Staff member

Oscar Castaño Linares
Staff member publications

López-Canosa, Adrián, Pérez-Amodio, Soledad, Engel, Elisabeth, Castaño, Oscar, (2022). Microfluidic 3D Platform to Evaluate Endothelial Progenitor Cell Recruitment by Bioactive Materials Acta Biomaterialia 151, 264-277

Li, JH, Tomasello, A, Requena, M, Canals, P, Tiberi, R, Galve, I, Engel, E, Kallmes, DF, Castano, O, Ribo, M, (2022). Trackability of distal access catheters: an in vitro quantitative evaluation of navigation strategies Journal Of Neurointerventional Surgery , 018889

Background In mechanical thrombectomy (MT), distal access catheters (DACs) are tracked through the vascular anatomy to reach the occlusion site. The inability of DACs to reach the occlusion site has been reported as a predictor of unsuccessful recanalization. This study aims to provide insight into how to navigate devices through the vascular anatomy with minimal track forces, since higher forces may imply more risk of vascular injuries. Methods We designed an experimental setup to monitor DAC track forces when navigating through an in vitro anatomical model. Experiments were recorded to study mechanical behaviors such as tension buildup against vessel walls, DAC buckling, and abrupt advancements. A multiple regression analysis was performed to predict track forces from the catheters' design specifications. Results DACs were successfully delivered to the target M1 in 60 of 63 in vitro experiments (95.2%). Compared to navigation with unsupported DAC, the concomitant coaxial use of a microcatheter/microguidewire and microcatheter/stent retriever anchoring significantly reduced the track forces by about 63% and 77%, respectively (p<0.01). The presence of the braid pattern in the reinforcement significantly reduced the track forces regardless of the technique used (p<0.05). Combined coil and braid reinforcement configuration, as compared with coil alone, and a thinner distal wall were predictors of lower track force when navigating with unsupported DAC. Conclusions The use of microcatheter and stent retriever facilitate smooth navigation of DACs through the vascular tortuosity to reach the occlusion site, which in turn improves the reliability of tracking when positioning the DAC closer to the thrombus interface.

JTD Keywords: Catheter, Navigation, Stroke, Thrombectomy, Vessel wall

Li, Jiahui, Castaño, Oscar, Tomasello, Alejandro, de Dios Lascuevas, Marta, Canals, Pere, Engel, Elisabeth, Ribo, Marc, (2022). Catheter tip distensibility substantially influences the aspiration force of thrombectomy devices Journal Of Neurointerventional Surgery 14, neurintsurg-2021-017487-67

BackgroundA direct aspiration first pass thrombectomy (ADAPT) is a fast-growing technique for which a broad catalog of catheters that provide a wide range of aspiration forces can be used. We aimed to characterize different catheters' aspiration performance on stiff clots in an in vitro vascular model. We hypothesized that labeled catheter inner diameter (labeled-ID) is not the only parameter that affects the aspiration force (asp-F) and that thrombus–catheter tip interaction and distensibility also play a major role.MethodsWe designed an experimental setup consisting of a 3D-printed carotid artery immersed in a water deposit. We measured asp-F and distensibility of catheter tips when performing ADAPT on a stiff clot analog larger than catheter labeled-ID. Correlations between asp-F, catheter ID, and tip distensibility were statistically assessed.ResultsExperimental asp-F and catheter labeled-ID were correlated (r=0.9601; P<0.01). The relative difference between experimental and theoretical asp-F (obtained by the product of the tip’s section area by the vacuum pressure) correlated with tip’s distensibility (r=0.9050; P<0.01), evidencing that ADAPT performance is highly influenced by catheter tip shape-adaptability to the clot and that the effective ID (eff-ID) may differ from the labeled-ID specified by manufacturers. Eff-ID showed the highest correlation with experimental asp-F (r=0.9944; P<0.01), confirming that eff-ID rather than labeled-ID should be considered to better estimate the device efficiency.ConclusionsCatheter tip distensibility can induce a significant impact on ADAPT performance when retrieving a stiff clot larger than the device ID. Our findings might contribute to optimizing thrombectomy strategies and the design of novel aspiration catheters.

JTD Keywords: catheter, endovascular thrombectomy, intervention, pressure, stroke, technique, thrombectomy, Acute ischemic-stroke, Catheter, Thrombectomy

Li J, Castaño O, Ribo M, (2022). Response to letter: How much will a catheter tip expand in aspiration thrombectomy? Journal Of Neurointerventional Surgery 14, 017919

López-Canosa A, Perez-Amodio S, Yanac-Huertas E, Ordoño J, Rodriguez-Trujillo R, Samitier J, Castaño O, Engel E, (2021). A microphysiological system combining electrospun fibers and electrical stimulation for the maturation of highly anisotropic cardiac tissue Biofabrication 13, 35047

The creation of cardiac tissue models for preclinical testing is still a non-solved problem in drug discovery, due to the limitations related to thein vitroreplication of cardiac tissue complexity. Among these limitations, the difficulty of mimicking the functional properties of the myocardium due to the immaturity of the used cells hampers the obtention of reliable results that could be translated into human patients.In vivomodels are the current gold standard to test new treatments, although it is widely acknowledged that the used animals are unable to fully recapitulate human physiology, which often leads to failures during clinical trials. In the present work, we present a microfluidic platform that aims to provide a range of signaling cues to immature cardiac cells to drive them towards an adult phenotype. The device combines topographical electrospun nanofibers with electrical stimulation in a microfabricated system. We validated our platform using a co-culture of neonatal mouse cardiomyocytes and cardiac fibroblasts, showing that it allows us to control the degree of anisotropy of the cardiac tissue inside the microdevice in a cost-effective way. Moreover, a 3D computational model of the electrical field was created and validated to demonstrate that our platform is able to closely match the distribution obtained with the gold standard (planar electrode technology) using inexpensive rod-shaped biocompatible stainless-steel electrodes. The functionality of the electrical stimulation was shown to induce a higher expression of the tight junction protein Cx-43, as well as the upregulation of several key genes involved in conductive and structural cardiac properties. These results validate our platform as a powerful tool for the tissue engineering community due to its low cost, high imaging compatibility, versatility, and high-throughput configuration capabilities.

JTD Keywords: bioreactor, cardiac tissue engineering, cardiomyocytes, electrospinning, fabrication, fibroblasts, heart-on-a-chip, heart-tissue, in vitro models, myocardium, orientation, platform, scaffolds, Cardiac tissue engineering, Electrospinning, Field stimulation, Heart-on-a-chip, In vitro models, Microphysiological system

Perez-Amodio, Soledad, Rubio, Nuria, Vila, Olaia F, Navarro-Requena, Claudia, Castano, Oscar, Sanchez-Ferrero, Aitor, Marti-Munoz, Joan, Alsina-Giber, Merce, Blanco, Jeronimo, Engel, Elisabeth, (2021). Polymeric Composite Dressings Containing Calcium-Releasing Nanoparticles Accelerate Wound Healing in Diabetic Mice Advances In Wound Care 10, 301-316

Objective: Wound healing is a complex process that involves the interaction between different cell types and bioactive factors. Impaired wound healing is characterized by a loss in synchronization of these interactions, resulting in nonhealing chronic wounds. Chronic wounds are a socioeconomic burden, one of the most prominent clinical manifestations of diabetes, however, they lack satisfactory treatment options. The objective of this study was to develop polymeric composites that deliver ions having wound healing properties and evaluate its performance using a pressure ulcer model in diabetic mice. Approach: To develop a polymeric composite wound dressing containing ion-releasing nanoparticles for chronic wound healing. This composite was chemically and physically characterized and evaluated using a pressure ulcer wound model in diabetic (db/db) mice to explore their potential as novel wound dressing. Results: This dressing exhibits a controlled ion release and a goodin vitrobioactivity. The polymeric composite dressing treatment stimulates angiogenesis, collagen synthesis, granulation tissue formation, and accelerates wound closure of ischemic wounds created in diabetic mice. In addition, the performance of the newly designed composite is remarkably better than a commercially available dressing frequently used for the treatment of low-exuding chronic wounds. Innovation: The developed nanoplatforms are cell- and growth factor free and control the host microenvironment resulting in enhanced wound healing. These nanoplatforms are available by cost-effective synthesis with a defined composition, offering an additional advantage in potential clinical application. Conclusion: Based on the obtained results, these polymeric composites offer an optimum approach for chronic wound healing without adding cells or external biological factors.

JTD Keywords: angiogenesis, bioactive dressings, chronic wounds, Angiogenesis, Bioactive dressings, Bioactive glass, Bioglass, Cells, Chronic wounds, Diabetes, Endothelial growth-factor, Expression, Hydrogel, Induction

Jurado, M, Castano, O, Zorzano, A, (2021). Stochastic modulation evidences a transitory EGF-Ras-ERK MAPK activity induced by PRMT5 Computers In Biology And Medicine 133, 104339

The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway involves a three-step cascade of kinases that transduce signals and promote processes such as cell growth, development, and apoptosis. An aberrant response of this pathway is related to the proliferation of cell diseases and tumors. By using simulation modeling, we document that the protein arginine methyltransferase 5 (PRMT5) modulates the MAPK pathway and thus avoids an aberrant behavior. PRMT5 methylates the Raf kinase, reducing its catalytic activity and thereby, reducing the activation of ERK in time and amplitude. Two minimal computational models of the epidermal growth factor (EGF)-Ras-ERK MAPK pathway influenced by PRMT5 were proposed: a first model in which PRMT5 is activated by EGF and a second one in which PRMT5 is stimulated by the cascade response. The reported results show that PRMT5 reduces the time duration and the expression of the activated ERK in both cases, but only in the first model PRMT5 limits the EGF range that generates an ERK activation. Based on our data, we propose the protein PRMT5 as a regulatory factor to develop strategies to fight against an excessive activity of the MAPK pathway, which could be of use in chronic diseases and cancer.

JTD Keywords: cancer, cell response modulation, computational model, egf-ras-erk signaling route, mapk pathway, methylation, Arginine methyltransferase 5, Cancer, Cell response modulation, Colorectal-cancer, Computational model, Egf-ras-erk signaling route, Epidermal-growth-factor, Factor receptor, Histone h3, Kinase cascade, Mapk pathway, Methylation, Negative-feedback, Pc12 cells, Prmt5, Protein, Signal-transduction

Blanco-Fernandez, B, Castano, O, Mateos-Timoneda, MA, Engel, E, Perez-Amodio, S, (2021). Nanotechnology Approaches in Chronic Wound Healing Advances In Wound Care 10, 234-256

Significance: The incidence of chronic wounds is increasing due to our aging population and the augment of people afflicted with diabetes. With the extended knowledge on the biological mechanisms underlying these diseases, there is a novel influx of medical technologies into the conventional wound care market. Recent Advances: Several nanotechnologies have been developed demonstrating unique characteristics that address specific problems related to wound repair mechanisms. In this review, we focus on the most recently developed nanotechnology-based therapeutic agents and evaluate the efficacy of each treatment in in vivo diabetic models of chronic wound healing. Critical Issues: Despite the development of potential biomaterials and nanotechnology-based applications for wound healing, this scientific knowledge is not translated into an increase of commercially available wound healing products containing nanomaterials. Future Directions: Further studies are critical to provide insights into how scientific evidences from nanotechnology-based therapies can be applied in the clinical setting.

JTD Keywords: chronic, diabetes, liposomes, nanofibers, nanoparticles, Chronic, Chronic wound, Diabetes, Diabetic wound, Diabetic-rats, Dressings, Drug mechanism, Extracellular-matrix, Growth-factor, Human, In-vitro, Liposome, Liposomes, Mesenchymal stem-cells, Metal nanoparticle, Nanofiber, Nanofibers, Nanofibrous scaffolds, Nanoparticles, Nanotechnology, Nonhuman, Polyester, Polymer, Polysaccharide, Priority journal, Protein, Review, Self assembled protein nanoparticle, Silk fibroin, Skin wounds, Wound healing, Wound healing promoting agent

Castaño O, López-Mengual A, Reginensi D, Matamoros-Angles A, Engel E, del Rio JA, (2021). Chemotactic TEG3 Cells’ Guiding Platforms Based on PLA Fibers Functionalized With the SDF-1α/CXCL12 Chemokine for Neural Regeneration Therapy Frontiers In Bioengineering And Biotechnology 9, 627805

(Following spinal cord injury, olfactory ensheathing cell (OEC) transplantation is a promising therapeutic approach in promoting functional improvement. Some studies report that the migratory properties of OECs are compromised by inhibitory molecules and potentiated by chemical concentration differences. Here we compare the attachment, morphology, and directionality of an OEC-derived cell line, TEG3 cells, seeded on functionalized nanoscale meshes of Poly(l/dl-lactic acid; PLA) nanofibers. The size of the nanofibers has a strong effect on TEG3 cell adhesion and migration, with the PLA nanofibers having a 950 nm diameter being the ones that show the best results. TEG3 cells are capable of adopting a bipolar morphology on 950 nm fiber surfaces, as well as a highly dynamic behavior in migratory terms. Finally, we observe that functionalized nanofibers, with a chemical concentration increment of SDF-1α/CXCL12, strongly enhance the migratory characteristics of TEG3 cells over inhibitory substrates.

JTD Keywords: cell migration, cxcl12, electrospinning, gradients, pla nanofibers, sdf-1alpha, Cell migration, Cxcl12, Electrospinning, Gradients, Olfactory ensheathing cells, Pla nanofibers, Sdf-1alpha

Rubi-Sans, G., Castaño, O., Cano, I., Mateos-Timoneda, M. A., Perez-Amodio, S., Engel, E., (2020). Engineering cell-derived matrices: From 3D models to advanced personalized therapies Advanced Functional Materials 30, (44), e2000496

Regenerative medicine and disease models have evolved in recent years from two to three dimensions, providing in vitro constructs that are more similar to in vivo tissues. By mimicking native tissues, cell-derived matrices (CDMs) have emerged as new modifiable extracellular matrices for a variety of tissues, allowing researchers to study basic cellular processes in tissue-like structures, test tissue regeneration approaches, and model disease development. In this review, different fabrication techniques and characterization methods of CDMs are presented and examples of their application in cell behavior studies, tissue regeneration, and disease models are provided. In addition, future guidelines and perspectives in the field of CDMs are discussed.

JTD Keywords: 3D models, Biomaterials, Cell-derived matrices, Extracellular matrix, Personalized therapies

Vila, A., Torras, N., Castaño, Albert G., García-Díaz, María, Comelles, Jordi, Pérez-Berezo, T., Corregidor, C., Castaño, O., Engel, E., Fernández-Majada, Vanesa, Martínez, Elena, (2020). Hydrogel co-networks of gelatine methacrylate and poly(ethylene glycol) diacrylate sustain 3D functional in vitro models of intestinal mucosa Biofabrication 12, 025008

Mounting evidence supports the importance of the intestinal epithelial barrier and its permeability both in physiological and pathological conditions. Conventional in vitro models to evaluate intestinal permeability rely on the formation of tightly packed epithelial monolayers grown on hard substrates. These two-dimensional (2D) models lack the cellular and mechanical components of the non-epithelial compartment of the intestinal barrier, the stroma, which are key contributors to the barrier permeability in vivo. Thus, advanced in vitro models approaching the in vivo tissue composition are fundamental to improve precision in drug absorption predictions, to provide a better understanding of the intestinal biology, and to faithfully represent related diseases. Here, we generate photo-crosslinked gelatine methacrylate (GelMA) - poly(ethylene glycol) diacrylate (PEGDA) hydrogel co-networks that provide the required mechanical and biochemical features to mimic both the epithelial and stromal compartments of the intestinal mucosa, i.e., they are soft, cell adhesive and cell-loading friendly, and suitable for long-term culturing. We show that fibroblasts can be embedded in the GelMA-PEGDA hydrogels while epithelial cells can grow on top to form a mature epithelial monolayer that exhibits barrier properties which closely mimic those of the intestinal barrier in vivo, as shown by the physiologically relevant transepithelial electrical resistance (TEER) and permeability values. The presence of fibroblasts in the artificial stroma compartment accelerates the formation of the epithelial monolayer and boosts the recovery of the epithelial integrity upon temporary barrier disruption, demonstrating that our system is capable of successfully reproducing the interaction between different cellular compartments. As such, our hydrogel co-networks offer a technologically simple yet sophisticated approach to produce functional three-dimensional (3D) in vitro models of epithelial barriers with epithelial and stromal cells arranged in a spatially relevant manner and near-physiological functionality.


Majchrowicz, A., Roguska, A., Krawczy, Lewandowska, M., Martí-Muñoz, J., Engel, E., Castano, O., (2020). In vitro evaluation of degradable electrospun polylactic acid/bioactive calcium phosphate ormoglass scaffolds Archives of Civil and Mechanical Engineering 20, (2), 50

Nowadays, the main limitation for clinical application of scaffolds is considered to be an insufficient vascularization of the implanted platforms and healing tissues. In our studies, we proposed a novel PLA-based hybrid platform with aligned and random fibrous internal structure and incorporated calcium phosphate (CaP) ormoglass nanoparticles (0, 10, 20 and 30 wt%) as an off-the-shelf method for obtaining scaffolds with pro-angiogenic properties. Complex morphological and physicochemical evaluation of PLA–CaP ormoglass composites was performed before and after in vitro degradation test in SBF solution to assess their biological potential. The degradation process of PLA–CaP ormoglass composites was accompanied by numerous CaP-based precipitations with extended topography and cauliflower-like shape which may enhance bonding of the material with the bone tissue and accelerate the regenerative process. Random fiber orientation was preferable for CaP compounds deposition upon in vitro degradation. CaP compounds precipitated firstly for randomly oriented composite nonwovens with 20 and 30 wt% addition of ormoglass. Moreover, the preliminary bioactivity test has shown that BSA adsorbed to PLA–CaP ormoglass composites (both aligned and randomly oriented) with 20 and 30 wt% of ormoglass nanoparticles which was not observed for pure PLA scaffolds.

JTD Keywords: Calcium phosphate ormoglass, Composites, Degradation, Electrospinning, PLA

Paoli, R., Bulwan, M., Castaño, O., Engel, E., Rodriguez-Cabello, J. C., Homs-Corbera, A., Samitier, J., (2020). Layer-by-layer modification effects on a nanopore's inner surface of polycarbonate track-etched membranes RSC Advances 10, (59), 35930-35940

The control of the morphology, as well as the physical and chemical properties, of nanopores is a key issue for many applications. Reducing pore size is important in nanopore-based sensing applications as it helps to increase sensitivity. Changes of other physical properties such as surface net charge can also modify transport selectivity of the pores. We have studied how polyelectrolyte layer-by-layer (LBL) surface modification can be used to change the characteristics of nanoporous membranes. Studies were performed with a custom made three-dimensional multilayer microfluidic device able to fit membrane samples. The device allowed us to efficiently control LBL film deposition over blank low-cost commercially available polycarbonate track-etched (PCTE) membranes. We have demonstrated pore diameter reduction and deposition of the layers inside the pores through confocal and SEM images. Posterior impedance measurement studies served to evaluate experimentally the effect of the LBL deposition on the net inner nanopore surface charge and diameter. Measurements using direct current (DC) and alternative current (AC) voltages have demonstrated contrasted behaviors depending on the number and parity of deposited opposite charge layers. PCTE membranes are originally negatively charged and results evidenced higher impedance increases for paired charge LBL depositions. Impedance decreased when an unpaired positive layer was added. These results showed a different influence on the overall ion motility due to the effect of different surface charges. Results have been fit into a model that suggested a strong dependence of nanopores' impedance module to surface charge on conductive buffers, such as Phosphate Buffer Saline (PBS), even on relatively large nanopores. In AC significant differences between paired and unpaired charged LBL depositions tended to disappear as the total number of layers increased.


Marti-Muñoz, Joan, Xuriguera, Elena, Layton, John W., Planell, Josep A., Rankin, Stephen E., Engel, Elisabeth, Castaño, Oscar, (2019). Feasible and pure P2O5-CaO nanoglasses: An in-depth NMR study of synthesis for the modulation of the bioactive ion release Acta Biomaterialia 94, 574-584

The use of bioactive glasses (e.g. silicates, phosphates, borates) has demonstrated to be an effective therapy for the restoration of bone fractures, wound healing and vascularization. Their partial dissolution towards the surrounding tissue has shown to trigger positive bioactive responses, without the necessity of using growth factors or cell therapy, which reduces money-costs, side effects and increases their translation to the clinics. However, bioactive glasses often need from stabilizers (e.g. SiO44−, Ti4+, Co2+, etc.) that are not highly abundant in the body and which metabolization is not fully understood. In this study, we were focused on synthesizing pure calcium phosphate glasses without the presence of such stabilizers. We combined a mixture of ethylphosphate and calcium 2-methoxyethoxide to synthesize nanoparticles with different compositions and degradability. Synthesis was followed by an in-depth nuclear magnetic resonance characterization, complemented with other techniques that helped us to correlate the chemical structure of the glasses with their physiochemical properties and reaction mechanism. After synthesis, the organically modified xerogel (i.e. calcium monoethylphosphate) was treated at 200 or 350 °C and its solubility was maintained and controlled due to the elimination of organics, increase of phosphate-calcium interactions and phosphate polycondensation. To the best of our knowledge, we are reporting the first sol-gel synthesis of binary (P2O5-CaO) calcium phosphate glass nanoparticles in terms of continuous polycondensated phosphate chains structure without the addition of extra ions. The main goal is to straightforward the synthesis, to get a safer metabolization and to modulate the bioactive ion release. Additionally, we shed light on the chemical structure, reaction mechanism and properties of calcium phosphate glasses with high calcium contents, which nowadays are poorly understood. Statement of Significance The use of bioactive inorganic materials (i.e. bioactive ceramics, glass-ceramics and glasses) for biomedical applications is attractive due to their good integration with the host tissue without the necessity of adding exogenous cells or growth factors. In particular, degradable calcium phosphate glasses are completely resorbable, avoiding the retention in the body of the highly stable silica network of silicate glasses, and inducing a more controllable degradability than bioactive ceramics. However, most calcium phosphate glasses include the presence of stabilizers (e.g. Ti4+, Na+, Co2+), which metabolization is not fully understood and complicates their synthesis. The development of binary calcium phosphate glasses with controlled degradability reduces these limitations, offering a simple and completely metabolizable material with higher transfer to the clinics.

JTD Keywords: Calcium phosphate glasses, Sol-gel process, NMR spectroscopy, Ion release, Biomaterials

Rey-Vinolas, S., Castaño, O., Ruiz-Macarrilla, L., Llorens, X., Mora, J. M., Engel, E., Mateos-Timoneda, M. A., (2019). Development of a novel automatable fabrication method based on electrospinning co electrospraying for rotator cuff augmentation patches PLoS ONE 14, (11), e0224661

Rotator cuff tear is one of the most common shoulder diseases. Rotator cuff augmentation (RCA) is trying to solve the high retear failure percentage after the surgery procedures (20–90%). The ideal augmentation patch must provide a temporal mechanical support during the healing process. In this work, we proposed a simple method for the fabrication of synthetic RCA patches. This method combines the use of electrospraying to produce poly-L-lactic-co-ε-caprolactone (PLC) films in an organogel form and electrospinning to produce poly(lactic) acid (PLA) nanofibers. The device consists in a combination of layers, creating a multilayered construct, enabling the possibility of tuning its mechanical properties and thickness. Besides, both techniques are simple to escalate for industrial production. A complete characterization has been performed to optimize the involved number of layers and production time of PLC films and PLA nanofibers fabrication, obtaining a final optimal configuration for RCA devices. Structural, mechanical and suture properties were evaluated. Also, the possibility of surface functionalization to improve the bioactivity of the scaffold was studied, adding aligned electrospun PLA nanofibers on the surface of the device to mimic the natural tendon topography. Surface modification was characterized by culturing adult normal human dermal fibroblasts. Lack of toxicity was detected for material presented, and cell alignment shape orientation guided by aligned fibers, mimicking tendon structure, was obtained. Cell proliferation and protein production were also evaluated.


Zalvidea, D., Castano, O., Baker, S., Castro, N., Engel, E., Trepat, X., (2019). Time-lapse intravital imaging of biomaterials integration in tissues using a multicolor multiphoton microscope Novel lasers, instruments and technology 2019 Conference on Lasers and Electro-Optics Europe and European Quantum Electronics Conference , IEEE (Munich, Germany) OSA Technical Digest (Optical Society of America, 2019), paper cl_3_1

Different mechanisms are triggered when tissue is exposed to a biomaterial. The success of the biomaterial targeted process, like the release of chemicals, promoted angiogenesis, tissue regeneration, etc. depends on its integration in the tissue [1]. Studying this interaction in vivo requires the ability to image simultaneously deep immersed proteins and biomaterials with high resolution and low damage. Several methods offer solutions but only multiphoton microscopy (MM) has the ability to image with high resolution deep inside the sample. Why is not MM more extensively applied as a platform for investigating biomaterial integration in vivo? The high cost of the typical source for multiphoton microscopy is a clear limitation. Furthermore, imaging several channels simultaneously becomes out of reach for most of the labs.


Castaño, O., Pérez-Amodio, S., Navarro, C., Mateos-Timoneda, M.A., Engel, E., (2018). Instructive microenvironments in skin wound healing: Biomaterials as signal releasing platforms Advanced Drug Delivery Reviews 129, 95-117

Skin wound healing aims to repair and restore tissue through a multistage process that involves different cells and signalling molecules that regulate the cellular response and the dynamic remodelling of the extracellular matrix. Nowadays, several therapies that combine biomolecule signals (growth factors and cytokines) and cells are being proposed. However, a lack of reliable evidence of their efficacy, together with associated issues such as high costs, a lack of standardization, no scalable processes, and storage and regulatory issues, are hampering their application. In situ tissue regeneration appears to be a feasible strategy that uses the body's own capacity for regeneration by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the wound site to promote repair and regeneration. The aim is to engineer instructive systems to regulate the spatio-temporal delivery of proper signalling based on the biological mechanisms of the different events that occur in the host microenvironment. This review describes the current state of the different signal cues used in wound healing and skin regeneration, and their combination with biomaterial supports to create instructive microenvironments for wound healing.

JTD Keywords: Instructive biomaterials, Skin regeneration, Wound healing, Signalling release, In situ tissue engineering

Navarro, C., Pérez-Amodio, S., Castaño, O., Engel, E., (2018). Wound healing-promoting effects stimulated by extracellular calcium and calcium-releasing nanoparticles on dermal fibroblasts Nanotechnology 29, (39), 395102

Extracellular calcium has been proved to influence the healing process of injuries and could be used as a novel therapy for skin wound healing. However, a better understanding of its effect, together with a system to obtain a controlled release is needed. In this study, we examined whether the ionic dissolution of the calcium–phosphate-based ormoglass nanoparticles coded SG5 may produce a similar stimulating effect as extracellular calcium (from CaCl2) on rat dermal fibroblast in vitro. Cells were cultured in the presence of medium containing different calcium concentrations, normally ranging from 0.1 to 3.5 mM Ca2+. A concentration of 3.5 mM of CaCl2 increased metabolic activity, in vitro wound closure, matrix metalloproteinases (MMP) activity, collagen synthesis and cytokine expression, and reduced cell contraction capacity. Interestingly, the levels of migration and contraction capacity measured followed a dose-dependent behavior. In addition, media conditioned with SG5 stimulated the same activities as media conditioned with CaCl2, but undesired effects in chronic wound healing such as inflammatory factor expression and MMP activity were reduced compared to the equivalent CaCl2 concentration. In summary, calcium-releasing particles such as SG5 are potential biological-free biostimulators to be applied in dressings for chronic wound healing.

JTD Keywords: Nanomaterials, Cell signaling, Skin wound healing

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.

JTD Keywords: Angiogenesis, Bone regeneration, Calcium phosphate ormoglasses

Sachot, N., Roguska, A., Planell, J. P., Lewandowska, M., Engel, E., Castaño, O., (2017). Fast-degrading PLA/ORMOGLASS fibrous composite scaffold leads to a calcium-rich angiogenic environment International Journal of Nanomedicine 12, 4901-4919

The success of scaffold implantation in acellular tissue engineering approaches relies on the ability of the material to interact properly with the biological environment. This behavior mainly depends on the design of the graft surface and, more precisely, on its capacity to biodegrade in a well-defined manner (nature of ions released, surface-to-volume ratio, dissolution profile of this release, rate of material resorption, and preservation of mechanical properties). The assessment of the biological behavior of temporary templates is therefore very important in tissue engineering, especially for composites, which usually exhibit complicated degradation behavior. Here, blended polylactic acid (PLA) calcium phosphate ORMOGLASS (organically modified glass) nanofibrous mats have been incubated up to 4 weeks in physiological simulated conditions, and their morphological, topographical, and chemical changes have been investigated. The results showed that a significant loss of inorganic phase occurred at the beginning of the immersion and the ORMOGLASS maintained a stable composition afterward throughout the degradation period. As a whole, the nanostructured scaffolds underwent fast and heterogeneous degradation. This study reveals that an angiogenic calcium-rich environment can be achieved through fast-degrading ORMOGLASS/PLA blended fibers, which seems to be an excellent alternative for guided bone regeneration.

JTD Keywords: Angiogenesis, Calcium release, Electrospinning, Fast degradation, Nanofibers, ORMOGLASSES

Echalier, C., Levato, R., Mateos-Timoneda, M. A., Castaño, O., Déjean, S., Garric, X., Pinese, C., Noël, D., Engel, E., Martinez, J., Mehdi, A., Subra, G., (2017). Modular bioink for 3D printing of biocompatible hydrogels: sol-gel polymerization of hybrid peptides and polymers RSC Advances 7, (20), 12231-12235

An unprecedented generic system allowing the 3D printing of peptide-functionalized hydrogels by soft sol-gel inorganic polymerization is presented. Hybrid silylated inorganic/bioorganic blocks are mixed in biological buffer in an appropriate ratio, to yield a multicomponent bioink that can be printed as a hydrogel without using any photochemical or organic reagent. Hydrolysis and condensation of the silylated precursors occur during the printing process and result in a covalent network in which molecules are linked through siloxane bonds. The viscosity of the colloidal solution used as bioink was monitored in order to set up the optimal conditions for extrusion printing. Grid-patterned hydrogel scaffolds containing a hybrid integrin ligand were printed using a pressure-driven rapid prototyping machine. Finally, they were seeded with mesenchymal stem cells, demonstrating their suitability for cell culture. The versatility of the sol-gel process and its biocompatibility makes this approach highly promising for the preparation of tailor-made cell-laden scaffolds.


Castaño, O., Pérez, S., Mateos-Timoneda, M. A., Engel, E., (2017). Cell Interactions with Calcium Phosphate Glasses RSC Smart Materials (ed. Boccaccini, Aldo R., Brauer, Delia S., Hupa, L.), Royal Society of Chemistry (London, UK) Bioactive Glasses: Fundamentals, Technology and Applications, 303-315

This chapter will review the interactions between calcium phosphate (CaP) glasses and different cell types. These glasses are less established in the biomaterials field than silicate-based glasses, but phosphate glasses generate interest owing to their higher solubility. CaP glasses have been less studied than silicate-based glasses, possibly due to the commercialization of Hench's Bioglass that allowed many laboratory groups to use them for different studies, including cell culture studies, without having to prepare them in-house. Studies on CaP glasses focused on compositional modification in order to elicit different properties to enhance biodegradability and bioactivity, two main properties for the application of these glasses. These properties have opened the application of these glasses and have enhanced the effect on cells allowing exploration of the bioactivity of ions released by these exceptionally interesting biomaterials.


Oliveira, Hugo, Catros, Sylvain, Boiziau, Claudine, Siadous, Robin, Marti-Munoz, Joan, Bareille, Reine, Rey, Sylvie, Castano, Oscar, Planell, Josep, Amédée, Joëlle, Engel, Elisabeth, (2016). The proangiogenic potential of a novel calcium releasing biomaterial: Impact on cell recruitment Acta Biomaterialia 29, 435-445

Abstract In current bone tissue engineering strategies the achievement of sufficient angiogenesis during tissue regeneration is still a major limitation in order to attain full functionality. Several strategies have been described to tackle this problem, mainly by the use of angiogenic factors or endothelial progenitor cells. However, when facing a clinical scenario these approaches are inherently complex and present a high cost. As such, more cost effective alternatives are awaited. Here, we demonstrate the potential of electrospun poly(lactic acid) (PLA) fiber-based membranes, containing calcium phosphate ormoglass (CaP) particles, to elicit angiogenesis in vivo, in a subcutaneous model in mice. We show that the current approach elicited the local expression of angiogenic factors, associated to a chemotactic effect on macrophages, and sustained angiogenesis into the biomaterial. As both PLA and CaP are currently accepted for clinical application these off-the-shelf novel membranes have great potential for guided bone regeneration applications. 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, our group has found that calcium ions released by the degradation of calcium phosphate ormoglasses (CaP) are effective angiogenic promoters. Based on this, in this work we successfully produced hybrid fibrous mats with different contents of CaP nanoparticles and thus with different calcium ion release rates, using an ormoglass – poly(lactic acid) blend approach. We show that these matrices, upon implantation in a subcutaneous site, could elicit the local expression of angiogenic factors, associated to a chemotactic effect on macrophages, and sustained angiogenesis into the biomaterial, in a CaP dose dependent manner. This off-the-shelf cost effective approach presents great potential to translate to the clinics.

JTD Keywords: Angiogenesis, Bone regeneration, Calcium phosphate ormoglass

Sachot, N., Castaño, O., Oliveira, H., Martí-Muñoz, J., Roguska, A., Amedee, J., Lewandowska, M., Planell, J. A., Engel, E., (2016). A novel hybrid nanofibrous strategy to target progenitor cells for cost-effective: In situ angiogenesis Journal of Materials Chemistry B 4, (43), 6967-6978

Although the impact of composites based on Ti-doped calcium phosphate glasses is low compared with that of bioglass, they have been already shown to possess great potential for bone tissue engineering. Composites made of polylactic acid (PLA) and a microparticle glass of 5TiO2-44.5CaO-44.5P2O5-6Na2O (G5) molar ratio have already demonstrated in situ osteo- and angiogenesis-triggering abilities. As many of the hybrid materials currently developed usually promote osteogenesis but still lack the ability to induce vascularization, a G5/PLA combination is a cost-effective option for obtaining new instructive scaffolds. In this study, nanostructured PLA-ORMOGLASS (organically modified glass) fibers were produced by electrospinning, in order to fabricate extra-cellular matrix (ECM)-like substrates that simultaneously promote bone formation and vascularization. Physical-chemical and surface characterization and tensile tests demonstrated that the obtained scaffolds exhibited homogeneous morphology, higher hydrophilicity and enhanced mechanical properties than pure PLA. In vitro assays with rat mesenchymal stem cells (rMSCs) and rat endothelial progenitor cells (rEPCs) also showed that rMSCs attached and proliferated on the materials influenced by the calcium content in the environment. In vivo assays showed that hybrid composite PLA-ORMOGLASS fibers were able to promote the formation of blood vessels. Thus, these novel fibers are a valid option for the design of functional materials for tissue engineering applications.


Sachot, N., Mateos-Timoneda, M. A., Planell, J. A., Velders, A. H., Lewandowska, M., Engel, E., Castaño, O., (2015). Towards 4th generation biomaterials: A covalent hybrid polymer-ormoglass architecture Nanoscale 7, (37), 15349-15361

Hybrid materials are being extensively investigated with the aim of mimicking the ECM microenvironment to develop effective solutions for bone tissue engineering. However, the common drawbacks of a hybrid material are the lack of interactions between the scaffold's constituents and the masking of its bioactive phase. Conventional hybrids often degrade in a non-homogeneous manner and the biological response is far from optimal. We have developed a novel material with strong interactions between constituents. The bioactive phase is directly exposed on its surface mimicking the structure of the ECM of bone. Here, polylactic acid electrospun fibers have been successfully and reproducibly coated with a bioactive organically modified glass (ormoglass, Si–Ca–P2 system) covalently. In comparison with the pure polymeric mats, the fibers obtained showed improved hydrophilicity and mechanical properties, bioactive ion release, exhibited a nanoroughness and enabled good cell adhesion and spreading after just one day of culture (rMSCs and rEPCs). The fibers were coated with different ormoglass compositions to tailor their surface properties (roughness, stiffness, and morphology) by modifying the experimental parameters. Knowing that cells modulate their behavior according to the exposed physical and chemical signals, the development of this instructive material is a valuable advance in the design of functional regenerative biomaterials.


Sachot, Nadège, Castano, Oscar, Planell, Josep A., Engel, Elisabeth, (2015). Optimization of blend parameters for the fabrication of polycaprolactone-silicon based ormoglass nanofibers by electrospinning Journal of Biomedical Materials Research - Part B: Applied Biomaterials , 103, (6), 1287–1293

Electrospinning is a method that can be used to efficiently produce scaffolds that mimic the fibrous structure of natural tissue, such as muscle structures or the extracellular matrix of bone. The technique is often used as a way of depositing composites (organic/inorganic materials) to obtain bioactive nanofibers which have the requisite mechanical properties for use in tissue engineering. However, many factors can influence the formation and collection of fibers, including experimental variables such as the parameters of the solution of the electrospun slurry. In this study, we assessed the influence of the polymer concentration, glass content and glass hydrolysis level on the morphology and thickness of fibers produced by electrospinning for a PCL-(Si-Ca-P2) bioactive ormoglass—organically modified glass—blend. Based on previous assays, this combination of materials shows good angiogenic and osteogenic properties, which gives it great potential for use in tissue engineering. The results of our study showed that blend preparation directly affected the features of the resulting fibers, and when the parameters of the blend are precisely controlled, fibers with a regular diameter could be produced fairly easily when 2,2,2-trifluoroethanol was used as a solvent instead of tetrahydrofuran. The diameter of the homogeneous fibers ranged from 360 to 620 nm depending on the experimental conditions used. This demonstrates that experimental optimization of the electrospinning process is crucial in order to obtain a deposit of hybrid nanofibers with a regular shape.

JTD Keywords: Si-based glasses, Ormoglass, Electrospinning, Hybrid materials, Bioactivity, Angiogenesis

Won, J. E., Mateos-Timoneda, M. A., Castaño, O., Planell, J. A., Seo, S. J., Lee, E. J., Han, C. M., Kim, H. W., (2015). Fibronectin immobilization on to robotic-dispensed nanobioactive glass/polycaprolactone scaffolds for bone tissue engineering Biotechnology Letters , 37, (4), 935-342

Bioactive nanocomposite scaffolds with cell-adhesive surface have excellent bone regeneration capacities. Fibronectin (FN)-immobilized nanobioactive glass (nBG)/polycaprolactone (PCL) (FN-nBG/PCL) scaffolds with an open pore architecture were generated by a robotic-dispensing technique. The surface immobilization level of FN was significantly higher on the nBG/PCL scaffolds than on the PCL scaffolds, mainly due to the incorporated nBG that provided hydrophilic chemical-linking sites. FN-nBG/PCL scaffolds significantly improved cell responses, including initial anchorage and subsequent cell proliferation. Although further in-depth studies on cell differentiation and the in vivo animal responses are required, bioactive nanocomposite scaffolds with cell-favoring surface are considered to provide promising three-dimensional substrate for bone regeneration.

JTD Keywords: Bone scaffolds, Cell response, Fibronectin, Nanobioactive glass, Nanocomposites, Polycaprolactone, Bone, Cell proliferation, Cells, Cytology, Glass, Nanocomposites, Polycaprolactone, Robotics, Bone scaffolds, Bone tissue engineering, Cell response, Fibronectin, Fibronectin immobilizations, Nano bioactive glass, Nanocomposite scaffolds, Three-dimensional substrates, Scaffolds (biology)

Álvarez, Z., Castaño, O., Castells, A. A., Mateos-Timoneda, M. A., Planell, J. A., Engel, E., Alcántara, S., (2014). Neurogenesis and vascularization of the damaged brain using a lactate-releasing biomimetic scaffold Biomaterials 35, (17), 4769-4781

Regenerative medicine strategies to promote recovery following traumatic brain injuries are currently focused on the use of biomaterials as delivery systems for cells or bioactive molecules. This study shows that cell-free biomimetic scaffolds consisting of radially aligned electrospun poly-l/dl lactic acid (PLA70/30) nanofibers release l-lactate and reproduce the 3D organization and supportive function of radial glia embryonic neural stem cells. The topology of PLA nanofibers supports neuronal migration while l-lactate released during PLA degradation acts as an alternative fuel for neurons and is required for progenitor maintenance. Radial scaffolds implanted into cavities made in the postnatal mouse brain fostered complete implant vascularization, sustained neurogenesis, and allowed the long-term survival and integration of the newly generated neurons. Our results suggest that the endogenous central nervous system is capable of regeneration through the invivo dedifferentiation induced by biophysical and metabolic cues, with no need for exogenous cells, growth factors, or genetic manipulation.

JTD Keywords: Lactate, Nanofibers, Neural stem cells, Neurogenesis, Regeneration, Vascularization

Castaño, O., Sachot, N., Xuriguera, E., Engel, E., Planell, J. A., Park, J. H., Jin, G. Z., Kim, T. H., Kim, J. H., Kim, H. W., (2014). Angiogenesis in bone regeneration: Tailored calcium release in hybrid fibrous scaffolds ACS Applied Materials & Interfaces 6, (10), 7512-7522

In bone regeneration, silicon-based calcium phosphate glasses (Bioglasses) have been widely used since the 1970s. However, they dissolve very slowly because of their high amount of Si (SiO2 > 45%). Recently, our group has found that calcium ions released by the degradation of glasses in which the job of silicon is done by just 5% of TiO2 are effective angiogenic promoters, because of their stimulation of a cell-membrane calcium sensing receptor (CaSR). Based on this, other focused tests on angiogenesis have found that Bioglasses also have the potential to be angiogenic promoters even with high contents of silicon (80%); however, their slow degradation is still a problem, as the levels of silicon cannot be decreased any lower than 45%. In this work, we propose a new generation of hybrid organically modified glasses, ormoglasses, that enable the levels of silicon to be reduced, therefore speeding up the degradation process. Using electrospinning as a faithful way to mimic the extracellular matrix (ECM), we successfully produced hybrid fibrous mats with three different contents of Si (40, 52, and 70%), and thus three different calcium ion release rates, using an ormoglass–polycaprolactone blend approach. These mats offered a good platform to evaluate different calcium release rates as osteogenic promoters in an in vivo subcutaneous environment. Complementary data were collected to complement Ca2+ release analysis, such as stiffness evaluation by AFM, ζ-potential, morphology evaluation by FESEM, proliferation and differentiation analysis, as well as in vivo subcutaneous implantations. Material and biological characterization suggested that compositions of organic/inorganic hybrid materials with a Si content equivalent to 40%, which were also those that released more calcium, were osteogenic. They also showed a greater ability to form blood vessels. These results suggest that Si-based ormoglasses can be considered an efficient tool for calcium release modulation, which could play a key role in the angiogenic promoting process.

JTD Keywords: Biological materials, Blood vessels, Calcium, Electrospinning, Glass, Hybrid materials, Silicon oxides, Sol-gel process, Sol-gels, Angiogenesis, Biological characterization, Calcium phosphate glass, Calcium-sensing receptors, Degradation process, Extracellular matrices, Organic/inorganic hybrid materials, ormoglasses, Silicon

Rajzer, I., Menaszek, E., Kwiatkowski, R., Planell, J. A., Castaño, O., (2014). Electrospun gelatin/poly(ε-caprolactone) fibrous scaffold modified with calcium phosphate for bone tissue engineering Materials Science and Engineering: C 44, 183-190

In this study gelatin (Gel) modified with calcium phosphate nanoparticles (SG5) and polycaprolactone (PCL) were used to prepare a 3D bi-layer scaffold by collecting electrospun PCL and gelatin/SG5 fibers separately in the same collector. The objective of this study was to combine the desired properties of PCL and Gel/SG5 in the same scaffold in order to enhance mineralization, thus improving the ability of the scaffold to bond to the bone tissue. The scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and the wide angle X-ray diffraction (WAXD) measurements confirmed that SG5 nanoparticles were successfully incorporated into the fibrous gelatin matrix. The composite Gel/SG5/PCL scaffold exhibited more enhanced mechanical properties than individual Gel and Gel/SG5 scaffolds. The presence of SG5 nanoparticles accelerated the nucleation and growth of apatite crystals on the surface of the composite Gel/SG5/PCL scaffold in simulated body fluid (SBF). The osteoblast response in vitro to developed electrospun scaffolds (PCL and Gel/SG5/PCL) was investigated by using normal human primary NHOst cell lines. NHOst cell culture studies showed that higher alkaline phosphatase (ALP) activity and better mineralization were obtained in the case of composite materials than in pure PCL scaffolds. The mechanically strong PCL scaffold served as a skeleton, while the Gel/SG5 fibers facilitated cell spreading and mineralization of the scaffold.

JTD Keywords: Bilayer fibrous scaffold, Ceramic nanoparticles, Electrospinning, Gelatin, Polycaprolactone, Biomechanics, Bone, Calcium phosphate, Cell culture, Electrospinning, Fourier transform infrared spectroscopy, Mechanical properties, Mineralogy, Nanoparticles, Phosphatases, Polycaprolactone, Scanning electron microscopy, X ray diffraction, Polycaprolactone, Alkaline phosphatase activity, Bone tissue engineering, Calcium phosphate nanoparticles, Ceramic nanoparticles, Fibrous scaffolds, Gelatin, Simulated body fluids, Wide-angle x-ray diffraction, Electrospuns, Scaffolds (biology), Electrospinning

Mateos-Timoneda, M. A., Castaño, O., Planell, J. A., Engel, E., (2014). Effect of structure, topography and chemistry on fibroblast adhesion and morphology Journal of Materials Science: Materials in Medicine , 25, (7), 1781-1787

Surface biofunctionalisation of many biodegradable polymers is one of the used strategies to improve the biological activity of such materials. In this work, the introduction of collagen type I over the surface of a biodegradable polymer (poly lactic acid) processed in the forms of films and fibers leads to an enhancing of the cellular adhesion of human dermal fibroblast when compared to unmodified polymer and biomolecule-physisorbed polymer surface. The change of topography of the material does not affect the cellular adhesion but results in a higher proliferation of the fibroblast cultured over the fibers. Moreover, the difference of topography governs the cellular morphology, i.e. cells adopt a more stretched conformation where cultured over the films while a more elongated with lower area morphology are obtained for the cells grown over the fibers. This study is relevant for designing and modifying different biodegradable polymers for their use as scaffolds for different applications in the field of Tissue Engineering and Regenerative Medicine.


Sachot, N., Engel, E., Castaño, O., (2014). Hybrid organic-inorganic scaffolding biomaterials for regenerative therapies Current Organic Chemistry , 18, (18), 2299-2314

The introduction of hybrid materials in regenerative medicine has solved some problems related to the mechanical and bioactive properties of biomaterials. Calcium phosphates and their derivatives have provided the basis for inorganic components, thanks to their good bioactivity, especially in bone regeneration. When mixed with biodegradable polymers, the result is a synergic association that mimics the composition of many tissues of the human body and, additionally, exhibits suitable mechanical properties. Together with the development of nanotechnology and new synthesis methods, hybrids offer a promising option for the development of a third or fourth generation of smart biomaterials and scaffolds to guide the regeneration of natural tissues, with an optimum efficiency/cost ratio. Their potential bioactivity, as well as other valuable features of hybrids, open promising new pathways for their use in bone regeneration and other tissue repair therapies. This review provides a comprehensive overview of the different hybrid organic-inorganic scaffolding biomaterials developed so far for regenerative therapies, especially in bone. It also looks at the potential for research into hybrid materials for other, softer tissues, which is still at an initial stage, but with very promising results.

JTD Keywords: Biodegradable polymer, Hybrid materials, Nanoparticles, Ormoglass

Castaño, Oscar, Planell, Josep A., (2014). Cements Bio-Ceramics with Clinical Applications (ed. Vallet-Regí, M.), John Wiley & Sons, Ltd (Chichester, UK) , 193-247

Calcium phosphate cements (CPCs) were meant to produce hydroxyapatite (HA), which is the calcium phosphate that usually results when the cements are mixed with or immersed in aqueous media. The golden age of CPCs was in the late 1990s and the beginning of the 21st century, when they were presented as promising bone substitutes and drug delivery systems. The different reactions that take part in the cement self-setting process depend on many experimental factors – the composition of the cement, the stability of the different components, pH, liquid-to-powder ratio (LPR), and temperature, among others. CPCs have demonstrated fair efficiency for bone regeneration. Cements have gradually been embraced in the wider field of composites by hybridizing their compositions in order that they may adapt to the new trends.

JTD Keywords: Calcium phosphate cements (CPCs), Cements, Hydroxyapatite (HA), Liquid-to-powder ratio (LPR)

Álvarez, Zaida, Mateos-Timoneda, Miguel A., Hyrossová, Petra, Castaño, Oscar, Planell, Josep A., Perales, José C., Engel, Elisabeth, Alcántara, Soledad, (2013). The effect of the composition of PLA films and lactate release on glial and neuronal maturation and the maintenance of the neuronal progenitor niche Biomaterials 34, (9), 2221-2233

To develop tissue engineering strategies useful for repairing damage in the central nervous system (CNS) it is essential to design scaffolds that emulate the NSC niche and its tight control of neural cell genesis, growth, and differentiation. In this study we tested two types of poly l/dl lactic acid (PLA95/5 and PLA70/30), a biodegradable material permissive for neural cell adhesion and growth, as materials for nerve regeneration. Both PLA were slightly hydrophobic and negatively charged but differed in crystallinity, stiffness and degradation rate. PLA95/5 films were highly crystalline, stiff (GPa), and did not degrade significantly in the one-month period analyzed in culture. In contrast, PLA70/30 films were more amorphous, softer (MPa) and degraded faster, releasing significant amounts of lactate into the culture medium. PLA70/30 performs better than PLA95/5 for primary cortical neural cell adhesion, proliferation and differentiation, maintaining the pools of neuronal and glial progenitor cells in vitro. l-lactate in the medium recapitulated PLA70/30's maintenance of neuronal restricted progenitors but did not sustain bipotential or glial restricted progenitors in the cultures, as occurred when neural cells were grown on PLA70/30. Our results suggest that PLA70/30 may mimic some of the physical and biochemical characteristics of the NSC niche. Its mechanical and surface properties may act synergistically in the modulation of bipotential and glial restricted progenitor phenotypes, while it is l-lactate, either added to the medium or released by the film that drives the maintenance of neuronal restricted progenitor cell phenotypes.

JTD Keywords: Polylactic acid, Degradation, Neurons, Progenitors, Lactate, Glial cells, NSC niche

Sachot, N., Castaño, Oscar, Mateos-Timoneda, Miguel A., Engel, Elisabeth, Planell, Josep A., (2013). Hierarchically engineered fibrous scaffolds for bone regeneration Journal of the Royal Society Interface , 10, (88), 20130684

Surface properties of biomaterials play a major role in the governing of cell functionalities. It is well known that mechanical, chemical and nanotopographic cues, for example, influence cell proliferation and differentiation. Here, we present a novel coating protocol to produce hierarchically engineered fibrous scaffolds with tailorable surface characteristics, which mimic bone extracellular matrix. Based on the sol–gel method and a succession of surface treatments, hollow electrospun polylactic acid fibres were coated with a silicon–calcium–phosphate bioactive organic–inorganic glass. Compared with pure polymeric fibres that showed a completely smooth surface, the coated fibres exhibited a nanostructured topography and greater roughness. They also showed improved hydrophilic properties and a Young's modulus sixfold higher than non-coated ones, while remaining fully flexible and easy to handle. Rat mesenchymal stem cells cultured on these fibres showed great cellular spreading and interactions with the material. This protocol can be transferred to other structures and glasses, allowing the fabrication of various materials with well-defined features. This novel approach represents therefore a valuable improvement in the production of artificial matrices able to direct stem cell fate through physical and chemical interactions.


Shin, Song-Hee, Purevdorj, Odnoo, Castano, Oscar, Planell, Josep A., Kim, Hae-Won, (2012). A short review: Recent advances in electrospinning for bone tissue regeneration Journal of Tissue Engineering 3, (1), 2041731412443530

Nanofibrous structures developed by electrospinning technology provide attractive extracellular matrix conditions for the anchorage, migration, and differentiation of tissue cells, including those responsible for the regeneration of hard tissues. Together with the ease of set up and cost-effectiveness, the possibility to produce nanofibers with a wide range of compositions and morphologies is the merit of electrospinning. Significant efforts have exploited the development of bone regenerative nanofibers, which includes tailoring of composite/hybrid compositions that are bone mimicking and the surface functionalization such as mineralization. Moreover, by utilizing bioactive molecules such as adhesive proteins, growth factors, and chemical drugs, in concert with the nanofibrous matrices, it is possible to provide artificial materials with improved cellular responses and therapeutic efficacy. These studies have mainly focused on the regulation of stem cell behaviors for use in regenerative medicine and tissue engineering. While there are some challenges in achieving controllable delivery of bioactive molecules and complex-shaped three-dimensional scaffolds for tissue engineering, the electrospun nanofibrous matrices can still have a beneficial impact in the area of hard-tissue regeneration.


Aguirre, A., Gonzalez, A., Navarro, M., Castano, O., Planell, J. A., Engel, E., (2012). Control of microenvironmental cues with a smart biomaterial composite promotes endothelial progenitor cell angiogenesis European Cells & Materials , 24, 90-106

Smart biomaterials play a key role when aiming at successful tissue repair by means of regenerative medicine approaches, and are expected to contain chemical as well as mechanical cues that will guide the regenerative process. Recent advances in the understanding of stem cell biology and mechanosensing have shed new light onto the importance of the local microenvironment in determining cell fate. Herein we report the biological properties of a bioactive, biodegradable calcium phosphate glass/polylactic acid composite biomaterial that promotes bone marrow-derived endothelial progenitor cell (EPC) mobilisation, differentiation and angiogenesis through the creation of a controlled bone healing-like microenvironment. The angiogenic response is triggered by biochemical and mechanical cues provided by the composite, which activate two synergistic cell signalling pathways: a biochemical one mediated by the calcium-sensing receptor and a mechanosensitive one regulated by non-muscle myosin II contraction. Together, these signals promote a synergistic response by activating EPCs-mediated VEGF and VEGFR-2 synthesis, which in turn promote progenitor cell homing, differentiation and tubulogenesis. These findings highlight the importance of controlling microenvironmental cues for stem/progenitor cell tissue engineering and offer exciting new therapeutical opportunities for biomaterialbased vascularisation approaches and clinical applications.

JTD Keywords: Calcium phosphate glass composite, Smart biomaterial, Endothelial progenitor cell, Angiogenesis, Mechanosensing, Calcium-sensing receptor

Castaño, O., Eltohamy, M., Kim, H. W., (2012). Electrospinning technology in tissue regeneration Nanotechnology in Regenerative Medicine - Methods and Protocols (Methods in Molecular Biology) (ed. Navarro, M., Planell, J. A.), Springer (New York, USA) 811, 127-140

Electrospinning is one of the most versatile and effective tools to produce nanostructured fibers in the biomedical science fields. The nanofibrous structure with diameters from tens to hundreds of nanometers largely mimics the native extracellular matrix (ECM) of many tissues. Thus far, a range of compositions including polymers and ceramics and their composites/hybrids have been successfully applied for generating electrospun nanofibers. Different processing tools in electrospinning set-ups and assemblies are currently developed to tune the morphology and properties of nanofibers. Herein, we demonstrate the electrospinning process and the electrospun biomaterials for specific use in tissue regeneration with some examples, involving different material combinations and fiber morphologies.

JTD Keywords: Ceramic, Composites, Electrospinning, Nanofi bers, Nanostructured fi bers, Polymer, Tissue regeneration

Rajzer, I., Castano, O., Engel, E., Planell, J. A., (2010). Injectable and fast resorbable calcium phosphate cement for body-setting bone grafts Journal of Materials Science-Materials in Medicine , 21, (7), 2049-2056

In this work a calcium phosphate (CPC)/polymer blend was developed with the advantage of being moldable and capable of in situ setting to form calcium deficient hydroxyapatite under physiological conditions in an aqueous environment at body temperature. The CPC paste consists in a mix of R cement, glycerol as a liquid phase carrier and a biodegradable hydrogel such as Polyvinyl alcohol, which acts as a binder. Microstructure and mechanical analysis shows that the CPC blend can be used as an injectable implant for low loaded applications and fast adsorption requirements. The storage for commercial distribution was also evaluated and the properties of the materials obtained do not significantly change during storage at -18A degrees C.

JTD Keywords: Clinical-applications, Composites, Regeneration, Behavior, Scaffold, Repair

Frontera, C., García-Muñoz, J. L., Castaño, O., Ritter, C., Brunelli, M., (2010). Structural properties, magnetic and oxygen-vacancies order in Y(Ba 1-xSrx)Co2O5.5 layered cobaltites Journal of Physics: Conference Series International Conference on Magnetism (ICM 2009) , IOP Publishing (Karlsruhe, Germany) 200, (Section 1), 012039 (4)

We present a study of the family Y(Ba1-xSrx)Co 2O5.5 (x = 0, 1/8, 1/4, 1/3, 3/8, 1/2). The complex magnetic behavior characterizing the parent (x = 0) compound and other RBaCo2O5.5 compounds can still be guessed in M(T) curves of x = 1/8 compound, but it disappears under substitution of Ba by Sr for all the studies cases (x ≥ 1/8). This is linked to the fact that the order of oxygen vacancies is lost, as found by neutron and synchrotron X-ray powder diffraction.


Jang, J. H., Castano, O., Kim, H. W., (2009). Electrospun materials as potential platforms for bone tissue engineering Advanced Drug Delivery Reviews 61, (12), 1065-1083

Nanofibrous materials produced by electrospinning processes have attracted considerable interest in tissue regeneration, including bone reconstruction. A range of novel materials and processing tools have been developed to mimic the native bone extracellular matrix for potential applications as tissue engineering scaffolds and ultimately to restore degenerated functions of the bone. Degradable polymers, bioactive inorganics and their nanocomposites/hybrids nanofibers with suitable mechanical properties and bone bioactivity for osteoblasts and progenitor/stem cells have been produced. The surface functionalization with apatite minerals and proteins/peptides as well as drug encapsulation within the nanofibers is a promising strategy for achieving therapeutic functions with nanofibrous materials. Recent attempts to endow a 3D scaffolding technique to the electrospinning regime have shown some promise for engineering 3D tissue constructs. With the improvement in knowledge and techniques of bone-targeted nanofibrous matrices, bone tissue engineering is expected to be realized in the near future.

JTD Keywords: Electrospun nanofiber, Bone tissue engineering, Biomimetic matrix, Bone bioactivity, 3D scaffolding

Navarro, M., Michiardi, A., Castano, O., Planell, J. A., (2008). Biomaterials in orthopaedics Journal of the Royal Society Interface , 5, (27), 1137-1158

At present, strong requirements in orthopaedics are still to be met, both in bone and joint substitution and in the repair and regeneration of bone defects. In this framework, tremendous advances in the biomaterials field have been made in the last 50 years where materials intended for biomedical purposes have evolved through three different generations, namely first generation (bioinert materials), second generation (bioactive and biodegradable materials) and third generation (materials designed to stimulate specific responses at the molecular level). In this review, the evolution of different metals, ceramics and polymers most commonly used in orthopaedic applications is discussed, as well as the different approaches used to fulfil the challenges faced by this medical field.

JTD Keywords: Biomaterials, Orthopaedics, Tissue engineering, Bioactive materials, Biodegradable materials, Bioinert materials