Publications

by Keyword: Repair


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Farré, Ramon, Otero, Jordi, Almendros, Isaac, Navajas, Daniel, (2018). Bioengineered lungs: A challenge and an opportunity Archivos de Bronconeumología 54, (1), 31-38

Lung biofabrication is a new tissue engineering and regenerative development aimed at providing organs for potential use in transplantation. Lung biofabrication is based on seeding cells into an acellular organ scaffold and on culturing them in an especial purpose bioreactor. The acellular lung scaffold is obtained by decellularizing a non-transplantable donor lung by means of conventional procedures based on application of physical, enzymatic and detergent agents. To avoid immune recipient's rejection of the transplanted bioengineered lung, autologous bone marrow/adipose tissue-derived mesenchymal stem cells, lung progenitor cells or induced pluripotent stem cells are used for biofabricating the bioengineered lung. The bioreactor applies circulatory perfusion and mechanical ventilation with physiological parameters to the lung during biofabrication. These physical stimuli to the organ are translated into the stem cell local microenvironment - e.g. shear stress and cyclic stretch - so that cells sense the physiological conditions in normally functioning mature lungs. After seminal proof of concept in a rodent model was published in 2010, the hypothesis that lungs can be biofabricated is accepted and intense research efforts are being devoted to the topic. The current experimental evidence obtained so far in animal tests and in ex vivo human bioengineered lungs suggests that the date of first clinical tests, although not immediate, is coming. Lung bioengineering is a disrupting concept that poses a challenge for improving our basic science knowledge and is also an opportunity for facilitating lung transplantation in future clinical translation.

Keywords: Tissue engineering, Regenerative medicine, Lung transplantation, Lung repair, Lung regeneration


Campillo, N., Falcones, B., Montserrat, J. M., Gozal, D., Obeso, A., Gallego-Martin, T., Navajas, D., Almendros, I., Farré, R., (2017). Frequency and magnitude of intermittent hypoxia modulate endothelial wound healing in a cell culture model of sleep apnea Journal of Applied Physiology , 123, (5), 1047-1054

Intermittent hypoxia (IH) has been implicated in the cardiovascular consequences of obstructive sleep apnea (OSA). However, the lack of suitable experimental systems has precluded assessment as to whether IH is detrimental, protective, or both for the endothelium. The aim of the work was to determine the effects of frequency and amplitude of IH oxygenation swings on aortic endothelial wound healing. Monolayers of human primary endothelial cells were wounded and subjected to constant oxygenation (1%, 4%, 13%, or 20% O2) or IH at different frequencies (0.6, 6, or 60 cycles/h) and magnitude ranges (13–4% O2 or 20–1% O2), using a novel well-controlled system, with wound healing being measured after 24 h. Cell monolayer repair was similar at 20% O2 and 13% O2, but was considerably increased (approximately twofold) in constant hypoxia at 4% O2. The magnitude and frequency of IH considerably modulated wound healing. Cycles ranging 13–4% O2 at the lowest frequency (0.6 cycles/h) accelerated endothelial wound healing by 102%. However, for IH exposures consisting of 20% to 1% O2 oscillations, wound closure was reduced compared with oscillation in the 13–4% range (by 74% and 44% at 6 cycles/h and 0.6 cycles/h, respectively). High-frequency IH patterns simulating severe OSA (60 cycles/h) did not significantly modify endothelial wound closure, regardless of the oxygenation cycle amplitude. In conclusion, the frequency and magnitude of hypoxia cycling in IH markedly alter wound healing responses and emerge as key factors determining how cells will respond in OSA. NEW & NOTEWORTHY Intermittent hypoxia (IH) induces cardiovascular consequences in obstructive sleep apnea (OSA) patients. However, the vast array of frequencies and severities of IH previously employed in OSA-related experimental studies has led to controversial results on the effects of IH. By employing an optimized IH experimental system here, we provide evidence that the frequency and magnitude of IH markedly alter human aortic endothelial wound healing, emerging as key factors determining how cells respond in OSA.

Keywords: Sleep apnea, Repair, Endothelium, Hypoxia, Reoxygenation


Vila, M., García, A., Girotti, A., Alonso, M., Rodríguez-Cabello, J. C., González-Vázquez, A., Planell, J. A., Engel, E., Buján, J., Garcíaa-Honduvilla, N., Vallet-Regí, M., (2016). 3D silicon doped hydroxyapatite scaffolds decorated with Elastin-like Recombinamers for bone regenerative medicine Acta Biomaterialia 45, 349-356

The current study reports on the manufacturing by rapid prototyping technique of three-dimensional (3D) scaffolds based on silicon substituted hydroxyapatite with Elastin-like Recombinamers (ELRs) functionalized surfaces. Silicon doped hydroxyapatite (Si-HA), with Ca10(PO4)5.7(SiO4)0.3(OH)1.7h0.3 nominal formula, was surface functionalized with two different types of polymers designed by genetic engineering: ELR-RGD that contain cell attachment specific sequences and ELR-SNA15/RGD with both hydroxyapatite and cells domains that interact with the inorganic phase and with the cells, respectively. These hybrid materials were subjected to in vitro assays in order to clarify if the ELRs coating improved the well-known biocompatible and bone regeneration properties of calcium phosphates materials. The in vitro tests showed that there was a total and homogeneous colonization of the 3D scaffolds by Bone marrow Mesenchymal Stromal Cells (BMSCs). In addition, the BMSCs were viable and able to proliferate and differentiate into osteoblasts. Statement of Significance Bone tissue engineering is an area of increasing interest because its main applications are directly related to the rising life expectancy of the population, which promotes higher rates of several bone pathologies, so innovative strategies are needed for bone tissue regeneration therapies. Here we use the rapid prototyping technology to allow moulding ceramic 3D scaffolds and we use different bio-polymers for the functionalization of their surfaces in order to enhance the biological response. Combining the ceramic material (silicon doped hydroxyapatite, Si-HA) and the Elastin like Recombinamers (ELRs) polymers with the presence of the integrin-mediate adhesion domain alone or in combination with SNA15 peptide that possess high affinity for hydroxyapatite, provided an improved Bone marrow Mesenchymal Stromal Cells (BMSCs) differentiation into osteoblastic linkage.

Keywords: Bone marrow Mesenchymal Stromal Cells (BMSCs), Bone repair, Elastin-like Recombinamers (ELRs), Rapid prototyped 3D scaffolds, Silicon doped hydroxyapatite (Si-HA), Tissue engineering


Mateos-Timoneda, M. A., Planell, J. A., Engel, E., (2011). Modifying biomaterial surfaces for the repair and regeneration of nerve cells Surface Modification of Biomaterials: Methods Analysis and Applications (ed. Williams, R.), Woodhead Publishing (Cambridge, UK) , 325-343

This chapter discusses the use of chemical and topographical modification of biomaterials in the field of repair and regeneration of nerve tissue. The chapter first reviews briefly the methods developed to chemically and topographically modify the surface of biomaterials. The chapter then discusses how these modified surfaces interact with nerve cells and guide cellular activities.

Keywords: Chemical modification, Nerve repair, Topographical modification


Santoro, R., Olivares, A. L., Brans, G., Wirz, D., Longinotti, C., Lacroix, D., Martin, I., Wendt, D., (2010). Bioreactor based engineering of large-scale human cartilage grafts for joint resurfacing Biomaterials 31, (34), 8946-8952

Apart from partial or total joint replacement, no surgical procedure is currently available to treat large and deep cartilage defects associated with advanced diseases such as osteoarthritis. In this work, we developed a perfusion bioreactor system to engineer human cartilage grafts in a size with clinical relevance for unicompartmental resurfacing of human knee joints (50 mm diameter x 3 mm thick). Computational fluid dynamics models were developed to optimize the flow profile when designing the perfusion chamber. Using the developed system, human chondrocytes could be seeded throughout large 50 mm diameter scaffolds with a uniform distribution. Following two weeks culture, tissues grown in the bioreactor were viable and homogeneously cartilaginous, with biomechanical properties approaching those of native cartilage. In contrast, tissues generated by conventional manual production procedures were highly inhomogeneous and contained large necrotic regions. The unprecedented engineering of human cartilage tissues in this large-scale opens the practical perspective of grafting functional biological substitutes for the clinical treatment for extensive cartilage defects, possibly in combination with surgical or pharmacological therapies to support durability of the implant. Ongoing efforts are aimed at integrating the up-scaled bioreactor based processes within a fully automated and closed manufacturing system for safe, standardized, and GMP compliant production of large-scale cartilage grafts.

Keywords: Bioreactor, Cartilage repair, Computational fluid dynamics, Scale-up, Regenerative medicine, Tissue engineering


Carreras, A., Rojas, M., Tsapikouni, T., Montserrat, J. M., Navajas, D., Farre, R., (2010). Obstructive apneas induce early activation of mesenchymal stem cells and enhancement of endothelial wound healing Respiratory Research , 11, (91), 1-7

Background: The aim was to test the hypothesis that the blood serum of rats subjected to recurrent airway obstructions mimicking obstructive sleep apnea (OSA) induces early activation of bone marrow-derived mesenchymal stem cells (MSC) and enhancement of endothelial wound healing. Methods: We studied 30 control rats and 30 rats subjected to recurrent obstructive apneas (60 per hour, lasting 15 s each, for 5 h). The migration induced in MSC by apneic serum was measured by transwell assays. MSC-endothelial adhesion induced by apneic serum was assessed by incubating fluorescent-labelled MSC on monolayers of cultured endothelial cells from rat aorta. A wound healing assay was used to investigate the effect of apneic serum on endothelial repair. Results: Apneic serum showed significant increase in chemotaxis in MSC when compared with control serum: the normalized chemotaxis indices were 2.20 +/- 0.58 (m +/- SE) and 1.00 +/- 0.26, respectively (p < 0.05). MSC adhesion to endothelial cells was greater (1.75 +/- 0.14 -fold; p < 0.01) in apneic serum than in control serum. When compared with control serum, apneic serum significantly increased endothelial wound healing (2.01 +/- 0.24 -fold; p < 0.05). Conclusions: The early increases induced by recurrent obstructive apneas in MSC migration, adhesion and endothelial repair suggest that these mechanisms play a role in the physiological response to the challenges associated to OSA.

Keywords: Induced acute lung, Sleep-apnea, Intermitent hypoxia, Cardiovascular-disease, Progenito Cells, Rat model, Inflammation, Mechanisms, Repair, Blood


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.

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


Merolli, A., Rocchi, L., Catalano, F., Planell, J., Engel, E., Martinez, E., Sbernardori, M. C., Marceddu, S., Leali, P. T., (2009). In vivo regeneration of rat sciatic nerve in a double-halved stitch-less guide: a pilot-study Microsurgery , 29, (4), 310-318

It is about 20 years that tubular nerve guides have been introduced into clinical practice as a reliable alternative to autograft, in gaps not-longer-than 20 mm, bringing the advantage of avoiding donor site sacrifice and morbidity. There are limitations in the application of tubular guides. First, tubular structure in itself makes surgical implantation difficult; second, stitch sutures required to secure the guide may represent a site of unfavorable fibroblastic reaction; third, maximum length and diameter of the guide correlate with the occurrence of a poorer central vascularization of regenerated nerve. We report on the in vivo testing of a new concept of nerve-guide (named NeuroBox) which is double-halved, not-degradable, rigid, and does not require any stitch to be held in place, employing acrylate glue instead. Five male Wistar rats had the new guide implanted in a 4-mm sciatic nerve defect; two guides incorporated a surface constituted of microtrenches aligned longitudinally. Further five rats had the 4-mm gap left without repair. Contralateral intact nerves were used as controls. After 2 months, nerve regeneration occurred in all animals treated by the NeuroBox; fine blood vessels were well represented. There was no regeneration in the un-treated animals. Even if the limited number of animals does not allow to draw definitive conclusions, some result can be highlighted: an easy surgical technique was associated with the box-shaped guide and acrylate glue was easily applied; an adequate intraneural vascularization was found concurrently with the regeneration of the nerve and no adverse fibroblastic proliferation was present.

Keywords: Peripheral-nerve, Polyglycolic acid, Guidance cues, Collagen tube, Median nerve, Repair, Growth, Cyanoacrylate, Complications, Anastomosis


Lacroix, D., (2009). Biomechanical aspects of bone repair Bone repair biomaterials (ed. Planell, J. A., Lacroix, D., Best, S., Merolli, A.), Woodhead (Cambridge, UK)

A fundamental aspect of the rapidly expanding medical care sector, bone repair continues to benefit from emerging technological developments. This text provides researchers and students with a comprehensive review of the materials science and engineering principles behind these developments. The first part reviews the fundamentals of bone repair and regeneration. Further chapters discuss the science and properties of biomaterials used in bone repair, including both metals and biocomposites. Final chapters analyze device considerations such as implant lifetime and failure, and discuss potential applications, as well as the ethical issues that continually confront researchers and clinicians.

Keywords: Bone composition and structure, Biomechanical properties of bone, Bone damage and repair


Planell, J. A., Navarro, M., (2009). Challenges in bone repair Bone repair biomaterials (ed. Planell, J. A., Lacroix, D., Best, S., Merolli, A.), Woodhead (Cambridge, UK) , 3-24

A fundamental aspect of the rapidly expanding medical care sector, bone repair continues to benefit from emerging technological developments. This text provides researchers and students with a comprehensive review of the materials science and engineering principles behind these developments. The first part reviews the fundamentals of bone repair and regeneration. Further chapters discuss the science and properties of biomaterials used in bone repair, including both metals and biocomposites. Final chapters analyze device considerations such as implant lifetime and failure, and discuss potential applications, as well as the ethical issues that continually confront researchers and clinicians.

Keywords: Social impact of musculoskeletal disease, Economic burden of musculoskeletal disease, Social aspects of dental and maxillofacial conditions, Some clinical challenges of bone repair, Conclusions and future trends, Sources of further information and advice