Franz J Baudenbacher

Research Focus

The Baudenbacher lab is centered on the development of a broad range of bioinstrumentation, bridging the gap from single cell scale Bio-micro-electro-mechanical systems (BioMEMS) to whole heart multimodal functional imaging workstations to investigate the interplay of cardiac metabolism, excitation-contraction coupling and its regulation under both physiological and pathological conditions. The broader impact lies an improved biophysical description of cellular cardiac function to guide the identification of possible therapies for heart failure and ischemia, and the applicability of the project’s micromachined PicoCalorimeters, NanoPhysiometers and microsensors to a broad range of research from molecular bioanalytics, chemistry, cell biology, and protein folding to toxicology and dynamic, high-throughput drug screening.

Current Projects

High Resolution Imaging of Biomagnetic Fields: Over the past two decades there has been a significant controversy regarding the source and the information content of the bioelectric and biomagnetic fields. We are on of the few laboratories world-wide which that can image the biomagnetic in biological tissue with sub-millimeter resolution using Superconducting QUantum Interference Devices (SQUID) microscopy. Our SQUID microscope sensors have sensitivities 8 orders of magnitude lower than the earth’s magnetic field at 100 µm. SQUID microscopy is therefore also ideally suited for high resolution geomagnetic studies and characterization of magnetic nanoparticles with unsurpassed moment sensitivity, and this application has contributed to their continued development. The Baudenbacher Lab constructed two instruments in leading paleomagnetism laboratories at MIT (Dr. Benjamin Weiss) and Caltech (Dr. Joe Kirschvink). The latest generation of SQUID microscope that we built is crycooled with an electronic gradiometer for noise suppression.

Detection of Single Magnetic Nanoparticles in Microfluidic Environments:
Magnetic particles are used for variety of biological application ranging for magnetic separation, immunoassay to MRI contrast agents. SQUID microscopy and microfluids allows us to measure all three vector components of single magnetic particles moving past a SQUID sensor in serpentine channels which demonstrates the feasibility of high content flow cytometry with magnetic beads as labels.

Microrheology and Cell-Cell Adhesion:
This work is based on the hypothesis that rheological properties allow the quantification of cell-cell adhesion and can be used to predict the probability of metastasis formation in cancer. This hypothesis has led to the development magnetic tweezers to characterize the rheological properties of cells linked to E-Cadherin coated magnetic beads. Current work is focused on the development of BioMEMS devices to investigate and quantify cell-cell adhesion in high throughput assays to identify new targets for anti-cancer drugs.

Microfluidic-Based Cellular Instrumentation:
Microfabrication and microfluidics are used to implement lab on a chip devices for point of care or global health. We also use the technology to confine cells in chemically controlled microenvironments to monitor multiple signaling and metabolic variables dynamically under “in vivo” like conditions. Deviations from homeostasis would indicate a metabolic challenge indicating cellular activation or toxin exposure. Multiple real-time sensing modalities would allow toxin or cellular activity identification. We have developed electrochemical sensing array for on-chip, single-cell measurements of the rates of acidification, glucose consumption and lactate production, thermopiles to measure the heat generation (NanoCalorimeter) of single cells, or microfluidics networks for on-chip perforated patch recordings from cardiac stem cells, and rapid solution switchers to study the synaptic transitions in neurons. The devices are combined with high resolution optical imaging technologies to measure intracellular, mitochondrial and sarcoplasmic reticulum (SR) Ca2+ concentrations, pH, NAD(P)H, sodium and potassium, contractility, transmembrane and mitochondrial potentials in single cardiac myocytes to quantify changes in Ca2+ handling, electrophysiology, contractility and bioenergetics.

Cardiac Force-Excitation-Coupling, Bioenergetics and Arrhythmogenisis:
Cardiomyopathy is literally a disease of the heart muscle with an incidence of 400,000 cases per year in the US. Mutations in metabolic enzymes and contractile proteins give rise to cardiac myopathies. We combine chemically controlled microenvironments and electrophysiological, mechanical and metabolic sensing techniques with advanced multimodal functional imaging techniques in isolated whole hearts to bridge the gap to single cell studies and address arrhythmias and sudden death in patients with mutations in certain metabolic enzymes and sarcomeric proteins (Troponin T) or during ischemia.  As a model system for the generation of polymorphic ventricular arrhythmias we use genetically modified mice lacking key enzymes (very-long-chain acyl-CoA dehydrogenase - VLCAD) required for metabolizing fatty acids and hypothesize altered Ca2+ handling and increased NaH-exchanger activity as a possible molecular mechanism contributing to these arrhythmias.  Sarcomeric mutations in mice expressing Ca2+- sensitizing variants of troponin T (TnT-I79N, TnT-F110I) have an increased incidence of ventricular arrhythmias that occur in the absence of myocardial hypertrophy or fibrosis. We currently address how the effects of Ca2+ and non-Ca2+ dependent changes affect action potentials and feed back onto conduction velocity (CV) restitution, short-term cardiac memory and electrotonic factors on the tissue level and act synergistically with tissue heterogeneity, dynamic instabilities and early afterdepolarizations (EADs) to promote the onset of fibrillation.

Publications

Baudenbacher F, Schober T, Pinto JR, Sidorov VY, Hilliard F, Solaro RJ, Potter JD, Knollmann BC, ”Myofilament Calcium Sensitization Causes Susceptibility To Cardiac Arrhythmia”, Journal of Clinical Investigation, 118(12), 3893-3903, 2008.

Ges IA, Baudenbacher FJ, “Microfluidic device to confine single cardiac myocytes in sub-nanoliter volumes for extracellular pH measurements”, Journal of Experimental Nanoscience., 3(1) 63-75, 2008

Xu J, Reiserer R, Tellinghuisen J, Wikswo JP, Baudenbacher FJ, “A Microfabricated Nanocalorimeter: Design, Characterization, and Chemical Calibration”, Analytical Chemistry, 80, 8, 2728 - 2733; 2008

Werdich AA, Lima EA, Dzhura I, Singh MV, Li J, Anderson ME, Baudenbacher FJ, “Differential effects of phospholamban and Ca2+/calmodulin-dependent kinase II on [Ca2+]i-transients in cardiac myocytes at physiological stimulation frequencies”, American Journal of Physiology-Heart and Circulatory Physiology, 294 (5), H2352-H2362, 2008.

Fong LE, Holzer JR, McBride KK, Lima EA, Baudenbacher,F., Radparvar M, “High-resolution room-temperature sample scanning superconducting quantum interference device microscope configurable for geological and biomagnetic applications.” Review of Scientific Instruments 76, 2005.