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Franz S.,University of Leipzig | Franz S.,Collaborative Research Center 67 | Allenstein F.,University of Leipzig | Allenstein F.,Collaborative Research Center 67 | And 10 more authors.
Acta Biomaterialia

The sequential phases of biomaterial integration and wound healing require different macrophage functions mediated by distinct macrophage subsets. During the initial phase of healing, pro-inflammatory M1 macrophages (MΦ1) are required to clear the wound from microbes and debris; however, their unopposed, persistent activation often leads to disturbed integration of biomaterials and perturbed wound healing. Here we investigated whether pro-inflammatory macrophage functions are affected by immunomodulatory biomaterials based on artificial extracellular matrices (aECM). To address this issue, we tested the capacity of two-dimensional aECM consisting of collagen I and hyaluronan or sulfated derivatives of hyaluronan to affect functions of in vitro polarized human pro-inflammatory MΦ1. The aECM containing high-sulfated hyaluronan substantially decreased inflammatory macrophage functions, including pathogen uptake and release of the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin-12 due to impaired activation of nuclear factor "kappa-light-chain-enhancer" of activated B-cells. Moreover, these macrophages secreted immunregulatory IL-10 and showed reduced activity of the transcription factors signal transducer and activator of transcription 1 and interferon-regulating factor 5, both controlling macrophage polarization to MΦ1 subsets. Our data reveal that the collagen I matrix containing high-sulfated hyaluronan possesses immunomodulating properties and dampens inflammatory macrophage activities by impeding signaling pathways crucial for polarization of pro-inflammatory MΦ1. We therefore suggest this aECM as a promising coating for biomaterials to modulate inflammatory macrophage functions during the healing response and recommend its further testing as a three-dimensional construct and in in vivo models. © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. Source

Franz S.,University of Leipzig | Franz S.,Collaborative Research Center 67 | Rammelt S.,Dresden University Hospital Carl Gustav Carus | Rammelt S.,Collaborative Research Center 67 | And 4 more authors.

A key for long-term survival and function of biomaterials is that they do not elicit a detrimental immune response. As biomaterials can have profound impacts on the host immune response the concept emerged to design biomaterials that are able to trigger desired immunological outcomes and thus support the healing process. However, engineering such biomaterials requires an in-depth understanding of the host inflammatory and wound healing response to implanted materials.One focus of this review is to outline the up-to-date knowledge on immune responses to biomaterials. Understanding the complex interactions of host response and material implants reveals the need for and also the potential of " immunomodulating" biomaterials. Based on this knowledge, we discuss strategies of triggering appropriate immune responses by functional biomaterials and highlight recent approaches of biomaterials that mimic the physiological extracellular matrix and modify cellular immune responses. © 2011 Elsevier Ltd. Source

Muller S.A.,Helmholtz Center for Environmental Research | Muller S.A.,Collaborative Research Center 67 | Van Der Smissen A.,Collaborative Research Center 67 | Van Der Smissen A.,University of Leipzig | And 5 more authors.
Journal of Materials Science: Materials in Medicine

Fibroblasts are the main matrix producing cells of the dermis and are also strongly regulated by their matrix environment which can be used to improve and guide skin wound healing processes. Here, we systematically investigated the molecular effects on primary dermal fibroblasts in response to high-sulfated hyaluronan [HA] (hsHA) by quantitative proteomics. The comparison of non- and highsulfated HA revealed regulation of 84 of more than 1,200 quantified proteins. Based on gene enrichment we found that sulfation of HA alters extracellular matrix remodeling. The collagen degrading enzymes cathepsin K, matrix metalloproteinases- 2 and -14 were found to be down-regulated on hsHA. Additionally protein expression of thrombospondin-1, decorin, collagen types I and XII were reduced, whereas the expression of trophoblast glycoprotein and collagen type VI were slightly increased. This study demonstrates that global proteomics provides a valuable tool for revealing proteins involved in molecular effects of growth substrates for further material optimization. © The Author(s) 2012. Source

Van Der Smissen A.,University of Leipzig | Van Der Smissen A.,Collaborative Research Center 67 | Samsonov S.,TU Dresden | Samsonov S.,Collaborative Research Center 67 | And 12 more authors.
Acta Biomaterialia

Sulfated glycosaminoglycans are promising components for functional biomaterials since sulfate groups modulate the binding of growth factors and thereby influence wound healing. Here, we have investigated the influence of an artificial extracellular matrix (aECM) consisting of collagen I (coll) and hyaluronan (HA) or highly sulfated HA (hsHA) on dermal fibroblasts (dFb) with respect to their differentiation into myofibroblasts (MFb). Fibroblasts were cultured on aECM in the presence of aECM-adsorbed or soluble transforming growth factor b1 (TGFβ1). The synthesis of a-smooth muscle actin (aSMA), collagen and the ED-A splice variant of fibronectin (ED-A FN) were analyzed at the mRNA and protein levels. Furthermore, we investigated the bioactivity and signal transduction of TGFβ1 in the presence of aECM and finally made interaction studies of soluble HA or hsHA with TGFβ1. Artificial ECM composed of coll and hsHA prevents TGFβ1-stimulated aSMA, collagen and ED-A FN expression. Our data suggest an impaired TGFβ1 bioactivity and downstream signaling in the presence of aECM containing hsHA, shown by massively reduced Smad2/3 translocation to the nucleus. These data are explained by in silico docking experiments demonstrating the occupation of the TGFβ-receptor I binding site by hsHA. Possibly, HA sulfation has a strong impact on TGFβ1-driven differentiation of dFb and thus could be used to modulate the properties of biomaterials. © 2013 Acta Materialia Inc. Published by Elsevier Ltd. Source

van der Smissen A.,University of Leipzig | van der Smissen A.,Collaborative Research Center 67 | Hintze V.,TU Dresden | Hintze V.,Collaborative Research Center 67 | And 12 more authors.

The application of native extracellular matrix (ECM) components is a promising approach for biomaterial design. Here, we investigated artificial ECM (aECM) consisting of collagen I (coll) and the glycosaminoglycans (GAGs) hyaluronan (HA) or chondroitin sulfate (CS). Additionally, GAGs were chemically modified by the introduction of sulfate groups to obtain low-sulfated and high-sulfated GAG derivatives. Sulfate groups are expected to bind and concentrate growth factors and improve their bioactivity. In this study we analyzed the effect of aECM on initial adhesion, proliferation, ECM synthesis and differentiation of human dermal fibroblasts (dFb) within 8-48 h. We show that initial adhesion and cell proliferation of dFb progressively increased in a sulfate dependent manner. In contrast, synthesis of ECM components coll and HA was decreased on high-sulfated aECM coll/HA3.0 and coll/CS3.1. Furthermore, the matrix metallo-proteinase-1 (MMP-1) was down-regulated on coll/HA3.0 and coll/CS3.1 on mRNA and protein level. The fibroblast differentiation marker α-smooth muscle actin (αSMA) is not affected by aECM on mRNA level. Artificial ECM consisting of coll and high-sulfated GAGs proves to be a suitable biomaterial for dFb adhesion and proliferation that induces a "proliferative phenotype" of dFb found in the early stages of cutaneous wound healing. © 2011 Elsevier Ltd. Source

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