244 results on '"Dalby MJ"'
Search Results
2. The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding
- Author
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Hughes, Kevin R, primary, Schofield, Z, additional, Dalby, MJ, additional, Caim, S, additional, Chalklen, L, additional, Bernuzzi, F, additional, Alcon-Giner, C, additional, Le Gall, G, additional, Watson, AJM, additional, and Hall, LJ, additional
- Published
- 2019
- Full Text
- View/download PDF
3. Towards the cell-instructive bactericidal substrate: exploring the combination of nanotopographical features and integrin selective synthetic ligands
- Author
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Fraioli R, Tsimbouri PM, Fisher LE, Nobbs AH, Su B, Neubauer S, Rechenmacher F, Kessler H, Ginebra MP, Dalby MJ, Manero JM, and Mas C
- Abstract
Engineering the interface between biomaterials and tissues is important to increase implant lifetime and avoid failures and revision surgeries. Permanent devices should enhance attachment and differentiation of stem cells, responsible for injured tissue repair, and simultaneously discourage bacterial colonization; this represents a major challenge. To take first steps towards such a multifunctional surface we propose merging topographical and biochemical cues on the surface of a clinically relevant material such as titanium. In detail, our strategy combines antibacterial nanotopographical features with integrin selective synthetic ligands that can rescue the adhesive capacity of the surfaces and instruct mesenchymal stem cell (MSC) response. To this end, a smooth substrate and two different high aspect ratio topographies have been produced and coated either with an avß3-selective peptidomimetic, an a5ß1-selective peptidomimetic, or an RGD/PHSRN peptidic molecule. Results showed that antibacterial effects of the substrates could be maintained when tested on pathogenic Pseudomonas aeruginosa. Further, functionalization increased MSC adhesion to the surfaces and the avß3-selective peptidomimetic-coated nanotopographies promoted osteogenesis. Such a dual physicochemical approach to achieve multifunctional surfaces represents a first step in the design of novel cell-instructive biomaterial surfaces.
- Published
- 2017
4. Osteoclastogenesis/osteoblastogenesis using human bone marrow-derived cocultures on nanotopographical polymer surfaces
- Author
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Young, PS, primary, Tsimbouri, PM, additional, Gadegaard, N, additional, Meek, RMD, additional, and Dalby, MJ, additional
- Published
- 2015
- Full Text
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5. Research Highlights
- Author
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Ross, L, primary, Riehle, MO, additional, McNamara, LE, additional, Burchmore, R, additional, Dalby, MJ, additional, McMurray, RJ, additional, Gadegaard, N, additional, Ahmed, S, additional, and Tsimbouri, PM, additional
- Published
- 2009
- Full Text
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6. Focal adhesions in osteoneogenesis.
- Author
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Biggs MJ, Dalby MJ, Biggs, M J P, and Dalby, M J
- Abstract
As materials technology and the field of tissue engineering advance, the role of cellular adhesive mechanisms, in particular, interactions with implantable devices, becomes more relevant in both research and clinical practice. A key tenet of medical device technology is to use the exquisite ability of biological systems to respond to the material surface or chemical stimuli in order to help to develop next-generation biomaterials. The focus of this review is on recent studies and developments concerning focal adhesion formation in osteoneogenesis, with an emphasis on the influence of synthetic constructs on integrin-mediated cellular adhesion and function. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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7. Special issue on bone tissue engineering.
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Tanner KE, Dalby MJ, Tanner, K Elizabeth, and Dalby, Matthew J
- Published
- 2010
8. Faecal microbiota and cytokine profiles of rural Cambodian infants linked to diet and diarrhoeal episodes.
- Author
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Dalby MJ, Kiu R, Serghiou IR, Miyazaki A, Acford-Palmer H, Tung R, Caim S, Phillips S, Kujawska M, Matsui M, Iwamoto A, Taking B, Cox SE, and Hall LJ
- Subjects
- Humans, Infant, Cambodia, Female, Male, Diet, Bacteria classification, Bacteria genetics, Bacteria isolation & purification, Shigella genetics, Shigella isolation & purification, Bacteroides genetics, Bacteroides isolation & purification, Klebsiella genetics, Klebsiella isolation & purification, Breast Feeding, DNA, Bacterial genetics, Whole Genome Sequencing, Milk, Human microbiology, Milk, Human chemistry, Feces microbiology, Gastrointestinal Microbiome, Cytokines metabolism, Rural Population, RNA, Ribosomal, 16S genetics, Diarrhea microbiology, Bifidobacterium genetics, Bifidobacterium isolation & purification
- Abstract
The gut microbiota of infants in low- to middle-income countries is underrepresented in microbiome research. This study explored the faecal microbiota composition and faecal cytokine profiles in a cohort of infants in a rural province of Cambodia and investigated the impact of sample storage conditions and infant environment on microbiota composition. Faecal samples collected at three time points from 32 infants were analysed for microbiota composition using 16S rRNA amplicon sequencing and concentrations of faecal cytokines. Faecal bacterial isolates were subjected to whole genome sequencing and genomic analysis. We compared the effects of two sample collection methods due to the challenges of faecal sample collection in a rural location. Storage of faecal samples in a DNA preservation solution preserved Bacteroides abundance. Microbiota analysis of preserved samples showed that Bifidobacterium was the most abundant genus with Bifidobacterium longum the most abundant species, with higher abundance in breast-fed infants. Most infants had detectable pathogenic taxa, with Shigella and Klebsiella more abundant in infants with recent diarrhoeal illness. Neither antibiotics nor infant growth were associated with gut microbiota composition. Genomic analysis of isolates showed gene clusters encoding the ability to digest human milk oligosaccharides in B. longum and B. breve isolates. Antibiotic-resistant genes were present in both potentially pathogenic species and in Bifidobacterium. Faecal concentrations of Interlukin-1alpha and vascular endothelial growth factor were higher in breast-fed infants. This study provides insights into an underrepresented population of rural Cambodian infants, showing pathogen exposure and breastfeeding impact gut microbiota composition and faecal immune profiles., (© 2024. The Author(s).)
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- 2024
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9. Investigating the self-assembly of 2NapFF and ureido-pyrimidinone multicomponent systems for cell culture.
- Author
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Wallace CM, Rovers MM, Bellan R, Rutten MGTA, Seddon A, Dalby MJ, Dankers PYW, and Adams DJ
- Abstract
Low molecular weight gels are formed via the self-assembly of small molecules into fibrous structures. In the case of hydrogels, these networks entrap large volumes of water, yielding soft materials. Such gels tend to have weak mechanical properties and a high permeability for cells, making them particularly appealing for regenerative medicine applications. Ureido-pyrimidinone (UPy) supramolecular gelators are self-assembling systems that have demonstrated excellent capabilities as biomaterials. Here, we combine UPy-gelators with another low molecular weight gelator, the functionalized dipeptide 2NapFF. We have successfully characterized these multicomponent systems on a molecular and bulk scale. The addition of 2NapFF to a crosslinked UPy hydrogel significantly increased hydrogel stiffness from 30 Pa to 1300 Pa. Small-angle X-ray scattering was used to probe the underlying structures of the systems and showed that the mixed UPy and 2NapFF systems resemble the scattering data produced by the pristine UPy systems. However, when a bifunctional UPy-crosslinker was added, the scattering was close to that of the 2NapFF only samples. The results suggest that the crosslinker significantly influences the assembly of the low molecular weight gelators. Finally, we analysed the biocompatibility of the systems using fibroblast cells and found that the cells tended to spread more effectively when the crosslinking species was incorporated. Our results emphasise the need for thorough characterisation at multiple length scales to finely control material properties, which is particularly important for developing novel biomaterials.
- Published
- 2024
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10. Nanotopography Influences Host-Pathogen Quorum Sensing and Facilitates Selection of Bioactive Metabolites in Mesenchymal Stromal Cells and Pseudomonas aeruginosa Co-Cultures.
- Author
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Cuahtecontzi Delint R, Ishak MI, Tsimbouri PM, Jayawarna V, Burgess KVE, Ramage G, Nobbs AH, Damiati L, Salmeron-Sanchez M, Su B, and Dalby MJ
- Subjects
- Humans, Host-Pathogen Interactions, Nanostructures chemistry, Pseudomonas aeruginosa physiology, Pseudomonas aeruginosa drug effects, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells cytology, Quorum Sensing drug effects, Biofilms drug effects, Coculture Techniques
- Abstract
Orthopedic implant-related bacterial infections and resultant antibiotic-resistant biofilms hinder implant-tissue integration and failure. Biofilm quorum sensing (QS) communication determines the pathogen colonization success. However, it remains unclear how implant modifications and host cells are influenced by, or influence, QS. High aspect ratio nanotopographies have shown to reduce biofilm formation of Pseudomonas aeruginosa , a sepsis causing pathogen with well-defined QS molecules. Producing such nanotopographies in relevant orthopedic materials (i.e., titanium) allows for probing QS using mass spectrometry-based metabolomics. However, nanotopographies can reduce host cell adhesion and regeneration. Therefore, we developed a polymer (poly(ethyl acrylate), PEA) coating that organizes extracellular matrix proteins, promoting bioactivity to host cells such as human mesenchymal stromal cells (hMSCs), maintaining biofilm reduction. This allowed us to investigate how hMSCs, after winning the race for the surface against pathogenic cells, interact with the biofilm. Our approach revealed that nanotopographies reduced major virulence pathways, such as LasR. The enhanced hMSCs support provided by the coated nanotopographies was shown to suppress virulence pathways and biofilm formation. Finally, we selected bioactive metabolites and demonstrated that these could be used as adjuncts to the nanostructured surfaces to reduce biofilm formation and enhance hMSC activity. These surfaces make excellent models to study hMSC-pathogen interactions and could be envisaged for use in novel orthopedic implants.
- Published
- 2024
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11. An In Vitro Model of the Blood-Brain Barrier for the Investigation and Isolation of the Key Drivers of Barriergenesis.
- Author
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Schofield C, Sarrigiannidis S, Moran-Horowich A, Jackson E, Rodrigo-Navarro A, van Agtmael T, Cantini M, Dalby MJ, and Salmeron-Sanchez M
- Abstract
The blood-brain barrier (BBB) tightly regulates substance transport between the bloodstream and the brain. Models for the study of the physiological processes affecting the BBB, as well as predicting the permeability of therapeutic substances for neurological and neurovascular pathologies, are highly desirable. Existing models, such as Transwell utilizing-models, do not mimic the extracellular environment of the BBB with their stiff, semipermeable, non-biodegradable membranes. To help overcome this, we engineered electrospun membranes from poly L-lactic acid in combination with a nanometric coating of poly(ethyl acrylate) (PEA) that drives fibrillogenesis of fibronectin, facilitating the synergistic presentation of both growth factors and integrin binding sites. Compared to commercial semi-porous membranes, these membranes significantly improve the expression of BBB-related proteins in brain endothelial cells. PEA-coated membranes in combination with different growth factors and extracellular protein coatings reveal nerve growth factor (NGF) and fibroblast growth factor (FGF-2) caused formation of better barriers in vitro. This BBB model offers a robust platform for studying key biochemical factors influencing barrier formation that marries the simplicity of the Transwell model with the highly tunable electrospun PEA-fibronectin membranes. This enables the generation of high-throughput drug permeability models without the need of complicated co-culture conditions., (© 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH.)
- Published
- 2024
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12. Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells.
- Author
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Donnelly H, Ross E, Xiao Y, Hermantara R, Taqi AF, Doherty-Boyd WS, Cassels J, Tsimbouri PM, Dunn KM, Hay J, Cheng A, Meek RMD, Jain N, West C, Wheadon H, Michie AM, Peault B, West AG, Salmeron-Sanchez M, and Dalby MJ
- Subjects
- Animals, Mice, Stem Cell Niche, Hydrogels chemistry, Bioengineering methods, Humans, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells cytology, Hematopoietic Stem Cell Transplantation, Antigens, CD34 metabolism, Collagen Type I metabolism, Cell Differentiation, Mice, Inbred C57BL, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells cytology, Nestin metabolism, Nestin genetics, Extracellular Matrix metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Hypoxia-Inducible Factor 1, alpha Subunit genetics
- Abstract
Long-term reconstituting haematopoietic stem cells (LT-HSCs) are used to treat blood disorders via stem cell transplantation. The very low abundance of LT-HSCs and their rapid differentiation during in vitro culture hinders their clinical utility. Previous developments using stromal feeder layers, defined media cocktails, and bioengineering have enabled HSC expansion in culture, but of mostly short-term HSCs and progenitor populations at the expense of naive LT-HSCs. Here, we report the creation of a bioengineered LT-HSC maintenance niche that recreates physiological extracellular matrix organisation, using soft collagen type-I hydrogels to drive nestin expression in perivascular stromal cells (PerSCs). We demonstrate that nestin, which is expressed by HSC-supportive bone marrow stromal cells, is cytoprotective and, via regulation of metabolism, is important for HIF-1α expression in PerSCs. When CD34
+ve HSCs were added to the bioengineered niches comprising nestin/HIF-1α expressing PerSCs, LT-HSC numbers were maintained with normal clonal and in vivo reconstitution potential, without media supplementation. We provide proof-of-concept that our bioengineered niches can support the survival of CRISPR edited HSCs. Successful editing of LT-HSCs ex vivo can have potential impact on the treatment of blood disorders., (© 2024. The Author(s).)- Published
- 2024
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13. Developing and Investigating a Nanovibration Intervention for the Prevention/Reversal of Bone Loss Following Spinal Cord Injury.
- Author
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Williams JA, Campsie P, Gibson R, Johnson-Love O, Werner A, Sprott M, Meechan R, Huesa C, Windmill JFC, Purcell M, Coupaud S, Dalby MJ, Childs P, Riddell JS, and Reid S
- Subjects
- Animals, Rats, Rats, Sprague-Dawley, X-Ray Microtomography, Osteogenesis drug effects, Female, Wearable Electronic Devices, Nanotechnology, Spinal Cord Injuries, Osteoporosis pathology, Osteoporosis prevention & control, Vibration
- Abstract
Osteoporosis disrupts the fine-tuned balance between bone formation and resorption, leading to reductions in bone quantity and quality and ultimately increasing fracture risk. Prevention and treatment of osteoporotic fractures is essential for reductions in mortality, morbidity, and the economic burden, particularly considering the aging global population. Extreme bone loss that mimics time-accelerated osteoporosis develops in the paralyzed limbs following complete spinal cord injury (SCI). In vitro nanoscale vibration (1 kHz, 30 or 90 nm amplitude) has been shown to drive differentiation of mesenchymal stem cells toward osteoblast-like phenotypes, enhancing osteogenesis and inhibiting osteoclastogenesis simultaneously. Here, we develop and characterize a wearable device designed to deliver and monitor continuous nanoamplitude vibration to the hindlimb long bones of rats with complete SCI. We investigate whether a clinically feasible dose of nanovibration (two 2 h/day, 5 days/week for 6 weeks) is effective at reversing the established SCI-induced osteoporosis. Laser interferometry and finite element analysis confirmed transmission of nanovibration into the bone, and microcomputed tomography and serum bone formation and resorption markers assessed effectiveness. The intervention did not reverse SCI-induced osteoporosis. However, serum analysis indicated an elevated concentration of the bone formation marker procollagen type 1 N -terminal propeptide (P1NP) in rats receiving 40 nm amplitude nanovibration, suggesting increased synthesis of type 1 collagen, the major organic component of bone. Therefore, enhanced doses of nanovibrational stimulus may yet prove beneficial in attenuating/reversing osteoporosis, particularly in less severe forms of osteoporosis.
- Published
- 2024
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14. Hybrid Micro-/Nanoprotein Platform Provides Endocrine-like and Extracellular Matrix-like Cell Delivery of Growth Factors.
- Author
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López-Laguna H, Tsimbouri PM, Jayawarna V, Rigou I, Serna N, Voltà-Durán E, Unzueta U, Salmeron-Sanchez M, Vázquez E, Dalby MJ, and Villaverde A
- Subjects
- Humans, Fibroblast Growth Factor 2 chemistry, Fibroblast Growth Factor 2 pharmacology, Cell Proliferation drug effects, Cell Differentiation drug effects, Nanostructures chemistry, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism, Mesenchymal Stem Cells drug effects, Extracellular Matrix chemistry, Extracellular Matrix metabolism, Fibronectins chemistry
- Abstract
Protein materials are versatile tools in diverse biomedical fields. Among them, artificial secretory granules (SGs), mimicking those from the endocrine system, act as mechanically stable reservoirs for the sustained release of proteins as oligomeric functional nanoparticles. Only validated in oncology, the physicochemical properties of SGs, along with their combined drug-releasing and scaffolding abilities, make them suitable as smart topographies in regenerative medicine for the prolonged delivery of growth factors (GFs). Thus, considering the need for novel, safe, and cost-effective materials to present GFs, in this study, we aimed to biofabricate a protein platform combining both endocrine-like and extracellular matrix fibronectin-derived (ECM-FN) systems. This approach is based on the sustained delivery of a nanostructured histidine-tagged version of human fibroblast growth factor 2. The GF is presented onto polymeric surfaces, interacting with FN to spontaneously generate nanonetworks that absorb and present the GF in the solid state, to modulate mesenchymal stromal cell (MSC) behavior. The results show that SGs-based topographies trigger high rates of MSCs proliferation while preventing differentiation. While this could be useful in cell therapy manufacture demanding large numbers of unspecialized MSCs, it fully validates the hybrid platform as a convenient setup for the design of biologically active hybrid surfaces and in tissue engineering for the controlled manipulation of mammalian cell growth.
- Published
- 2024
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15. Building bones for blood and beyond: the growing field of bone marrow niche model development.
- Author
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Doherty-Boyd WS, Donnelly H, Tsimbouri MP, and Dalby MJ
- Subjects
- Humans, Animals, Models, Biological, Bone Marrow Cells metabolism, Bone Marrow Cells cytology, Stem Cell Niche, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Bone Marrow metabolism, Hematopoiesis
- Abstract
The bone marrow (BM) niche is a complex microenvironment that provides the signals required for regulation of hematopoietic stem cells (HSCs) and the process of hematopoiesis they are responsible for. Bioengineered models of the BM niche incorporate various elements of the in vivo BM microenvironment, including cellular components, soluble factors, a three-dimensional environment, mechanical stimulation of included cells, and perfusion. Recent advances in the bioengineering field have resulted in a spate of new models that shed light on BM function and are approaching precise imitation of the BM niche. These models promise to improve our understanding of the in vivo microenvironment in health and disease. They also aim to serve as platforms for HSC manipulation or as preclinical models for screening novel therapies for BM-associated disorders and diseases., Competing Interests: Conflict of Interest Disclosure The authors declare no conflicts of interests., (Copyright © 2024 International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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16. Mechanotransducive surfaces for enhanced cell osteogenesis, a review.
- Author
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Cuahtecontzi Delint R, Jaffery H, Ishak MI, Nobbs AH, Su B, and Dalby MJ
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- Humans, Titanium chemistry, Animals, Cell Differentiation, Surface Properties, Biocompatible Materials chemistry, Extracellular Matrix metabolism, Extracellular Matrix physiology, Extracellular Matrix chemistry, Mechanotransduction, Cellular, Osteogenesis physiology
- Abstract
Novel strategies employing mechano-transducing materials eliciting biological outcomes have recently emerged for controlling cellular behaviour. Targeted cellular responses are achieved by manipulating physical, chemical, or biochemical modification of material properties. Advances in techniques such as nanopatterning, chemical modification, biochemical molecule embedding, force-tuneable materials, and artificial extracellular matrices are helping understand cellular mechanotransduction. Collectively, these strategies manipulate cellular sensing and regulate signalling cascades including focal adhesions, YAP-TAZ transcription factors, and multiple osteogenic pathways. In this minireview, we are providing a summary of the influence that these materials, particularly titanium-based orthopaedic materials, have on cells. We also highlight recent complementary methodological developments including, but not limited to, the use of metabolomics for identification of active biomolecules that drive cellular differentiation., Competing Interests: Declaration of competing interest All authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this review article “Mechanotransducive Surfaces for Enhanced Cell Osteogenesis, a review”., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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17. Engineered Surfaces That Promote Capture of Latent Proteins to Facilitate Integrin-Mediated Mechanical Activation of Growth Factors.
- Author
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Dhawan U, Williams JA, Windmill JFC, Childs P, Gonzalez-Garcia C, Dalby MJ, and Salmeron-Sanchez M
- Subjects
- Animals, Humans, Fibronectins metabolism, Fibronectins chemistry, Latent TGF-beta Binding Proteins metabolism, Latent TGF-beta Binding Proteins chemistry, Bone Regeneration, Surface Properties, Integrins metabolism, Protein Binding, Integrin beta1 metabolism, Signal Transduction, Osteogenesis, Transforming Growth Factor beta1 metabolism
- Abstract
Conventional osteogenic platforms utilize active growth factors to repair bone defects that are extensive in size, but they can adversely affect patient health. Here, an unconventional osteogenic platform is reported that functions by promoting capture of inactive osteogenic growth factor molecules to the site of cell growth for subsequent integrin-mediated activation, using a recombinant fragment of latent transforming growth factor beta-binding protein-1 (rLTBP1). It is shown that rLTBP1 binds to the growth-factor- and integrin-binding domains of fibronectin on poly(ethyl acrylate) surfaces, which immobilizes rLTBP1 and promotes the binding of latency associated peptide (LAP), within which inactive transforming growth factor beta 1 (TGF-β1) is bound. rLTBP1 facilitates the interaction of LAP with integrin β1 and the subsequent mechanically driven release of TGF-β1 to stimulate canonical TGF-β1 signaling, activating osteogenic marker expression in vitro and complete regeneration of a critical-sized bone defect in vivo., (© 2024 The Authors. Advanced Materials published by Wiley‐VCH GmbH.)
- Published
- 2024
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18. Gallium and silver-doped titanium surfaces provide enhanced osteogenesis, reduce bone resorption and prevent bacterial infection in co-culture.
- Author
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Piñera-Avellaneda D, Buxadera-Palomero J, Delint RC, Dalby MJ, Burgess KV, Ginebra MP, Rupérez E, and Manero JM
- Subjects
- Humans, Mice, Animals, Bone Resorption pathology, Surface Properties, RAW 264.7 Cells, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Bacterial Infections prevention & control, Titanium chemistry, Titanium pharmacology, Silver pharmacology, Silver chemistry, Gallium pharmacology, Gallium chemistry, Mesenchymal Stem Cells drug effects, Osteogenesis drug effects, Coculture Techniques, Pseudomonas aeruginosa drug effects
- Abstract
Bacterial infection remains a significant problem associated with orthopaedic surgeries leading to surgical site infection (SSI). This unmet medical need can become an even greater complication when surgery is due to malignant bone tumor. In the present study, we evaluated in vitro titanium (Ti) implants subjected to gallium (Ga) and silver (Ag)-doped thermochemical treatment as strategy to prevent SSI and improve osteointegration in bone defects caused by diseases such as osteoporosis, bone tumor, or bone metastasis. Firstly, as Ga has been reported to be an osteoinductive and anti-resorptive agent, its performance in the mixture was proved by studying human mesenchymal stem cells (hMSC) and pre-osteoclasts (RAW264.7) behaviour. Then, the antibacterial potential provided by Ag was assessed by resembling "The Race for the Surface" between hMSC and Pseudomonas aeruginosa in two co-culture methods. Moreover, the presence of quorum sensing molecules in the co-culture was evaluated. The results highlighted the suitability of the mixture to induce osteodifferentiation and reduce osteoclastogenesis in vitro. Furthermore, the GaAg surface promoted strong survival rate and retained osteoinduction potential of hMSCs even after bacterial inoculation. Therefore, GaAg-modified titanium may be an ideal candidate to repair bone defects caused by excessive bone resorption, in addition to preventing SSI. STATEMENT OF SIGNIFICANCE: This article provides important insights into titanium for fractures caused by osteoporosis or bone metastases with high incidence in surgical site infection (SSI) because in this situation bacterial infection can become a major disaster. In order to solve this unmet medical need, we propose a titanium implant modified with gallium and silver to improve osteointegration, reduce bone resorption and avoid bacterial infection. For that aim, we study osteoblast and osteoclast behavior with the main novelty focused on the antibacterial evaluation. In this work, we recreate "the race for the surface" in long-term experiments and study bacterial virulence factors (quorum sensing). Therefore, we believe that our article could be of great interest, providing a great impact on future orthopedic applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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19. Strengths and opportunities in research into extracellular matrix ageing: A consultation with the ECMage research community.
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Dalby MJ, Pekovic-Vaughan V, Shanley DP, Swift J, White LJ, and Canty-Laird EG
- Subjects
- Animals, Humans, United Kingdom, Aging, Extracellular Matrix metabolism
- Abstract
Ageing causes progressive decline in metabolic, behavioural, and physiological functions, leading to a reduced health span. The extracellular matrix (ECM) is the three-dimensional network of macromolecules that provides our tissues with structure and biomechanical resilience. Imbalance between damage and repair/regeneration causes the ECM to undergo structural deterioration with age, contributing to age-associated pathology. The ECM 'Ageing Across the Life Course' interdisciplinary research network (ECMage) was established to bring together researchers in the United Kingdom, and internationally, working on the emerging field of ECM ageing. Here we report on a consultation at a joint meeting of ECMage and the Medical Research Council / Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, held in January 2023, in which delegates analysed the key questions and research opportunities in the field of ECM ageing. We examine fundamental biological questions, enabling technologies, systems of study and emerging in vitro and in silico models, alongside consideration of the broader challenges facing the field., (© 2024 The Authors. BioEssays published by Wiley Periodicals LLC.)
- Published
- 2024
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20. Nanotextured titanium inhibits bacterial activity and supports cell growth on 2D and 3D substrate: A co-culture study.
- Author
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Ishak MI, Delint RC, Liu X, Xu W, Tsimbouri PM, Nobbs AH, Dalby MJ, and Su B
- Subjects
- Coculture Techniques, Surface Properties, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Bacteria, Titanium pharmacology, Bacterial Adhesion
- Abstract
Medical implant-associated infections pose a significant challenge to modern medicine, with aseptic loosening and bacterial infiltration being the primary causes of implant failure. While nanostructured surfaces have demonstrated promising antibacterial properties, the translation of their efficacy from 2D to 3D substrates remains a challenge. Here, we used scalable alkaline etching to fabricate nanospike and nanonetwork topologies on 2D and laser powder-bed fusion printed 3D titanium. The fabricated surfaces were compared with regard to their antibacterial properties against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and mesenchymal stromal cell responses with and without the presence of bacteria. Finite elemental analysis assessed the mechanical properties and permeability of the 3D substrate. Our findings suggest that 3D nanostructured surfaces have potential to both prevent implant infections and allow host cell integration. This work represents a significant step towards developing effective and scalable fabrication methods on 3D substrates with consistent and reproducible antibacterial activity, with important implications for the future of medical implant technology., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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21. Editorial: Harnessing biomechanotransduction to influence cell fate.
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Wang PY, Shahsaverani H, Chen HY, and Dalby MJ
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
- Published
- 2024
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22. Questioning the foundations of the gut microbiota and obesity.
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Dalby MJ
- Subjects
- Humans, Animals, Mice, Obesity etiology, Body Weight, Adipose Tissue, Gastrointestinal Microbiome, Microbiota
- Abstract
The role of the gut microbiota in determining body fatness has been a prominent area of research and has received significant public attention. Based largely on animal studies, recent attempts to translate these findings into interventions in humans have not been successful. This review will outline the key mouse research that initiated this area of study, examine whether those results warranted the initial enthusiasm and progress into human studies, and examine whether later follow-up research supported earlier conclusions. It will look at whether the absence of a gut microbiota protects germ-free mice from obesity, whether microbiota can transfer obesity into germ-free mice, the evidence for the role of immune system activation as a causal mechanism linking the gut microbiota to body weight, and consider the evidence for effects of individual bacterial species. Finally, it will examine the outcomes of randomized controlled trials of microbiota transfer in human participants that have not shown effects on body weight. With a more critical reading, early studies did not show as large an effect as first appeared and later research, including human trials, has failed to support a role of the gut microbiota in shaping body weight. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.
- Published
- 2023
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23. Biosynthesis of Zinc Oxide Nanoparticles on l-Carnosine Biofunctionalized Polyacrylonitrile Nanofibers; a Biomimetic Wound Healing Material.
- Author
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Homaeigohar S, Assad MA, Azari AH, Ghorbani F, Rodgers C, Dalby MJ, Zheng K, Xu R, Elbahri M, and Boccaccini AR
- Subjects
- Staphylococcus aureus, Biomimetics, Endothelial Cells, Wound Healing, Anti-Bacterial Agents chemistry, Zinc Oxide pharmacology, Zinc Oxide chemistry, Carnosine pharmacology, Nanofibers chemistry, Nanoparticles chemistry
- Abstract
Multifunctional biohybrid nanofibers (NFs) that can simultaneously drive various cellular activities and confer antibacterial properties are considered desirable in producing advanced wound healing materials. In this study, a bionanohybrid formulation was processed as a NF wound dressing to stimulate the adhesion and proliferation of fibroblast and endothelial cells that play a major role in wound healing. Polyacrylonitrile (PAN) electrospun NFs were hydrolyzed using NaOH and biofunctionalized with l-carnosine (CAR), a dipeptide which could later biosynthesize zinc oxide (ZnO) nanoparticles (NPs) on the NFs surface. The morphological study verified that ZnO NPs are uniformly distributed on the surface of CAR/PAN NFs. Through EDX and XRD analysis, it was validated that the NPs are composed of ZnO and/or ZnO/Zn(OH)
2 . The presence of CAR and ZnO NPs brought about a superhydrophilicity effect and notably raised the elastic modulus and tensile strength of Zn-CAR/PAN NFs. While CAR ligands were shown to improve the viability of fibroblast (L929) and endothelial (HUVEC) cells, ZnO NPs lowered the positive impact of CAR, most likely due to their repulsive negative surface charge. A scratch assay verified that CAR/PAN NFs and Zn-CAR/PAN NFs aided HUVEC migration more than PAN NFs. Also, an antibacterial assay implied that CAR/PAN NFs and Zn-CAR/PAN NFs are significantly more effective in inhibiting Staphylococcus aureus ( S. aureus ) than neat PAN NFs are (1000 and 500%, respectively). Taken together, compared to the neat PAN NFs, CAR/PAN NFs with and without the biosynthesized ZnO NPs can support the cellular activities of relevance for wound healing and inactivate bacteria.- Published
- 2023
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24. Surface-Modified Piezoelectric Copolymer Poly(vinylidene fluoride-trifluoroethylene) Supporting Physiological Extracellular Matrixes to Enhance Mesenchymal Stem Cell Adhesion for Nanoscale Mechanical Stimulation.
- Author
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Donnelly H, Sprott MR, Poudel A, Campsie P, Childs P, Reid S, Salmerón-Sánchez M, Biggs M, and Dalby MJ
- Abstract
There is an unmet clinical need to provide viable bone grafts for clinical use. Autologous bone, one of the most commonly transplanted tissues, is often used but is associated with donor site morbidity. Tissue engineering strategies to differentiate an autologous cell source, such as mesenchymal stromal cells (MSCs), into a potential bone-graft material could help to fulfill clinical demand. However, osteogenesis of MSCs can typically require long culture periods that are impractical in a clinical setting and can lead to significant cost. Investigation into strategies that optimize cell production is essential. Here, we use the piezoelectric copolymer poly(vinylidene fluoride-trifluoroethylene) (PVDF-TrFE), functionalized with a poly(ethyl acrylate) (PEA) coating that drives fibronectin network formation, to enhance MSC adhesion and to present growth factors in the solid phase. Dynamic electrical cues are then incorporated, via a nanovibrational bioreactor, and the MSC response to electromechanical stimulation is investigated.
- Published
- 2023
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25. An efficient method for high molecular weight bacterial DNA extraction suitable for shotgun metagenomics from skin swabs.
- Author
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Serghiou IR, Baker D, Evans R, Dalby MJ, Kiu R, Trampari E, Phillips S, Watt R, Atkinson T, Murphy B, Hall LJ, and Webber MA
- Subjects
- Adult, Humans, DNA, Bacterial genetics, Molecular Weight, Sequence Analysis, DNA methods, High-Throughput Nucleotide Sequencing methods, RNA, Ribosomal, 16S genetics, Bacteria genetics, DNA, Metagenomics methods, Microbiota genetics
- Abstract
The human skin microbiome represents a variety of complex microbial ecosystems that play a key role in host health. Molecular methods to study these communities have been developed but have been largely limited to low-throughput quantification and short amplicon-based sequencing, providing limited functional information about the communities present. Shotgun metagenomic sequencing has emerged as a preferred method for microbiome studies as it provides more comprehensive information about the species/strains present in a niche and the genes they encode. However, the relatively low bacterial biomass of skin, in comparison to other areas such as the gut microbiome, makes obtaining sufficient DNA for shotgun metagenomic sequencing challenging. Here we describe an optimised high-throughput method for extraction of high molecular weight DNA suitable for shotgun metagenomic sequencing. We validated the performance of the extraction method, and analysis pipeline on skin swabs collected from both adults and babies. The pipeline effectively characterised the bacterial skin microbiota with a cost and throughput suitable for larger longitudinal sets of samples. Application of this method will allow greater insights into community compositions and functional capabilities of the skin microbiome.
- Published
- 2023
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26. Keeping It Organized: Multicompartment Constructs to Mimic Tissue Heterogeneity.
- Author
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Sanchez-Rubio A, Jayawarna V, Maxwell E, Dalby MJ, and Salmeron-Sanchez M
- Subjects
- Hydrogels chemistry, Tissue Engineering methods, Biocompatible Materials chemistry, Tissue Scaffolds chemistry, Printing, Three-Dimensional, Bioprinting
- Abstract
Tissue engineering aims at replicating tissues and organs to develop applications in vivo and in vitro. In vivo, by engineering artificial constructs using functional materials and cells to provide both physiological form and function. In vitro, by engineering three-dimensional (3D) models to support drug discovery and enable understanding of fundamental biology. 3D culture constructs mimic cell-cell and cell-matrix interactions and use biomaterials seeking to increase the resemblance of engineered tissues with its in vivo homologues. Native tissues, however, include complex architectures, with compartmentalized regions of different properties containing different types of cells that can be captured by multicompartment constructs. Recent advances in fabrication technologies, such as micropatterning, microfluidics or 3D bioprinting, have enabled compartmentalized structures with defined compositions and properties that are essential in creating 3D cell-laden multiphasic complex architectures. This review focuses on advances in engineered multicompartment constructs that mimic tissue heterogeneity. It includes multiphasic 3D implantable scaffolds and in vitro models, including systems that incorporate different regions emulating in vivo tissues, highlighting the emergence and relevance of 3D bioprinting in the future of biological research and medicine., (© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)
- Published
- 2023
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27. Editorial: Materials for mechanotransduction and beyond.
- Author
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Sonam S, Malmstrom J, Kamei KI, and Dalby MJ
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2023
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28. Fibronectin matrix assembly and TGFβ1 presentation for chondrogenesis of patient derived pericytes for microtia repair.
- Author
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Donnelly H, Kurjan A, Yong LY, Xiao Y, Lemgruber L, West C, Salmeron-Sanchez M, and Dalby MJ
- Subjects
- Humans, Pericytes, Chondrogenesis, Fibronectins, Cartilage, Congenital Microtia surgery
- Abstract
Tissue engineered cartilage for external ear reconstruction of congenital deformities, such as microtia or resulting from trauma, remains a significant challenge for plastic and reconstructive surgeons. Current strategies involve harvesting autologous costal cartilage or expanding autologous chondrocytes ex vivo. However, these procedures often lead to donor site morbidity and a cell source with limited expansion capacity. Stromal stem cells such as perivascular stem cells (pericytes) offer an attractive alternative cell source, as they can be isolated from many human tissues, readily expanded in vitro and possess chondrogenic differentiation potential. Here, we successfully isolate CD146+ pericytes from the microtia remnant from patients undergoing reconstructive surgery (Microtia pericytes; MPs). Then we investigate their chondrogenic potential using the polymer poly(ethyl acrylate) (PEA) to unfold the extracellular matrix protein fibronectin (FN). FN unfolding exposes key growth factor (GF) and integrin binding sites on the molecule, allowing tethering of the chondrogenic GF transforming growth factor beta 1 (TGFβ1). This system leads to solid-phase, matrix-bound, GF presentation in a more physiological-like manner than that of typical chondrogenic induction media (CM) formulations that tend to lead to off-target effects. This simple and controlled material-based approach demonstrates similar chondrogenic potential to CM, while minimising proclivity toward hypertrophy, without the need for complex induction media formulations., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Manuel Salmeron-Sanchez has patent MATERIALS AND METHODS FOR TISSUE REGENERATION pending to University of Glasgow. Co-author is Editor-in-Chief of Biomaterials Advances - MSS., (Copyright © 2023. Published by Elsevier B.V.)
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- 2023
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29. Engineered dual affinity protein fragments to bind collagen and capture growth factors.
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Sarrigiannidis SO, Dobre O, Navarro AR, Dalby MJ, Gonzalez-Garcia C, and Salmeron-Sanchez M
- Abstract
Collagen type I lacks affinity for growth factors (GFs) and yet it is clinically used to deliver bone morphogenic protein 2 (BMP-2), a potent osteogenic growth factor. To mitigate this lack of affinity, supra-physiological concentrations of BMP-2 are loaded in collagen sponges leading to uncontrolled BMP-2 leakage out of the material. This has led to important adverse side effects such as carcinogenesis. Here, we design recombinant dual affinity protein fragments, produced in E. Coli , which contain two regions, one that spontaneously binds to collagen and a second one that binds BMP-2. By adding the fragment to collagen sponges, BMP-2 is sequestered enabling solid phase presentation of BMP-2. We demonstrate osteogenesis in vivo with ultra-low doses of BMP-2. Our protein technology enhances the biological activity of collagen without using complex chemistries or changing the manufacturing of the base material and so opens a pathway to clinical translation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Manuel Salmeron-Sanchez reports financial support was provided by 10.13039/501100000853University of Glasgow., (© 2023 The Authors.)
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- 2023
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30. Clinical NEC prevention practices drive different microbiome profiles and functional responses in the preterm intestine.
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Neumann CJ, Mahnert A, Kumpitsch C, Kiu R, Dalby MJ, Kujawska M, Madl T, Kurath-Koller S, Urlesberger B, Resch B, Hall LJ, and Moissl-Eichinger C
- Subjects
- Infant, Infant, Newborn, Humans, Female, RNA, Ribosomal, 16S genetics, Ecosystem, Intestines, Feces microbiology, Bifidobacterium longum subspecies infantis genetics, Infant, Premature, Gastrointestinal Microbiome
- Abstract
Preterm infants with very low birthweight are at serious risk for necrotizing enterocolitis. To functionally analyse the principles of three successful preventive NEC regimens, we characterize fecal samples of 55 infants (<1500 g, n = 383, female = 22) longitudinally (two weeks) with respect to gut microbiome profiles (bacteria, archaea, fungi, viruses; targeted 16S rRNA gene sequencing and shotgun metagenomics), microbial function, virulence factors, antibiotic resistances and metabolic profiles, including human milk oligosaccharides (HMOs) and short-chain fatty acids (German Registry of Clinical Trials, No.: DRKS00009290). Regimens including probiotic Bifidobacterium longum subsp. infantis NCDO 2203 supplementation affect microbiome development globally, pointing toward the genomic potential to convert HMOs. Engraftment of NCDO 2203 is associated with a substantial reduction of microbiome-associated antibiotic resistance as compared to regimens using probiotic Lactobacillus rhamnosus LCR 35 or no supplementation. Crucially, the beneficial effects of Bifidobacterium longum subsp. infantis NCDO 2203 supplementation depends on simultaneous feeding with HMOs. We demonstrate that preventive regimens have the highest impact on development and maturation of the gastrointestinal microbiome, enabling the establishment of a resilient microbial ecosystem that reduces pathogenic threats in at-risk preterm infants., (© 2023. The Author(s).)
- Published
- 2023
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31. Enhanced and Stem-Cell-Compatible Effects of Nature-Inspired Antimicrobial Nanotopography and Antimicrobial Peptides to Combat Implant-Associated Infection.
- Author
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Ishak MI, Eales M, Damiati L, Liu X, Jenkins J, Dalby MJ, Nobbs AH, Ryadnov MG, and Su B
- Abstract
Nature-inspired antimicrobial surfaces and antimicrobial peptides (AMPs) have emerged as promising strategies to combat implant-associated infections. In this study, a bioinspired antimicrobial peptide was functionalized onto a nanospike (NS) surface by physical adsorption with the aim that its gradual release into the local environment would enhance inhibition of bacterial growth. Peptide adsorbed on a control flat surface exhibited different release kinetics compared to the nanotopography, but both surfaces showed excellent antibacterial properties. Functionalization with peptide at micromolar concentrations inhibited Escherichia coli growth on the flat surface, Staphylococcus aureus growth on the NS surface, and Staphylococcus epidermidis growth on both the flat and NS surfaces. Based on these data, we propose an enhanced antibacterial mechanism whereby AMPs can render bacterial cell membranes more susceptible to nanospikes, and the membrane deformation induced by nanospikes can increase the surface area for AMPs membrane insertion. Combined, these effects enhance bactericidal activity. Since functionalized nanostructures are highly biocompatible with stem cells, they make promising candidates for next generation antibacterial implant surfaces., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)
- Published
- 2023
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32. Nanotopography reveals metabolites that maintain the immunomodulatory phenotype of mesenchymal stromal cells.
- Author
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Ross EA, Turner LA, Donnelly H, Saeed A, Tsimbouri MP, Burgess KV, Blackburn G, Jayawarna V, Xiao Y, Oliva MAG, Willis J, Bansal J, Reynolds P, Wells JA, Mountford J, Vassalli M, Gadegaard N, Oreffo ROC, Salmeron-Sanchez M, and Dalby MJ
- Subjects
- Multipotent Stem Cells metabolism, Cell Differentiation, Immunomodulation, Phenotype, Mesenchymal Stem Cells metabolism
- Abstract
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that are of considerable clinical potential in transplantation and anti-inflammatory therapies due to their capacity for tissue repair and immunomodulation. However, MSCs rapidly differentiate once in culture, making their large-scale expansion for use in immunomodulatory therapies challenging. Although the differentiation mechanisms of MSCs have been extensively investigated using materials, little is known about how materials can influence paracrine activities of MSCs. Here, we show that nanotopography can control the immunomodulatory capacity of MSCs through decreased intracellular tension and increasing oxidative glycolysis. We use nanotopography to identify bioactive metabolites that modulate intracellular tension, growth and immunomodulatory phenotype of MSCs in standard culture and during larger scale cell manufacture. Our findings demonstrate an effective route to support large-scale expansion of functional MSCs for therapeutic purposes., (© 2023. The Author(s).)
- Published
- 2023
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33. Acetylcholine Receptors in Mesenchymal Stem Cells.
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Alqahtani S, Butcher MC, Ramage G, Dalby MJ, McLean W, and Nile CJ
- Subjects
- Humans, Cholinergic Agents, Nicotine, Receptors, Nicotinic genetics, Receptors, Nicotinic metabolism, Receptors, Muscarinic genetics, Receptors, Muscarinic metabolism, Mesenchymal Stem Cells, Receptors, Cholinergic genetics, Receptors, Cholinergic metabolism
- Abstract
Mesenchymal stem cells (MSCs) are well known for their regenerative potential. Even though the ability of MSCs to proliferate and differentiate has been studied extensively, there remains much to learn about the signaling mechanisms and pathways that control proliferation and influence the differentiation phenotype. In recent years, there has been growing evidence for the utility of non-neuronal cholinergic signaling systems and that acetylcholine (ACh) plays an important ubiquitous role in cell-to-cell communication. Indeed, cholinergic signaling is hypothesized to occur in stem cells and ACh synthesis, as well as in ACh receptor (AChR) expression, has been identified in several stem cell populations, including MSCs. Furthermore, AChRs have been found to influence MSC regenerative potential. In humans, there are two major classes of AChRs, muscarinic AChRs and nicotinic AChRs, with each class possessing several subtypes or subunits. In this review, the expression and function of AChRs in different types of MSC are summarized with the aim of highlighting how AChRs play a pivotal role in regulating MSC regenerative function.
- Published
- 2023
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34. Noninvasive Fecal Cytokine and Microbiota Profiles Predict Commencement of Necrotizing Enterocolitis in a Proof-of-Concept Study.
- Author
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Zenner C, Chalklen L, Adjei H, Dalby MJ, Mitra S, Cornwell E, Shaw AG, Sim K, Kroll JS, and Hall LJ
- Abstract
Background and Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease and the most common gastrointestinal emergency in premature infants. Accurate early diagnosis is challenging. Modified Bell's staging is routinely used to guide diagnosis, but early diagnostic signs are nonspecific, potentially leading to unobserved disease progression, which is problematic given the often rapid deterioration observed. We investigated fecal cytokine levels, coupled with gut microbiota profiles, as a noninvasive method to discover specific NEC-associated signatures that can be applied as potential diagnostic markers., Methods: Premature babies born below 32 weeks of gestation were admitted to the 2-site neonatal intensive care unit (NICU) of Imperial College hospitals (St. Mary's or Queen Charlotte's & Chelsea) between January 2011 and December 2012. During the NICU stay, expert neonatologists grouped individuals by modified Bell's staging (healthy, NEC1, NEC2/3) and fecal samples from diapers were collected consecutively. Microbiota profiles were assessed by 16S rRNA gene amplicon sequencing and cytokine concentrations were measured by V-Plex multiplex assays., Results: Early evaluation of microbiota profiles revealed only minor differences. However, at later time points, significant changes in microbiota composition were observed for Bacillota (adj. P = .0396), with Enterococcus being the least abundant in Bell stage 2/3 NEC. Evaluation of fecal cytokine levels revealed significantly higher concentrations of IL-1α ( P = .045), IL-5 ( P = .0074), and IL-10 ( P = .032) in Bell stage 1 NEC compared to healthy individuals., Conclusion: Differences in certain fecal cytokine profiles in patients with NEC indicate their potential use as diagnostic biomarkers to facilitate earlier diagnosis. Additionally, associations between microbial and cytokine profiles contribute to improving knowledge about NEC pathogenesis., (© 2023 The Authors.)
- Published
- 2023
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35. Living Biomaterials to Engineer Hematopoietic Stem Cell Niches.
- Author
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Petaroudi M, Rodrigo-Navarro A, Dobre O, Dalby MJ, and Salmeron-Sanchez M
- Subjects
- Humans, Biocompatible Materials metabolism, Ligands, Hematopoietic Stem Cells, Hydrogels metabolism, Fibronectins metabolism, Thrombopoietin metabolism
- Abstract
Living biointerfaces are a new class of biomaterials combining living cells and polymeric matrices that can act as biologically active and instructive materials that host and provide signals to surrounding cells. Here, living biomaterials based on Lactococcus lactis to control hematopoietic stem cells in 2D surfaces and 3D hydrogels are introduced. L. lactis is modified to express C-X-C motif chemokine ligand 12 (CXCL12), thrombopoietin (TPO), vascular cell adhesion protein 1 (VCAM1), and the 7th-10th type III domains of human plasma fibronectin (FN III
7-10 ), in an attempt to mimic ex vivo the conditions of the human bone marrow. These results suggest that living biomaterials that incorporate bacteria expressing recombinant CXCL12, TPO, VCAM1, and FN in both 2D systems direct hematopoietic stem and progenitor cells (HSPCs)-bacteria interaction, and in 3D using hydrogels functionalized with full-length human plasma fibronectin allow for a notable expansion of the CD34+ /CD38- /CD90+ HSPC population compared to the initial population. These results provide a strong evidence based on data that suggest the possibility of using living materials based on genetically engineered bacteria for the ex-vivo expansion of HSPC with eventual practical clinical applications in HSPCs transplantation for hematological disorders., (© 2022 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)- Published
- 2022
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36. Material-driven fibronectin and vitronectin assembly enhances BMP-2 presentation and osteogenesis.
- Author
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Xiao Y, Donnelly H, Sprott M, Luo J, Jayawarna V, Lemgruber L, Tsimbouri PM, Meek RMD, Salmeron-Sanchez M, and Dalby MJ
- Abstract
Mesenchymal stem cell (MSC)-based tissue engineering strategies are of interest in the field of bone tissue regenerative medicine. MSCs are commonly investigated in combination with growth factors (GFs) and biomaterials to provide a regenerative environment for the cells. However, optimizing how biomaterials interact with MSCs and efficiently deliver GFs, remains a challenge. Here, via plasma polymerization, tissue culture plates are coated with a layer of poly (ethyl acrylate) (PEA), which is able to spontaneously permit fibronectin (FN) to form fibrillar nanonetworks. However, vitronectin (VN), another important extracellular matrix (ECM) protein forms multimeric globules on the polymer, thus not displaying functional groups to cells. Interestingly, when FN and VN are co-absorbed onto PEA surfaces, VN can be entrapped within the FN fibrillar nanonetwork in the monomeric form providing a heterogeneous, open ECM network. The combination of FN and VN promote MSC adhesion and leads to enhanced GF binding; here we demonstrate this with bone morphogenetic protein-2 (BMP2). Moreover, MSC differentiation into osteoblasts is enhanced, with elevated expression of osteopontin (OPN) and osteocalcin (OCN) quantified by immunostaining, and increased mineralization observed by von Kossa staining. Osteogenic intracellular signalling is also induced, with increased activity in the SMAD pathway. The study emphasizes the need of recapitulating the complexity of native ECM to achieve optimal cell-material interactions., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)
- Published
- 2022
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37. Current insights into the bone marrow niche: From biology in vivo to bioengineering ex vivo.
- Author
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Xiao Y, McGuinness CS, Doherty-Boyd WS, Salmeron-Sanchez M, Donnelly H, and Dalby MJ
- Subjects
- Bioengineering, Biology, Bone Marrow Cells, Hematopoietic Stem Cells physiology, Bone Marrow, Stem Cell Niche
- Abstract
Hematopoietic stem cells (HSCs) are fundamental to the generation of the body's blood and immune cells. They reside primarily within the bone marrow (BM) niche microenvironment, which provides signals responsible for the regulation of HSC activities. While our understanding of these signalling mechanisms continues to improve, our ability to recapitulate them in vitro to harness the clinical potential of the HSC populations is still lacking. Recent studies have applied novel engineering techniques combined with traditional in vitro work to establish ex vivo BM niche models. These models exhibit promising potential for research and clinical applications. In this review, BM niche factors that regulate the HSCs in vivo are discussed and their applications in the engineering of BM biomaterial-based platforms are considered. Many questions remain regarding the heterogeneity of niche components and the interactions of HSCs with their microenvironment. A greater understanding of the niche would help to elucidate these remaining questions, leading to the development of novel therapeutic tools., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2022
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38. Maternal gut microbiota Bifidobacterium promotes placental morphogenesis, nutrient transport and fetal growth in mice.
- Author
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Lopez-Tello J, Schofield Z, Kiu R, Dalby MJ, van Sinderen D, Le Gall G, Sferruzzi-Perri AN, and Hall LJ
- Subjects
- Animals, Bifidobacterium, Female, Fetal Development, Humans, Mice, Nutrients, Pregnancy, Gastrointestinal Microbiome, Placenta metabolism
- Abstract
The gut microbiota plays a central role in regulating host metabolism. While substantial progress has been made in discerning how the microbiota influences host functions post birth and beyond, little is known about how key members of the maternal gut microbiota can influence feto-placental growth. Notably, in pregnant women, Bifidobacterium represents a key beneficial microbiota genus, with levels observed to increase across pregnancy. Here, using germ-free and specific-pathogen-free mice, we demonstrate that the bacterium Bifidobacterium breve UCC2003 modulates maternal body adaptations, placental structure and nutrient transporter capacity, with implications for fetal metabolism and growth. Maternal and placental metabolome were affected by maternal gut microbiota (i.e. acetate, formate and carnitine). Histological analysis of the placenta confirmed that Bifidobacterium modifies placental structure via changes in Igf2P0, Dlk1, Mapk1 and Mapk14 expression. Additionally, B. breve UCC2003, acting through Slc2a1 and Fatp1-4 transporters, was shown to restore fetal glycaemia and fetal growth in association with changes in the fetal hepatic transcriptome. Our work emphasizes the importance of the maternal gut microbiota on feto-placental development and sets a foundation for future research towards the use of probiotics during pregnancy., (© 2022. The Author(s).)
- Published
- 2022
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39. Cell-controlled dynamic surfaces for skeletal stem cell growth and differentiation.
- Author
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Anderson HJ, Sahoo JK, Wells J, van Nuffel S, Dhowre HS, Oreffo ROC, Zelzer M, Ulijn RV, and Dalby MJ
- Subjects
- Cell Differentiation, Cells, Cultured, Oligopeptides pharmacology, Pancreatic Elastase, Osteogenesis physiology, Stem Cells
- Abstract
Skeletal stem cells (SSCs, or mesenchymal stromal cells typically referred to as mesenchymal stem cells from the bone marrow) are a dynamic progenitor population that can enter quiescence, self-renew or differentiate depending on regenerative demand and cues from their niche environment. However, ex vivo, in culture, they are grown typically on hard polystyrene surfaces, and this leads to rapid loss of the SSC phenotype. While materials are being developed that can control SSC growth and differentiation, very few examples of dynamic interfaces that reflect the plastic nature of the stem cells have, to date, been developed. Achieving such interfaces is challenging because of competing needs: growing SSCs require lower cell adhesion and intracellular tension while differentiation to, for example, bone-forming osteoblasts requires increased adhesion and intracellular tension. We previously reported a dynamic interface where the cell adhesion tripeptide arginine-glycine-aspartic acid (RGD) was presented to the cells upon activation by user-added elastase that cleaved a bulky blocking group hiding RGD from the cells. This allowed for a growth phase while the blocking group was in place and the cells could only form smaller adhesions, followed by an osteoblast differentiation phase that was induced after elastase was added which triggered exposure of RGD and subsequent cell adhesion and contraction. Here, we aimed to develop an autonomous system where the surface is activated according to the need of the cell by using matrix metalloprotease (MMP) cleavable peptide sequences to remove the blocking group with the hypothesis that the SSCs would produce higher levels of MMP as the cells reached confluence. The current studies demonstrate that SSCs produce active MMP-2 that can cleave functional groups on a surface. We also demonstrate that SSCs can grow on the uncleaved surface and, with time, produce osteogenic marker proteins on the MMP-responsive surface. These studies demonstrate the concept for cell-controlled surfaces that can modulate adhesion and phenotype with significant implications for stem cell phenotype modulation., (© 2022. The Author(s).)
- Published
- 2022
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40. An ossifying landscape: materials and growth factor strategies for osteogenic signalling and bone regeneration.
- Author
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Dhawan U, Jaffery H, Salmeron-Sanchez M, and Dalby MJ
- Subjects
- Cell Differentiation, Signal Transduction, Bone Regeneration, Osteogenesis genetics
- Abstract
Breakthroughs in our understanding of the complex interplay between cellular nanoenvironment and biomolecular signalling pathways are facilitating development of targeted osteogenic platforms. As critical biomolecules for osteogenesis, growth factors stimulate osteogenesis by activating key genes and transcription factors. The first half of this review presents emerging interconnectedness and recent discoveries of osteogenic signalling pathways initiating from growth factors for example, bone morphogenetic protein 2 (BMP-2). To complement this, the second half of review proposes a number of strategies to induce osteogenesis which include metallic, organic implants, nanotopological environments as well as growth factor immobilization techniques. The drawbacks of traditional osteogenic implants and how these have been overcome by biomedical engineers in the recent years without producing side-effects have also been summarized., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2022
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41. Materials-driven fibronectin assembly on nanoscale topography enhances mesenchymal stem cell adhesion, protecting cells from bacterial virulence factors and preventing biofilm formation.
- Author
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Damiati LA, Tsimbouri MP, Hernandez VL, Jayawarna V, Ginty M, Childs P, Xiao Y, Burgess K, Wells J, Sprott MR, Meek RMD, Li P, Oreffo ROC, Nobbs A, Ramage G, Su B, Salmeron-Sanchez M, and Dalby MJ
- Subjects
- Bacterial Adhesion, Biofilms, Cell Adhesion, Cell Differentiation, Humans, Osteogenesis, Virulence Factors metabolism, Fibronectins metabolism, Mesenchymal Stem Cells
- Abstract
Post-operative infection is a major complication in patients recovering from orthopaedic surgery. As such, there is a clinical need to develop biomaterials for use in regenerative surgery that can promote mesenchymal stem cell (MSC) osteospecific differentiation and that can prevent infection caused by biofilm-forming pathogens. Nanotopographical approaches to pathogen control are being identified, including in orthopaedic materials such as titanium and its alloys. These topographies use high aspect ratio nanospikes or nanowires to prevent bacterial adhesion but these features also significantly reduce MSC adhesion and activity. Here, we use a poly (ethyl acrylate) (PEA) polymer coating on titanium nanowires to spontaneously organise fibronectin (FN) and to deliver bone morphogenetic protein 2 (BMP2) to enhance MSC adhesion and osteospecific signalling. Using a novel MSC-Pseudomonas aeruginosa co-culture, we show that the coated nanotopographies protect MSCs from cytotoxic quorum sensing and signalling molecules, enhance MSC adhesion and osteoblast differentiation and reduce biofilm formation. We conclude that the PEA polymer-coated nanotopography can both support MSCs and prevent pathogens from adhering to a biomaterial surface, thus protecting from biofilm formation and bacterial infection, and supporting osteogenic repair., (Copyright © 2021. Published by Elsevier Ltd.)
- Published
- 2022
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42. The influence of nanotopography on cell behaviour through interactions with the extracellular matrix - A review.
- Author
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Luo J, Walker M, Xiao Y, Donnelly H, Dalby MJ, and Salmeron-Sanchez M
- Abstract
Nanotopography presents an effective physical approach for biomaterial cell manipulation mediated through material-extracellular matrix interactions. The extracellular matrix that exists in the cellular microenvironment is crucial for guiding cell behaviours, such as determination of integrin ligation and interaction with growth factors. These interactions with the extracellular matrix regulate downstream mechanotransductive pathways, such as rearrangements in the cytoskeleton and activation of signal cascades. Protein adsorption onto nanotopography strongly influences the conformation and distribution density of extracellular matrix and, therefore, subsequent cell responses. In this review, we first discuss the interactive mechanisms of protein physical adsorption on nanotopography. Secondly, we summarise advances in creating nanotopographical features to instruct desired cell behaviours. Lastly, we focus on the cellular mechanotransductive pathways initiated by nanotopography. This review provides an overview of the current state-of-the-art designs of nanotopography aiming to provide better biomedical materials for the future., Competing Interests: All authors have given approval to the final version of the manuscript, and have no conflict of interest., (© 2022 The Authors.)
- Published
- 2021
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43. Biophysical phenotyping of mesenchymal stem cells along the osteogenic differentiation pathway.
- Author
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Gavazzo P, Viti F, Donnelly H, Oliva MAG, Salmeron-Sanchez M, Dalby MJ, and Vassalli M
- Subjects
- Biomarkers, Cell Differentiation, Cells, Cultured, Mesenchymal Stem Cells, Osteogenesis
- Abstract
Mesenchymal stem cells represent an important resource, for bone regenerative medicine and therapeutic applications. This review focuses on new advancements and biophysical tools which exploit different physical and chemical markers of mesenchymal stem cell populations, to finely characterize phenotype changes along their osteogenic differentiation process. Special attention is paid to recently developed label-free methods, which allow monitoring cell populations with minimal invasiveness. Among them, quantitative phase imaging, suitable for single-cell morphometric analysis, and nanoindentation, functional to cellular biomechanics investigation. Moreover, the pool of ion channels expressed in cells during differentiation is discussed, with particular interest for calcium homoeostasis.Altogether, a biophysical perspective of osteogenesis is proposed, offering a valuable tool for the assessment of the cell stage, but also suggesting potential physiological links between apparently independent phenomena., (© 2021. Springer Nature B.V.)
- Published
- 2021
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44. Nanovibrational stimulation inhibits osteoclastogenesis and enhances osteogenesis in co-cultures.
- Author
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Kennedy JW, Tsimbouri PM, Campsie P, Sood S, Childs PG, Reid S, Young PS, Meek DRM, Goodyear CS, and Dalby MJ
- Subjects
- Bone Marrow Cells metabolism, Humans, Nanotechnology, Osteoclasts metabolism, Osteoclasts pathology, Bone Marrow Cells cytology, Cell Differentiation, Coculture Techniques methods, Osteoclasts cytology, Osteogenesis, Vibration
- Abstract
Models of bone remodelling could be useful in drug discovery, particularly if the model is one that replicates bone regeneration with reduction in osteoclast activity. Here we use nanovibrational stimulation to achieve this in a 3D co-culture of primary human osteoprogenitor and osteoclast progenitor cells. We show that 1000 Hz frequency, 40 nm amplitude vibration reduces osteoclast formation and activity in human mononuclear CD14
+ blood cells. Additionally, this nanoscale vibration both enhances osteogenesis and reduces osteoclastogenesis in a co-culture of primary human bone marrow stromal cells and bone marrow hematopoietic cells. Further, we use metabolomics to identify Akt (protein kinase C) as a potential mediator. Akt is known to be involved in bone differentiation via transforming growth factor beta 1 (TGFβ1) and bone morphogenetic protein 2 (BMP2) and it has been implicated in reduced osteoclast activity via Guanine nucleotide-binding protein subunit α13 (Gα13). With further validation, our nanovibrational bioreactor could be used to help provide humanised 3D models for drug screening., (© 2021. The Author(s).)- Published
- 2021
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45. A novel chlorhexidine-hexametaphosphate coating for titanium with antibiofilm efficacy and stem cell cytocompatibility.
- Author
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Garner SJ, Dalby MJ, Nobbs AH, and Barbour ME
- Subjects
- Biocompatible Materials chemistry, Biocompatible Materials pharmacology, Cell Adhesion, Chlorhexidine chemistry, Humans, Mesenchymal Stem Cells physiology, Phosphates chemistry, Surface Properties, Biofilms drug effects, Chlorhexidine pharmacology, Mesenchymal Stem Cells drug effects, Phosphates pharmacology, Titanium chemistry
- Abstract
Dental implants are an increasingly popular way to replace missing teeth. Whilst implant survival rates are high, a small number fail soon after placement, with various factors, including bacterial contamination, capable of disrupting osseointegration. This work describes the development of chlorhexidine-hexametaphosphate coatings for titanium that hydrolyse to release the antiseptic agent chlorhexidine. The aim was to develop a coating for titanium that released sufficient chlorhexidine to prevent biofilm formation, whilst simultaneously maintaining cytocompatibility with cells involved in osseointegration. The coatings were characterised with respect to physical properties, after which antibiofilm efficacy was investigated using a multispecies biofilm model, and cytocompatibility determined using human mesenchymal stem cells. The coatings exhibited similar physicochemical properties to some implant surfaces in clinical use, and significantly reduced formation of multispecies biofilm biomass up to 72 h. One coating had superior cytocompatibility, with mesenchymal stem cells able to perform normal functions and commence osteoblastic differentiation, although at a slower rate than those grown on uncoated titanium. With further refinement, these coatings may have application in the prevention of bacterial contamination of dental implants at the time of surgery. This could aid a reduction in rates of early implant failure., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
46. Dynamically Modulated Core-Shell Microfibers to Study the Effect of Depth Sensing of Matrix Stiffness on Stem Cell Fate.
- Author
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Wei D, Charlton L, Glidle A, Qi N, Dobson PS, Dalby MJ, Fan H, and Yin H
- Subjects
- Animals, Animals, Newborn, Cattle, Cell Line, Extracellular Matrix metabolism, Humans, Cell Culture Techniques, Cell Differentiation drug effects, Culture Media pharmacology, Mesenchymal Stem Cells cytology, Osteogenesis
- Abstract
It is well known that extracellular matrix stiffness can affect cell fate and change dynamically during many biological processes. Existing experimental means for in situ matrix stiffness modulation often alters its structure, which could induce additional undesirable effects on cells. Inspired by the phenomenon of depth sensing by cells, we introduce here core-shell microfibers with a thin collagen core for cell growth and an alginate shell that can be dynamically stiffened to deliver mechanical stimuli. This allows for the maintenance of biochemical properties and structure of the surrounding microenvironment, while dynamically modulating the effective modulus "felt" by cells. We show that simple addition of Sr
2+ in media can easily increase the stiffness of initially Ca2+ cross-linked alginate shells. Thus, despite the low stiffness of collagen cores (<5 kPa), the effective modulus of the matrix "felt" by cells are substantially higher, which promotes osteogenesis differentiation of human mesenchymal stem cells. We show this effect is more prominent in the stiffening microfiber compared to a static microfiber control. This approach provides a versatile platform to independently and dynamically modulate cellular microenvironments with desirable biochemical, physical, and mechanical stimuli without an unintended interplay of effects, facilitating investigations of a wide range of dynamic cellular processes.- Published
- 2021
- Full Text
- View/download PDF
47. Nanofibrous Gelatin-Based Biomaterial with Improved Biomimicry Using D-Periodic Self-Assembled Atelocollagen.
- Author
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Borrego-González S, Dalby MJ, and Díaz-Cuenca A
- Abstract
Design of bioinspired materials that mimic the extracellular matrix (ECM) at the nanoscale is a challenge in tissue engineering. While nanofibrillar gelatin materials mimic chemical composition and nano-architecture of natural ECM collagen components, it lacks the characteristic D-staggered array (D-periodicity) of 67 nm, which is an important cue in terms of cell recognition and adhesion properties. In this study, a nanofibrous gelatin matrix with improved biomimicry is achieved using a formulation including a minimal content of D-periodic self-assembled atelocollagen. We suggest a processing route approach consisting of the thermally induced phase separation of the gelatin based biopolymeric mixture precursor followed by chemical-free material cross-linking. The matrix nanostructure is characterized using field emission gun scanning electron microscopy (FEG-SEM), transmission electron microscopy (TEM), wide angle X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR). The cell culture assays indicate that incorporation of 2.6 wt.% content of D-periodic atelocollagen to the gelatin material, produces a significant increase of MC3T3-E1 mouse preosteoblast cells attachment and human mesenchymal stem cells (hMSCs) proliferation, in comparison with related bare gelatin matrices. The presented results demonstrate the achievement of an efficient route to produce a cost-effective, compositionally defined and low immunogenic "collagen-like" instructive biomaterial, based on gelatin.
- Published
- 2021
- Full Text
- View/download PDF
48. Populating preterm infants with probiotics.
- Author
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Dalby MJ and Hall LJ
- Subjects
- Double-Blind Method, Humans, Infant, Infant, Newborn, Infant, Premature, Gastrointestinal Microbiome, Infant, Premature, Diseases, Probiotics
- Abstract
A randomized placebo-controlled trial by Martí et al.
1 shows that probiotic supplementation of premature infants can modulate the infant gut microbiota soon after birth., (© 2021 The Author(s).)- Published
- 2021
- Full Text
- View/download PDF
49. You Talking to Me? Cadherin and Integrin Crosstalk in Biomaterial Design.
- Author
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Barcelona-Estaje E, Dalby MJ, Cantini M, and Salmeron-Sanchez M
- Subjects
- Biocompatible Materials, Cell Adhesion, Epithelial-Mesenchymal Transition, Cadherins, Integrins
- Abstract
While much work has been done in the design of biomaterials to control integrin-mediated adhesion, less emphasis has been put on functionalization of materials with cadherin ligands. Yet, cell-cell contacts in combination with cell-matrix interactions are key in driving embryonic development, collective cell migration, epithelial to mesenchymal transition, and cancer metastatic processes, among others. This review focuses on the incorporation of both cadherin and integrin ligands in biomaterial design, to promote what is called the "adhesive crosstalk." First, the structure and function of cadherins and their role in eliciting mechanotransductive processes, by themselves or in combination with integrin mechanosensing, are introduced. Then, biomaterials that mimic cell-cell interactions, and recent applications to get insights in fundamental biology and tissue engineering, are critically discussed., (© 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF
50. The use of nanovibration to discover specific and potent bioactive metabolites that stimulate osteogenic differentiation in mesenchymal stem cells.
- Author
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Hodgkinson T, Tsimbouri PM, Llopis-Hernandez V, Campsie P, Scurr D, Childs PG, Phillips D, Donnelly S, Wells JA, O'Brien FJ, Salmeron-Sanchez M, Burgess K, Alexander M, Vassalli M, Oreffo ROC, Reid S, France DJ, and Dalby MJ
- Subjects
- Cell Differentiation, Mesenchymal Stem Cells metabolism, Osteogenesis
- Abstract
Bioactive metabolites have wide-ranging biological activities and are a potential source of future research and therapeutic tools. Here, we use nanovibrational stimulation to induce osteogenic differentiation of mesenchymal stem cells, in the absence of off-target, nonosteogenic differentiation. We show that this differentiation method, which does not rely on the addition of exogenous growth factors to culture media, provides an artifact-free approach to identifying bioactive metabolites that specifically and potently induce osteogenesis. We first identify a highly specific metabolite, cholesterol sulfate, an endogenous steroid. Next, a screen of other small molecules with a similar steroid scaffold identified fludrocortisone acetate with both specific and highly potent osteogenic-inducing activity. Further, we implicate cytoskeletal contractility as a measure of osteogenic potency and cell stiffness as a measure of specificity. These findings demonstrate that physical principles can be used to identify bioactive metabolites and then enable optimization of metabolite potency can be optimized by examining structure-function relationships., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)
- Published
- 2021
- Full Text
- View/download PDF
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