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Mateo Blanco has performed over 10 plastic surgeries so far and still has plans to do more.
Mateo Blanco is known as the king of the BBLs (Brazilian Butt Lifts).
He has attracted public attention after his apparent facial surgeries and physical changes.
D Mateo Blanco Have Plastic Surgery? Before And After Photos On Instagram
Mateo Blanco had plastic surgery and it’s clearly event in his face and body features.
He’s had about 16 or 17 surgeries to achieve the fabulous body he has now. Some of the surgeries he has performed are eyebrow lifts, rhinoplasty, veneers, two chin liposuctions, abdominal etching, three BBLS and many more.
And he also plans surgeries to enhance his beauty even more.
As per social media, he spent more than $100,000 on her look. When we see his photos on the internet, his larger than normal lips and big and luscious butt catch the viewer’s attention.
On Instagram, Mateo Blanco d not share his photos before operations and there are only images from his current performances, that is, after operations.
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Mateo Blanco Age & Wiki
Mateo Blanco is around 30 to 40 years old.
Since no details on her year of birth and exact age have been found, we have only made a guess based on his visual images.
Mateo Blanco does not have a Wikipedia page but has an active presence on networking sites. Ase from being available on Instagram and Twitter, the Los Angeles-based model is also present on Onlyfans, where subscribers could see uncensored, 18+ posts, collaboration videos, and unlimited messaging.
For the one-month subscription to his Onlyfans posts, people have to pay $15 per month. Likewise, Blanco charges $40.50, $76.50, and $135 for three-month, six, and 12-month access, respectively.
@mateoblancoxxx Uh-oh 😳 #dsl #lipfiller #filler #surgery #blonde ♬ Shy Ronnie 2: Ronnie & Clyde – Album Version – The Lonely Island
Mateo Blanco Gender Revealed
Mateo Blanco’s gender entity is gay.
He belongs to the LGBTQ community and lets himself be carried along with a male partner.
Megan Fox SHOCKING Plastic Surgery Transformation
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Who is Mateo Blanco Wiki, Biography, Age, Spouse, Net Worth, Fast Facts
Mateo Blanco is known as the king of the BBL (Brazilian Butt Lifts). He later came to the attention of the public for his clear medical interventions on his face and beyond that for his real changes. Mateo Blanco has undergone plastic medical surgery and can often be clearly seen in the reflections on his face and body. He went through about 16 or 17 medical procedures to achieve the amazing body he has now.
Some of the medical procedures he performs are a brow lift, rhinoplasty, facade, two liposuctions on the jaw, scraping of the abs, three BBLS and a few more. In addition, you also want to use medical procedures to further increase your excellence. As revealed by web-based media, he has spent over $100,000 on his looks. The moment we see her photos on the internet, her larger than normal lips and big, curvy roots catch the viewer’s attention. Through Instagram, Mateo Blanco did not share his photos before the medical interventions and there are only accessible images of his current performances, such as subsequent medical interventions. Mateo Blanco has a maturity of about 30 to 40 years. Since no subtleties were found regarding her long birth time and exact age, we simply made an assumption from her visual images. @mateoblancoxxx #Latex Y ♬ original sound – Mateo Blanco 🇲🇽 #fur season 🥶 #fyp Mateo Blanco is scarce on Wikipedia but has a functional presence in sysadmin targets. In addition to her accessibility on Instagram and Twitter, the Los Angeles-based model also has a presence on Onlyfans, where supporters can view 18+ uncensored posts, collaborative shots, and unlimited info. For a month of membership in your onlyfans posts, people have to pay $15 every month. Likewise, Blanco for a long time, six and one year access, costs $40.50, $76.50 and $135 individually. Mateo Blanco’s sexual orientation figure is gay. He has a seat with the LGBTQ group and is taking part in a demonstration with one of his male accomplices.
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Father’s name is not available. We have no further information about his father; We will try to collect information and update it soon.
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Also, we have no idea about his brother and sister, nor do we know their names.
However, we are trying to collect all information about him and will update you soon.
His girlfriend/boyfriend’s name is not available. You are in relationship from the last few years of a strong relationship. We have no information about his girlfriend/boyfriend.
But we are sure that it is not available and his spouse’s name is not available. Now his relationship is perfect. We have no further information about his wife.
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Where is Benidorm cast now Career changes, cosmetic surgery and tragedy
Three years after the end of hit ITV sitcom Benidorm, here’s what happened to cast members like Johnny Vegas, Sherrie Hewson, Danny Walters and more
Where will Benidorm be occupied now? Career changes, cosmetic surgeries and tragedies
It ran for 10 series since its big debut on ITV in 2007, but sitcom Benidorm ended almost four years ago.
The comedy show followed the holidaymakers and staff at an all-inclusive resort in Benidorm, Spain, and all the hilarious antics that ensued there.
Series creator and writer Derren Little confirmed this in 2018: “Yes folks it’s true after months of speculation I can finally confirm that Benidorm Series 10 was the LAST TV SERIES from @BenidormTVshow”.
When the popular comedy came to an end on ITV, the cast parted ways and embarked on new ventures, but what became of them?
Danny Walter
Image: BBC / Jack Barnes) BBC / Jack Barnes)
The 27-year-old Essex actor played Tiger Dyke on the ITV sitcom from 2014 to 2017.
However, Danny made a big change when he left comedy and joined BBC One soap opera EastEnders in the role of the handsome Keanu Taylor.
As part of the noisy Taylor clan, Keanu was quickly drawn into chaos, but in his big story he began an affair with Sharon Mitchell (Letitia Dean) while he was with her stepdaughter Louise (Tilly Keeper) – and later with each of them fathered a child.
Danny stayed with EastEnders until retiring in 2019, with Keanu’s final scenes airing in early 2020 as his storyline with the Mitchell clan came to an end.
He is active on Instagram @danny_walters and now has representation in the UK and US.
Jake Canuso
(Image: Mike Marsland/WireImage) Mike Marsland/WireImage)
Jake Canuso, the longest serving Benidorm cast member, the Italian-British actor and dancer, played Solana barman Mateo Castellanos throughout the comedy’s run.
After graduating from Benidorm in 2018, Jake joined several other performers in Derren Little’s Benidorm live stage show which toured the UK for 250 shows from September 2018 to April 2019.
Since his run with Benidorm ended, Jake has worked again with Derren on his BBC One sitcom Scarborough, playing the role of Tony Peroni in the 2019 series.
Jake currently offers paid personalized messaging as Mateo through video service Memmo and tweeted last year “I heard Mateo saves a lot of work to send personalized video messaging direct from the Costa Blanca”.
Sheila Reid
The lovable Madge Harvey was played by Sheila Reid in the first six series of Benidorm, returning in 2016 for a recurring role in the seventh run and a guest appearance in the eighth series.
Since leaving Benidorm, Sheila has appeared in Channel 4 sci-fi drama Humans as Iris in 2018, along with a role on BBC One’s daytime soap Doctors as ‘Speedy Sue’ last year.
In 2018, Sheila also appeared in the Royal Shakespeare Company’s production of Troilus and Cressida
Sherry Hewson
Sherrie Hewson is best known to British viewers for her soap opera roles on Coronation Street, Crossroads and Emmerdale, but also for her role as a panelist on Loose Women from 2003 to 2017.
In 2013, Sherrie joined Benidorm in the fifth season of Benidorm in the role of Joyce Temple-Savage, the new manager of the Solana Hotel.
Hewson remained a regular part of the cast until the show’s cancellation after its tenth run.
Last year, Sherrie appeared as Joan in a celebrity special on ITV game show Tipping Point and British crime drama The Krays: New Blood.
In 2020, Sherrie also appeared on Loose Women to discuss her decision to undergo a cosmetic facelift procedure.
She revealed: “I’m not stupid, I know how old I am, I have wrinkles, I just wanted some fullness back and feel a little bit better.
“It made me feel like I could look in the mirror.”
Olivier Stokes
Oliver played the role of cheeky Michael Garvey in the first seven seasons of Benidorm from 2007 to 2015.
After leaving Benidorm, Oliver starred in two episodes of Casualty in 2017 as Sean McKern.
Since taking a less active role in the entertainment industry, 22-year-old Oliver can now be seen on Instagram posting proud photos of his young son and showing off his passion for fishing.
Hannah Hobley
32-year-old actress Hannah Hobley played the teenage Chantelle Garvey in the first three Benidorm series from 2007-2009, and memorably became a young mother on the series.
Since leaving Benidorm, Hannah has taken on theater roles including roles in stage productions of The Sleeping Beauty and Dick Whittington.
Hannah is very active on social media, including Instagram and TikTok, and can often be seen producing amusing content.
The actress also shares a series of throwbacks to her time in Benidorm as part of the Garvey clan.
Last year, amid the coronavirus pandemic, Hannah wrote: “In the spirit of remembering Benidorm’s first #TBT season. If you’re self-isolating and need a giggle, you can find all the seasons on Netflix.”
Kenny Ireland
Scottish actor and theater director Kenny Ireland played the popular role of Donald Stewart in Benidorm from inception until his death aged 68 in 2014.
Kenny’s battle with brain cancer was announced a month before his death in July 2014, with his final episodes of Benidorm appearing in the sixth series.
Derren Little wrote on Twitter at the time: “Very sad news folks. Kenny Ireland lost his very long battle with cancer this morning. Miss you so much already, dear friend. x”.
The character of Donald was subsequently killed off and mourned onscreen during the eighth run of the show.
As Eliot
Image: ITV) ITV)
British actor and singer Asa Elliot performed as himself in Benidorm from 2010 to 2014 and later joined Benidorm Live after the show ended.
In 2018, Asa also appeared and sang on PBS’ Doo Wop Generations where he performed These Magic Changes.
In 2020, Asa revealed he had been singing on cruise ships until the Covid pandemic disrupted his work.
He then took up work as an Asda delivery driver to supplement his income during these difficult times.
Asa told BBC Look North about the impact of the pandemic on the entertainment industry, according to The List: “It’s really hit us completely. We still don’t know when we’re going to go back to work.”
He added of his time as a delivery driver: “I’ve only met a couple of ‘Benidorm’ fans. I recently made a delivery to a lady in Hornsea and she was very impressed.”
Tony Maudsley
English actor Tony Maudsley is best known for his role as hairdresser Kenneth Du Beke in Benidorm, a role he played from 2011 until the show ended in 2018.
Tony, 53, also reprized the role of Kenneth for the 2018-19 Benidorm Live run.
Since the sitcom ended, he has appeared as Spearman in the BBC Two Cold War drama series Summer of Rockets and later landed the humorous role of undertaker George Shuttleworth on Coronation Street in 2020 and has been a regular on the soap opera Intro since.
Johnny Vegas
Comics legend Johnny Vegas appeared as Geoff Maltby aka “The Oracle” in the first three series of Benidorm and returned to reprise his role in the seventh through ninth series from 2014-2017.
Since leaving Benidorm, Johnny has appeared as a regular panelist on BBC quiz show QI and also on the celebrity edition of Gogglebox, along with the voice of Asbo in the 2018 Aardman Animation film Early Man.
Johnny has also had guest appearances on other comedy shows such as the sitcom Red Dwarf and the game show Taskmaster.
On his personal life, Johnny split from his wife and TV presenter Maïa Dunphy last year after getting married in 2011.
Dunphy told Dublin Live last year: “Johnny and I are not together now. It is difficult and heartbreaking and a source of daily sadness for me.
“It’s something I’m purposely nebulous about because I don’t want it to define Tom [the couple’s son] or me, and I don’t want to speak publicly about it.
“Like many people in the same situation, I’m just doing my best to get on with life in painful circumstances.”
Siobhan Finneran
Former Downton Abbey actress Siobhan Finneran played Janice Garvey in Benidorm from 2007 until the show’s seventh run in 2015.
She and Steve Pemberton announced their decision to leave the show during Benidorm’s sixth series, and Siobhan explained on TV at the time: “We were in a terrible state. It was our decision to quit, but it was still heartbreaking. A lot of guest stars – brilliant people like David Bradley – have said it’s a pleasure from a job, and they’re right.
She added, “So saying goodbye to the cast and crew was really, really upsetting. You know you’ll never work with them again. Then coming home and thinking, ‘Damn, we actually made it,’ is quite something.”
Since leaving Benidorm, Siobhan has appeared as Clare Cartwright in the dark BBC One crime drama Happy Valley, the crime drama The Moorside, based on the disappearance of Shannon Matthews, the BBC comedy series The Other One” and last year in the hit Netflix thriller The Unknown Man.
Steve Pemberton
Acclaimed The League of Gentleman star Steve Pemberton, who played Mick Garvey on the show from 2007 to 2015, left Benidorm at the same time Siobhan was her on-screen husband.
Since leaving Benidorm, Steve has continued to star in the comedy anthology series Inside No. 9, appeared in the Amazon Prime Video fantasy series Good Omens, played Mr Braithwaite in Worzel Gummidge and joined the cast of Killing Eve Season 3 as the raunchy Paul.
In 2019, Steve won a BAFTA television award for Best Male Comedy Performance for his work on Inside No. 9.
Steve is a father of three with his longtime partner Alison Rowles.
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Institute for Bioengineering of Catalonia
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Hristova-Panusheva K, Keremidarska-Markova M, Altankov G, Krasteva N, (2017). Age-related changes in the adhesive phenotype of bone marrow-derived mesenchymal stem cells on extracellular matrix proteins Journal of New Results in Science, 6, (1), 11-19
Mesenchymal stem cells (MSCs) are a promising cell source for cell-based therapies due to their potential for self-renewal and multilineage differentiation. Unlike embryonic stem cells, adult stem cells are subject to aging processes and the associated loss of function. Age-related changes in MSCs need to be well understood in order to develop clinical techniques and therapeutics based on these cells. In this work, we investigated the effect of aging on the adhesive behavior of bone marrow-derived MSC and MG-63 osteoblast cells to three extracellular matrix proteins: fibronectin (FN), vitronectin (VN), and collagen I (Coll I). The results showed significant differences in the adhesion behavior of both cell types during 21 days in culture. Bone marrow-derived MSCs significantly decreased their adhesion affinity to all proteins studied after day 7 in culture with further incubation. In contrast, MG-63 cells showed a stable cell-adhesive phenotype with high affinity for FN and Coll I and low affinity for vitronectin over the entire culture period. These data suggest that the adhesion behavior of MSCs to matrix proteins, in contrast to MG-63 cells, is influenced by aging processes and the age-related changes must be taken into account when expanding adult stem cells for clinical applications.
Key words: cell morphology, cell attachment and spreading, fibronectin, vitronectin, collagen I
Barbeck, Mike, Serra, Tiziano, Booms, Patrick, Stojanovic, Sanja, Najman, Stevo, Engel, Elisabeth, Sader, Robert, Kirkpatrick, Charles James, Navarro, Melba, Ghanaati, Shahram, (2017). Analysis of In Vitro Degradation and In Vivo Tissue Response to Two-Layer 3D-Printed Scaffolds Combining PLA and PLA/Bioglass Biphasic Components – Guiding the Inflammatory Response as a Basis for Osteochondral Regeneration Bioactive Materials , 2, (4), 208-223
Summary The aim of the present study was the in vitro and in vivo analysis of a two-layer 3D-printed scaffold combining a PLA layer and a biphasic PLA/Bioglass G5 layer for the regeneration of osteochondral defects in vivo. The focus of the in vitro analysis was on the (molecular weight) weight loss and the morphological and mechanical changes after immersion in SBF. The in vivo study focused on the analysis of tissue responses and differences in implant bed vascularization using an established subcutaneous implantation model in CD-1 mice and established histological and histomorphometric methods. Both scaffold parts retained their structural integrity while changes in morphology were observed, particularly for the PLA/G5 scaffold. Mechanical properties decreased with progressive degradation, while the PLA/G5 scaffolds exhibited a higher bulk modulus than PLA scaffolds. Tissue response to PLA included low numbers of BMGCs and minimal vascularization of the implant sites, while addition of G5 resulted in higher numbers of BMGCs and higher vascularization of the implant sites. The analysis revealed that the use of a two-layer scaffold shows the possibility of observing a significant in vivo response despite the physical proximity of PLA and PLA/G5 layers. Overall, the results showed that the addition of G5 makes it possible to reduce framework weight loss and increase mechanical strength. Furthermore, the addition of G5 resulted in a higher vascularization of the implant bed, which is required as a basis for bone tissue regeneration, mediated by a higher number of BMGCs, while within the PLA parts a significantly lower vascularization was found than optimal for chondral regeneration became. Thus, these data show that the analyzed bilayer scaffold can serve as an ideal basis for the regeneration of osteochondral tissue defects. In addition, the results indicate that the number of test animals required may be reduced as it may be possible to analyze tissue response to more than one implant in a test animal.
Key words: bioactive glass, polylactic acid (PLA), bilayer scaffold, multinucleated giant cells, bone substitute, vascularization, calcium phosphate glass
Valls-Comamala V, Guivernau B, Bonet J, Puig M, Perálvarez-Marín A, Palomer E, Fernández-Busquets X, Altafaj X, Tajes M. , Puig-Pijoan, A, Vicente, R, Oliva, B, Muñoz, FJ, (2017). The antigen-binding fragment of human gamma-immunoglobulin prevents the folding of the amyloid β-peptide into a β-sheet to form oligomers. Oncotarget 8, (25), 41154-41165
The amyloid beta peptide (Aβ) plays a leading role in the physiopathology of Alzheimer’s disease (AD). Although monomeric forms of Aβ are harmless to cells, Aβ can aggregate into β-sheet oligomers and fibrils, both of which are neurotoxic. Therefore, one of the most important therapeutic approaches to cure or delay the onset and progression of AD is to target Aβ aggregation. In the present study, we show that a pool of human gamma-immunoglobulins (IgG) protected cortical neurons from challenge with Aβ oligomers, as assessed by MTT reduction, caspase-3 activation, and cytoskeletal integrity. In addition, we report the inhibitory effect of IgG on Aβ aggregation as demonstrated by thioflavin T assay, size exclusion chromatography, and atomic force microscopy. Similar results were obtained with palivizumab, a human anti-sincinal virus antibody. To dissect the important domains, we digested the human IgG pool with papain to obtain Fab and Fc fragments. Using these cleaved fragments, we functionally identified Fab as the immunoglobulin fragment that inhibits Aβ aggregation, a result that was further confirmed by an in silico structural model. Interestingly, bioinformatic tools reveal a highly conserved structure capable of binding amyloid in the Fab region. Overall, our data strongly support the inhibitory effect of human IgG on Aβ aggregation and its neuroprotective role.
Keywords: Alzheimer’s disease, amyloid, immunoglobulin, Fab, oligomers
Venkova, Tatiana, Juárez, Antonio, Espinosa, Manuel, (2017). Editorial: Modulation of prokaryotic lifestyle by DNA-binding proteins: Learning from (apparently) simple systems Frontiers in Molecular Biosciences 3, article 86
Within molecular biology research, an important field over the years has been the analysis of how prokaryotes regulate the expression of their genes and the consequences of these activities. Prokaryotes have attracted the interest of researchers not only because the processes taking place in their world are important to cells, but also because many of the effects can often be easily measured, both at the single cell level and in large populations. Adding to the interest of the present topic is the fact that modulation of gene activity involves sensing of intra- and intercellular conditions, DNA binding and DNA dynamics, and interaction with the cell’s replication/transcription machinery. All of these processes are fundamental to the functioning of a biological entity and they determine its lifestyle. In addition, the discoveries made in the bacterial world have been of great use in eukaryotes. In addition to the fundamental interest in understanding the modulation of prokaryotic lifestyle by DNA-binding proteins, there is an additional interest from a healthcare perspective. It is well known that antibiotic-resistant strains of pathogenic bacteria represent a major global problem, so that innovative solutions are urgently needed. Human and animal infectious diseases cause enormous costs worldwide in the form of lost human and livestock lives, reduced productivity and the heavy economic burden of disease. The global dimension of international trade, personal travel and population migration is expanding at an ever-accelerating pace. This increased mobility leads to a broader and faster spread of bacterial pathogens and a rapid spread of antibiotic resistance. The majority of newly acquired resistance is spread horizontally between bacteria of the same or different species by processes of lateral (horizontal) gene transfer, so the discovery of new antibiotics is not a definitive solution to combating infectious diseases. There is an absolute need to find new alternatives to the “classical” approach to treating infections caused by bacterial pathogens, and these new avenues must involve the discovery and introduction of new antibacterial agents, the development of alternative strategies, and the discovery of new bacterial targets. However, all of these approaches will falter if we researchers fail to gain a better understanding of the mechanistic processes underlying bacterial gene expression. Therefore, it is imperative to gain further insight into the basic mechanisms by which bacterial cells regulate the expression of their genes. For this reason, our research topic, hosted by Frontiers in Molecular Biosciences, was timely and the result offers new and updated perspectives on the “simple” bacterial world.
Keywords: DNA-protein interactions, gene regulation in prokaryotes, replication control, regulation of bacterial gene expression, global regulatory networks
Calve, Pablo, Gorostiza, Pau, (2017). Estrategias optogeneticas y fotofarmacológicas para restablecer la vision Visión, 51, 6-13
La mayoría de los casos de ceguera están causados por defectos en el ojo. Generalmente, estas alteraciones se produced por daños en las vias ópticas que conducen a la retina y son necesarias para el enfoque de las imágenes. A día de hoy, it posible tratar y curar estos impedimentos ópticos. Por ejemplo, la cirugía de cataratas para extraer una lente opaca y reemplazarla con una lente artificial se lleva a cabo rutinariamente en muchas partes del mundo y los trasplantes de córnea con córneas naturales o artificiales comúnmente tienen éxito. Sin embargo, casos de ceguera que affectan exist un porcentaje considerably de la población y no disponen de tratamiento. The mayor parte de las cegueras incurables son debidas a las enfermedades neurodegenerativas de la retina, que se caracterizan, la mayoría de las veces, por pérdida de las células fotorreceptoras. En estas enfermedades, los fotorreceptores se dañan y mueren en un process de apoptosis que eventualmente provoca la ceguera. Sin embargo, las neuronas situadas en las capas internas de la retina permanently intactas durante un periodo de tiempo prolongado, antes de que la retina sufra procesos de remodelización en las etapas finales de la enfermedad. Entre las enfermedades neurodegeneratives de la retina, la retinosis pigmentaria y la degeneración macular asociada a la edad son las más comunes. De este modo, debido a que las neurodegeneraciones retinianas provocan affectaciones en la vision y pueden inducir ceguera completa en los casos más graves, it necesario buscar y estudiar nuevos tratamientos terapéuticos. Hoy en day, muchos laboratorios de investigación están desarrollando terapias para este tipo de enfermedades, dirigidas a restaurar la función de las células fotorreceptoras en el ojo ciego o bien a sustituir la pérdida de la función fotorreceptora, pretendiendo que las neuronas retinianas restantes sean direct à la Luz. Estas aproximaciones terapéuticas engloban desde prótesis electrónicas hasta células madre y terapia génica.
L. Neri, M. Lasa, A. Elosegui-Artola, D. D’Avola, B. Carte, C. Gazquez, S. Alve, P. Roca-Cusachs, M. Iñarrairaegui. , Herrero J, Prieto J, Sangro B, Aldabe R, (2017). NatB-mediated protein N-α-terminal acetylation is a potential therapeutic target in hepatocellular carcinoma Oncotarget 8, (25), 40967-40981
The identification of new targets for systemic therapy of hepatocellular carcinoma (HCC) is an urgent unmet medical need. Recently, we showed that hNatB catalyzes the N-α-terminal acetylation of 15% of the human proteome and that this action is necessary for proper structure and function of the actin cytoskeleton. In tumors, changes in the cytoskeleton affect motility, invasion, survival, cell growth and tumor progression, making the cytoskeleton a very attractive antitumor target. Here we show that hNatB subunits are upregulated in over 59% HCC tumors compared to non-tumor tissue and that this upregulation is associated with microscopic vascular invasion. We found that hNatB silencing blocks proliferation and tumorigenesis in HCC cell lines associated with impaired DNA synthesis and impaired progression through S and G2/M phases. Growth inhibition is mediated by the degradation of two hNatB substrates, tropomyosin and CDK2, which occurs when these proteins lack N-α-terminal acetylation. In addition, hNatB inhibition disrupts the actin cytoskeleton, focal adhesions, and tight/adherens junctions, thereby aborting two proliferative signaling pathways, Hippo/YAP and ERK1/2. Therefore, inhibition of NatB activity represents an interesting new approach to treat HCC by blocking cell proliferation and disrupting actin cytoskeletal function.
Keywords: CDK2, cell cycle arrest, cell-cell junctions, focal adhesions, tropomyosin
Parmar, J., Villa, K., Vilela, D., Sánchez, S., (2017). Cobalt Ferrite-Based Platinum-Free Micromotors for Antibiotic Removal Applied Materials Today 9, 605-611
Self-propelled micromotors have previously been shown to improve pollutant removal compared to non-mobile nano-micro particles. However, these systems are expensive, difficult to scale up, and require a surfactant to operate efficiently. Efficient and inexpensive micromotors are desirable for their practical applications in water treatment technologies. We describe cobalt-ferrite-based (CFO)-based micromotors, fabricated by a simple and scalable synthesis, that generate hydroxyl radicals via a Fenton-like reaction and utilize the oxygen gas generated during this reaction for self-propulsion. Once the reaction is complete, the CFO micromotors can be easily separated and collected due to their magnetic nature. The CFO micromotors will be demonstrated for the highly efficient advanced oxidative removal of tetracycline antibiotics from water. In addition, the effects of different concentrations of micromotors and hydrogen peroxide on antibiotic degradation as well as the formation of the highly reactive hydroxyl radicals responsible for the oxidation reaction were studied.
Keywords: degradation, Fenton reaction, microbots, nanomotors, self-propelled micromotors, water purification
Oria, Roger, Wiegand, Tina, Escribano, Jorge, Elosegui-Artola, Alberto, Uriarte, Juan Jose, Moreno-Pulido, Cristian, Platzman, Ilia, Delcanale, Pietro, Albertazzi, Lorenzo, Navajas, Daniel, Trepat, Xavier, García -Aznar, José Manuel, Cavalcanti-Adam, Elisabetta Ada, Roca-Cusachs, Pere, (2017). Force loading explains spatial acquisition of ligands by cells Nature 552, 219-224
Cells can sense the density and distribution of extracellular matrix (ECM) molecules via individual integrin proteins and larger, integrin-containing adhesion complexes within the cell membrane. This spatial awareness drives cellular activity in a variety of normal and pathological contexts1,2. Previous studies on cells on rigid glass surfaces have shown that spatial acquisition of ECM-ligands occurs on the nanometer scale, affecting integrin clustering and subsequent focal adhesion formation when individual integrin-ligand bonds are separated by more than a few tens of nanometers are3,4,5,6. It was therefore suggested that a cross-linking ‘adaptor’ protein of this size could connect integrins to the actin cytoskeleton and act as a molecular ruler that directly senses ligand spacing3,7,8,9. Here we develop gels whose stiffness and distribution of ECM ligands can be controlled and changed on the nanometer scale. We find that increasing the distance between ligands promotes the growth of focal adhesions on low-stiffness substrates, but leads to adhesion breakdown on stiffer substrates. Furthermore, perturbation of ligand distribution drastically increases adhesion growth but decreases the stiffness threshold for adhesion collapse. The growth and breakdown of focal adhesions are reflected by the nuclear and cytosolic localization of the transcriptional regulator protein YAP, respectively. We explain these findings not by directly assessing the ligand spacing, but by using an extended computational molecular coupling model10,11 in which individual integrin-ECM bonds—the molecular couplings—respond to force loading by recruiting additional integrins up to a maximum value . This creates more clutches, redistributing the total force between them and reducing the force load per clutch. With high stiffness and large ligand spacing, maximum recruitment is achieved, preventing further force redistribution and leading to adhesion breakdown. Measurements of cellular traction forces and actin flow velocities support our model. Our results provide a general framework for how cells perceive nanoscale spatial and physical information by fine-tuning the range of conditions under which they form adhesions and activate transcriptional regulation.
C Malinverno, S Corallino, F Giavazzi, M Bergert, Q Li, M Leoni, A Disanza, E Frittoli, A Oldani, E Martini, Lendenmann, T., Deflorian, G., Beznoussenko, G.V., Poulikakos, D., Ong, K.H., Uroz, M., Trepat, X., Parazzoli, D., Maiuri, P., Yu, W., Ferrari, A., Cerbino, R., Scita, G., (2017). Endocytic motility reawakening in congested epithelia Nature Materials 16, 587-596
The dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or stiffness transition. However, how cells control such phase transitions is unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility across dozens of cells and ballistic motion in otherwise kinetically arrested monolayers. This is associated with increased traction forces and elongation of cell protrusions that align with local velocity. Molecularly, impairment of endocytosis, macropinocytosis, or increased fluid outflow abolishes RAB5A-induced collective motility. A simple model based on mechanical junction tension and an active cell reorientation mechanism for the speed of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local decluttering. These changes in multicellular dynamics allow collectives to migrate under physical constraints and can be exploited by tumors for interstitial spread.
P Rodriguez-Franco, A Brugués, A Marin-Llaurado, V Conte, G Solanas, E Batlle, JJ Fredberg, P Roca-Cusachs, R Sunyer, Trepat, X., (2017). Long-lasting force patterns and strain waves at shedding epithelial borders Nature Materials 16, (10), 1029-1036
For an organism to develop and maintain homeostasis, cell types with different functions must often be separated by physical boundaries. The formation and maintenance of such borders are usually attributed to mechanisms confined to the cells lining the border. Here we show that besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-range mechanical events. Upon contact between two epithelial monolayers expressing EphB2 and its ligand EphrinB1, respectively, both monolayers exhibit oscillating patterns of tensile forces and intercellular stresses that tend to pull cell-matrix adhesions away from the boundary. Over time, monolayers become jammed, accompanied by the emergence of strain waves that propagate away from the boundary. This phenomenon is not specific to EphB2/EphrinB1 rejection but also occurs during the formation of boundaries with an inert interface and during the fusion of homotypic epithelial layers. Our results thus reveal a global physical mechanism that maintains tissue separation independent of the biochemical and mechanical features of the local tissue boundary.
Keywords: Biological Physics, Cellular Motility
Elosegui-Artola, A., Andreu, I., Beedle, AEM, Lezamiz, A., Uroz, M., Kosmalska, A.J., Oria, R., Kechagia, J.Z., Rico-Lastres, P., Le Roux, AL. , Shanahan, CM, Trepat, X, Navajas, D, Garcia-Manyes, S, Roca-Cusachs, P, (2017). Force triggers YAP nuclear entry by regulating transport through nuclear pores Cell 171, (6), 1397-1410
YAP is a mechanosensitive transcriptional activator with a crucial role in cancer, regeneration and organ size control. Here we show that the force exerted on the nucleus directly drives YAP nuclear translocation by reducing the mechanical constraint of nuclear pores on molecular transport. Exposure to a rigid environment causes cells to create a mechanical connection between the nucleus and the cytoskeleton, allowing forces exerted by focal adhesions to reach the nucleus. Power transmission then leads to core flattening, which stretches the core pores, reducing their mechanical resistance to molecular transport and increasing YAP core import. Transport constraint is further regulated by the mechanical stability of the transported protein, which governs both active nuclear transport of YAP and passive transport of small proteins. Our results reveal a mechanosensory mechanism mediated directly by nuclear pores that has been demonstrated for YAP, but with potential general applicability in transcriptional regulation. Force-dependent changes in nuclear pores control protein access to the nucleus.
Key words: atomic force microscopy, Hippo signaling pathway, mechanosensorics, mechanotransduction, molecular mechanical stability, nuclear mechanics, nuclear pores, nuclear transport, rigidity detection, transcriptional regulation
Garreta, Elena, Oria, Roger, Tarantino, Carolina, Pla-Roca, Mateu, Prado, Patricia, Fernández-Avilés, Francisco, Campistol, Josep Maria, Samitier, Josep, Montserrat, Nuria, (2017). Tissue Engineering by Decellularization and 3D Bioprinting Materials Today, 20, (4), 166-178
Discarded human donor organs have been shown to provide decellularized extracellular matrix (dECM) scaffolds suitable for organ engineering. The search for appropriate cell sources to meet the needs of multiple cell types to fully repopulate dECM scaffolds from human organs has opened new avenues for using human pluripotent stem cells (hPSCs) for recellularization. In addition, three-dimensional (3D) bioprinting techniques are advancing toward the fabrication of biomimetic cell-loaded biomaterial constructs. Here we review recent advances in decellularization/recellularization and 3D bioprinting technologies aimed at producing autologous tissue grafts and organs with implications for regenerative medicine.
Duro-Castano, Aroa, Nebot, Vicent J., Niño-Pariente, Amaya, Armiñán, Ana, Arroyo-Crespo, Juan J., Paul, Alison, Feiner-Gracia, Natalia, Albertazzi, Lorenzo, Vicent, María J., (2017). Capture “extraordinary” soft-assembled charge-like polypeptides as a strategy for nanocarrier design Advanced Materials 29, (39), 1702888
The rational design of nanomedicines is a challenging task given the complex architectures required to construct nanosized carriers with embedded therapeutic properties and the complex interface of these materials with the biological environment. Here, an unexpected charge-like attraction mechanism of self-assembly for star-shaped polyglutamates in non-saline aqueous solutions is identified, consistent with the ubiquitous “ordinary–extraordinary” phenomenon previously described by physicists. Also, for the first time, a bottom-up method for stabilizing these soft-composite, nano-sized star-shaped polyglutamates is described, allowing the transfer of theoretical research to nanomaterials with applicability in the field of drug delivery. The covalent attachment of these labile assemblies provides access to unprecedented architectures that can be used as nanocarriers. The improved in vitro and in vivo properties of these novel nanoconstructs as drug delivery systems underscore the potential of this approach for tumor-localized as well as lymphotropic delivery.
Key words: charge-like, drug delivery, polymer therapeutics, polypeptides, self-assembly
Gállego, Isaac, Manning, Brendan, Prades, Joan Daniel, Mir, Mònica, Samitier, Josep, Eritja, Ramon, (2017). DNA origami controlled lithography for structuring on gold surfaces with a resolution below 10 nm Advanced Materials 29, 1603233
Katuri, Jaideep, Ma, Xing, Stanton, Morgan M., Sánchez, Samuel, (2017). Development of micro and nano floats for specific applications Accounts of Chemical Research 50, (1), 2-11
Conspectus: Self-propelling colloids have emerged as a new class of drugs over the past decade. These are micron-sized colloidal objects that take free energy from their surroundings and turn it into directed motion. The self-propelled colloids are in many ways the synthetic analogues of biological self-propelled entities such as algae or bacteria. Although powered by very different mechanisms, biological swimmers are typically powered by flagellar motion and synthetic swimmers are powered by local chemical reactions, but they share a number of common features related to swimming behavior. They exhibit running and tumbling behavior, respond to environmental stimuli, and can even chemically interact with nearby swimmers. An understanding of self-propelled colloids could help us understand the complex behaviors that occur in populations of natural microswimmers. Self-propelled colloids also offer some advantages over natural microswimmers, as the surface properties, propulsion mechanisms, and particle geometry can be easily modified to meet specific requirements. From a more practical perspective, a number of applications have been envisioned for these systems, ranging from environmental remediation to targeted drug delivery. These applications rely on the basic functionalities of self-propelled colloids: directional motion, sensing of the local environment, and the ability to respond to external cues. Due to the very different nature of each of these applications, it becomes necessary to optimize the design decisions in these colloids. Significant effort has been expended to develop a range of self-propelled synthetic colloids to meet the specific conditions required for various processes. For example, tubular self-propelled colloids are ideal for decontamination processes due to their bubble propulsion mechanism that improves mixing in systems, but are incompatible with biological systems due to the toxic propellant fuel and the formation of oxygen bubbles. Spherical floats serve as model systems to understand the fundamental aspects of propulsion mechanism, collective behavior, response to external stimuli, etc. They are also the preferred nanoscale form due to their ease of manufacture. In jüngerer Zeit wurden auch biohybride Schwimmer entwickelt, die versuchen, die Vorteile synthetischer Kolloide beizubehalten, während sie ihren Antrieb von biologischen Schwimmern wie Spermien und Bakterien ableiten und die Mittel für biokompatibles Schwimmen bieten. In diesem Bericht werden wir unsere Bemühungen und die anderer Gruppen bei der Gestaltung und Entwicklung von Kolloiden mit Eigenantrieb mit unterschiedlichen strukturellen Eigenschaften und angetrieben durch unterschiedliche Antriebsmechanismen zusammenfassen. Wir werden auch kurz auf die Anwendungen eingehen, die für diese Schwimmerdesigns vorgeschlagen und teilweise demonstriert wurden.
Labernadie, A., Kato, T., Brugués, A., Serra-Picamal, X., Derzsi, S., Arwert, E., Weston, A., González-Tarragó, V., Elosegui-Artola, A. , Albertazzi, L., Alcaraz, J., Roca-Cusachs, P., Sahai, E., Trepat, X., (2017). Eine mechanisch aktive heterotypische E-Cadherin/N-Cadherin-Adhäsion ermöglicht es Fibroblasten, die Invasion von Krebszellen voranzutreiben Nature Cell Biology 19, (3), 224-237
Krebsassoziierte Fibroblasten (CAFs) fördern die Tumorinvasion und Metastasierung. Wir zeigen, dass CAFs eine physikalische Kraft auf Krebszellen ausüben, die ihre kollektive Invasion ermöglicht. Die Kraftübertragung wird durch eine heterophile Adhäsion vermittelt, an der N-Cadherin an der CAF-Membran und E-Cadherin an der Krebszellmembran beteiligt sind. Diese Adhäsion ist mechanisch aktiv; Wenn es einer Kraft ausgesetzt wird, löst es die Rekrutierung von β-Catenin und eine Adhäsionsverstärkung aus, die von der Interaktion von α-Catenin / Vinculin abhängt. Die Beeinträchtigung der E-Cadherin/N-Cadherin-Adhäsion hebt die Fähigkeit von CAFs auf, die kollektive Zellmigration zu steuern, und blockiert die Invasion von Krebszellen. N-Cadherin vermittelt auch die Repolarisation der CAFs weg von den Krebszellen. Parallel dazu werden Nektine und Afadin an die Grenzfläche zwischen Krebszelle und CAF rekrutiert, und die CAF-Repolarisation ist Afadin-abhängig. Heterotypische Verbindungen zwischen CAFs und Krebszellen werden in von Patienten stammendem Material beobachtet. Zusammen zeigen unsere Ergebnisse, dass eine mechanisch aktive heterophile Adhäsion zwischen CAFs und Krebszellen eine kooperative Tumorinvasion ermöglicht.
Roca-Cusachs, Pere, Conte, Vito, Trepat, Xavier, (2017). Kräfte in der Zellbiologie quantifizieren Nature Cell Biology 19, (7), 742-751
Zellen üben, spüren und reagieren auf physikalische Kräfte durch eine erstaunliche Vielfalt von Mechanismen. Hier überprüfen wir kürzlich entwickelte Werkzeuge zur Quantifizierung der von Zellen erzeugten Kräfte. Wir besprechen zunächst Technologien, die auf Sensoren mit bekannten oder angenommenen mechanischen Eigenschaften basieren, und diskutieren ihre Anwendbarkeit und Grenzen. Anschließend ziehen wir eine Analogie zwischen diesen vom Menschen hergestellten Sensoren und der Kraftmessung in der Zelle. Da sich zunehmend herausstellt, dass die Mechanik eine grundlegende Rolle bei der Zellfunktion spielt, gehen wir davon aus, dass Werkzeuge zur Quantifizierung physikalischer Kräfte bald in biowissenschaftlichen Labors weit verbreitet sein werden.
Trebicka, J., Gluud, L. L., (2017). Antwort auf: „Hinzufügen einer Embolisation zur TIPS-Implantation: Eine bessere Therapie zur Kontrolle von Blutungen aus ektopischen Varizen?“ Zeitschrift für Hepatologie 67, (1), 202-203
Wir möchten Perricone und Kollegen für ihren Brief und das Interesse an dem Artikel „Emergency TIPS in a Child-Pugh B patient: When does the window of opportunity open and close?“ danken.1 Der Brief wirft eine wichtige Frage auf, nämlich das Management von Blutungen aus ektopischen Varizen. Blutungen aus anderen ektopischen Varizen als Fundusvarizen sind eine seltene und herausfordernde Komplikation. Eine Anleitung für die klinische Praxis ist erforderlich.
Ruiz, Marta P., Aragones, Albert C., Camarero, Nuria, Vilhena, J. G., Ortega, Maria, Zotti, Linda Angela, Perez, Ruben, Cuevas, Juan Carlos, Gorostiza, Pau, Díez-Pérez, Ismael, (2017 ). Bioengineering a single-protein junction Journal of the American Chemical Society 139, (43), 15337–15346
Bioelectronics moves toward designing nanoscale electronic platforms that allow in vivo determinations. Such devices require interfacing complex biomolecular moieties as the sensing units to an electronic platform for signal transduction. Inevitably, a systematic design goes through a bottom-up understanding of the structurally related electrical signatures of the biomolecular circuit, which will ultimately lead us to tailor its electrical properties. Toward this aim, we show here the first example of bioengineered charge transport in a single-protein electrical contact. The results reveal that a single point-site mutation at the docking hydrophobic patch of a Cu-azurin causes minor structural distortion of the protein blue Cu site and a dramatic change in the charge transport regime of the single-protein contact, which goes from the classical Cu-mediated two-step transport in this system to a direct coherent tunneling. Our extensive spectroscopic studies and molecular-dynamics simulations show that the proteins’ folding structures are preserved in the single-protein junction. The DFT-computed frontier orbital of the relevant protein segments suggests that the Cu center participation in each protein variant accounts for the different observed charge transport behavior. This work is a direct evidence of charge transport control in a protein backbone through external mutagenesis and a unique nanoscale platform to study structurally related biological electron transfer.
Aragonès, A. C., Aravena, D., Valverde-Muñoz, F. J., Real, J. A., Sanz, F., Díez-Pérez, I., Ruiz, E., (2017). Metal-controlled magnetoresistance at room temperature in single-molecule devices Journal of the American Chemical Society 139, (16), 5768-5778
The appropriate choice of the transition metal complex and metal surface electronic structure opens the possibility to control the spin of the charge carriers through the resulting hybrid molecule/metal spinterface in a single-molecule electrical contact at room temperature. The single-molecule conductance of a Au/molecule/Ni junction can be switched by flipping the magnetization direction of the ferromagnetic electrode. The requirements of the molecule include not just the presence of unpaired electrons: the electronic configuration of the metal center has to provide occupied or empty orbitals that strongly interact with the junction metal electrodes and that are close in energy to their Fermi levels for one of the electronic spins only. The key ingredient for the metal surface is to provide an efficient spin texture induced by the spin-orbit coupling in the topological surface states that results in an efficient spin-dependent interaction with the orbitals of the molecule. The strong magnetoresistance effect found in this kind of single-molecule wire opens a new approach for the design of room-temperature nanoscale devices based on spin-polarized currents controlled at molecular level.
Feiner-Gracia, Natalia, Buzhor, Marina, Fuentes, Edgar, Pujals, S., Amir, Roey J., Albertazzi, Lorenzo, (2017). Micellar stability in biological media dictates internalization in living cells Journal of the American Chemical Society 139, (46), 16677-16687
The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG–dendron hybrids and their self-assembled micelles in order to determine their structure–stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability–activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.
Stanton, Morgan M., Park, Byung-Wook, Vilela, Diana, Bente, Klaas, Faivre, Damien, Sitti, Metin, Sanchez, Samuel, (2017). Magnetotactic bacteria powered biohybrids target E. coli biofilms ACS Nano 11, (10), 9968-9978
Biofilm colonies are typically resistant to general antibiotic treatment and require targeted methods for their removal. One of these methods include the use of nanoparticles as carriers for antibiotic delivery, where they randomly circulate in fluid until they make contact with the infected areas. However, the required proximity of the particles to the biofilm results in only moderate efficacy. We demonstrate here that the non-pathogenic magnetotactic bacteria, Magnetosopirrillum gryphiswalense (MSR-1), can be integrated with drug-loaded mesoporous silica microtubes (MSMs) to build controllable microswimmers (biohybrids) capable of antibiotic delivery to target an infectious biofilm. Applying external magnetic guidance capability and swimming power of the MSR-1 cells, the biohybrids are directed to and forcefully pushed into matured Escherichia coli (E. coli) biofilms. Release of the antibiotic, ciprofloxacin (CFX), is triggered by the acidic microenvironment of the biofilm ensuring an efficient drug delivery system. The results reveal the capabilities of a non-pathogenic bacteria species to target and dismantle harmful biofilms, indicating biohybrid systems have great potential for anti-biofilm applications.
Stanton, Morgan M., Sánchez, Samuel, (2017). Pushing bacterial biohybrids to in vivo applications Trends in Biotechnology , 35, (10), 910-913
Bacterial biohybrids use the energy of bacteria to manipulate synthetic materials with the goal of solving biomedical problems at the micro- and nanoscale. We explore current in vitro studies of bacterial biohybrids, the first attempts at in vivo biohybrid research, and problems to be addressed for the future.
Keywords: Bacteria, Biohybrid, Microswimmers, Micromotors, Drug delivery
Agusil, Juan Pablo, Torras, Núria, Duch, Marta, Esteve, Jaume, Pérez-García, Lluïsa, Samitier, Josep, Plaza, José A., (2017). Highly anisotropic suspended planar-array chips with multidimensional sub-micrometric biomolecular patterns Advanced Functional Materials 27, 1605912
Suspended planar-array (SPA) chips embody millions of individual miniaturized arrays to work in extremely small volumes. Here, the basis of a robust methodology for the fabrication of SPA silicon chips with on-demand physical and chemical anisotropies is demonstrated. Specifically, physical traits are defined during the fabrication process with special focus on the aspect ratio, branching, faceting, and size gradient of the final chips. Additionally, the chemical attributes augment the functionality of the chips with the inclusion of complete coverage or patterns of selected biomolecules on the surface of the chips with contact printing techniques, offering an extremely high versatility, not only with the choice of the pattern shape and distribution but also in the choice of biomolecular inks to pattern. This approach increases the miniaturization of printed arrays in 3D structures by two orders of magnitude compared to those previously demonstrated. Finally, functional micrometric and sub-micrometric patterned features are demonstrated with an antibody binding assay with the recognition of the printed spots with labeled antibodies from solution. The selective addition of physical and chemical attributes on the suspended chips represents the basis for future biomedical assays performed within extremely small volumes.
Keywords: Microcontact printing, Microparticles, Molecular multiplexing, Polymer pen lithography, Silicon chip technology
Caballero, D., Palacios, L., Freitas, P. P., Samitier, J., (2017). An interplay between matrix anisotropy and actomyosin contractility regulates 3D-directed cell migration Advanced Functional Materials 27, (35), 1702322
Directed cell migration is essential for many biological processes, such as embryonic development or cancer progression. Cell contractility and adhesion to the extracellular matrix are known to regulate cell locomotion machinery. However, the cross-talk between extrinsic and intrinsic factors at the molecular level on the biophysical mechanism of three dimensional (3D)-directed cell migration is still unclear. In this work, a novel physiologically relevant in vitro model of the extracellular microenvironment is used to reveal how the topological anisotropy of the extracellular matrix synergizes with actomyosin contractility to modulate directional cell migration morphodynamics. This study shows that cells seeded on polarized 3D matrices display asymmetric protrusion morphodynamics and in-vivo-like phenotypes. It is found that matrix anisotropy significantly enhances cell directionality, but strikingly, not the invasion distance of cells. In Rho-inhibited cells, matrix anisotropy counteracts the lack of actomyosin-driven forces to stabilize cell directionality suggesting a myosin-II-independent mechanism for cell guidance. Finally, this study shows that on isotropic 3D environments, cell directionality is independent of actomyosin contractility. Altogether, this study provides novel quantitative data on the biomechanical regulation of directional cell motion and shows the important regulatory role of matrix anisotropy and actomyosin forces to guide cell migration in 3D microenvironments.
Keywords: Anisotropy, Directed cell migration, Extracellular matrices, Migration modes, Three dimensional microenvironments
Carini, M., Ruiz, M. P., Usabiaga, I., Fernández, J. A., Cocinero, E. J., Melle-Franco, M., Diez-Perez, I., Mateo-Alonso, A., (2017). High conductance values in π-folded molecular junctions Nature Communications 8, 15195
Folding processes play a crucial role in the development of function in biomacromolecules. Recreating this feature on synthetic systems would not only allow understanding and reproducing biological functions but also developing new functions. This has inspired the development of conformationally ordered synthetic oligomers known as foldamers. Herein, a new family of foldamers, consisting of an increasing number of anthracene units that adopt a folded sigmoidal conformation by a combination of intramolecular hydrogen bonds and aromatic interactions, is reported. Such folding process opens up an efficient through-space charge transport channel across the interacting anthracene moieties. In fact, single-molecule conductance measurements carried out on this series of foldamers, using the scanning tunnelling microscopy-based break-junction technique, reveal exceptionally high conductance values in the order of 10-1 G0 and a low length decay constant of 0.02 Ã…-1 that exceed the values observed in molecular junctions that make use of through-space charge transport pathways.
Valon, L., Marín-Llauradó, A., Wyatt, T., Charras, G., Trepat, X., (2017). Optogenetic control of cellular forces and mechanotransduction Nature Communications 8, 14396
Contractile forces are the end effectors of cell migration, division, morphogenesis, wound healing and cancer invasion. Here we report optogenetic tools to upregulate and downregulate such forces with high spatiotemporal accuracy. The technology relies on controlling the subcellular activation of RhoA using the CRY2/CIBN light-gated dimerizer system. We fused the catalytic domain (DHPH domain) of the RhoA activator ARHGEF11 to CRY2-mCherry (optoGEF-RhoA) and engineered its binding partner CIBN to bind either to the plasma membrane or to the mitochondrial membrane. Translocation of optoGEF-RhoA to the plasma membrane causes a rapid and local increase in cellular traction, intercellular tension and tissue compaction. By contrast, translocation of optoGEF-RhoA to mitochondria results in opposite changes in these physical properties. Cellular changes in contractility are paralleled by modifications in the nuclear localization of the transcriptional regulator YAP, thus showing the ability of our approach to control mechanotransductory signalling pathways in time and space.
Aragonès, A. C., Darwish, N., Ciampi, S., Sanz, F., Gooding, J. J., Díez-Pérez, I., (2017). Single-molecule electrical contacts on silicon electrodes under ambient conditions Nature Communications 8, 15056
The ultimate goal in molecular electronics is to use individual molecules as the active electronic component of a real-world sturdy device. For this concept to become reality, it will require the field of single-molecule electronics to shift towards the semiconducting platform of the current microelectronics industry. Here, we report silicon-based single-molecule contacts that are mechanically and electrically stable under ambient conditions. The single-molecule contacts are prepared on silicon electrodes using the scanning tunnelling microscopy break-junction approach using a top metallic probe. The molecular wires show remarkable current-voltage reproducibility, as compared to an open silicon/nano-gap/metal junction, with current rectification ratios exceeding 4,000 when a low-doped silicon is used. The extension of the single-molecule junction approach to a silicon substrate contributes to the next level of miniaturization of electronic components and it is anticipated it will pave the way to a new class of robust single-molecule circuits.
Perez-Mockus, Gantas, Mazouni, Khalil, Roca, Vanessa, Corradi, Giulia, Conte, Vito, Schweisguth, François, (2017). Spatial regulation of contractility by Neuralized and Bearded during furrow invagination in Drosophila Nature Communications 8, (1), 1594
Embryo-scale morphogenesis arises from patterned mechanical forces. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells, leading to furrow formation and mesoderm invagination. It remains unclear whether and how mechanical properties of the ectoderm influence this process. Here, we show that Neuralized (Neur), an E3 ubiquitin ligase active in the mesoderm, regulates collective apical constriction and furrow formation. Conversely, the Bearded (Brd) proteins antagonize maternal Neur and lower medial–apical contractility in the ectoderm: in Brd-mutant embryos, the ventral furrow invaginates properly but rapidly unfolds as medial MyoII levels increase in the ectoderm. Increasing contractility in the ectoderm via activated Rho similarly triggers furrow unfolding whereas decreasing contractility restores furrow invagination in Brd-mutant embryos. Thus, the inhibition of Neur by Brd in the ectoderm differentiates the mechanics of the ectoderm from that of the mesoderm and patterns the activity of MyoII along the dorsal–ventral axis.
Keywords: Drosophila, Gastrulation, Morphogenesis
Gómez-Santacana, Xavier, Pittolo, Silvia, Rovira, Xavier, Lopez, Marc, Zussy, Charleine, Dalton, James A. R., Faucherre, Adèle, Jopling, Chris, Pin, Jean-Philippe, Ciruela, Francisco, Goudet, Cyril, Giraldo, Jesús, Gorostiza, Pau, Llebaria, Amadeu, (2017). Illuminating phenylazopyridines to photoswitch metabotropic glutamate receptors: From the flask to the animals ACS Central Science , 3, (1), 81-91
Phenylazopyridines are photoisomerizable compounds with high potential to control biological functions with light. We have obtained a series of phenylazopyridines with light dependent activity as negative allosteric modulators (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5). Here we describe the factors needed to achieve an operational molecular photoisomerization and its effective translation into in vitro and in vivo receptor photoswitching, which includes zebrafish larva motility and the regulation of the antinociceptive effects in mice. The combination of light and some specific phenylazopyridine ligands displays atypical pharmacological profiles, including light-dependent receptor overactivation, which can be observed both in vitro and in vivo. Remarkably, the localized administration of light and a photoswitchable compound in the peripheral tissues of rodents or in the brain amygdalae results in an illumination-dependent analgesic effect. The results reveal a robust translation of the phenylazopyridine photoisomerization to a precise photoregulation of biological activity.
Hernández-Vega, Amayra, Marsal, María, Pouille, Philippe-Alexandre, Tosi, Sébastien, Colombelli, Julien, Luque, Tomás, Navajas, Daniel, Pagonabarraga, Ignacio, Martín-Blanco, Enrique, (2017). Polarized cortical tension drives zebrafish epiboly movements EMBO Journal 36, (1), 25-41
The principles underlying the biomechanics of morphogenesis are largely unknown. Epiboly is an essential embryonic event in which three tissues coordinate to direct the expansion of the blastoderm. How and where forces are generated during epiboly, and how these are globally coupled remains elusive. Here we developed a method, hydrodynamic regression (HR), to infer 3D pressure fields, mechanical power, and cortical surface tension profiles. HR is based on velocity measurements retrieved from 2D+T microscopy and their hydrodynamic modeling. We applied HR to identify biomechanically active structures and changes in cortex local tension during epiboly in zebrafish. Based on our results, we propose a novel physical description for epiboly, where tissue movements are directed by a polarized gradient of cortical tension. We found that this gradient relies on local contractile forces at the cortex, differences in elastic properties between cortex components and the passive transmission of forces within the yolk cell. All in all, our work identifies a novel way to physically regulate concerted cellular movements that might be instrumental for the mechanical control of many morphogenetic processes.
Keywords: Epiboly, Hydrodynamics, Mechanics, Morphogenesis, Zebrafish
Grice, L. F., Gauthier, M. E. A., Roper, K. E., Fernàndez-Busquets, X., Degnan, S. M., Degnan, B. M., (2017). Origin and evolution of the sponge aggregation factor gene family Molecular Biology and Evolution , 34, (5), 1083-1099
Although discriminating self from nonself is a cardinal animal trait, metazoan allorecognition genes do not appear to be homologous. Here, we characterize the Aggregation Factor (AF) gene family, which encodes putative allorecognition factors in the demosponge Amphimedon queenslandica, and trace its evolution across 24 sponge (Porifera) species. The AF locus in Amphimedon is comprised of a cluster of five similar genes that encode Calx-beta and Von Willebrand domains and a newly defined Wreath domain, and are highly polymorphic. Further AF variance appears to be generated through individualistic patterns of RNA editing. The AF gene family varies between poriferans, with protein sequences and domains diagnostic of the AF family being present in Amphimedon and other demosponges, but absent from other sponge classes. Within the demosponges, AFs vary widely with no two species having the same AF repertoire or domain organization. The evolution of AFs suggests that their diversification occurs via high allelism, and the continual and rapid gain, loss and shuffling of domains over evolutionary time. Given the marked differences in metazoan allorecognition genes, we propose the rapid evolution of AFs in sponges provides a model for understanding the extensive diversification of self-nonself recognition systems in the animal kingdom.
Keywords: Aggregation factor, Allorecognition, Intron phase, Polymorphism, Porifera, RNA editing
Arroyo, M., Trepat, X., (2017). Hydraulic fracturing in cells and tissues: fracking meets cell biology Current Opinion in Cell Biology 44, 1-6
The animal body is largely made of water. A small fraction of body water is freely flowing in blood and lymph, but most of it is trapped in hydrogels such as the extracellular matrix (ECM), the cytoskeleton, and chromatin. Besides providing a medium for biological molecules to diffuse, water trapped in hydrogels plays a fundamental mechanical role. This role is well captured by the theory of poroelasticity, which explains how any deformation applied to a hydrogel causes pressure gradients and water flows, much like compressing a sponge squeezes water out of it. Here we review recent evidence that poroelastic pressures and flows can fracture essential biological barriers such as the nuclear envelope, the cellular cortex, and epithelial layers. This type of fracture is known in engineering literature as hydraulic fracturing or ‘fracking’.
Stanton, M. M., Park, B. W., Miguel-López, A., Ma, X., Sitti, M., Sánchez, S., (2017). Biohybrid microtube swimmers driven by single captured bacteria Small 13, (19), 1603679
Bacteria biohybrids employ the motility and power of swimming bacteria to carry and maneuver microscale particles. They have the potential to perform microdrug and cargo delivery in vivo, but have been limited by poor design, reduced swimming capabilities, and impeded functionality. To address these challenge, motile Escherichia coli are captured inside electropolymerized microtubes, exhibiting the first report of a bacteria microswimmer that does not utilize a spherical particle chassis. Single bacterium becomes partially trapped within the tube and becomes a bioengine to push the microtube though biological media. Microtubes are modified with “smart” material properties for motion control, including a bacteria-attractant polydopamine inner layer, addition of magnetic components for external guidance, and a biochemical kill trigger to cease bacterium swimming on demand. Swimming dynamics of the bacteria biohybrid are quantified by comparing “length of protrusion” of bacteria from the microtubes with respect to changes in angular autocorrelation and swimmer mean squared displacement. The multifunctional microtubular swimmers present a new generation of biocompatible micromotors toward future microbiorobots and minimally invasive medical applications.
Keywords: Biohybrids, E. coli, Micromotors, Microswimmers, Polydopamine
López-Martínez, Montserrat, Artés, Juan Manuel, Sarasso, Veronica, Carminati, Marco, Díez-Pérez, Ismael, Sanz, Fausto, Gorostiza, Pau, (2017). Differential electrochemical conductance imaging at the nanoscale Small 13, (36), 1700958
Electron transfer in proteins is essential in crucial biological processes. Although the fundamental aspects of biological electron transfer are well characterized, currently there are no experimental tools to determine the atomic-scale electronic pathways in redox proteins, and thus to fully understand their outstanding efficiency and environmental adaptability. This knowledge is also required to design and optimize biomolecular electronic devices. In order to measure the local conductance of an electrode surface immersed in an electrolyte, this study builds upon the current–potential spectroscopic capacity of electrochemical scanning tunneling microscopy, by adding an alternating current modulation technique. With this setup, spatially resolved, differential electrochemical conductance images under bipotentiostatic control are recorded. Differential electrochemical conductance imaging allows visualizing the reversible oxidation of an iron electrode in borate buffer and individual azurin proteins immobilized on atomically flat gold surfaces. In particular, this method reveals submolecular regions with high conductance within the protein. The direct observation of nanoscale conduction pathways in redox proteins and complexes enables important advances in biochemistry and bionanotechnology.
Keywords: Differential electrochemical conductance, ECSTM, Electron transport pathway, Iron passivation, Redox metalloproteins
Aragonès, Albert C., Medina, Ernesto, Ferrer-Huerta, Miriam, Gimeno, Nuria, Teixidó, Meritxell, Palma, Julio L., Tao, Nongjian, Ugalde, Jesus M., Giralt, Ernest, Díez-Pérez, Ismael, Mujica, Vladimiro, (2017). Measuring the spin-polarization power of a single chiral molecule Small 13, (2), 1602519
The electronic spin filtering capability of a single chiral helical peptide is measured. A ferromagnetic electrode source is employed to inject spin-polarized electrons in an asymmetric single-molecule junction bridging an α-helical peptide sequence of known chirality. The conductance comparison between both isomers allows the direct determination of the polarization power of an individual chiral molecule.
Keywords: Alpha-helical peptides, Chiral transport, Single-molecule wires, Spin-polarization power, Spin-polarized transmission
Feiner-Gracia, Natalia, Beck, Michaela, Pujals, Sílvia, Tosi, Sébastien, Mandal, Tamoghna, Buske, Christian, Linden, Mika, Albertazzi, Lorenzo, (2017). Super-resolution microscopy unveils dynamic heterogeneities in nanoparticle protein corona Small 13, (41), 1701631
The adsorption of serum proteins, leading to the formation of a biomolecular corona, is a key determinant of the biological identity of nanoparticles in vivo. Therefore, gaining knowledge on the formation, composition, and temporal evolution of the corona is of utmost importance for the development of nanoparticle-based therapies. Here, it is shown that the use of super-resolution optical microscopy enables the imaging of the protein corona on mesoporous silica nanoparticles with single protein sensitivity. Particle-by-particle quantification reveals a significant heterogeneity in protein absorption under native conditions. Moreover, the diversity of the corona evolves over time depending on the surface chemistry and degradability of the particles. This paper investigates the consequences of protein adsorption for specific cell targeting by antibody-functionalized nanoparticles providing a detailed understanding of corona-activity relations. The methodology is widely applicable to a variety of nanostructures and complements the existing ensemble approaches for protein corona study.
Keywords: Heterogeneity, Mesoporous silica nanoparticles, Protein corona, Super-resolution imaging, Targeting
Ojosnegros’, Samuel, Cutrale, Francesco, Rodríguez, Daniel, Otterstrom, Jason J., Chiu, Chi Li, Hortigüela, Verónica, Tarantino, Carolina, Seriola’, Anna, Mieruszynski, Stephen, Martínez, Elena, Lakadamyali, Melike, Raya, Angel, Fraser, Scott E., (2017). Eph-ephrin signaling modulated by polymerization and condensation of receptors Proceedings of the National Academy of Sciences of the United States of America 114, (50), 13188-13193
Eph receptor signaling plays key roles in vertebrate tissue boundary formation, axonal pathfinding, and stem cell regeneration by steering cells to positions defined by its ligand ephrin. Some of the key events in Eph-ephrin signaling are understood: ephrin binding triggers the clustering of the Eph receptor, fostering transphosphorylation and signal transduction into the cell. However, a quantitative and mechanistic understanding of how the signal is processed by the recipient cell into precise and proportional responses is largely lacking. Studying Eph activation kinetics requires spatiotemporal data on the number and distribution of receptor oligomers, which is beyond the quantitative power offered by prevalent imaging methods. Here we describe an enhanced fluorescence fluctuation imaging analysis, which employs statistical resampling to measure the Eph receptor aggregation distribution within each pixel of an image. By performing this analysis over time courses extending tens of minutes, the information-rich 4D space (x, y, oligomerization, time) results were coupled to straightforward biophysical models of protein aggregation. This analysis reveals that Eph clustering can be explained by the combined contribution of polymerization of receptors into clusters, followed by their condensation into far larger aggregates. The modeling reveals that these two competing oligomerization mechanisms play distinct roles: polymerization mediates the activation of the receptor by assembling monomers into 6- to 8-mer oligomers; condensation of the preassembled oligomers into large clusters containing hundreds of monomers dampens the signaling. We propose that the polymerization–condensation dynamics creates mechanistic explanation for how cells properly respond to variable ligand concentrations and gradients.
Keywords: Eph, Ephrin, Receptor tyrosine kinase, Gradients, Cell communication
Moles, E., Galiano, S., Gomes, A., Quiliano, M., Teixeira, C., Aldana, I., Gomes, P., Fernàndez-Busquets, X., (2017). ImmunoPEGliposomes for the targeted delivery of novel lipophilic drugs to red blood cells in a falciparum malaria murine model Biomaterials 145, 178-191
Most drugs currently entering the clinical pipeline for severe malaria therapeutics are of lipophilic nature, with a relatively poor solubility in plasma and large biodistribution volumes. Low amounts of these compounds do consequently accumulate in circulating Plasmodium-infected red blood cells, exhibiting limited antiparasitic activity. These drawbacks can in principle be satisfactorily dealt with by stably encapsulating drugs in targeted nanocarriers. Here this approach has been adapted for its use in immunocompetent mice infected by the Plasmodium yoelii 17XL lethal strain, selected as a model for human blood infections by Plasmodium falciparum. Using immunoliposomes targeted against a surface protein characteristic of the murine erythroid lineage, the protocol has been applied to two novel antimalarial lipophilic drug candidates, an aminoquinoline and an aminoalcohol. Large encapsulation yields of >90% were obtained using a citrate-buffered pH gradient method and the resulting immunoliposomes reached in vivo erythrocyte targeting and retention efficacies of >80%. In P. yoelii-infected mice, the immunoliposomized aminoquinoline succeeded in decreasing blood parasitemia from severe to uncomplicated malaria parasite densities (i.e. from ≥25% to ca. 5%), whereas the same amount of drug encapsulated in non-targeted liposomes had no significant effect on parasite growth. Pharmacokinetic analysis indicated that this good performance was obtained with a rapid clearance of immunoliposomes from the circulation (blood half-life of ca. 2 h), suggesting a potential for improvement of the proposed model.
Keywords: Immunoliposomes, Malaria, Nanomedicine, Plasmodium falciparum, Plasmodium yoelii 17XL, Targeted drug delivery
Pontes, B., Monzo, P., Gole, L., Le Roux, A. L., Kosmalska, A. J., Tam, Z. Y., Luo, W., Kan, S., Viasnoff, V., Roca-Cusachs, P., Tucker-Kellogg, L., Gauthier, N. C., (2017). Membrane tension controls adhesion positioning at the leading edge of cells Journal of Cell Biology , 216, (9), 2959-2977
Cell migration is dependent on adhesion dynamics and actin cytoskeleton remodeling at the leading edge. These events may be physically constrained by the plasma membrane. Here, we show that the mechanical signal produced by an increase in plasma membrane tension triggers the positioning of new rows of adhesions at the leading edge. During protrusion, as membrane tension increases, velocity slows, and the lamellipodium buckles upward in a myosin II-independent manner. The buckling occurs between the front of the lamellipodium, where nascent adhesions are positioned in rows, and the base of the lamellipodium, where a vinculin-dependent clutch couples actin to previously positioned adhesions. As membrane tension decreases, protrusion resumes and buckling disappears, until the next cycle. We propose that the mechanical signal of membrane tension exerts upstream control in mechanotransduction by periodically compressing and relaxing the lamellipodium, leading to the positioning of adhesions at the leading edge of cells.
Vilela, D., Stanton, M. M., Parmar, J., Sánchez, S., (2017). Microbots decorated with silver nanoparticles kill bacteria in aqueous media ACS Applied Materials & Interfaces 9, (27), 22093-22100
Water contamination is one of the most persistent problems of public health. Resistance of some pathogens to conventional disinfectants can require the combination of multiple disinfectants or increased disinfectant doses, which may produce harmful byproducts. Here, we describe an efficient method for disinfecting Escherichia coli and removing the bacteria from contaminated water using water self-propelled Janus microbots decorated with silver nanoparticles (AgNPs). The structure of a spherical Janus microbot consists of a magnesium (Mg) microparticle as a template that also functions as propulsion source by producing hydrogen bubbles when in contact with water, an inner iron (Fe) magnetic layer for their remote guidance and collection, and an outer AgNP-coated gold (Au) layer for bacterial adhesion and improving bactericidal properties. The active motion of microbots increases the chances of the contact of AgNPs on the microbot surface with bacteria, which provokes the selective Ag+ release in their cytoplasm, and the microbot self-propulsion increases the diffusion of the released Ag+ ions. In addition, the AgNP-coated Au cap of the microbots has a dual capability of capturing bacteria and then killing them. Thus, we have demonstrated that AgNP-coated Janus microbots are capable of efficiently killing more than 80% of E. coli compared with colloidal AgNPs that killed only less than 35% of E. coli in contaminated water solutions in 15 min. After capture and extermination of bacteria, magnetic properties of the cap allow collection of microbots from water along with the captured dead bacteria, leaving water with no biological contaminants. The presented biocompatible Janus microbots offer an encouraging method for rapid disinfection of water.
Keywords: Bactericidal, Magnetic control, Micromotors, Microswimmers, Self-propulsion, Silver nanoparticles
Barba, A., Diez-Escudero, A., Maazouz, Y., Rappe, K., Espanol, M., Montufar, E. B., Bonany, M., Sadowska, J. M., Guillem-Marti, J., Öhman-Mägi, C., Persson, C., Manzanares, M. C., Franch, J., Ginebra, M. P., (2017). Osteoinduction by Foamed and 3D-Printed Calcium Phosphate Scaffolds: Effect of Nanostructure and Pore Architecture ACS Applied Materials & Interfaces 9, (48), 41722-41736
Some biomaterials are osteoinductive, that is, they are able to trigger the osteogenic process by inducing the differentiation of mesenchymal stem cells to the osteogenic lineage. Although the underlying mechanism is still unclear, microporosity and specific surface area (SSA) have been identified as critical factors in material-associated osteoinduction. However, only sintered ceramics, which have a limited range of porosities and SSA, have been analyzed so far. In this work, we were able to extend these ranges to the nanoscale, through the foaming and 3D-printing of biomimetic calcium phosphates, thereby obtaining scaffolds with controlled micro- and nanoporosity and with tailored macropore architectures. Calcium-deficient hydroxyapatite (CDHA) scaffolds were evaluated after 6 and 12 weeks in an ectopic-implantation canine model and compared with two sintered ceramics, biphasic calcium phosphate and β-tricalcium phosphate. Only foams with spherical, concave macropores and not 3D-printed scaffolds with convex, prismatic macropores induced significant ectopic bone formation. Among them, biomimetic nanostructured CDHA produced the highest incidence of ectopic bone and accelerated bone formation when compared with conventional microstructured sintered calcium phosphates with the same macropore architecture. Moreover, they exhibited different bone formation patterns; in CDHA foams, the new ectopic bone progressively replaced the scaffold, whereas in sintered biphasic calcium phosphate scaffolds, bone was deposited on the surface of the material, progressively filling the pore space. In conclusion, this study demonstrates that the high reactivity of nanostructured biomimetic CDHA combined with a spherical, concave macroporosity allows the pushing of the osteoinduction potential beyond the limits of microstructured calcium phosphate ceramics.
Keywords: 3D-printing, Calcium phosphate, Foaming, Nanostructure, Osteoinduction
Hoyos-Nogués, M., Velasco, F., Ginebra, M. P., Manero, J. M., Gil, F. J., Mas-Moruno, C., (2017). Regenerating bone via multifunctional coatings: The blending of cell integration and bacterial inhibition properties on the surface of biomaterials ACS Applied Materials & Interfaces 9, (26), 21618-21630
In dentistry and orthopedics, it is well accepted that implant fixation is a major goal. However, an emerging concern is bacterial infection. Infection of metallic implants can be catastrophic and significantly reduce patient quality of life. Accordingly, in this work, we focus on multifunctional coatings to simultaneously address and mitigate both these problems. We have developed a tailor-made peptide-based chemical platform that integrates the well-known RGD cell adhesive sequence and the lactoferrin-derived LF1-11 antimicrobial peptide. The platform was covalently grafted on titanium via silanization and the functionalization process characterized by contact angle, XPS, and QCM-D. The presence of the platform statistically improved the adhesion, proliferation and mineralization of osteoblast-like cells compared to control surfaces. At the same time, colonization by representative bacterial strains was significantly reduced on the surfaces. Furthermore, the biological potency of the multifunctional platform was verified in a co-culture in vitro model. Our findings demonstrate that this multifunctional approach can be useful to functionalize biomaterials to both improve cell integration and reduce the risk of bacterial infection.
Keywords: Antimicrobial peptides, Cell adhesive peptides, Multifunctionality, Osseointegration, Surface functionalization
Caballero, D., Samitier, J., (2017). Topological control of extracellular matrix growth: A native-like model for cell morphodynamics studies ACS Applied Materials & Interfaces 9, (4), 4159-4170
The interaction of cells with their natural environment influences a large variety of cellular phenomena, including cell adhesion, proliferation, and migration. The complex extracellular matrix network has challenged the attempts to replicate in vitro the heterogeneity of the cell environment and has threatened, in general, the relevance of in vitro studies. In this work, we describe a new and extremely versatile approach to generate native-like extracellular matrices with controlled morphologies for the in vitro study of cellular processes. This general approach combines the confluent culture of fibroblasts with microfabricated guiding templates to direct the three-dimensional growth of well-defined extracellular networks which recapitulate the structural and biomolecular complexity of features typically found in vivo. To evaluate its performance, we studied fundamental cellular processes, including cell cytoskeleton organization, cell-matrix adhesion, proliferation, and protrusions morphodynamics. In all cases, we found striking differences depending on matrix architecture and, in particular, when compared to standard two-dimensional environments. We also assessed whether the engineered matrix networks influenced cell migration dynamics and locomotion strategy, finding enhanced migration efficiency for cells seeded on aligned matrices. Altogether, our methodology paves the way to the development of high-performance models of the extracellular matrix for potential applications in tissue engineering, diagnosis, or stem-cell biology.
Keywords: Biomimetics, Cell migration, Engineered cell-derived matrices, Extracellular matrix, In vitro model
Matalonga, J., Glaria, E., Bresque, M., Escande, C., Carbó, J. M., Kiefer, K., Vicente, R., León, T. E., Beceiro, S., Pascual-García, M., Serret, J., Sanjurjo, L., Morón-Ros, S., Riera, A., Paytubi, S., Juarez, A., Sotillo, F., Lindbom, L., Caelles, C., Sarrias, M. R., Sancho, J., Castrillo, A., Chini, E. N., Valledor, A. F., (2017). The nuclear receptor LXR limits bacterial infection of host macrophages through a mechanism that impacts cellular NAD metabolism Cell Reports 18, (5), 1241-1255
Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.
Keywords: Bacterial infection, CD38, Cytoskeleton, LXR, Macrophage, NAD, Nuclear receptor
Lagunas, Anna, Tsintzou, Iro, Vida, Yolanda, Collado, Daniel, Pérez-Inestrosa, Ezequiel, Pereira, Cristina Rodríguez, Magalhaes, Joana, Andrades, José A., Samitier, Josep, (2017). Tailoring RGD local surface density at the nanoscale toward adult stem cell chondrogenic commitment Nano Research , 10, (6), 1959-1971
Arginine-glycine-aspartic acid (RGD) dendrimer-based nanopatterns on poly(L-lactic acid) were used as bioactive substrates to evaluate the impact of the RGD local surface density on the chondrogenic induction of adult human mesenchymal stem cells. During chondrogenic commitment, active extracellular matrix (ECM) remodeling takes place, playing an instructive role in the differentiation process. Although three-dimensional environments such as pellet or micromass cultures are commonly used for in vitro chondrogenic differentiation, these cultures are rather limited with respect to their ability to interrogate cells in cell–ECM interactions. In the present study, the nanopatterns of the tunable RGD surface density were obtained as a function of the initial dendrimer concentration. The local RGD surface density was quantified through probability contour plots for the minimum interparticle distance, constructed from the corresponding atomic force microscopy images, and correlated with the cell adhesion and differentiation response. The results revealed that the local RGD surface density at the nanoscale acts as a regulator of chondrogenic commitment, and that intermediate adhesiveness of cells to the substrates favors mesenchymal cell condensation and early chondrogenic differentiation.
Vilela, D., Hortelao, A. C., Balderas-Xicohtencatl, R., Hirscher, M., Hahn, K., Ma, X., Sanchez, S., (2017). Facile fabrication of mesoporous silica micro-jets with multi-functionalities Nanoscale 9, 13990
Self-propelled micro/nano-devices have been proved as powerful tools in various applications given their capability of both autonomous motion and on-demand task fulfilment. Tubular micro-jets stand out as an important member in the family of self-propelled micro/nano-devices and are widely explored with respect to their fabrication and functionalization. A few methods are currently available for the fabrication of tubular micro-jets, nevertheless there is still a demand to explore the fabrication of tubular micro-jets made of versatile materials and with the capability of multi-functionalization. Here, we present a facile strategy for the fabrication of mesoporous silica micro-jets (MSMJs) for tubular micromotors which can carry out multiple tasks depending on their functionalities. The synthesis of MSMJs does not require the use of any equipment, making it facile and cost-effective for future practical use. The MSMJs can be modified inside, outside or both with different kinds of metal nanoparticles, which provide these micromotors with a possibility of additional properties, such as the anti-bacterial effect by silver nanoparticles, or biochemical sensing based on surface enhanced Raman scattering (SERS) by gold nanoparticles. Because of the high porosity, high surface area and also the easy surface chemistry process, the MSMJs can be employed for the efficient removal of heavy metals in contaminated water, as well as for the controlled and active drug delivery, as two proof-of-concept examples of environmental and biomedical applications, respectively. Therefore, taking into account the new, simple and cheap method of fabrication, highly porous structure, and multiple functionalities, the mesoporous silica based micro-jets can serve as efficient tools for desired applications.
Marques, J., Valle-Delgado, J. J., Urbán, P., Baró, E., Prohens, R., Mayor, A., Cisteró, P., Delves, M., Sinden, R. E., Grandfils, C., de Paz, J. L., García-Salcedo, J. A., Fernàndez-Busquets, X., (2017). Adaptation of targeted nanocarriers to changing requirements in antimalarial drug delivery Nanomedicine: Nanotechnology, Biology, and Medicine 13, (2), 515-525
The adaptation of existing antimalarial nanocarriers to new Plasmodium stages, drugs, targeting molecules, or encapsulating structures is a strategy that can provide new nanotechnology-based, cost-efficient therapies against malaria. We have explored the modification of different liposome prototypes that had been developed in our group for the targeted delivery of antimalarial drugs to Plasmodium-infected red blood cells (pRBCs). These new models include: (i) immunoliposome-mediated release of new lipid-based antimalarials; (ii) liposomes targeted to pRBCs with covalently linked heparin to reduce anticoagulation risks; (iii) adaptation of heparin to pRBC targeting of chitosan nanoparticles; (iv) use of heparin for the targeting of Plasmodium stages in the mosquito vector; and (v) use of the non-anticoagulant glycosaminoglycan chondroitin 4-sulfate as a heparin surrogate for pRBC targeting. The results presented indicate that the tuning of existing nanovessels to new malaria-related targets is a valid low-cost alternative to the de novo development of targeted nanosystems.
Keywords: Glycosaminoglycans, Malaria, Nanomedicine, Plasmodium, Targeted drug delivery
Caddeo, C., Manca, M. L., Matos, M., Gutierrez, G., Díez-Sales, O., Peris, J. E., Usach, I., Fernàndez-Busquets, X., Fadda, A. M., Manconi, M., (2017). Functional response of novel bioprotective poloxamer-structured vesicles on inflamed skin Nanomedicine: Nanotechnology, Biology, and Medicine 13, (3), 1127-1136
Resveratrol and gallic acid, a lipophilic and a hydrophilic phenol, were co-loaded in innovative, biocompatible nanovesicles conceived for ensuring the protection of the skin from oxidative- and inflammatory-related affections. The basic vesicles, liposomes and glycerosomes, were produced by a simple, one-step method involving the dispersion of phospholipid and phenols in water or water/glycerol blend, respectively. Liposomes and glycerosomes were modified by the addition of poloxamer, a stabilizer and viscosity enhancer, thus obtaining viscous or semisolid dispersions of structured vesicles. The vesicles were spherical, unilamellar and small in size (~70 nm in diameter). The superior ability of the poloxamer-structured vesicles to promote the accumulation of both phenols in the skin was demonstrated, as well as their low toxicity and great ability to protect fibroblasts from chemically-induced oxidative damage. The in vivo administration of the vesicular phenols on TPA (phorbol ester)-exposed skin led to a significant reduction of oedema and leukocyte infiltration.
Keywords: Fibroblasts, Mice, Phenol, Phospholipid vesicle, Poloxamer, Skin inflammation
O’Neill, R., McCarthy, H. O., Montufar, E. B., Ginebra, M. P., Wilson, D. I., Lennon, A., Dunne, N., (2017). Critical review: Injectability of calcium phosphate pastes and cements Acta Biomaterialia 50, 1-19
Calcium phosphate cements (CPC) have seen clinical success in many dental and orthopaedic applications in recent years. The properties of CPC essential for clinical success are reviewed in this article, which includes properties of the set cement (e.g. bioresorbability, biocompatibility, porosity and mechanical properties) and unset cement (e.g. setting time, cohesion, flow properties and ease of delivery to the surgical site). Emphasis is on the delivery of calcium phosphate (CaP) pastes and CPC, in particular the occurrence of separation of the liquid and solid components of the pastes and cements during injection; and established methods to reduce this phase separation. In addition a review of phase separation mechanisms observed during the extrusion of other biphasic paste systems and the theoretical models used to describe these mechanisms are discussed. Statement of Significance Occurrence of phase separation of calcium phosphate pastes and cements during injection limits their full exploitation as a bone substitute in minimally invasive surgical applications. Due to lack of theoretical understanding of the phase separation mechanism(s), optimisation of an injectable CPC that satisfies clinical requirements has proven difficult. However, phase separation of pastes during delivery has been the focus across several research fields. Therefore in addition to a review of methods to reduce phase separation of CPC and the associated constraints, a review of phase separation mechanisms observed during extrusion of other pastes and the theoretical models used to describe these mechanisms is presented. It is anticipated this review will benefit future attempts to develop injectable calcium phosphate based systems.
Keywords: Bone cements, Calcium phosphates, Injectability, Material properties, Phase separation
Diez-Escudero, A., Espanol, M., Beats, S., Ginebra, M. P., (2017). In vitro degradation of calcium phosphates: Effect of multiscale porosity, textural properties and composition Acta Biomaterialia 60, 81-92
The capacity of calcium phosphates to be replaced by bone is tightly linked to their resorbability. However, the relative importance of some textural parameters on their degradation behavior is still unclear. The present study aims to quantify the effect of composition, specific surface area (SSA), and porosity at various length scales (nano-, micro- and macroporosity) on the in vitro degradation of different calcium phosphates. Degradation studies were performed in an acidic medium to mimic the osteoclastic environment. Small degradations were found in samples with interconnected nano- and micropores with sizes below 3 µm although they were highly porous (35–65%), with maximum weight loss of 8 wt%. Biomimetic calcium deficient hydroxyapatite, with high SSA and low crystallinity, presented the highest degradation rates exceeding even the more soluble β-TCP. A dependence of degradation on SSA was indisputable when porosity and pore sizes were increased. The introduction of additional macroporosity with pore interconnections above 20 µm significantly impacted degradation, more markedly in the substrates with high SSA (>15 m2/g), whereas in sintered substrates with low SSA (<1 m2/g) it resulted just in a linear increase of degradation. Up to 30 % of degradation was registered in biomimetic substrates, compared to 15 % in β-TCP or 8 % in sintered hydroxyapatite. The incorporation of carbonate in calcium deficient hydroxyapatite did not increase its degradation rate. Overall, the study highlights the importance of textural properties, which can modulate or even outweigh the effect of other features such as the solubility of the compounds. Statement of Significance The physicochemical features of calcium phosphates are crucial to tune biological events like resorption during bone remodeling. Understanding in vitro resorption can help to predict the in vivo behavior. Besides chemical composition, other parameters such as porosity and specific surface area have a strong influence on resorption. The complexity of isolating the contribution of each parameter lies in the close interrelation between them. In this work, a multiscale study was proposed to discern the extent to which each parameter influences degradation in a variety of calcium phosphates, using an acidic medium to resemble the osteoclastic environment. The results emphasize the importance of textural properties, which can modulate or even outweigh the effect of the intrinsic solubility of the compounds. Keywords: Calcium phosphates, Degradation, Porosity, Textural properties Ciapetti, G., Di Pompo, G., Avnet, S., Martini, D., Diez-Escudero, A., Montufar, E. B., Ginebra, M. P., Baldini, N., (2017). Osteoclast differentiation from human blood precursors on biomimetic calcium-phosphate substrates Acta Biomaterialia 50, 102-113 The design of synthetic bone grafts to foster bone formation is a challenge in regenerative medicine. Understanding the interaction of bone substitutes with osteoclasts is essential, since osteoclasts not only drive a timely resorption of the biomaterial, but also trigger osteoblast activity. In this study, the adhesion and differentiation of human blood-derived osteoclast precursors (OCP) on two different micro-nanostructured biomimetic hydroxyapatite materials consisting in coarse (HA-C) and fine HA (HA-F) crystals, in comparison with sintered stoichiometric HA (sin-HA, reference material), were investigated. Osteoclasts were induced to differentiate by RANKL-containing supernatant using cell/substrate direct and indirect contact systems, and calcium (Ca++) and phosphorus (P5+) in culture medium were measured. We observed that OCP adhered to the experimental surfaces, and that osteoclast-like cells formed at a rate influenced by the micro- and nano-structure of HA, which also modulate extracellular Ca++. Qualitative differences were found between OCP on biomimetic HA-C and HA-F and their counterparts on plastic and sin-HA. On HA-C and HA-F cells shared typical features of mature osteoclasts, i.e. podosomes, multinuclearity, tartrate acid phosphatase (TRAP)-positive staining, and TRAP5b-enzyme release. However, cells were less in number compared to those on plastic or on sin-HA, and they did not express some specific osteoclast markers. In conclusion, blood-derived OCP are able to attach to biomimetic and sintered HA substrates, but their subsequent fusion and resorptive activity are hampered by surface micro-nano-structure. Indirect cultures suggest that fusion of OCP is sensitive to topography and to extracellular calcium. Statement of Significance: The novelty of the paper is the differentiation of human blood-derived osteoclast precursors, instead of mouse-derived macrophages as used in most studies, directly on biomimetic micro-nano structured HA-based surfaces, as triggered by osteoblast-produced factors (RANKL/OPG), and influenced by chemistry and topography of the substrate(s). Biomimetic HA-surfaces, like those obtained in calcium phosphate cements, are very different from the conventional calcium phosphate ceramics, both in terms of topography and ion exchange. The role of these factors in modulating precursors’ differentiation and activity is analysed. The system is closely reproducing the physiological process of attachment of host cells and further maturation to osteoclasts toward resorption of the substrate, which occurs in vivo after filling bone defects with the calcium phosphate grafts. Keywords: Bone resorption, Differentiation, Hydroxyapatite, Ionic exchange, Osteoclasts, Topography Oliveira, H., Catros, S., Castano, O., Rey, Sylvie, Siadous, R., Clift, D., Marti-Munoz, J., Batista, M., Bareille, R., Planell, J., Engel, E., Amédée, J., (2017). The proangiogenic potential of a novel calcium releasing composite biomaterial: Orthotopic in vivo evaluation Acta Biomaterialia 54, 377-385 Insufficient angiogenesis remains a major hurdle in current bone tissue engineering strategies. An extensive body of work has focused on the use of angiogenic factors or endothelial progenitor cells. However, these approaches are inherently complex, in terms of regulatory and methodologic implementation, and present a high cost. We have recently demonstrate the potential of electrospun poly(lactic acid) (PLA) fiber-based membranes, containing calcium phosphate (CaP) ormoglass particles, to elicit angiogenesis in vivo, in a subcutaneous model in mice. Here we have devised an injectable composite, containing CaP glass-ceramic particles, dispersed within a (Hydroxypropyl)methyl cellulose (HPMC) matrix, with the capacity to release calcium in a more sustained fashion. We show that by tuning the release of calcium in vivo, in a rat bone defect model, we could improve both bone formation and increase angiogenesis. The bone regeneration kinetics was dependent on the Ca2+ release rate, with the faster Ca2+ release composite gel showing improved bone repair at 3 weeks, in relation to control. In the same line, improved angiogenesis could be observed for the same gel formulation at 6 weeks post implantation. This methodology allows to integrate two fundamental processes for bone tissue regeneration while using a simple, cost effective, and safe approach. Statement of Significance In current bone tissue engineering approaches the achievement of sufficient angiogenesis, during tissue regeneration, is a major limitation in order to attain full tissue functionality. Recently, we have shown that calcium ions, released by the degradation of calcium phosphate ormoglasses (CaP), are effective angiogenic promoters, in both in vitro and in a subcutaneous implantation model. Here, we devised an injectable composite, containing CaP glass-ceramic particles, dispersed within a HPMC matrix, enabling the release of calcium in a more sustained fashion. We show that by tuning the release of calcium in vivo, in a rat bone defect model, we could improve both bone formation and increase angiogenesis. This simple and cost effective approach holds great promise to translate to the clinics. Keywords: Angiogenesis, Bone regeneration, Calcium phosphate ormoglasses Maazouz, Y., Montufar, E. B., Malbert, J., Espanol, M., Ginebra, M. P., (2017). Self-hardening and thermoresponsive alpha tricalcium phosphate/pluronic pastes Acta Biomaterialia 49, 563-574 Although calcium phosphate cements (CPCs) are used for bone regeneration in a wide range of clinical applications, various physicochemical phenomena are known to hinder their potential use in minimally invasive surgery or in highly vascularized surgical sites, mainly because of their lack of injectability or their low washout resistance. The present work shows that the combination of CPCs with an inverse-thermoresponsive hydrogel is a good strategy for finely tuning the cohesive and rheological properties of CPCs to achieve clinical acceptable injectability to prevent phase separation during implantation and cohesion to avoid washout of the paste. The thermoresponsive CPC developed combines alpha-tricalcium phosphate with an aqueous solution of pluronic F127, which exhibits an inverse thermoresponsive behaviour, with a gelling transformation at around body temperature. These novel CPCs exhibited temperature-dependent properties. Addition of the polymer enhanced the injectability of the paste, even at a low liquid-to-powder ratio, and allowed the rheological properties of the cement to be tuned, with the injection force decreasing with the temperature of the paste. Moreover, the cohesion of the paste was also temperature-dependent and increased as the temperature of the host medium increased due to gelling induced in the paste. The thermoresponsive cement exhibited excellent cohesion and clinically acceptable setting times at 37 °C, irrespective of the initial temperature of the paste. The addition of pluronic F127 slightly delayed the setting reaction in the early stages but did not hinder the full transformation to calcium-deficient hydroxyapatite. Moreover, the frozen storage of premixed thermoresponsive cement pastes was explored, the main physicochemical properties of the cements being maintained upon thawing, even after 18 months of frozen storage. This avoids the need to mix the cement in the operating theatre and allows its use off-the-shelf. The reverse thermoresponsive cements studied herein open up new perspectives in the surgical field, where the sequential gelling/hardening of these novel cements could allow for a better and safer clinical application. Statement of Significance: Calcium phosphate cements are attractive bone substitutes due to their similarity to the bone mineral phase. Although they can be injectable, cohesion and stability of the paste are crucial in terms of performance and safety. A common strategy is the combination with hydrogels. However, this often results in a decrease of viscosity with increasing temperature, which can lead to extravasation and particle leakage from the bone defect. The preferred evolution would be the opposite: a low viscosity would enhance mixing and injection, and an instantaneous increase of viscosity after injection would ensure washout resistance to the blood flow. Here we develop for the first time a calcium phosphate cement exhibiting reverse thermoresponsive properties using a poloxamer featuring inverse thermal gelling. Keywords: Calcium phosphate cement, Cohesion, Hydroxyapatite, Injectability, Pluronic, Thermoresponsive Van Onzen, A. H. A. M., Albertazzi, L., Schenning, A. P. H. J., Milroy, L. G., Brunsveld, L., (2017). Hydrophobicity determines the fate of self-assembled fluorescent nanoparticles in cells Chemical Communications 53, (10), 1626-1629 The fate of small molecule nanoparticles (SMNPs) composed of self-assembling intrinsically fluorescent Ï€-conjugated oligomers was studied in cells as a function of side-chain hydrophobicity. While the hydrophobic SMNPs remained intact upon cellular uptake, the more hydrophilic SMNPs disassembled and dispersed throughout the cytosol. Pujals, S., Tao, K., Terradellas, A., Gazit, E., Albertazzi, L., (2017). Studying structure and dynamics of self-Assembled peptide nanostructures using fluorescence and super resolution microscopy Chemical Communications 53, (53), 7294-7297 Understanding the formation and properties of self-Assembled peptide nanostructures is the basis for the design of new architectures for various applications. Here we show the potential of fluorescence and super resolution imaging to unveil the structural and dynamic features of peptide nanofibers with high spatiotemporal resolution. Frau-Méndez, Margalida A., Fernández-Vega, Iván, Ansoleaga, Belén, Blanco, Rosa, Carmona, Margarita, Antonio del Rio, Jose, Zerr, Inga, Llorens, Franc, Zarranz, Juan José, Ferrer, Isidro, (2017). Fatal familial insomnia: Mitochondrial and protein synthesis machinery decline in the mediodorsal thalamus Brain Pathology 27, (1), 95-106 The expression of subunits of mitochondrial respiratory complexes and components of the protein synthesis machinery from the nucleolus to the ribosome was analyzed in the mediodorsal thalamus in seven cases of Fatal Familial Insomnia (FFI) compared with age-matched controls. NDUFB8 (complex I subunit), SDHB (complex II subunit), UQCRC2 (complex III subunit), COX2 (complex IV subunit) and ATP50 (complex V subunit) expression levels, as revealed by western blotting, were reduced in FFI. Voltage-dependent anion channel (VDAC) and ATP5H were also reduced due to the marked depopulation of neurons. In contrast, a marked increase in superoxide dismutase 2 (SOD2) was found in reactive astrocytes thus suggesting that astrocytes are key factors in oxidative stress responses. The histone-binding chaperones nucleolin and nucleoplasmin 3, and histone H3 di-methylated K9 were markedly reduced together with a decrease in the expression of protein transcription elongation factor eEF1A. These findings show severe impairment in the expression of crucial components of mitochondrial function and protein synthesis in parallel with neuron loss in mediodorsal thalamus at terminal stages of FFI. Therapeutic measures must be taken long before the appearance of clinical symptoms to prevent the devastating effects of FFI. Keywords: Fatal familial insomnia, Mitochondria, Protein synthesis, Mitochondrial respiratory chain, Nucleolus, Ribosome Canal, C., Fontelo, R., Hamouda, I., Guillem-Marti, J., Cvelbar, U., Ginebra, M. P., (2017). Plasma-induced selectivity in bone cancer cells death Free Radical Biology and Medicine , 110, 72-80 Background: Current therapies for bone cancers - either primary or metastatic – are difficult to implement and unfortunately not completely effective. An alternative therapy could be found in cold plasmas generated at atmospheric pressure which have already demonstrated selective anti-tumor action in a number of carcinomas and in more relatively rare brain tumors. However, its effects on bone cancer are still unknown. Methods: Herein, we employed an atmospheric pressure plasma jet (APPJ) to validate its selectivity towards osteosarcoma cell line vs. osteoblasts & human mesenchymal stem cells. Results: Cytotoxicity following direct interaction of APPJ with cells is comparable to indirect interaction when only liquid medium is treated and subsequently added to the cells, especially on the long-term (72 h of cell culture). Moreover, following contact of the APPJ treated medium with cells, delayed effects are observed which lead to 100% bone cancer cell death through apoptosis (decreased cell viability with incubation time in contact with APPJ treated medium from 24 h to 72 h), while healthy cells remain fully viable and unaffected by the treatment. Conclusions: The high efficiency of the indirect treatment indicates that an important role is played by the reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the gaseous plasma stage and then transmitted to the liquid phase, which overall lead to lethal and selective action towards osteosarcoma cells. These findings open new pathways for treatment of metastatic bone disease with a minimally invasive approach. Keywords: Atmospheric pressure plasma jet, Bone cancer, hMSC, HOb, Liquids, Osteoblasts, Osteosarcoma, SaOS-2 Caballero, David, Blackburn, Sophie M., de Pablo, Mar, Samitier, Josep, Albertazzi, Lorenzo, (2017). Tumour-vessel-on-a-chip models for drug delivery Lab on a Chip 17, 3760-3771 Nanocarriers for drug delivery have great potential to revolutionize cancer treatment, due to their enhanced selectivity and efficacy. Despite this great promise, researchers have had limited success in the clinical translation of this approach. One of the main causes of these difficulties is that standard in vitro models, typically used to understand nanocarriers' behaviour and screen their efficiency, do not provide the complexity typically encountered in living systems. In contrast, in vivo models, despite being highly physiological, display serious bottlenecks which threaten the relevancy of the obtained data. Microfluidics and nanofabrication can dramatically contribute to solving this issue, providing 3D high-throughput models with improved resemblance to in vivo systems. In particular, microfluidic models of tumour blood vessels can be used to better elucidate how new nanocarriers behave in the microcirculation of healthy and cancerous tissues. Several key steps of the drug delivery process such as extravasation, immune response and endothelial targeting happen under flow in capillaries and can be accurately modelled using microfluidics. In this review, we will present how tumour-vessel-on-a-chip systems can be used to investigate targeted drug
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