From developmental biology to tissue-engineering: printing blood vessels

Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 15, 2010).The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file.Dissertation advisor: Dr. Gabor Forgacs.Vita.Includes bibliographical references.Ph.D. University of Missouri--Columbia 2009.Dissertations, Academic -- University of Missouri--Columbia -- Biological sciences.Cardiovascular disease is a leading cause of death and often requires vascular reconstruction. However, the use of synthetic materials and scaffold-based approaches has shown several limitations for small-diameter blood vessel tissue-engineering, evidenced by the fact that they can elicit adverse host responses and interfere with, rather than guide, direct cellcell interaction as well as assembly and alignment of cell-produced extracellular matrix. Understanding the physical principles of biological self-assembly is thus essential for developing efficient strategies to build living tissues and organs. Here we exploit well-established liquid-like developmental processes (such as tissue fusion, envelopment or cell-sorting phenomena) to engineer scaffold-free, multilayered, small-diameter blood vessels. In particular, we show that apparent surface tensions of the three major vascular cell types (endothelial cells, smooth muscle cells and fibroblasts), determined through the exact solution of Laplace equation, guide their segregation in a multilayered fashion in vitro. Moreover, we introduce a novel rapid-prototyping technology (bioprinting) that allows for directing the self-assembly of the vascular cell types into custom-shaped tubular tissue structures, from single vascular tubes to complex hierarchical macrovascular trees. In addition to its potential for fulfilling the crucial need for small diameter vascular grafts and providing new strategies for vascularization of tissues for transplantation, this physically based approach provides a new insight into cell-patterning and structure formation and questions the paradigm of scaffold-based tissue-engineering

Experimental evaluation of apparent tissue surface tension based on the exact solution of the Laplace equation

The notion of apparent tissue surface tension offered a systematic way to interpret certain morphogenetic processes in early development. It also allowed deducing quantitative information on cellular and molecular parameters that is otherwise difficult to obtain. To accurately determine such tensions we combined novel experiments with the exact solution of the Laplace equation for the profile of a liquid drop under the employed experimental conditions and used the exact solution to evaluate data collected on tissues. Our results confirm that tissues composed of adhesive and motile cells indeed can be characterized in terms of well-defined apparent surface tension. Our experimental technique presents a way to measure liquid interfacial tensions under conditions when known methods fail.This work was supported by the National Science Foundation [FIBR-0526854]

L’hospitalisation psychiatrique de courte durée aux urgences d’un hôpital général : une étude rétrospective sur les facteurs prédictifs d’orientation à l’issue de la prise en charge

The availability of short-stay beds for brief admission (less than 72 hours) of crisis patients presenting to the emergency room is a model that has gained a growing interest because it allows time for developing alternatives to psychiatric hospitalization and favors a maintained functioning in the community. The primary objective of this study was to determine the factors predicting aftercare dispositions: transfer for further hospitalization, or return to the community. All patients (n=255) admitted to the short-stay unit of the Emergency Department of Rambouillet General Hospital during a one year period were included in the study. Logistic regression analysis was used to determine which factors, among patients clinical and socio-demographic characteristics, were associated with further hospitalization decision at discharge. Statistically significant factors associated with a higher probability of hospitalization included the patient’s initial wish to be hospitalized, the presence of a comorbid disorder, a referral by family or friends, a history of psychiatric hospitalization and suicidal ideation on arrival in the emergency room. Conversely, significant factors associated with a lower probability of hospitalization were the presence of a personality disorder, a precipitating conflict situation, age between 20 and 39 years, being employed. Our study confirms that clinical factors such as the presence of a personality disorder or the context of a precipitating conflict situation are predictive of a community return. Interestingly, it points out the importance of the patient’s initial wish in the hospitalization decision.L’hospitalisation psychiatrique de courte durée (HPCD) < 72h a montré son intérêt pour la prise en charge de patients en situation de crise, en favorisant la solution du suivi ambulatoire plutôt qu’une hospitalisation en milieu psychiatrique. Cependant les facteurs influençant la décision d’orientation à l’issue d’une HPCD sont encore peu connus. L’objectif de cette étude était de décrire les caractéristiques cliniques et socio-démographiques des patients admis en HPCD au sein des urgences d’un hôpital général et de déterminer les facteurs prédictifs d’une hospitalisation en psychiatrie à partir de celle-ci. Les données ont été collectées rétrospectivement à partir des dossiers informatisés des patients ayant bénéficié d’une HPCD (n=255) aux urgences de l’hôpital général de Rambouillet sur une période d’un an, puis analysés avec une méthode par régression logistique. Les facteurs associés de manière significative à une plus grande probabilité d’être hospitalisé étaient un souhait initial d’hospitalisation exprimé par le patient, l’existence d’une comorbidité, une demande de consultation émanant de l’entourage, un antécédent d’hospitalisation en psychiatrie, la présence d’idées suicidaires à l’arrivée aux urgences. Inversement, les facteurs associés à une probabilité plus faible d’hospitalisation étaient un diagnostic de trouble de la personnalité, un conflit avec l’entourage participant à la crise, un âge entre 20 et 39 ans, l’existence d’une activité professionnelle. Cette étude met ainsi en évidence les facteurs décisionnels d’intérêt orientant le devenir des patients admis en HPCD et notamment le poids de la demande initiale du patient

From developmental biology to tissue-engineering (printing blood vessels)

Les maladies cardiovasculaires représentent actuellement une des causes principales de mortalité et nécessitent souvent le recours à la chirurgie vasculaire reconstructrice. Nous exploitons ici des processus développementaux comparables aux phénomènes associés aux liquides (tels que la fusion de tissus, leur enveloppement mutuel ou les phénomènes de sorting cellulaire) dans le but de fabriquer des vaisseaux sanguins de petit calibre, comportant des couches cellulaires distinctes. En particulier, nous montrons que les tensions de surface associées aux trois types cellulaires vasculaires majeurs (cellules endothéliales, cellules musculaires lisses, et fibroblastes), et calculées en utilisant la solution exacte de l équation de Laplace, guident leur ségrégation en couches distinctes in vitro. Une nouvelle technologie de prototypage rapide, appelée bioprinting , permet de guider l auto-assemblage des différents types cellulaires vasculaires en structures tissulaires tubulaires de géométrie sur mesure, de tubes vasculaires simples à des arbres vasculaires complexes, potentiellement utilisables pour la médecine régénératrice.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Vingt groupes industriels français et le redéploiement

Twenty Major French Corporations and Redeployment, by Hugues Bertrand, Cyrille Mansuy and Michel Norotte. Economic restrictions, which have become tighter since 1974, have had a definite influence on corporate strategy. The narrowing of prospects has thus stimulated, even provoked what can justifiably be called the redeployment of forces of these corporations. These same corporations, after a period of formation and diversification, now seem preoccupied with general restructuration at all levels. As seen from both the quantitative and qualitative aspects (despite the inherent risks in any interpretation), the study of twenty of the most powerful French corporations affords a more accurate look at the means of redeployment. First is redeployment of sectors, showing how the corporations gave up their most solid holdings in order to concentrate on consolidating and broadening their activity in the most profitable sectors. Second is geographic redeployment aimed at greater penetration and implantation in foreign countries, especially in the developed nations. Lastly, a more reasonable management of the labor force considering the numerous problems due to overstaffing. At stake in these great maneuvers: the survival of a limited number of corporations in each industrial sector capable of holding on to particularly solid production and trade activities at the international level.Vingt grands groupes industriels français et le redéploiement, par Huges Bertrand, Cyrille Mansuy et Michel Norotte. Les contraintes économiques qui pèsent d'un poids nouveau depuis 1974 ont exercé une influence certaine sur la stratégie des groupes industriels. La contraction relative des débouchés a ainsi stimulé, sinon provoqué, ce qu'il est convenu d'appeler le redéploiement de ces groupes industriels. Ces derniers, après une période au cours de laquelle ils se sont formés et ont commencé à se diversifier, semblent désormais engagés dans une politique de restructuration en profondeur. Menée à partir d'éléments quantitatifs mais aussi qualitatifs (qui doivent être interprétés avec tous les risques que cela comporte), l'étude détaillée d'une vingtaine de groupes industriels français figurant parmi les plus puissants permet de mieux préciser les modalités de ce redéploiement : redéploiement sectoriel d'abord, les groupes se dégageant des positions jugées les plus solides afin de mieux concentrer leurs moyens pour renforcer et élargir leurs activités les plus rentables, redéploiement géographique ensuite par un effort accru de pénétration et d'implantation à l'étranger, en particulier vers les pays développés, enfin, gestion plus serrée de leur main-d'œuvre face aux nombreux problèmes de «sureffectifs». L'enjeu de ces « grandes manœuvres » est la survie dans chaque domaine d'activité d'un nombre limité de groupes industriels jouissant de positions productives et commerciales particulièrement solides à l'échelle mondiale.Bertrand Hugues, Mansuy Cyrille, Norotte Michel. Vingt groupes industriels français et le redéploiement. In: Économie & prévision, n°51, 1981-6. pp. 3-41

Tissue Engineering by Self-Assembly and Bioprinting of Living Cells

Biofabrication of living structures with desired topology and functionality requires the interdisciplinary effort of practitioners of the physical, life and engineering sciences. Such efforts are being undertaken in many laboratories around the world. Numerous approaches are pursued, such as those based on the use of natural or artificial scaffolds, decellularized cadaveric extracellular matrices and, most lately, bioprinting. To be successful in this endeavor, it is crucial to provide in vitro micro-environmental clues for the cells resembling those in the organism. Therefore, scaffolds, populated with differentiated cells or stem cells, of increasing complexity and sophistication are being fabricated. However, no matter how sophisticated scaffolds are, they can cause problems stemming from their degradation, eliciting immunogenic reactions and other a priori unforeseen complications. It is also being realized that ultimately the best approach might be to rely on the self-assembly and self-organizing properties of cells and tissues and the innate regenerative capability of the organism itself, not just simply prepare tissue and organ structures in vitro followed by their implantation. Here we briefly review the different strategies for the fabrication of three-dimensional biological structures, in particular bioprinting. We detail a fully biological, scaffoldless, print-based engineering approach that uses self-assembling multicellular units as bio-ink particles and employs early developmental morphogenetic principles, such as cell sorting and tissue fusion

From tissue liquidity to vascular printing [abstract]

Abstract only availableFaculty Mentor: Dr. Gabor Forgacs, Physics and AstronomyOver the last decades, many tissues have been shown to share common properties with liquids: tissue fragments round up as liquid drops and fuse with similar kinetics of liquids. Also of interest is the phase separation phenomenon undergone by mixed cell populations of different adhesiveness mimicking the "breaking" of a dispersion or emulsion of two immiscible liquids. For a system to show such behavior it must (1) be composed of many subunits that (2) cohere while (3) being mobile. These are the defining characteristics of a liquid. In ordinary liquids the subunits are molecules and the mobility is Brownian. Rearranging cell populations also possess these same three properties that underlie liquid behavior, but their subunits are living cells whose mobility may be either active, driven by intracellular forces, or passive, pulled by external forces. In the present study, we used tissue-liquidity to generate microtissue droplets of smooth muscle cells, fibroblasts and endothelial cells that can serve as minimal building units for vascular tissue-engineering. Size-specific spheroids of SMCs and fibroblasts were first generated by cell aggregation in P96 well plates. As the extracellular matrix content of the vessel wall is essential for obtaining adequate mechanical properties in tissue-engineered vascular grafts, those tissue droplets were then matured over 4 weeks in the presence of ascorbic acid or TGF-1 and insulin, and then analyzed at various times by histology in order to assess collagen and elastin production. At last, straight and branching tubes of different diameters were achieved by the fusion of CHO cells tissue spheroids deposited by hand or by a bioprinter. In conclusion, we show that the understanding of the physical mechanisms underlying tissue organization can be easily applied in the field of tissue-engineering