Mechanical cues are involved in triggering gliotic and inflammatory reactions around foreign bodies. (A) Schematic drawing of a composite foreign body (cFB) consisting of a compliant (G’ = 100 Pa) and a stiff part (G’ = 30 kPa), both made from polyacrylamide. (B) Schematic coronal section and top view of a rat brain indicating the location of the cFB (dotted lines). The dashed gray line indicates the region visible in (C), which shows brain tissue at the end of an experiment. Scale bar: 1 mm. (D) Immunohistochemistry of brain tissue in the vicinity of the compliant and (E) stiff part of a cFB (asterisks) implanted for three weeks; blue: Hoechst stained nuclei, red: CD11b (OX 42) showing activated microglial cells, green: GFAP showing activated astrocytes. Inflammatory and astrogliotic reactions are considerably increased around the stiff material. Scale bar: 50 mm. Figure reproduced from [1].

Cells actively sense and respond to a variety of mechanical signals – a process known as mechanosensing. Mechanical cues provided by the extracellular environment can modulate a wide spectrum of cellular processes, including cell proliferation, differentiation and migration.
In order to examine the impact of microenvironment stiffness on cell behaviour we use different 2D and 3D hydrogel-based systems. The main advantage of the employed gels is the possibility to independently control the mechanical and biochemical properties of the substrate. Moreover, the stiffness values obtained through tissue mechanics measurements enable us to better tune the hydrogels and perform mechanosensing studies both in physiological and non-physiological mechanical conditions.
As summarised in Franze et al. [2], we have begun to understand that mechanics plays an important role in the development, functioning and disorders of the nervous system. We have shown that CNS glial cells respond to mechanical cues in vitro and in vivo. Substrates with a stiffness far above the physiological microenvironment of the brain cause both microglia and astrocytes to display an acute and late chronic inflammatory response typical for reactive gliosis [1, 3]. Moreover, we have revealed that substrate stiffness influences oligodendrocyte progenitor cells’ survival, proliferation, differentiation and migration capacities in vitro [4]. Recently, colleagues have shown that local tissue stiffness influences neuronal growth and pathfinding even in vivo [5].
Besides neurons and glial cells, our lab also investigates the mechanosensing abilities of other cell types, including neutrophils, macrophages, adipocytes and cancer cells. For example, we have demonstrated the suitability of engineered 3D peptide-functionalised hydrogels to investigate in vitro how the interactions between cancer cells and the extracellular matrix proteins around them modulate tumour development and progression [6].
Insights gained from these projects may ultimately lead to a better understanding of physiological processes and may open novel avenues to treat the underlying degenerative pathologies such as neurodegenerative diseases or, as emphasised in Lacour et al. [7], to improve implant biocompatibility and design.

[1] [doi] P. Moshayedi, G. Ng, J. C. F. Kwok, G. S. H. Yeo, C. E. Bryant, J. W. Fawcett, K. Franze, and J. Guck, “The relationship between glial cell mechanosensitivity and foreign body reactions in the central nervous system,” Biomaterials, vol. 35, iss. 13, p. 3919–3925, 2014.
Title = {{The relationship between glial cell mechanosensitivity and foreign body reactions in the central nervous system}},
Author = {Moshayedi, Pouria and Ng, Gilbert and Kwok, Jessica C.F. and Yeo, Giles S.H. and Bryant, Clare E. and Fawcett, James W. and Franze, Kristian and Guck, Jochen},
Journal = {{Biomaterials}},
Year = {2014},
Number = {13},
Pages = {3919--3925},
Volume = {35},
Annote = {Paper used as a reference in candidate's recruitment.},
Doi = {10.1016/j.biomaterials.2014.01.038},
ISSN = {01429612},
Keywords = {CNS,Guck,Mechanobiology,Mechanosensing,Microglia},
Mendeley-tags = {CNS,Guck,Mechanobiology,Mechanosensing,Microglia},
Publisher = {Elsevier Ltd}
[2] [doi] K. Franze, P. a. Janmey, and J. Guck, “Mechanics in neuronal development and repair.,” Annual Review of Biomedical Engineering, vol. 15, iss. 1, p. 227–51, 2013.
Title = {{Mechanics in neuronal development and repair.}},
Author = {Franze, Kristian and Janmey, Paul a. and Guck, Jochen},
Journal = {{Annual Review of Biomedical Engineering}},
Year = {2013},
Number = {1},
Pages = {227--51},
Volume = {15},
Abstract = {Biological cells are well known to respond to a multitude of chemical signals. In the nervous system, chemical signaling has been shown to be crucially involved in development, normal functioning, and disorders of neurons and glial cells. However, there are an increasing number of studies showing that these cells also respond to mechanical cues. Here, we summarize current knowledge about the mechanical properties of nervous tissue and its building blocks, review recent progress in methodology and understanding of cellular mechanosensitivity in the nervous system, and provide an outlook on the implications of neuromechanics for future developments in biomedical engineering to aid overcoming some of the most devastating and currently incurable CNS pathologies such as spinal cord injuries and multiple sclerosis.},
Doi = {10.1146/annurev-bioeng-071811-150045},
File = {:C$\backslash$:/Users/Joan Carles Escolano/Desktop/PhD Dresden/Literature/Reviews/Annu Rev Biomed Eng 2013 Franze.pdf:pdf},
ISBN = {1545-4274 (Electronic)$\backslash$n1523-9829 (Linking)},
ISSN = {1545-4274},
Keywords = {Animals,Axons,Axons: pathology,Biomechanical Phenomena,Biomedical Engineering,Biomedical Engineering: methods,Brain,Brain: anatomy {\&} histology,Central Nervous System,Central Nervous System: anatomy {\&} histology,Cytoskeleton,Cytoskeleton: metabolism,Elasticity,Extracellular Matrix,Extracellular Matrix: pathology,Humans,Mechanical,Multiple Sclerosis,Multiple Sclerosis: physiopathology,Neuroglia,Neuroglia: cytology,Neurons,Neurons: metabolism,Neurons: pathology,Signal Transduction,Spinal Cord,Spinal Cord Injuries,Spinal Cord Injuries: pathology,Spinal Cord: physiopathology,Stress,brain,glial cells,mechanosensitivity,neurons,stiffness,viscoelasticity},
Pmid = {23642242}
[3] [doi] P. Moshayedi, L. F. da Costa, A. Christ, S. P. Lacour, J. Fawcett, J. Guck, and K. Franze, “Mechanosensitivity of astrocytes on optimized polyacrylamide gels analyzed by quantitative morphometry,” Journal of Physics: Condensed Matter, vol. 22, p. 194114, 2010.
Title = {{Mechanosensitivity of astrocytes on optimized polyacrylamide gels analyzed by quantitative morphometry}},
Author = {Moshayedi, Pouria and Costa, Luciano da F. and Christ, Andreas and Lacour, Stephanie P. and Fawcett, James and Guck, Jochen and Franze, Kristian},
Journal = {{Journal of Physics: Condensed Matter}},
Year = {2010},
Pages = {194114},
Volume = {22},
Abstract = {Cells are able to detect and respond to mechanical cues from their environment. Previous studies have investigated this mechanosensitivity on various cell types, including neural cells such as astrocytes. In this study, we have carefully optimized polyacrylamide gels, commonly used as compliant growth substrates, considering their homogeneity in surface topography, mechanical properties, and coating density, and identified several potential pitfalls for the purpose of mechanosensitivity studies. The resulting astrocyte response to growth on substrates with shear storage moduli of G' = 100 Pa and G' = 10 kPa was then evaluated as a function of coating density of poly-D-lysine using quantitative morphometric analysis. Astrocytes cultured on stiff substrates showed significantly increased perimeter, area, diameter, elongation, number of extremities and overall complexity if compared to those cultured on compliant substrates. A statistically significant difference in the overall morphological score was confirmed with an artificial intelligence-based shape analysis. The dependence of the cells' morphology on PDL coating density seemed to be weak compared to the effect of the substrate stiffness and was slightly biphasic, with a maximum at 10-100 µg ml(-1) PDL concentration. Our finding suggests that the compliance of the surrounding tissue in vivo may influence astrocyte morphology and behavior.},
Doi = {10.1088/0953-8984/22/19/194114},
ISBN = {1361-648X (Electronic)$\backslash$r0953-8984 (Linking)},
ISSN = {1361-648X},
Keywords = {Acrylic Resins,Animals,Astrocytes,Astrocytes: cytology,Astrocytes: physiology,Biological,Cell Adhesion,Cell Adhesion: physiology,Cells,Cellular,Cellular: physiology,Computer Simulation,Cultured,Focal Adhesions,Focal Adhesions: physiology,Gels,Humans,Mechanical,Mechanotransduction,Models,Rats,Shear Strength,Shear Strength: physiology,Stress},
Pmid = {21386440}
[4] [doi] A. Jagielska, A. L. Norman, G. Whyte, K. V. J. Vliet, J. Guck, and R. J. M. Franklin, “Mechanical Environment Modulates Biological Properties of Oligodendrocyte Progenitor Cells,” Stem Cells and Development, vol. 21, iss. 16, 2012.
Title = {{Mechanical Environment Modulates Biological Properties of Oligodendrocyte Progenitor Cells}},
Author = {Jagielska, Anna and Norman, Adele L and Whyte, Graeme and Vliet, Krystyn J Van and Guck, Jochen and Franklin, Robin J M},
Journal = {{Stem Cells and Development}},
Year = {2012},
Number = {16},
Volume = {21},
Abstract = {Myelination and its regenerative counterpart remyelination represent one of the most complex cell–cell interactions in the central nervous system (CNS). The biochemical regulation of axon myelination via the proliferation, migration, and differentiation of oligodendrocyte progenitor cells (OPCs) has been characterized extensively. However, most biochemical analysis has been conducted in vitro on OPCs adhered to substrata of stiffness that is orders of magnitude greater than that of the in vivo CNS environment. Little is known of how variation in mechanical properties over the physiological range affects OPC biology. Here, we show that OPCs are mechanosensitive. Cell survival, proliferation, migration, and differentiation capacity in vitro depend on the mechanical stiffness of polymer hydrogel substrata. Most of these properties are optimal at the intermediate values of CNS tissue stiffness. Moreover, many of these properties measured for cells on gels of optimal stiffness differed significantly from those measured on glass or polystyrene. The dependence of OPC differentiation on the mechanical properties of the extracellular environment provides motivation to revisit results obtained on nonphysiological, rigid surfaces. We also find that OPCs stiffen upon differentiation, but that they do not change their compliance in response to substratum stiffness, which is similar to embryonic stem cells, but different from adult stem cells. These results form the basis for further investigations into the mechanobiology of cell function in the CNS and may specifically shed new light on the failure of remyelination in chronic demyelinating diseases such as multiple sclerosis.},
Doi = {10.1089/scd.2012.0189},
File = {:C$\backslash$:/Users/Joan Carles Escolano/Desktop/PhD Dresden/Literature/Lab Recommendations/Mechanical Environment Modulates Biological Properties of Oligodendrocyte Progenitor Cells(Stem Cells and Dev 2012).pdf:pdf},
Owner = {paul},
Timestamp = {2017.01.25}
[5] [doi] D. E. Koser, A. J. Thompson, S. K. Foster, A. Dwivedy, E. K. Pillai, G. K. Sheridan, H. Svoboda, M. Viana, L. F. da Costa, J. Guck, C. E. Holt, and K. Franze, “Mechanosensing is critical for axon growth in the developing brain,” Nature Neuroscience, vol. 19, iss. 12, p. 1592–1598, 2016.
Title = {{Mechanosensing is critical for axon growth in the developing brain}},
Author = {Koser, David E and Thompson, Amelia J and Foster, Sarah K and Dwivedy, Asha and Pillai, Eva K and Sheridan, Graham K and Svoboda, Hanno and Viana, Matheus and Costa, Luciano da F and Guck, Jochen and Holt, Christine E and Franze, Kristian},
Journal = {{Nature Neuroscience}},
Year = {2016},
Month = {sep},
Number = {12},
Pages = {1592--1598},
Volume = {19},
Abstract = {During nervous system development, neurons extend axons along well-defined pathways. The current understanding of axon pathfinding is based mainly on chemical signaling. However, growing neurons interact not only chemically but also mechanically with their environment. Here we identify mechanical signals as important regulators of axon pathfinding. In vitro, substrate stiffness determined growth patterns of Xenopus retinal ganglion cell axons. In vivo atomic force microscopy revealed a noticeable pattern of stiffness gradients in the embryonic brain. Retinal ganglion cell axons grew toward softer tissue, which was reproduced in vitro in the absence of chemical gradients. To test the importance of mechanical signals for axon growth in vivo, we altered brain stiffness, blocked mechanotransduction pharmacologically and knocked down the mechanosensitive ion channel piezo1. All treatments resulted in aberrant axonal growth and pathfinding errors, suggesting that local tissue stiffness, read out by mechanosensitive ion channels, is critically involved in instructing neuronal growth in vivo.},
Doi = {10.1038/nn.4394},
File = {:C$\backslash$:/Users/Joan Carles Escolano/Desktop/PhD Dresden/Literature/Lab Recommendations/Mechanosensing is critical for axon growth in the developing brain (Nat Neur 2016).pdf:pdf},
ISSN = {1097-6256},
Owner = {paul},
Publisher = {Nature Research},
Timestamp = {2017.01.25}
[6] [doi] A. V. Taubenberger, L. J. Bray, B. Haller, A. Shaposhnykov, M. Binner, U. Freudenberg, J. Guck, and C. Werner, “3D extracellular matrix interactions modulate tumour cell growth, invasion and angiogenesis in engineered tumour microenvironments,” Acta Biomaterialia, vol. 36, p. 73–85, 2016.
Title = {{3D extracellular matrix interactions modulate tumour cell growth, invasion and angiogenesis in engineered tumour microenvironments}},
Author = {Taubenberger, Anna V. and Bray, Laura J. and Haller, Barbara and Shaposhnykov, Artem and Binner, Marcus and Freudenberg, Uwe and Guck, Jochen and Werner, Carsten},
Journal = {{Acta Biomaterialia}},
Year = {2016},
Pages = {73--85},
Volume = {36},
Abstract = {Interactions between tumour cells and extracellular matrix proteins of the tumour microenvironment play crucial roles in cancer progression. So far, however, there are only a few experimental platforms available that allow us to study these interactions systematically in a mechanically defined three-dimensional (3D) context. Here, we have studied the effect of integrin binding motifs found within common extracellular matrix (ECM) proteins on 3D breast (MCF-7) and prostate (PC-3, LNCaP) cancer cell cultures, and co-cultures with endothelial and mesenchymal stromal cells. For this purpose, matrix metalloproteinase-degradable biohybrid poly(ethylene) glycol-heparin hydrogels were decorated with the peptide motifs RGD, GFOGER (collagen I), or IKVAV (laminin-111). Over 14 days, cancer spheroids of 100-200 ??m formed. While the morphology of poorly invasive MCF-7 and LNCaP cells was not modulated by any of the peptide motifs, the aggressive PC-3 cells exhibited an invasive morphology when cultured in hydrogels comprising IKVAV and GFOGER motifs compared to RGD motifs or nonfunctionalised controls. PC-3 (but not MCF-7 and LNCaP) cell growth and endothelial cell infiltration were also significantly enhanced in IKVAV and GFOGER presenting gels. Taken together, we have established a 3D culture model that allows for dissecting the effect of biochemical cues on processes relevant to early cancer progression. These findings provide a basis for more mechanistic studies that may further advance our understanding of how ECM modulates cancer cell invasion and how to ultimately interfere with this process. Statement of Significance Threedimensional in vitro cancer models have generated great interest over the past decade. However, most models are not suitable to systematically study the effects of environmental cues on cancer development and progression. To overcome this limitation, we have developed an innovative hydrogel platform to study the interactions between breast and prostate cancer cells and extracellular matrix ligands relevant to the tumour microenvironment. Our results show that hydrogels with laminin- and collagen-derived adhesive peptides induce a malignant phenotype in a cell-line specific manner. Thus, we have identified a method to control the incorporation of biochemical cues within a three dimensional culture model and anticipate that it will help us in better understanding the effects of the tumour microenvironment on cancer progression.},
Doi = {10.1016/j.actbio.2016.03.017},
ISSN = {18787568},
Keywords = {3D model,Angiogenesis,Extracellular matrix,Integrin,Tumour microenvironment},
Pmid = {26971667},
Publisher = {Acta Materialia Inc.}
[7] [doi] S. P. Lacour, G. Courtine, and J. Guck, “Materials and technologies for soft implantable neuroprostheses,” Nature Reviews Materials, vol. 1, p. 16063, 2016.
Title = {{Materials and technologies for soft implantable neuroprostheses}},
Author = {Lacour, St{\'{e}}phanie P and Courtine, Gr{\'{e}}goire and Guck, Jochen},
Journal = {{Nature Reviews Materials}},
Year = {2016},
Month = {sep},
Pages = {16063},
Volume = {1},
Abstract = {Implantable neuroprostheses are engineered systems designed to restore or substitute function for individuals with neurological deficits or disabilities. These systems involve at least one uni- or bidirectional interface between a living neural tissue and a synthetic structure, through which information in the form of electrons, ions or photons flows. Despite a few notable exceptions, the clinical dissemination of implantable neuroprostheses remains limited, because many implants display inconsistent long-term stability and performance, and are ultimately rejected by the body. Intensive research is currently being conducted to untangle the complex interplay of failure mechanisms. In this Review, we emphasize the importance of minimizing the physical and mechanical mismatch between neural tissues and implantable interfaces. We explore possible materials solutions to design and manufacture neurointegrated prostheses, and outline their immense therapeutic potential.},
Doi = {10.1038/natrevmats.2016.63},
File = {:C$\backslash$:/Users/Joan Carles Escolano/Desktop/PhD Dresden/Literature/Reviews/Materials and technologies for soft implantable neuroprostheses (Nat Rev Materials 2016).pdf:pdf},
Publisher = {Macmillan Publishers Limited}