Jörg Hampl

Technische Universität Ilmenau

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Andreas Schober

Technische Universität Ilmenau

Frank Weise

Natural and Medical Sciences Institute

Uta Fernekorn

Technische Universität Ilmenau

Michael Gebinoga

Technische Universität Ilmenau

Maren Klett

Technische Universität Ilmenau

Sukhdeep Singh

Post Graduate Institute of Medical Education and Research

Gregor Schlingloff

Technische Universität Ilmenau

Christian Hildmann

TU Dresden

Caroline Augspurger

Technische Universität Ilmenau

Dana Brauer

Technische Universität Ilmenau

Cooperative Institutions

Technische Universität Ilmenau

Friedrich Schiller University Jena

Jena University Hospital

Martin Luther University Halle-Wittenberg

University of Cologne

Leibniz Institute on Aging - Fritz Lipmann Institute (FLI)

Kirchhoff (Germany)

Witten/Herdecke University

Leibniz Institute of Photonic Technology

Karlsruhe Institute of Technology

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Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds

Scientific Reports (2021)

Lisa Marx-Blümel Christian Marx Jürgen Sonnemann Frank Weise Jörg Hampl

Abstract Hematopoietic stem cell (HSC) transplantation is successfully applied since the late 1950s. However, its efficacy can be impaired by insufficient numbers of donor HSCs. A promising strategy to overcome this hurdle is the use of an advanced ex vivo culture system that supports the proliferation and, at the same time, maintains the pluripotency of HSCs. Therefore, we have developed artificial 3D bone marrow-like scaffolds made of polydimethylsiloxane (PDMS) that model the natural HSC niche in vitro. These 3D PDMS scaffolds in combination with an optimized HSC culture medium allow the amplification of high numbers of undifferentiated HSCs. After 14 days in vitro cell culture, we performed transcriptome and proteome analysis. Ingenuity pathway analysis indicated that the 3D PDMS cell culture scaffolds altered PI3K/AKT/mTOR pathways and activated SREBP, HIF1α and FOXO signaling, leading to metabolic adaptations, as judged by ELISA, Western blot and metabolic flux analysis. These molecular signaling pathways can promote the expansion of HSCs and are involved in the maintenance of their pluripotency. Thus, we have shown that the 3D PDMS scaffolds activate key molecular signaling pathways to amplify the numbers of undifferentiated HSCs ex vivo effectively.

10.1038/s41598-021-00619-6

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Citations (14)

Microbioreactor design for 3-D cell cultivation to create a pharmacological screening system

Engineering in Life Sciences (2011)

Uta Fernekorn Jörg Hampl Frank Weise Caroline Augspurger Christian Hildmann

Abstract A biocompatible cell culture environment that enables continued existence of three dimensionally aggregated cells in a polycarbonate‐based scaffold structure was developed. A micro structured polymeric scaffold allows perfusion of cells due to a microporous structure generated by ion track etching and micro thermoforming. Biocompatibility and sterilizability was approved for the whole system. As oxygenation and mass transport within a closed system is most relevant for 3‐D cell culture, two approaches of pumping systems were tested. The human hepatocarcinoma cell line HepG2 was used to examine basic cytological parameters in response to the enviroment. Our data indicate that an actively perfused 3‐D cell culture induces a more differentiated phenotype in HepG2 cells than the 2‐D setup. Thus, our results provide further support to the theory that 3‐D‐cultivated cells display a non‐proliferative behavior. In this respect, 3‐D cultures resemble in vivo conditions more closely. Microreactors are widely applied for organic syntheses, but can also be used for screening applications in drug discovery and medical research. The bioreactor versions presented here were equipped with active fluidic components.

10.1002/elsc.201000145

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Citations (20)

Biomimetic reconstruction of the hematopoietic stem cell niche for in vitro amplification of human hematopoietic stem cells

PLoS ONE (2020)

Lisa Marx-Blümel Christian Marx Frank Weise Jessica Frey Birgit Perner

Hematopoietic stem cell transplantation is successfully applied since the late 1950s; however, its efficacy still needs to be increased. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an improved ex vivo culture system that supports proliferation and maintains HSC pluripotency would override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro, we optimized the HSC medium composition with a panel of cytokines and valproic acid and used an artificial 3D bone marrow-like scaffold made of polydimethylsiloxane (PDMS). This 3D scaffold offered a suitable platform to amplify human HSCs in vitro and, simultaneously, to support their viability, multipotency and ability for self-renewal. Silicon oxide-covering of PDMS structures further improved amplification of CD34+ cells, although the conservation of naïve HSCs was better on non-covered 3D PDMS. Finally, we found that HSC cultivated on non-covered 3D PDMS generated most pluripotent colonies within colony forming unit assays. In conclusion, by combining biological and biotechnological approaches, we optimized in vitro HSCs culture conditions, resulting in improved amplification, multipotency maintenance and vitality of HSCs.

Hematopoietic stem cell

10.1371/journal.pone.0234638

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Citations (12)

Bio-inspired 3D micro structuring of a liver lobule via direct laser writing: A comparative study with SU-8 and SUEX

Journal of Laser Applications (2021)

Lisa Zeußel Jörg Hampl Frank Weise Sukhdeep Singh Andreas Schober

Real biological tissues show a great variety of different geometric morphologies with special features on different geometric scales. An interesting example is the liver lobule that is the basic subunit of a liver. The lobule is a quasihexagonal macroscopic structure with periodic like so-called sinusoidal elements with structural features on the micro- and macroscale made of proteins, cells, and fluids. Various tools from micromachining and nanotechnology have demonstrated their capabilities to construct micromorphologies precisely, but even the reconstruction of such a system in technical polymers is challenging. In this work, the rapidly evolving technique of multiphoton polymerization has been explored for the construction of a scaffold that mimics the micromorphology of the liver with high resolution and detail up to the millimeter scale. At the end, a highly complex fluidically perfusable structure was achieved and simulations showed that the occurring shear stress, fluid velocity, and stream lines are comparable to the native liver lobule. Hereby, the photoresists SU-8 and SUEX TDFS were compared in terms of their processability, achievable resolution, and suitability for the intended application. Our results have shown that SUEX needs lower writing velocities but is easier to process and achieves a considerable higher resolution than SU-8. The scaffold could provide a base frame with a geometrically defined morphology for hepatic cells to adhere to, which could act as a starting point for cells to build new liver tissue for further integration in more complex systems.

Lobules of liver

Liver tissue

Template

Structuring

Deposition

10.2351/7.0000433

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Citations (8)

Development of Microstructuring Technologies of Polycarbonate for Establishing Advanced Cell Cultivation Systems

Uta Fernekorn Jörg Hampl Frank Weise Sukhdeep Singh Justyna Borowiec

This chapter contains sections titled: Introduction Material Properties of Polycarbonate Use of Polycarbonate Foils in Structuration Processes Simulation of Microstructuring of a Polycarbonate Foil Chemical Functionalization of Polycarbonate Surface Micropatterning of Polycarbonate Application Examples Conclusion and Further Perspectives Acknowledgements

Polycarbonate

Micropatterning

Surface Modification

10.1002/9781119041412.ch3

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Developmental Potential of the Murine Embryonic Stem Cells Transplanted into the Healthy Rat Brain - Novel Insights into Tumorigenesis

Cellular Physiology and Biochemistry (2009)

Marek Molčányi Peter Rieß Nadia Nabil Haj‐Yasein Kristine Bentz Mario Loehr

Although engraftment of undifferentiated pluripotent embryonic stem cells (ESCs) into the injured central nervous system (CNS) may lead to targeted cell replacement of lost/damaged cells, sustained proliferative activity combined with uncontrolled differentiation of implanted cells presents a risk of tumor formation. As tumorigenic potential is thought to be associated with pluripotency of embryonic stem cells, pre-differentiation may circumvent this problem. Recently, it has been demonstrated that tumorigenesis occurs despite pre-differentiation if the neural precursor cells are implanted into the brain of a homologous animal (e.g., mouse to mouse). However, xenotransplantation (e.g., mouse to rat) without pre-differentiation, lead to the development of healthy neuronal cells, in absence of tumor formation, suggesting that tumor-suppressive effects of host tissue on engrafted ESCs may play a role in transplant tumorigenesis. We critically investigated tumorigenesis and possible mechanisms of anticipated tumor-suppressive effect under conditions analogous to previously published studies. Xenotransplantation of D-3 murine ESCs into uninjured adult rat brains lacking any preliminary inflammatory potential was found to lead to tumor formation in 5 out of 8 of animals within 2 weeks postimplantation. Tumor-suppressive effects, reflected by Erdo et. al could possibly be ascribed to immunomodulatory activity of macrophages scavenging the tumorigenic fraction of the implanted cells. The importance of number of engrafted cells, implantation site and immunosuppressive effects are discussed as possible variables determining tumorigenic outcome after ESC transplantation.

Xenotransplantation

10.1159/000227816

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Citations (18)

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

Engineering in Life Sciences (2013)

Andreas Schober Uta Fernekorn Sukhdeep Singh Gregor Schlingloff Michael Gebinoga

Combining modern methods in microsystem technology with the latest advancements in the life sciences, namely those in tissue engineering and advanced cell culturing, is promoting the development of a promising toolbox for modeling biological systems. The core problem to solve using this toolbox is the design of 3D artificial cellular environments, both in fluidic systems and on solid substrates. The construction of 3D biological fluidic environments involves the use of microfluidic devices where fluid direction and behavior can be tightly regulated in a geometrically constrained environment for advanced cell cultivation. This is used in modern cultivation devices, such as bioreactors and multicompartment systems, including systems with integrated multielectrode arrays in both 2D and 3D. The construction of 3D cell cultures on substrates involves various fabrication techniques that use different polymers and biopolymers processed by micromachining, chemical pattern guided cell cultivation, photopolymerization, and organ printing methods. These methods together have the potential to create an artificial system with the complete hierarchical, geometrical, and functional organization found in an actual biological system. In this review, we describe representative developments in this research area and the fusion of formerly unrelated disciplines that are generating new beneficial applications in life sciences.

Fluidics

Microsystem

Toolbox

Structuring

Embossing

10.1002/elsc.201200088

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Citations (29)

Microfluidic 3D HepG2 cell culture: Reproducing hepatic tumor gene and protein expression in in vitro scaffolds

Engineering in Life Sciences (2015)

Uta Fernekorn Jörg Hampl Frank Weise Maren Klett Annette Läffert

As for 3D cell culture in general, it is also true for tumor cells that 3D conditions create a spatial microenvironment that is stimulated by concentration gradients of nutrients and gases. Cellular vitality and metabolic activity were examined in 2D and scaffold‐based 3D cultures of HepG2 cells. We compared gene and protein expression levels of tumor‐ and hepato‐specific markers such as alpha‐fetoprotein, albumin, integrin beta 1, insulin‐like growth factor , vascular endothelial growth factor A, and matrix metalloproteinase 11. Although similar biological functions were influenced under 3D static and perfused conditions, their gene expression levels differed. Immunofluorescence stainings detected increased integrin beta 1 expression while alpha‐fetoprotein was downregulated both in static and perfused 3D cultures of HepG2 cells. We hypothesized that improved mass flow in the bioreactors enables the cells to retain their nutrient supply, which is indicated by moderate or even downregulated expression of genes related to angiogenesis and apoptosis. Potential hypoxic stress in static 3D cultures of HepG2 cells resulted in upregulated vascular endothelial growth factor A expression and enhanced caspase 3 activity. Tuning the mass flow in 3D tumor cultures may lead to promising tools to investigate the metabolism and differentiation state of tumor tissues in vitro.

3D cell culture

10.1002/elsc.201400083

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Microfluidics and biosensors as tools for NanoBioSystems research with applications in the “Life Science”

Materials Science and Engineering B (2009)

Andreas Schober Caroline Augspurger Uta Fernekorn Karl‐Friedrich Weibezahn Gregor Schlingloff

Nanosensor

Microtechnology

Fluidics

Biocompatible material

10.1016/j.mseb.2009.12.042

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Citations (13)

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

Materialwissenschaft und Werkstofftechnik (2011)

Andreas Schober Uta Fernekorn B. Lübbers Jörg Hampl Frank Weise

Abstract Applications 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.

Microtechnology

Nanosensor

Fluidics

Biocompatible material

10.1002/mawe.201100746

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Citations (6)