pwc-archive/papers-with-abstracts huggingface dataset:
Silicon substituted hydroxyapatite/VEGF scaffolds stimulate bone regeneration in osteoporotic sheep
Authors: L. Casarrubios, N. Gomez-Cerezo, S. Sanchez-Salcedo, M. J. Feito, M. C. Serrano, M. Saiz-Pardo, L. Ortega, D. de Pablo, I. Diaz-Guemes, B. Fernandez-Tome, S. Enciso, F. M. Sanchez-Margallo, M. T. Portoles, D. Arcos, M. Vallet-Regi
Date: 2021-03-24 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vascularization and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre-osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothelial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone regeneration purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher presence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis.
The effect of biomimetic mineralization of 3D-printed mesoporous bioglass scaffolds on physical properties and in vitro osteogenicity
Authors: M. Natividad Gomez-Cerezo, Daniel Lozano, Daniel Arcos, Maria Vallet-Regi, Cedryck Vaquette
Date: 2021-03-21 00:00:00

Three-dimensional Mesoporous bioactive glasses (MBGs) scaffolds has been widely considered for bone regeneration purposes and additive manufacturing enables the fabrication of highly bioactive patient-specific constructs for bone defects. Commonly, this process is performed with the addition of polymeric binders that facilitate the printability of scaffolds. However, these additives cover the MBG particles resulting in the reduction of their osteogenic potential. The present work investigates a simple yet effective phosphate-buffered saline immersion method for achieving polyvinyl alcohol binder removal while enables the maintenance of the mesoporous structure of MBG 3D-printed scaffolds. This resulted in significantly modifying the surface of the scaffold via the spontaneous formation of a biomimetic mineralized layer which positively affected the physical and biological properties of the scaffold. The extensive surface remodeling induced by the deposition of the apatite-like layer lead to a 3-fold increase in surface area, a 5-fold increase in the roughness, and 4-fold increase in the hardness of the PBS-immersed scaffolds when compared to the as-printed counterpart. The biomimetic mineralization also occurred throughout the bulk of the scaffold connecting the MBGs particles and was responsible for the maintenance of structural integrity. In vitro assays using MC3T3-E1 pre-osteoblast like cells demonstrated a significant upregulation of osteogenic-related genes for the scaffolds previously immersed in PBS when compared to the as-printed PVA-containing scaffolds. Although the pre-immersion scaffolds performed equally towards osteogenic cell differentiation, our data suggest that a short immersion in PBS of MBG scaffolds is beneficial for the osteogenic properties and might accelerate bone formation after implantation.
The response of pre-osteoblasts and osteoclasts to gallium containing mesoporous bioactive glasses
Authors: N. Gomez-Cerezo, E. Verron, V. Montouillout, F. Fayon, P. Lagadec, J. M. Bouler, B. Bujoli, D. Arcos, M. Vallet-Regi
Date: 2021-03-21 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Mesoporous bioactive glasses (MBGs) in the system SiO2-CaO-P2O5-Ga2O3 have been synthesized by the evaporation induced self-assembly method and subsequent impregnation with Ga cations. Two different compositions have been prepared and the local environment of Ga(III) has been characterized using 29Si, 71Ga and 31P NMR analysis, demonstrating that Ga(III) is efficiently incorporated as both, network former (GaO4 units) and network modifier (GaO6 units). In vitro bioactivity tests evidenced that Ga-containing MBGs retain their capability for nucleation and growth of an apatite-like layer in contact with a simulated body fluid with ion concentrations nearly equal to those of human blood plasma. Finally, in vitro cell culture tests evidenced that Ga incorporation results in a selective effect on osteoblasts and osteoclasts. Indeed, the presence of this element enhances the early differentiation towards osteoblast phenotype while disturbing osteoclastogenesis. Considering these results, Ga-doped MBGs might be proposed as bone substitutes, especially in osteoporosis scenarios.
Molecular gates in mesoporous bioactive glasses for the treatment of bone tumors and infection
Authors: L Polo, N Gomez-Cerezo, E Aznar, JL Vivancos, F Sancenon, D Arcos, M Vallet-Regi, R Martinez-Manez
Date: 2021-03-18 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Silica mesoporous nanomaterials have been proved to have meaningful application in biotechnology and biomedicine. Particularly, mesoporous bioactive glasses are recently gaining importance thanks to their bone regenerative properties. Moreover, the mesoporous nature of these materials makes them suitable for drug delivery applications, opening new lines in the field of bone therapies. In this work, we have developed innovative nanodevices based on the implementation of adenosine triphosphate (ATP) and {\epsilon}-poly-L-lysine molecular gates using a mesoporous bioglass as an inorganic support. The systems have been previously proved to work properly with a fluorescence probe and subsequently with an antibiotic (levofloxacin) and an antitumoral drug (doxorubicin). The bioactivity of the prepared materials has also been tested, giving promising results. Finally, in vitro cell culture studies have been carried out; demonstrating that this gated devices can provide useful approaches for bone cancer and bone infection treatments.
Collagenase Nanocapsules: An Approach to Fibrosis Treatment
Authors: MR Villegas, A Baeza, A Usategui, PL Ortiz-Romero, JL Pablos, M Vallet-Regi
Date: 2021-03-18 00:00:00

Fibrosis is a common lesion in different pathologic diseases and is defined by the excessive accumulation of collagen. Different approaches have been used to treat different conditions characterized by fibrosis. FDA and EMA approved collagenase to treat palmar fibromatosis, Dupuyten disease. EMA approved additionally its use in severe Peyronie disease, but it has been used off label in other conditions.1, 2. Approved treatment includes up to 3, in palmar fibromatosis or up to 8, in penile fibromatosis, injections followed by finger extension or penile modelling procedures, typically causing severe pain. Frequently single injections are enough to treat palmar fibromatosis. 3, The need to inject repeatedly doses of this enzyme can be originated by by the labile nature of collagenase which exhibits a complete activity loss after short periods of time. Herein, a novel strategy to manage this enzyme based on the synthesis of polymeric nanocapsules which contains collagenase housed within their matrix is presented. These nanocapsules have been engineered for achieving a gradual release of the encapsulated enzyme for longer times which can be up to ten days. The efficacy of these nanocapsules have been tested in murine model of local dermal fibrosis yielding higher fibrosis reduction in comparison with the injection of free enzyme which represent a significant improvement over conventional therapy.
Ultrasound-mediated Cavitation-enhanced extravasation of mesoporous silica nanoparticles for controlled-release drug delivery
Authors: JL Paris, C Mannris, M Cabanas, R Calisle, M Manzano, M Vallet-Regi, CC Coussios
Date: 2021-03-17 00:00:00

Mesoporous silica nanoparticles have been reported as suitable drug carriers, but their successful delivery to target tissues following systemic administration remains a challenge. In the present work, ultrasound-induced inertial cavitation was evaluated as a mechanism to promote their extravasation in a flow-through tissue-mimicking agarose phantom. Two different ultrasound frequencies, 0.5 or 1.6 MHz, with pressures in the range 0.5-4 MPa were used to drive cavitation activity which was detected in real time. The optimal ultrasound conditions identified were employed to deliver dye-loaded nanoparticles as a model for drug-loaded nanocarriers, with the level of extravasation evaluated by fluorescence microscopy. The same nanoparticles were then co-injected with submicrometric polymeric cavitation nuclei as a means to promote cavitation activity and decrease the required in-situ acoustic pressure required to attain extravasation. The overall cavitation energy and penetration of the combination was compared to mesoporous silica nanoparticles alone. The results of the present work suggest that combining mesoporous silica nanocarriers and submcrometric cavitation nuclei may help enhance the extravasation of the nanocarrier, thus enabling subsequent sustained drug release to happen from those particles already embedded in the tumour tissue.
Suicide-Gene Transfection of Tumor-tropic Placental Stem Cells employing Ultrasound-Responsive Nanoparticles
Authors: Juan L. Paris, Paz de la Torre, M. Victoria Cabanas, Miguel Manzano, Ana I. Flores, Maria Vallet-Regi
Date: 2021-03-16 00:00:00

A Trojan-horse strategy for cancer therapy employing tumor-tropic mesenchymal stem cells transfected with a non-viral nanovector is here presented. In this sense, ultrasound-responsive mesoporous silica nanoparticles were coated with a polycation (using two different molecular weights), providing them with gene transfection capabilities that were evaluated using two different plasmids. First, the expression of Green Fluorescent Protein was analyzed in Decidua-derived Mesenchymal Stem Cells after incubation with the silica nanoparticles. The most successful nanoparticle was then employed to induce the expression of two suicide genes: cytosine deaminase and uracil phosphoribosyl transferase, which allow the cells to convert a non-toxic pro-drug (5-fluorocytosine) into a toxic drug (5-Fluorouridine monophosphate). The effect of the production of the toxic final product was also evaluated in a cancer cell line (NMU cells) co-cultured with the transfected vehicle cells, Decidua-derived Mesenchymal Stem Cells.
Incorporation and effects of mesoporous SiO2-CaO nanospheres loaded with ipriflavone on osteoblast/osteoclast cocultures
Authors: Laura Casarrubios, Natividad Gomez-Cerezo, Maria Jose Feito, Maria Vallet-Regi, Daniel Arcos, Maria Teresa Portoles
Date: 2021-03-15 00:00:00

Mesoporous nanospheres in the system SiO2-CaO (NanoMBGs) with a hollow core surrounded by a radial arrangement of mesopores were characterized, labeled with FITC (FITC-NanoMBGs) and loaded with ipriflavone (NanoMBG-IPs) in order to evaluate their incorporation and their effects on both osteoblasts and osteoclasts simultaneously and maintaining the communication with each other in coculture. The influence of these nanospheres on macrophage polarization towards pro-inflammatory M1 or reparative M2 phenotypes was also evaluated in basal and stimulated conditions through the expression of CD80 (as M1 marker) and CD206 (as M2 marker) by flow cytometry and confocal microscopy. NanoMBGs did not induce the macrophage polarization towards the M1 pro-inflammatory phenotype, favoring the M2 reparative phenotype and increasing the macrophage response capability against stimuli as LPS and IL-4. NanoMBG-IPs induced a significant decrease of osteoclast proliferation and resorption activity after 7 days in coculture with osteoblasts, without affecting osteoblast proliferation and viability. Drug release test demonstrated that only a fraction of the payload is released by diffusion, whereas the rest of the drug remains within the hollow core after 7 days, thus ensuring the local long-term pharmacological treatment beyond the initial fast IP release. All these data ensure an appropriate immune response to these nanospheres and the potential application of NanoMBG-IPs as local drug delivery system in osteoporotic patients.
3D scaffold with effective multidrug sequential release against bacteria biofilm
Authors: Rafaela Garcia-Alvarez, Isabel Izquierdo-Barba, Maria Vallet-Regi
Date: 2021-03-12 00:00:00

Bone infection is a feared complication following surgery or trauma that remains as an extremely difficult disease to deal with. So far, the outcome of therapy could be improved with the design of 3D implants, which combine the merits of osseous regeneration and local multidrug therapy so as to avoid bacterial growth, drug resistance and the feared side effects. Herein, hierarchical 3D multidrug scaffolds based on nanocomposite bioceramic and polyvinyl alcohol (PVA) prepared by rapid prototyping with an external coating of gelatin-glutaraldehyde (Gel-Glu) have been fabricated. These 3D scaffolds contain three antimicrobial agents (rifampin, levofloxacin and vancomycin), which have been localized in different compartments of the scaffold to obtain different release kinetics and more effective combined therapy. Levofloxacin was loaded into the mesopores of nanocomposite bioceramic part, vancomycin was localized into PVA biopolymer part and rifampin was loaded in the external coating of Gel-Glu. The obtained results show an early and fast release of rifampin followed by sustained and prolonged release of vancomycin and levofloxacin, respectively, which are mainly governed by the progressive in vitro degradability rate of these scaffolds. This combined therapy is able to destroy Gram-positive and Gram-negative bacteria biofilms as well as inhibit the bacteria growth; in addition, these multifunctional scaffolds exhibit excellent bioactivity as well as good biocompatibility with complete cell colonization of preosteoblast in the entire surface, ensuring good bone regeneration. These findings suggest that these hierarchical 3D multidrug scaffolds are promising candidates as platforms for local bone infection therapy.
Numerical predictions of shear stress and cyclic stretch in the healthy pulmonary vasculature
Authors: Michelle A. Bartolo, M. Umar Qureshi, Mitchel J. Colebank, Naomi C. Chesler, Mette S. Olufsen
Date: 2021-03-05 00:00:00

Isolated post-capillary pulmonary hypertension (Ipc-PH) occurs due to left heart failure, which contributes to 1 out of every 9 deaths in the United States. In some patients, through unknown mechanisms, Ipc-PH transitions to combined pre-/post-capillary PH (Cpc-PH), diagnosed by an increase in pulmonary vascular resistance and associated with a dramatic increase in mortality. We hypothesize that altered mechanical forces and subsequent vasoactive signaling in the pulmonary capillary bed drive the transition from Ipc-PH to Cpc-PH. However, even in a healthy pulmonary circulation, the mechanical forces in the smallest vessels (the arterioles, venules, and capillary bed) have not been quantitatively defined. This study is the first to examine this question via a computational fluid dynamics model of the human pulmonary arteries, veins, arterioles, and venules. Using this model we predict temporal and spatial dynamics of cyclic stretch and wall shear stress. In the large vessels, numerical simulations show that shear stress increases coincides with larger flow and pressure. In the microvasculature, we found that as vessel radius decreases, shear stress increases and flow decreases. In arterioles, this corresponds with lower pressures; however, the venules and smaller veins have higher pressure than larger veins. Our model provides predictions for pressure, flow, shear stress, and cyclic stretch that provides a way to analyze and investigate hypotheses related to disease progression in the pulmonary circulation.
Time-dependent Clearance of Cyclosporine in Adult Renal Transplant Recipients: A Population Pharmacokinetic Perspective
Authors: Junjun Mao, Xiaoyan Qiu, Weiwei Qin, Luyang Xu, Ming Zhang, Mingkang Zhong
Date: 2021-03-02 00:00:00

Aim The pharmacokinetic (PK) properties of cyclosporine (CsA) in renal transplant recipients are patient- and time-dependent. Knowledge of this time-related variability is necessary to maintain or achieve CsA target exposure. Here, we aimed to identify factors explaining variabilities in CsA PK properties and characterise time-dependent clearance (CL/F) by performing a comprehensive analysis of CsA PK factors using population PK (popPK) modelling of long-term follow-up data from our institution. Methods In total, 3,674 whole-blood CsA concentrations from 183 patients who underwent initial renal transplantation were analysed using nonlinear mixed-effects modelling. The effects of potential covariates were selected according to a previous report and well-accepted theoretical mechanisms. Model-informed individualised therapeutic regimens were also conducted. Results A two-compartment model adequately described the data and the estimated mean CsA CL/F was 32.6 L h-1 (5%). Allometrically scaled body size, haematocrit (HCT) level, CGC haplotype carrier status, and postoperative time may contribute to CsA PK variability. The CsA bioavailability in patients receiving a prednisolone dose (PD) of 80 mg was 20.6% lower than that in patients receiving 20 mg. A significant decrease (52.6%) in CL/F was observed as the HCT increased from 10.5% to 60.5%. The CL/F of the non-CGC haplotype carrier was 14.4% lower than that of the CGC haplotype carrier at 3 months post operation. CsA dose adjustments should be considered in different postoperative periods. Conclusions By monitoring body size, HCT, PD, and CGC haplotype, changes in CsA CL/F over time could be predicted. Such information could be used to optimise CsA therapy.
Organ-specific Branching Morphogenesis
Authors: Christine Lang, Lisa Conrad, Dagmar Iber
Date: 2021-02-27 00:00:00
Tasks: Position

A common developmental process, called branching morphogenesis, generates the epithelial trees in a variety of organs, including the lungs, kidneys, and glands. How branching morphogenesis can create epithelial architectures of very different shapes and functions remains elusive. In this review, we compare branching morphogenesis and its regulation in lungs and kidneys and discuss the role of signaling pathways, the mesenchyme, the extracellular matrix, and the cytoskeleton as potential organ-specific determinants of branch position, orientation, and shape. Identifying the determinants of branch and organ shape and their adaptation in different organs may reveal how a highly conserved developmental process can be adapted to different structural and functional frameworks and should provide important insights into epithelial morphogenesis and developmental disorders.
A synergic approach to enhance long term culture and manipulation of MiaPaCa-2 pancreatic cancer spheroids
Authors: Marta Cavo, Donatella Delle Cave, Eliana D'Amone, Giuseppe Gigli, Enza Lonardo, Loretta L. del Mercato
Date: 2021-02-25 00:00:00
Tasks: Cultural Vocal Bursts Intensity Prediction

Tumour spheroids have the potential to be used as preclinical chemosensitivity assays. However, the production of three dimensional (3D) tumour spheroids remains challenging as not all tumour cell lines form spheroids with regular morphologies and spheroid transfer often induces disaggregation. In the field of pancreatic cancer, the MiaPaCa-2 cell line is an interesting model for research but it is known for its difficulty to form stable spheroids; also, when formed, spheroids from this cell line are weak and arduous to manage and to harvest for further analyses such as multiple staining and imaging. In this work, we compared different methods (i.e. hanging drop, round bottom wells and Matrigel embedding, each of them with or without methylcellulose in the media) to evaluate which one allowed to better overpass these limitations. Morphometric analysis indicated that hanging drop in presence of methylcellulose leaded to well-organized spheroids; interestingly, quantitative PCR (qPCR) analysis reflected the morphometric characterization, indicating that same spheroids expressed the highest values of CD44, VIMENTIN, TGF beta1 and Ki67. In addition, we investigated the generation of MiaPaCa-2 spheroids when cultured on substrates of different hydrophobicity, in order to minimize the area in contact with the culture media and to further improve spheroid formation.
Mathematical modeling of the vascular system
Authors: Ju Liu, Ingrid S. Lan, Alison L. Marsden
Date: 2021-02-19 00:00:00

In this article, we review the mathematical modeling for the vascular system.
Prospect for application of mathematical models in combination cancer treatments
Authors: Joseph Malinzi, Kevin Bosire Basita, Sara Padidar, Henry A. Adeola
Date: 2020-11-12 00:00:00
Tasks: Management

The long-term efficacy of targeted therapeutics for cancer treatment can be significantly limited by the type of therapy and development of drug resistance, inter alia. Experimental studies indicate that the factors enhancing acquisition of drug resistance in cancer cells include cell heterogeneity, drug target alteration, drug inactivation, DNA damage repair, drug efflux, cell death inhibition, as well as microenvironmental adaptations to targeted therapy, among others. Combination cancer therapies (CCTs) are employed to overcome these molecular and pathophysiological bottlenecks and improve the overall survival of cancer patients. CCTs often utilize multiple combinatorial modes of action and thus potentially constitute a promising approach to overcome drug resistance. Considering the colossal cost, human effort, time and ethical issues involved in clinical drug trials and basic medical research, mathematical modeling and analysis can potentially contribute immensely to the discovery of better cancer treatment regimens. In this article, we review mathematical models on CCTs developed thus far for cancer management. Open questions are highlighted and plausible combinations are discussed based on the level of toxicity, drug resistance, survival benefits, preclinical trials and other side effects.