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

09 – 10 July 2021 at Leipzig University,  Paulinum, Augustusplatz 10, 04109 Leipzig, Germany

Dear colleagues,

Thank you for your participation in our 3rd International Symposium “Frontiers in Biomaterial Science” which was organized by our collaborative research center TRR 67.

The symposium focused on the following TOPICS:

  • Innovative Biomaterials
  • Wound Healing and Repair
  • Highlights from the Transregio 67
  • Bone Inflammation and Regeneration
  • Special Topic: Interleukin-17

We also presented the most interesting projects from our collaborative research center and hoping to welcome you again.

If you have questions, please contact the office of the TRR67 by e-mail.

With kind regards,
Prof. Dr. Jan Simon
Prof. Dr. Carsten Werner

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

Program & Speakers

July 9, 2021 

Session 1: INNOVATIVE BIOMATERIALS

Injectable synthetic building blocks to regenerate structured tissues

We apply polymeric molecular and nano- to micron-scale building blocks to assemble soft 3D biomaterials with anisotropic and dynamic properties. Microgels and fibers are produced by technologies based on fiber spinning, microfluidics, and in-mold polymerization. To arrange the building blocks in a spatially controlled manner, self-assembly mechanisms and assembly by external magnetic fields are employed. For example, the Anisogel technology offers a solution to regenerate sensitive tissues with an oriented architecture, which requires a low invasive therapy. It can be injected as a liquid and structured in situ in a controlled manner with defined biochemical, mechanical, and structural parameters. Magnetoceptive, anisometric microgels or short fibers are incorporated to create a unidirectional structure. Cells and nerves grow in a linear manner and the fibronectin produced by fibroblasts is aligned. Regenerated nerves are functional with spontaneous activity and electrical signals propagating along the anisotropy axis of the material. Another developed platform is a thermoresponsive hydrogel system, encapsulated with plasmonic gold-nanorods, which actuates by oscillating light. This system elucidates how rapid hydrogel beating leads to a reduction in cell migration, while enhancing focal adhesions, native production of extracellular matrix, and nuclear translocation of mechanosensitive proteins, depending on the amplitude and frequency of actuation.

Contact
Prof. Dr. Laura De Laporte
DWI – Leibniz Institute for Interactive Materials, Aachen, Germany                                                                                                                                                                    Polymeric Biomaterials, Institute of Technical and Macromolecular Chemistry, RWTH University Aachen, Germany                                                                              Advanced Materials for Biomedicine, Institute for Applied Medical Engineering, University Hospital RWTH Aachen, Germany

Website: https://www.dwi.rwth-aachen.de/person/laura-de-laporte 

Light-responsive hydrogels that talk to cells

 

Contact
Prof. Dr. Aránzazu del Campo
Scientific Director
INM-Leibniz Institute for New Materials gGmbH – Campus D2 2 – D-66123 Saarbrücken

Website: https://www.leibniz-inm.de/en/research/bio-interfaces/dynamic-biomaterials/

Mechanobiology of Antigen Presenting Cells

Cells of the body are subjected to external loading as well as inherent physiological forces and they respond to these biomechanical cues. Cells of the immune system are not spared from being exposed to such biomechanical forces that can come in the manner of cell-cell interaction, interstitial fluid shear forces, resistance during migration within tissues, etc. Antigen presenting cells (APC) of the innate immune system are crucial cells that partake in primary defense against antigens (Ag) and also communicate with cells of the adaptive immune system to educate a secondary defense that is more precise and rapid in response. Dendritic cells (DC) are present during physiological homeostasis as well as pathophysiological events, each cell is therefore exposed to a spectrum of biophysical signals within their own microenvironment. First, I will report findings on the effects of lab-simulated tissue stiffness on DC immune response. Using collagen hydrogels as a 3D cell culture substrate, we investigated (1) the effects of dimensionality as well as (2) density of collagen on macrophage and DC immune phenotype as well as immune function. We assess DC immune function using a multidisciplinary approach involving conventional immunobiology assays and custom developed computational platforms, yielding results that demonstrated tissue modulation of APC phenotype and function. Also in this presentation, I will briefly introduce the progress of Space DC biology, or DC immune response when lacking biomechanical forces, that our lab, the Laboratory for Immuno Bioengineering and Applications (LIBRA) will embark on.

Contact 
Prof. Dr. Jeremy Teo
Assistant Professor of Mechanical and Biomedical Engineering
NYU – New York University Abu Dhabi
E-Mail: jeremy.teo@nyu.edu

Website: https://nyuad.nyu.edu/en/academics/divisions/engineering/faculty/jeremy-teo.html

Mechanobiology of Extracellular Matrix:  from cell culture to healthy and diseased organs

Reciprocal mechanical signaling between cells and their environment is key to the spatio-temporal coordination of tissue growth and regenerative processes, and if miss-balanced can tip the niche towards pathological transformations.  Yet, these processes are difficult to quantify in real organs. Translating what was learned in Mechanobiology mostly on single cells to the tissue level is hampered by at least two challenges, the lack of nanoscale sensors to probe forces or tissue fiber tension in organs, as well as appropriate de novo grown 3D microtissues to mimic essential aspects of healthy versus diseased tissue niches.  To address these shortcomings, we developed a peptide based-stretch sensor to probe the tensional states of ECM fibers in animal models and in human tissues, which is significant as forces can switch the structure-function relationships of proteins by stretching them. Our recent results from healthy and diseased organs will be discussed.

Contact
Prof. Dr. Viola Vogel
Professur Angew. Mechanobiologie
ETH Zurich
Institute of Translational Medicine, Department of Health Sciences and Technologies
Vladimir-​Prelog-Weg 1-5/10, 8093 Zürich, Switzerland

Website: https://hest.ethz.ch/en/studies/health-sciences-and-technology/master-hst/majors/tutors/tutors-a-z/viola-vogel.html

Kristi L. Kiick, Ph.D.Programming phase separation of peptides to make collagen-targeting, nanostructured biomaterials

Significant attention has been paid to the sequence specificity of intrinsically disordered peptide and proteins owing to their importance in regulating spatiotemporal organization of membraneless organelles in cells and their demonstrated versatility in producing hydrogels, nanoparticles, and sensor platforms. In our laboratory, we have employed amino acid sequences inspired by structural proteins such as collagen, elastin, and resilin, and have tailored their stimuli-responsive behavior to enable finely tuned control over both microscale and nanoscale structures. Their conjugation via chemical methods affords biomaterials with diverse properties responsive to multiple triggers, and select modification of their sequences facilitates nuanced manipulation of their assembly and responsiveness. We have also investigated the controlled retention and release of cargo via biomimetic mechanisms, offering substantial improvement in activity for both small molecule and macromolecular cargo, with targeted applications in tissue repair.

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/

Session 2: WOUND HEALING AND REPAIR

Development of TSG-6-based biological drugs for inflammatory and tissue degenerative disease

TSG-6 is a secreted protein that is not constitutively expressed in most adult tissues but upregulated in response to inflammatory mediators. TSG-6 has been implicated in protecting tissues during inflammation and is responsible for many of the tissue protective and immunomodulatory activities of human MSCs. The molecular mechanisms underlying its anti-inflammatory and regenerative properties are not fully understood. Nevertheless, it is well established that TSG-6 is a multifunctional protein interacting with numerous ligands (that include ECM components, chemokines and growth factors) with roles in matrix reorganisation, and regulation of cellular and immune functions. There is a wealth of information showing that the full-length TSG-6 protein has therapeutic effects in a broad range of disease models including cardiovascular, musculoskeletal and neurological indications (see [1]); moreover, TSG-6 enhances wound healing of the skin, liver and other organs, without fibrosis. However, full-length TSG-6 is hard to make and has poor solution properties meaning it is likely not amenable for therapeutic development. Conversely, the recombinant Link module of human TSG-6 (Link_TSG6), a domain that mediates most of TSG-6’s ligand-binding activities, is a much more suitable drug target; Link_TSG6 is highly soluble and stable in solution and is being developed for osteoarthritis and ocular indications. For example, we have tested Link_TSG6 in two different mouse models of dry eye disease (spontaneous and desiccation-induced) and found that topical treatment over 7 or 10 days, respectively, leads to accelerated corneal epithelial wound healing [2]; Link_TSG6 was superior to cyclosporin (Restasis). In addition, there was a reduction in inflammatory mediators and infiltrating leukocytes, improved tear production and preservation of goblet cells. These data indicate that Link_TSG6 has potential to treat the signs and symptoms of this common form of eye disease.

[1] Day & Milner (2019) Matrix Biology 78-79, 60-83. doi:10.1016/j.matbio.2018.01.011.
[2] Oh, Milner & Day, unpublished; WO/2021/013452

Contact
Prof. Dr. Anthony Day
Wellcome Trust Centre for Cell-Matrix Research & Lydia Becker Institute of Immunology & Inflammation, Division of Cell-Matrix Biology & Regenerative Medicine School of Biological Sciences, Faculty of Biology, Medicine & Health
University of Manchester, UK

E-Mail: anthony.day@manchester.ac.uk

Website: https://www.research.manchester.ac.uk/portal/anthony.day.html

Univ.-Prof. Dr. Sabine EmingResTORing barrier function in the skin

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

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

Prof. Dr. Boris HinzWounds around body-foreign objects: Mechanical considerations for implant fibrosis

Tissues lose integrity upon injury. To rapidly restore mechanical stability, a variety of different cell types are activated to become 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. Rapid repair comes at the cost of tissue contracture due to the inability of the myofibroblast to regenerate tissue. When contracture 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 chronic presence of inflammatory cells.

After a brief overview on our current projects, I will develop how mechanical factors orchestrate the development of myofibroblasts in a persisting wound environment – using the foreign body response to implanted silicone materials as an example. In a nutshell, modulating the stiffness of their surface reduces fibrotic encapsulation and enhance the lifetime of silicone implants. Soft surfaces suppress acute mechanical activation of myofibroblasts and reduce the activation of pro-fibrotic transforming growth factor (TGF-β1) – a process that is dependent on mechanical resistance of the environment. By understanding and manipulating myofibroblast mechanoperception, we will be able to devise better therapies to reduce scarring and support normal wound healing in organ and implant fibrosis.

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

Webiste: hinzlab.com

Contact

Prof. Valerie Horsley
Associate Professor of Molecular, Cellular, and Developmental Biology and Associate Professor of Dermatology
Yale University, USA

Website: https://medicine.yale.edu/profile/valerie_horsley/

Scar or regeneration by heterogeneous fibroblasts

The skin is home to a collection of fibroblastic cell types from various embryonic origins. These varying fibroblastic lineages display unique genetic programs and in vivo functions. Studying the diversity of fibroblastic cells is emerging as an important area for cutaneous biology, wound repair and regenerative medicine. I will discuss the distinct embryonic origins, microenvironments, and transcriptomic profiles of fibroblastic lineages, and how these varying lineages shape the skin’s wound response across injury depths, anatomic locations, and developmental time to promote either scarring or regeneration.

 

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

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

GAG-based immunomodulating hydrogels – a promising novel approach for the treatment of chronic wounds.

Non-healing chronic wounds of the skin represent a significant health problem with increasing incidence due to demographic change and the association of chronic wounds with comorbidities such as obesity, diabetes and vascular diseases that also increase worldwide. Chronic wounds are characterized by a persistent inflammation that is driven by uncontrolled infiltration and activation of immune cells (granulocytes, monocytes and macrophages). This leads to excessive tissue breakdown and prevents the injured skin tissue from healing. Resolution of this unrestrained inflammatory loop represents an unmet challenge in the treatment of non-healing wounds. Glycosaminoglycans (GAG) as part of the native extracellular matrix are known to guide function of immune cells either directly or via modulating the bioactivity of factors controlling immune cell activities. Using these principles, we develop in colaboration with colleagues of the TRR67 GAG-based biomaterials with versatile immunomodulatory capacities to support healing of chronic wounds [1]. In this talk, I will shortly present two approaches of GAG-based biomaterials that intervened chronic inflammatory processes as they occur in non-healing wounds. Both materials improved defective tissue repair in diabetic db/db mice, a relevant in vivo model for chronic wounds in human [2,3].

The first approach is based on capturing inflammatory chemokines, which sustain persistent invasion of immune cells. For this purpose, modular hydrogels based on star-shaped polyethylene glycol and heparin derivatives were tailored to achieve maximum sequestration of immune cell-attracting chemokines from the wound site while sparing wound healing-promoting pro-regenerative growth factors [2]. In the second approach, we used hyaluronic acid (HA) to particularly modulate the activity of macrophages, which have been recognized as key regulator of inflammation during wound healing. HA was chemically modified by sulfation. Introduction of specific sulfation patterns uncoupled the anti-inflammatory activity of HA from its molecular size and enhanced its anti-inflammatory activity on macrophages [4,5]. For in vivo translation, sulfated HA was integrated into hyaluronan/collagen (HA-AC/coll)-based hydrogels that allow delivery of sHA into wounds over a period of at least one week [3].

[1] Franz S, et al.  Immune responses to implants – a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011. 32(28):6692-709

[2] Lohmann N, et al. Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice. Sci Transl Med. 2017. 19; 9(386)

[3] Hauck S, et al. Collagen/hyaluronan based hydrogels releasing sulfated hyaluronan improve dermal wound healing in diabetic mice via reducing inflammatory macrophage activity. Bioactive Materials 2021. 6:4342–59.

[4] Jouy F, et al. Sulfated hyaluronan attenuates inflammatory signaling pathways in macrophages involving induction of antioxidants. Proteomics. 2017. 17(10):e1700082

[5] Franz S, et al.  Artificial extracellular matrices composed of collagen I and high-sulfated hyaluronan promote phenotypic and functional modulation of human pro-inflammatory M1 macrophages. Acta Biomater. 2013. 9(3):5621-9.

Contact
PD Dr. Sandra Franz
Faculty of Medicine, Leipzig University
Clinic for Dermatology, Venerology and Dermatology
Max-Bürger-Forschungszentrum
Johannisallee 30, 04103 Leipzig

E-Mail: sandra.franz@medizin.uni-leipzig.de
Website: www.uniklinikum-leipzig.de/einrichtungen/dermatologie

PD Dr. rer.nat. Vera Hintze, Research Assistant and Junior Research Group LeaderStructural and functional insights into modulation of angiogenic processes by sulfated glycosaminoglycans (sGAG) – implications for the design of functional biomaterials  

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 for 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, which are thus important regulators of angiogenic processes. Chemically modified, polymeric and oligomeric sGAG derivatives were utilized for evaluating the structural requirements of sGAG for controlling and tuning VEGF-A function, aiming to translate these findings to the design of functional biomaterials. The combination of biophysical and immunobiochemical analyses with molecular modeling 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]. Further, sGAG derivatives were found to alter VEGF-A/tissue inhibitor of metalloproteinase-3 (TIMP-3) regulated VEGFR-2 signaling suggesting a novel mechanism by which sGAG derivatives control angiogenesis [2]. A dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells was exposed. While sGAG alone promote proliferation and sprouting, they downregulate VEGF-A-mediated signaling and, thereby, elicit VEGF-A-independent and -dependent effects [1, 3, 4]. 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.

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

[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).
[4] Rother S, [..], Hintze V. ACS Appl. Bio Mater. 2021, 4, 1, 494–506.

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 

S. Kühn, J. Thiele, U. Freudenberg, C. Werner
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[2,3,4,5], 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 – 200 µm and highly comparable mechanical properties. The modulation of the microgel charge, through 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. Here, the likewise heparin-based bulk hydrogel served as a scaffold material mimicking important ECM properties to facilitate cell adhesion, migration, matrix remodelling as well as morphogen presentation and gradient formation. The local VEGF gradients forming around the microgels in this multiphasic setup were controlled through the microgel charge and the morphogen loading to ultimately shape the cell response (formation pre-vascular network structures) in a spatially defined manner extending from < 100 µm up to > 1 mm away from the source. The results demonstrate the potential of precisely engineered microgels to emulate the function of signalling centres in multiphasic gel-in-gel approaches in order to address the dynamic and heterogeneous conditions of tissue development, homeostasis and disease.

References: 

  • Kühn et al.: Cell-instructive multiphasic gel-in-gel materials. Adv. Funct. Mater. 2020, 30(26):1908857.
  • Freudenberg et al.: Using mean field theory to guide biofunctional materials design. Adv. Funct. Mater. 2012, 22(7):1391–1398.
  • Zieris et al.: Biohybrid networks of selectively desulfated glycosaminoglycans for tunable growth factor delivery. Biomacromolecules 2014, 15(12):4439–4446.
  • Lohmann et al.: Glycosaminoglycan-based hydrogels capture inflammatory chemokines and rescue defective wound healing in mice. Sci. Trans. Med. 2017, 9(386).
  • Atallah et al.: In situ-forming, cell-instructive hydrogels based on glycosaminoglycans with varied sulfation patterns. Biomaterials 2018, 181:227-239.

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. RammeltWatching the bone grow. Functional imaging of the early stages of bone healing

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 favorable 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 sulfation 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).

Several in vivo studies revealed that coating with CS and hypersulfated HA in particular was beneficial for bone healing which correlates with the accumulation of PET tracer (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.

[1] Förster Y et al. (2020) Mater Sci Eng C 116:111157; [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

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])

Stefan Rammelt1, Sabine Schulze1, Christin Neuber2, Jens Pietzsch2
1University Center of Orthopaedics, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus, Dresden, Germany
2Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department Radiopharmaceutical and Chemical Biology, Dresden, Germany

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

Website: B5 – Rammelt / Pietzsch

Prof. Dr. Michael HackerThe TriLA platform of biodegradable macromers for biomedical applications

Macromers, here defined as short polymers or oligomers with two or more reactive groups, 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 adapted 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 were focused on developing two oligomer-based material platforms, one yielding biodegradable solids and another that constitutes two-component hydrogels from anhydride-containing oligomers and natural polymers such as gelatin or chitosan. This presentation will focus on the platform of three-armed macromers with biodegradable oligolactide blocks, so called TriLA macromers, and summarize their synthesis and processing into two- and three-dimensional matrices. Through cross-copolymerization with heterobifunctional building blocks, biodegradable materials can be build up that are available for bioconjugation. TriLA-based surfaces covalently functionalized with sulfated glycosaminoglycans have been shown to deplete Wnt antagonists from supernatant media which improved osteogenic differentiation of adherent stem cells. With regard to a broader adaptability of the degradation profiles of TriLA-based matrices, effects of structural variations of the biodegradable block will be described.

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

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

Immobilisation and Controlled Release of Mediators in Wound Healing

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

July 10, 2021 

Session 4: BONE INFLAMMATION AND REGENERATION 

Prof. Thomas L. Clemens, Ph.D. Understanding Osteoblast Bioenergetics: Lessons for Improving Skeletal Health and Engineering Novel Bone Biomimetics  

The emergence of the endochondral skeleton in terrestrial animals enabled ambulation against increased gravitational forces and provided a storage site for scarce minerals essential for life.  This skeletal upgrade increased overall fuel requirements and altered global energy balance, prompting the evolution of endocrine networks to coordinate energy expenditure.  Bone-forming osteoblasts require a large and constant supply of energy substrates to fuel bone matrix production and mineralization.  When fuel demands are unmet, bone quality and strength are compromised. Studies in genetically altered mice have confirmed a link between bone cells and global metabolism and have led to the identification of hormonal interactions between the skeleton and other tissues.  These observations have prompted examination of the nature of the mechanisms of fuel sensing and processing in the osteoblast and their contribution to overall energy utilization and homeostasis.  This work has led to the notion that key developmental signaling pathways (e.g. Wnt) are coupled to bioenergetic programs (e.g. anaerobic glycolysis) to accommodate changes in energy requirements at different stages in the osteoblast lifecycle.  Other studies have identified mechanisms whereby citrate, produced during the TCA cycle, is transported into bone mineral where it functions to regulate hydroxyapatite crystal growth. Together, such findings are reshaping our understanding of the role of the osteoblast in healthy and diseased bone and should also inspire novel strategies for the design of bone biomimetics.

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

Website: https://www.hopkinsmedicine.org/orthopaedic-surgery/research-clinical-trials/basic-science/clemens-lab.html

Prof. Dr. Ulf Müller-LadnerMetaflammation and Bone

Inflammation is one of the driving factors of remodeling and destruction of articular tissue and the adjacent osseus structures. Inreasing data show that not only the innate and adaptive immune system and their effector molecules and cells are driving the respective deleterious processes. Amongst the novel drivers are molecules of the so-called metabolic system, which support the evolving idea of metabolic inflammation or „metaflammation“. Known molecules of the metabolic system are the adipokines, primarily adipose tissue-derived factors. The do not only play an important role in metabolism but also influence other central processes of the body, including inflammation. In autoimmune diseases, adipokines are involved in inflammatory pathways affecting different cell types. Many rheumatic diseases belong to the group of autoimmune diseases, for example rheumatoid arthritis (RA) and psoriatic arthritis buts also low-grade inflammatroy entities such as chronic osteoarthritis. Due to the long-term inflammatory responses and vicious circles, a chronic inflammatory milieu develops, which finally affects the whole organism, not only the connective tissue structures. Metabolic alterations such as obesity further influence these inflammatory responses many arthritic diseases. In the affected joints, not only synoviocytes but also bone remodeling cells such as osteoclasts, osteoblasts, and chondrocytes are affected by adipokines. Vice versa they also can produce several adipokines, thus contributing to the inflammatory microenvironment but also to matrix and bone remodeling and destruction.

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

Prof. Dr. Nicola NapoliContact
Prof. Dr. Nicola Napoli, Associate Professor of Endocrinology and Metabolism
Campus Bio-Medico University of Rome, Italy

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

Prof. Tonia Vincent FRCPOsteoarthritis: a disease of failed cartilage regeneration?

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 that covers all articulating surfaces, we now know that OA is due to mechanical sensing of the cells within cartilage and other tissues of the joint, to trigger a number of intracellular pathways that influence disease. The main ways by which cartilage cells sense mechanical effects are either when cartilage is sheared as it slides or through compression of the joint surfaces. The former activates inflammatory signalling by a process that we have termed “mechanoflammation” which leads to degradation of the matrix. The latter leads to release of matrix-bound growth factors that drive cartilage regeneration. Evidence that damaged human cartilage can regenerate has emerged from recent clinical and experimental studies, as well as from agnostic genome wide association studies. Collectively we believe that there is strong intrinsic capacity for damaged articular cartilage to repair. The molecules that orchestrate this in the joint, the mechanisms that lead to their appropriate release, and the prospects for future OA therapies 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 

Session 5:  SPECIAL TOPIC: INTERLEUKIN-17

Aline BozecThe dietary fat – intestinal microbiome axis modulates spleen γd T cell IL-17 production associated to psoriasis-like skin exacerbation

Psoriasis is strongly associated with metabolic disturbances. For instance, obesity worsens psoriasis. While it is known that dietary metabolic stress can enhance psoriatic lesions, the mechanistic connection between diet and skin lesions is not well established. I will present that dietary fat exacerbated psoriatic disease was associated with changes in the intestinal mucus layer and microbiota composition by high-fat diet. By using IL-17 reporter mice, I will show that dietary metabolic stress facilitates a systemic IL-17-mediated γδ T cell response involving the mesenteric lymph nodes and the spleen. Finally I will briefly talk about intervention within the intestinal microbiota via vancomycin treatment or administration of Akkermansia muciniphila by oral gavage that both effectively blocked activation of psoriatic skin inflammation by dietary metabolic stress and inhibited the systemic IL-17 responses. In conclusion, our data suggest that dietary metabolic stress exacerbates psoriatic skin inflammation through changing the mucus barrier and the microbial composition in the intestine, which leads to a systemic IL-17 response.

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

The role of IL17 in arthritis

Contact

Prof. Dr. Georg Schett
Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Deutsches Zentrum Immuntherapie, Medizin 3, Universitätsklinikum Erlangen

Website: https://www.medizin3.uk-erlangen.de/aktuelles/nachrichten/detail/prof-schett-neuer-fau-vizepraesident/ 

Prof. Dr. Michael P. SchönPsoriasis – a prototype IL-17-mediated disorder

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

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

Prof. Dr. Ari WaismanHow Interleukin 1controls the permeability of the blood brain barrier

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

Glycosaminoglycan recognition by chemokines

Chemokines, especially neutrophil-activating chemokines, bind to glycosaminoglycans (GAGs) and this interaction modulates their roles in vivo. Interestingly, homologous chemokines present vastly different GAG-binding sites, which implies that the geometry of GAG – chemokine complexes are different. Despite the heterogeneity of natural GAGs, nature appears to exploit these differences by optimizing the role of specificity and plasticity in these molecular interactions. Our work using computational methods affords detailed insights into these interactions, which could lead to the discovery of GAG mimetics that tame hyperinflammatory responses.

 

 

Contact
Prof. Dr. Umesh Desai
Alfred and Frances Burger Professor of Medicinal Chemistry Chair
Department of Medicinal Chemistry & Director
Institute for Structural Biology, Drug Discovery and Development (ISB3D)
Richmond, VA 23219

Webpage: https://app.pharmacy.vcu.edu/urdesai

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 admission to all scientific sessions.

POSTER SUBMISSION
Participants have the opportunity to present a poster during the international symposium. 

DEADLINE for poster registration is July 7, 2021.

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.

  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