Prof. Dr. Silvia Budday

Thecentral nervous system (CNS) is our most complex organ system. Despite tremendousprogress in our understanding of the biochemical, electrical, and geneticregulation of CNS functioning and malfunctioning, many fundamental processesand diseases are still not fully understood. For example, axon growth patterns inthe developing brain can currently not be well-predicted based solely on thechemical landscape that neurons encounter, several CNS-related diseases cannotbe precisely diagnosed in living patients, and neuronal regeneration can stillnot be promoted after spinal cord injuries.

Duringmany developmental and pathological processes, neurons and glial cells aremotile. Fundamentally, motion is drivenby forces. Hence, CNS cells mechanicallyinteract with their surrounding tissue. They adhere to neighbouring cells and extracellular matrix using celladhesion molecules, which provide friction, and generate forces usingcytoskeletal proteins.  These forces aretransmitted to the outside world not only to locomote but also to probe themechanical properties of the environment, which has a long overseen huge impacton cell function.

Onlyrecently, groups of several project leaders in this consortium, and a few other groupsworldwide, have discovered an important contribution of mechanical signalsto regulating CNS cell function. For example, they showed that brain tissuemechanics instructs axon growth and pathfinding in vivo, that mechanicalforces play an important role for cortical folding in the developing humanbrain, that the lack of remyelination in the aged brain is due to an increasein brain stiffness in vivo, and that many neurodegenerative diseases areaccompanied by changes in brain and spinal cord mechanics. These first insights strongly suggest thatmechanics contributes to many other aspects of CNS functioning, and it islikely that chemical and mechanical signals intensely interact at the cellularand tissue levels to regulate many diverse cellular processes.

The CRC 1540 EBM synergises the expertise of engineers, physicists,biologists, medical researchers, and clinicians in Erlangen to explore mechanicsas an important yet missing puzzle stone in our understanding of CNSdevelopment, homeostasis, and pathology. Our strongly multidisciplinary teamwith unique expertise in CNS mechanics integrates advanced invivo, in vitro, and in silico techniques across time(development, ageing, injury/disease) and length (cell, tissue, organ) scalesto uncover how mechanical forces and mechanical cell and tissue properties,such as stiffness and viscosity, affect CNS function. We especially focus on(A) cerebral, (B) spinal, and (C) cellular mechanics. Invivo and in vitro studies provide a basic understanding ofmechanics-regulated biological and biomedical processes in different regions ofthe CNS. In addition, they help identify key mechano-chemical factors forinclusion in in silico models and provide data for model calibration andvalidation. In silico models, in turn, allow us to test hypotheses without the need of excessive or even inaccessibleexperiments. In addition, they enable the transfer and comparison of mechanics data and findingsacross species and scales. They also empower us to optimise processparameters for the development of in vitro brain tissue-like matricesand in vivo manipulation of mechanical signals, and, eventually, pavethe way for personalised clinical predictions.

Insummary, we exploit mechanics-based approaches to advance ourunderstanding of CNS function and to provide the foundation for futureimprovement of diagnosis and treatment of neurological disorders.

Ziel dieses Projekts ist es, eine Plattformtechnologie zu entwickeln, um in Raum und Zeit klar definierte und reproduzierbare Gradienten herzustellen, diese zu analysieren und in silico zu modellieren, um ihre Auswirkung auf Zell-Biomaterial-Interaktionen untersuchen zu können. Hierfür sollen zunächst Druckköpfe entwickelt werden, mit denen sich kontrolliert Übergänge von Materialien aus den A-/B-Projekten, Wirkstoffen und Zellen erzeugen lassen. Durch die umfassende Charakterisierung der gedruckten Gradienten mithilfe mechanischer Testmethoden in Kombination mit bildgebenden Verfahren wird das Ergebnis bezüglich der Anforderungen der C-Projekte stetig analysiert und verbessert. Zusätzlich werden kontinuumsmechanische Modellierung und Simulation gezielt eingesetzt, um Prozessparameter, das Druckmuster und die 3D-Anordung im Konstrukt zu optimieren.

The current research project aims to develop microstructurallymotivated mechanical models for brain tissue that facilitate early diagnosticsof neurodevelopmental or neurodegenerative diseases and enable the developmentof novel treatment strategies. In a first step, we will experimentallycharacterize the behavior of brain tissue across scales by using versatiletesting techniques on the same sample. Through an accompanying microstructuralanalysis of both cellular and extra-cellular components, we will evaluate thecomplex interplay of brain structure, mechanics and function. We will alsoexperimentally investigate dynamic changes in tissue properties duringdevelopment and disease, due to changes in the mechanical environment of cells (mechanosensing),or external loading. Based on the simultaneous analysis of experimental andmicrostructural data, we will develop microstructurally motivated constitutive lawsfor the regionally varying mechanical behavior of brain tissue. In addition, wewill develop evolution laws that predict remodeling processes duringdevelopment, homeostasis, and disease. Through the implementation within afinite element framework, we will simulate the behavior of brain tissue underphysiological and pathological conditions. We will predict how known biologicalprocesses on the cellular scale, such as changes in the tissue’smicrostructure, translate into morphological changes on the macroscopic scale,which are easily detectable through modern imaging techniques. We will analyzeprogression of disease or mechanically-induced loss of brain function. The novelexperimental procedures on the borderline of mechanics and biology, togetherwith comprehensive theoretical and computational models, will form thecornerstone for predictive simulations that improve early diagnostics of pathologicalconditions, advance medical treatment strategies, and reduce the necessity ofanimal and human tissue experimentation. The established methodology will furtheropen new pathways in the biofabrication of artificial organs.