, Chung JJ, Sum BST, Li S, Stevens MM, Georgiou TK, Jones JRet al., 2017, Effect of Comonomers on Physical Properties and Cell Attachment to Silica-Methacrylate/Acrylate Hybrids for Bone Substitution., Macromol Rapid Commun, Vol: 38, Pages: 1700168-1700168, ISSN: 1022-1336

Hybrids with a silica network covalently bonded to a polymer are promising materials for bone repair. Previous work on synthesizing methyl methacrylate (MMA) based copolymers by reversible addition-fragmentation chain transfer (RAFT) polymerization gives high tailorability of mechanical properties since sophisticated polymer structures can be designed. However, more flexible hybrids would be beneficial. Here, n-butyl methacrylate (BMA) and methyl acrylate (MA) based hybrids are produced. Unlike MMA, BMA and MA hybrids do not show plastic deformation, and BMA hybrid has strain to failure of 33%. Although the new hybrids are more flexible, preosteoblast cells do not adhere on their surfaces, due to higher hydrophobicity and lower stiffness. Comonomer choice is crucial for bone regenerative hybrids.

JOURNAL ARTICLE

Clarke DE, Pashuck ET, Bertazzo S, Weaver JVM, Stevens MM, Clarke DE, Pashuck ET, Bertazzo S, Weaver JVM, Stevens MM, Clarke DE, Pashuck ET, Bertazzo S, Weaver JVM, Stevens MM, Clarke DE, Pashuck ET, Bertazzo S, Weaver JVM, Stevens MM, Clarke D, Pashuck ET, Bertazzo S, Weaver JVM, Stevens MMet al., 2017, Self-Healing, Self-Assembled beta-Sheet Peptide Poly(gamma-glutamic acid) Hybrid Hydrogels, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, Vol: 139, Pages: 7250-7255, ISSN: 0002-7863

Self-assembled biomaterials are an important class of materials that can be injected and formed in situ. However, they often are not able to meet the mechanical properties necessary for many biological applications, losing mechanical properties at low strains. We synthesized hybrid hydrogels consisting of a poly(γ-glutamic acid) polymer network physically cross-linked via grafted self-assembling β-sheet peptides to provide non-covalent cross-linking through β-sheet assembly, reinforced with a polymer backbone to improve strain stability. By altering the β-sheet peptide graft density and concentration, we can tailor the mechanical properties of the hydrogels over an order of magnitude range of 10-200 kPa, which is in the region of many soft tissues. Also, due to the ability of the non-covalent β-sheet cross-links to reassemble, the hydrogels can self-heal after being strained to failure, in most cases recovering all of their original storage moduli. Using a combination of spectroscopic techniques, we were able to probe the secondary structure of the materials and verify the presence of β-sheets within the hybrid hydrogels. Since the polymer backbone requires less than a 15% functionalization of its repeating units with β-sheet peptides to form a hydrogel, it can easily be modified further to incorporate specific biological epitopes. This self-healing polymer-β-sheet peptide hybrid hydrogel with tailorable mechanical properties is a promising platform for future tissue-engineering scaffolds and biomedical applications.

JOURNAL ARTICLE

Fiocco L, Li S, Stevens MM, Bernardo E, Jones JR, Fiocco L, Li S, Stevens MM, Bernardo E, Jones JR, Fiocco L, Li S, Stevens MM, Bernardo E, Jones JR, Fiocco L, Li S, Stevens MM, Bernardo E, Jones JR, Fiocco L, Li S, Stevens MM, Bernardo E, Jones JR, Fiocco L, Li S, Stevens MM, Bernardo E, Jones JRet al., 2017, Biocompatibility and bioactivity of porous polymer-derived Ca-Mg silicate ceramics, ACTA BIOMATERIALIA, Vol: 50, Pages: 56-67, ISSN: 1742-7061

Magnesium is a trace element in the human body, known to have important effects on cell differentiation and the mineralisation of calcified tissues. This study aimed to synthesise highly porous Ca-Mg silicate foamed scaffolds from preceramic polymers, with analysis of their biological response. Akermanite (Ak) and wollastonite-diopside (WD) ceramic foams were obtained from the pyrolysis of a liquid silicone mixed with reactive fillers. The porous structure was obtained by controlled water release from selected fillers (magnesium hydroxide and borax) at 350°C. The homogeneous distribution of open pores, with interconnects of modal diameters of 160-180μm was obtained and maintained after firing at 1100°C. Foams, with porosity exceeding 80%, exhibited compressive strength values of 1-2MPa. In vitro studies were conducted by immersion in SBF for 21days, showing suitable dissolution rates, pH and ionic concentrations. Cytotoxicity analysis performed in accordance with ISO10993-5 and ISO10993-12 standards confirmed excellent biocompatibility of both Ak and WD foams. In addition, MC3T3-E1 cells cultured on the Mg-containing scaffolds demonstrated enhanced osteogenic differentiation and the expression of osteogenic markers including Collagen Type I, Osteopontin and Osteocalcin, in comparison to Mg-free counterparts. The results suggest that the addition of magnesium can further enhance the bioactivity and the potential for bone regeneration applications of Ca-silicate materials. STATEMENTS OF SIGNIFICANCE: Here, we show that the incorporation of Mg in Ca-silicates plays a significant role in the enhancement of the osteogenic differentiation and matrix formation of MC3T3-E1 cells, cultured on polymer-derived highly porous scaffolds. Reduced degradation rates and improved mechanical properties are also observed, compared to Mg-free counterparts, suggesting the great potential of Ca-Mg silicates as bone tissue engineering materials. Excellent biocompatibility of the

JOURNAL ARTICLE

Guex AG, Spicer CD, Armgarth A, Gelmi A, Humphrey EJ, Terracciano CM, Harding SE, Stevens MM, Guex AG, Spicer CD, Armgarth A, Gelmi A, Humphrey EJ, Terracciano CM, Harding SE, Stevens MM, Guex AG, Spicer CD, Armgarth A, Gelmi A, Humphrey EJ, Terracciano CM, Harding S, Stevens MMet al., 2017, Electrospun aniline-tetramer-co-polycaprolactone fibers for conductive, biodegradable scaffolds, MRS Communications, Pages: 1-8, ISSN: 2159-6859

Copyright © Materials Research Society 2017 This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Conjugated polymers have been proposed as promising materials for scaffolds in tissue engineering applications. However, the restricted processability and biodegradability of conjugated polymers limit their use for biomedical applications. Here we synthesized a block-co-polymer of aniline tetramer and PCL (AT–PCL), and processed it into fibrous non-woven scaffolds by electrospinning. We showed that fibronectin (Fn) adhesion was dependent on the AT–PCL oxidative state, with a reduced Fn unfolding length on doped membranes. Furthermore, we demonstrated the cytocompatibility and potential of these membranes to support the growth and osteogenic differentiation of MC3T3-E1 cells over 21 days.

JOURNAL ARTICLE

Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R, Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R, Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R, Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani R, Hall CE, Yao Z, Choi M, Tyzack GE, Serio A, Luisier R, Harley J, Preza E, Arber C, Crisp SJ, Watson PMD, Kullmann DM, Abramov AY, Wray S, Burley R, Loh SHY, Martins LM, Stevens MM, Luscombe NM, Sibley CR, Lakatos A, Ule J, Gandhi S, Patani Ret al., 2017, Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS, CELL REPORTS, Vol: 19, Pages: 1739-1749, ISSN: 2211-1247

Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

JOURNAL ARTICLE

He M, Callanan A, Lagaras K, Steele JAM, Stevens MM, He M, Callanan A, Lagaras K, Steele JAM, Stevens MM, He M, Callanan A, Lagaras K, Steele JAM, Stevens MM, He M, Callanan A, Lagaras K, Steele JA, Stevens MMet al., 2017, Optimization of SDS exposure on preservation of ECM characteristics in whole organ decellularization of rat kidneys., J Biomed Mater Res B Appl Biomater, 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, 105B: 1352-1360, 2017.

JOURNAL ARTICLE

Higgins SG, Stevens MM, Higgins SG, Stevens MM, Higgins SG, Stevens MM, Higgins SG, Stevens MM, Higgins SG, Stevens MM, Higgins SG, Stevens MMet al., 2017, Extracting the contents of living cells, SCIENCE, Vol: 356, Pages: 379-380, ISSN: 0036-8075

Being able to monitor cells at different times is key to tracking fundamental cellular processes such as differentiation and cellular senescence, as well as disease progression and the effectiveness of drugs. However, most approaches are destructive and involve lysing the cells. Different time points can be studied by using parallel cell cultures, but the inferred changes could also be the result of cell heterogeneity (1, 2). Techniques for extracting small quantities of the cytosol for long-term tracking of a single cell's response must manipulate picoliter-scale volumes, maintain high cell viability, and give an accurate reflection of the cell's multiple biological components, as well as avoid influencing the ongoing development of the cell (see the figure) (1, 3). Cao et al. approached this problem by culturing cells on top of a random arrangement of hollow cylinders, which they call nanostraws (2). These 150-nm-diameter alumina tubes can sample 5 to 10% of proteins, messenger RNA (mRNA), and small molecules from the cells but only reduce cell viability by ∼5%. Their approach allows intracellular sampling and characterization at multiple time points from the same cells to track changes.

JOURNAL ARTICLE

Horejs C-M, St-Pierre J-P, Ojala JRM, Steele JAM, da Silva PB, Rynne-Vidal A, Maynard SA, Hansel CS, Rodriguez-Fernandez C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, Lopez-Cabrera M, Stevens MM, Horejs C-M, St-Pierre J-P, Ojala JRM, Steele JAM, da Silva PB, Rynne-Vidal A, Maynard SA, Hansel CS, Rodríguez-Fernández C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, López-Cabrera M, Stevens MM, Horejs C-M, St-Pierre J-P, Ojala JRM, Steele JAM, da Silva PB, Rynne-Vidal A, Maynard SA, Hansel CS, Rodríguez-Fernández C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, López-Cabrera M, Stevens MM, Horejs C-M, St-Pierre J-P, Ojala JRM, Steele JAM, da Silva PB, Rynne-Vidal A, Maynard SA, Hansel CS, Rodríguez-Fernández C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, López-Cabrera M, Stevens MM, Horejs CM, St-Pierre JP, Ojala JRM, Steele JAM, Barros da Silva P, Rynne-Vidal A, Maynard SA, Hansel CS, Rodriguez-Fernandez C, Mazo MM, You AYF, Wang AJ, von Erlach T, Tryggvason K, Lopez-Cabrera M, Stevens MMet al., 2017, Preventing tissue fibrosis by local biomaterials interfacing of specific cryptic extracellular matrix information, NATURE COMMUNICATIONS, Vol: 8, Pages: 15509-15509, ISSN: 2041-1723

Matrix metalloproteinases (MMPs) contribute to the breakdown of tissue structures such as the basement membrane, promoting tissue fibrosis. Here we developed an electrospun membrane biofunctionalized with a fragment of the laminin β1-chain to modulate the expression of MMP2 in this context. We demonstrate that interfacing of the β1-fragment with the mesothelium of the peritoneal membrane via a biomaterial abrogates the release of active MMP2 in response to transforming growth factor β1 and rescues tissue integrity ex vivo and in vivo in a mouse model of peritoneal fibrosis. Importantly, our data demonstrate that the membrane inhibits MMP2 expression. Changes in the expression of epithelial-to-mesenchymal transition (EMT)-related molecules further point towards a contribution of the modulation of EMT. Biomaterial-based presentation of regulatory basement membrane signals directly addresses limitations of current therapeutic approaches by enabling a localized and specific method to counteract MMP2 release applicable to a broad range of therapeutic targets.

JOURNAL ARTICLE

Kallepitis C, Bergholt MS, Mazo MM, Leonardo V, Skaalure SC, Maynard SA, Stevens MM, Kallepitis C, Bergholt MS, Mazo MM, Leonardo V, Skaalure SC, Maynard SA, Stevens MM, Kallepitis C, Bergholt MS, Mazo MM, Leonardo V, Skaalure SC, Maynard SA, Stevens MM, Kallepitis C, Bergholt MS, Mazo MM, Leonardo V, Skaalure SC, Maynard SA, Stevens MM, Kallepitis C, Bergholt MS, Mazo MM, Leonardo V, Skaalure SC, Maynard SA, Stevens MMet al., 2017, Quantitative volumetric Raman imaging of three dimensional cell cultures, NATURE COMMUNICATIONS, Vol: 8, Pages: 14843-14843, ISSN: 2041-1723

The ability to simultaneously image multiple biomolecules in biologically relevant three-dimensional (3D) cell culture environments would contribute greatly to the understanding of complex cellular mechanisms and cell-material interactions. Here, we present a computational framework for label-free quantitative volumetric Raman imaging (qVRI). We apply qVRI to a selection of biological systems: human pluripotent stem cells with their cardiac derivatives, monocytes and monocyte-derived macrophages in conventional cell culture systems and mesenchymal stem cells inside biomimetic hydrogels that supplied a 3D cell culture environment. We demonstrate visualization and quantification of fine details in cell shape, cytoplasm, nucleus, lipid bodies and cytoskeletal structures in 3D with unprecedented biomolecular specificity for vibrational microspectroscopy.

JOURNAL ARTICLE

Kim E, Howes PD, Crowder SW, Stevens MM, Kim E, Howes PD, Crowder SW, Stevens MM, Kim E, Howes PD, Crowder SW, Stevens MM, Kim E, Howes PD, Crowder SW, Stevens MM, Kim E, Howes PD, Crowder SW, Stevens MMet al., 2017, Multi-Amplified Sensing of MicroRNA by a Small DNA Fragment-Driven Enzymatic Cascade Reaction, ACS SENSORS, Vol: 2, Pages: 111-118, ISSN: 2379-3694

Combining technological developments such as nanomaterials, DNA nanotechnology, and functional enzymes has great potential to facilitate next generation high performance molecular diagnostic systems. In this work, we describe a microRNA (miRNA) detection assay that combines target recycling and isothermal amplification in an elegantly designed enzyme-mediated cascade reaction. Target recycling is driven by the action of duplex-specific nuclease (DSN), resulting in highly amplified translation of input miRNA to short output DNA fragments. These fragments act as highly specific initiators of rolling circle amplification (RCA), an isothermal reaction that outputs a large volume of polymeric DNAzymes per initiator, and finally a fluorogenic output signal. Based on careful electrophoretic analysis we observed that the DSN produces ca. 10 nt DNA fragments from DNA/miRNA duplexes, regardless of the length of DNA strands. Target recycling yielded ca. 5 orders of magnitude amplification through the DSN-assisted recycling system on magnetic particles, and the RCA yielded a further 2 orders of magnitude. The final assay exhibited a limit of detection of 1.8 fM of miRNA spiked into 20% human serum, and showed excellent selectivity for miR-21 versus single base-mismatched sequences and other cancer-related miRNAs. The developed assay was further employed to determine accurate amounts of miR-21 in total RNA samples extracted from human cancer cell lines and normal cells, confirming the applicability of the assay for direct and absolute quantification of mature specific miRNA in real biological samples.

JOURNAL ARTICLE

Kim E, Zwi-Dantsis L, Reznikov N, Hansel CS, Agarwal S, Stevens MM, Kim E, Zwi-Dantsis L, Reznikov N, Hansel CS, Agarwal S, Stevens MM, Kim E, Zwi-Dantsis L, Reznikov N, Hansel CS, Agarwal S, Stevens MM, Kim E, Zwi-Dantsis L, Reznikov N, Hansel CS, Agarwal S, Stevens MM, Kim E, Zwi Dantsis L, Reznikov N, Hansel CS, Agarwal S, Stevens MMet al., 2017, One-Pot Synthesis of Multiple Protein-Encapsulated DNA Flowers and Their Application in Intracellular Protein Delivery, ADVANCED MATERIALS, Vol: 29, Pages: 1701086-1701086, ISSN: 0935-9648

Inspired by biological systems, many biomimetic methods suggest fabrication of functional materials with unique physicochemical properties. Such methods frequently generate organic-inorganic composites that feature highly ordered hierarchical structures with intriguing properties, distinct from their individual components. A striking example is that of DNA-inorganic hybrid micro/nanostructures, fabricated by the rolling circle technique. Here, a novel concept for the encapsulation of bioactive proteins in DNA flowers (DNF) while maintaining the activity of protein payloads is reported. A wide range of proteins, including enzymes, can be simultaneously associated with the growing DNA strands and Mg2 PPi crystals during the rolling circle process, ultimately leading to the direct immobilization of proteins into DNF. The unique porous structure of this construct, along with the abundance of Mg ions and DNA molecules present, provides many interaction sites for proteins, enabling high loading efficiency and enhanced stability. Further, as a proof of concept, it is demonstrated that the DNF can deliver payloads of cytotoxic protein (i.e., RNase A) to the cells without a loss in its biological function and structural integrity, resulting in highly increased cell death compared to the free protein.

JOURNAL ARTICLE

Lin Y, Pashuck ET, Thomas MR, Amdursky N, Wang S-T, Chow LW, Stevens MM, Lin Y, Pashuck ET, Thomas MR, Amdursky N, Wang S-T, Chow LW, Stevens MM, Lin Y, Pashuck ET, Thomas MR, Amdursky N, Wang S-T, Chow LW, Stevens MM, Lin Y, Pashuck ET, Thomas MR, Amdursky N, Wang S-T, Chow LW, Stevens MM, Lin Y, Pashuck ET, Thomas MR, Amdursky N, Wang S-T, Chow LW, Stevens MMet al., 2017, Plasmonic Chirality Imprinting on Nucleobase-Displaying Supramolecular Nanohelices by Metal-Nucleobase Recognition, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 56, Pages: 2361-2365, ISSN: 1433-7851

Supramolecular self-assembly is an important process that enables the conception of complex structures mimicking biological motifs. Herein, we constructed helical fibrils through chiral self-assembly of nucleobase-peptide conjugates (NPCs), where achiral nucleobases are helically displayed on the surface of fibrils, comparable to polymerized nucleic acids. Selective binding between DNA and the NPC fibrils was observed with fluorescence polarization. Taking advantage of metal-nucleobase recognition, we highlight the possibility of deposition/assembly of plasmonic nanoparticles onto the fibrillar constructs. In this approach, the supramolecular chirality of NPCs can be adaptively imparted to metallic nanoparticles, covering them to generate structures with plasmonic chirality that exhibit significantly improved colloidal stability. The self-assembly of rationally designed NPCs into nanohelices is a promising way to engineer complex, optically diverse nucleobase-derived nanomaterials.

JOURNAL ARTICLE

Macon ALB, Jacquemin M, Page SJ, Li S, Bertazzo S, Stevens MM, Hanna JV, Jones JR, Maçon ALB, Jacquemin M, Page SJ, Li S, Bertazzo S, Stevens MM, Hanna JV, Jones JR, Maçon ALB, Jacquemin M, Page SJ, Li S, Bertazzo S, Stevens MM, Hanna JV, Jones JR, Macon ALB, Jacquemin M, Page SJ, Li S, Bertazzo S, Stevens MM, Hanna JV, Jones JRet al., 2017, Lithium-silicate sol-gel bioactive glass and the effect of lithium precursor on structure-property relationships, JOURNAL OF SOL-GEL SCIENCE AND TECHNOLOGY, Vol: 81, Pages: 84-94, ISSN: 0928-0707

© 2016, The Author(s). Abstract: This work reports the synthesis of lithium-silicate glass, containing 10 mol% of Li 2 O by the sol–gel process, intended for the regeneration of cartilage. Lithium citrate and lithium nitrate were selected as lithium precursors. The effects of the lithium precursor on the sol–gel process, and the resulting glass structure, morphology, dissolution behaviour, chondrocyte viability and proliferation, were investigated. When lithium citrate was used, mesoporous glass containing lithium as a network modifier was obtained, whereas the use of lithium nitrate produced relatively dense glass-ceramic with the presence of lithium metasilicate, as shown by X-ray diffraction, 29 Si and 7 Li MAS NMR and nitrogen sorption data. Nitrate has a better affinity for lithium than citrate, leading to heterogeneous crystallisation from the mesopores, where lithium salts precipitated during drying. Citrate decomposed at a lower temperature, where the crystallisation of lithium-silicate crystal is not thermodynamically favourable. Upon decomposition of the citrate, a solid-state salt metathesis reaction between citrate and silanol occurred, followed by the diffusion of lithium within the structure of the glass. Both glass and glass-ceramic released silica and lithium ions in culture media, but release rate was lower for the glass-ceramic. Both samples did not affect chondrocyte viability and proliferation. Graphical Abstract: [Figure not available: see fulltext.]

JOURNAL ARTICLE

Pacheco-Moreno CM, Schreck M, Scaccabarozzi AD, Bourgun P, Wantz G, Stevens MM, Dautel OJ, Stingelin N, Pacheco-Moreno CM, Schreck M, Scaccabarozzi AD, Bourgun P, Wantz G, Stevens MM, Dautel OJ, Stingelin N, Pacheco-Moreno CM, Schreck M, Scaccabarozzi AD, Bourgun P, Wantz G, Stevens MM, Dautel OJ, Stingelin N, Pacheco-Moreno CM, Schreck M, Scaccabarozzi AD, Bourgun P, Wantz G, Stevens MM, Dautel OJ, Stingelin N, Pacheco-Moreno CM, Schreck M, Scaccabarozzi AD, Bourgun P, Wantz G, Stevens MM, Dautel OJ, Stingelin Net al., 2017, The Importance of Materials Design to Make Ions Flow: Toward Novel Materials Platforms for Bioelectronics Applications, ADVANCED MATERIALS, Vol: 29, Pages: 1604446-1604446, ISSN: 0935-9648

Chemical design criteria for materials for bioelectronics applications using a series of copolymer derivatives based on poly(3-hexylthiophene) are established. Directed chemical design via side-chain functionalization with polar groups allows manipulation of ion transport and ion-to-electron transduction. Insights gained will permit increased use of the plethora of materials employed in the organic electronics area for application in the bioelectronics field.

JOURNAL ARTICLE

Parmar PA, St-Pierre J-P, Chow LW, Spicer CD, Stoichevska V, Peng YY, Werkmeister JA, Ramshaw JAM, Stevens MM, Parmar PA, St-Pierre J-P, Chow LW, Spicer CD, Stoichevska V, Peng YY, Werkmeister JA, Ramshaw JAM, Stevens MM, Parmar PA, St-Pierre J-P, Chow LW, Spicer CD, Stoichevska V, Peng YY, Werkmeister JA, Ramshaw JAM, Stevens MM, Parmar PA, St-Pierre J-P, Chow LW, Spicer CD, Stoichevska V, Peng YY, Werkmeister JA, Ramshaw JAM, Stevens MM, Parmar PA, St-Pierre JP, Chow LW, Spicer CD, Stoichevska V, Peng YY, Werkmeister JA, Ramshaw JAM, Stevens MMet al., 2017, Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen mimetic hydrogels, ACTA BIOMATERIALIA, Vol: 51, Pages: 75-88, ISSN: 1742-7061

Recapitulation of the articular cartilage microenvironment for regenerative medicine applications faces significant challenges due to the complex and dynamic biochemical and biomechanical nature of native tissue. Towards the goal of biomaterial designs that enable the temporal presentation of bioactive sequences, recombinant bacterial collagens such as Streptococcal collagen-like 2 (Scl2) proteins can be employed to incorporate multiple specific bioactive and biodegradable peptide motifs into a single construct. Here, we first modified the backbone of Scl2 with glycosaminoglycan-binding peptides and cross-linked the modified Scl2 into hydrogels via matrix metalloproteinase 7 (MMP7)-cleavable or non-cleavable scrambled peptides. The cross-linkers were further functionalized with a tethered RGDS peptide creating a system whereby the release from an MMP7-cleavable hydrogel could be compared to a system where release is not possible. The release of the RGDS peptide from the degradable hydrogels led to significantly enhanced expression of collagen type II (3.9-fold increase), aggrecan (7.6-fold increase), and SOX9 (5.2-fold increase) by human mesenchymal stem cells (hMSCs) undergoing chondrogenesis, as well as greater extracellular matrix accumulation compared to non-degradable hydrogels (collagen type II; 3.2-fold increase, aggrecan; 4-fold increase, SOX9; 2.8-fold increase). Hydrogels containing a low concentration of the RGDS peptide displayed significantly decreased collagen type I and X gene expression profiles, suggesting a major advantage over either hydrogels functionalized with a higher RGDS peptide concentration, or non-degradable hydrogels, in promoting an articular cartilage phenotype. These highly versatile Scl2 hydrogels can be further manipulated to improve specific elements of the chondrogenic response by hMSCs, through the introduction of additional bioactive and/or biodegradable motifs. As such, these hydrogels have the possibility to be used for other

JOURNAL ARTICLE

Pelaz B, Alexiou C, Alvarez -Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WCW, Chen C, Chen X, Chen X, Cheng Z, Cui D, Du J, Dullin C, Escudero A, Feliu N, Gao M, George M, Gogotsi Y, Grunweller A, Gu Z, Halas NJ, Hampp N, Hartmann RK, Hersam MC, Hunziker P, Jian J, Jiang X, Jungebluth P, Kadhiresan P, Kataoka K, Khademhosseini A, Kopecek J, Kotov NA, Krug HF, Lee DS, Lehr C-M, Leong KW, Liang X-J, Lim ML, Liz-Marzan LM, Ma X, Macchiarini P, Meng H, Mohwald H, Mulvaney P, Nel AE, Nie S, Nordlander P, Okano T, Oliveira J, Park TH, Penner RM, Prato M, Puntes V, Rotello VM, Samarakoon A, Schaak RE, Shen Y, Sjoqvist S, Skirtach AG, Soliman MG, Stevens MM, Sung H-W, Tang BZ, Tietze R, Udugama BN, VanEpps JS, Weil T, Weiss PS, Willner I, Wu Y, Yang L, Yue Z, Zhang Q, Zhang Q, Zhang X-E, Zhao Y, Zhou X, Parak WJ, Pelaz B, Alexiou C, Alvarez-Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WCW, Chen C, Chen X, Chen X, Cheng Z, Cui D, Du J, Dullin C, Escudero A, Feliu N, Gao M, George M, Gogotsi Y, Grünweller A, Gu Z, Halas NJ, Hampp N, Hartmann RK, Hersam MC, Hunziker P, Jian J, Jiang X, Jungebluth P, Kadhiresan P, Kataoka K, Khademhosseini A, Kopeček J, Kotov NA, Krug HF, Lee DS, Lehr C-M, Leong KW, Liang X-J, Ling Lim M, Liz-Marzán LM, Ma X, Macchiarini P, Meng H, Möhwald H, Mulvaney P, Nel AE, Nie S, Nordlander P, Okano T, Oliveira J, Park TH, Penner RM, Prato M, Puntes V, Rotello VM, Samarakoon A, Schaak RE, Shen Y, Sjöqvist S, Skirtach AG, Soliman MG, Stevens MM, Sung H-W, Tang BZ, Tietze R, Udugama BN, VanEpps JS, Weil T, Weiss PS, Willner I, Wu Y, Yang L, Yue Z, Zhang Q, Zhang Q, Zhang X-E, Zhao Y, Zhou X, Parak WJ, Pelaz B, Alexiou C, Alvarez-Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WCW, Chen C, Chen X, Chen X, Cheng Z, Cui D, Du J, Dullin C, Escudero A, Feliu N, Gao Met al., 2017, Diverse Applications of Nanomedicine, ACS NANO, Vol: 11, Pages: 2313-2381, ISSN: 1936-0851

The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

JOURNAL ARTICLE

Reznikov N, Phillips C, Cooke M, Garbout A, Ahmed F, Stevens MM, Reznikov N, Phillips C, Cooke M, Garbout A, Ahmed F, Stevens MM, Reznikov N, Phillips C, Cooke M, Garbout A, Ahmed F, Stevens MM, Reznikov N, Phillips C, Cooke M, Garbout A, Ahmed F, Stevens MMet al., 2017, Functional Adaptation of the Calcaneus in Historical Foot Binding., J Bone Miner Res, ISSN: 0884-0431

The normal structure of human feet is optimized for shock dampening during walking and running. Foot binding was a historical practice in China aimed at restricting the growth of female feet for aesthetic reasons. In a bound foot the shock-dampening function normally facilitated by the foot arches is withdrawn, resulting in the foot functioning as a rigid extension of the lower leg. An interesting question inspiring this study regards the nature of adaptation of the heel bone to this nonphysiological function using the parameters of cancellous bone anisotropy and 3D fabric topology and a novel intertrabecular angle (ITA) analysis. We found that the trabecular microarchitecture of the normal heel bone, but not of the bound foot, adapts to function by increased anisotropy and preferred orientation of trabeculae. The anisotropic texture in the normal heel bone consistently follows the physiological stress trajectories. However, in the bound foot heel bone the characteristic anisotropy pattern fails to develop, reflecting the lack of a normal biomechanical input. Moreover, the basic topological blueprint of cancellous bone investigated by the ITA method is nearly invariant in both normal and bound foot. These findings suggest that the anisotropic cancellous bone texture is an acquired characteristic that reflects recurrent loading conditions; conversely, an inadequate biomechanical input precludes the formation of anisotropic texture. This opens a long-sought-after possibility to reconstruct bone function from its form. The conserved topological parameters characterize the generic 3D fabric of cancellous bone, which is to a large extent independent of its adaptation to recurrent loading and perhaps determines the mechanical competence of trabecular bone regardless of its functional adaptation. © 2017 American Society for Bone and Mineral Research.

JOURNAL ARTICLE

Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Paiva MA, Schneider MD, Stevens MM, Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Abreu Paiva M, Schneider MD, Stevens MM, Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Abreu Paiva M, Schneider MD, Stevens MM, Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Abreu Paiva M, Schneider MD, Stevens MM, Speidel AT, Stuckey DJ, Chow LW, Jackson LH, Noseda M, Abreu Pavia M, Schneider MD, Stevens MMet al., 2017, Multimodal Hydrogel-Based Platform To Deliver and Monitor Cardiac Progenitor/Stem Cell Engraftment, ACS CENTRAL SCIENCE, Vol: 3, Pages: 338-348, ISSN: 2374-7943

Retention and survival of transplanted cells are major limitations to the efficacy of regenerative medicine, with short-term paracrine signals being the principal mechanism underlying current cell therapies for heart repair. Consequently, even improvements in short-term durability may have a potential impact on cardiac cell grafting. We have developed a multimodal hydrogel-based platform comprised of a poly(ethylene glycol) network cross-linked with bioactive peptides functionalized with Gd(III) in order to monitor the localization and retention of the hydrogel in vivo by magnetic resonance imaging. In this study, we have tailored the material for cardiac applications through the inclusion of a heparin-binding peptide (HBP) sequence in the cross-linker design and formulated the gel to display mechanical properties resembling those of cardiac tissue. Luciferase-expressing cardiac stem cells (CSC-Luc2) encapsulated within these gels maintained their metabolic activity for up to 14 days in vitro. Encapsulation in the HBP hydrogels improved CSC-Luc2 retention in the mouse myocardium and hind limbs at 3 days by 6.5- and 12- fold, respectively. Thus, this novel heparin-binding based, Gd(III)-tagged hydrogel and CSC-Luc2 platform system demonstrates a tailored, in vivo detectable theranostic cell delivery system that can be implemented to monitor and assess the transplanted material and cell retention.

JOURNAL ARTICLE

Spicer CD, Booth MA, Mawad D, Armgarth A, Nielsen CB, Stevens MM, Spicer CD, Booth MA, Mawad D, Armgarth A, Nielsen CB, Stevens MM, Spicer CD, Booth MA, Mawad D, Armgarth A, Nielsen CB, Stevens MM, Spicer CD, Booth MA, Mawad D, Armgarth A, Nielsen CB, Stevens MM, Spicer C, Booth M, Mawad D, Armgarth A, Nielsen C, Stevens MMet al., 2017, Synthesis of Hetero-bifunctional, End-Capped Oligo-EDOT Derivatives, CHEM, Vol: 2, Pages: 125-138, ISSN: 2451-9294

Conjugated oligomers of 3,4-ethylenedioxythiophene (EDOT) are attractive materials for tissue engineering applications and as model systems for studying the properties of the widely used polymer poly(3,4-ethylenedioxythiophene). We report here the facile synthesis of a series of keto-acid end-capped oligo-EDOT derivatives (n = 2-7) through a combination of a glyoxylation end-capping strategy and iterative direct arylation chain extension. Importantly, these structures not only represent the longest oligo-EDOTs reported but are also bench stable, in contrast to previous reports on such oligomers. The constructs reported here can undergo subsequent derivatization for integration into higher-order architectures, such as those required for tissue engineering applications. The synthesis of hetero-bifunctional constructs, as well as those containing mixed-monomer units, is also reported, allowing further complexity to be installed in a controlled manner. Finally, we describe the optical and electrochemical properties of these oligomers and demonstrate the importance of the keto-acid in determining their characteristics.

JOURNAL ARTICLE

Wang S-T, Lin Y, Hsu C-C, Aindursky N, Spicer CD, Stevens MM, Wang S-T, Lin Y, Hsu C-C, Amdursky N, Spicer CD, Stevens MM, Wang S-T, Lin Y, Hsu C-C, Amdursky N, Spicer CD, Stevens MM, Wang S-T, Lin Y, Hsu C-C, Amdursky N, Spicer CD, Stevens MM, Wang C, Lin Y, Hsu C, Amdursky N, Spicer C, Stevens MMet al., 2017, Probing amylin fibrillation at an early stage via a tetracysteine-recognising fluorophore, TALANTA, Vol: 173, Pages: 44-50, ISSN: 0039-9140

Amyloid fibrillation is a nucleation-dependent process known be involved in the development of more than 20 progressive and chronic diseases. The detection of amyloid formation at the nucleation stage can greatly advance early diagnoses and treatment of diseases. In this work, we developed a new assay for the early detection of amylin fibrillation using the biarsenical dye 4,5-bis(1,3,2-dithiarsolan-2-yl)fluorescein (FlAsH), which could recognise tetracysteine motifs and transform from non-fluorescent form into strongly fluorescent complexes. Due to the close proximity of two cysteine residues within the hydrophilic domain of amylin, a non-contiguous tetracysteine motif can form upon amylin dimerisation or oligomerisation, which can be recognised by FlAsH and emit strong fluorescence. This enables us to report the nucleation-growth process of amylin without modification of the protein sequence. We showed that the use of this assay not only allowed the tracking of initial nucleation events, but also enabled imaging of amyloid fibrils and investigation of the effects of amyloid inhibitor/modulator toward amylin fibrillation.

JOURNAL ARTICLE

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