Imperial College London

Professor Molly Stevens

Faculty of EngineeringDepartment of Materials

Professor of Biomedical Materials and 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

416 results found

Nagelkerke A, Ojansivu M, van der Koog L, Whittaker T, Cunnane E, Silva AM, Dekker N, Stevens Met al., 2021, Extracellular vesicles for tissue repair and regeneration: evidence, challenges and opportunities, Advanced Drug Delivery Reviews, Vol: 175, Pages: 1-28, ISSN: 0169-409X

Extracellular vesicles (EVs) are biological nanoparticles naturally secreted by cells, acting as delivery vehicles for molecular messages. During the last decade, EVs have been assigned multiple functions that have established their potential as therapeutic mediators for a variety of diseases and conditions. In this review paper, we report on the potential of EVs in tissue repair and regeneration. The regenerative properties that have been associated with EVs are explored, detailing the molecular cargo they carry that is capable of mediating such effects, the signaling cascades triggered in target cells and the functional outcome achieved. EV interactions and biodistribution in vivo that influence their regenerative effects are also described, particularly upon administration in combination with biomaterials. Finally, we review the progress that has been made for the successful implementation of EV regenerative therapies in a clinical setting.

Journal article

Becce M, Kloeckner A, Higgins S, Penders J, Hachim Diaz DJ, Bashor CJ, Edwards A, Stevens Met al., 2021, Assessing the impact of silicon nanowires on bacterial transformation and viability of Escherichia coli, Journal of Materials Chemistry B, Vol: 9, Pages: 4906-4914, ISSN: 2050-750X

We investigated the biomaterial interface between the bacteria Escherichia coli DH5α and silicon nanowire patterned surfaces. We optimised the engineering of silicon nanowire coated surfaces using metal-assisted chemical etching. Using a combination of focussed ion beam scanning electron microscopy, and cell viability and transformation assays, we found that with increasing interfacing force, cell viability decreases, as a result of increasing cell rupture. However, despite this aggressive interfacing regime, a proportion of the bacterial cell population remains viable. We found that the silicon nanowires neither resulted in complete loss of cell viability nor partial membrane disruption and corresponding DNA plasmid transformation. Critically, assay choice was observed to be important, as a reduction-based metabolic reagent was found to yield false-positive results on the silicon nanowire substrate. We discuss the implications of these results for the future design and assessment of bacteria–nanostructure interfacing experiments.

Journal article

Chung JJ, Yoo J, Sum BST, Li S, Lee S, Kim TH, Li Z, Stevens MM, Georgiou TK, Jung Y, Jones JRet al., 2021, 3D printed porous methacrylate/silica hybrid scaffold for bone substitution, Advanced Healthcare Materials, Vol: 10, Pages: 1-13, ISSN: 2192-2640

Inorganic–organic hybrid biomaterials made with star polymer poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate) and silica, which show promising mechanical properties, are 3D printed as bone substitutes for the first time, by direct ink writing of the sol. Three different inorganic:organic ratios of poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate)-star-SiO2 hybrid inks are printed with pore channels in the range of 100–200 µm. Mechanical properties of the 3D printed scaffolds fall within the range of trabecular bone, and MC3T3 pre-osteoblast cells are able to adhere to the scaffolds in vitro, regardless of their compositions. Osteogenic and angiogenic properties of the hybrid scaffolds are shown using a rat calvarial defect model. Hybrid scaffolds with 40:60 inorganic:organic composition are able to instigate new vascularized bone formation within its pore channels and polarize macrophages toward M2 phenotype. 3D printing inorganic–organic hybrids with sophisticated polymer structure opens up possibilities to produce novel bone graft materials.

Journal article

Guagliardo R, Herman L, Penders J, Zamborlin A, De Keersmaecker H, Van de Vyver T, Verstraeten S, Merckx P, Mingeot-Leclercq M-P, Echaide M, Pérez-Gil J, Stevens MM, De Smedt SC, Raemdonck Ket al., 2021, Surfactant protein B promotes cytosolic SiRNA delivery by adopting a virus-like mechanism of action, ACS Nano, Vol: 15, Pages: 8095-8109, ISSN: 1936-0851

RNA therapeutics are poised to revolutionize medicine. To unlock the full potential of RNA drugs, safe and efficient (nano)formulations to deliver them inside target cells are required. Endosomal sequestration of nanocarriers represents a major bottleneck in nucleic acid delivery. Gaining more detailed information on the intracellular behavior of RNA nanocarriers is crucial to rationally develop delivery systems with improved therapeutic efficiency. Surfactant protein B (SP-B) is a key component of pulmonary surfactant (PS), essential for mammalian breathing. In contrast to the general belief that PS should be regarded as a barrier for inhaled nanomedicines, we recently discovered the ability of SP-B to promote gene silencing by siRNA-loaded and lipid-coated nanogels. However, the mechanisms governing this process are poorly understood. The major objective of this work was to obtain mechanistic insights into the SP-B-mediated cellular delivery of siRNA. To this end, we combined siRNA knockdown experiments, confocal microscopy, and focused ion beam scanning electron microscopy imaging in an in vitro non-small-cell lung carcinoma model with lipid mixing assays on vesicles that mimic the composition of (intra)cellular membranes. Our work highlights a strong correlation between SP-B-mediated fusion with anionic endosomal membranes and cytosolic siRNA delivery, a mode of action resembling that of certain viruses and virus-derived cell-penetrating peptides. Building on these gained insights, we optimized the SP-B proteolipid composition, which dramatically improved delivery efficiency. Altogether, our work provides a mechanistic understanding of SP-B-induced perturbation of intracellular membranes, offering opportunities to fuel the rational design of SP-B-inspired RNA nanoformulations for inhalation therapy.

Journal article

Datta-Chaudhuri T, Zanos T, Chang EH, Olofsson PS, Bickel S, Bouton C, Grande D, Rieth L, Aranow C, Bloom O, Mehta AD, Civillico G, Stevens MM, Głowacki E, Bettinger C, Schüettler M, Puleo C, Rennaker R, Mohanta S, Carnevale D, Conde SV, Bonaz B, Chernoff D, Kapa S, Berggren M, Ludwig K, Zanos S, Miller L, Weber D, Yoshor D, Steinman L, Chavan SS, Pavlov VA, Al-Abed Y, Tracey KJet al., 2021, The Fourth Bioelectronic Medicine Summit "Technology Targeting Molecular Mechanisms": current progress, challenges, and charting the future., Bioelectronic Medicine, Vol: 7, ISSN: 2332-8886

There is a broad and growing interest in Bioelectronic Medicine, a dynamic field that continues to generate new approaches in disease treatment. The fourth bioelectronic medicine summit "Technology targeting molecular mechanisms" took place on September 23 and 24, 2020. This virtual meeting was hosted by the Feinstein Institutes for Medical Research, Northwell Health. The summit called international attention to Bioelectronic Medicine as a platform for new developments in science, technology, and healthcare. The meeting was an arena for exchanging new ideas and seeding potential collaborations involving teams in academia and industry. The summit provided a forum for leaders in the field to discuss current progress, challenges, and future developments in Bioelectronic Medicine. The main topics discussed at the summit are outlined here.

Journal article

Booth MA, Gowers SAN, Hersey M, Samper IC, Park S, Anikeeva P, Hashemi P, Stevens MM, Boutelle MGet al., 2021, Fiber-based electrochemical biosensors for monitoring pH and transient neurometabolic lactate., Analytical Chemistry, Vol: 93, Pages: 6646-6655, ISSN: 0003-2700

Developing tools that are able to monitor transient neurochemical dynamics is important to decipher brain chemistry and function. Multifunctional polymer-based fibers have been recently applied to monitor and modulate neural activity. Here, we explore the potential of polymer fibers comprising six graphite-doped electrodes and two microfluidic channels within a flexible polycarbonate body as a platform for sensing pH and neurometabolic lactate. Electrodes were made into potentiometric sensors (responsive to pH) or amperometric sensors (lactate biosensors). The growth of an iridium oxide layer made the fiber electrodes responsive to pH in a physiologically relevant range. Lactate biosensors were fabricated via platinum black growth on the fiber electrode, followed by an enzyme layer, making them responsive to lactate concentration. Lactate fiber biosensors detected transient neurometabolic lactate changes in an in vivo mouse model. Lactate concentration changes were associated with spreading depolarizations, known to be detrimental to the injured brain. Induced waves were identified by a signature lactate concentration change profile and measured as having a speed of ∼2.7 mm/min (n = 4 waves). Our work highlights the potential applications of fiber-based biosensors for direct monitoring of brain metabolites in the context of injury.

Journal article

Xianyu Y, Lin Y, Chen Q, Belessiotis-Richards A, Stevens M, Thomas Met al., 2021, Iodide-mediated rapid and sensitive surface etching of gold nanostars for biosensing, Angewandte Chemie International Edition, Vol: 60, Pages: 9891-9896, ISSN: 1433-7851

Iodide‐mediated surface etching can tailor the surface plasmon resonance of gold nanostars through etching of the high‐energy facets of the nanoparticle protrusions in a rapid and sensitive way. By exploring the underlying mechanisms of this etching and the key parameters influencing it (such as iodide, oxygen, pH, and temperature), we show its potential in a sensitive biosensing system. Horseradish peroxidase‐catalyzed oxidation of iodide enables control of the etching of gold nanostars to spherical gold nanoparticles, where the resulting spectral shift in the surface plasmon resonance yields a distinct color change of the solution. We further develop this enzyme‐modulated surface etching of gold nanostars into a versatile platform for plasmonic immunoassays, where a high sensitivity is possible by signal amplification via magnetic beads and click chemistry.

Journal article

Sabnis A, Haggard K, Kloeckner A, Becce M, Evans L, Furniss R, Mavridou D, Stevens M, Murphy R, Davies J, Clarke T, Edwards Aet al., 2021, Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane, eLife, Vol: 10, Pages: 1-26, ISSN: 2050-084X

Colistin is an antibiotic of last resort, but has poor efficacy and resistance is a growing problem. Whilst it is well established that colistin disrupts the bacterial outer membrane (OM) by selectively targeting lipopolysaccharide (LPS), it was unclear how this led to bacterial killing. We discovered that MCR-1 mediated colistin resistance in Escherichia coli is due to modified LPS at the cytoplasmic rather than OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). We then exploited this information to devise a new therapeutic approach. Using the LPS transport inhibitor murepavadin, we were able to cause LPS accumulation in the CM of Pseudomonas aeruginosa, which resulted in increased susceptibility to colistin in vitro and improved treatment efficacy in vivo. These findings reveal new insight into the mechanism by which colistin kills bacteria, providing the foundations for novel approaches to enhance therapeutic outcomes.

Journal article

Nelson M, Li S, Page SJ, Shi X, Lee PD, Stevens MM, Hanna JV, Jones JRet al., 2021, 3D printed silica-gelatin hybrid scaffolds of specific channel sizes promote collagen Type II, Sox9 and Aggrecan production from chondrocytes, Materials Science and Engineering: C, Vol: 123, Pages: 1-12, ISSN: 0928-4931

Inorganic/organic hybrids have co-networks of inorganic and organic components, with the aim of obtaining synergy of the properties of those components. Here, a silica-gelatin sol-gel hybrid “ink” was directly 3D printed to produce 3D grid-like scaffolds, using a coupling agent, 3-glycidyloxypropyl)trimethoxysilane (GPTMS), to form covalent bonds between the silicate and gelatin co-networks. Scaffolds were printed with 1 mm strut separation, but the drying method affected the final architecture and properties. Freeze drying produced <40 μm struts and large ~700 μm channels. Critical point drying enabled strut consolidation, with ~160 μm struts and ~200 μm channels, which improved mechanical properties. This architecture was critical to cellular response: when chondrocytes were seeded on the scaffolds with 200 μm wide pore channels in vitro, collagen Type II matrix was preferentially produced (negligible amount of Type I or X were observed), indicative of hyaline-like cartilaginous matrix formation, but when pore channels were 700 μm wide, Type I collagen was prevalent. This was supported by Sox9 and Aggrecan expression. The scaffolds have potential for regeneration of articular cartilage regeneration, particularly in sports medicine cases.

Journal article

Maynard SA, Pchelintseva E, Zwi-Dantsis L, Nagelkerke A, Gopal S, Korchev YE, Shevchuk A, Stevens Met al., 2021, IL-1β mediated nanoscale surface clustering of integrin α5β1 regulates the adhesion of mesenchymal stem cells, Scientific Reports, Vol: 11, Pages: 1-14, ISSN: 2045-2322

Clinical use of human mesenchymal stem cells (hMSCs) is limited due to their rapid clearance, reducing their therapeutic efficacy. The inflammatory cytokine IL-1β activates hMSCs and is known to enhance their engraftment. Consequently, understanding the molecular mechanism of this inflammation-triggered adhesion is of great clinical interest to improving hMSC retention at sites of tissue damage. Integrins are cell–matrix adhesion receptors, and clustering of integrins at the nanoscale underlies cell adhesion. Here, we found that IL-1β enhances adhesion of hMSCs via increased focal adhesion contacts in an α5β1 integrin-specific manner. Further, through quantitative super-resolution imaging we elucidated that IL-1β specifically increases nanoscale integrin α5β1 availability and clustering at the plasma membrane, whilst conserving cluster area. Taken together, these results demonstrate that hMSC adhesion via IL-1β stimulation is partly regulated through integrin α5β1 spatial organization at the cell surface. These results provide new insight into integrin clustering in inflammation and provide a rational basis for design of therapies directed at improving hMSC engraftment.

Journal article

Kim N, Kim E, Kim H, Thomas M, Najer A, Stevens Met al., 2021, Tumor-targeting cholesterol-decorated DNA nanoflowers for intracellular ratiometric aptasensing, Advanced Materials, Vol: 33, Pages: 1-10, ISSN: 0935-9648

Probing endogenous molecular profiles is of fundamental importance to understand cellular function and processes. Despite the promise of programmable nucleic‐acid‐based aptasensors across the breadth of biomolecular detection, target‐responsive aptasensors enabling intracellular detection are as of yet infrequently realized. Several challenges remain, including the difficulties in quantification/normalization of quencher‐based intensiometric signals, stability issues of the probe architecture, and complex sensor operations often necessitating extensive structural modeling. Here, the biomimetic crystallization‐empowered self‐assembly of a tumor‐targetable DNA–inorganic hybrid nanocomposite aptasensor is presented, which enables Förster resonance energy transfer (FRET)‐based quantitative interpretation of changes in the cellular target abundance. Leveraging the design programmability and high‐throughput fabrication of rolling circle amplification‐driven DNA nanoarchitecture, this designer platform offers a method to self‐assemble a robust nanosensor from a multifunctionality‐encoded template that includes a cell‐targeting aptamer, a ratiometric aptasensor, and a cholesterol‐decorating element. Taking prostate cancer cells and intracellular adenosine triphosphate molecules as a model system, a synergistic effect in the targeted delivery by cholesterol and aptamers, and the feasibility of quantitative intracellular aptasensing are demonstrated. It is envisioned that this approach provides a highly generalizable strategy across wide‐ranging target systems toward a biologically deliverable nanosensor that enables quantitative monitoring of the abundance of endogenous biomolecules.

Journal article

Horgan C, Bergholt MS, Thin MZ, Nagelkerke A, Kennedy R, Kalber TL, Stuckey D, Stevens Met al., 2021, Image-guided Raman spectroscopy probe-tracking for tumor margin delineation, Journal of Biomedical Optics, Vol: 26, Pages: 1-15, ISSN: 1083-3668

Significance: Tumor detection and margin delineation are essential for successful tumor resection. However, postsurgical positive margin rates remain high for many cancers. Raman spectroscopy has shown promise as a highly accurate clinical spectroscopic diagnostic modality, but its margin delineation capabilities are severely limited by the need for pointwise application.Aim: We aim to extend Raman spectroscopic diagnostics and develop a multimodal computer vision-based diagnostic system capable of both the detection and identification of suspicious lesions and the precise delineation of disease margins.Approach: We first apply visual tracking of a Raman spectroscopic probe to achieve real-time tumor margin delineation. We then combine this system with protoporphyrin IX fluorescence imaging to achieve fluorescence-guided Raman spectroscopic margin delineation.Results: Our system enables real-time Raman spectroscopic tumor margin delineation for both ex vivo human tumor biopsies and an in vivo tumor xenograft mouse model. We then further demonstrate that the addition of protoporphyrin IX fluorescence imaging enables fluorescence-guided Raman spectroscopic margin delineation in a tissue phantom model.Conclusions: Our image-guided Raman spectroscopic probe-tracking system enables tumor margin delineation and is compatible with both white light and fluorescence image guidance, demonstrating the potential for our system to be developed toward clinical tumor resection surgeries.

Journal article

Kit-Anan W, Mazo M, Wang BX, Leonardo V, Pence I, Gopal S, Gelmi A, Becce M, Chiappini C, Harding SE, Terracciano C, Stevens Met al., 2021, Multiplexing physical stimulation on single human induced pluripotent stem cell-derived cardiomyocytes for phenotype modulation, Biofabrication, Vol: 13, Pages: 1-16, ISSN: 1758-5082

Traditional in vitro bioengineering approaches whereby only individual biophysical cues are manipulated at any one time are highly inefficient, falling short when recapitulating the complexity of the cardiac environment. Multiple biophysical cues are present in the native myocardial niche and are essential during development, as well as in maintenance of adult cardiomyocyte (CM) phenotype in both health and disease. This study establishes a novel biofabrication workflow to study and manipulate hiPSC-CMs and to understand how these cells respond to a multiplexed biophysical environment, namely microscopic topography (3D shape resembling that of adult CM) and substrate stiffness, at a single cell level. Silicon masters were fabricated and developed to generate pillars of the desired 3D shapes, which would be used to mould the designed microwell arrays into a hydrogel. Polyacrylamide was modified with the incorporation of acrylic acid to provide a carboxylic group conjugation site for adhesion motifs, without comprising its capacity to modulate the stiffness. In this manner, individual parameters can be finely tuned independently within the hydrogel: the dimension of 3D shaped microwell and its stiffness. The design allows the platform to isolate single hiPSC-CMs to study solely biophysical cues in an absence of cell-cell physical interaction. Under physiologic-like physical conditions (3D shape resembling that of adult CM and 9.83 kPa substrate stiffness), isolated single hiPSC-CMs exhibit increased Cx-43 density, cell Peer reviewed version of the manuscript published in final form at Biofabrication (2020). membrane stiffness and calcium transient amplitude; co-expression of the subpopulation-related MYL2- MYL7 proteins; while displaying higher anisotropism in comparison to pathologic-like conditions (flat surface and 112 kPa substrate stiffness). This demonstrates that supplying a physiological or pathological microenvironment to an isolated single hiPSC-CM in absen

Journal article

Pinna A, Baghbaderani MT, Hernandez VV, Naruphontjirakul P, Li S, McFarlane T, Hachim D, Stevens MM, Porter AE, Jones JRet al., 2021, Nanoceria provides antioxidant and osteogenic properties to mesoporous silica nanoparticles for osteoporosis treatment, ACTA BIOMATERIALIA, Vol: 122, Pages: 365-376, ISSN: 1742-7061

Journal article

Lin Y, Penna M, Spicer CD, Higgins SG, Gelmi A, Kim N, Wang S-T, Wojciechowski JP, Pashuck ET, Yarovsky I, Stevens MMet al., 2021, High-throughput peptide derivatization toward supramolecular diversification in microtiter plates, ACS Nano, Vol: 15, Pages: 4034-4044, ISSN: 1936-0851

The evolution of life on earth eventually leads to the emergence of species with increased complexity and diversity. Similarly, evolutionary chemical space exploration in the laboratory is a key step to pursue the structural and functional diversity of supramolecular systems. Here, we present a powerful tool that enables rapid peptide diversification and employ it to expand the chemical space for supramolecular functions. Central to this strategy is the exploitation of palladium-catalyzed Suzuki-Miyaura cross-coupling reactions to direct combinatorial synthesis of peptide arrays in microtiter plates under an open atmosphere. Taking advantage of this in situ library design, our results unambiguously deliver a fertile platform for creating a set of intriguing peptide functions including green fluorescent protein-like peptide emitters with chemically encoded emission colors, hierarchical self-assembly into nano-objects, and macroscopic hydrogels. This work also offers opportunities for quickly surveying the diversified peptide arrays and thereby identifying the structural factors that modulate peptide properties.

Journal article

Puetzer JL, Ma T, Sallent I, Gelmi A, Stevens Met al., 2021, Driving hierarchical collagen fiber formation for functional tendon, ligament and meniscus replacement, Biomaterials, Vol: 269, Pages: 1-10, ISSN: 0142-9612

Hierarchical collagen fibers are the primary source of strength in musculoskeletal tendons, ligaments, and menisci. It has remained a challenge to develop these large fibers in engineered replacements or in vivo after injury. The objective of this study was to investigate the ability of restrained cell-seeded high density collagen gels to drive hierarchical fiber formation for multiple musculoskeletal tissues. We found boundary conditions applied to high density collagen gels were capable of driving tenocytes, ligament fibroblasts, and meniscal fibrochondrocytes to develop native-sized hierarchical collagen fibers 20–40 μm in diameter. The fibers organize similar to bovine juvenile collagen with native fibril banding patterns and hierarchical fiber bundles 50–350 μm in diameter by 6 weeks. Mirroring fiber organization, tensile properties of restrained samples improved significantly with time, reaching ~1 MPa. Additionally, tendon, ligament, and meniscal cells produced significantly different sized fibers, different degrees of crimp, and different GAG concentrations, which corresponded with respective juvenile tissue. To our knowledge, these are some of the largest, most organized fibers produced to date in vitro. Further, cells produced tissue specific hierarchical fibers, suggesting this system is a promising tool to better understand cellular regulation of fiber formation to better stimulate it in vivo after injury.

Journal article

Li C, Ouyang L, Armstrong J, Stevens Met al., 2021, Advances in the fabrication of biomaterials for gradient tissue engineering, Trends in Biotechnology, Vol: 39, Pages: 150-164, ISSN: 0167-7799

Natural tissues and organs exhibit an array of spatial gradients, from the polar-ized neural tube during embryonic development to the osteochondral interfacepresent at articulating joints. The strong structure–function relationships inthese heterogeneous tissues have sparked intensive research into the develop-ment of methods that can replicate physiological gradients in engineered tis-sues. In this Review, we consider different gradients present in natural tissuesand discuss their critical importance in functional tissue engineering. Using thisbasis, we consolidate the existing fabrication methods into four categories: addi-tive manufacturing, component redistribution, controlled phase changes, andpostmodification. We have illustrated this with recent examples, highlightedprominent trends in thefield, and outlined a set of criteria and perspectives forgradient fabrication.

Journal article

Solanki A, Lali F, Autefage H, Agarwal S, Nommeots-Nomm A, Metcalfe A, Stevens M, Jones Jet al., 2021, Bioactive glasses and electrospun composites that release cobalt to stimulate the HIF pathway for wound healing applications, Biomaterials Research, Vol: 25, ISSN: 2055-7124

BackgroundBioactive glasses are traditionally associated with bonding to bone through a hydroxycarbonate apatite (HCA) surface layer but the release of active ions is more important for bone regeneration. They are now being used to deliver ions for soft tissue applications, particularly wound healing. Cobalt is known to simulate hypoxia and provoke angiogenesis. The aim here was to develop new bioactive glass compositions designed to be scaffold materials to locally deliver pro-angiogenic cobalt ions, at a controlled rate, without forming an HCA layer, for wound healing applications.MethodsNew melt-derived bioactive glass compositions were designed that had the same network connectivity (mean number of bridging covalent bonds between silica tetrahedra), and therefore similar biodegradation rate, as the original 45S5 Bioglass. The amount of magnesium and cobalt in the glass was varied, with the aim of reducing or removing calcium and phosphate from the compositions. Electrospun poly(ε-caprolactone)/bioactive glass composites were also produced. Glasses were tested for ion release in dissolution studies and their influence on Hypoxia-Inducible Factor 1-alpha (HIF-1α) and expression of Vascular Endothelial Growth Factor (VEGF) from fibroblast cells was investigated.ResultsDissolution tests showed the silica rich layer differed depending on the amount of MgO in the glass, which influenced the delivery of cobalt. The electrospun composites delivered a more sustained ion release relative to glass particles alone. Exposing fibroblasts to conditioned media from these composites did not cause a detrimental effect on metabolic activity but glasses containing cobalt did stabilise HIF-1α and provoked a significantly higher expression of VEGF (not seen in Co-free controls).ConclusionsThe composite fibres containing new bioactive glass compositions delivered cobalt ions at a sustained rate, which could be mediated by the magnesium content of the glass. The dis

Journal article

Horgan C, Bergholt M, Nagelkerke A, Thin MZ, Pence IJ, Kauscher U, Kalber TL, Stuckey D, Stevens Met al., 2021, Integrated photodynamic Raman theranostic system for cancer diagnosis, treatment, and post-treatment molecular monitoring, Theranostics, Vol: 11, Pages: 2006-2019, ISSN: 1838-7640

Theranostics, the combination of diagnosis and therapy, has long held promise as a means to achieving personalised precision cancer treatments. However, despite its potential, theranostics has yet to realise significant clinical translation, largely due the complexity and overriding toxicity concerns of existing theranostic nanoparticle strategies.Methods: Here, we present an alternative nanoparticle-free theranostic approach based on simultaneous Raman spectroscopy and photodynamic therapy (PDT) in an integrated clinical platform for cancer theranostics.Results: We detail the compatibility of Raman spectroscopy and PDT for cancer theranostics, whereby Raman spectroscopic diagnosis can be performed on PDT photosensitiser-positive cells and tissues without inadvertent photosensitiser activation/photobleaching or impaired diagnostic capacity. We further demonstrate that our theranostic platform enables in vivo tumour diagnosis, treatment, and post-treatment molecular monitoring in real-time.Conclusion: This system thus achieves effective theranostic performance, providing a promising new avenue towards the clinical realisation of theranostics.

Journal article

Sero JE, Stevens MM, 2021, Nanoneedle-Based Materials for Intracellular Studies, BIO-NANOMEDICINE FOR CANCER THERAPY, Editors: Fontana, Santos, Publisher: SPRINGER INTERNATIONAL PUBLISHING AG, Pages: 191-219, ISBN: 978-3-030-58173-2

Book chapter

Richards DA, Thomas M, Szijj P, Foote J, Chen Y, Nogueira CF, Chudasama V, Stevens Met al., 2021, Employing defined bioconjugates to generate chemically functionalised gold nanoparticles for in vitro diagnostic applications, Nanoscale, ISSN: 2040-3364

Journal article

Potter M, Najer A, Kloeckner A, Zhang S, Holme MN, Nele V, Che J, Penders J, Saunders C, Doutch JJ, Edwards A, Ces O, Stevens Met al., 2020, Controlled dendrimersome nanoreactor system for localised hypochlorite-induced killing of bacteria, ACS Nano, Vol: 14, Pages: 17333-17353, ISSN: 1936-0851

Antibiotic resistance is a serious global health problem necessitating new bactericidal approaches such as nanomedicines. Dendrimersomes (DSs) have recently become a valuable alternative nanocarrier to polymersomes and liposomes due to their molecular definition and synthetic versatility. Despite this, their biomedical application is still in its infancy. Inspired by the localized antimicrobial function of neutrophil phagosomes and the versatility of DSs, a simple three-component DS-based nanoreactor with broad-spectrum bactericidal activity is presented. This was achieved by encapsulation of glucose oxidase (GOX) and myeloperoxidase (MPO) within DSs (GOX-MPO-DSs), self-assembled from an amphiphilic Janus dendrimer, that possesses a semipermeable membrane. By external addition of glucose to GOX-MPO-DS, the production of hypochlorite (−OCl), a highly potent antimicrobial, by the enzymatic cascade was demonstrated. This cascade nanoreactor yielded a potent bactericidal effect against two important multidrug resistant pathogens, Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), not observed for H2O2 producing nanoreactors, GOX-DS. The production of highly reactive species such as –OCl represents a harsh bactericidal approach that could also be cytotoxic to mammalian cells. This necessitates the development of strategies for activating –OCl production in a localized manner in response to a bacterial stimulus. One option of locally releasing sufficient amounts of substrate using a bacterial trigger (released toxins) was demonstrated with lipidic glucose-loaded giant unilamellar vesicles (GUVs), envisioning, e.g., implant surface modification with nanoreactors and GUVs for localized production of bactericidal agents in the presence of bacterial growth.

Journal article

Maynard S, Gelmi A, Skaalure S, Pence I, Lee-Reeves C, Sero J, Whittaker T, Stevens Met al., 2020, Nanoscale molecular quantification of stem cell-hydrogel interactions, ACS Nano, Vol: 14, Pages: 17321-17332, ISSN: 1936-0851

A common approach to tailoring synthetic hydrogels for regenerative medicine applications involves incorporating RGD cell adhesion peptides, yet assessing the cellular response to engineered microenvironments at the nanoscale remains challenging. To date, no study has demonstrated how RGD concentration in hydrogels affects the presentation of individual cell surface receptors. Here we studied the interaction between human mesenchymal stem cells (hMSCs) and RGD-functionalized poly(ethylene glycol) hydrogels, by correlating macro- and nanoscale single-cell interfacial quantification techniques. We quantified RGD unbinding forces on a synthetic hydrogel using single cell atomic force spectroscopy, revealing that short-term binding of hMSCs was sensitive to RGD concentration. We also performed direct stochastic optical reconstruction microscopy (dSTORM) to quantify the molecular interactions between integrin α5β1 and a biomaterial, unexpectedly revealing that increased integrin clustering at the hydrogel-cell interface correlated with fewer available RGD binding sites. Our complementary, quantitative approach uncovered mechanistic insights into specific stem cell-hydrogel interactions, where dSTORM provides nanoscale sensitivity to RGD-dependent differences in cell surface localization of integrin α5β1. Our findings reveal that it is possible to precisely determine how peptide-functionalized hydrogels interact with cells at the molecular scale, thus providing a basis to fine-tune the spatial presentation of bioactive ligands.

Journal article

Belessiotis-Richards A, Higgins S, Sansom MSP, Alexander-Katz A, Stevens Met al., 2020, Coarse Grained Simulations Suggest the Epsin N-Terminal Homology Domain Can Sense Membrane Curvature Without its Terminal Amphipathic Helix, ACS Nano, Vol: 14, Pages: 16919-6928, ISSN: 1936-0851

Nanoscale membrane curvature is a common feature in cell biology required for functions such as endocytosis, exocytosis and cell migration. These processes require the cytoskeleton to exert forces on the membrane to deform it. Cytosolic proteins contain specific motifs which bind to the membrane, connecting it to the internal cytoskeletal machinery. These motifs often bind charged phosphatidylinositol phosphate lipids present in the cell membrane which play significant roles in signaling. These lipids are important for membrane deforming processes, such as endocytosis, but much remains unknown about their role in the sensing of membrane nanocurvature by protein domains. Using coarse-grained molecular dynamics simulations, we investigated the interaction of a model curvature active protein domain, the epsin N-terminal homology domain (ENTH), with curved lipid membranes. The combination of anionic lipids (phosphatidylinositol 4,5-bisphosphate and phosphatidylserine) within the membrane, protein backbone flexibility, and structural changes within the domain were found to affect the domain's ability to sense, bind, and localize with nanoscale precision at curved membrane regions. The findings suggest that the ENTH domain can sense membrane curvature without the presence of its terminal amphipathic α helix <i>via</i> another structural region we have denoted as H3, re-emphasizing the critical relationship between nanoscale membrane curvature and protein function.

Journal article

J C, Najer A, Blakney A, McKay P, Bellahcene M, Winter C, Sintou A, Tang J, Keane TJ, Schneider M, Shattock R, Sattler S, Stevens Met al., 2020, Neutrophils enable local and non-invasive liposome delivery to inflamed skeletal muscle and ischemic heart, Advanced Materials, Vol: 32, Pages: 1-10, ISSN: 0935-9648

Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease, and cancer. Improving localized delivery of immunosuppressive drugs to inflamed tissue in a non‐invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Here, a neutrophil‐mediated delivery system able to transport drug‐loaded nanocarriers to inflamed tissue by exploiting the inherent ability of neutrophils to migrate to inflammatory tissue is reported. This hybrid system (neutrophils loaded with liposomes ex vivo) efficiently migrates in vitro following an inflammatory chemokine gradient. Furthermore, the triggered release of loaded liposomes and reuptake by target macrophages is studied. The migratory behavior of liposome‐loaded neutrophils is confirmed in vivo by demonstrating the delivery of drug‐loaded liposomes to an inflamed skeletal muscle in mice. A single low‐dose injection of the hybrid system locally reduces inflammatory cytokine levels. Biodistribution of liposome‐loaded neutrophils in a human‐disease‐relevant myocardial ischemia reperfusion injury mouse model after i.v. injection confirms the ability of injected neutrophils to carry loaded liposomes to inflammation sites. This strategy shows the potential of nanocarrier‐loaded neutrophils as a universal platform to deliver anti‐inflammatory drugs to promote tissue regeneration in inflammatory diseases.

Journal article

Armstrong JPK, Keane TJ, Roques AC, Stephen Patrick P, Mooney CM, Kuan W-L, Pisupati V, Oreffo ROC, Stuckey D, Watt FM, Forbes SJ, Barker RA, Stevens Met al., 2020, A blueprint for translational regenerative medicine, Science Translational Medicine, Vol: 12, ISSN: 1946-6234

The last few decades have produced a large number of proof-of-concept studies in regenerative medicine.However, the route to clinical adoption is fraught with technical and translational obstacles that frequentlyconsign promising academic solutions to the so-called “valley of death.” This review is intended to serve as ablueprint for translational regenerative medicine: we suggest principles to help guide cell and materialselection, present key in vivo imaging modalities and argue that the host immune response should beconsidered throughout therapeutic development. Finally, we suggest a pathway to navigate the oftencomplex regulatory and manufacturing landscape of translational regenerative medicine.

Journal article

Hogset H, Horgan C, Bergholt M, Armstrong J, Torraca V, Chen Q, Keane TJ, Bugeon L, Dallman M, Mostowy S, Stevens Met al., 2020, In vivo biomolecular imaging of zebrafish embryos using confocal Raman spectroscopy, Nature Communications, Vol: 11, Pages: 1-12, ISSN: 2041-1723

Zebrafish embryos provide a unique opportunity to visualize complex biological processes, yet conventional imaging modalities are unable to access intricate biomolecular information without compromising the integrity of the embryos. Here, we report the use of confocal Raman spectroscopic imaging for the visualization and multivariate analysis of biomolecular information extracted from unlabeled zebrafish embryos. We outline broad applications of this method in: (i) visualizing the biomolecular distribution of whole embryos in three dimensions, (ii) resolving anatomical features at subcellular spatial resolution, (iii) biomolecular profiling and discrimination of wild type and ΔRD1 mutant Mycobacterium marinum strains in a zebrafish embryo model of tuberculosis and (iv) in vivotemporal monitoring of the wound response in living zebrafish embryos.Overall, this study demonstrates the application of confocal Raman spectroscopic imaging for the comparative bimolecular analysis in fully intact and living zebrafish embryos.

Journal article

Finbloom JA, Sousa F, Stevens MM, Desai TAet al., 2020, Engineering the drug carrier biointerface to overcome biological barriers to drug delivery, Advanced Drug Delivery Reviews, Vol: 167, Pages: 89-108, ISSN: 0169-409X

Micro and nanoscale drug carriers must navigate through a plethora of dynamic biological systems prior to reaching their tissue or disease targets. The biological obstacles to drug delivery come in many forms and include tissue barriers, mucus and bacterial biofilm hydrogels, the immune system, and cellular uptake and intracellular trafficking. The biointerface of drug carriers influences how these carriers navigate and overcome biological barriers for successful drug delivery. In this review, we examine how key material design parameters lead to dynamic biointerfaces and improved drug delivery across biological barriers. We provide a brief overview of approaches used to engineer key physicochemical properties of drug carriers, such as morphology, surface chemistry, and topography, as well as the development of dynamic responsive materials for barrier navigation. We then discuss essential biological barriers and how biointerface engineering can enable drug carriers to better navigate and overcome these barriers to drug delivery.

Journal article

Maynard S, Winter C, Cunnane E, Stevens Met al., 2020, Advancing cell instructive biomaterials through increased understanding of cell receptor spacing and material surface functionalization, Regenerative Engineering and Translational Medicine, ISSN: 2364-4133

Regenerative medicine is aimed at restoring normal tissue function and can benefit from the application of tissue engineering and nano-therapeutics. In order for regenerative therapies to be effective, the spatiotemporal integration of tissue-engineered scaffolds by the native tissue, and the binding/release of therapeutic payloads by nano-materials, must be tightly controlled at the nanoscale in order to direct cell fate. However, due to a lack of insight regarding cell–material interactions at the nanoscale and subsequent downstream signaling, the clinical translation of regenerative therapies is limited due to poor material integration, rapid clearance, and complications such as graft-versus-host disease. This review paper is intended to outline our current understanding of cell–material interactions with the aim of highlighting potential areas for knowledge advancement or application in the field of regenerative medicine. This is achieved by reviewing the nanoscale organization of key cell surface receptors, the current techniques used to control the presentation of cell-interactive molecules on material surfaces, and the most advanced techniques for characterizing the interactions that occur between cell surface receptors and materials intended for use in regenerative medicine.Lay SummaryThe combination of biology, chemistry, materials science, and imaging technology affords exciting opportunities to better diagnose and treat a wide range of diseases. Recent advances in imaging technologies have enabled better understanding of the specific interactions that occur between human cells and their immediate surroundings in both health and disease. This biological understanding can be used to design smart therapies and tissue replacements that better mimic native tissue. Here, we discuss the advances in molecular biology and technologies that can be employed to functionalize materials and characterize their interaction with biological entities to facilita

Journal article

Higgins S, Lo Fiego A, Patrick I, Creamer A, Stevens Met al., 2020, Organic bioelectronics: using highly conjugated polymers to interface with biomolecules, cells and tissues in the human body, Advanced Materials Technologies, Vol: 5, Pages: 1-35, ISSN: 2365-709X

Conjugated polymers exhibit interesting material and optoelectronic properties that makethem well-suited to the development of biointerfaces. Their biologically relevant mechanicalcharacteristics, ability to be chemically modified, and mixed electronic and ionic chargetransport are captured within the diverse field of organic bioelectronics. Conjugated polymershave been used in wide range of device architectures, and cell and tissue scaffolds. Thesedevices enable biosensing of many biomolecules, such as metabolites, nucleic acids and more.Devices can be used to both stimulate and sense the behavior of cells and tissues. Similarly,tissue interfaces permit interaction with complex organs, aiding both fundamental biologicalunderstanding and providing new opportunities for stimulating regenerative behaviors andbioelectronic based therapeutics. Applications of these materials are broad, and muchcontinues to be uncovered about their fundamental properties. This report covers the currentunderstanding of the fundamentals of conjugated polymer biointerfaces and their interactionswith biomolecules, cells and tissues in the human body. An overview of current materials anddevices is presented, along with highlighted major in vivo and in vitro applications. Finally,open research questions and opportunities are discussed.

Journal article

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