Applied nano bio systems with microfluidics and biosensors for three‐dimensional cell culture

Abstract

1Applications of nanotechnology and microtechnology lead to a field which could be called nanosystems integration. The next step is the development of nanobiotechnological systems, which could reflect the hierarchical organization of biological systems that utilise scales and laws of nature on all metric scales. As one example of such systems we present the design and construction of a new class of micro bioreactors. It has been shown that 3D culture systems reveal the in vivo situation much better than the cultivation of 2D one cell type alone. For this purpose we have to construct and arrange fluidic devices and a cell-biological environment in such a way, that living cells can survive in a three-dimensional, organ-like structure, enabled by technical devices. Such organ-like cell structures may lead to new ways in medicinal chemistry for the determination of ADME/Tox (absorption-distribution-metabolism-excretion and toxicity) properties of potential drugs. One part of the construction principle is the integration of sensors, preferable novel AlGaN/GaN nanosensors. The latter nanosensors offer the possibility to estimate reactions of cells attached to the sensor surface non-destructively and label-free. These sensors are highly sensitive and biocompatible to cells. Furthermore, they are transparent to enable microscopic and other optical observations of the cells. In an advanced version the sensor is to be integrated to give a better insight into cellular processes of the cells that are cultivated in such micro bioreactors.Keywords: Nanobiotechnology / micro-nanointegration / nanosensors / AlGaN-sensors / microfluidics / assays / advanced cell culture / Die Aufgabe mikro-und nanochtechnologisch hergestellte Funktionselemente zu ganzen Systemen bzw. zu makroskopischen Systemen zu assemblieren, hat zu einem Gebiet geführt, dass man NanoSystemintegration oder auch Mikro-Nanointegration nennen kann. Im Bereich der Nanobiotechnologie führt diese Entwicklung zu Systemen, die die hierarchische Organisation der biologischen Systeme nachbildet, die auf allen geometrischen Skalen von der Nano-über die Mikro-bis zur Makroebene präsent ist bzw. die dort wirkenden Naturgesetze nutzbar macht. Als ein Beispiel stellen wir eine neue Klasse von Mikrobioreaktoren vor. Es konnte gezeigt werden, dass 3D Zellkultursysteme die in vivo Situation wesentlich besser darstellen als 2 dimensionale Zellkultursysteme. Für diesen Zweck müssen wir mikrofluidische Systeme und eine zellbiologische Umgebung so konstruieren, dass lebende Zellen in einer dreidimensionalen, organartigen Struktur, die durch technische Baugruppen gebildet wird, überleben können. Solche organ-ähnlichen Zellverbände können zu neuen Methoden in der medizinischen Wirkstoffforschung führen, um z. B. ADME/Tox Eigenschaften zu bestimmen. Ein Teil der Konstruktion bezieht sich auf die Integration von Sensoren, vorzugsweise von AlGaN-Nanosensoren. Die letzteren ermöglichen es adhärente Zellen nicht destruktiv bzw. labelfrei zu untersuchen. Diese Sensoren sind hoch sensitiv un...

Microfluidic Organ‐on‐a‐Chip Technology for Advancement of Drug Development and Toxicology

“…Reproduced with permission: lung, [ 26 ] Copyright 2011, Springer; gut, [ 40 ] Copyright 2012, The Royal Society of Chemistry; liver, [ 16 ] Copyright 2013, Elsevier; kidney, [ 50 ] Copyright 2013, The Royal Society of Chemistry; heart, [ 58 ] Copyright 2010, American Chemical Society; bone marrow, [ 67 ] Copyright 2014, Nature Publishing Group; brain, [ 69 ] Copyright 2012, Springer; spleen, [ 70 ] Copyright 2014, The Royal Society of Chemistry; and vasculature, [ 66 ] Copyright 2011, American Institute of Physics. Characterizing the toxicity of several compounds using liver co-culture and SMART-scale analysis HepG2/C3A and MDCK [20] Drug metabolism using liver and intestinal slices Harvested rat liver and intestinal slices [22] Testing the effects of ethanol-induced toxicity on liver slices Harvested rat liver slices [21] Functional analysis Creating model with bile canaliculi formation Harvested rat hepatocytes [14] Incorporated biosensors for pH monitoring in chip HepG2 [15] The kinetic reactions representing metabolism, measured and compared with mathematical model…”

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The evolution of manufacturing processes for micro‐featured epoxy resin mold

“…Residual stresses in the plastic optical components were induced by solidification process . This means that the fabricated precision epoxy resin mold has a potential for producing the microdevices, such as micro‐fluidics, micro‐optical components and micro‐reactors using micro‐hot embossing .…”

Mimicking the biological world: Methods for the 3D structuring of artificial cellular environments

“…For example, polymers with substrates prestructured by the methods described in Section 2, could be chemically modified in such a way (Section 3.2) that cells are guided by specific molecules to their place according to the desired design of a tissue (Singh, S., Schober, A., Gross, A., Gebinoga, M. et al, Verfahren zur Bestimmung der Ansiedelbarkeit von biologischen Zellen auf Strukturen aus einem Polymer sowie Ver-fahren zur Herstellung solcher Strukturen, DE 10 2012DE 10 101 240.7, 2012. [137]). If it is possible for cells to specifically adhere with natural material on a biocompatible substrate or in a specific biocompatible polymer solution, the following construction cycles may become possible.…”

“…A brief review of some of the current applications was published recently [137,138]. A brief review of some of the current applications was published recently [137,138].…”