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Berthod, François

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Berthod

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François

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Université Laval. Département de chirurgie

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  • PublicationRestreint
    Tissue-engineered human skin substitutes developed from collagen-populated hydrated gels : clinical and fundamental applications
    (Springer, 1998-11-01) Germain, Lucie; Auger, François A.; Rouabhia, Mahmoud; Berthod, François; Goulet, Francine; Moulin, Véronique
    The field of tissue engineering has opened several avenues in biomedical sciences, through ongoing progress. Skin substitutes are currently optimised for clinical as well as fundamental applications. The paper reviews the development of collagen-populated hydrated gels for their eventual use as a therapeutic option for the treatment of burn patients or chronic wounds: tools for pharmacological and toxicological studies, and cutaneous models for in vitro studies. These skin substitutes are produced by culturing keratinocytes on a matured dermal equivalent composed of fibroblasts included in a collagen gel. New biotechnological approaches have been developed to prevent contraction (anchoring devices) and promote epithelial cell differentiation. The impact of dermo-epidermal interactions on the differentiation and organisation of bio-engineered skin tissues has been demonstrated with human skin cells. Human skin substitutes have been adapted for percutaneous absorption studies and toxicity assessment. The evolution of these human skin substitutes has been monitored in vivo in preclinical studies showing promising results. These substitutes could also serve as in vitro models for better understanding of the immunological response and healing mechanism in human skin. Thus, such human skin substitutes present various advantages and are leading to the development of other bio-engineered tissues, such as blood vessels, ligaments and bronchi.
  • PublicationAccès libre
    What is new in mechanical properties of tissue-engineered organs
    (Springer, 1999-01-01) Germain, Lucie; Auger, François A.; Berthod, François; Goulet, Francine
    Tissue engineering is a promising new field based on expertise in cell biology, medicine and mechanical engineering. It raises exciting hopes of producing autologous tissue substitutes to replace altered organs. This challenge involves highly specialized technology in order to provide the proper shape to the tissue and promote the maintenance of its native physiological properties. Primary cell populations may lose some of their functional and morphological properties in vitro in the absence of a proper environment. In order to maintain cell integrity, a three-dimensional matrix that mimics the in vivo environment as closely as possible was developed, according to the type of tissue produced [1, 5, 18, 26, 27, 29, 34, 35].
  • PublicationRestreint
    Engineering human tissues for in vivo applications
    (New York Academy of Sciences, 2002-06-01) Germain, Lucie; Auger, François A.; Berthod, François; Goulet, Francine; Moulin, Véronique
    Tissue engineering is a rapidly developing field. This technology could offer a new alternative for wound repair and organ replacement. It is based on the ability of living cells, with or without biomaterials, to be assembled as three-dimensional tissues. The in vivo applications extend from specialized dressings that improve host tissue repair (e.g., ulcer) to permanent grafts that restore the function of the tissue (e.g., skin grafting for burn patients).
  • PublicationRestreint
    Principles of living organ reconstruction by tissue engineering
    (Marcel Dekker, 2004-01-01) Germain, Lucie; Auger, François A.; Berthod, François; Goulet, Francine; Moulin, Véronique
    Tissue engineering is a novel sector arising from the biomaterial field, which is developing rapidly as a result of the dramatic cIinicalneed for organ replacement,since there is unfortunately an ever-growing lack of organs for transplantation. Various approaches are presently being developed in different laboratories and companies based on the utilization of biomaterials, extracellular matrix components, and cellsto produce substitutesto aJlowthe replacement of wounded or diseased tissues. Theorgan reconstructionby tissue engineering presented in this chapter are of living tissues. This concept entails that the various cells incorporated in our constructs or tissues are not only readily dividing, but also metabolically active. Thus, mesenchymal cells (fibroblasts, smooth muscle cells) incorporated into the stromal component of these substitutes are also significantly involved in the reorganization of the extracellular matrix. Furthermore, the interactions between the mesenchymal cells and the epithelial cells improve the very nature, structure, and function of the resulting organ. Lastly, the presence of living cells, within the in vitro engineered tissues, adds the benefit of tissue remodeling and healing after transplantation in vivo. The source of cells that can be used for tissue reconstruction is dictated by the foreseen application. Autologous cells will be necessary for the production of living tissue substitutes when striving for permanent replacement of organs in order to prevent any histocompatibility mismatch and the ensuing predictable rejection (e.g., skin grafting for full-thickness burns). However, the rejection process has been shown to vary with the type of cells involved, and it may be possible to graft allogeneic engineered tissue under some appropriate conditions. But in such cases as keratinocytes, dentritic cells and endothelial cells that are privileged targets for rejection, autologous ceIls are necessary to permanently replace tissues encompassing these cells. ln sharp contrast, when the living tissue substitute is destined to improve wound healing, such as in the case of uIcers,allogeneic cells are sufficientsince they act as a temporary coverage, enhancing the natural healing process, and will be replaced over time by cells from the receiver. The firststep in reconstructing a living organ by tissue engineering in vitro is the isolation and culture of each cell type. The most stringent conditions must be met during this step since it has a direct impact on the quality of the desired tissue engineered product. The ideal cellsource for tissue reconstructionshouldprovide celIswith extensive proliferation potential (self-renewal capacity) and appropriate differentiation abilities (able to give rise to a differentiated progeny). Each cell culture method must be characterized in such a manner to ensure that the isolation method and culture conditions (e.g., culturé medium and growth factors) during the growth as weil as during the maturation period are the most appropriate to conserve cell purity and phenotype. This chapter wilI focus on the various approachesdevelopedover the years by the Laboratoire d'Organogénèse Expérimental (LOEX) (Hôpital du Saint-Sacrement, Chauq, Quebec) to obtain three-dimensional tissues such as reconstructed epidermis, skin, blood vessel, comea, bronchi, and ligament.
  • PublicationRestreint
    Comparative study of bovine, porcine and avian collagens for the production of a tissue engineered dermis
    (Elsevier, 2011-06-17) Germain, Lucie; Parenteau-Bareil, Rémi; Gauvin, Robert; Cliche, Simon.; Gariépy, Claude; Berthod, François
    Combining bovine collagen with chitosan followed by freeze-drying has been shown to produce porous scaffolds suitable for skin and connective tissue engineering applications. In this study collagen extracted from porcine and avian skin was compared with bovine collagen for the production of tissue engineered scaffolds. A similar purity of the collagen extracts was shown by electrophoresis, confirming the reliability of the extraction process. Collagen was solubilized, cross-linked by adding chitosan to the solution and freeze-dried to generate a porous structure suitable for tissue engineering applications. Scaffold porosity and pore morphology were shown to be source dependant, with bovine collagen and avian collagen resulting into the smallest and largest pores, respectively. Scaffolds were seeded with dermal fibroblasts and cultured for 35 days to evaluate the suitability of the different collagen–chitosan scaffolds for long-term tissue engineered dermal substitute maturation in vitro. Cell proliferation and scaffold biocompatibility were found to be similar for all the collagen–chitosan scaffolds, demonstrating their capability to support long-term cell adhesion and growth. The scaffolds contents was assessed by immunohistochemistry and showed increased deposition of extracellular matrix by the cells as a function of time. These results correlate with measurements of the mechanical properties of the scaffolds, since both the ultimate tensile strength and tensile modulus of the cell seeded scaffolds had increased by the end of the culture period. This experiment demonstrates that porcine and avian collagen could be used as an alternative to bovine collagen in the production of collagen–chitosan scaffolding materials.
  • PublicationRestreint
    Multiple applications of tissue-engineered human skin
    (Thieme, 2001-01-01) Carlos, A.; Germain, Lucie; Auger, François A.; López Valle, Carlos Antonio; Berthod, François; Goulet, Francine; Moulin, Véronique
    The progress in tissue engineering has lead to the development of tri-dimensional tissues that can be used in vitro for various applications. Different methods have been designed to produce reconstructed dermis or skin in vitro. This chapter describes the human skin models and substitutes with respect to the evolution of their complexity as well as some of their potential applications. Dermal fibroblasts or myofibroblasts included in floating collagen gels produce useful wound healing models. Bi-layered human skin constructs comprising both the dermis and the epidermis could serve. for fundamental (eg. cell-matrix interactions) or applied (e.g. dermatoabsorption) studies. Another skin substitute is produced by seeding keratinocytes on fibroblasts. cultured in a collagen-chondroitin 4-6 sulfates and. chitosan sponge. The addition of endothelial cells to this model lead to the formation of capillary-like structure in the dermis. Finally, a method of human reconstructed skin production by the "auto-assembly" approach is presented. This model is developped from cells that produce their own extracellular matrix. No synthetic material or exogenous matrix is added. Thus, it could be completely autologous. Tissue engineered skin is an attractive tissue for gene therapy. Cells could be transplanted safely in vitro, evaluated for gene expression before their incorporation in reconstructed tissue and grafting in vivo. Of particular importance will be skin stem cells that have a long term regeneration potential and that can he cultured in vitro. The progress accomplished in tissue. engineering of skin is now applied to the reconstruction of other tissues and more complex organs such as ligaments, bronchi, bladder, cornea and blood vessels. These tissues could provide therapeutic alternatives in organ transplantation as well as models for varions in vitro applications.
  • PublicationRestreint
    Tissue-engineered skin substitutes: from in vitro constructs to in vivo applications
    (Wiley, 2004-06-01) Germain, Lucie; Auger, François A.; Berthod, François; Moulin, Véronique; Pouliot, Roxane
    The field of skin tissue engineering is a paradigm for the various efforts towards the reconstruction of other tissues and organ substitutes. As skin replacement, this biotechnological approach has evolved from simple cultured autologous epidermal sheets to more complex bilayered cutaneous substitutes. The various types of such substitutes are herein presented with their intended use. However, two integrative characteristics are analysed more specifically because of their critical role: neovascularization and re-innervation. Furthermore, the in vitro use of these various skin substitutes has shed light on various physiological and pathological phenomena. Thus, not only the in vivo application of these skin substitutes as grafts, but also their in vitro value as skin models, are presented.
  • PublicationRestreint
    A tissue-engineered endothelialized dermis to study the modulation of angiogenic and angiostatic molecules on capillary-like tube formation in vitro
    (Blackwell Scientific, 2003-06-27) Hudon, Valérie.; Germain, Lucie; Black, Annie.; Damour, Odile; Auger, François A.; Berthod, François
    Background: Because angiogenesis is a major feature of different physiological and pathological situations, the identification of factors that stimulate or inhibit this process and the elucidation of their mechanisms of action are most certainly of clinical relevance. We have produced a new model of endothelialized reconstructed dermis that promotes the spontaneous formation of a human capillary-like network and its stabilization in vitro for a period longer than 1 month. Objectives: The aim of this work was to describe the three-dimensional structure of the capillary-like network. Thereafter we strove to study, quantitatively and qualitatively, the influence of angiogenic and angiostatic drugs on capillary-like tube (CLT) formation in vitro in the model. Methods: The endothelialized dermis was prepared by coculturing two human cell types, dermal fibroblasts and umbilical vein endothelial cells, in a collagen sponge biomaterial. Results: The visualization by confocal microscopy of the tubes present in the model showed that the endothelial structures were not cord-like but rather CLTs with well-defined lumina. Moreover, these tubes were organized in a complex network of branching structures. When angiogenic factors (vascular endothelial growth factor 10 ng mL-1 or basic fibroblast growth factor 10 ng mL-1) were added to the model, 1.8 and 1.4 times more capillaries, respectively, were observed, whereas the addition of progesterone (10 microg x mL(-1)) reduced by 2.4 times the number of tubes compared with the control. Conclusions: These results suggest that this model is a highly efficient assay for the screening of potentially angiogenic and angiostatic compounds.
  • PublicationAccès libre
    In vitro evaluation of the angiostatic potential of drugs using an endothelialized tissue-engineered connective tissue
    (Williams & Wilkins, 2005-11-01) Germain, Lucie; Tremblay, Pierre-Luc; Auger, François A.; Berthod, François
    The development of a new pharmacological strategy, the angiostatic therapy, to inhibit solid tumor progression has increased the need of powerful in vitro models to screen the angiostatic potential of new drug candidates. We produced an endothelialized reconstructed connective tissue (ERCT) that promotes the spontaneous formation of a human capillary-like network by coculture of human endothelial cells isolated from umbilical cord or from newborn foreskin, with dermal fibroblasts in a collagen sponge. Three inhibitors of angiogenesis, tamoxifen, ilomastat, and echistatin, were used to assess the efficiency of our ERCT to discriminate, in vitro, an angiostatic potential. The capillary-like structures were characterized by their immunoreactivity to human platelet-endothelial cellular adhesion molecule-1 antibodies and were quantified on histological cross-sections of biopsies taken after 10, 17, 24, and 31 days of culture. A dose-response significant inhibition of the capillary-like formation was detected when increasing concentrations of tamoxifen, ilomastat, or echistatin were added for 1 week to the culture medium of the ERCT. Tamoxifen was found to be angiogenic at 10 μM and to have a cytotoxic effect at 40 μM 1 week after drug removal. Echistatin induced a rapid, slight, and reversible inhibition of capillary-like formation, whereas ilomastat caused a very precocious, strong, and reversible inhibition of angiogenesis. In addition, a 16-h hypoxia promoted the formation of 10 times larger vessels (>300 μm2), compared with normoxic condition. These results suggest that our model could be efficiently used to study the long-term angiostatic potential of drugs in vitro in a very physiological environment.
  • PublicationRestreint
    Inosculation of tissue-engineered capillaries with the host's vasculature in a reconstructed skin transplanted on mice.
    (Blackwell, 2005-02-17) Hudon, Valérie.; Germain, Lucie; Tremblay, Pierre-Luc; Auger, François A.; Berthod, François
    The major limitation for the application of an autologous in vitro tissue-engineered reconstructed skin (RS) for the treatment of burnt patients is the delayed vascularization of its relatively thick dermal avascular component, which may lead to graft necrosis. We have developed a human endothelialized reconstructed skin (ERS), combining keratinocytes, fibroblasts and endothelial cells (EC) in a collagen sponge. This skin substitute then spontaneously forms a network of capillary-like structures (CLS) in vitro. After transplantation to nude mice, we demonstrated that CLS containing mouse blood were observed underneath the epidermis in the ERS in less than 4 days, a delay comparable to our human skin control. In comparison, a 14-day period was necessary to achieve a similar result with the non-endothelialized RS. Furthermore, no mouse blood vessels were ever observed close to the epidermis before 14 days in the ERS and the RS. We thus concluded that the early vascularization observed in the ERS was most probably the result of inosculation of the CLS network with the host's capillaries, rather than neovascularization, which is a slower process. These results open exciting possibilities for the clinical application of many other tissue-engineered organs requiring a rapid vascularization.