@article {2991, title = {On the adhesion-cohesion balance and oxygen consumption characteristics of liver organoids}, journal = {Plos One}, year = {2017}, month = {03/2017}, abstract = {

Liver organoids (LOs) are of interest in tissue replacement, hepatotoxicity and pathophysiological studies. However, it is still unclear what triggers LO self-assembly and what the optimal environment is for their culture. Hypothesizing that LO formation occurs as a result of a fine balance between cell-substrate adhesion and cell-cell cohesion, we used 3 cell types (hepatocytes, liver sinusoidal endothelial cells and mesenchymal stem cells) to investigate LO self-assembly on different substrates keeping the culture parameters (e.g. culture media, cell types/number) and substrate stiffness constant. As cellular spheroids may suffer from oxygen depletion in the core, we also sought to identify the optimal culture conditions for LOs in order to guarantee an adequate supply of oxygen during proliferation and differentiation. The oxygen consumption characteristics of LOs were measured using an O2 sensor and used to model the O2 concentration gradient in the organoids. We show that no LO formation occurs on highly adhesive hepatic extra-cellular matrix-based substrates, suggesting that cellular aggregation requires an optimal trade-off between the adhesiveness of a substrate and the cohesive forces between cells and that this balance is modulated by substrate mechanics. Thus, in addition to substrate stiffness, physicochemical properties, which are also critical for cell adhesion, play a role in LO self-assembly.

}, keywords = {Bioengineering}, doi = {http://dx.doi.org/10.1371/journal.pone.0173206}, url = {http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0173206}, author = {G. Mattei and C. Magliaro and S. Giusti and S. D. Ramachandran and S. Heinz and J. Braspenning and A. Ahluwalia} } @conference {2278, title = {Autonomous bioreactor modules for disease models and detection of systemic toxicity}, booktitle = {ALTEX Proceedings}, year = {2014}, pages = {43}, address = {Prague, Czech Republic}, abstract = {

Advanced systems based on bioreactors and scaffolds are an essential step towards the development of more predictive and ethical alternatives to animal experiments. Size, modularity, automation, monitoring and essential design are crucial because these elements will ease the transition from old technology and accelerate their acceptance into mainstream research. Based on these requirements, the interconnected transparent sensorised {\^a}{\texteuro}{\oe}lego{\^a}{\texteuro} bioreactors designed in our labs have been used to generate physiologically relevant disease and toxicity models which recapitulate systemic responses impossible to observe in standard cell cultures. The disease model is an interconnected bioreactor circuit with i) adipose tissue in 3D in 3 different concentrations representing normo-weight, over weight and obese body mass indices, ii) human hepatocytes on porous collagen scaffolds and iii) monolayers of human endothelial cells. High adiposity and elevated glucose levels induce systemic and endothelial inflammation in the circuit, as observed in overweight and diabetic humans (Iori et al., 2012). Using similar technology a three-tissue circuit for monitoring the absorption, distribution, metabolism and toxicity of nanoparticles was developed in the context of the EU project InLiveTox (Ucciferri et al., 2014). The results were strikingly similar to those observed in animal experiments demonstrating that the dynamic 3D in-vitro models are ethical, meaningful and economically viable replacements.

}, keywords = {Bioengineering}, author = {A. Ahluwalia and S. Giusti and Sbrana, T. and M. Wilkinson and A. Misto and Lehr, C.-M. and M. Liley}, editor = {S. Horst and D. J{\'\i}rov{\'a}} } @article {2276, title = {Design Criteria for Generating Physiologically Relevant In Vitro Models in Bioreactors}, journal = {Processes}, volume = {2}, year = {2014}, pages = {548{\textendash}569}, abstract = {

In this paper, we discuss the basic design requirements for the development of physiologically meaningful in vitro systems comprising cells, scaffolds and bioreactors, through a bottom up approach. Very simple micro- and milli-fluidic geometries are first used to illustrate the concepts, followed by a real device case-study. At each step, the fluidic and mass transport parameters in biological tissue design are considered, starting from basic questions such as the minimum number of cells and cell density required to represent a physiological system and the conditions necessary to ensure an adequate nutrient supply to tissues. At the next level, we consider the use of three-dimensional scaffolds, which are employed both for regenerative medicine applications and for the study of cells in environments which better recapitulate the physiological milieu. Here, the driving need is the rate of oxygen supply which must be maintained at an appropriate level to ensure cell viability throughout the thickness of a scaffold. Scaffold and bioreactor design are both critical in defining the oxygen profile in a cell construct and are considered together. We also discuss the oxygen-shear stress trade-off by considering the levels of mechanical stress required for hepatocytes, which are the limiting cell type in a multi-organ model. Similar considerations are also made for glucose consumption in cell constructs. Finally, the allometric approach for generating multi-tissue systemic models using bioreactors is described.

}, keywords = {Bioengineering}, issn = {2227-9717}, doi = {10.3390/pr2030548}, url = {http://www.mdpi.com/2227-9717/2/3/548/}, author = {G. Mattei and S. Giusti and A. Ahluwalia} } @conference {2273, title = {Fluid dynamics in porous scaffolds stimulated with cyclic squeeze pressure in the S2PR bioreactor}, booktitle = {Gruppo Nazionale Bioingegneria IV Congresso}, year = {2014}, address = {Pavia, 25-27 June}, abstract = {

In cardiac tissue engineering, the use of bioreactors is fundamental for applying controlled mechanical stimuli on the cells and recreate a physiological environment for cardiomyocytes cultures. This work is focused on an innovative Sensorized Squeeze PRessure (S2PR) bioreactor, able to apply a periodic contactless hydrodynamic pressures on 3D porous constructs. The fluid-dynamic environment inside the bioreactor was fully characterized using computational models, focusing on the pressures and fluid velocity profiles generated in the porous scaffold during the cyclic stimulation.

}, keywords = {Bioengineering}, author = {M. Ferroni and S. Giusti and G. Spatafora and F. Boschetti and A. Ahluwalia} } @conference {2277, title = {Fluid dynamics in porous scaffolds stimulated with cyclic squeeze pressure in the S2PR bioreactor}, booktitle = {Proceedings of ICMMB2014}, year = {2014}, pages = {363{\textendash}68}, keywords = {Bioengineering}, doi = {10.6092/unibo/amsacta/4085. In: Proceedings ICMMB A cura di: Zannoli, Romani ; Corazza, Ivan ; Stagni, Rita.}, url = {http://amsacta.unibo.it/4085/1/Proceedings{\.I}CMMB2014.pdf}, author = {M. Ferroni and S. Giusti and G. Spatafora and F. Boschetti and A. Ahluwalia} } @conference {2280, title = {Multi-organ-on-plate system for in-vitro studies of intestinal drug absorption and hepatotoxicity}, booktitle = {ESTIV 2014}, year = {2014}, pages = {107}, address = {Egmond aan Zee, The Netherlands}, abstract = {

More meaningful in-vitro models which simulate the physiological conditions of native tissue are becoming essential in the pharmaceutical field, for early and rapid screening of drug candidates. Here, we describe a multi-organ-on-plate system based on single and double flow mini bioreactor modules for dynamic in-vitro studies of intestinal drug absorption, drug metabolism and more relevant toxicity studies. The double flow module for membrane culture was firstly characterized using computational fluid dynamic models and measurements of pressure gradients, in order to indentify the optimal flow rates for maximizing the passage of solutes through the membrane. Then, cell culture experiments were performed with fully differentiated Caco-2 cells seeded on the semi-permeable membrane as a dynamic model of the intestinal epithelium, connected to a single flow chamber with metabolically competent human upcyte{\^A}{\textregistered} hepatocytes (Medicyte GmbH, Germany) seeded on a 3D collagen cryogel. First we assessed the role of flow in modulating the passage of compounds across the epithelial barrier. Then toxicity tests were performed by administering different concentrations of hepatotoxic compounds (i.e. Diclofenac, Nimesulide, industrial nanoparticles) in the apical compartment of the MB, compared the data with cell cultures in transwells. Our results show: i) the presence of flow significantly increases translocation of all molecules tested across the membrane, ii) flow conditioned Caco-2 cells are more permeable to small hydrophilic compounds, despite having high TEER values iii) although they display higher levels of phenotypic markers (tight junctions, albumin expression etc), cells in the system are more susceptible to drug induced toxicity. In conclusion, the multi-organ-on-plate system predicts drug adsorption and toxicity better than traditional cell cultures and could be used to reduce, refine and eventually replace animal tests.

}, keywords = {Bioengineering}, author = {S. Giusti and Sbrana, T. and D. Giacopelli and V. Di Patria and A. Ahluwalia} } @conference {2279, title = {The need of innovative technologies for new 3D relevant in-vitro models and the answer of Ivtech}, booktitle = {ALTEX Proceedings}, year = {2014}, pages = {45{\textendash}6}, address = {Prague, Czech Republic}, abstract = {

New relevant in-vitro models are priorities in pharmaco-toxicology, cosmetic and food research to reduce the animal tests. Therefore, invivo models show ethical issues, are not time and cost effective and are progressively showing scientific limitations: for instance they fail in detection of pathogens that are species specific (Mazzoleni et al., 2009). The search of more relevant pre-clinical models forced the researcher to move from 2D to 3D in-vitro models in order to maintain the phenotype of cells (Lovit et al., 2013; Mattei et al., 2014). Even if the significant progress in material science, the metabolic requirement of 3D tissues is higher than a 2D culture and the scaffold is a limitation in nutrients transport. Dynamic cell culture chambers are then required to assure the gas/nutrient supply, waste elimination, mechanical stimulation of cells, study of cross talk between different tissues and real time monitoring of cells. Nowadays the only systems that meet all these specifications are the Ivtech technologies. Ivtech is an innovative Italian start-up that grows up to solve the needs of in-vitro experts, offering and customizing several type of transparent, dynamic and modular cell culture systems, organizing workshops and training. The goal is to expand the 3D approach and permits a significant evolution towards highly relevant in-vitro models.

}, keywords = {Bioengineering}, author = {Sbrana, T. and G. Mattei and S. Giusti and A. Ahluwalia}, editor = {J. Dagmar and S. Horst} } @article {2274, title = {A novel dual-flow bioreactor simulates increased fluorescein permeability in epithelial tissue barriers}, journal = {Biotechnology journal}, year = {2014}, abstract = {

Permeability studies across epithelial barriers are of primary importance in drug delivery as well as in toxicology. However, traditional in vitro models do not adequately mimic the dynamic environment of physiological barriers. Here, we describe a novel two-chamber modular bioreactor for dynamic in vitro studies of epithelial cells. The fluid dynamic environment of the bioreactor was characterized using computational fluid dynamic models and measurements of pressure gradients for different combinations of flow rates in the apical and basal chambers. Cell culture experiments were then performed with fully differentiated Caco-2 cells as a model of the intestinal epithelium, comparing the effect of media flow applied in the bioreactor with traditional static transwells. The flow increases barrier integrity and tight junction expression of Caco-2 cells with respect to the static controls. Fluorescein permeability increased threefold in the dynamic system, indicating that the stimulus induced by flow increases transport across the barrier, closely mimicking the in vivo situation. The results are of interest for studying the influence of mechanical stimuli on cells, and underline the importance of developing more physiologically relevant in vitro tissue models. The bioreactor can be used to study drug delivery, chemical, or nanomaterial toxicity and to engineer barrier tissues.

}, keywords = {Bioengineering}, issn = {1860-7314}, doi = {10.1002/biot.201400004}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24756869}, author = {S. Giusti and Sbrana, T. and La Marca, M and V. Di Patria and V. Martinucci and Tirella, A and C. Domenici and A. Ahluwalia} } @conference {2275, title = {Sensorized Squeeze Pressure Bioreactor For mechanical modulation of cardiomyocyte phenotype}, booktitle = {Journal of tissue engineering and regenerative medicine}, volume = {8 Suppl 1}, year = {2014}, pages = {67{\textendash}8}, keywords = {Bioengineering}, doi = {10.1002/term.1943}, url = {http://www.ncbi.nlm.nih.gov/pubmed/24912686}, author = {S. Giusti and Vozzi, F. and F. Pagliari and Tirella, A and D. Mazzei and Cabiati, M and S. del Ry and A. Ahluwalia} } @article {2281, title = {SQPR 3.0: A Sensorized Bioreactor for Modulating Cardiac Phenotype}, journal = {Procedia Engineering}, volume = {59}, year = {2013}, pages = {219{\textendash}225}, abstract = {

In cardiac tissue engineering, the use of bioreactors is fundamental for applying controlled mechanical stimuli on cells and recreate a physiological environment for cardiomyocyte cultures. This work is focused on the design of a sensorized Squeeze Pressure bioreactor (SQPR 3.0) able to apply a periodic contactless hydrodynamic pressure on tissue constructs. This system was then tested with H2c9, a murine cardiomyoblast cell line, to investigate the effect of different stimulation times (2h, 24h, 30h) on cell shape and cardiotypic marker expression.

}, keywords = {Bioengineering}, issn = {18777058}, doi = {10.1016/j.proeng.2013.05.114}, url = {http://linkinghub.elsevier.com/retrieve/pii/S187770581301028X}, author = {S. Giusti and F. Pagliari and Vozzi, F. and Tirella, A and D. Mazzei and Cabiati, M and S. del Ry and A. Ahluwalia} } @conference {1803, title = {A multi-stimuli environment for cardiac tissue engineering}, booktitle = {TERMIS 3rd World Congress}, year = {2012}, address = {Vienna, Austria}, abstract = {

The identification of the ideal cell source to generate cardiac tissue able to integrate into the host myocardium and with the contractile system is crucial for cardiac engineering. Amongst different cell sources so far proposed, human adult Cardiac Progenitor Cells (hCPCs) show the ability to proliferate and differentiate toward cardiac lineages when grown in appropriate microenvironmental conditions. It is widely accepted that conventional 2D cultures may provide a physiological environment for growing cells. For this reason the need to have an engineered microenvironment, matching physiological requirements, is crucial. A 3D context with spatial and time varying distribution of regulatory factors using mechanically matched scaffolds and bioreactors could represent an in vitro cell culture model being able to more closely reflects the in vivo conditions. In the present study, the possibility of using biocompatible and biodegradable scaffolds of collagen based or derivatives hydrogels in combination with Linneg/Sca-1pos hCPCs gathered from human heart biopsies was investigated. Bio-constructs were placed in the low shear, high flow MCmB (MultiCompartment modular Bioreactor) and the combined effects of dynamic culture conditions and 3D scaffolds on cell morphology and differentiation were studied in order to investigate the possibility of fabricating stem cell-derived cardiac patches to replace infarcted tissue.

}, keywords = {Bioengineering, Bioreactors, Dynamic 3D Cultures}, author = {Tirella, A and A. Ahluwalia and P. Di Nardo and Gaudiello, E and S. Giusti and F. Pagliari} } @conference {2282, title = {Real Time and In-Situ control of environmental parameters in a modular bioreactor}, booktitle = {Journal of tissue engineering and regenerative medicine}, volume = {6 Suppl 1}, year = {2012}, pages = {331}, address = {Vien, Austria}, abstract = {

Many researchers now recognize the importance of the external environment in which cells are cultured for cell function and differentiation. Most of the systems able to apply physiological-like stimuli also need a classical incubator or a specifically designed system to control the environmental parameters at some distance from the cells. Here, a standalone platform for cell, tissue and organ culture is described. The SUITE (Supervising Unit for In-vitro Testing) system can control local environmental variables like pH, temperature and hydrostatic pressure over long periods, to provide the optimal environment for cells outside the classical incubator and also to apply mechanical and chemical stimuli to simulate the physiological milieu. The SUITE platform is used with Multi-Compartmental modular Bioreactors (MCmB) to perform dynamic cultures of hepatocytes as in-vitro liver model. Preliminary tests demonstrated the capability of the system to maintain the target parameters for more than 72 h generating different hydrostatic pressures (20{\^a}{\texteuro}{\textquotedblleft}30{\^a}{\texteuro}{\textquotedblleft}40{\^a}{\texteuro}{\textquotedblleft}50 mmHg). Then, two bioreactors were connected in series and cultured for 24 h in the SUITE platform with hydrostatic pressures of 20{\^a}{\texteuro}{\textquotedblleft}30{\^a}{\texteuro}{\textquotedblleft}40 mmHg. Static and dynamic controls were placed in the classical humidified incubator at 37{\^A}{\textdegree}C, 5\% CO2. The results show that cell function is enhanced in SUITE at up to 30 mmHg of hydrostatic pressure, as confirmed by viability, metabolic function and morphological analysis.

}, keywords = {Bioengineering}, doi = {10.1002/term.1586}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22941753}, author = {S. Giusti and D. Mazzei and A. Ahluwalia} } @conference {2283, title = {Replicating the 3D cardiomyocyte environment in the squeeze pressure bioreactor}, booktitle = {Journal of tissue engineering and regenerative medicine}, volume = {6 Suppl 1}, year = {2012}, pages = {341}, keywords = {Bioengineering}, doi = {10.1002/term.1586}, url = {http://www.ncbi.nlm.nih.gov/pubmed/22941753}, author = {S. Giusti and Tirella, A and Galli, E and Vozzi, F. and Cabiati, M and A. Ahluwalia} } @conference {1792, title = {Replicating the cardiac environment in the Squeeze Pressure Bioreactor}, booktitle = {TERMIS 3rd World Congress}, year = {2012}, keywords = {Bioengineering}, author = {S. Giusti and Tirella, A and Galli, E and Vozzi, F. and Cabiati, M and A. Ahluwalia} } @inbook {1286, title = {Multi-Compartmental Modular Bioreactor as Innovative System for Dynamic Cell Cultures and Co-Cultures}, booktitle = {Bioreactors: Design, Properties and Applications}, number = {978-1-62100-164-5}, year = {2011}, pages = {159 - 178}, publisher = {Nova Science Publishers, Inc}, organization = {Nova Science Publishers, Inc}, chapter = {Multi-Compartimental Modular Bioreactor as Innovative System for Dynamic Cell Cultures and Co-Cultures}, abstract = {

In this chapter, the design, fabrication process and preliminary tests of a Multi- Compartmental Modular Bioreactor used as a system for dynamic cell cultures and co-cultures is described. Although the microwell (MW) plate has become a standard in cell culture, the complexity of the physiological environment is not replicated in petri dishes or microplates. All cells are exquisitely sensitive to their micro-environment which is rich with cues from other cells and from mechanical stimuli due to flow, perfusion and movement. Microwells do not offer any form of dynamic chemical or physical stimulus to cells, such as concentration gradients, flow, pressure or mechanical stress. This is a major limitation in experiments investigating cellular responses in-vitro since the complex interplay of mechanical and biochemical factors is absent. Most researchers and industry have started to accept that classical in vitro experiments offer poor predictive value or mechanistic understanding and are shifting their interests to new technologies such as bioreactors. For this reason, a large number of bioreactor systems for cell culture have been recently designed and described. With the purpose of developing cell culture models to establish a physiological-like interaction between different cell types, a novel Multi-Compartmental Modular Bioreactor (MCmB)was realized. The modular chamber was designed with shape and dimensions similar to the 24-MultiWell allowing an easy transfer of microwell protocols. The MCmB consists of a cell culture chamber made of bio-compatible silicon polymer, with excellent self-sealing proprieties, transparency and flexibility. The modular chambers can be also connected together in series or in parallel as desired, in order to allow cell-cell cross-talk or replicate in vitro models of metabolism or diseases using allometric design principles. In this chapter we describe the bioreactor design process starting from a finite-element method (FEM) model, developed in order to study the shear stress and the oxygen concentration at the cell surface. A further version of the MCmB is also described, in which a semipermeable membrane is placed into the bioreactor allowing to create a double-chamber system (MCmB-dc) for biological barriers simulation like for example lung or intestine. Allometric methods for designing in-vitro organ models using combinations of different cell types or tissues cultured in different chambers are also presented. Allometric laws mathematically correlate non linear quantities such as organ mass, blood flow, blood retention time and metabolic rate. Using these laws the modules can be assembled in various configurations enabling organ and system physiology to be recapitulated in vitro. Preliminary experiments using the modules are also described.

}, keywords = {Bioengineering}, issn = {978-1-62100-164-5}, author = {D. Mazzei and S. Giusti and Sbrana, T. and A. Ahluwalia}, editor = {Antolli, P. G. and Zhiming Liu} } @article {2284, title = {Squeeze pressure bioreactor: a hydrodynamic bioreactor for noncontact stimulation of cartilage constructs}, journal = {Tissue engineering. Part C, Methods}, volume = {17}, year = {2011}, pages = {757{\textendash}64}, abstract = {

A novel squeeze pressure bioreactor for noncontact hydrodynamic stimulation of cartilage is described. The bioreactor is based on a small piston that moves up and down, perpendicular to a tissue construct, in a fluid-filled chamber. Fluid displaced by the piston generates a pressure wave and shear stress as it moves across the sample, simulating the dynamic environment of a mobile joint. The fluid dynamics inside the squeeze pressure bioreactor was modeled using analytical and computational methods to simulate the mechanical stimuli imposed on a construct. In particular, the pressure, velocity field, and wall shear stress generated on the surface of the construct were analyzed using the theory of hydrodynamic lubrication, which describes the flow of an incompressible fluid between two surfaces in relative motion. Both the models and in-situ pressure measurements in the bioreactor demonstrate that controlled cyclic stresses of up to 10 kPa can be applied to tissue constructs. Initial tests on three-dimensional scaffolds seeded with chondrocytes show that glycosaminoglycan production is increased with regard to controls after 24 and 48 h of cyclic noncontact stimulation in the bioreactor.

}, keywords = {Bioengineering}, issn = {1937-3392}, doi = {10.1089/ten.TEC.2011.0002}, url = {http://online.liebertpub.com/doi/abs/10.1089/ten.tec.2011.0002 http://www.ncbi.nlm.nih.gov/pubmed/21410315}, author = {C. De Maria and S. Giusti and D. Mazzei and A. Crawford and A. Ahluwalia} } @inbook {2285, title = {The Squeeze Pressure Bioreactor: Design and Modelling of a Non-Contact Device for Mechanical Stimulation of Tissue Engineered Constructs}, booktitle = {Bioreactors: Design, Properties and Applications}, year = {2011}, pages = {199{\textendash}214}, publisher = {Nova Science Publishers, Inc.}, organization = {Nova Science Publishers, Inc.}, address = {Hauppauge NY}, abstract = {

Diseases of hyaline cartilage represent one of the major health problems, especially in industrialized countries with high life expectancy. The erosion of the articulating surfaces of joints, known as osteoarthritis, currently affects more than 200 million citizens worldwide, and more than 50\% of the patients need or will need a surgical treatment. Articular cartilage is a three dimensional avascular tissue, which covers the ends of all synovial joints. During normal daily function, articular cartilage can be repeatedly subjected to forces up to several time body weight, but it is able to provide articulating joints with a nearly frictionless motion. Despite its tremendously important function, articular cartilage has limited capacity for auto regeneration after degenerative and rheumatic diseases, like arthritis, as well as traumatic injuries. Cartilage problems are a huge and still unsolved medical issue, which therefore represents one of the most important tissue engineering targets requiring high quality products as fast as possible. For this reason, the possibility to recreate in vitro cartilage substitutes as a real alternative to total joint replacement represents an increasing and hopeful market, in which many research groups are still working. At the moment, one of the main findings in invitro cartilage studies is the importance of the role of mechanical stimuli and dynamic loads for the chondrocytes growth and differentiation. Several studies using cartilage explants or chondrocytes seeded in 3D scaffolds have shown that mechanical compressive loads affect the cells metabolic activity and their matrix production. In order to simulate the in vivo environment, the use of bioreactors is becoming fundamental: bioreactors can provide the chemical and mechanical signals that optimize tissue development. Furthermore, bioreactors could be an important instrument to reduce the cost of clinical studies, used as in vitro predictors of in vivo performance. In this way,the use of bioreactors can reduce animal studies, helping the scientists to focus their attention in the right direction before starting pre-clinical studies, which are usually more expensive than preliminary research. In the past few years, several systems for the application of different mechanical stimuli to chondrocytes have been developed. Most of these can generate biomechanical-like forces such as the direct compression, tensile and shear forces, or hydrostatic pressure, in order to stimulate the articular chondrocyctes to increase their matrix production. Generally, the most important requirements that a culture system has to satisfy are high reliability and usability, perfect sterility, easy control of all the important culture parameters and low cost. In this work, a new system, inspired by the synovial environment of mobile joints and able to apply an innovative type of stimulation on articular chondrocytes is described and modeled. The SQPR (SQueeze PRessure) bioreactor chamber is designed to impose a cyclic hydrodynamic pressure on cell cultures, constructs or tissues slices. The basic principle of this new system is the generation of a localized contact less overpressure on articular chondrocytes, using a simple vertical piston movement. This kind of stimulation is particularly useful for neo-tissue or fresh-constructs, in which cells require a dynamic environment to maintain their differentiate state, but at the same time do not tolerate direct compression or high shear stress. When the piston moves down, a controlled hydrodynamic overpressure and a shear stress is generated over the cell surface, stimulating the chondrocytes to improve their matrix production. The fluid dynamics inside the SQPR bioreactor is illustrated from an analytical and numerical point of view. We show how these models can predict the pressure, velocity field and wall shear stress generated on the cell surface of the construct. The bioreactor design is presented in detail and validation tests on chondrocytes are described.

}, keywords = {Bioengineering}, url = {https://www.novapublishers.com/catalog/product\_info.php?products\_id=22653}, author = {S. Giusti and A. Ahluwalia and C. De Maria}, editor = {Antolli, P. G. and Z. Liu} } @article {1283, title = {A low shear stress modular bioreactor for connected cell culture under high flow rates.}, journal = {Biotechnol Bioeng}, volume = {106}, year = {2010}, month = {May}, pages = {127{\textendash}137}, abstract = {

A generic "system on a plate" modular multicompartmental bioreactor array which enables microwell protocols to be transferred directly to the bioreactor modules, without redesign of cell culture experiments or protocols is described. The modular bioreactors are simple to assemble and use and can be easily compared with standard controls since cell numbers and medium volumes are quite similar. Starting from fluid dynamic and mass transport considerations, a modular bioreactor chamber was first modeled and then fabricated using "milli-molding," a technique adapted from soft lithography. After confirming that the shear stress was extremely low in the system in the range of useful flow rates, the bioreactor chambers were tested using hepatocytes. The results show that the bioreactor chambers can increase or maintain cell viability and function when the flow rates are below 500 microL/min, corresponding to wall shear stresses of 10(-5) Pa or less at the cell culture surface.

}, keywords = {Bioengineering, Bioreactors}, doi = {http://dx.doi.org/10.1002/bit.22671}, author = {D. Mazzei and M. A. Guzzardi and S. Giusti and A. Ahluwalia} }