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Engineering in Medicine: BBCEE

Active projects in Biomedical, Biochemical, Chemical & Environmental Engineering (BBCEE) with applications for engineering in medicine:

See also Decision analytic evaluation of emerging technologies

Cell-based protein purification systems offer advantages over conventional protein purification approaches which rely mostly on chromatographic methods to stepwise enrich for a desired protein of interest. We are developing approaches by which cells are engineered to produce their own affinity matrix to selectively sequester a desired recombinant protein. This allows for the expression and affinity purification of desired proteins in a single host, thereby obviating the need for external chromatographic purification.
(Faculty contact: Gerngross)

Cellular engineering of protein expression hosts provides the ability to modify proteins in a site specific and controlled fashion—something increasingly important for the development of therapeutic proteins. We are developing methods by which cells are genetically engineered to incorporate sugars on a recombinant protein in a site-specific sequence dependent manner. Once a sugar is positioned on a given protein, conventional chemical modification such as PEGlylation can be used to further modify the protein and improve its therapeutic properties.
(Faculty contact: Gerngross)

Dynamic multimodal imaging (DMI) is a framework of physiological models and solvers for reconstructing images of neural and vascular dynamics in the human brain. DMI combines concurrently recorded data from multiple imaging modalities such as electroencephalography, near-infrared spectroscopy, and functional magnetic resonance imaging.
(Faculty contact: Diamond)

Enzyme therapeutics are a potential means of addressing the emerging health care crisis resulting from drug resistant microbial pathogens. Efforts are focused on the redesign of antimicrobial proteins for enhanced bactericidal activity towards various clinically relevant targets. One facet of this work relates to complications associated with the genetic disease cystic fibrosis, and is being investigated in conjunction with the Cystic Fibrosis Foundation Research Development Program at Dartmouth Medical School.
(Faculty contact: Griswold)

Fermentation processes with high cell densities are important for the production of most bio-therapeutics which is conducted in highly controlled fed-batch processes. Commercial yeast- and E.coli-based fermentation processes often reach cell-densities in excess of 50g/l in fed-batch culture. Our laboratory has developed processes for the high cell density cultivation of Ralstonia eutropha allowing us to reach cell densities of over 150g/l and the expression of recombinant proteins at titers exceeding 10g/l. Much of this is achieved by implementing computer controlled feeding algorithms.
(Faculty contact: Gerngross)

Fluorescence-guided neurosurgery is important for the resection of some types of cancerous tumors where the tumor and normal tissue are similar in appearance and texture, and patient prognosis depends heavily on the completeness of resection. By selectively tagging tumor tissue with fluorescent dies, it becomes possible to visually discriminate between normal and tumor tissues and improve significantly the completeness of tumor resection.
(Faculty contacts: Paulsen, Pogue, Hartov)

Fluorescence imaging is being used to track molecular signals and tags in tissue. Several fluorescent contrast agents are in pre-clinical and clinical studies to image cancer tumors in vivo, or vascular diseases. Systems and algorithms for diffuse fluorescence imaging of tissue are studied, both as a stand-alone system, and as coupled to magnetic resonance imaging and computed tomography imaging. Work in this area is focused on cancer tumor imaging, and characterizing systems that can make optimally useful measurements of the tumors, and their response to therapy.
(Faculty contact: Pogue)

Functional biomarkers for Alzheimer's Disease (AD) are needed for diagnostic purposes and as measures of efficacy as new drugs enter clinical trials. Concurrent measurements with electroencephalography and near-infrared spectroscopy in humans enable time-series analysis neurovascular coupling to reveal physiologic abnormalities that can serve as functional biomarkers of early AD.
(Faculty contact: Diamond)

Glyco-engineering of proteins is being developed as a method to control the composition of glycans on glycoproteins. Such methods are of great importance in the biopharmaceutical industry because glyocoproteins constitute over 60% of all approved therapeutic proteins; and the therapeutic properties of many glycoproteins strongly depend on the composition of their glycans.
(Faculty contact: Gerngross)

Humanization of glycosylation in yeast enables the use of yeast-based protein expression systems which offer inherent advantages over conventional mammalian cell culture. By engineering yeast-based systems to perform human-like glycosylation fully-humanized therapeutic proteins can be produced in these glyco-engineered hosts. (See also: www.glycofi.com)
(Faculty contact: Gerngross)

Hydrolytic enzymes are of industrial interest, specifically as catalysts in the synthesis of enantiomerically pure pharmaceutical intermediates. We are exploring novel strategies for high throughput screening of esterases, lipases, and alkyl sulfatases.
(Faculty contact: Griswold)

Image-guided neurosurgery gives the surgeon the ability to track instruments in reference to subsurface anatomical structures. Using clinical brain displacement data, a computational technique is being developed to model the brain deformation that typically occurs during neurosurgery. The resulting deformation predictions are then used to update the patient's preoperative magnetic resonance images seen by the surgeon during the procedure.
(Faculty contact: Paulsen, Hartov, Ji)

Models of cerebral circulation, gas exchange and regulatory physiology are increasingly important tools for the interpretation of neuroimaging data. For instance, biophysical models can describe dynamic cerebral autoregulation (CA), which maintains relatively constant cerebral blood flow despite changes in arterial blood pressure. Medical images that spatially map CA function could provide important new information to improve treatment decisions for patients with traumatic brain injury (TBI). Better models of the background physiological fluctuations in neuroimaging data can also help to isolate the functional hemodynamic response to brain activity.
(Faculty contact: Diamond)

Near-infrared imaging (NIR) provides a way to quantify blood and water concentrations in tissue, as well as structural and functional parameters. Since normal tissue, benign tumors, and malignant tumors each carry different concentrations of both hemoglobin and water, and have different levels of oxygen demand and ultrastructural scattering, NIR spectroscopy can be combined into standard imaging systems as an effective method of to provide additional information for breast cancer detection and diagnosis. Work is ongoing to improve techniques for better image reconstruction, display and integration with magnetic resonance imaging (MRI) and computed tomography (CT) imaging.
See also Near Infrared Imaging Group
(Faculty contacts: Pogue, Paulsen, Jiang)

Non-linear image reconstruction techniques are at the core of the medical imaging projects. Excitation-induced measurements from each instrument are compared with calculations from corresponding numerical models to compute updated property images of the biological target. As the images are progressively updated (or refined) in a non-linear iterative process, important features and functional information related to the objects physiological status – tumor, benign tissue, etc. – become more apparent. The computational core of the breast imaging project works synergistically with all four groups to improve our fundamental understanding of these mathematical systems to improve overall image quality and resolution. These processes have been developed for both 2D and 3D geometries in each modality and are being expanded to exploit emerging parallel computing capabilities.
(Faculty contacts: Paulsen, Meaney)

Novel protein expression systems are being developed based on the soil bacterium Ralstonia eutropha as an alternative to E.coli-based protein expression. This bacterial host can be grown to cell densities in excess of 150g/l in ultra high cell density culture and allow for the recovery of proteins that are prone to inclusion body formation in E.coli. Specific model proteins have been expressed at levels 100 fold higher than in E.coli thereby providing the impetus for further developing Ralstonia eutropha for the production of therapeutic proteins including monoclonal antibodies and peptides.
(Faculty contact: Gerngross)

Photodynamic therapy (PDT) is a newly emerging therapy for displastic tissues, such as cancer, age-related blindness, pre-malignant transformation or psoriasis. The therapy involves the administration of a photosensitizing agent, together with the application of moderate intensity light to active the molecules to produce local doses of singlet oxygen. Ongoing research topics include, developing improved dosimetry instrumentation and software, fluorescence tomography imaging to sense drug localization, and assaying unique tumor biology and treatment effects in experimental cancers.
(Faculty contacts: Pogue, Hoopes)

Therapy monitoring is an important emerging application of imaging modalities. These and other current research topics include:

  • near-infrared imaging of brain tissue;
  • near-infrared spectroscopy for diagnosing peripheral vascular disease;
  • electrical impedance spectroscopy for radiation therapy monitoring;
  • magnetic resonance elastography for detecting brain or prostate lesions; to follow the progression of diabetic damage in the foot; and to answer basic questions of wave propagation in tissue;
  • microwave imaging spectroscopy for hyperthermia therapy monitoring, brain imaging, and detection of early-stage osteoporosis.

(Faculty contacts: Paulsen, Meaney)

Tumor pathophysiologic analysis and modeling is being carried out to examine and understand the vascular, oxygenation, and growth changes which occur in response to photodynamic therapy and radiation.
(Faculty contact: Pogue)