The in vitro models are receiving growing attention in studies on skin permeation, penetration, and irritancy, especially for the preclinical development of new transcutaneous drugs. However, synthetic membranes or cell cultures are unable to effectively mimic the permeability and absorption features of the cutaneous barrier. The use of explanted skin samples maintained in a fluid dynamic environment would make it possible for an in vitro experimentation closer to in vivo physiological conditions. To this aim, in the present study, we have modified a bioreactor designed for cell culture to host explanted skin samples. The preservation of the skin was evaluated by combining light, transmission, and scanning electron microscopy, for the histo/cytological characterization, with nuclear magnetic resonance spectroscopy, for the identification in the culture medium of metabolites indicative of the functional state of the explants. Our morphological and metabolomics results demonstrated that fluid dynamic conditions ameliorate significantly the structural and functional preservation of skin explants in comparison with conventional culture conditions. Our in vitro system is, therefore, reliable to test novel therapeutic agents intended for transdermal administration in skin samples from biopsies or surgical materials, providing predictive information suitable for focused in vivo research and reducing animal experimentation.

Vascular stenosis, the abnormal narrowing of blood vessels, arises from defective developmental processes or atherosclerosis-related adult pathologies. Stenosis triggers a series of adaptive cellular responses that induces adverse remodeling, which can progress to partial or complete vessel occlusion with numerous fatal outcomes. Despite its severity, the cellular interactions and biophysical cues that regulate this pathological progression are poorly understood. Here, we report the design and fabrication of a three-dimensional (3D) in vitro system to model vascular stenosis so that specific cellular interactions and responses to hemodynamic stimuli can be investigated. Tubular cellularized constructs (cytotubes) were produced, using a collagen casting system, to generate a stenotic arterial model. Fabrication methods were developed to create cytotubes containing co-cultured vascular cells, where cell viability, distribution, morphology, and contraction were examined. Fibroblasts, bone marrow primary cells, smooth muscle cells (SMCs), and endothelial cells (ECs) remained viable during culture and developed location- and time-dependent morphologies. We found cytotube contraction to depend on cellular composition, where SMC-EC co-cultures adopted intermediate contractile phenotypes between SMC- and EC-only cytotubes. Our fabrication approach and the resulting artery model can serve as an in vitro 3D culture system to investigate vascular pathogenesis and promote the tissue engineering field.

Complex biological products, such as those used to treat various forms of cancer, are typically produced by mammalian cells in bioreactors. The most important class of such biological medicines is proteins. These typically bind to sugars (glycans) in a process known as glycosylation, creating glycoproteins, which are more stable and effective medicines. The glycans are large polymers that are formed by a long sequence of enzyme catalysed reactions. This sequence is not always completed, thus leading to a heterogeneous glycoprotein distribution. A better comprehension of this distribution could lead to more efficient production of high quality drugs. To understand how the manufacturing process can affect the extent of glycosylation of protein, a non-linear ODE model of glycoprotein production is developed which describes the bioreactor configuration as well as the protein production and glycosylation reactions within the cell. The entire system evolves eventually to a stable steady state. The earlier evolution is critical however, as the amount of product produced and its quality varies over time. The model is considered as two coupled systems: the bioreactor submodel and the glycosylation submodel. To investigate the early time evolution within the bioreactor submodel, analytical and numerical properties are derived using matched asymptotic expansions and a finite difference scheme for a range of initial conditions. This leads to qualitatively different regimes for aglycosylated protein production, which affect the glycosylation submodel. The discrete glycoprotein distribution is approximated as continuous and written as a first-order PDE, with good agreement between the discrete and continuous models. The PDE is found to admit shocks, but the existence of these shocks is dependent on the early time evolution within the bioreactor submodel and leads to higher levels of glycosylation at early time. This suggests that changing the bioreactor configuration can lead to higher quality product at certain times.

This paper analyses the steady-state operation of a generalized bioreactor model that encompasses a continuous-flow bioreactor and an idealized continuous-flow membrane bioreactor as limiting cases. A biodegradation of organic materials is modelled using Contois growth kinetics. The bioreactor performance is analysed by finding the steady-state solutions of the model and determining their stability as a function of the dimensionless residence time. We show that an effective recycle parameter improves the performance of the bioreactor at moderate values of the dimensionless residence time. However, at sufficiently large values of the dimensionless residence time, the performance of the bioreactor is independent of the recycle ratio.

We analyse the steady-state operation of a continuous flow bioreactor in which the biochemical reaction is governed by noncompetitive substrate inhibition (Andrews kinetics). A generalized reactor model is used in which the well-stirred bioreactor and the idealized membrane bioreactor are special cases. As generic properties of systems subject to substrate inhibition have been obtained by other authors, we discuss reaction engineering features specific to Andrews kinetics.

We consider a time optimal control problem arisen from the optimalmanagement of a bioreactor devoted to the treatment ofeutrophicated water. We formulate this realistic problem as astate-control constrained time optimal control problem. Afteranalyzing the state system (a complex system of coupled partialdifferential equations with non-smooth coefficients foradvection-diffusion-reaction with Michaelis-Menten kinetics,modelling the eutrophication processes) we demonstrate theexistence of, at least, an optimal solution. Then we present adetailed derivation of a first order optimality condition(involving the corresponding adjoint systems) characterizing theseoptimal solutions. Finally, a numerical example is shown.

In China, medicinal plants enjoy an inherent and prominent role in the general health service. Due to excessive collection in the wild of rare and endangered plants, the natural resources of medicinal plants are depleting fast. In order to protect the medicinal plant resources, the Chinese government has implemented Good Agricultural Practice (GAP) programmes to cultivate the main popular medicinal plants in China. Thus far, around 800 GAP cultivation bases have been established nationwide and the total cultivation area of medicinal plants has reached 5000 km2. Besides GAP cultivation of medicinal plants, tissue cultural biotechnology has been applied to serve as an alternative for the supply of medicinal plant materials in China. Thus far, shoot production by tissue culture technology has been successful in medicinal plants such as Anoectochilus formosanus, Dalbergia odorifera, Dendrobium, Momordica grosvenorii, Pseudostellaria heterophylla and Taxus chinensis. In addition, the cell culture of Lithospermum erythrorhizon and Saussurea involucrata has been industrialized in 300–20,000-litre bioreactors. Besides the production of shoot and cell culture in bioreactors, tissue culture technology is also being practised for the conservation of rare medicinal plants.