A01 | Alginate-based bioinks with tailored microstructural properties for controlled cell behavior

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The aim of subproject A01 is the modification of adhesive, microstructural as well as microscopic and macroscopic mechanical properties of alginate-based biofabricated hierarchical tissue analogues for controlling desired cell behavior. This goal will be achieved by adjusting the porosity through sacrificial structures and by establishing localized durotactic gradients using two-phase (core/shell) printing. By simultaneously printing bioinks with different mechanical, adhesive and structural properties that are loaded with different cell types, a high degree of complexity can be achieved to control durotaxis, cell migration, cell differentiation and tissue structure formation

Prof. Dr. Aldo R. Boccaccini
Prof. Dr. Ben Fabry

A02 | Hyaluronic acid-based bioink platform with multi-functional crosslinkers for the controlled differentiation of mesenchymal stem cells

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 Hyaluronic acid (HA) represents a major component of the human extracellular matrix, however, so far highly versatile HA-based materials for biofabrication are lacking. The overall aim of this project is to develop a HA-based bioink platform utilizing multi-functional crosslinkers (PEG, modified biopolymers) that enables the controlled differentiation of mesenchymal stem cells. The modification with peptides and growth factors as well as the processing into gradient materials will further promote the development of coherent tissues within the printed 3D constructs. For the long term, this work aims to generate bioinks for the development of clinically relevant tissue models.

Prof. Dr. Torsten Blunk
Dr. habil. Jörg Teßmar

A06 | Cell-loaded microgels as mechanical protection and controlled microenvironment for cells in bioinks

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Aim of this project is the generation of cell-loaded microgels with uniform size and their establishment as additives in bioinks. The microgels shall on the one side act as mechanical protection from shearforces during printing and thereby extend the biofabrication window towards bioinks with higher viscosity and towards higher shear forces. In addition to that, biochemical functionalization and adjusting microgel degradability shall be used to tailor the microenvironment of the encapsulated cells and control their behavior. Prospectively, this project aims at establishing suspensions of cell-loaded microgels as bioink especially for the simultaneous printing of different cell types. 

Prof. Dr. Stephan Förster
Prof. Dr. Jürgen Groll

A07 | Influence of anisotropic fiber-reinforcement on cell behavior and printability of bioinks

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In subproject A07, electrospinning is applied to generate submicron-fibers, which can be printed as fillers in composite bioinks. Such fiber reinforcement can be conducted to reduce the hydrogel’s polymer concentration resulting in enhanced cell mobility within the printed construct while maintaining the bioink’s printability in terms of shape fidelity. Furthermore, flow-induced anisotropically aligned fibers can serve as a substrate for cell-adhesion contributing to oriented cell growth. Based on the first funding period, cell-specific reactions will now be identified applying tailored fiber-matrix-formulations and the shear-rheological characterization will be expanded to include extensional rheological models representing 3D-printing.

Dr. Gregor Lang
Prof. Dr. Dirk Schubert
Dr. Natascha Schäfer

A08 | Vascular supply for 3D tissue based on shape-changing polymers and recombinant spider silk

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The aim of this project is the fabrication of hierarchically structured tissues with integrated fiber-based structures, which give the matrix anisotropic properties for directed cell growth, as well as tubular elements for the supply of nutrients and oxygen. To implement the project, various manufacturing methods such as 4D biofabrication approaches and established 3D printing and fiber spinning processes will be combined. The integrated tubular structures should also provide a basis for a later vascularization of the constructs after tissue maturation.  

Prof. Dr. Thomas Scheibel
Prof. Dr. Leonid Ionov

B02 | Endothelialized perfusable microvascular networks for biofabrication of standardized in vitro tissue models

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The aim of this project is biofabrication of perfusable and endothelialized microvascular networks, which will be produced by MEW of sacrificial thermoresponsive polyoxazolines. Particular focus will be placed on adapting the network geometry and the surrounding cell-containing hydrogels to tissue-specific requirements of B and C projects and to the design of appropriate microscopy-compliant bioreactors. Besides, extensive investigations of endothelial function in the fabricated tissue models are planned, including angiogenesis, interactions with circulating cells, barrier function and regulation of physiological processes in the hydrogel-contained cells.

Prof. Dr. Iwona Cicha
Prof. Dr. Jürgen Groll

B03 | Printing of biofabricate and customized bioreactors for skeletal muscle tissue

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The aim of subproject B03 is the development of different composite bioinks with ion-releasing (bioreactive) particles and electrically conductive fillers for the bioprinting of skeletal muscle tissue. Basically, synergistic stimulation of cells and cell growth through electrical and biochemical factors for the formation of highly mature muscle tissue will be investigated in vitro. For this purpose, a bioreactor with complex structure and functionalities will be designed and fabricated using additive manufacturing, which will be tissue-specific and will enable the electromechanical stimulation of skeletal muscle tissue.

Prof. Dr. Aldo R. Boccaccini
Dr. Sahar Salehi
Prof. Dr. Frank Döpper

B04 | 3D printing of vascular structures from vascular wall-resident stem cells

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Aim of this project is the biofabrication of artificial vascular structures with correct hierarchical organization and wall morphology consisting of intima, media and adventitia. This shall be reached by the exploitation of the cellular plasticity of vascular wall-resident stem cells (VW-SCs). These cells have been shown to possess the necessary cellular plasticity to deliver such structures. By printing of VW-SC loaded bioinks into self-healing support gels, the use of vessel wall specific matrix components and perfusion of the structures, we aim on a medium to long term to biofabricate complex and hierarchically organized vascular structures.

Prof. Dr. Süleyman Ergün
Prof. Dr. Jürgen Groll

B05 | Membrane-engineering as a tool to control the behavior of mesenchymal stem cells in biofabrication processes

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The interaction of cells with bioinks, as well as direct cell-cell interaction, is essential for biofabrication of tissue constructs. This project aims to reduce shear stress during bioprinting, to increase cell proliferation in the hydrogel, to influence cell-cell aggregation and spheroid formation, and to optimize cell-ink interaction by coupling a specific galectin-1 ligand via cell surface modification by membrane engineering. The long-term goal is to apply membrane engineering for cell and bioink modification to optimize the post-fabrication behavior of cells in biofabricated constructs.

Prof. Dr. Regina Ebert
Prof. Dr. Jürgen Seibel

B06 | Reporter-conjugated bioinks for the investigation of cellular interactions in biofabrication

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The aim of B06 is the development of a modular reporter ink for biofabrication. The interactions between cells are to be systematically investigated in detail via integrated reporter functions in the bioink after the printing process. For this purpose, a reporter ink platform is to be developed that can be precisely printed, delivers stable 3D constructs and can be modified site-specifically in order to be able to functionally incorporate the reporters for cell adhesion and proteolytic degradation. In the long term, the reporter’s ink should enable insights into biochemical and biomechanical processes during the maturation of cells in 3D constructs.

Prof. Dr. Tessa Lühmann
Dr. Rainer Detsch

B07 | Development of sensor particles and computer simulations for the determination of mechanical cell stress during biofabrication

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Hydrodynamic forces can cause enduring damage to living cells. Here we will develop microgel-based sensor particles together with computer simulations to understand in detail the mechanical stress on cells during biofabrication. For this, we will carry out microfluidic experiments in order to investigate shear stress in prototypical situations. Based on these efforts, we will develop a transparent printhead in order to monitor the deformation of cells and sensor particles in-situ during printing. Comparing sensor particles and living cells together with suitable modeling approaches will allow us to distinguish between passive mechanical and active biological responses of the cell.

Dr. Krystyna Albrecht
Prof. Dr. Stephan Gekle
Prof. Dr. Georg Papastavrou

B09 | Biofabricated gradients for functional tissue models

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The aim of this project is to develop a platform technology to biofabricate defined and reproducible gradients in space and time, to analyze them and to model them in silico in order to be able to investigate their effects on cell-biomaterial interactions. For this purpose, we will first develop print heads that enable us to print controlled transitions of materials from the A / B projects, active substances and cells. Through the comprehensive characterization of the printed gradients using mechanical testing methods in combination with image processing, we will constantly analyze and improve the result with regard to the requirements of the C projects. In addition, we will use continuum mechanics modeling and simulation to systematically optimize process parameters, the print pattern and the 3D arrangement within the construct

Dr. Tomasz Jüngst
Dr.-Ing. Silvia Budday

C01 | Biofabrication of heart substitute tissue based on bioink from spider silk proteins

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Heart diseases are a major socioeconomic burden. Despite considerable progress in the prevention and minimization of heart damage, the prevalence of heart insufficiency increases continuously. The aim of this subproject is the reproducible production of hierarchically organized human cardiac substitute tissue using 3D printing technology. For this purpose, hiPSC-derived cardiac cells, spider silk proteins developed during the first funding period, aligned fibers, and perfusable tubular structures will be used. The long-term goal is the treatment of heart diseases.

Prof. Dr. Felix Engel
Prof. Dr. Thomas Scheibel

C02 | Biofabrication of a 3D model for the functional investigation of stromal parameters influencing the behavior of breast cancer cells

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This project aims at the biofabrication of a complex tumor-stroma model to specifically study the behavior of breast cancer cells as a function of stromal parameters. Using 3D bioprinting and bioinks with independently controllable physicochemical properties, the interactions of breast cancer and stromal cells will be investigated especially regarding correlations between cancer cell migration, protein secretion, and ECM remodeling. The modular approach allows us to recapitulate relevant aspects of the tumor microenvironment and to gain important mechanistic insights into how tumor-stroma interactions contribute to tumorigenesis.

Prof. Dr. Torsten Blunk
Prof. Dr. Ben Fabry

C03 | Analysis of tumor dormancy and progression in biofabricated vascularized 3D models

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The aim of the second funding period is the in vitro biofabrication of in vivo tumor models as well as in vivo evaluation of tumor models in the vascularized AV loop model. The primary focus will be the evaluation of tumor dormancy and progression and the influence of the tumor microenvironment. Based on our previous studies, more complex tumor models will be biofabricated using different areas, stiffnesses and cell types and the tumor cell behavior will be analyzed also on molecular level.

Prof. Dr. Andreas Arkudas
Prof. Dr. Anja Boßerhoff
PD Dr. Annika Kengelbach-Weigand

C04 | Biofabrication of cellularized and by the AV loop vascularized tissue container for the transplantation of cells producing therapeutic proteins

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Principle aim of the project is the development of a transplantable tissue container which enables the in vivo production of recombinant therapeutic proteins for the treatment of autoimmune diseases and cancer. As a model biological TNFR2-Fc is used which corresponds to the clinically approved TNF-blocker Enbrel®. In the first funding period bioinks supplemented with TNFR2-Fc producer cells have been developed, which will now be used to print structured containers or container inlets enabling accelerated in vivo vascularization. This should allow durable and stable biological production and release in vivo. The effectiveness of the therapeutic tissue container will be assessed in the pristan induced rat arthritis model.

Prof. Dr. Dr. h.c. Raymund Horch
Prof. Dr. Harald Wajant

C05 | Ultraweak hydrogels for molecular and biological functional analyses of cell-matrix and cell-cell 3D networks in neuronal cell culture systems

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Within the first grant period of the SFB, 3D Matrix-scaffold composites were established composed of ultra-weak hydrogels (100-150 Pa), MEW scaffolds and single cell types (neurons, astrocytes, Glioblastoma cells). In the new grant period, we will further develop this model system to understand cell-cell interactions between primary neuronal and tumor cells. The focus of the project will be to study the influence of the extracellular environment, such as matrix, scaffold and the resulting biomechanics on tumor progression using co-cultures as well as spheroids of primary neuronal cells and tumor cells.

Prof. Dr. Reiner Strick
Prof. Dr. Carmen Villmann

C06 | Biofabrication of a glomerular ex vivo model by stepwise mimicking functional core components

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By combining top-down fabrication methods and bottom up strategies, we will generate a 3D glomerular ex vivo model. Therefore, we will study cellular behavior of glomerular endothelial cells and podocytes in a co-culture system on different sides of an artificial basement membrane. Next, we will mimic the glomerular structure by integrating mesangial spheroids into capillary loops consisting of glomerular endothelial cells, artificial basement membrane and podocytes (bioassembly). Thereby, we will study 3D structure, self-assembly, maturation, paracrine cell interaction and generation of extracellular matrix.

Prof. Dr. Janina Müller-Deile
Dr. Taufiq Ahmad

Z01 | Central Tasks

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The subproject “central tasks” (management) plans and coordinates the research programmes of the individual subprojects and their publications, processes the administrative tasks of the SFB, in particular the cooperation with the German Research Foundation (DFG), and is responsible for the external representation of the Collaborative Research Centre (SFB).

Key task of subproject Z is monitoring the compliance with the agreed budgets of individual subprojects within the SFB/TRR 225 with the help of suitable controlling instruments. Other tasks include:

General administration
Overview of the overall finances of the SFB, issue of reports on the expenditure of funds, recruitment and dismissal of staff, accounting for the different subprojects, ordering procedures, filing, inventory, general correspondence, establishment and maintenance of a World Wide Web server for the international presentation of the SFB via electronic media and easier exchange of information within the SFB.

Administrative coordination of research within the subprojects
Administrative coordination of research activities, preparation of regular progress reports, implementation and update of project management, participation in working group meetings, organization and implementation of regular meetings according to the arrangements the SFB, in particular the board committee meetings, coordination and compilation of research reports including all duties involved in the publication of the reports and research proposals, administrative coordination of symposiums, conferences and seminars.

General public relations
Established as press office of the SFB, assistance in organizing and hosting of events for the presentation of the SFB to the general public, presentation of the SFB at meetings etc.

Dr. Jennifer Ritzer
Eva Hilpert

Z02 | Quantitative imaging and analysis of biofabricate quality and maturation

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The new project Z02 will develop and provide standardized methods for acquiring, processing, and evaluating imaging data for the entire TRR/SFB, starting off with selected model systems in project areas B and C. In particular, solutions for sample chambers and (fluorescence) imaging, e.g. customized light-sheet microscopy, as well as image data processing and analysis, tuned for the special demands of biofabricates, will be key. Cross-validation of complementary imaging modalities in the three involved laboratories will allow for establishing robust and versatile approaches for the entire collaborative research center.

Prof. Dr. Katrin Heinze
Prof. Dr. Dr. Oliver Friedrich
Prof. Dr. Matthias Weiss

Z03 | Fluorescent reporter cells for live-cell imaging in biofabrication

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TP Z03 provides all sub projects in the TRR225 reporter cells and systems, which make stress conditions of the cells measurable during the printing process, as well as in the maturing biofabricates. Using lentiviral fluorescence-based reporter constructs and cells, the (molecular) responses of different cell types will be analyzed as a function of the applied biomaterials, printing conditions, matrix stiffness, etc.

Prof. Dr. Anja Bosserhoff

A03 | Thermo-gelling poly(2-oxazolin) based hydrogels with temporal mechanical control

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This project aims at developing a synthetic, cell-compatible and modular bioink-platform. Diblock copolymers based on poly(2-oxazoline)s will be deployed exhibiting suitable thermo- and shearresponsive behavior. This novel bioink platform will be modified by a dual-crosslinking mechanism to (i) guarantee mechanical stability after printing and (ii) to modulate the stiffness of the ink during cell-culture experiments.  

PD Dr. Tessa Lühmann
Prof. Dr. Robert Luxenhofer

A04 | Expansion of the biofabrication window using 2.5D scaffolds made from (AB)n-segmented copolymers

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The aim of the project is the expansion of the biofabrication window of bioinks. By using 2.5D scaffolds – a structurally stable substrate – for the bioprinting process a better precision and reproducibility of the bioink depostion can be achieved. For this purpose, new (AB)n-segmented copolymers with hydrophilic soft segments and supramolecular hard segments are developed, which can be processed by Melt Electrospinning Writing. By selective swelling with biological media hydrogel scaffolds are formed covering a wide range of Young’s Moduli and enabling different cellular interactions. Until today, this cannot be realized with conventional biofabrication processes. 

Prof. Dr. Hans-Werner Schmidt
Prof. Dr. Paul Dalton

B08 | Time-resolved biophotonics approach cellular signaling, cell-matrix interactions and matrix remodeling mechanisms in biofabricated constructs

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In this optical engineering and bioprocess engineering project we aim to develop new systems to study in situ maturation and regulation of cell-matrix junctions of biofabricated constructs over long time periods. To this end, (i) we will advance high resolution/depth penetrating multiphoton- and light sheet technology towards a 2-photon single plane illumination microscopy (2P-SPIM), and (ii) design and engineer precision positioned mobile mini-bioreactors. We will validate these systems for selected bioconstructs within the consortium regarding (iii) visualization of 3D spatial patterning of focal adhesion proteins between cell and matrix as well as matrix production during long-term maturation of constructs.

Prof. Dr. Dr. Andreas Beilhack
Prof. Dr. Dr. Oliver Friedrich