Creating Biomedical Technologies to Improve Health

Section on Biophotonics

This is a picture of the laser configuration for optical imaging in the section on high resolution imaging

The Section on High Resolution Optical Imaging (HROI) develops novel technologies for studying biological processes at unprecedented speed and resolution. Research includes improving the performance of 3D optical imaging microscopes, particularly with respect to resolution and depth (e.g. multifocal structured illumination microscopy, MSIM) and speed and phototoxicity (e.g. inverted selective plane illumination microscopy, iSPIM). We collaborate closely with intra- and extramural researchers (both academic and commercial) to ensure that our microscopes are both easily and widely used. Along with researchers at Sloan-Kettering (Zhirong Bao) and Yale University (Daniel Colon-Ramos), we are using one of our technologies (iSPIM) to construct the first atlas of 4D neurodevelopment in an animal.

This is a collage of multi-functional nanomedicine platform. The Multi-functional nanoparticle can load siRNA and hydrophobic anticancer drugs simultaneously and can deliver the multiple cargos into cancer cells
Multi-functional nanomedicine platform (Angewandte Chemie International Edition cover art): Multi-functional nanoparticle (Zn-DPA-labeled HA-NP, HADPA-Zn-NP) can load siRNA and hydrophobic anticancer drugs simultaneously and can deliver the multiple cargos into cancer cells (Angew Chem Int Ed Engl. 2012 Jan 9;51(2):445-9).

Theranostic Nanomedicine is the medical application of nanobiotechnology and refers to highly specific medical intervention at the nanoscale for diagnosing, curing or preventing diseases. Theranostic Nanomedicine involves the creation and application of nanobiomaterials and devices at the molecular level for personalized diagnosis, imaging and therapy.

Using a multidisciplinary approach, our lab builds new systems for various nanobiomedical applications ranging from the medical use of nanoplatform-based diagnostic agents, to therapeutic agents, and even possible future applications of theranostics (diagnosis + therapy). By integrating state-of-the-art molecular imaging and nanomedicine with peptide/protein chemistry, polymer/inorganic chemistry, nanobioconjugation chemistry, cell/molecular biology as well as clinical medicine, we are developing future nanoplatforms which enable i) early detection of diseases, ii) monitoring therapeutic response, and iii) targeted delivery of therapeutic agents. Its improved practical potency highlights its potential as new personalized strategies to help improve patient management and outcomes in the near future.

This is an immunlfluorescence image of a tumor.  There are many blue spots which are DAPI stains of cell nuclei. The tumor vasculature is stained red using an antibody against CD31 and a FITC conjugated antibody was used to stain epidermal growth factor recpetor green.
Ex vivo Immunofluorescence Image. The tumor vasculature was stained with anti-CD31 antibody (red color). The green color is from FITC conjugated antibody against EGFR. The blue color is from DAPI for nuclei visualization.

The Biological Molecular Imaging Section focuses on identification of disease-specific biomarkers; development of new molecular imaging probes with cellular and molecular biology oriented techniques and methods; application of the developed probes into multimodality imaging; and collaborates with the other two LOMIN sections to characterize novel imaging or therapeutic agents, both in vitro and in vivo.

This is a computer generated model that shows differences in the molecular structure of the human and C. intestinalis crystallin protein which is a protein found in the vertebrate eye lens. The N terminal domain of the human protein is in yellow and the C. intestinalis is gray. Identical residues are highlighted in blue. Residues in the human protein that have higher dn over dc value compared to those at the same position in the C. intestinalis are red.

The Section of the Dynamics of Macromolecular Assembly develops biophysical methods to study protein interactions and the assembly of multi-protein complexes. Hallmarks of multi-protein complexes are multi-valent interactions and cooperativity. In the molecular machinery of cellular processes these constitute ubiquitous mechanisms for the integration and transfer of information. Therefore, our focus is on the development of approaches for multi-component systems where several different macromolecular components interact to allow association and dissociation of different co-existing complexes in different states. We are interested in the characterization of the number of assembly states, and their size, shape, and the interaction energetics. Complementary to crystallographic techniques, such solution interaction studies can provide information on the assembly principles of structurally polymorph multi-protein complexes.  

The Laboratory of Molecular Imaging and Nanomedicine (LOMIN) specializes in synthesizing molecular imaging probes for positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), optical (bioluminescence, fluorescence and Raman), contrast enhanced ultrasound, photoacoustic imaging, as well as multimodality imaging. This research group aims to develop a molecular imaging toolbox for better understanding of biology, early diagnosis of disease, monitoring therapy response, and guiding drug discovery/development. LOMIN puts special emphasis on high-sensitivity nanosensors for biomarker detection and theranostic nanomedicine for imaging, gene and drug delivery, and monitoring of treatment.

 

 

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LOMIN Lab group photo

 

This is an image of a rendered three dimensional model of a malaria infected erythrocyte obtained by scanning transmission electron tomography

The Laboratory of Cellular Imaging and Macromolecular Biophysics (LCIMB) specializes in the development and application of cutting-edge technologies based upon engineering, mathematics, and the physical sciences, for the solution of problems in biology and medicine. It collaborates with intramural scientists, as well as proposes and develops theoretical and experimental methods important to the long-term needs of the NIH. Its unique expertise spans technologies ranging in scale from near-atomic resolution to intact organisms.

Fluorescent proteins come in multiple colors and have similar structures consisting of 11-strand beta-barrels with the chromophore located inside the barrel.  This is an image of a chromophore which is a cyclized tripeptide which forms in the absence of any exogeneous factors with the exception of molecular oxygen. This property makes fluorescent proteins invaluable for the tagging of specific proteins of interest and their study inside living cells.
Fluorescent proteins come in multiple colors and have similar structures consisting of 11-strand beta-barrels with the chromophore located inside the barrel. The chromophore is a cyclized tripeptide which forms in the absence of any exogeneous factors with the exception of molecular oxygen. This property makes fluorescent proteins invaluable for the tagging of specific proteins of interest and their study inside living cells. This image was made using Cn3D and pdb file 1EMA.

The NIBIB Section on Biophotonics develops probes and techniques for use in diffraction limited and sub-diffraction limited fluorescence imaging of cells and tissues. Major emphasis is placed on developing new and improving existing genetically encoded fluorescent proteins for use as markers and sensors. Methods and technologies include confocal, TIRF, and widefield microscopies, single molecule imaging, fluorescence spectroscopy, and protein engineering.

Rendered 3D model of pancreatic beta cells obtained by scanning transmission electron tomography
Rendered 3D model of pancreatic beta cells obtained by scanning transmission electron tomography (A.A. Sousa et al., J. Struct. Biol. 2011; 174: 107-114).

The Cellular and Supramolecular Structure and Function (CSSF) Section develops new methods based on electron microscopy and related techniques.  Our aim is to expand knowledge about complex biological and disease processes, as well as to characterize morphologically the action of diagnostic markers and therapeutic agents in cells.  The nanometer scale of biological electron microscopy lies between the realms of live-cell optical microscopy and atomic-scale structural tools that require extraction and purification of cellular components. Current research includes development of techniques for (1) determining the tertiary and quaternary structures of macromolecular assemblies, (2) visualizing 3D ultrastructure, (3) mapping the elemental composition of subcellular compartments quantitatively, and (4) studying bionanoparticles and their interactions with cells.  We are applying these methods to structural biology, cellular biology, neurobiology, cancer biology, and nanomedicine. 

 

 

Intramural Research Training Award Program/CSSF Alumni

This is an image is a three dimensional graph that shows the elastic properties of a section of cartilage at high resolution by mapping nanoindentations across an array of points on the cartilage

The Biomedical Engineering and Physical Science (BEPS) shared resource supports NIH’s intramural basic and clinical scientists on applications of engineering, physics, imaging, measurement and analysis.  BEPS is centrally located on the main NIH campus, and provides expertise that spans technologies ranging in scale from near-atomic resolution to intact organisms. 

Please click on the links below to learn more about BEPS’s six Units:

MICROANALYTICAL lab image
MICROANALYTICAL lab image

The Micro Analytical Immunochemistry Unit of the BEPS Shared Resource specializes in the following:

  • Micro-immunoaffinity capillary electrophoresis to quantify analyte concentrations in biological samples
  • Development of novel immunoassays for microliter and sub-microliter biological fluid and tissue samples
  • SELEX via capillary electrophoresis to generate aptamers with specificity for protein targets
  • Multianalyte ELISA arrays using QuansysTM imaging system
  • MALDI-TOF analysis of proteins, antibodies and other biological molecules
  • Characterization of biological molecule interactions using Surface Plasmon Resonance (SPR)
  • Trace metal analysis in biological samples, via Inductively-Coupled-Plasma Optical Emission Spectrometry (ICP-OES)

We are located in Building 13 on the NIH campus. 

This is an image of a typical sedimentation velocity profiles represented as black circles in an overlay with best-fit curves which are red lines obtained by numerical modeling.
Typical sedimentation velocity profiles (black circles) in overlay with best-fit curves (red line) obtained by numerical modeling

The Quantitative Methods for Macromolecular Interactions (QMMI) Unit of the BEPS Shared Resource is located on the 3rd floor of Building 13 on the NIH campus in Bethesda, MD. Please contact us to schedule a meeting or tour our labs.

We have expertise in:

  • Characterization of individual macromolecules
  • Characterization of interactions of macromolecules (self- and hetero association) and small ligands

 

microfabrication lab image
microfabrication lab image

The Microfabrication and Microfluidics Unit of the BEPS Shared Resource specializes in the following:

  • Design, fabrication and implementation of microfluidic devices
  • Rapid turnaround of single or multi-layer templates down to ~1.5 µm lateral dimensions
  • Microfabricated devices made from silicon/glass, PDMS, thermoplastics, and agarose.
  • Structured surface modification, including microcontact printing
  • Developing in vitro platforms that model tissue environments for realistic studies of cellular interactions.  Methods include microfabrication, electrospinning, hydrogel fabrication and characterization, and finite element analysis 

Our goal is close collaboration and rapid, iterative design. Although our preferred mode of operation is to disseminate microfabrication technology by having researchers from other laboratories participate actively in device fabrication, we can make templates and devices if desired. 

We are located in Building 13 on the NIH campus.

Infrared lab image
Infrared lab image

The mission of the Infrared Imaging and Thermometry Unit is to provide state-of–the-art expertise, instrumentation, training and services for clinical research in the areas of:

  • Intraoperative and bedside optical imaging of tissue perfusion and temperature
  • Monitoring of tissue perfusion, oxygen content and temperature
  • Passive microwave thermometry
  • Multi-spectral molecular imaging without use of contrast agents
  • In vivo optical imaging to guide functional tests, targeted drug delivery, and ex vivo organ resuscitation
  • Design and validation of wireless electronic patches and cellular phone technology for longitudinal monitoring in clinical research
  • Image processing and data mining
  • Clinical capillaroscopy

 

Image taken by a scanning electron microscope

The Electron Microscopy Unit of the BEPS provides state-of-the-art instrumentation, training, and services.

 

This is an image of a protein absorbed onto a multicomponent supported lipid bilayer. The protein forms patches of partially embedded proteins and is localized by antibodies targeting the protein
RS1 protein adsorbed onto a multicomponent supported lipid bilayer. RS1 forms patches of partially embedded proteins and is localized by antibodies targeting the protein

The Scanning Probe Microscopy Unit of the BEPS Shared Resource specializes in the following:

  • Sub-nm resolution imaging of molecular complexes, supported lipid bilayers, cells, and tissues
  • Molecular recognition, protein unfolding
  • Force spectroscopy, visco-elastic properties
  • Simultaneous, co-localized AFM and fluorescence (including TIRF and confocal) microscopy
  • Mathematical modeling, finite element analysis

We are located in Building 13 on the NIH campus.

This is an image of a histogram that describes the unraveling of clathrin
Histogram distribution of unfolding/unraveling events in clathrin-AP180 coats from single molecular force spectroscopy (SMFS) with a 3D AFM image insert showing dynamic conformations of three triskelia on a 130 nm grid under fluid .

The LCIMB’s Nanoinstrumentation and Force Spectroscopy (NFS) Section develops specialized instrumentations and their applications at macromolecular, cellular and tissue level in areas of biomedical research and medicine. NFS scientists collaborate closely with other intramural and extramural investigators to provide innovative approaches through biophysical modeling, mathematical analysis, and custom instrumentation primarily for nanoscale characterizations. Our current focus includes the development and applications of high-resolution and high-speed atomic force microscopy (AFM) for force spectroscopy and nanometric bioimaging of biological and soft materials. We also develop related technologies such as laser and optical technologies for spectroscopic analysis of biochemical reaction kinetics, multimodal instrumentations, and broader biomedical characterizations.

thumbnail showing two bright blobs that represent radioactive tracers on a PET scan

The PET Radiochemistry and Imaging Core Facility develops novel methods for incorporating radionuclides and fluorophores into molecules for the study of biologically important processes. All of our projects are in support of principal investigator-initiated research. We seek to collaborate with clinical and biological investigators who share our goal of providing new imaging tools for clinical studies and the study of biological processes. Our research efforts are driven by a desire to improve understanding of human biology and disease and to generate tools that have clinical application. We have produced probes with applications to many important biological processes, including inflammation, metabolism, proliferation, angiogenesis, metastasis, lymphogenesis, and apoptosis.

 

drawing of a chemistry apparatus

The Chemistry and Radiochemistry Section (CRS) is part of the Laboratory of Molecular Imaging and Nanomedicine (LOMIN), NIBIB. The CRS furthers LOMIN’s multidisciplinary efforts to develop chemical entities and biological procedures to diagnose and treat human diseases. The CRS does this by development of: 1) chemical syntheses that create robust, selective entities to carry radionuclides and fluorophores for diagnostic imaging, 2) conjugation procedures that allow targeted delivery and specific release of therapeutic drugs, and 3) activatable probes with sensitivity to an in vivo parameter, such as pH, temperature, NO concentration, etc.