3rd International Symposium of the Transregio 67
FRONTIERS IN BIOMATERIAL SCIENCE

20.-21. March 2020 at Leipzig University,  Paulinum, Augustusplatz 10, 04109 Leipzig, Germany

FBS 2020 canceled due to coronavirus

Due to current developments, the 3rd international symposium on 20-21 March 2020 at the Leipzig University has unfortunately to be canceled.

This decision was not an easy one, especially since there are very high registration numbers for this year’s symposium. But for reasons of precautionary health protection, we have decided that it is more important not to endanger the well-being of the visitors of the symposium. Even though the symposium is not one of the “major events with more than 1,000 participants”, several hundred people, including from abroad and with long travel distances, would have been expected at this year’s date. This would increase the risk of a further spread of the corona virus.

The organizers ask for your understanding for this decision and hope to contribute actively and to the best of their knowledge and belief to the protection of health. A new alternative date for the 3rd International Symposium will be announced shortly.

With the best wishes

Prof. Dr. Jan Simon & Prof. Dr. Carsten Werner
(Chairspersons)

Conference Office

Leipzig University
Department of Dermatology, Venerology and Allergology
Philipp-Rosenthal-Straße 23
04103 Leipzig

Phone +49 (0) 341 97 - 18605
Mail sfb.trr67@medizin.uni-leipzig.de

Send me new date

Programm & Speakers

MARCH 20, 2020 

Session 1: BIOMATERIALS

Kristi L. Kiick, Ph.D.Phase-separating (poly)peptides in the design of advanced biomaterials

Macromolecular structures that are capable of selectively and efficiently engaging cellular targets offer important approaches for mediating biological events and in the development of hybrid materials. We have employed a combination of biosynthetic tools, bioconjugation strategies, and biomimetic assembly in the design of multiple types of biopolymer conjugates of thermoresponsive (poly)peptides including those derived from sequences of resilin, elastin, and collagen. PEG-biopolymer conjugates have been used in the formation of hydrogels by covalent click-based chemistries that are selectively degradable under pathological conditions. These materials can be designed to control the release of both small-molecule and macromolecular cargo with tuned release profiles, and materials with select mechanical properties have demonstrated promise for healing vascular graft materials in vivo. The incorporation of (poly)peptides affords materials that not only show controllable micro- and nanoscale morphologies, but that also have promise for targeting drug delivery to damaged tissue.

Biographical Information
Kristi Kiick is the Blue and Gold Distinguished Professor of Materials Science and Engineering at the University of Delaware, holding affiliated faculty appointments in the Departments of Biological Sciences and of Biomedical Engineering at the University of Delaware and in the School of Pharmacy at the University of Nottingham, where Kiick is conducting research as a Leverhulme Visiting Professor and Fulbright Scholar. Her internationally recognized research focuses on the synthesis, characterization, and application of protein, peptide, and self-assembled materials for applications in tissue engineering, drug delivery, and bioengineering, with specific research in cardiovascular, vocal fold, and cancer therapies. A Fellow of the American Chemical Society, she has published more than 150 articles, book chapters, and patents, and has delivered over 160 invited and award lectures. Kiick’s honors have included several awards (Camille and Henry Dreyfus Foundation New Faculty, Beckman Young Investigator, NSF CAREER, DuPont Young Professor, and Delaware Biosciences Academic Research Award) as well as induction as a fellow of the American Institute for Medical and Biological Engineering, of the American Chemical Society and of the American Chemical Society Division of Polymer Chemistry. She also serves on the advisory and editorial boards for multiple international journals and research organizations. Kiick received her bachelor of science in chemistry from UD as a Eugene du Pont Memorial Distinguished Scholar, where she graduated summa cum laude, and a master of science in chemistry as an NSF graduate fellow at the University of Georgia. She worked in industry (Kimberly Clark Corporation) as a research scientist prior to obtaining master of science and doctoral degrees in polymer science and engineering at the University of Massachusetts Amherst, completing her doctoral research at the California Institute of Technology as a recipient of a National Defense Science and Engineering Graduate (NDSEG) fellowship.

Contact
Prof. Kristi L. Kiick, Blue and Gold Distinguished Professor
Department of Materials Science and Engineering, University of Delaware
Leverhulme Visiting Professor, University of Nottingham
US-UK Fulbright Scholar, University of Nottingham
102 DuPont Hall, Newark, DE 19711

Website: https://sites.udel.edu/kiickgroup/

Morphogenesis guided by 3D patterning of growth factors in biological matrices

The possibility to control in 3D the positioning of bioactive cues is fundamental to study cell guidance and morphogenesis in defined system, as well as to form engineered tissues. In recent research at the Zenobi-Wong, Bode and Lutolf labs, we developed tools which enables two-photon patterning (2PP) of sensitive biological cues, such as growth factors, not only within inert hydrogels such as alginate, but also within natural mammalian matrices such as collagen, fibrin, enzymatically cross-linked hyaluronan and laminin-rich basement membrane extract (Matrigel). Our approach further enables incubation free patterning, which paves the road towards in vivo applications of 2PP. To achieve this, we harnessed the outstanding kinetics, biocompatibility and orthogonality of the bacterial ligase Sortase A (SA) to perform specific covalent couplings in physiological conditions, in the presence of complex biological matrices and of living cells. Modified avidin was used as a universal carrier for biotinylated bioactive molecules, which imparts great flexibility to the method. Our efforts to improve pattern quality led us to develop new biochemical tools such as protein functionalization reagents with improved reactivity and linkage stability. As we further noticed that traditional hydrophobic cages were considerably increasing the non-specific adsorption of proteins to functionalized hydrogels, we developed new high yielding synthesis routes for hydrophilic two-photon active cages and their peptide derivatives. Finally, we developed an open-source library to control the scanning pattern of standard commercial two-photon microscopes, in order to enable the patterning of complex 3D shapes and gradients using existing infrastructure. As a proof-of-concept study, we demonstrated axonal guidance from dorsal root ganglia (DRG) primary neurons using nerve growth factor (NGF) patterns in a brain-mimetic matrix. By systematically addressing limitations of current photopatterning methods, we aim to provide new opportunities to study tissue development and regeneration in defined systems.

Contributors
Nicolas Broguiere [1,2], Ines Lüchtefeld [1], Lucca Trachsel [1], Dmitry Mazunin [3], Jeffrey Bode [3], Matthias P. Lutolf [2], Marcy Zenobi-Wong [1]
1. Tissue Engineering and Biofabrication Laboratory, Department of Health Sciences & Technology, ETH Zürich, Zürich, Switzerland.
2. Laboratory of Stem Cell Bioengineering, Institute of Bioengineering, School of Life Sciences and School of Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
3. Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH Zürich, Zürich, Switzerland

Contact
Dr. Nicolas Broguiere
Stem Cell Bioengineering Laboratory (LSCB, Prof. Lutolf), Institute of bioengineering (IBI)
École Polytechnique Fédérale de Lausanne, Switzerland

Website:
https://www.epfl.ch/labs/lutolf-lab/

Jürgen Groll Modulating the reaction of primary human immune cells to 3D printed scaffolds
(Tina Tylek, Carina Blum, Katrin Schlegelmilch, Jürgen Groll)

Influencing the innate immune response after implantation remains one of the major chal-lenges in the development of biomaterials. Macrophages are key players of the innate immune system that can roughly be divided into the pro-inflammatory M1 type and the anti-inflamma-tory, pro-healing M2 type. One strategy to drive macrophage polarization is precise control over biomaterial geometry. Melt electrowriting (MEW) is especially suitable in this context as it enables the production of highly defined scaffold geometries built of fibers with diameters in the lower micrometer range. Our group has demonstrated the ability of cells to attach, infiltrate, and proliferate upon seeding onto MEW scaffolds [1], and that the scaffold surface can be modified for specific interaction with cells [2]. 
This talk will present our findings on immunomodulatory effects of MEW scaffolds with a variety of pore geometries (rectangular, triangular and round). These scaffolds facilitate primary hu-man macrophage elongation accompanied by differentiation towards the M2 type, which was most pronounced for box-shaped pores with 40 μm inter-fiber spacing [3]. Moreover, novel double-hierarchical MEW scaffolds will be presented that induce an even stronger M2-type differentiation stimulus for human macrophages.

Literature
[1] G. Hochleitner, et al: Additive manufacturing of scaffolds with sub-micron filaments via melt electro-spinning writing. Biofabrication 2015, 7, 035002.
[2] C. Blum, et al: Extracellular matrix-modified fiber scaffolds as a pro-adipogenic mesenchymal stromal cell delivery platform. ACS Biomaterials Science & Engineering, 2019, 5, 12, 6655-6666.
[3] T. Tylek, et al: Precisely Defined Fiber Scaffolds with 40 μm Porosity Induce Elongation Driven M2-like Polarization of Human Macrophages. Biofabrication, https://doi.org/10.1088/1758-5090/ab5f4e

Contact
Prof. Dr. Jürgen Groll, Chair for Functional Materials in Medicine and Dentistry and Bavarian Polymer Institute
University of Würzburg, Pleicherwall 2, 97070 Würzburg, Germany

Aldo R. BoccacciniBioactive glasses with tuned ion releasing capability as versatile biomaterials for tissue engineering

Bioactive glasses (BGs) are being investigated for tissue engineering (TE) applications for 20+ years, starting with pioneering research work at Imperial College London led by the late Prof. L. Hench [1]. The success of BGs in hard and soft TE applications is based on the biochemical reactions occurring at the interface between BGs and the biological environment, involving the release of biologically active ionic dissolution products from the BG matrix [2]. The progress in the development and characterization of TE scaffolds made purely by BGs or by combining BGs and biopolymers, including their application in biofabrication approaches, will be discussed with focus on the effect of different biologically active ions released from BGs on osteogenesis and angiogenesis. Research involves BGs incorporating a variety of biologically active ions, such as B, Sr, Cu, Nb, Co, Li, Mn [3]. Indirect cell culture methods using endothelial cells with or without BMSCs in cell culture inserts exposed to ion dissolution products from BG scaffolds (e.g. Cu doped) will be presented to show that BMSCs secrete an increased concentration of vascular endothelial growth factor, thus confirming the angiogenic potential of such BGs. The results are evaluated regarding the stimulating effect of metallic ions on stem cells, also based on a growing amount of relevant results from the literature. The variation of ion concentration in medium as function of time and the time dependent effects on stem cells will be discussed, which is required for the comprehensive assessment of the long-term biological performance of BGs with implication for clinical applications.

Literature
[1] L. L. Hench, Bioactive materials: The potential for tissue regeneration, J. Biomed. Mater. Res. 41 (1998) 511-518.
[2] A. Hoppe, et al., A review of the biological response to ionic dissolution products from bioactive glasses and glass-ceramics, Biomaterials 32 (2011) 2757-2774.
[3] V. Mourino, et al., Enhancing biological activity of bioactive glass scaffolds by inorganic ion delivery for bone tissue engineering, Curr. Op. Biomed. Eng. 10 (2019) 23-34. 

Contact
Prof. Dr. Aldo Boccaccini
Institute of Biomaterials, University of Erlangen-Nuremberg
Cauerstr. 6, 91058 Erlangen, Germany
Email: aldo.boccaccini@ww.uni-erlangen.de

Internet: www.biomat.techfak.uni-erlangen.org

Session 2: BONE

Prof. Dr. Nicola NapoliBone fragility in diabetes mellitus

The risk of fragility fractures is increased in patients with either type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM). Although BMD is decreased in T1DM, BMD in T2DM is often normal or even slightly elevated compared with an age-matched control population. Both animal and human models have proven increased trabecular BMD with cortical deficits like higher cortical porosity. Analysis of bone strenght has brough mixed results because of the difficult assessment in humans. When surrogate markers of bone strength are applied with HRpQCT, lower bone strength is observed in both T1D and T2D, regardless of BMD. Direct biomechanic tests on femur heads have confirmed mechanical deficits but these data are often obtained in well controlled diabetics. It is likely that long term exposure to hypeglycaemia has a major impact on all parameters of bone strength, explaining the high risk of fractures in these patients. In both T1DM and T2DM, however, bone turnover is decreased and the bone material properties and microstructure of bone are altered; the latter particularly when microvascular complications are present. The pathophysiological mechanisms underlying bone fragility in diabetes mellitus are complex, and include hyperglycaemia, oxidative stress and the accumulation of advanced glycation endproducts that compromise collagen properties, increase marrow adiposity, release inflammatory factors and adipokines from visceral fat, and potentially alter the function of osteocytes. Additional factors including treatment-induced hypoglycaemia, certain antidiabetic medications with a direct effect on bone and mineral metabolism (such as thiazolidinediones), as well as an increased propensity for falls, all contribute to the increased fracture risk in patients with diabetes mellitus.

Contact
Prof. Dr. Nicola Napoli, Associate Professor of Endocrinology and Metabolism
Campus Bio-Medico University of Rome, Italy / Washington University in St. Louis, Missouri, US

Websitehttps://www.campusbiomedicohospital.com/doctors-and-medical-staff/prof-nicola-napoli 

Univ.-Prof. Dr. med. Thomas PapMechanisms of local bone remodelling in chronic inflammatory arthritis

Rheumatoid arthritis (RA) is the prototype of an inflammatory arthritis that is characterized by systemic autoimmunity, chronic inflammation, and progressive joint destruction. Development of RA is marked by the hyperplasia of the synovial membrane as caused by an infiltration and accumulation of inflammatory cells as well as an increase in the number of resident mesenchymal cells. Mesenchymal fibroblast-like synoviocytes (FLS) are a key part of the local immune system in the joints and integrate signals from different sources into a pathological tissue response. Resorption of the juxtaarticular bone is part of this pathological response and is denoted as focal bone erosion which occurs early in this disease and is associated with significant morbidity. Focal bone erosions are observed at the interface of pannus and bone tissue both marginally, where pannus invades cortical bone, and in the immediate subchondral bone, where the pannus invades the marrow space. Many of the cytokines and growth factors implicated in the inflammatory processes are secreted by FLS and have been demonstrated to impact directly or indirectly on osteoblast and/or osteoclast differentiation and function. However, research of the last years has also identified some novel pathways by which osteoclast- mediated bone resorption is regulated and fine-tuned under inflammatory conditions and that link inflammatory bone resorption to other features of systemic autoimmunity such as the activation of developmental pathways or muscle weakness. This lecture will review some of these novel mediators and pathways, including members of the Wnt- signalling pathway such as sclerostin, members of the GDF- family of growth differentiation factors such as myostatin and cell surface anchored proteoglycans, particularly syndecans. Focusing on the role of these molecules in the FLS- mediated regulation of osteoclastic bone resorption, the lecture will point to general principles of inflammatory bone remodelling and discuss potential therapeutic implications for RA.

Contact
Prof. Dr. Thomas Pap
Institute of Musculoskeletal Medicine (IMM), University of Münster, Münster, Germany

Website: http://www.campus.uni-muenster.de/iemm.html

Prof. Tonia Vincent FRCPCartilage, heal thyself?

Osteoarthritis (OA) is the most common form of joint disease, affecting most people over 60, and younger individuals following joint trauma. Once considered a ‘passive’ disease of excessive wear of the cartilage layer coating joint surfaces, we now know that OA is due to mechanical sensing of the cells within cartilage, causing them to produce enzymes that start its breakdown. The main ways by which cartilage cells sense mechanical effects are either when cartilage is sheared as it slides, which triggers enzymatic breakdown of the cartilage; or through compression of the joint surfaces, which leads to production of molecules that are known to promote cartilage protection. Evidence that damaged human cartilage can regenerate has emerged from recent studies. Specifically, regeneration occurs when the joint is immobilized in such a way as to allow compression but no sliding or shear of the surfaces (a procedure called surgical joint distraction). From mouse and human studies we conclude that this leads to release of molecules that drive cartilage regeneration and suppress shear-induced production of cartilage-degrading enzymes.       
Collectively we believe that there is strong intrinsic capacity for damaged articular cartilage to repair. The molecules that orchestrate this in the joint, as well as the mechanisms that lead to their appropriate release, will be discussed.

Contact
Prof. Tonia Vincent FRCP
Professor of Musculoskeletal Biology
Director, Centre for Osteoarthritis Pathogenesis &
Consultant Rheumatologist Kennedy Institute of Rheumatology, University of
Oxford Roosevelt Drive, Oxford OX3 7FY

Websitehttps://www.kennedy.ox.ac.uk/team/tonia-vincent 

Prof. Thomas L. Clemens, Ph.D. Structural Role for Osteoblast-derived Citrate in Bone

Converging evidence from both historical and contemporary studies implicate citrate as a structural component of the apatite-collagen nanocomposite. Citrate is used by all aerobic organisms to produce usable chemical energy and is present in bone at strikingly high concentrations (1-5 wt%). Two independent studies using high resolution NMR to model the citrate molecule within the apatite crystal suggest that the degree of incorporation of citrate, as well as its spatial orientation within the mineral structure, is critical for maintaining favorable biomechanical properties. These observations prompt several fundamental questions that form the basis for this proposal: 1) What is the source and mechanism of delivery of citrate to bone; and 2) Does the concentration of citrate in bone impact its structural integrity? In this project, we propose to characterize a new metabolic pathway, which enables the osteoblast to regulate bone citrate accumulation. Our recent studies demonstrate functional expression of a PTH responsive extracellular Na+/citrate cotransporter, Slc13a5, in mineralizing osteoblasts. Interference of Slc13a5 mediated citrate transport either genetically or pharmacologically disrupts osteoblast mediated mineral deposition. Mice lacking Slc13a5 show reduced bone volume with defects in tooth enamel, pathological features similar to those seen in humans with mutations in SLC13A5. Metabolic flux analysis revealed striking elevations in 13C glucose-derived citrate in apatite deposited by Slc13a5 null osteoblasts compatible with increased mitochondrial export at the level of the zinc dependent mitochondrial aconitase. These findings and other data suggest the existence of osteoblast specific mechanisms that control both the production and delivery of citrate to bone.

Contact
Prof. Thomas L. Clemens, Ph.D.
Department of Orthopaedic Surgery, Johns Hopkins University

Website: https://www.hopkinsmedicine.org/profiles/results/directory/profile/0000004/thomas-clemens

Prof. Dr. Ulf Müller-LadnerMetaflammation and Bone

Rheumatic diseases encompass a diverse group of chronic disorders that commonly affect musculoskeletal structures. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the two most common, leading to considerable functional limitations and irreversible disability, especially when osseus structures are affected. Although many pathophysiologic and immunologic mechanisms are known, the knowldege of the links between the immune system, metabolic effector molecules and osteodestruction is still growing. Within this interactive system, adipokines, which are not only obesity-associated, but represent also a wide variety of bioactive, immune and inflammatory mediators mainly released by adipocytes, act as signalling molecules in the metabolic-immune interactions. Adipokines be synthesized by synoviocytes, osteoclasts, osteoblasts, chondrocytes and inflammatory cells in the Joint microenvironment, showing potent modulatory properties on diffeerent ffector cells in OA and RA pathogenesis. Moreover, other metabolically active molecules such as free fatty acids (FFA) can also influence osteocytes significantly. For example, when stimulated with FFA, osteoblasts from RA and OA patients secrete higher amounts of proinflammatory cytokines and chemokines. Vice versa, mineralization activity of osteoblasts correlate inversely with the level of FFA-induced IL-6 secretion. Moeover, with respect to the innate immune system, Toll-like receptor 4 blockade significantly reduced fatty acid-induced IL-8 secretion by osteoblasts, and in osteoclasts, IL-8 secretion was enhanced by fatty acids. Taken together, these data indicate a direct influence of adipose tissue on bone metabolism in inflammatory rheumatic entities.

Contact
Prof. Dr. Ulf Müller-Ladner
Abteilung für Innere Medizin mit Schwerpunkt Rheumatologie, Campus Kerckhoff
Justus-Liebig Universität Giessen Benekestr. 2, D- 61231 Bad Nauheim, Germany

Webiste: www.kerckhoff-klinik.de

Session 3: HIGHLIGHTS OF TRANSREGIO 67

Sulfated glycosaminoglycans and bone regeneration

Osteoporotic fractures are a major clinical challenge as bone regeneration and osseointegration of implants are commonly impaired. With increasing age and comorbidities, osteoporotic fractures are estimated to quadruple by 2050, highlighting the need for new, more biologically active biomaterials.
Therefore, we investigated the functional role of glycosaminoglycans (GAG) for their osteogenic potential. Our study revealed that GAG sulfation had profound effects on all stages of osteoclast and osteoblast differentiation. Whereas the viability of osteoclasts was increased, osteoclast numbers and their activity were significantly decreased. On the other hand, pro-osteogenic activity of osteoblasts and osteocyte-like cells were increased. We further demonstrated that sGAG by virtue of their chemical structure can directly bind to several key bone proteins that have a heparin-binding domain such as osteoprotegerin and sclerostin, thus interfering with their bioactivity. These findings were validated in an in vivo fracture healing study of compromised bone healing. To this end diabetic Zucker diabetic fatty (ZDF) rats were subjected to a critical size defect, that was filled with scaffold materials coated with or without sGAGs. Histological analysis of the defect area demonstrated a better regeneration with GAG coatings, whereas the sGAGs significantly increased the bone healing of the diabetic animals significantly to a healing potential similar to non-diabetic animals. Futhermore cells penetrated deeper into the sGAG coated scaffolds and the area covered by these cells was increased. In part these effects can be attributed to a local scavenging of sclerostin as demonstrated by immunohistochemical staining.
Here we demonstrated that GAG sulfation both directly and indirectly increases osteogenesis and reduces osteoclastogenesis thus, significantly altering the bone cell cross talk. This data suggests that finetuning GAG composition and linking GAG function to surfaces could represent a suitable tool to enhance local bone regeneration.

Contact
Prof. Dr. Lorenz C. Hofbauer
Medizinische Klinik III / Haus 27
Universitätsklinikum „Carl Gustav Carus“ der Technischen Universität Dresden
Fetscherstraße 74
D-01307 Dresden

PD Dr. rer.nat. Vera Hintze, Research Assistant and Junior Research Group LeaderStructural and functional insights into GAG modulation of angiogenic processes – implications for the design of functional biomaterial

Pathological healing characterized by abnormal angiogenesis as well as impaired wound healing of damaged vascularized tissues represent a serious burden to patients’ quality of life especially in elderly multimorbid patients. Both require innovative biomaterial-based treatment strategies to control the activity of angiogenic factors. Vascular endothelial growth factor-A (VEGF-A) is a key player of angiogenesis interacting with sulfated glycosaminoglycans (sGAG) within the extracellular matrix. The latter are thus important regulators of angiogenic processes. We used chemically modified, polymeric and oligomeric sGAG derivatives for evaluating the structural requirements of GAGs to control and tune VEGF-A function, aiming to translate these findings to the design of functional biomaterials. By combining biophysical and immunobiochemical analyses with molecular modeling, we revealed how sGAG derivatives influence the interplay of VEGF-A and its heparin-binding domain with the signaling receptor VEGFR-2 up to atomic detail [1]. We demonstrated that sGAG derivatives alter VEGF-A/tissue inhibitor of metalloproteinase-3 (TIMP-3) regulated VEGFR-2 signaling and thereby identified a novel mechanism by which sulfated GAG derivatives control angiogenesis [2]. A dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells was exposed. While GAG alone promote proliferation and sprouting, they downregulate VEGF-A-mediated signaling and, thereby, elicit VEGF-A-independent and -dependent effects [1, 3]. These findings provide novel insights into the modulatory potential of sGAG derivatives on angiogenic processes and point towards their prospective application for both, treating abnormal angiogenesis as well as improving impaired wound healing.
For the latter we demonstrated that hyaluronan (HA)/collagen-based hydrogels containing crosslinked sGAG derivatives with different substitution patterns function as multivalent carbohydrate-based scaffolds to tune binding and release of active growth factors and to directly stimulate endothelial cell response, which might translate into an improved healing of injured, vascularized tissues.

Contributors
Rother S, Koehler L, Scharnweber D, Djordjevic S, Schnabelrauch M, Hempel U, Rademann J, Pisabarro MT, Hintze V.

References
[1] Koehler L, [..], Hintze V. Sci Rep. 2019, 9(1):18143.
[2] Rother S, [..], Hintze V. ACS Appl Mater Interfaces 2017, 9(11):9539-9550.
[3] Rother S, [..], Hintze V. Macromol Biosci. 2017, 17 (11).

Contact
PD Dr. Vera Hintze, Research Assistant and Research Group Leader
Dresden University of Technology, Faculty of Mechanical Engineering
Max Bergmann Center for Biomaterials, Budapester Straße 27, 01062 Dresden

Website
: https://tu-dresden.de/ing/maschinenwesen/ifww/biomaterialien/forschung/funktionelle-biomaterialien

Sebastian KühnGlycosaminoglycan-based microgels to guide cell morphogenesis

Spatiotemporally controlled signalling is critically important for successful tissue development and adaptation and represents a key milestone in designing cell-instructive biomaterials[1]. Addressing this challenge, we have developed a highly versatile platform of engineered heparin-based hydrogel microparticles (i.e. microgels) for the local control of signalling cues that can ultimately guide cell development in a spatially defined manner. Based on our previously established starPEG-heparin hydrogel system[2,3], we have processed the gel matrices into microgels with adjustable size, mechanical and biochemical properties. The in-situ crosslinking of thiol terminated 4arm starPEG and maleimide functionalised heparin via Michel type addition resulted in highly monodisperse microgels with tunable sizes over a range of 25 – 180 μm and highly comparable mechanical properties. Using the same chemistry, the microgels can also be crosslinked through enzymatically degradable peptide sequences and functionalised with fluorescent dyes, rendering the microgels responsive to their environment and enabling colour coding for combinatorial approaches. The modulation of the heparin concentration within the microgels as well as the sulfation degree of heparin derivatives allows for precise control over the affinity of the microgels for signalling molecules and was utilised to fine tune the release of the pro-angiogenic growth factor VEGF165. In a gel-in-gel approach, the microgels were introduced as VEGF-sources into a hydrogel-based in vitro model of human umbilical vein endothelia cell (HUVEC) morphogenesis. Adjusting the microgel properties and their density within the cell-laden bulk gel allowed for a locally confined formation of pre-vascular network structures only in the vicinity of the microgels. The results demonstrate the potential of precisely engineered microgels to emulate the function of signalling centres in gel-in-gel approaches in order to address the dynamic and heterogeneous conditions of tissue development, homeostasis and disease.

Contributors
J. Thiele, U. Freudenberg, C. Werner, S. Kühn

References
1. Kühn et al.: Cell-instructive multiphasic gel-in-gel materials. Advanced Functional Materials. Wiley Online Library; 2020 (accepted).
2. Freudenberg et al.: Using mean field theory to guide biofunctional materials design. Advanced Functional Materials. Wiley Online Library; 2012;22(7):1391–8.
3. Zieris et al.: Biohybrid networks of selectively desulfated glycosaminoglycans for tunable growth factor delivery. Biomacromolecules. ACS Publications; 2014;15(12):4439–46.

Contact
Sebastian Kühn, PhD Student
Leibniz-Institut of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden
Hohe Straße 6, 01069 Dresden

Websitehttps://www.ipfdd.de/en/organization/departments/institute-of-biofunctional-polymer-materials/

Prof. Dr. RammeltProf. Dr. PietzschMonitoring and enhancing bone regeneration

Stefan Rammelt, Jens Pietzsch

The treatment of critical size bone defects represents a significant clinical problem. Extensive research has focused on the development of biodegradable bone substitute materials. One promising approach to improve the osteoconductive and osteoinductive properties of degradable scaffolds is the application of components of the organic extracellular matrix (ECM) that mimic a favourable environment for osteoblasts and their progenitors [1]. The influence of an artificial ECM (aECM) on bone healing was investigated in a series of in vitro and in vivo experiments. To understand and influence the basic mechanisms of bone healing, several imaging modalities were employed.
Biomaterial-assisted bone healing was investigated in a series of small animal experiments using a rat femoral defect model with different polymer scaffolds, coated with various aECM consisting of collagen (Col) and glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) or hyaluronan (HA) of different sulfatation degrees. [18F]FDG and [18F]fluoride PET 4 and 8 weeks after implantation of aECM-coated PCL scaffolds provided an in vivo measure of cellular activation and bone mineralization [2]. PET measurements were combined with CT imaging (in vivo/ex vivo), histological and immunohistochemical investigations (ex vivo).
These studies revealed that coating with CS and hypersulfated HA in particular was beneficial for bone healing (Fig. 1) [3]. Besides known cytokines (IL-6, TGF-b), proteomic and metabolomic analysis of microdialysates from the defect site identified possible key players of inflammation and early ECM remodeling like chemoattractants (CXCL 1-3), neutrophil cytosolic proteins (NGP, NCF2 and NCF4), neutrophil migration factors (ITGB2, S1009A), and neutrophil-released proteases (Cat-G, MMP8 and PR3) [4]. Enzymes like COX-2 and TGase 2 are potential candidates for targeted adjuvant therapy in different bone healing phases. The dual tracer approach for PET/CT imaging can be extended to further PET tracers for the characterization of physiological processes such as hypoxia/reperfusion or selected molecular players.

Fig. 1: [18F]fluoride accumulation (bone mineralization) within determined volumes of interest (VOI) showing bone formation in critical size femoral defects filled with PCL scaffolds containing an aECM of collagen (Col), physiologically sulfated chondroitin sulfate (CS) and highly sulfated hyaluronic acid (sHA3). (from [3])

References
[1] Förster Y et al. (2013) BioNanoMaterials 14: 143-152
[2] Neuber C et al. (2019) Clin Hemorheol Microcirc 73: 177-194
[3] Förster Y et al. (2017) Mater Sci Eng C 71: 84-92
[4] Förster Y et al. (2016) PLoS One 11(7):e0159580
[5] Rothe R et al. (2019) Clin Hemorheol Microcirc 73:381-488

Contact
Prof. Dr. Stefan Rammelt
University Center of Orthopaedics and Trauma Surgery, University Hospital Carl Gustav Carus, Dresden, Germany

Prof. Dr. Jens Pietzsch 
Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany 

Website: B5 – Rammelt / Pietzsch

Prof. Dr. Michael HackerAnhydride-containing oligomers for biomedical materials design

Macromers, here defined as reactive short polymers or oligomers, are versatile tools for the fabrication of biomaterials with widely adjustable chemical and mechanical properties. Such material platforms hold great promise in biomaterial science as they can be adopted to different target tissues, can be conveniently processed by conventional techniques and additive manufacturing, and can be designed as injectable formulations. Within the cooperative research consortium TRR 67, we have been focused on developing two oligomer-based material platforms, one yielding biodegradable solids and another that yields hydrogels. This presentation will focus on the latter platform and present different anhydride-containing oligomers for the formulation of 2-component hydrogel materials with biological macromolecules, such as gelatinous peptides, gelatin and chitosan. Gel-forming networks are obtained by the covalent reaction of anhydride groups with primary amines of the biomacromolecules. These widely adjustable materials have been processed into prefabricated hydrogels, injectable hydrogels, tubes, ribbons, and microparticles. Two types of injectable hydrogels have been developed and the effects of network properties on hydrogel characteristics and on fate of encapsulated cells are presented. In addition, the possibility of convenient chemical bulk modification by partial derivatization of anhydride groups of the oligomers prior to network formation and an additive manufacturing application utilizing these 2-component hydrogels are described.

Contact
Prof. Dr. Michael Hacker
Institute of Pharmacy, Pharmaceutical Technoogy, Medical Faculty at Leipzig University (Guest Scientist)
Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-Universität Düsseldorf

Webhttps://pharmazie.medizin.uni-leipzig.de/technologie/mitarbeiterinnen-und-mitarbeiter/dr-michael-hacker/

Bio-Inspired Peptide Coatings for improved Cell-Implant-Interactions

Contact
Prof. Dr. Annette G. Beck-Sickinger
Institute of Biochemistry
Leipzig University
Brüderstrasse 34, D 04103 Leipzig

MARCH 21, 2020 

Session 4: WOUND HEALING

Prof. Dr. Sabine WernerSignaling pathways controlling wound healing and cancer development

There are remarkable cellular parallels between tissue repair and cancer. An important common feature in both conditions is the migration and proliferation of fibroblasts and their differentiation into myofibroblasts. Transcriptional profiling of wound and tumor fibroblasts identified strong expression of genes controlling cell migration, proliferation, collagen contraction and matrix deposition in wounded skin and in skin cancers. We show that many of these genes are under control of activin A. Expression of this member of the TGF- superfamily of growth and differentiation factors is strongly upregulated in skin wounds and in different squamous cancers. Activin overexpression promoted wound repair, but also formation of malignant squamous tumors in different mouse cancer models through generation of a pro-tumorigenic microenvironment. This involves alterations in different immune cells, but also reprogramming of dermal fibroblasts. This example highlights the role of fibroblasts in tissue repair and cancer and the molecular parallels between both conditions.

Contact
Prof. Dr. Sabine Werner
Institute of Molecular Health Sciences, ETH Zurich, Switzerland

Website: https://mhs.biol.ethz.ch/research/werner.html 

Univ.-Prof. Dr. Sabine EmingMaintaining and restoring the epidermal barrier

A decline in skin regenerative capacity, with disturbed barrier function, impaired wound healing and increased carcinogenesis are leading causes of increasing morbidity and mortality in the elderly. Understanding the underlying molecular and cellular mechanisms is important for the development of strategies to intervene in aging- and disease-associated loss of skin function. We hypothesized a critical role of the mammalian target of rapamycin (mTOR) kinase in epidermal barrier formation and homeostasis. mTOR senses and integrates environmental cues from nutrients and growth factors, acting as important nexus for cellular signals to control growth and metabolism.
To dissect the role of mTOR pathway activation in epidermal development and homeostasis we specifically disrupted individual components of this pathway in mice by conditional gene targeting. TOR mediates its activities through the assembly of two structurally distinct multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), and we generated multiple mouse lines that specifically inactivated these complexes in the epidermis. We found that mTOR signaling is essential for skin morphogenesis as epidermal-specific Mtor mutants (mTOREKO) are viable but die shortly after birth due to lack of a protective epidermal barrier. To determine whether mTOR function in epidermal development is primarily mediated by mTORC1 or mTORC2, in addition we generated mice with epidermal loss specifically for mTORC1 or mTORC2. Interestingly, epidermis-specific loss of Rptor (RapEKO), which encodes an essential component of mTORC1, confers the same skin phenotype as seen in mTOREKO mutants. In contrast, newborns with an epidermal deficiency of Rictor (RicEKO), an essential component of mTORC2, survive despite a hypoplastic epidermis.
Collectively, we provide genetic evidence for a fundamental role of mTOR signaling in the formation and maintenance of a protective epidermal barrier. We discovered distinct functions for mTORC1 and mTORC2 in skin barrier formation, which cannot compensate for each other. Our findings unravel important and novel mechanistic insights in epidermal development, maintenance and disease.

Contact
Univ.-Prof. Dr. Sabine Eming
Department of Dermatology, University of Cologne, Cologne, Germany

Website: http://www.eming.uni-koeln.de/

A cell lineage perspective on scar development and its diversity

Dermal tissues are an organized lattice of fibroblasts and extracellular matrix protein fibers. Upon skin injury this lattice is replaced by scars, which diminish the skin’s tensile strength, growth and functions. Early fetuses respond to injuries by simply regenerating, and the scarring response only arrives later in embryonic development. Understanding this irreversible transition is key to new clinical avenues for regenerative medicine and for developing anti-scar therapies. Here we characterize dermal morphogenesis by following two distinct embryonic fibroblast lineages, which either do or do not have a history of expression of the Engrailed1 gene. We use single cell fate mapping, live confocal 3D imaging and in silico analysis coupled with immuno-labeling to reveal unanticipated structural and regional complexity and dynamics within the dermis. We show that dermal development is driven by Engrailed1-history-naive fibroblasts. Dermal lattice regenerates during fetal life exclusively from these cells, whose cell numbers subsequently decline. We show that the lineage of fibroblasts with a history of Engrailed1 expression has scarring abilities at this early stage and their expansion later on in embryogenesis drives scar emergence. We demonstrate that the transition can be reversed, locally, by transplanting Engrailed1- naive cells. Fibroblastic lineage replacement thus couples the decline of regeneration with the emergence of scarring, and creates potential new clinical avenues to reduce scar damage.

Contact
Dr. Yuval Rinkevich, Groupleader
Helmholtz Zentrum München
Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH)
Ingolstädter Landstr. 1
85764 Neuherberg

Website: https://www.helmholtz-muenchen.de/ilbd/research/ilbdcpc-junior-research-groups/cellular-therapeutics-in-chronic-lung-disease-rinkevich-lab/scientific-focus/index.html

Prof. Dr. Boris HinzMechanical education enhances skin regenerative capacities of human mesenchymal stem cells

To rapidly restore the integrity of injured tissues, various mesenchymal cells activate into so-called myofibroblasts. Hallmarks of the myofibroblast are secretion of extracellular matrix (ECM), development of adhesion structures with the ECM, and formation of contractile stress fiber bundles. These features enable myofibroblasts to contract provisional ECM into mechanically stabilizing scar tissue. However, rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to truly regenerate tissues. When myofibroblast contraction and ECM remodeling become progressive and manifest as organ fibrosis, stiff scar tissue obstructs and ultimately destroys organ function. Pivotal for the formation and persistence of myofibroblasts are mechanical stimuli arising during tissue repair and the chronic persistence of inflammatory cells. I will give an overview on our current projects that address how mechanical factors orchestrate the development of myofibroblasts and communication with inflammatory cells. I will present recent data, supporting that expansion on skin-soft cell culture surfaces suppresses and imprints scar-reducing features in mesenchymal stomal cells (MSC). Such ‘mechanical memory’ persists after MSC transplantation to splinted hypertrophic rat wounds and improves healing compared to wounds receiving conventionally expanded myofibroblastic MSCs. The beneficial wound healing effect of skin-soft-primed MSCs is mediated by mechanically imprinted functions that control macrophage recruitment and phenotype during early wound inflammation. By understanding and manipulating myofibroblast mechanoperception and interactions with macrophages, we will be able to devise better therapies to reduce scarring and support normal wound healing.

Contact
Prof. Dr. Boris Hinz
Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada

Webiste: hinzlab.com

Session 5: INTERLEUKIN-17

Prof. Dr. Ari WaismanIL-17 links the skin to heart and the gut to the brain

IL-17A is a cytokine produce by a restricted number of lymphocyte populations, including Th17, Tc17, yd T cells and ILC3. Its main function is to modulate the tissues of the body, and therefore it serves as a link between the adaptive immune system and the body tissue. We could show that IL-17 contribute to the development of psoriasis by directly targeting the keratinocytes in the skin. In contrast, IL-17 effect on brain autoimmunity is not direct, but stems from its effect on the gut barrier and the interplay of the microbiome with the innate immune system. Importantly, we show that IL-17 is critical for maintaining the body barriers, be that in the skin or in the gut, and its effect on autoimmunity development is a result of this function.

Contact
Prof. Dr. Ari Waisman
University Hospital Mainz, Institut für Molekulare Medizin
Geb. 308A, 1. OG, Zi. 1.201, Langenbeckstraße 1, 55131 Mainz

Website: http://www.unimedizin-mainz.de/molekulare-medizin/uebersicht.html

Prof. Dr. Michael P. SchönAdaptive and innate immune mechanisms in psoriasis, a prototype IL-17-mediated disorder

Psoriasis is a systemic chronic inflammatory disease that mainly manifests itself on the skin, but is also associated with concomitant diseases of other organs. Although it has been clear for some years now that psoriasis is mediated essentially by IL-17A, its pathophysiology is complex and in many details not yet well understood. The lack of adequate preclinical models hampers research into the pathophysiology of psoriasis. We have learned only recently that other IL-17 isoforms may also contribute to psoriasis in different ways.
Both adaptive and innate immune mechanisms play important roles in psoriasis. The balance of these immune mechanisms with central involvement of IL-17 essentially determines the clinical appearance of the disease and whether it is chronic-stationary or acutely inflammatory. Several putative autoantigens have been identified that can trigger specific T-cellular immune responses in psoriasis. These include complexes of self-DNA and the antimicrobial peptide LL37 as well as the melanocytic antigen ADAMTSL5. In addition, cells of the innate immune system, such as plasmacytoid dendritic cells, are important for initiating the psoriatic inflammatory cascade. Neutrophil granulocytes are also increasingly becoming the focus of scientific interest as central components. We have been working on biophysical factors that influence the functional state of these cells, especially the formation of NETs (neutrophil extracellular traps), which are also found in psoriatic lesions. To this end, the phases of NET formation and the molecular mechanisms driving them could be characterized more precisely. It also became apparent that NET formation can be induced by electromagnetic radiation in the range of visible and long-wave ultraviolet light. The physical properties of the extracellular matrix also influence the functional activation of neutrophils.
All in all, psoriasis is an instructive example on which different aspects of a complex IL-17-mediated inflammatory disease can be studied, some of which will be highlighted here. 

Contact
Prof. Dr. Michael P. Schön
Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen

Website: http://www.dermatologie.med.uni-goettingen.de

Aline BozecThe fat food – intestinal microbiome axis regulates gd-T cell IL-17 production exacerbating psoriasis-like skin inflammation

Obese patients present several diseases complications including for psoriatic diseases. In addition, dysbiosis is a comorbidity of psoriatic diseases. The object of our current work is to disentangle the association of psoriatic diseases, obesity and dysbiosis. To do so, C57BL/6 mice were fed with different diets containing an increase amount of fat for 6 weeks. Imiquimod (IMQ) induced psoriasis-like skin inflammation model was used to assess the effect of dietary treatment. In addition to the local inflammation in the skin, inflammation in systemic organs such as spleen, lymph nodes and intestine was evaluated. The intestinal microbiota of the different diets-fed mice was analyzed by 16S-DNA sequencing, and antibiotics and bacteria gavages were used in interventions to the intestinal microbiota, to confirm the gut microbiome effect on inflammation in skin and systemic organs.
In the presentation, I will show you the contribution of high fat diet dependent intestinal microbiota to local and skin inflammation, independent of the weight. I will also present the mechanism of gamma delta T cells as dominant source of systemic IL-17 in response to HFD, which is leading to exacerbation of the psoriasis-like skin inflammation.

Contact
Prof. Dr. Aline Bozec
Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Department of Internal Medicine 3 – Rheumatology and Immunology, Universitätsklinikum Erlangen

Websitehttps://www.medizin3.uk-erlangen.de/index.php

Registration & Poster abstract submission

The online registration and poster abstract submission to the 3rd International Symposium is open.

Attendance at the symposium is free of charge. The Registration covers conference materials and admission to all scientific sessions (incl. lunch buffets and coffee breaks). Participants must book and pay for their travel costs and hotels by themselves. We have reserved a contingent at Radisson Blue Leipzig (Augustusplatz, 106 EUR/night). Please send your reservation request to sfb.trr67@medizin.uni-leipzig.de. Participants had the opportunity to present a poster during the international symposium. It is not necessary to present a poster in order to participate in the conference.

POSTER SUBMISSION
Abstracts must be submitted in English with accurate grammar and spelling of a quality suitable for publication. Abstracts may be submitted only electronically using the online form. In the case that electronic submission is not possible, please contact the Confernce Office (sfb.trr67@medizin.uni-leipzig.de). All abstracts submitted will be reviewed by the committee and you will be notified if your poster has been accepted.

DEADLINE for all poster abstract submission is March 1, 2020.

The maximum acceptable size for a poster is A0 (height 119 cm x with 84 cm) and should be in portrait format. Participants are asked to bring their printed poster with them as no poster printers will be available at the conference.

 

* LETTER OF INVITATION
Participants needing an official invitation letter to attend the congress may contact the scientific secretariat specifying the necessary details. This service is designed only to assist participants who need a visa or permission to attend the congress. The letter of invitation does not financially obligate the conference organizers in any way. All expenses incurred in relation to the conference are the sole responsibility of the attendee.

  Online registration

Last name, first name (department, institute)

Previous events

2nd International Symposium of the TRR67 and CRC1052

Frontiers in Biomaterial Science
June 24-25, 2016 in Leipzig

1st International Symposium of the TRR67

Frontiers in Biomaterial Science
September 1-2, 2011 in Dresden