Imperial College London

Professor Molly Stevens

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

364 results found

Ouyang L, Armstrong J, Salmeron-Sanchez M, Stevens Met al., 2020, Assembly of living building blocks to engineer complex tissues, Advanced Functional Materials, ISSN: 1616-301X

The great demand for tissue and organ grafts, compounded by an aging demographic and a shortage of available donors, has driven the development of bioengineering approaches that can generate biomimetic tissues in vitro. Despite the considerable progress in conventional scaffold‐based tissue engineering, the recreation of physiological complexity has remained a challenge. Bottom‐up tissue engineering strategies have opened up a new avenue for the modular assembly of living building blocks into customized tissue architectures. This Progress Report overviews the recent progress and trends in the fabrication and assembly of living building blocks, with a key highlight on emerging bioprinting technologies that can be used for modular assembly and complexity in tissue engineering. By summarizing the work to date, providing new classifications of different living building blocks, highlighting state‐of‐the‐art research and trends, and offering personal perspectives on future opportunities, this Progress Report aims to aid and inspire other researchers working in the field of modular tissue engineering.

Journal article

Wang ST, Gray MA, Xuan S, Lin Y, Byrnes J, Nguyen AI, Todorova N, Stevens M, Bertozzi CR, Zuckermann RN, Gang Oet al., DNA Origami Protection and Molecular Interfacing through Engineered Sequence-Defined Peptoids, Proceedings of the National Academy of Sciences of USA, ISSN: 0027-8424

Journal article

Spicer CD, Pujari-Palmer M, Autefage H, Insley G, Procter P, Engqvist H, Stevens M, Stevens Met al., Synthesis of phospho-amino acid analogues as tissue adhesive cement additives, ACS Central Science, ISSN: 2374-7943

Journal article

Blache U, Stevens M, Gentleman E, Harnessing the secreted extracellular matrix to engineer tissues, Nature Biomedical Engineering, ISSN: 2157-846X

Journal article

Higgins S, Becce M, Belessiotis Richards A, Seong H, Sero J, Stevens Met al., High-aspect-ratio nanostructured surfaces as biological metamaterials, Advanced Materials, ISSN: 0935-9648

Materials patterned with high-aspect-ratio nanostructures have features on similar lengthscales to cellular components. These surfaces are an extreme topography on the cellular leveland have become useful tools for perturbing and sensing the cellular environment. Motivationcomes from the ability of high-aspect-ratio nanostructures to deliver cargoes into cells andtissues, access the intracellular environment, and control cell behavior. These structuresdirectly perturb cells’ ability to sense and respond to external forces, influencing cell fate andenabling new mechanistic studies. Through careful design of their nanoscale structure, thesesystems act as biological metamaterials, eliciting unusual biological responses. Whilepredominantly used to interface eukaryotic cells, there is growing interest in non-animal andprokaryotic cell interfacing. Both experimental and theoretical studies have attempted todevelop a mechanistic understanding for the observed behaviors, predominantly focusing onthe cell – nanostructure interface. Here, we consider how high-aspect-ratio nanostructuredsurfaces are used to both stimulate and sense biological systems and discuss remainingresearch questions.

Journal article

Kim N, Thomas MR, Bergholt MS, Pence IJ, Seong H, Charchar P, Todorova N, Nagelkerke A, Belessiotis-Richard A, Payne D, Gelmi A, Yarovsky I, Stevens Met al., Surface enhanced raman scattering artificial nose for high dimensionality fingerprinting, Nature Communications, ISSN: 2041-1723

Label-free surface-enhanced Raman spectroscopy (SERS) can interrogate systems by directly fingerprinting its components’ unique physicochemical properties. In complex biological systemshowever, this can yield highly overlapping spectra that hinder sample identification. Here, we present an artificial-nose inspired SERS fingerprinting approach where spectral data is obtained as a function of sensor surface chemical functionality. Supported by molecular dynamics modelling, we show that mildly selective self-assembled monolayers can influence the strength and configuration in which analytes interact with plasmonic surfaces, diversifying the resulting SERS fingerprints. Since each sensor generates a modulated signature, the implicit value of increasing the dimensionality of datasets is shown using cell lysates for all possible combinations of up to 9 fingerprints. Reliable improvements in mean discriminatory accuracy towards 100% is achieved with each additional surface functionality. This arrayed label-free platform illustrates the wide-ranging potential of high dimensionality artificial-nose based sensing systems for more reliable assessment of complex biological matrices.

Journal article

Nele V, Schutt CE, Wojciechowski J, Kit-Anan W, Doutch JJ, Armstrong J, Stevens Met al., Ultrasound-triggered enzymatic gelation, Advanced Materials, ISSN: 0935-9648

Hydrogels are formed using various triggers, including light irradiation, pH adjustment, heating,cooling or chemical addition. In this report, a new method for forming hydrogels is introduced:ultrasound-triggered enzymatic gelation. Specifically, ultrasound is used as a stimulus to liberateliposomal calcium ions, which then trigger the enzymatic activity of transglutaminase. Theactivated enzyme catalyzes the formation of fibrinogen hydrogels through covalent intermolecularcrosslinking. The catalysis and gelation processes are monitored in real time and both the enzymekinetics and final hydrogel properties are controlled by varying the initial ultrasound exposure time.This technology is extended to microbubble-liposome conjugates, which exhibit a stronger responseto the applied acoustic field and are also used for ultrasound-triggered enzymatic hydrogelation. Tothe best of our knowledge, these results are the first instance in which ultrasound has been used as atrigger for either enzyme catalysis or enzymatic hydrogelation. This approach is highly versatile and Peer reviewed version of the manuscript published in final form at Advanced Materials (2020)2could be readily applied to different ion-dependent enzymes or gelation systems. Moreover, thiswork paves the way for the use of ultrasound as a remote trigger for in vivo hydrogelation.

Journal article

Ouyang L, Armstrong J, Chen Q, Lin Y, Stevens Met al., 2020, Void-free 3D bioprinting for in-situ endothelialization and microfluidic perfusion, Advanced Functional Materials, Vol: 30, ISSN: 1616-301X

Two major challenges of 3D bioprinting are the retention of structural fidelity and efficient endothelialization for tissue vascularization. We address both of these issues by introducinga versatile3D bioprinting strategy, in which a templating bioink is deposited layer-by-layer alongside a matrix bioink to establish void-free multimaterial structures. After crosslinking the matrix phase, the templating phase issacrificedto create a well-defined 3D network of interconnected tubular channels. This void-free 3D printing (VF-3DP) approachcircumvents the traditional concerns of structural collapse, deformation and oxygen inhibition, moreover, it can be readily used to printmaterials that are widely considered “unprintable”. By pre-loading endothelial cells into the templating bioink, the inner surface of the channels can be efficiently cellularized with a confluent endothelial layer. This in-situ endothelializationmethod can be used to produce endothelium with a far greater uniformity than can be achieved using the conventional post-seeding approach. This VF-3DP approach canalsobe extended beyond tissue fabrication and towards customized hydrogel-based microfluidics and self-supported perfusable hydrogel constructs.

Journal article

Hansel C, Holme M, Gopal S, Stevens Met al., 2020, Advances in high-resolution microscopy for the study of intracellular interactions with biomaterials, Biomaterials, Vol: 226, ISSN: 0142-9612

The study of sophisticated biomaterials and their cellular targets requires visualization methods with exquisite spatial and temporal resolution to discern cell organelles and molecular events. Monitoring cell-material interactions at high resolution is key for the continued development and optimization of biomaterials, for monitoring cell uptake of cargo, and for understanding the cell response to extracellular cues. This review evaluates the advantages and disadvantages of different forms of electron microscopy and super-resolution microscopy in elucidating how biomaterial surface chemistry and topography can affect intracellular events at the nanoscale.

Journal article

Liu H, Du Y, St-Pierre J-P, Bergholt MS, Autefage H, Wang J, Cai M, Yang G, Stevens M, Shengmin Zet al., Bioenergetic-active materials enhance tissue regeneration by modulating cellular metabolic state, Science Advances, ISSN: 2375-2548

Cellular bioenergetics (CBE) plays a critical role in tissue regeneration. Physiologically, an enhanced metabolic state facilitates anabolic biosynthesis and mitosis to accelerate regeneration. However, the development of approaches to reprogram CBE, towards the treatment of substantial tissue injuries, hasbeen limited thus far. Here, we show that induced repair in a rabbit model of weight-bearing bone defects is greatly enhanced using a bioenergetic-active material (BAM) scaffold, compared to commercialized poly (lactic acid) and calcium phosphate ceramic scaffolds. This material was composed of energy-active units that can be released in a sustained degradation-mediated fashion once implanted. By establishing an intramitochondrial metabolic bypass, the internalized energy-active units significantly elevatemitochondria membrane potential (ΔΨm) to supply increased bioenergetic levels and accelerate bone formation. The ready-to-use material developed here represents a highly efficient and easy-to-implement therapeutic approach toward tissue regeneration, withpromise for bench-to-bedside translation.

Journal article

Zwi Dantsis L, Wang B, Marijon C, Zonetti S, Ferrini A, Massi L, Stuckey DJ, Terracciano C, Stevens Met al., Remote magnetic nanoparticle manipulation enables the dynamic patterning of cardiac tissues, Advanced Materials, ISSN: 0935-9648

The ability to manipulate cellular organization within soft materials has important potential in biomedicine and regenerative medicine; however, it often requires complex fabrication procedures. Here, we develop a simple, cost-effective, and one-step approach that enables the control of cell orientation within 3-dimensional (3D) collagen hydrogels to dynamically create various tailored microstructures of cardiac tissues. This isachieved by incorporating iron-oxide nanoparticles into human cardiomyocytes (CMs) and applying a short-term external magnetic field to orient the cells along the applied field to impart different shapes without any mechanical supports. The patterned constructs areviable and functional, canbe detected by T2*-weighted MRI and induceno alteration to normal cardiac function after grafting onto rat hearts. This strategy paves the way to creating customized, macroscale, 3D tissue constructs with various cell-types for therapeutic and bioengineering applications, as well as providing powerful models for investigating tissue behavior.

Journal article

Bjornmalm A, Wong LM, Wojciechowski J, Penders J, Horgan C, Booth MA, Martin NG, Sattler S, Stevens Met al., 2019, In vivo biocompatibility and immunogenicity of metal-phenolic gelation, Chemical Science, Vol: 10, Pages: 10179-10194, ISSN: 2041-6520

In vivo forming hydrogels are of interest for diverse biomedical applications due totheir ease-of-use and minimal invasiveness and therefore high translational potential. Supramolecular hydrogels that can be assembled usingmetal–phenolic coordination of naturally occurring polyphenols and group IV metal ions (e.g. TiIVor ZrIV) provide a versatile and robust platform for engineering such materials. However, the in situformation and in vivoresponse tothis new class of materials has not yet been reported. Here, we demonstrate that metal–phenolic supramolecular gelation occurs successfully in vivo and we investigate the host response to the material over 14 weeks. TheTiIV–tannic acid materials form stable gels that are well-tolerated following subcutaneous injection. Histology reveals a mild foreign body reaction, and titanium biodistribution studies show low accumulation in distal tissues. Compared to poloxamer-based hydrogels (commonly used for in vivogelation), TiIV–tannic acid materials show a substantially improved in vitrodrug release profile for the corticosteroid dexamethasone (from <1 dayto >10 days). These results provide essential in vivo characterization for this new class of metal–phenolic hydrogels, and highlight their potential suitability for biomedical applications in areas such as drug deliveryand regenerative medicine

Journal article

Hachim D, Whittaker TE, Kim H, Stevens Met al., 2019, Glycosaminoglycan-based biomaterials for growth factor and cytokine delivery: making the right choices, Journal of Controlled Release, Vol: 313, Pages: 131-147, ISSN: 0168-3659

Controlled, localized drug delivery is a long-standing goal of medical research, realization of which could reduce the harmful side-effects of drugs and allow more effective treatment of wounds, cancers, organ damage and other diseases. This is particularly the case for protein “drugs” and other therapeutic biological cargoes, which can be challenging to deliver effectively by conventional systemic administration. However, developing biocompatible materials that can sequester large quantities of protein and release them in a sustained and controlled manner has proven challenging. Glycosaminoglycans (GAGs) represent a promising class of bio-derived materials that possess these key properties and can additionally potentially enhance the biological effects of the delivered protein. They are a diverse group of linear polysaccharides with varied functionalities and suitabilities for different cargoes. However, most investigations so far have focused on a relatively small subset of GAGs – particularly heparin, a readily available, promiscuously-binding GAG. There is emerging evidence that for many applications other GAGs are in fact more suitable for regulated and sustained delivery. In this review, we aim to illuminate the beneficial properties of various GAGs with reference to specific protein cargoes, and to provide guidelines for informed choice of GAGs for therapeutic applications.

Journal article

Loynachan C, Soleimany AP, Dudani JS, Lin Y, Najer A, Bekdemir A, Chen Q, Bhatia SN, Stevens Met al., 2019, Renal clearable catalytic gold nanoclusters for in vivo disease monitoring, Nature Nanotechnology, Vol: 14, Pages: 883-890, ISSN: 1748-3387

Ultra-small gold nanoclusters (AuNCs) have emerged as agile probes for in vivo imaging, asthey exhibit exceptional tumour accumulation and efficient renal clearance properties.However, their intrinsic catalytic activity, which can enable increased detection sensitivity, hasyet to be explored for in vivo sensing. By exploiting the peroxidase-mimicking activity of AuNCsand the precise nanometer size filtration of the kidney, we designed multifunctional proteasenanosensors that respond to disease microenvironments to produce a direct colorimetricurinary readout of disease state in less than 1 h. We monitored the catalytic activity of AuNCsin collected urine of a mouse model of colorectal cancer where tumour-bearing mice showeda 13-fold increase in colorimetric signal compared to healthy mice. Nanosensors wereeliminated completely through hepatic and renal excretion within 4 weeks after injection withno evidence of toxicity. We envision that this modular approach will enable rapid detection ofa diverse range of diseases by exploiting their specific enzymatic signatures.

Journal article

Wang S-T, Lin Y, NIelsen MH, Song CY, Thomas MT, Spicer C, Kroger R, Ercius P, Aloni S, Stevens Met al., 2019, Shape-controlled synthesis and in situ characterisation of anisotropic AU nanomaterials using liquid cell transmission electron microscopy, Nanoscale, Vol: 36, Pages: 16801-16809, ISSN: 2040-3364

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

Journal article

Gopal S, Chiappini C, Armstrong J, Chen Q, Serio A, Hsu C, Meinert C, Klein TJ, Hutmacher DW, Stevens Met al., 2019, Immunogold FIB-SEM: combining volumetric ultrastructure visualization with 3D biomolecular analysis to dissect cell-environment interactions, Advanced Materials, Vol: 31, Pages: 1-8, ISSN: 0935-9648

Volumetric imaging techniques capable of correlating structural and functional information with nanoscale resolution are necessary to broaden the insight into cellular processes within complex biological systems. The recent emergence of focused ion beam scanning electron microscopy (FIB‐SEM) has provided unparalleled insight through the volumetric investigation of ultrastructure; however, it does not provide biomolecular information at equivalent resolution. Here, immunogold FIB‐SEM, which combines antigen labeling with in situ FIB‐SEM imaging, is developed in order to spatially map ultrastructural and biomolecular information simultaneously. This method is applied to investigate two different cell–material systems: the localization of histone epigenetic modifications in neural stem cells cultured on microstructured substrates and the distribution of nuclear pore complexes in myoblasts differentiated on a soft hydrogel surface. Immunogold FIB‐SEM offers the potential for broad applicability to correlate structure and function with nanoscale resolution when addressing questions across cell biology, biomaterials, and regenerative medicine.

Journal article

Armstrong J, Stevens M, Using remote fields for complex tissue engineering, Trends in Biotechnology, ISSN: 0167-7799

Great strides have been taken towards the in vitro engineering of clinically-relevant tissue constructsusing the classic triad of cells, materials and biochemical factors. In this perspective, we highlight ways in which these elements can be manipulated or stimulated using a fourth component: the application of remote fields.This arena has gained great momentum over the last few years, with a recent surge of interest in using magnetic, optical and acoustic fields to guide the organization of cells, materials and growth factors. We summarize recent developments and trends in this arena and then lay out a series of challenges that we believe, if met, could enable the widespread adoption of remote fields in mainstream tissue engineering.

Journal article

Belessiotis-Richards A, Higgins SG, Butterworth B, Stevens MM, Alexander-Katz Aet al., 2019, Single-nanometer changes in nanopore geometry influence curvature, local properties, and protein localization in membrane simulations, Nano Letters, Vol: 19, Pages: 4770-4778, ISSN: 1530-6984

Nanoporous surfaces are used in many applications in intracellular sensing and drug delivery. However, the effects of such nanostructures on cell membrane properties are still far from understood. Here, we use coarse-grained molecular dynamics simulations to show that nanoporous substrates can stimulate membrane-curvature effects and that this curvature-sensing effect is much more sensitive than previously thought. We define a series of design parameters for inducing a nanoscale membrane curvature and show that nanopore taper plays a key role in membrane deformation, elucidating a previously unexplored fabrication parameter applicable to many nanostructured biomaterials. We report significant changes in the membrane area per lipid and thickness at regions of curvature. Finally, we demonstrate that regions of the nanopore-induced membrane curvature act as local hotspots for an increased bioactivity. We show spontaneous binding and localization of the epsin N-terminal homology (ENTH) domain to the regions of curvature. Understanding this interplay between the membrane curvature and nanoporosity at the biointerface helps both explain recent biological results and suggests a pathway for developing the next generation of cell-active substrates.

Journal article

Wang Y, Kim E, Lin Y, Kim N, Kit-Anan W, Gopal S, Agarwal S, Howes P, Stevens Met al., 2019, Rolling circle transcription-amplified hierarchically structured organic-inorganic hybrid RNA flowers for enzyme immobilization, ACS Applied Materials and Interfaces, Vol: 11, Pages: 22932-22940, ISSN: 1944-8244

Programmable nucleic acids have emerged as powerful building blocks for the bottom-up fabrication of two- or three-dimensional nano- and microsized constructs. Here we describe the construction of organic–inorganic hybrid RNA flowers (hRNFs) via rolling circle transcription (RCT), an enzyme-catalyzed nucleic acid amplification reaction. These hRNFs are highly adaptive structures with controlled sizes, specific nucleic acid sequences, and a highly porous nature. We demonstrated that hRNFs are applicable as potential biological platforms, where the hRNF scaffold can be engineered for versatile surface functionalization and the inorganic component (magnesium ions) can serve as an enzyme cofactor. For surface functionalization, we proposed robust and straightforward approaches including in situ synthesis of functional hRNFs and postfunctionalization of hRNFs that enable facile conjugation with various biomolecules and nanomaterials (i.e., proteins, enzymes, organic dyes, inorganic nanoparticles) using selective chemistries (i.e., avidin–biotin interaction, copper-free click reaction). In particular, we showed that hRNFs can serve as soft scaffolds for β-galactosidase immobilization and greatly enhance enzymatic activity and stability. Therefore, the proposed concepts and methodologies are not only fundamentally interesting when designing RNA scaffolds or RNA bionanomaterials assembled with enzymes but also have significant implications on their future utilization in biomedical applications ranging from enzyme cascades to biosensing and drug delivery.

Journal article

Autefage H, Allen F, Tang HM, Kallepitis C, Gentleman E, Reznikov N, Nitiputri K, Nommeots-Nomm A, Young G, Lee PD, Pierce BF, Wagermaier W, Fratzl P, Goodship A, Jones JR, Blunn G, Stevens Met al., 2019, Multiscale analyses reveal native-like lamellar bone repair and near perfect bone-contact with porous strontium-loaded bioactive glass, Biomaterials, Vol: 209, Pages: 152-162, ISSN: 0142-9612

The efficient healing of critical-sized bone defects using synthetic biomaterial-based strategies is promising but remains challenging as it requires the development of biomaterials that combine a 3D porous architecture and a robust biological activity. Bioactive glasses (BGs) are attractive candidates as they stimulate a biological response that favors osteogenesis and vascularization, but amorphous 3D porous BGs are difficult to produce because conventional compositions crystallize during processing. Here, we rationally designed a porous, strontium-releasing, bioactive glass-based scaffold (pSrBG) whose composition was tailored to deliver strontium and whose properties were optimized to retain an amorphous phase, induce tissue infiltration and encourage bone formation. The hypothesis was that it would allow the repair of a critical-sized defect in an ovine model with newly-formed bone exhibiting physiological matrix composition and structural architecture. Histological and histomorphometric analyses combined with indentation testing showed pSrBG encouraged near perfect bone-to-material contact and the formation of well-organized lamellar bone. Analysis of bone quality by a combination of Raman spectral imaging, small-angle X-ray scattering, X-ray fluorescence and focused ion beam-scanning electron microscopy demonstrated that the repaired tissue was akin to that of normal, healthy bone, and incorporated small amounts of strontium in the newly formed bone mineral. These data show the potential of pSrBG to induce an efficient repair of critical-sized bone defects and establish the importance of thorough multi-scale characterization in assessing biomaterial outcomes in large animal models.

Journal article

Barrioni BR, Naruphontjirakul P, Norris E, Li S, Kelly NL, Hanna J, Stevens MM, Jones JR, Pereira MDMet al., 2019, Effects of manganese incorporation on the morphology, structure and cytotoxicity of spherical bioactive glass nanoparticles, Journal of Colloid and Interface Science, Vol: 547, Pages: 382-392, ISSN: 0021-9797

Bioactive glass nanoparticles (BGNPs) are of great interest in tissue engineering as they possess high dissolution rate and capability of being internalized by cells, releasing their dissolution products with therapeutic benefits intracellularly. A modified Stöber process can be applied to obtain different BGNPs compositions containing therapeutic ions while maintaining controllable particle morphology, monodispersity and reduce agglomeration. Here, BGNPs containing Mn, an ion that has been shown to influence the osteoblast proliferation and bone mineralization, were evaluated. Particles with up to 142.3 ± 10.8 nm and spherical morphology were obtained after MnO incorporation in the SiO2 – CaO system. X-ray photoelectron spectroscopy (XPS) indicated the presence of Mn2+ species and also a reduction in the number of bridging oxygen bonds due to the Ca and Mn. The Ca and Mn network modifier role on the silica network was also confirmed by magic-angle spinning 29Si solid-state nuclear magnetic resonance (MAS NMR). MTT evaluation showed no reduction in the mitochondrial metabolic activity of human mesenchymal stem cells exposed to the glass ionic products. Thus, evaluation showed that Mn could be incorporated into BGNPs by the modified Stöber method while maintaining their spherical morphology and features as a promising strategy for tissue regeneration.

Journal article

Zhao S, Caruso F, Dähne L, Decher G, De Geest BG, Fan J, Feliu N, Gogotsi Y, Hammond PT, Hersam MC, Khademhosseini A, Kotov N, Leporatti S, Li Y, Lisdat F, Liz-Marzán LM, Moya S, Mulvaney P, Rogach AL, Roy S, Shchukin DG, Skirtach AG, Stevens MM, Sukhorukov GB, Weiss PS, Yue Z, Zhu D, Parak WJet al., 2019, The future of layer-by-layer assembly: A tribute to ACS Nano associate editor Helmuth Möhwald, ACS Nano, Vol: 13, Pages: 6151-6169, ISSN: 1936-0851

Layer-by-layer (LbL) assembly is a widely used tool for engineering materials and coatings. In this Perspective, dedicated to the memory of ACS Nano associate editor Prof. Dr. Helmuth Möhwald, we discuss the developments and applications that are to come in LbL assembly, focusing on coatings, bulk materials, membranes, nanocomposites, and delivery vehicles.

Journal article

Kim H, Park Y, Stevens MM, Kwon W, Hahn SKet al., 2019, Multifunctional hyaluronate - nanoparticle hybrid systems for diagnostic, therapeutic and theranostic applications, Journal of Controlled Release, Vol: 303, Pages: 55-66, ISSN: 0168-3659

Diagnostic and therapeutic nanoparticles have been actively investigated for the last few decades as new platforms for biomedical applications. Despite their great versatility and potency, nanoparticles have generally required further modification with biocompatible materials such as biopolymers and synthetic polymers for in vivo administration to improve their biological functions, stability, and biocompatibility. Among a variety of natural and synthetic biomaterials, hyaluronate (HA) has been considered a promising biomolecule with which to construct nanohybrid systems, as it can enable long-term and efficient delivery of nanoparticles to target sites as well as physiological stabilization of nanoparticles by forming hydrophilic shells. In this review, we first describe various kinds of HA derivatives and their interactions with nanoparticles, and discuss how to design and develop optimal HA-nanoparticle hybrid systems for biomedical applications. Furthermore, we show several exemplary applications of HA-nanoparticle hybrid systems and provide our perspectives to their futuristic translational applications.

Journal article

Ghouse S, Reznikov N, Boughton O, Babu S, Ng KCG, Blunn G, Cobb J, Stevens M, Jeffers Jet al., 2019, The design and in vivo testing of a locally stiffness-matched porous scaffold, Applied Materials Today, Vol: 15, Pages: 377-388, ISSN: 2352-9407

An increasing volume of work supports utilising the mechanobiology of bone for bone ingrowth into a porous scaffold. However, typically during in vivo testing of implants, the mechanical properties of the bone being replaced are not quantified. Consequently there remains inconsistencies in the literature regarding ‘optimum’ pore size and porosity for bone ingrowth. It is also difficult to compare ingrowth results between studies and to translate in vivo animal testing to human subjects without understanding the mechanical environment. This study presents a clinically applicable approach to determining local bone mechanical properties and design of a scaffold with similar properties. The performance of the scaffold was investigated in vivo in an ovine model.The density, modulus and strength of trabecular bone from the medial femoral condyle from ovine bones was characterised and power-law relationships were established. A porous titanium scaffold, intended to maintain bone mechanical homeostasis, was additively manufactured and implanted into the medial femoral condyle of 6 ewes. The stiffness of the scaffold varied throughout the heterogeneous structure and matched the stiffness variation of bone at the surgical site. Bone ingrowth into the scaffold was 10.73 ± 2.97% after 6 weeks. Fine woven bone, in the interior of the scaffold, and intense formations of more developed woven bone overlaid with lamellar bone at the implant periphery were observed. The workflow presented will allow future in vivo testing to test specific bone strains on bone ingrowth in response to a scaffold and allow for better translation from in vivo testing to commercial implants.

Journal article

Mohammed AA, Aviles Milan J, Li S, Chung JJ, Stevens MM, Georgiou TK, Jones JRet al., 2019, Open vessel free radical photopolymerization of double network gels for biomaterial applications using glucose oxidase, Journal of Materials Chemistry B, Vol: 7, Pages: 4030-4039, ISSN: 2050-750X

Polymerization of certain gels in the presence of oxygen can lead to hindered reaction rates and low conversion rates, limiting the use of open vessel polymerization and material synthesis. Here, the oxido-reductase enzyme glucose oxidase (GOx) was used to enable open vessel free radical photopolymerization (FRP) of neutral polyacrylamide (PAAm), and polyelectrolyte poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (PAMPS) under ambient conditions. GOx successfully blocks the inhibition pathways created by O2 in FRP, dramatically increasing the polymer conversion rate for both polymers. In the presence of GOx, PAAm and PAMPS achieved conversion of 78% and 100% respectively at a photoinitiator (PI) concentration of 0.05 wt% with GOx, compared to 0% without GOx at the same PI concentration. Cytotoxicity studies of these polymers show high cell viability after GOx is denatured. Double network hydrogels (DNHGs) were successfully produced using the polymers and use of GOx improved compressive fracture stress by a factor of ten. Vinyl functionalized silica nanoparticles (VSNPs) were used as cross linkers of the first network to further enhance the mechanical properties.

Journal article

Nele V, Holme M, Kauscher U, Thomas MR, Doutch JJ, Stevens Met al., 2019, Effect of formulation method, lipid composition and PEGylation on vesicle lamellarity: a small-angle neutron scattering study, Langmuir, Vol: 35, Pages: 6064-6074, ISSN: 0743-7463

Liposomes are well-established systems for drug delivery and biosensing applications. The design of a liposomal carrier requires careful choice of lipid composition and formulation method. These determine many vesicle properties including lamellarity, which can have a strong effect on both encapsulation efficiency and the efflux rate of encapsulated active compounds. Despite this, a comprehensive study on how the lipid composition and formulation method affect vesicle lamellarity is still lacking. Here, we combine small-angle neutron scattering and cryogenic transmission electron microscopy to study the effect of three different well-established formulation methods followed by extrusion through 100 nm polycarbonate membranes on the resulting vesicle membrane structure. Specifically, we examine vesicles formulated from the commonly used phospholipids 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) via film hydration followed by (i) agitation on a shaker or (ii) freeze–thawing, or (iii) the reverse-phase evaporation vesicle method. After extrusion, up to half of the total lipid content is still assembled into multilamellar structures. However, we achieved unilamellar vesicle populations when as little as 0.1 mol % PEG-modified lipid was included in the vesicle formulation. Interestingly, DPPC with 5 mol % PEGylated lipid produces a combination of cylindrical micelles and vesicles. In conclusion, our results provide important insights into the effect of the formulation method and lipid composition on producing liposomes with a defined membrane structure.

Journal article

Armstrong J, Stevens M, 2019, Emerging technologies for tissue engineering: from gene editing to personalized medicine, Tissue Engineering: Parts A, B, and C, Vol: 25, ISSN: 1937-3341

Technological innovation has been integral to the development of tissue engineering over the last 25 years. Future advances will require the next-generation of tissue engineers to embrace emerging technologies. Here, we discuss four key areas of opportunity in which technology can play a role: biological manipulation, advanced characterization, process automation and personalized medicine. This encompasses key developments in transdifferentiation, gene editing, spatially-resolved -omics and 3D bioprinting. Taken together, we can imagine an idealized future in which computational predictions made by machine learning algorithms are used to programme cells and materials to create personalized tissue constructs within an automated culture system.

Journal article

Li C, Ouyang L, Pence I, Moore A, Lin Y, Winter C, Armstrong J, Stevens Met al., 2019, Buoyancy-driven gradients for biomaterial fabrication and tissue engineering, Advanced Materials, Vol: 31, ISSN: 0935-9648

The controlled fabrication of gradient materials is becoming increasingly important as the next generation of tissue engineering seeks to produce inhomogeneous constructs with physiological complexity. Current strategies for fabricating gradient materials can require highly specialized materials or equipment and cannot be generally applied to the wide range of systems used for tissue engineering. Here, the fundamental physical principle of buoyancy is exploited as a generalized approach for generating materials bearing well‐defined compositional, mechanical, or biochemical gradients. Gradient formation is demonstrated across a range of different materials (e.g., polymers and hydrogels) and cargos (e.g., liposomes, nanoparticles, extracellular vesicles, macromolecules, and small molecules). As well as providing versatility, this buoyancy‐driven gradient approach also offers speed (<1 min) and simplicity (a single injection) using standard laboratory apparatus. Moreover, this technique is readily applied to a major target in complex tissue engineering: the osteochondral interface. A bone morphogenetic protein 2 gradient, presented across a gelatin methacryloyl hydrogel laden with human mesenchymal stem cells, is used to locally stimulate osteogenesis and mineralization in order to produce integrated osteochondral tissue constructs. The versatility and accessibility of this fabrication platform should ensure widespread applicability and provide opportunities to generate other gradient materials or interfacial tissues.

Journal article

Paxton NC, Ren J, Ainsworth MJ, Solanki AK, Jones JR, Allenby MC, Stevens M, Woodruff MAet al., 2019, Rheological characterization of biomaterials directs additive manufacturing of strontium-substituted bioactive Gglass/polycaprolactone microfibers, Macromolecular Rapid Communications, Vol: 40, Pages: 1-6, ISSN: 1022-1336

Additive manufacturing via melt electrowriting (MEW) can create ordered microfiber scaffolds relevant for bone tissue engineering; however, there remain limitations in the adoption of new printing materials, especially in MEW of biomaterials. For example, while promising composite formulations of polycaprolactone with strontium‐substituted bioactive glass have been processed into large or disordered fibres, from what is known, biologically‐relevant concentrations (>10 wt%) have never been printed into ordered microfibers using MEW. In this study, rheological characterization is used in combination with a predictive mathematical model to optimize biomaterial formulations and MEW conditions required to extrude various PCL and PCL/SrBG biomaterials to create ordered scaffolds. Previously, MEW printing of PCL/SrBG composites with 33 wt% glass required unachievable extrusion pressures. The composite formulation is modified using an evaporable solvent to reduce viscosity 100‐fold to fall within the predicted MEW pressure, temperature, and voltage tolerances, which enabled printing. This study reports the first fabrication of reproducible, ordered high‐content bioactive glass microfiber scaffolds by applying predictive modeling.

Journal article

Kim E, Agarwal S, Kim N, Hage FS, Gelmi A, Stevens Met al., 2019, Bio-inspired fabrication of DNA-inorganic hybrid composites using synthetic DNA, ACS Nano, Vol: 13, Pages: 2888-2900, ISSN: 1936-0851

Nucleic acid nanostructures have attracted significant interest as potential therapeutic and diagnostic platforms due to their intrinsic biocompatibility and biodegradability, structural and functional diversity, and compatibility with various chemistries for modification and stabilization. Among the fabrication approaches for such structures, the rolling circle techniques have emerged as particularly promising, producing morphologically round, flower-shaped nucleic acid particles: typically hybrid composites of long nucleic acid strands and inorganic magnesium pyrophosphate (Mg2PPi). These constructs are known to form via anisotropic nucleic acid-driven crystallization in a sequence-independent manner, rendering monodisperse and densely packed RNA or DNA–inorganic composites. However, it still remains to fully explore how flexible polymer-like RNA or DNA strands (acting as biomolecular additives) mediate the crystallization process of Mg2PPi and affect the structure and properties of the product crystals. To address this, we closely examined nanoscale details to mesoscopic features of Mg2PPi/DNA hybrid composites fabricated by two approaches, namely rolling circle amplification (RCA)-based in situ synthesis and long synthetic DNA-mediated crystallization. Similar to the DNA constructs fabricated by RCA, the rapid crystallization of Mg2PPi was retarded on a short-range order when we precipitated the crystals in the presence of presynthesized long DNA, which resulted in effective incorporation of biomolecular additives such as DNA and enzymes. These findings further provide a more feasible way to encapsulate bioactive enzymes within DNA constructs compared to in situ RCA-mediated synthesis, i.e., by not only protecting them from possible denaturation under the reaction conditions but also preventing nonselective association of proteins arising from the RCA reaction mixtures.

Journal article

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