Prof. Dr. Oliver Friedrich

Institute of Medical Biotechnology

The Institute of Medical Biotechnology designs and engineers new systems technologies that allow to investigate and manipulate optical and mechanical properties of biological tissues in health, disease and tissue engineering.

Research projects

  • Optical technologies
  • Opto-Biomechatronics
  • Bioreactor technologies
  • Multiphoton endoscopy technologies
  • Image processing, pattern recognition & AI
  • Label-free optical metrologies for tissue diagnostics
  • Multidimensional cell and tissue stretch systems technologies for mechanobiology
  • Bioprocess engineering for optical tissue clearing
  • High pressure biotechnology
  • Robophotonics

  • "Bleibt daheim" - virtuelle Realität Opto-Biomechatronik Skills Labore in einer 3D Rollenspiel-Umgebung für die Studenten-Ausbildung als Ersatz für Präsenzveranstaltungen

    (Third Party Funds Single)

    Term: 1. January 2021 - 31. December 2021
    Funding source: Bayerische Forschungsallianz (BayFOR)
  • Speedy Structure? SHG Morphometry in 'gene-of-speed' Muscle

    (Third Party Funds Single)

    Term: 1. January 2020 - 31. December 2021
    Funding source: Deutscher Akademischer Austauschdienst (DAAD)

    Skeletal muscle defines our motoric quality of life. Although most muscle diseases, either inherited or acquired, present with reduced muscle performance and clinical weakness, some other genetic mutations can come along with gain-of-function or modified fine-tuning towards a specific performance regime. The actn3 gene encodes for alpha-actinin-3, an isoform of a-actinin inherent to fast-twitch skeletal muscle. The protein ACTN3 belongs to the cytoskeleton protein family of actinins that mechanically stabilize the actin filaments at the z-disks. ACTN3 is exclusively expressed in fast-twitch type-II, i.e. glycolytic, skeletal muscle fibres while ACTN2 is expressed in all fibre types. About 20% of the world population presents with a common nonsense polymorphism in the actn3 gene that completely blunts ACTN3 expression in fast fibres. However, this mutation is not associtaed with a disease phenotype, but rather with a genetic predisposition towards enudrance performance and cold pre-acclimatization of fast muscle (Head et al. 2015, PLoS Genet). This phenotype is not associated with molecular switches in the expression of slow myosin isoforms in fast muscle but more with metabolic changes and changes in Ca2+ homeostasis that resemble the slow muscle, i.e. oxidative, phenotype. However, since ACTN3 is also a structural cytoskeletal protein, the question arises whether altered structural cytoarchitecture in 3D might be associated with the aforementioned changes that would render myofibrillar architecture more disordered and thus, limit maximum force in actn3 null fast muscle to that seen in more ordered slow muscle. Also, since actn2 is also upregulated in the null fibres, there is currently no information available of whether an intrinsic genetically enforced upregulation of actn2 may also be responsible for cytoarchitectural changes. Multiphoton Second Harmonic Generation (SHG) microscopy in conjunction with quantitative morphometry of muscle cytoarchitecture in single fibres and whole muscle using optical clearing techniques (all having been established in the labs of the German partner) is suggested to be a suitable and feasible set of tools to address this question in a focussed international collaborative research project.

     

    The specific scientific goals during this collaboration initiative are:

     

    1)         To assess the 3D cytoarchitecture of the myofibrillar lattice of single EDL muscle fibres from adult and old ACTN3 KO mice using Second Harmonic Generation microscopy. The ultrastructural parameters cosine angle sum (CAS) and Vernier Density (VD) will be assessed at those two ages to quantify cellular remodeling related to the null mutation and age. Single soleus (SOL) muscle fibres will serve as internal controls expressing predominantly ACTN2 as well as from wt EDL muscle fibres expressing predominantly ACTN3.

    2)      To assess the 3D cytoarchitecture and intercellular collagen fibril distribution of the extracellular matrix in whole EDL muscles following optical clearing with thiodiethanol (TDE) protocols (established at the German partner’s labs). SOL muscles will serve as control, as well as wt EDL muscles.

    3)      To correlate structural cytoarchitecture data with direct isometric force recordings in single fibres from ACTN3 KO fibres. Control wt results have been already obtained in a current study of the German partner using a novel engineered MechaMorph system to combine biomechatronics with SHG recordings.

  • Pacing the Brain at low Cost – Development and Validation of novel electro-conductive Elastomer Multi-Electrode Arrays for Neuroscience

    (Third Party Funds Single)

    Term: 1. January 2020 - 31. December 2021
    Funding source: Deutscher Akademischer Austauschdienst (DAAD)

    Excitable tissues, e.g. brain, nerves or muscle,are characterised by their responsiveness to electrical signal transmission.They respond to changes in internal ionic currents or external electric fieldswith modulation of ion channels, intracellular signaling cascades, evenmechanical movement (muscle). Neuroscience research has taught us many conceptsof electro-chemical signal reception, processing and transmission that underliemotor control, neurosensory reception and memory in the brain. For neuroscienceresearch, almost all of our knowledge of the cellular and molecular mechanismsof neuro-circuits and systems regulation has emerged from experimentalapproaches involving isolation of tissue sections (slices) from the brains of animalmodels and keeping these tissue sections viable for several hours inappropriate bioreactor environments. For decades, electrical signals have beenevoked and analysed using micro-pipette based patch and voltage-clamptechniques, where glass capillaries are melted and pulled to fine end tips thatcan be inserted into, or attached onto, neurons to establish electrical contactfor recording of ionic currents. These tedious approaches, while allowingsingle cellular electrical resolution however, were not capable of allowinghigh-content recordings from many cells. As a consequence, multi-electrode-arrays(MEAs) were subsequently developed that included fine arrays of wire electrodesembedded in glass chambers with finely scored grooves, building an external wirednetwork that could be electrically stimulated to create a planar electric fieldto stimulate whole layers of cells within brain slices positioned above theelectrodes. Microscope stage-adapted designs of such MEAs allow large scaleelectrical stimulation of nerve cells and optical recording of cellularreactions in a high content configuration to maximize readouts. However, commerciallyavailable MEAs are usually made from die casting or injection mouldingtechniques using glass materials and wire embedding in a two-stagemanufacturing process, rendering such chambers very expensive and delicate inhandling. Furthermore, commercial MEAs usually offer little flexibilityregarding hardware modifications and are only compatible with the specific interfaceboards and field generators of the MEA suppliers. Costs of about 400 USD perMEA-chamber are not unusual (https://www.multichannelsystems.com/), limiting parallelization and multi user availability in many labs.This becomes even more of a bottleneck considering the fact that from onebrain, usually multiple slices could be processed and recorded at once, if moreaffordable and modular MEA chambers were available. This would also reduceanimal numbers in neuroscience and comply with the 3R concept of reduction,refinement, replacement. An alternative strategy to produce MEAs is reflectedby modern additive manufacturing processes, involving rapid prototyping and3D-printing of transparent polymer materials. As such, polycarbonate with aglass transition temperature of 147 °C can be well printed in a fluidicphase above 155 °C through a nozzle-based cartridge using MakerBots with lower tens of micronaccuracy. The German partner’s (OF) Institute of Medical Biotechnology hassubstantial expertise and experience in design and additive manufacturing oftissue chambers tailored for bioresearch. Apart fromacrylonitrile-butadiene-styrol materials, also polycarbonate and other materialblends have been fabricated in past projects. A novel development that now evenallows to manufacture low resistance electrodes into polycarbonate material isreflected by advanced electro-conductive poly-dimethyl-siloxane elastomersdoped with carbon nanotube particles to create electric conduits in solutionsuitable for external field stimulation (preliminary results). OF has visitedthe Australian partner (AM) in 2018 to explore possibilities for projectscomplementing their expertise. AM is a renowned neurophysiologist and hasworked in the field of electrophysiology and ion channels to studyneurophysiological mechanisms of pain, stroke and learning. More recently, he hasused brain slices of rodent brains to study genetic models of epilepsy. Thecurrent project idea was born through a shortage of affordable and more modularMEA systems that could be flexibly designed and being of tougher material ascompared to glass. Also, the opportunity to include elastomer-based electrodeswould reflect a reduction in electrolysis otherwise seen with metal electrodes.Both partners will benefit from each other’s expertise. OF’s team will designand fabricate new low-cost MEA systems to be validated by AM’s team to increasecontent for multicellular research in brain slices from epileptic mice. OF willreserve one travel slot while planning three travel slots to the partnerlaboratories for PhD students/young academics. We expect a combinedbioengineering-neuroscience publication as basis for follow-up project funding.

  • Fat and weak? Structural Correlate for Muscle Weakness revealed by Second Harmonic Generation (SHG) Morphometry in Muscle from a Mouse Model of Obesity

    (Third Party Funds Single)

    Term: 1. January 2020 - 31. December 2021
    Funding source: Deutscher Akademischer Austauschdienst (DAAD)

    Skeletal muscle is our majoreffector organ system for voluntary locomotion and contributes substantially toour quality of life. Muscle weakness is a symtpom not inherent to one specificdisease but rather to a multiplicity of diseases of various origin, bothhereditary and acquired. This is because muscle performance, i.e. forceproduction, is the final result of a complex activation sequence involvingelectrical, chemical and mechanical components when muscle responds to neuronalsignals. However, muscle is also an organ with an incredible plasticity,responding to exercise, hormones and external factors, like nutrition. The factthat muscle also receives hormonal signals as well as also being a site ofactive ‘myokine’ production embeds it in a concerted multi-organ communicationsystem. In this way, many systemic diseases, e.g. systemic inflammation,cancer, heart disease, etc., are associated with muscle atrophy and weakness.Obesity and diabetes are other systemic metabolic diseases that are oftenassociated with muscle weakness in humans. Type 2 diabetes usually develops asa result of obesity and the pathophysiological mechanisms of insulin resistanceand glucose imbalance are major determinants of abrogated muscle anabolism andgrowth. However, apart from detrimental effetcs on signaling and muscle growth(e.g. atrophy), almost nothing is known about the long-term effects regardingremodelling of muscle cytoarchitecture on the cellular level that may limitmaximum cellular force production.

    The German partner has introducedand optimized sophisticated label-free multiphoton-based morphometrytechnologies applying Second HarmonicGeneration (SHG) imaging and structural analysis and classification ofmyofibrillar lattice orientation in single fibres from muscles of variousdisease (animal) models (e.g. Duchenne muscular dystrophy, desminopathy, etc.).More recently, he and his team even obtained force and structure simultaneouslythrough bioengineering of innovative systems technologies applicable to muscletissue and cells. The American partner is a renowned neurologist and researcherwho has developed novel minimally invasive diagnostic tools to assessneuromuscular health and muscle performance in humans and animals in vivo. Much of his research involvesthe application of electrophysiological measures, imaging modalities, andinnovative bioengineering approaches to diagnose and treat such disorders.These techniques include electrical impedance myography, quantitativeultrasound, magnetic resonance imaging, and nerve and muscle excitabilitytechniques. He is also interested in studying mechanisms of diseasepathogenesis and testing new therapeutic agents that can improve function andhealth. In the Rutkove lab, a current focus is in the area of obesity anddiabetes-induced muscle dysfunction involving the so-called BKS db mouse modelthat is used to model phases I to III of type II diabetes and obesity. Micehomozygous for the diabetes spontaneous mutation (Leprdb) manifest morbidobesity, chronic hyperglycemia, pancreatic beta cell atrophy and hypoinsulinemia.Obesity starts at just 3 to 4 weeks of age.

    Both partners are ideallysuited to complement each other to investigate the origin of weakness inobesity-related diabetic muscle dysfunction, both in regard to short-termsignaling and excitability and the long-term structural remodeling aspect ofmyopathy to obtain a holistic picture of muscle weakness. During bilateralproject visits, the German team will obtain muscle samples from BKS db mice atdifferent ages and severity of obesity and diabetes from which the Americanpartner has obtained quantitative measures using motor nerve and direct musclestimulation. The latter techniques can be taught to the German partner for knowledgetransfer, while the German partner will apply muscle fixation and opticalclearing protocols for subsequent label-free multiphoton SHG imaging and morphometryin 3D. Those will be performed at the German partner’s institution and alsoduring visits by the American partner and his team members (additional fundingwill be sought by the US side to support such visits).

    To support one visit by theAmerican partner, the FAU Visiting Professorship Program is currently beingapplied for on the German side (application submitted by OF, May 2019). TheGerman team will include two short-term visits by the German PI (OF) to developthis new collaboration and to prepare and supervise the PhD student andPost-Doc together with the American partner. It will involve focused planningand transfer of muscle samples for SHG morphometry back in Germany and whilebeing at the Harvard host, connecting with interdisciplinary seminarpresentations, and preparation of joint grant initiatives.

  • Application of an IsoStretcher biomechatronics platform and engineering of a novel parallelized MultiStretcher technology for studies of cardiac mechano-signaling in HL-1 atrial cardiomyocytes

    (Non-FAU Project)

    Term: 1. July 2019 - 30. June 2022

    The heart transforms electrical signals into mechanical action tocontinuously pump blood through our circulation. In reverse, mechanical stimuliduring active contraction or passive filling distention are sensed and modulateelectrical signals through so called cardiac mechano-electric feedback(MEF)[1]. The MEF involves complex activation of mechanical biosensorsinitiating short-term and long-term effects through Ca2+ signals incardiomyocytes in acute and chronic pressure overload scenarios (e.g. heartfailure). How mechanical forces alter cardiac function at the molecular levelremains unknown. In this innovative project, we aim to study how definedmechanical stimuli (stress) deform the cell membrane (strain) leading toactivation of mechanosensitive channels (MSC), including the recentlydiscovered family of Piezo channels[3] suspected to play a major role indevelopment of cardiac hypertrophy and heart failure[2]. We will first focus onthe murine immortalised atrial cardiomyocytes HL-1 cell line to investigate Ca2+signalling through aberrantly activated MSC and subsequent MEF before studyingmammalian adult ventricular cardiomyocytes. One part of this internationalcollaborative project consists in redesigning an existing IsoStretcher biomechatronics system[4] into a next generation MultiStretcher system for scaling uphigh-content screening of cellular signalling pathways and control ofbiological batch-to-batch variation. While the engineering of this parallelizedMultiStretcher will be carried out at the institution (Medical BiotechnologyInstitute at Friedrich Alexander University, FAU, Erlangen-Nürnberg) by theteam of Prof Oliver Friedrich, our long-standing collaborator and internationalco-investigator on this project, the application of the Iso- and MultiStretcherfor investigations of MEF-related cell biology and pharmacology will be carriedout at the Victor Chang Cardiac Research Institute (VCCRI). The systemtechnology will be transferred to VCCRI for the ongoing support of cardiacmechanotransduction research.

  • Application of an IsoStretcher biomechatronics platform and engineering of a novel palallelised MultiStretcher technology for studies of cardiac mechano-signalling in HL-1 atrial cardiomyocytes

    (Third Party Funds Single)

    Term: 1. July 2019 - 30. June 2022
    Funding source: andere Förderorganisation

2021

2020

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