{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:47:37Z","timestamp":1760147257602,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T00:00:00Z","timestamp":1674172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["59397982"],"award-info":[{"award-number":["59397982"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although chronic inflammation inhibits bone healing, the healing process is initiated by an inflammatory phase. In a well-tuned sequence of molecular events, pro-inflammatory cytokines are secreted to orchestrate the inflammation response to injury and the recruitment of progenitor cells. These events in turn activate the secretion of anti-inflammatory signaling molecules and attract cells and mediators that antagonize the inflammation and initiate the repair phase. Sulfated glycosaminoglycanes (sGAG) are known to interact with cytokines, chemokines and growth factors and, thus, alter the availability, duration and impact of those mediators on the local molecular level. sGAG-coated polycaprolactone-co-lactide (PCL) scaffolds were inserted into critical-size femur defects in adult male Wistar rats. The femur was stabilized with a plate, and the defect was filled with either sGAG-containing PCL scaffolds or autologous bone (positive control). Wound fluid samples obtained by microdialysis were characterized regarding alterations of cytokine concentrations over the first 24 h after surgery. The analyses revealed the inhibition of the pro-inflammatory cytokines IL-1\u03b2 and MIP-2 in the sGAG-treated groups compared to the positive control. A simultaneous increase of IL-6 and TNF-\u03b1 indicated advanced regenerative capacity of sGAG, suggesting their potential to improve bone healing.<\/jats:p>","DOI":"10.3390\/ijms24032077","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T06:52:41Z","timestamp":1674197561000},"page":"2077","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Microdialysis Reveals Anti-Inflammatory Effects of Sulfated Glycosaminoglycanes in the Early Phase of Bone Healing"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2135-5858","authenticated-orcid":false,"given":"Sabine","family":"Schulze","sequence":"first","affiliation":[{"name":"University Center for Orthopedics, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany"},{"name":"Center for Translational Bone, Joint and Soft Tissue Research, Medical Faculty, TU Dresden, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0646-5808","authenticated-orcid":false,"given":"Christin","family":"Neuber","sequence":"additional","affiliation":[{"name":"Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"M\u00f6ller","sequence":"additional","affiliation":[{"name":"Biomaterials Department, INNOVENT e. V., Pr\u00fcssingstrasse 27B, 07745 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1610-1493","authenticated-orcid":false,"given":"Jens","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany"},{"name":"Faculty of Chemistry and Food Chemistry, School of Science, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus-Dieter","family":"Schaser","sequence":"additional","affiliation":[{"name":"University Center for Orthopedics, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1141-6493","authenticated-orcid":false,"given":"Stefan","family":"Rammelt","sequence":"additional","affiliation":[{"name":"University Center for Orthopedics, Trauma and Plastic Surgery, University Hospital Carl Gustav Carus at TU Dresden, 01307 Dresden, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.3233\/CH-199102","article-title":"Adjuvant Drug-Assisted Bone Healing: Part I\u2014Modulation of Inflammation","volume":"73","author":"Rothe","year":"2020","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1515\/hsz-2021-0170","article-title":"Men Who Stare at Bone: Multimodal Monitoring of Bone Healing","volume":"402","author":"Schulze","year":"2021","journal-title":"Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zorzi, A.R., and de Miranda, J.B. (2016). Advanced Techniques in Bone Regeneration, IntechOpen Limited.","DOI":"10.5772\/61425"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1089\/ten.teb.2014.0677","article-title":"Boon and Bane of Inflammation in Bone Tissue Regeneration and Its Link with Angiogenesis","volume":"21","author":"Kwee","year":"2015","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5561","DOI":"10.1016\/j.biomaterials.2006.06.034","article-title":"Coating of Titanium Implants with Collagen, RGD Peptide and Chondroitin Sulfate","volume":"27","author":"Rammelt","year":"2006","journal-title":"Biomaterials"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"152","DOI":"10.22203\/eCM.v032a10","article-title":"The Crucial Role of Neutrophil Granulocytes in Bone Fracture Healing","volume":"32","author":"Kovtun","year":"2016","journal-title":"Eur. Cell Mater."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.msec.2016.09.071","article-title":"Collagen\/Glycosaminoglycan Coatings Enhance New Bone Formation in a Critical Size Bone Defect\u2014A Pilot Study in Rats","volume":"71","author":"Bernhardt","year":"2017","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.biomaterials.2016.04.013","article-title":"Sulfated Hyaluronan Improves Bone Regeneration of Diabetic Rats by Binding Sclerostin and Enhancing Osteoblast Function","volume":"96","author":"Picke","year":"2016","journal-title":"Biomaterials"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"111157","DOI":"10.1016\/j.msec.2020.111157","article-title":"The Influence of Different Artificial Extracellular Matrix Implant Coatings on the Regeneration of a Critical Size Femur Defect in Rats","volume":"116","author":"Schulze","year":"2020","journal-title":"Mater. Sci. Eng. C Mater. Biol. Appl."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"36418","DOI":"10.1038\/srep36418","article-title":"Sulfated Hyaluronan Alters Fibronectin Matrix Assembly and Promotes Osteogenic Differentiation of Human Bone Marrow Stromal Cells","volume":"6","author":"Vogel","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"938368","DOI":"10.1155\/2014\/938368","article-title":"Artificial Extracellular Matrices with Oversulfated Glycosaminoglycan Derivatives Promote the Differentiation of Osteoblast-Precursor Cells and Premature Osteoblasts","volume":"2014","author":"Hempel","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1242\/jcs.023820","article-title":"The Extracellular Matrix at a Glance","volume":"123","author":"Frantz","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6692","DOI":"10.1016\/j.biomaterials.2011.05.078","article-title":"Immune Responses to Implants\u2014A Review of the Implications for the Design of Immunomodulatory Biomaterials","volume":"32","author":"Franz","year":"2011","journal-title":"Biomaterials"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"76","DOI":"10.3109\/17453674.2013.769080","article-title":"Monitoring of the First Stages of Bone Healing with Microdialysis","volume":"84","author":"Gao","year":"2013","journal-title":"Acta Orthop."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"F\u00f6rster, Y., Schmidt, J.R., Wissenbach, D.K., Pfeiffer, S.E.M., Baumann, S., Hofbauer, L.C., von Bergen, M., Kalkhof, S., and Rammelt, S. (2016). Microdialysis Sampling from Wound Fluids Enables Quantitative Assessment of Cytokines, Proteins, and Metabolites Reveals Bone Defect-Specific Molecular Profiles. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159580"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 Family in Innate Inflammation and Acquired Immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00418-018-1643-3","article-title":"Inflammation, Mesenchymal Stem Cells and Bone Regeneration","volume":"149","author":"Liu","year":"2018","journal-title":"Histochem. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1177\/0022034510393967","article-title":"Infection, Inflammation, and Bone Regeneration: A Paradoxical Relationship","volume":"90","author":"Thomas","year":"2011","journal-title":"J. Dent. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"eaai9044","DOI":"10.1126\/scitranslmed.aai9044","article-title":"Glycosaminoglycan-Based Hydrogels Capture Inflammatory Chemokines and Rescue Defective Wound Healing in Mice","volume":"9","author":"Lohmann","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3233\/CH-199208","article-title":"Biomaterials in Repairing Rat Femoral Defects: In Vivo Insights from Small Animal Positron Emission Tomography\/Computed Tomography (PET\/CT) Studies","volume":"73","author":"Neuber","year":"2019","journal-title":"Clin. Hemorheol. Microcirc."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1002\/jbm.b.31953","article-title":"Biological Functionalization of Dental Implants with Collagen and Glycosaminoglycans\u2014A Comparative Study","volume":"100","author":"Stadlinger","year":"2012","journal-title":"J. Biomed. Mater. Res. B Appl. Biomater."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"42791","DOI":"10.1038\/srep42791","article-title":"Interleukin 10 Inhibits Pro-Inflammatory Cytokine Responses and Killing of Burkholderia Pseudomallei","volume":"7","author":"Kessler","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e2017889118","DOI":"10.1073\/pnas.2017889118","article-title":"Early Systemic Immune Biomarkers Predict Bone Regeneration after Trauma","volume":"118","author":"Cheng","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Wood, S., Jayaraman, V., Huelsmann, E.J., Bonish, B., Burgad, D., Sivaramakrishnan, G., Qin, S., DiPietro, L.A., Zloza, A., and Zhang, C. (2014). Pro-Inflammatory Chemokine CCL2 (MCP-1) Promotes Healing in Diabetic Wounds by Restoring the Macrophage Response. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091574"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40634-014-0017-6","article-title":"Immune Modulation as a Therapeutic Strategy in Bone Regeneration","volume":"2","author":"Schlundt","year":"2015","journal-title":"J. Exp. Orthop."},{"key":"ref_26","first-page":"28","article-title":"Inflammation, Ageing, and Bone Regeneration","volume":"10","author":"Gibon","year":"2017","journal-title":"J. Orthop. Transl."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ishikawa, M., Ito, H., Kitaori, T., Murata, K., Shibuya, H., Furu, M., Yoshitomi, H., Fujii, T., Yamamoto, K., and Matsuda, S. (2014). MCP\/CCR2 Signaling Is Essential for Recruitment of Mesenchymal Progenitor Cells during the Early Phase of Fracture Healing. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104954"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3389\/fendo.2020.00386","article-title":"Modulation of the Inflammatory Response and Bone Healing","volume":"11","author":"Maruyama","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s11914-017-0381-0","article-title":"Osteoimmunology in Bone Fracture Healing","volume":"15","author":"Ono","year":"2017","journal-title":"Curr. Osteoporos. Rep."},{"key":"ref_30","first-page":"2670","article-title":"A Crosstalk Triggered by Hypoxia and Maintained by MCP-1\/MiR-98\/IL-6\/P38 Regulatory Loop between Human Aortic Smooth Muscle Cells and Macrophages Leads to Aortic Smooth Muscle Cells Apoptosis via Stat1 Activation","volume":"8","author":"Wang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3043","DOI":"10.3748\/wjg.v23.i17.3043","article-title":"Macrophage Inflammatory Protein-2 as Mediator of Inflammation in Acute Liver Injury","volume":"23","author":"Qin","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e159","DOI":"10.1111\/clr.12979","article-title":"The Influence of Titanium Surface Characteristics on Macrophage Phenotype Polarization during Osseous Healing in Type I Diabetic Rats: A Pilot Study","volume":"28","author":"Lee","year":"2017","journal-title":"Clin. Oral. Implant. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1128\/IAI.67.5.2590-2601.1999","article-title":"Neutralization of Macrophage Inflammatory Protein 2 (MIP-2) and MIP-1alpha Attenuates Neutrophil Recruitment in the Central Nervous System during Experimental Bacterial Meningitis","volume":"67","author":"Diab","year":"1999","journal-title":"Infect. Immun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"495","DOI":"10.5483\/BMBRep.2008.41.7.495","article-title":"Osteoimmunology: Cytokines and the Skeletal System","volume":"41","author":"Lee","year":"2008","journal-title":"BMB Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s10719-009-9270-9","article-title":"Sulfated Hyaluronan Derivatives Reduce the Proliferation Rate of Primary Rat Calvarial Osteoblasts","volume":"27","author":"Kunze","year":"2010","journal-title":"Glycoconj. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"8938","DOI":"10.1016\/j.biomaterials.2011.08.025","article-title":"Growth Promoting Substrates for Human Dermal Fibroblasts Provided by Artificial Extracellular Matrices Composed of Collagen I and Sulfated Glycosaminoglycans","volume":"32","author":"Hintze","year":"2011","journal-title":"Biomaterials"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.carbpol.2012.05.085","article-title":"Synthesis and Antiherpetic Activity of Carboxymethylated and Sulfated Hyaluronan Derivatives","volume":"90","author":"Schmidtke","year":"2012","journal-title":"Carbohydr. Polym."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.actbio.2011.10.026","article-title":"Artificial Extracellular Matrices Composed of Collagen I and Sulfated Hyaluronan with Adsorbed Transforming Growth Factor \u03921 Promote Collagen Synthesis of Human Mesenchymal Stromal Cells","volume":"8","author":"Hempel","year":"2012","journal-title":"Acta Biomater."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/217078","article-title":"ECM Inspired Coating of Embroidered 3D Scaffolds Enhances Calvaria Bone Regeneration","volume":"2014","author":"Rentsch","year":"2014","journal-title":"BioMed. Res. Int."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2077\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:11:55Z","timestamp":1760119915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2077"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,20]]},"references-count":39,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032077"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032077","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,1,20]]}}}