In Vitro Modeling of Non-Solid Tumors: How Far Can Tissue Engineering Go?

[EN] In hematological malignancies, leukemias or myelomas, malignant cells present bone marrow (BM) homing, in which the niche contributes to tumor development and drug resistance. BM architecture, cellular and molecular composition and interactions define differential microenvironments that govern cell fate under physiological and pathological conditions and serve as a reference for the native biological landscape to be replicated in engineered platforms attempting to reproduce blood cancer behavior. This review summarizes the different models used to efficiently reproduce certain aspects of BM in vitro; however, they still lack the complexity of this tissue, which is relevant for fundamental aspects such as drug resistance development in multiple myeloma. Extracellular matrix composition, material topography, vascularization, cellular composition or stemness vs. differentiation balance are discussed as variables that could be rationally defined in tissue engineering approaches for achieving more relevant in vitro models. Fully humanized platforms closely resembling natural interactions still remain challenging and the question of to what extent accurate tissue complexity reproduction is essential to reliably predict drug responses is controversial. However, the contributions of these approaches to the fundamental knowledge of non-solid tumor biology, its regulation by niches, and the advance of personalized medicine are unquestionable.PROMETEO/2016/063 project is acknowledged. The CIBER-BBN initiative is funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program. CIBER actions are financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. 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El pensamiento crítico como un paso adelante en la Formación Profesional. Estudiantes de Formación Profesional inmersos en centros de alta tecnología

[EN] This communication summarizes the results of the Erasmus+ project "CRİTİCAL THİNKİNG AS A STEP FORWARD İN VET EDUCATİON: VET students immersed in high technology teams" in which european technologybased companies, higher research centers and vocational training centers have participated. For two years, strategies have been designed to develop training in critical thinking tools in vocational students during internships in high-tech centers. We have chosen a reduced set of critical thinking skills that we think can act as a catalyst for student training throughout their professional careers, and in creative work that contributes effectively to the company's objectives. The debate has crystallized in the writing of two tools: a template of help to the tutor in the company for the preparation of the work plan of the student and another template for the student's laboratory notebook. In one case and in another the writing of these notebooks requires the student and the tutor to reflect on the critical thinking skills that are intended to develop in the student.[ES] Esta comunicación resume parte de los resultados del proyecto Erasmus+ “CRİTİCAL THİNKİNG AS A STEP FORWARD İN VET EDUCATİON: VET students immersed in high technology teams” en el que han participado empresas de base tecnológica, centros superiores de investigación y centros de formación profesional europeos. Durante dos años se han diseñado estrategias para desarrollar la formación en herramientas de pensamiento crítico en los estudiantes de formación profesional durante prácticas realizadas en centros de alta tecnología. Se ha elegido un conjunto reducido de capacidades de pensamiento crítico que pensamos que pueden actuar de desencadenante de la formación del estudiante a lo largo de toda su carrera profesional, y en un trabajo creativo que contribuya de forma efectiva a los objetivos de la empresa. El debate ha cristalizado en la redacción de dos herramientas: una plantilla de ayuda al tutor en la empresa para la preparación del plan de trabajo del estudiante y otra plantilla para el cuaderno de laboratorio del estudiante. En un caso y en otro la redacción de estos cuadernos obliga al estudiante y al tutor a una reflexión relacionada con las capacidades de pensamiento crítico que se pretenden desarrollar en el estudiante.Este trabajo ha sido financiado por el programa Erasmus + de la dentro del proyecto 2017-1-ES01-KA202-038469, Servicio Español para la Internacionalización de la Educación (SEPIE) referencia nacional ZZ02Solano-Martínez, C.; Clara Trujillo, S.; Guillot Ferriols, MT.; Gómez Estrada, L.; Gómez Ribelles, JL. (2019). El pensamiento crítico como un paso adelante en la Formación Profesional. Estudiantes de Formación Profesional inmersos en centros de alta tecnología. En IN-RED 2019. V Congreso de Innovación Educativa y Docencia en Red. Editorial Universitat Politècnica de València. 1342-1353. https://doi.org/10.4995/INRED2019.2019.10340OCS1342135

Conformation and dynamics of a diluted chain in the presence of an adsorbing wall: A simulation with the bond fluctuation model

The bond fluctuation model has been used to simulate the adsorption process of a single long polymer chain on an adsorbing surface. Simulations start at high temperature with the chain in an equilibrium coil structure. The inter- and intra chain energy potential were selected in such a way that on cooling the polymer chain vitrifies without any indication of chain ordering or chain folding. The structure attained on cooling is analysed for arrange of values of the interaction potential between the surface and the polymer segments. Adsorption is measured by the fraction of polymer segments situated on the adsorbingwallwhilst crystalline ordering is characterized by the pair correlation function g(r), the bond order parameter P2(r) and the bond correlation functionM(j). Isothermal adsorption is followed as well as a function of temperature. The work shows that adsorbing surface nucleates crystalline order by suppressing one dimension in the segmental mobility of the polymer chain, along with factors as thermal treatment and inter and intra-potentials.RSS gratefully acknowledges the support of the Spanish Ministerio de Economia y Competitividad (MINECO) and FEDER funds under the project MAT2012-38359-C03-01.Sabater I Serra, R.; Torregrosa Cabanilles, C.; Meseguer Dueñas, JM.; Gómez Ribelles, JL.; Molina Mateo, J. (2014). Conformation and dynamics of a diluted chain in the presence of an adsorbing wall: A simulation with the bond fluctuation model. Journal of Non-Crystalline Solids. 402:7-15. https://doi.org/10.1016/j.jnoncrysol.2014.05.009S71540

A new waterborne chitosan-based polyurethane hydrogel as a vehicle to transplant bone marrow mesenchymal cells improved wound healing of ulcers in a diabetic rat model

[EN] Foot ulcers, a common complication of diabetes, can cause physical incapacity and are derived from several factors, including poor wound healing. New therapeutic strategies are needed to minimize this complication for the sake of patients' health. We therefore developed a new chitosan- polyurethane hydrogel membrane (HPUC) and the WA results confirmed that HPUC present low cytotoxicity and improved wound healing when used with mononuclear bone marrow fraction cells in the diabetic rat model. The biodegradable hydrogels were produced in block copolymer networks with a combination of chitosan blocks and biodegradable polyurethane. The membranes were characterized by FTIR, C-13-NMR and thermogravimetry. Swelling and hydrolytic degradation were also evaluated. The non-solubility of the membranes in good solvents and the chemical characterization confirmed that the network structure was formed between the PU and the chitosan through urea/urethane bonds. The findings confirm that the HPUC have interesting properties that make them suitable for wound healing applications.This work was funded by: Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior -doctoral fellowships to Viezzer, C (CAPES/PDSE-BEX: 1408/11-9) and the Spanish Ministry of Economy and Competitiveness (MINECO) through the MAT2016-76039-C4-1-R Project, including FEDER financial support. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund.Viezzer, C.; Mazzuca, R.; Machado, DC.; Forte, MMDC.; Gómez Ribelles, JL. (2020). A new waterborne chitosan-based polyurethane hydrogel as a vehicle to transplant bone marrow mesenchymal cells improved wound healing of ulcers in a diabetic rat model. Carbohydrate Polymers. 231:1-10. https://doi.org/10.1016/j.carbpol.2019.115734S110231Ahmed, R., Tariq, M., Ali, I., Asghar, R., Noorunnisa Khanam, P., Augustine, R., & Hasan, A. (2018). Novel electrospun chitosan/polyvinyl alcohol/zinc oxide nanofibrous mats with antibacterial and antioxidant properties for diabetic wound healing. International Journal of Biological Macromolecules, 120, 385-393. doi:10.1016/j.ijbiomac.2018.08.057Andrade, F., Goycoolea, F., Chiappetta, D. A., das Neves, J., Sosnik, A., & Sarmento, B. (2011). Chitosan-Grafted Copolymers and Chitosan-Ligand Conjugates as Matrices for Pulmonary Drug Delivery. International Journal of Carbohydrate Chemistry, 2011, 1-14. doi:10.1155/2011/865704Baltzis, D., Eleftheriadou, I., & Veves, A. (2014). Pathogenesis and Treatment of Impaired Wound Healing in Diabetes Mellitus: New Insights. Advances in Therapy, 31(8), 817-836. doi:10.1007/s12325-014-0140-xBarikani, M., Honarkar, H., & Barikani, M. (2010). Synthesis and characterization of chitosan-based polyurethane elastomer dispersions. Monatshefte für Chemie - Chemical Monthly, 141(6), 653-659. doi:10.1007/s00706-010-0309-1Boulton, A. J. M. (2013). The Pathway to Foot Ulceration in Diabetes. Medical Clinics of North America, 97(5), 775-790. doi:10.1016/j.mcna.2013.03.007Casettari, L., Vllasaliu, D., Castagnino, E., Stolnik, S., Howdle, S., & Illum, L. (2012). PEGylated chitosan derivatives: Synthesis, characterizations and pharmaceutical applications. Progress in Polymer Science, 37(5), 659-685. doi:10.1016/j.progpolymsci.2011.10.001Chen, L., Tredget, E. E., Wu, P. Y. G., & Wu, Y. (2008). Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing. PLoS ONE, 3(4), e1886. doi:10.1371/journal.pone.0001886Chen, S.-H., Tsao, C.-T., Chang, C.-H., Wu, Y.-M., Liu, Z.-W., Lin, C.-P., … Hsieh, K.-H. (2012). 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Electrospun PVA/Bentonite Nanocomposites Mats for Drug Delivery

Electrospun mats and films of polyvinyl alcohol (PVA) hydrogel are produced for drug delivery. To provide mechanical consistency to the gel a reinforcement by nanoclays is introduced in the polymer matrix. Four different suspensions of nanoparticles in the polymer solution are prepared in an adequate solvent. These suspensions are subjected to an electrospinning process to produce the nanofiber mat, while films are produced by casting. The influence of the process parameters over the nanofibers microstructure is analyzed by scanning electron microscopy (SEM). The effectiveness of nanoclay encapsulation in the nanocomposites is tested by a thermogravimetric analysis. A crosslinking reaction in solution is carried out to prevent the dissolution of the nanocomposites in aqueous media. A model protein (bovine serum albumin, BSA) is absorbed in the nanocomposites to characterize the release kinetics in phosphate-buffered saline (PBS)

Hydrolytic degradation of PLLA/PCL microporous membranes prepared by freeze extraction

Poly(L-lactic acid) Poly(e-caprolactone) blends (PLLA/PCL) porous membranes were prepared by freeze extraction (a modification of freeze drying) with ratios 100/0, 80/20, 60/40, 40/60, 20/80, 0/100 in weight. Degradation of the membranes in phosphate buffer solution (PBS) up to 65 weeks was studied using weight loss measurements, high performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), mechanical indentation, gel permeation chromatography (GPC), and scanning electron microscopy (SEM). Degradation rate as observed by weight loss and reduction of molecular weight and mechanical properties depended on the composition of the blends. In most blends the degradation was more prominent in the PLLA phase and was accompanied by consequent recrystallization that formed a crystalline phase with increased resistance to hydrolysis. Occurrence of such crystalline phases and degradation of intercrystalline domain led to formation of nearly monodisperse molecular weight populations. Membranes with only 20% PCL presented favorable behavior compared to pure PLLA membranes as reflected in a lower degradation rate and a limited loss of the mechanical properties. At the same time, degradation rate of 80/20 membranes was enhanced with respect to pure PCL, and membranes were stiffer than PCL membranes at all degradation times. This composition could thus be useful for use in tissue engineering for bone or cartilage applications.Luis Andres Gaona wishes to thank "Programa de Doctorados Nacionales 2009" of COLCIENCIAS (Departamento Administrativo de Ciencia, Tecnologia e Innovacion Colombia) and COOPEN Project (Colombia, Costa Rica, Panama and European Network) for supporting his PhD studies. Myriam Lebourg acknowledges UPV for funding through project PAID 06-10, and CIBER-BBN for funding her postdoc research. CIBER-BBN is an initiative funded by the VI National R&D&i Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. Jose Luis Gomez Ribelles acknowledges the support of the Spanish Ministry of Science and Innovation through MAT2010-21611-C03-01 (including the FEDER financial support) and funding in the Centro de Investigacion Principe Felipe in the field of Regenerative Medicine through the collaboration agreement from the Conselleria de Sanidad (Generalitat Valenciana), and the Instituto de Salud Carlos III (Ministry of Science and Innovation). The authors wish also to thank the Microscopy Service and Instituto de Tecnologia Quimica of Universidad Politecnica de Valencia for useful help and advices.Gaona, LA.; Gómez Ribelles, JL.; Perilla, JE.; Lebourg, MM. (2012). Hydrolytic degradation of PLLA/PCL microporous membranes prepared by freeze extraction. Polymer Degradation and Stability. 97(9):1621-1632. https://doi.org/10.1016/j.polymdegradstab.2012.06.031S1621163297

Biodegradable polyester networks including hydrophilic groups favor BMSCs differentiation and can be eroded by macrophage action

The aim of this study is to show that introducing a small fraction of hydrophilic groups into a hydrophobic polyester favor the macrophage activity by accelerating the degradation action in aqueous media. It is also seen that differentiation of MSCs cultured in monolayer towards bone in specific differentiation media is favored in these materials with respect to the corresponding pristine polyesters. Polymer networks based in polycarpolactone or poly(L-lactide) and containing a small fraction of poly(-hydroxyethyl acrylate) have been synthesized. Degradation kinetics "in vitro" was monitored by mass loss and swelling capacity of the polymer network in good solvents, the later as representative of chain cleavage. Hydrolytic and enzymatic degradation is accelerated by the inclusion of poly(hydroxyethyl acrylate) blocks in the network. Macrophages were cultured on the surface of the network films, showing its capacity to erode the material surface but also to accelerate bulk degradation. Bone marrow mesenchymal stem cells were cultured in monolayer on the membranes in osteogenic media, showing an increase of specific markers expression in comparison to pristine polyesters.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasLaboratorio de Investigación en Osteopatías y Metabolismo Minera

Effect of the physicochemical properties of pure chitosan-coated poly(lactic acid) scaffolds on the chondrogenic differentiation of mesenchymal stem cells from osteoarthritic patients

Due to the attractive properties of poly(L-lactic acid) (PLLA) and chitosan (CHT) for tissue engineering applications, this study is aimed at analyzing the chondrogenic potential of human bone marrow-derived mesenchymal stem cells (BM-MSCs) derived from osteoarthritic (OA) patients, in pure or CHT-coated PLLA, using different coating methodologies. Although PLLA scaffolds coated in one-step (PLLA-CHT1) yielded CHT smooth pellicles filling the PLLA macropores, a two-step strategy resulted in a CHT fiber-like thin coating covering PLLA pore walls (PLLA-CHT2). Both strategies led to the incorporation of similar content of CHT and a two-fold increase in the scaffold's water uptake capacity, providing elastic moduli values comparable to the ones found for human articular cartilage. After confirming OA-derived BM-MSCs, metabolic activity in the scaffolds, the chondrogenic potential was tested at 30 and 60 days, in a chondrogenic differentiation medium. PLLA scaffolds improved the chondrogenic differentiation of BM-MSCs, regarding cell pellet conventional culture and presented a typical cartilage zonal distribution, although was not able to revert a terminal differentiation. In PLLA-CHT1, on a short term, a rather heterogeneous tissue was formed, with confined areas of either slower cell infiltration or a faster maturation, with enhanced chondrogenic phenotype. In PLLA-CHT2, a similar tissue to PLLA was obtained, albeit on the long term, these scaffolds helped to maintain a hyaline-like phenotype and prevented the advance of the hypertrophic process. These results demonstrate the importance of the scaffolds microenvironment on the cellular events of chondrogenesis.The authors are thankful to the microscopy service of UPV for useful help and service; the Department of Orthopedic Surgery-CHUAC for providing human samples; T.H. Gomez and M.J. Sanchez for cell isolation and SCH of INIBIC for histological processing. The Biomedical Research Networking Center in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN) is a national initiative of ISCIII. This study was supported by Program ACI-PRO-MOCIONA (ACI2010-1095), MAT2010-21611-CO3-01, Iniciativa Ingenio 2010, and Consolider Program.Magalhaes, J.; Lebourg, MM.; Deplaine, H.; Gómez Ribelles, JL.; Blanco, FJ. (2015). Effect of the physicochemical properties of pure chitosan-coated poly(lactic acid) scaffolds on the chondrogenic differentiation of mesenchymal stem cells from osteoarthritic patients. Tissue Engineering: Parts A, B, and C. 21(3-4):716-728. https://doi.org/10.1089/ten.tea.2014.0133S716728213-

Protein-Functionalized Microgel for Multiple Myeloma Cells’ 3D Culture

Multiple myeloma is a hematologic neoplasm caused by an uncontrolled clonal proliferation of neoplastic plasma cells (nPCs) in the bone marrow. The development and survival of this disease is tightly related to the bone marrow environment. Proliferation and viability of nPCs depend on their interaction with the stromal cells and the extracellular matrix components, which also influences the appearance of drug resistance. Recapitulating these interactions in an in vitro culture requires 3D environments that incorporate the biomolecules of interest. In this work, we studied the proliferation and viability of three multiple myeloma cell lines in a microgel consisting of biostable microspheres with fibronectin (FN) on their surfaces. We also showed that the interaction of the RPMI8226 cell line with FN induced cell arrest in the G0/G1 cell cycle phase. RPMI8226 cells developed a significant resistance to dexamethasone, which was reduced when they were treated with dexamethasone and bortezomib in combination

Microfluidic processing of piezoelectric and magnetic responsive electroactive microspheres

Poly(vinylidene fluoride) (PVDF) combined with cobalt ferrites particles (CFO) is one of the most common and effective polymeric magnetoelectric composites. Processing PVDF into its electroactive phase is a mandatory condition for featuring electroactive behavior and specific (post)processing may be needed to achieve this state. However, by processing at a temperature below 60 ºC, electroactive phase crystallization is favored. Besides, different experimental techniques are used to process various forms of PVDF-CFO nanocomposites structures being aware that high CFO dispersion must be achieved. Microfluidics offers the possibility of processing PVDF-CFO microspheres with high reproducibility, size tunability, and time and resources efficiency. Moreover, magnetoelectric microspheres are produced in a one-step approach. Thus, the present work describes the production of high content electroactive phase PVDF and PVDF-CFO microspheres using microfluidic technology. A flow-focusing polydimethylsiloxane (PDMS) device is fabricated based on a 3D printed polylactic acid (PLA) master. The device enables the production of spherical microspheres with mean diameters ranging from 80 and 330 µm depending on the continuous/discontinuous feeding ratio. The microspheres feature internal and external cavernous structures and good CFO distribution with an encapsulation efficacy of 80%. Moreover, the microspheres prove to be in the electroactive γ-phase with a mean content of 75%. Thus, the prepared microspheres show suitable characteristics as active materials for tissue regeneration strategies