by Keyword: Regenerative medicine

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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

Planell, J. A., Navarro, M., Engel, E., (2017). Developing targeted biocomposites in tissue engineering and regenerative medicine Biomedical Composites (ed. Ambrosio, L.), Woodhead Publishing (Duxfor, UK) Biomaterials, 569-587

Regenerative medicine is a relatively new field with new requirements for smart materials, where composites will have a strong role to play. The new paradigm of regenerative medicine and tissue engineering requires biomaterials with high specificity, where physical and chemical properties are duly tailored and combined with appropriate mechanical and degradation features in order to trigger specific cell events and functions involved in the regenerative process. In this chapter, the chemical, physical, and biological elements that have to be targeted by biocomposites in regenerative medicine are described.

Keywords: Biocomposite, Regenerative medicine, Tissue engineering, Scaffolds, Cell/material interactions

González-Vázquez, A., Planell, J. A., Engel, E., (2014). Extracellular calcium and CaSR drive osteoinduction in mesenchymal stromal cells Acta Biomaterialia 10, (6), 2824–2833

Bone is the main store of calcium and progenitor cells in the body. During the resorption process, the local calcium concentration reaches 8-40 mM, and the surrounding cells are exposed to these fluctuations in calcium. This stimulus is a signal that is detected through the calcium sensing receptor (CaSR), which modulates chemotactic and proliferative G protein-dependent signaling pathways. The objective of the present work is to evaluate the roles of extracellular calcium ([Ca2+]o) and the CaSR in osteoinduction. Rat bone marrow mesenchymal stromal cells (rBMSCs) were stimulated with 10 mM of Ca2+. Several experiments were conducted to demonstrate the effect of [Ca2+]o on chemotaxis, proliferation and differentiation on the osteoblastic lineage. It was found that [Ca2+]o induces rBMSCs to migrate and proliferate in a concentration-dependent manner. Real-time polymerase chain reaction and immunofluorescence also revealed that 10 mM Ca2+ stimulates overexpression of osteogenic markers in rBMSCs, including alkaline phosphatase (ALP), bone sialoprotein, collagen Ia1 and osteocalcin. Functional assays determining ALP activity and mineralization tests both corroborate the increased expression of these markers in rBMSCs stimulated with Ca2+. Moreover, CaSR blockage inhibited the cellular response to stimulation with high concentrations of [Ca2+]o, revealing that the CaSR is a key modulator of these cellular responses.

Keywords: Calcium sensing receptor (CaSR), Extracellular calcium, Mesenchymal stromal cells (MSCs), Osteoinduction, Regenerative medicine

Navarro, M., Planell, J. A., (2012). Is nanotechnology the key to unravel and engineer biological processes? Nanotechnology in Regenerative Medicine - Methods and Protocols (Methods in Molecular Biology) (ed. Navarro, M., Planell, J. A.), Springer (New York, USA) 811, 1-16

Regenerative medicine is an emerging field aiming to the development of new reparative strategies to treat degenerative diseases, injury, and trauma through developmental pathways in order to rebuild the architecture of the original injured organ and take over its functionality. Most of the processes and interactions involved in the regenerative process take place at subcellular scale. Nanotechnology provides the tools and technology not only to detect, to measure, or to image the interactions between the different biomolecules and biological entities, but also to control and guide the regenerative process. The relevance of nanotechnology for the development of regenerative medicine as well as an overview of the different tools that contribute to unravel and engineer biological systems are presented in this chapter. In addition, general data about the social impact and global investment in nanotechnology are provided.

Keywords: Nanotechnology, Regenerative medicine, Tissue engineering

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

Engel, E., Michiardi, A., Navarro, M., Lacroix, D., Planell, J. A., (2008). Nanotechnology in regenerative medicine: the materials side Trends in Biotechnology , 26, (1), 39-47

Regenerative medicine is an emerging multidisciplinary field that aims to restore, maintain or enhance tissues and hence organ functions. Regeneration of tissues can be achieved by the combination of living cells, which will provide biological functionality, and materials, which act as scaffolds to support cell proliferation. Mammalian cells behave in vivo in response to the biological signals they receive from the surrounding environment, which is structured by nanometre-scaled components. Therefore, materials used in repairing the human body have to reproduce the correct signals that guide the cells towards a desirable behaviour. Nanotechnology is not only an excellent tool to produce material structures that mimic the biological ones but also holds the promise of providing efficient delivery systems. The application of nanotechnology to regenerative medicine is a wide issue and this short review will only focus on aspects of nanotechnology relevant to biomaterials science. Specifically, the fabrication of materials, such as nanoparticles and scaffolds for tissue engineering, and the nanopatterning of surfaces aimed at eliciting specific biological responses from the host tissue will be addressed.

Keywords: Animals, Biocompatible Materials/ metabolism, Humans, Nanoparticles, Nanotechnology/ methods, Regenerative Medicine/ methods, Tissue Scaffolds