J. Crayton Pruitt Family Department of BiomeDical engineering

J. Crayton Pruitt Family
Department of Biomedical Engineering
J. Crayton Pruitt Family
Department of Biomedical Engineering
Biomedical Sciences Building | Room JG56 | P.O. Box 116131 | Gainesville, FL 32611-6131
P
352.273.9222
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352.273.9221
www.bme.ufl.edu
Welcome from the Chair
T
BME Undergraduate Program
he J. Crayton Pruitt Family Department of Biomedical Engineering
has come a long way in the ten
years since it was launched in 2002. The
department has grown to 16 faculty, one
instructor, six research faculty, nearly 50 affiliate faculty, six staff members, 20 undergraduate and over 140 graduate students.
We have graduated 171 M.S. and 76 Ph.D.
students, received over $26M in external research funding and
published more than 300 peer reviewed scientific papers. In
2009 the Department moved into the brand new Biomedical
Sciences Building located in the University of Florida Health
Sciences complex and only a very short walk to engineering. In
all we have a great start and are well-poised for another period
of growth and excitement.
The J. Crayton Pruitt Family Department of Biomedical
Engineering is proud to have started its undergraduate BME
degree program this fall, with its first class of 20 exceptional
students. The program is scheduled to grow to 70 students per
year so as to help fulfill the tremendous demand at UF and
to help keep in Florida many students who would otherwise
leave the state for a BME degree program. Demand is growing,
as industry, graduate and professional schools recognize the
value of ambitious students who have come with the intellectual approach of a well-trained engineer yet are well informed
as to basic physiological and biomolecular science.
To accomplish this, Department faculty are collaborating
with other engineering and life science departments for courses, especially in the short run, anticipating further development of much more integrated BME courses.
BRIGHT FUTURES FOR BME
New Building for BME
We are most excited that Dr. Christine
Schmidt will join the BME Faculty in January
2013 as Department Chair. She comes to us
from the University of Texas at Austin, with
an exceptional record in all of teaching, research, and service, having contributed substantially to that department’s rapid growth
to national prominence. Dr. Schmidt has
ambitious plans to increase the faculty size to over 20, grow
research activity substantially, and raise the visibility of the
UF BME Department. She sees the tremendous opportunities
available due to the proximity of the UF Health Sciences and
the entrepreneurial spirit that pervades Gainesville.
PRUITT LEGACY
The Department owes its success to the J. Crayton Pruitt
Family, for their endowment of the department with a $10M
gift which was matched by the State of Florida. The gift has
since been augmented by the Pruitt Family with funds for endowed professorships. We note the passing last year of our
benefactor, Dr. J. Crayton Pruitt, Sr. Among all the other amazing things he accomplished was the invention of a biomedical
engineering device – the very successful Pruitt-Inahara Shunt
for cardiovascular surgery. Dr. Pruitt showed great interest in
all aspects of the department, including very obvious excitement for novel research performed by individual faculty. The
Pruitt Family legacy has enabled all of us – new faculty and
students especially – to prosper in this great field.
The Department occupies 18,000 square feet of excellent
research space, and 27,000 square feet overall, in the new Biomedical Sciences Building, which is located on medical campus
and is shared with the College of Medicine. This will suffice for
a portion of our planned expansion. The department’s medical physics faculty have separate offices and facilities in the
Nuclear Sciences Building, which is also home to our undergraduate laboratories.
understanding the interplay of materials with the immune response, magnetic biomaterials, novel materials for cardiovascular and neural system applications, and to study degenerative joint diseases.
Faculty affiliates are involved in a much broader array of
interests, including biomaterials, drug development, biomechanics, orthopedics, rehabilitation engineering, MR imaging,
and computational bioengineering. Overall we are developing
strong collaborations with our sister engineering departments
and multiple departments in the Health Sciences.
Faculty affiliates are involved in a much broader array of
interests, including biomaterials, drug development, orthopedics, rehabilitation engineering, MR imaging, and computational bioengineering.
LOOKING FORWARD
It has been an honor to have served as Acting Chair for nearly four years and especially to have seen tremendous growth
in the department. I look forward to the even greater excitement and progress that is to come. We truly are carrying out
Dr. Pruitt’s vision as we pursue Excellence in Biomedical Engineering Education & Research to Improve Human Health
Sincerely,
RESEARCH EXPERTISE
Bruce C. Wheeler, Acting Chair
The Department has several exceptional areas of expertise.
Perhaps the largest area is neural engineering, which engages six of our principal faculty and a number of our affiliates.
The expertise includes computational, recording and imaging
Christine
E.
Schmidt,
Chair
(1/1/2013)
technologies for understanding cognition and pathologies in
humans; microfabrication technology for controlling cultured neural networks; neural stem
cell engineering and innovative biomaterials for
BME FACTS
neural growth.
Optical imaging is a real strength, with em1. Largest and most comprehensive BME department in Florida
phases on photoacoustic tomography for several medical applications including breast cancer.
2. One of a very few BME departments in the nation to be co-located
Medical physics faculty are active in the areas
with a medical college.
of dosimetry and PET imaging, including computational approaches.
3. Basic and applied research tackles medical problems; spinoffs
provide cost-effective health care delivery.
Overlapping faculty interests in biomaterials , tissue engineering, and biomechanics
4. Rapid increase in research funding makes UF BME competitive
provides a growing substrate for research into
3
KYLE ALLEN
Assistant Professor
Ph.D. 2006, Rice University
Degenerative Joint Diseases
Osteoarthritis
Biomechanics
Gait and Locomotion
Biomarkers
degenerative joint diseases
D
egenerative joint diseases include osteoarthritis,
degenerative disc disease, and other pathologies
that destroy articulating joints. In degenerative joint
diseases, cartilage is slowly destroyed, leading to joint pain
and disability. These diseases are classically described by the
severity of cartilage loss; however, recent work has evolved to
think of the joint as an organ, examining the interplay between
cartilage, bone, ligament, tendon, and synovial tissues. Our
laboratory embraces the ‘joint as an organ’ approach, aiming
to identify changes in the joint biology and mechanics that
ultimately lead to pain and disability.
LINKING DISEASE MEDIATORS TO PAIN AND
DISABILITY
T­ reatment of osteoarthritis (OA) raised 2007 US healthcare
expenditures by $185.5 billion. In addition, the average annual
out-of-pocket expense for an OA patient is nearly equivalent to
3 weeks pay for an average American. Despite this immense
socioeconomic burden, OA therapies have been difficult to
translate from the lab to the clinic. While the primary reasons OA patients seek treatment are pain and disability, the
symptomatic consequences of OA are not always evaluated in
preclinical OA models. Thus, preclinical studies centered on
structural changes alone may not identify diagnostics with the
potential to predict OA-related pain and disability, nor identify therapeutics and interventions with the potential to reduce disease symptoms. Our laboratory has developed new
methods to measure OA related pain and disability in rodent
OA models. Our gait analysis methods (Figure 1) are capable
of detecting compensations that are not visible to the human
4
eye. We are currently developing new behavioral methods
to assess TMJ pain and dysfunction in rodent models of TMJ
disorders. Using these new behavioral analyses, we hope to
develop a new understanding of the relationship between disease mediators and the development of pain and disability, as
well as new OA diagnostics and therapeutics.
Figure 1: Image of our dynamic
gait arena. Force plates are
embedded in the floor of the
arena that record ground reaction forces as a rodent walks
across the arena
MAGNETIC COLLECTION OF OA BIOMARKERS
­ Clinically, degenerative joint diseases are diagnosed through
radiographs and physical exams. However, these diagnostics
are relatively poor at detecting early-stage OA, a stage where
interventions are likely to have a higher success rate. A need
exists for technologies that facilitate early OA diagnosis.
The OA research community has recently placed a special
emphasis on the development of OA biomarkers, diagnostics
that can identify OA disease processes before traditional
radiographs. Promising OA biomarkers have been identified in
urine and serum. However, serum- and urine-level biomarkers
are not specific to an affected joint, are likely dilute relative
to levels in the affected joint, and may not be detectable at
the earliest stages of OA. In collaboration with Dr. Jon Dobson
and Dr. David Arnold, our laboratory recently developed new
techniques to remove OA biomarkers and disease mediators
from the joint space without the need to remove the synovial
fluid that lubricates and supports joint function (Figure 2). We
are also investigating new techniques to evaluate synovial fluid
mechanics with Dr. Carlos Rinaldi.
Figure 2: Fluorescent, magnetic particles collecting on the tip of a magnetic probe
CELLULAR THERAPIES FOR DEGENERATIVE DISC
DISEASE
­ In the US, low back pain is 2nd only to flu and cold symp-
toms on the list of reasons why patients schedule doctor
visits. While back pain is often characterized by acute episodes, approximately 14% of the population will experience
back pain lasting more than 2 weeks. Lumbar disc degeneration, or degenerative disc disease, is strongly implicated as
a source of chronic low back pain. In addition to our work
linking disease biology to pain and disability, our laboratory
is developing new cellular therapy methods to treat degenerative disc disease. During intervertebral disc degeneration, the number of notochordal cells in the intervertebral
disc decreases. Notochordal cells are a population of stem
cells that is believed to help support and protect the cells
of the intervertebral disc. In collaboration with Dr. Brian
Harfe, our laboratory is investigating new techniques to isolate and culture populations of notochordal cells, with the
hopes of developing cellular therapies for disc degeneration in the future.
Figure 3: Clusters of mouse notochordal cells on a decellularized porcine
nucleus pulposus
Wesley BOLCH
Professor
Ph.D. , 1988, University of Florida
Radiation Dosimetry
Computational Phantoms
Dosimetry Models of the Skeleton
Computed Tomography
Interventional Fluoroscopy
Nuclear Medicine
Radiotherapy
Homeland Security
Radiation Dosimetry
R
adiation dosimetry encompasses the calculation and
measurement of energy deposition within the human
body resulting from exposure to radiation sources at
the workplace, in the environment, or from medical applications
to imaging or cancer therapy. These exposures may result from
either radiation sources external to the body (e.g., CT imaging)
or internal to the body (e.g., radiopharmaceuticals). In most
instances, radiation doses to the internal organs and tissues is
nearly impossible to directly measure, and thus computational
simulations of radiation transport and energy transfer are
required using either patient or individual specific anatomical
models, or computerize replicas of patient anatomy.
COMPUTATIONAL PHANTOMS
The Advanced Laboratory for Radiation Dosimetry Studies
(ALRADS) at the University of Florida is a world leader in the
development of hybrid computational phantoms of human
anatomy – based upon the application of polygon mesh and
NURBS surface modeling of internal organs and the outer
body contour. A series of reference (50th percentile) models
of the newborn to 15-year adolescent were developed at
UF and recently adopted as international standards by the
International Commission on Radiological Protection (ICRP).
Other work has resulted in a 400+ member phantom library
covering pediatric and adult males and females representing
the current height/weight distribution of the US population.
These phantoms are serving as the basis for pre-computed dose
libraries for a broad range of medical imaging modalities – CT,
fluoroscopy, and nuclear medicine. Other work has resulted
in some of the most detailed anatomic models of developing
embryo, fetus, and pregnant female for applications to both
environmental and medical dose assessment.
DOSIMETRY MODELS OF THE SKELETAL TISSUES
The hematopoietically active tissues of bone marrow are the
most radiosensitive tissues in the human body. At low radiation
doses, exposure can increase the risk of leukemia induction,
while at high doses – such as during radionuclide therapy
– marrow suppression and toxicity may result. Predictive
models of radiation dose to bone marrow are exceedingly
difficult to develop owing to the complex microstructure of
trabecular spongiosa, variations in marrow cellularity, and
variations in bone mineral status of the individual or patient.
UF has pioneered the use of CT and microCT imaging of human
cadaveric bone to the application of radiation transport
simulation and predictive models of marrow dosimetry. MR
techniques for non-invasively assessing marrow cellularity
have been developed and validated in a canine model. Skeletal
models have been developed for both adults and pediatric
phantoms, as well as the developing fetus.
APPLICATIONS
THERAPY
TO
MEDICAL
IMAGING
APPLICATIONS TO EPIDEMIOLOGY & HOMELAND
SECURITY
The computational models developed at UF have also
been applied to studies of the Southern Urals populations
exposed to radionuclides released during past USSR
nuclear weapons development in the 1950s. These studies
will significantly enhance our understanding radiation
risks. Work at UF has also resulted in the development of
computer software to assist first-responders in performing
radiological triage of victims following radiological terrorist
events.
Share identical anatomy except gender organs
AND
The ALRADS laboratory is actively engaged in the
development of predictive models of patient radiation dose
for all major forms of diagnostic medical imaging. UF is
working with the National Cancer Institute to develop software
to predict organ doses to patients undergoing computed
tomography imaging, including those scanned under
tube current modulation. UF is also developing real-time
software to predict and map skin dose to patients undergoing
fluoroscopically-guided interventions, and to report organ
doses using cloud-computing radiation transport simulation.
Finally, UF is a key partner in national efforts to optimize the
quantity of radiopharmaceuticals given to pediatric patients
that will maximize image quality while minimizing risk of
second cancers. In radiation therapy, the ALRADS laboratory
has partnered with Oraya Therapeutics, Inc. to develop a noninvasive x-ray treatment for age-related macular degeneration.
Newborn
1-year
5-year
10-year
15-year male 15-year female
5
Mingzhou Ding
J. Crayton Pruitt Family Professor
PhD., 1990, University of Maryland
Neural engineering
Cognitive neuroscience
Signal processing
Dynamical systems
and neural modeling
O
ur long-term research objective is to understand the
neural basis of higher brain functions and their impairments by neurological and psychiatric disorders.
In particular, applying quantitative engineering approaches
to multimodal neural data, including single unit spike train,
multiunit activity, local field potential, electroencephalogram,
electrocorticogram, and fMRI data, we address fundamental
questions in the dynamic organization of brain networks and
its disruption in disease. A theoretical framework, which integrates human physiology, monkey physiology, and computational modeling, is formulated to interpret the findings. Some
specific areas of interest are as follows.
Analyzing information flow in neuronal networks: Multielectrode neurophysiological recording and functional brain
imaging produce massive quantities of data. Multivariate time
series analysis provides the foundation for analyzing the patterns of neural interactions in the data. Neural interactions,
being mediated by the synaptic transmission of action potentials, are directional. Our ability to assess the directionality of
neural interactions and information flow in brain networks
holds the key to understanding the cooperative nature of neural computation. Research over the last few years has proven
that Granger causality is a statistical technique furnishing this
capability. Our lab has pioneered the application of Granger
causality to neuroscience. Recently completed projects using
the technique include: (1) laminar organization of alpha oscillations in primate visual cortex, (2) functional characterization
of beta oscillations in a large-scale network in sensorimotor
cortex, (3) top-down control of visual and somatosensory
processing by the frontal-parietal attention network, and (4)
memory-modulated directional interaction between frontal
and medial-temporal lobes.
Single trial analysis of event-related signals: Neural data following the onset of a stimulus is comprised of an event-related
6
Network organizations of alpha oscillations in visual cortex revealed by current source density analysis (left) and Granger causality (right).
Arrows represent directions of information flow.
Cognitive brain machine interface: Brain machine interface (BMI) enables direct communication between
the brain and an external device. While BMI research has
been mainly focused on improving sensory-motor functions
of paralyzed individuals, the same concept can be exploited to
augment human cognition. Based on our recent physiological
and methodological advances, a closed-loop cognitive brain
machine interface (cBMI) is being designed and implemented,
in which the stimulus presentation is conditioned on the occurrence of optimal brain states and the stimulus evoked response, separated from ongoing neural activity, is classified by
machine learning methods.
Electrode arrays implanted over the cortex of three epilepsy patients undergoing evaluation for surgical therapy (left). Information flow patterns between
prefrontal cortex (PFC) and medial temporal lobe (MTL) during recall of
memory and during baseline .
component that is relatively time-locked to stimulus onset and
ongoing brain activity. These two types of signals, generated
by possibly different neural mechanisms, may reflect different
aspects of cognitive information processing. In collaboration
with colleagues in the College of Engineering and from other
institutions, we have developed methods capable of separating the two signals on a trial-by-trial basis. These methods are
being used to answer questions in areas ranging from network
basis of decision-making to improved target detection in cognitive brain machine interface to determination of the time
course of emotional conditioning.
Studies of translational relevance: New discoveries are being
made constantly in basic science labs around the world. How
to translate our growing knowledge into improved healthcare
is a critical issue facing today’s biomedical researchers. We are
working with physicians and clinical scientists to address problems in the following areas: (1) effect of anticonvulsant drugs on
language production and executive control of brain function, (2)
disruption of cortical and subcortical network dynamics in depression and obsessive compulsive disorder, and (3) cognitive
fatigue in Parkinson’s disease.
JON DOBSON
Professor & Director, Institute for Cell Engineering and
Regenerative Medicine, ICERM
Ph.D. 1991, Swiss Federal Inst. of Technology, ETH-Zurich
A
B
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Magnetic Biomaterials
Nanomagnetic Gene Transfection
Nanomagnetic Cell Actuation
Brain Iron and Nerodegeneration
E
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I
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K
L
T
he main focus of our group falls into several interrelated categories as outlined below. The underlying
theme of all this work is the novel use of magnetic
nanoparticles to develop technologies for bionanotechnology/
nanomedicine applications in fields as diverse as gene therapy,
stem cell therapy, tumour targeting and tissue engineering/
regenerative medicine. In addition, we have been developing
synchrotron x-ray and MRI-based techniques to exploit naturally occurring magnetic iron oxides in the brain for diagnostic
and mechanistic studies of neurodegenerative diseases, such
as Alzheimer’s and Parkinson’s.
Nanomagnetic Actuation: tissue engineering and stem cell therapy
Magnetic nanoparticles are being used to target and
manipulate cellular processes and functions and to control
stem cell differentiation, primarily through the activation
of ion channels. These nanoparticles are coated with a
functionalizable polymer to which surface antigens/targeting
molecules may be bound. These antigens may target either
specific ion channels, such as the mechanosensitive TREK-1
potassium channel, or non-specific cell surface receptors such
as integrins. By applying a static or time-varying magnetic
field, forces exerted on the particles activate either specific ion
channels or general membrane and cytoskeletal deformation
activates adjacent mechanosensitive ion channels, initiating
biochemical processes within the cell. We have used this
technology to speed up bone matrix production, to control the
differentiation of stem cells without chemicals, and to enhance
production of cartilage and upregulate cartilage-related genes
both in vitro and in vivo. These devices, Magnetic Ion Channel
Activation (MICA) systems are being commercialized by a spinoff company.
HBMSC
HBMSC + TGFβ3
HBMSC + TREK-K+
HBMSC + RGD
Histology and immunohisto-chemistry of HBMSCs only; HBMSCs and transforming growth factor b3; and HBMSCs labeled with TREK-1 or HBMSCs labeled
with RGD particles encapsulated into alginate/chitosan capsules, implanted
subcutaneously in MF-1 nu/nu mice, and exposed to a magnetic field for 21
days, 1 h/day (Mon., Wed. & Fri.). Representative 6 mm tissue sections stained
for Alcian blue/Sirius red (A–D), type-1 collagen (E–H), and type-2 collagen
(I–L). Arrows indicate positively stained HBMSCs for type-1 collagen. Scale
bars1/4100 mm.
Nanomagnetic
dElivery
Gene
transfection
and
With the sequencing of the human genome and the advent
of gene therapy has come the need to develop effective delivery and transfection agents. These agents must be able to
target therapeutic and reporter genes to the relevant cells and
organs both in vitro for basic investigations as well as in vivo
for therapeutic applications. Recent safety concerns over the
use of viral vectors has begun to shift the emphasis toward the
development of non-viral delivery agents, primarily cationic
lipids. Our group has been working on the development of a
novel magnetic nanoparticle-based gene transfection systems
based on oscillating arrays of magnets. In these “magnefect”
systems, DNA or siRNA is attached to magnetic nanoparticles
and oscillating arrays of magnets placed underneath a cell cul-
Nanomagnetic transfection of green fluorescent
protein (GFP) into PC12 neuronal cells.
magnefect-LT
ture plate are used to stimulate particle uptake and improve
gene expression. In addition, we are developing novel, highgradient magnet arrays and new motion control systems to
improve efficiency. These systems also have been commercialized. Our in vivo work in this area has focused not only
on the delivery of nanoparticle/drug/gene complexes but
also cells. The aim of this work is to load cells with biocompatible magnetic nanoparticles and re-introduce them into
the body, using magnets to target them to repair sites or tumours. We have successfully enhanced the natural tumour
homing ability of human macrophages by loading them
with magnetic nanoparticle/reporter gene complexes. The
uptake of these “therapeutically armed” cells into the nonvascularized, hypoxic cores of solid tumours was enhanced
by more than three-fold over non-magnetized cells. Once
inside the tumour, the cells can deliver a payload of “suicide” genes or cytotoxic compounds, after which AC electromagnetic fields are used to heat the particles, destroying
the macrophages before they build a new blood supply to
the tumour core. We have also used the technology to target human mesenchymal stem cells to tissue repair sites in
small animal models.
magnetic nanoparticle synthesis and
characterization
Our group is also active in the development of techniques
for the synthesis of novel magnetic nanoparticles for biomedical applications. This work focuses on producing particles with enhanced magnetic properties or surface chemistry, as well as investigating new methods for enhanced DNA
loading. Techniques such as High- Resolution Transmission
Electron Microscopy and Superconducting Quantum Interference Device (SQUID) magnetometry are used for characterization of the particles.
Nanoscale iron compounds in neurodeGenerative Disease
Over the past 15 years we have pioneered SQUID and
synchrotron-based detection techniques in order to quantify, characterize and map specific iron compounds in neurodegenerative tissue. This work aims to provide a better
understanding of the role of disrupted iron homeostasis in
neuro-degenerative diseases and to guide the development
of chelation therapies. More recently, data from these studies has been used by us and other groups in the continuing
development of MRI-based diagnostic techniques, which
aim to use iron compounds formed due to neurodegenera-
7
David R. Gilland
Associate Professor
Ph.D., 1989, University of North Carolina, Chapel Hill
Medical Imaging
Positron Emission Tomography (PET)
Single Photon Emission Computed
Tomography (SPECT)
O
ur lab focuses on advancements in medical imaging
with emphasis on emission tomography. We have
developed a new mobile PET/SPECT system for bedside imaging. The system is capable of being moved within a
hospital to image patients who cannot be easily transported to
a conventional imaging facility, for example, patients in an intensive care unit. This unique device, which is currently under
clinical evaluation, promises to deliver PET and SPECT imaging
technology to a critically-ill patient population. We are also
currently developing advanced motion compensation/image
reconstruction algorithms for cardiac imaging in PET, SPECT,
and CT Angiography. These algorithms have the potential to
improve image quality by reducing motion blur due to cardiac
contraction. The algorithms also provide a means of spatially
registering images across imaging modalities.
We have initiated a project with the focus of developing
an improved method for imaging prostate cancer (PCa). The
project includes collaborators from Johns Hopkins University, who are involved in the design of radiotracers that target prostate-specfic membrane antigens (PSMA), and from
Gamma Medica-Ideas, Inc., an industry partner who are world
leaders in advanced SPECT imaging detector devices. We are
investigating a unique detector design that can potentially deliver improved spatial resolution and detection sensitivity for a
dedicated SPECT prostate cancer imager. The potential impact
of this study is to improve the staging of PCa through effective imaging methods as well as to improve the detection of
recurrent cancer following treatment. The higher spatial resolution and detection sensitivity of the proposed imaging device, combined with more effective imaging agents that target
PSMA, have the potential to localize small lesions in the area
of the prostate gland and pelvic lymph nodes and determine
the extent of intra- and extra-glandular disease.
8
A
B
C
(A) SPECT imaging of anthropomorphic phantoms, (B,C) Mobile PET/SPECT imaging system.
Rigid motion estimation for cardiac CT and SPECT
Schematic of a dedicated SPECT prostate imager.
Aysegul GUNDUZ
Assistant Professor
Ph.D. , 2008, University of Florida
Neural Engineering
Cognitive Neuroscience
Neurorehabilitation
Brain-Computer Interfaces
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ATTENTION AND MEMORY
Button Press
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Our research program studies the neural bases and interaction of attention and memory in humans. These mechanisms
have evolved in tandem because the human brain is limited
in its resources to process and store information. Attention
and memory are thought to be interdependent as attention
promotes improved storage of information, and retrieved
information from past experiences can guide what should
be attended in the current scenario. The contribution of this
work would be significant as attention- and memory-deficit
disorders are highly associated with learning disabilities in
children and aging adults.
Rehabilitation of chronically lost motor functions is currently a challenge in the treatment of stroke survivors.
Our goal is to determine whether surface-acquired brain
signals (EEG) can feasibly be trained for recovery of volitional motor control after stroke in humans. A potential
novel approach for the restoration of function and improving the quality of life of these patients could be the
use of brain–computer interface (BCI) systems. So far,
there is no information on whether training a patient to
produce more normal brain signal features will improve
motor function that involves the same areas that produce
those signals. These unknown factors include the extent
to which patients have detectable brain signals that can
support training strategies; which brain signal features
are best suited for use in restoring motor functions; and
what the most effective formats are for the BCIs aimed at
improving motor functions (e.g., what guidance should be
provided to the user to maximize training that produces
beneficial changes in brain signals). The eventual value of
BCI technologies for improving motor function in individuals who have strokes or other neurological disorders depends on adequate answers to these questions.
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BRAIN-COMPUTER INTERFACES & NEUROREHABILITATION
200 Hz 100 Hz
he human brain consists of numerous networks distributed over space and connected over time to orchestrate meaningful interaction with the external
world. Studying precursors to behavior and aftereffects of
sensory stimulation in these recruited networks enables direct
interpretation and control of this interaction. Our research
aims to identify neural correlates of behavior and information
processing in electrocorticographic signals (ECoG) in humans,
which are collected via subdural electrodes placed on the surface of the cortex. ECoG research has strong clinical ties, as
the signals are recorded from patients awaiting surgery for the
treatment of intractable epilepsy. This setting facilitates rare
access to the human cortex and opens unparalleled avenues
for human brain research. ECoG enables the investigation of
cortical networks with high spatial and temporal precision.
LANGUAGE AND MEMORY
Language is a distinctly human trait. No other non-human
communication system compares to human language in its
complexity and expressive power, and no animal aptitude approaches the universal human capacity for vocabulary. Our
research is aimed at identifying the functional neocortical organization of semantic processing in humans, and to localize
cortical areas of semantic memory that are distinctive from
articulatory and comprehensive processing. Alterations in
the cortical mechanisms supporting semantic processing lie
at the heart of many language-based learning disabilities. It is
estimated that developmental disorders of language (which
include deficits in both oral and written language) occur in up
to 20% of preschool and school-age children. Thus, revealing mechanisms by which the brain encodes comprehension
and semantic memory bears important implications for our
understanding of these disorders, and more importantly, will
guide strategies for their amelioration.
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david hintenlang
Associate Professor
Ph.D. , 1985, Brown University
Diplomate, American Board of Radiology
Medical Physics
Imaging and Dosimetry
Computed Tomography
Mammography
Image Guidance
PATIENT RISK/BENEFIT
PROCEDURES
T
FROM
RADIOLOGIC
he benefits of ionizing radiation procedures for clinical
applications have been long established but continue
to find new applications through faster and new
imaging technologies. Many procedures are incorporated
into medical specialties that have not traditionally utilized
radiological techniques making it of paramount importance to
accurately characterize and balance patient risks and benefits
and subsequently optimize new procedures. Our laboratory
focuses on the development of tools and techniques that
facilitate the quantitative evaluations of dose assessment and
image quality.
ANTHROPOMORPHIC PHANTOMS
Our laboratory has a long history of designing and fabricating anthropomorphic phantoms that accurately mimic
human anatomy. It is important that the materials used in
these phantoms represent the radiological properties of living human tissues, and we have developed a variety of tissue
simulant materials that meet this goal. These “tissue-equivalent” materials provide the basis for fabricating whole body
phantoms with accurate anatomical detail. The phantoms’
anatomy are based on high resolution CT data sets and are
fabricated with state-of-the-art computer controlled machining and molding processes. Based on this methodology we
have developed a family of phantoms representing newborns, pediatrics at several ages, adult females, adult males,
and obese adult males. Combined with our specialized
plastic scintillation detector based array dosimetry system,
we have developed unique abilities to quantify organ doses
10
Figure 1: Anatomical detail represented in the cross section of an
anthropomorphic phantom of a newborn.
and image quality for a wide variety of patients and clinical
procedures.
PSD DOSIMETRY SYSTEM
In order to measure radiation doses in organs distributed
throughout the anthropomorphic phantoms we have developed a dosimetry system to meet the specific requirements
of clinical based dosimetry. We have integrated small (a few
mm) plastic scintillation detectors with a coupled fiber optic
array, reader and laptop PC to provide a portable dosimetry
system capable of accurately and rapidly measuring organ
doses. The small physical size and near tissue-equivalence of
the dosimeters and fibers are incorporated into the phantoms
without perturbing the radiological integrity of the phantom
tissues. The system permits sampling from an array of organ
locations with instantaneous and real-time monitoring capabilities. This high resolution data provides insight into the
spatial and temporal dose delivery patterns associated with
modern imaging and radiation therapy systems. Current research is advancing the dosimetry system development to
larger arrays and application specific detectors.
Figure 2: An adult male phantom torso integrated with the PSD dosimetry
system undergoing a CT procedure
phantom/dosimetry system, along with image quality
evaluations, allows us to better characterize, understand
and develop techniques that maximize patient benefits
and minimize the risks from radiological procedures.
Some of the specific procedures that have been, or are
under investigation include, pediatric radiography and
CT, mammography, multi-detector CT, and cone-beam CT
image guidance in radiation therapy. We are also actively
extending phantom and tissue simulants to develop useful
products for a variety of other clinical training simulators
and tools.
CLINICAL APPLICATIONS
Our laboratory leads the development of accurate organ
dose assessment from clinical procedures. The integrated
Figure 3: Image quality comparison from two cone beam CT image guidance
systems used in radiation therapy.
Huabei Jiang
J. Crayton Pruitt Family Professor
Ph.D., 1988, University of Electronic Science
and Technology of China
Ph.D., 1995, Dartmouth College
Diffuse Optical Tomography
Photoacoustic Imaging
Fluorescence Molecular Tomography
Multi-modal Imaging
Diffuse Optical Tomography
of Breast Cancer
B
reast cancer has been one of the leading causes of
death for women in the United States. Yet, the best
way of combating the increased incidence of breast
cancer is early detection. Therefore, there is a critical need to
investigate breast cancer detection methods that could serve
either a complementary or competitive role with respect to
conventional x-ray mammography, which has unacceptable
false negative rate for patients with radiodense breast tissues.
The fundamental hypothesis of our research is that spatially
and spectrally resolved NIR diffuse optical tomography (DOT)
approaches offer unparallel opportunity to access the molecular and cellular signatures in breast tissue through endogenous
contrast mechanisms. To clinically evaluate optical tomography based on absorption chromophores and scattering parameters, three clinical prototype imagers have been constructed.
We have also developed a new contrast mechanism for NIR
tomography based on refractive index/phase contrast: the initial clinical results show that the addition of refractive index
can significantly improve our ability for distinguishing between
malignant and benign breast lesions. Further, the opportunity
exists to explore the possibility of obtaining cellular density
and size from scattering spectra which together with functional parameters and refractive index should form the foundation
of next generation NIR tomography for more complete characterization of breast abnormalities.
Photoacoustic Imaging of Epilepsy
Approximately 2.5 million Americans live with epilepsy and
epilepsy-related deficits today. However, 80 percent of individuals
with medication resistant epilepsy might be cured through surgery if one were able to precisely localize the seizure focus. Our
research aims to significantly advance the ability to localize the focus, and thereby offer curative epilepsy surgery for this devastating disease. Photoacoustic tomography (PAT) uniquely combines
the high contrast advantage of optical imaging and the high resolution advantage of ultrasound imaging in a single modality. In addition to high resolution structural information, PAT is also able
to provide functional information that are strongly correlated
with regional or focal seizure activity, including blood volume and
blood oxygenation because of the high sensitivity of optical contrast to oxyhemoglobin and deoxyhemoglobin concentrations,
and thus offers the possibility to non-invasively track dynamical
changes during seizure occurrence.
Multi-modal Imaging of
Osteoarthritis
Osteoarthritis (OA) is the most common arthritic condition worldwide
and is estimated to affect nearly 60 million Americans. Besides the knees
and hips, there is a subset of individuals with a predilection for developing
OA of the hands and a more generalized form of OA. Due to the fact that
DOT can provide high-contrast joint tissue imaging with low resolution,
while x-ray can offer high-resolution joint structure with low contrast in
soft tissues, we present an optimized approach that combines x-ray and
optical imaging for early diagnosis of osteoarthritis in the finger joints.
Fluorescence Molecular Tomography of
Margin Identification
of Breast Cancer
Breast-conserving surgery or
lumpectomy is the most common
surgical procedure for patients
with early invasive stages of breast
cancer. However, there is no accurate method to identify tumor
margins pre- or intra-operatively.
To develop a sensitive approach for
the detection of residual tumors in
breast tissues, we have developed
the Cy5.5 ATF-IO tumor targeted
nanoparticles, and in combination
with sensitive and high resolution
NIR fluorescence tomography system, should have great potential
for determining tumor margins
during surgery, preventing tumor
reoccurrence and therefore, increasing survival of breast cancer
patients.
PAT is able to image epileptic events as they are happening. The arrow in this image indicates the detected seizure.
11
Benjamin G. Keselowsky
Assistant Professor
Ph.D., 2004, Georgia Institute of Technology
Biomaterials
Cell Adhesion
Vaccines
Type 1 Diabetes
T
he Biomaterial Immuno-Engineering Lab focuses on
the engineering of biomaterial-cell interactions, and
targeted controlled release of immune modulating
factors in order to direct immune cell function. Biomaterials
undergo complex interactions with cells of the immune system upon implantation. These interactions are incompletely
understood and poorly controlled, complicating the ability to
achieve favorable outcomes in clinical applications. Our efforts
focus on both a basic understanding of interactions of immune
cells with biomaterials as well as the engineering of biomaterials capable of directing immunological processes. This
work has wide-ranging implications in diverse fields such as
implanted devices, therapeutic vaccines and tissue engineering. We are particularly interested in the biomaterials-based
modulation of the phagocytic antigen present cell types of
dendritic cells and macrophages.
Microparticle-based vaccines for type 1
(autoimmune) diabetes
We are engineering polymeric biomaterials-based
microparticles as an injectable vaccine system to retrain
the immune system, correcting aberrant activation toward
pancreatic self-antigens. Microparticles with encapsulated
immunomodulatory factors and insulin antigen provide
targeted, controlled delivery to both intracellular and cell
surface receptors of dendritic cells in vivo in order to promote
tolerance in diabetes. While systemic administration of
immune-modulating agents can often result in harmful offtarget effects due to uncontrolled dosing of bystander tissues,
encapsulation into biodegradable microparticles can reduce
the total dose required and limiting off-target effects. (Middle
two panels)
12
High-throughput screening of immune
cell responses to immuno-modulatory
microparticles
We are developing high-throughput methods to screen in
vitro, microparticle-based vaccines targeting dendritic cells.
The goal is to identify microparticle formulations able to shift
dendritic cell phenotype toward the ability to induce regulatory T-cells and tolerance.
Other research topics include:
• Immune cell adhesion (to extracellular matrix
proteins, to nanotopographies, and response to
mechanical strain)
• Receptor-mediated mechanisms of macrophage
phagocytosis of orthopedic implant wear debris
for the mitigation of peri-implant osteolysis in joint
replacement patients
Funding is gratefully acknowledged from the following
sources:
• National Institutes of Health (R01 DK091658, R21
AI094360)
• National Science Foundation (CMMI 0927918)
• Juvenile Diabetes Research Foundation
• Arthritis Foundation
Peter S. McFetridge
Assistant Professor
PhD. 2002, University of Bath, United Kingdom
Research Assistant Professor/Assistant Professor, 20022009, University of Oklahoma
Biomaterials and Tissue Engineering
Cardiovascular Tissue Engineering
Temporomandibular Joint regeneration
Conductive biomaterials
Periodontal Soft tissue repair
Nerve regeneration
Biomaterials and Tissue Engineering
F
rom vision and hearing implants to an artificial heart
and blood vessels, biomedical engineering has become a crucial component of the drive to improve the
quality of life in our ageing society. Our laboratories research
aims to develop medical devices that improve the life style
and reduce suffering of those afflicted with organ loss or failure. Our focus is on the use of a unique biomaterial that is
used as a 3D template or bioscaffold to promote tissue/organ
regeneration. This approach, called ‘Tissue Engineering’, has
shown significant promise as a medical therapy, but translation from the research lab to clinic has proven difficult due
to extended in vitro culture times. In light of these issues our
investigations aim to understand key conditions that enhance
the regenerative capacity of tissue constructs.
Research objectives
Our main research objective is to develop viable alternatives
to autologous and synthetic transplant materials that behave
more appropriately when implanted resulting in improved repair or regeneration of diseased tissues.
for the repair of damaged peripheral nerves and temporomandibular joint regeneration. More specific investigations
include furthering our understanding of scaffold design and
function, cell adhesion, conductivity modulation and effects
on cell function, and the influence of gas concentrations on
organ development.
Research strategy
Using a patented process, vascular tissues can be rapidly, and
uniformly, dissected from surrounding connective tissues,
which are then processed to remove immunogenic components. This process is called decellularization and aim to minimize any immune rejection once implanted. Using the autodissection process a biomaterial with uniform mechanics and
a significant potential to regenerate into neo-tissue is generated. The unique structure of these materials allows a number
of vascular and non-vascular projects to be investigated, the
material can be used as a direct implant (acellular), or as a
re-seeded ‘living’ construct. Constructs are grown under controlled chemical and mechanical conditions within specifically
designed bioreactors to circulate in vivo environment to improve tissue regeneration..
Figure 2: Biomechanics. Investigations include the analysis of material biomechanical properties during remodeling processes. Shown in Figure 2, the Young’s
Modulus of cell seeded vascular scaffolds after 7 and 21 days in culture. These
vascular scaffolds are cultured with human smooth muscle cells and show an
increase in vessel elasticity when stimulated under perfusion flow conditions.
specific research
Projects are under investigation include; developing coronary
and peripheral bypass grafts, tissue engineered soft-tissue
implants for periodontal wound repair, conductive materials
Our research encompasses the three main
phases of the tissue engineering approach:
1) Biomaterial/scaffold development and characterization
2) Bioreactor design (to grow the living tissue)
3) In vitro culture of the re-seeded scaffolds under replicated
physiological conditions.
Figure 1: Vascular Tissue Engineering. In addition to developing functional vascular implants, our investigations focus on cellular interactions with materials
with the aim to modulate the in vitro cell phenotype typically associated with
diseased tissues to produce functional bypass grafts. Above left, engineered
small diameter vascular graft (5mm ID) derived from human umbilical vein implanted in an ovine model to assess patency as a carotid bypass. Above right,
color Doppler ultrasound monitoring graft patency and diameter after implantation.
Figure 3: The interactions between novel biomaterials and cell systems. Investigations include vascular endothelial cells, smooth muscle cells, gingival fibroblasts, TMJ chondrocytes, and as above (left), neuronal cells on engineered
nerves. Development and analysis of typically includes the use of unique bioreactor systems to culture cells under conditions that mimic the in vivo environment (right).
13
Brandi K. Ormerod
Assistant Professor
Ph.D. 2003, University of British Columbia
Neural Engineering
Regenerative Medicine
Stem Cell Engineering
Age-related Cognitive Decline
Neurodegenerative Disease
Biomarkers
STEM CELL ENGINEERING
The hippocampus is an excellent model for discovering the
cues the guide stem cell growth and differentiation because it
permits/promotes neurogenesis and the rate of neurogenesis
can be controlled through systems variables, hormones and
drugs. We are currently exploring such factors. For example,
we are interested in identifying and capitalizing upon unique
neurogenic features of hippocampal vasculature to stimulate
neuron production in other brain regions because neurogenesis occurs in tight association with hippocampal vasculature. .
Stem Cell Strategies for Neurodegenerative
Disease
Figure 3: When plated on mature neural networks, neural progenitor cells generate mature neurons that stimulate re-emergent developmental neuronal plasticity. Stephens et al., 2012.
T
he progressive death of one or more cell types in the
brain is called neurodegenerative disease. Parkinson’s
disease and Alzheimer’s disease are examples of incurable neurodegenerative diseases that leave patients with
progressively debilitating symptoms. The Ormerod Laboratory
focuses its research upon understanding how transplantable
or endogenous stem/progenitor cells ccould be used to repair
the diseased or damaged CNS.
DCX (new neurons)
BrdU (new cells)
DCX/BrdU (new neurons)
BIOMARKERS OF COGNITIVE AGING NEUROINFLAMMATION
Figure 2: Engineering niches receptive to neuron addition may be critical for the
success of neuronal regeneration strategies using stem cells. Hippocampal vasculature may contain unique features that stimulate neurogenesis that could be
employed to engineer niches conducive to neuronal regeneration outside of the
hippocampus. Munikoti et al., 2011
MEA CULTURE PLATFORM FOR TESTING THE VIABILITY AND SAFETY OF STEM CELL STRATEGIES
Figure 1: In the hippocampus of men and mice alike, new neurons are added
each day throughout life to the hippocampus (a learning and memory center)
and the olfactory bulbs (important for smell). Neural progenitor cells, capable
of generating new neurons, reside throughout the adult brain. Discovering factors that control the behavior of these cells is the key to unlocking new brain
repair strategies with endogenous and transplantable stem cells.
14
The incidence of age-related cognitive decline grows exponentially with the advancing age of our baby boomer population. In collaboration with Dr. Tom Foster, we are discovering
prognostic and diagnostic biomarkers of cognitive aging using
a combined proteomic and pathway analysis approach. Because we have discovered evidence that compromised neurogenesis may accompany age-related cognitive decline and that
neuroinflammation ablates neurogenesis, we are interested in
developing novel immunomodulatory strategies with our biomarker data that may promote healthy aging and more effective neuronal regeneration, because all CNS injury and disease
is accompanied by neuroinflammation.
If you could make the perfect neuron or glial cell to replace
those lost in neurodegenerative disease, would you restore neural activity and therefore reverse the symptoms of the disease?
In collaboration with Dr. Tom DeMarse, we are employing microelectrode array technology to develop strategies to integrate of
stem cell-derived cells into naïve and damaged long-term cultures
and test their safety. We have discovered that these cells stimulate plasticity in neural networks and are currently exploring ways
to capitalize on this phenomenon to restore activity in neural circuitry compromised by injuries, such as stroke.
Figure 4: Potential biomarkers of impaired learning, memory and neurogenesis.
Carlos Rinaldi
Professor
Ph.D. , 2002, Massachusetts Institute of Technology
Probing Biological Environments Using
Magnetic Nanoparticles
Nanomedicine
Cancer Nanotechnology
Magnetic Nanoparticles
Colloidal Hydrodynamics
Transport Phenomena
Suspensions of Magnetic Nanoparticles
M
y group studies the behavior and applications
of suspensions of magnetic nanoparticles in
applied magnetic fields. This field has seen
explosive growth due to potential in biomedical applications
such as magnetic resonance and magnetic particle imaging,
biosensors, targeted delivery and triggered release of drugs,
magnetomechanical actuation of cell response, and the
ability to deliver magnetic energy at the nanoscale in the
form of heat or shear. We combine expertise in synthesis
and surface modification of magnetic nanoparticles; physical,
chemical, and magnetic characterization; and modeling of the
coupling of magnetic, hydrodynamic, and Brownian forces
and torques to answer fundamental questions regarding the
behavior of magnetic nanoparticle suspensions, understand
their interaction with biological entities, and develop novel
biomedical applications taking advantage of their unique
properties.
Engineering Cell Fate Through Nanoscale
Energy Delivery by Magnetic Nanoparticles
Magnetic nanoparticles can be engineered to target specific
cells or even cellular components. Under an applied alternating
magnetic field magnetic nanoparticles can deliver energy
locally, in the form of shear due to nanoparticle rotation or in
the form of heat. This ability to deliver energy at the nanoscale
and selectively to targeted cells or cellular components
allows for novel applications where the fate of the cell can be
engineered.
In one potential biomedical application, magnetic
nanoparticles can be made to target cancer cells and destroy
these by localized hyperthermia or through disruption of
cellular components. In vitro and in vivo experiments in which
cancer cells are in contact with magnetic nanoparticles and
subjected to high frequency alternating magnetic fields have
shown that the particles may induce significant reductions
in cancer cell survival. Furthermore, because traditional
cancer treatments can have synergistic effects with thermal
treatment, their combination with hyperthermia induced
by magnetic nanoparticles is very promising. My group is
interested in understanding how nanoscale energy delivery
by magnetic nanoparticles kills cancer cells, with the objective
of engineering novel, more effective magnetic nanoparticlebased strategies to treat cancer.
In a broader biomedical context, nanoscale energy delivery,
in the form of heat and/or shear, by magnetic nanoparticles
can be a tool to engineer cell fate by mechanical/thermal
actuation of receptor-mediated pathways and by selective
denaturation/destruction of biomacromolecules and/or
cellular compartments
As noted, magnetic nanoparticles can be made to rotate
due to the application of alternating magnetic fields. In
this line of research we take advantage of the fact that
such rotation is sensitive to the mechanical properties
of the environment surrounding the nanoparticles and
to the presence of biomacromolecules that bind to the
nanoparticle surface. In turn, the rotation of collections
of magnetic nanoparticles can be observed directly
with specialized microscopy techniques or remotely by
monitoring their magnetization. We apply our fundamental
understanding of the coupling of magnetic, hydrodynamic,
and Brownian forces and torques to use magnetic
nanoparticles as probes in biological complex fluids.
We have recently demonstrated that by monitoring the
response of magnetic nanoparticles to oscillating magnetic
fields information can be obtained of the mechanical
(e.g. viscous) properties of the surrounding fluid. The
method requires small sample volumes (<100 ul), provides
information on structural features at the scale of the
probe nanoparticles, and does not require optical access
to the sample. We have applied this method to study
temperature-induced changes in biomacromolecules and
to study breakdown of the Stokes-Einstein relationship in
polymer melts. Current work aims to apply this technique
to study disease-induced changes in biological fluids.
Representative Recent Publications
Calero, et al., Soft Matter, 7(9):4497-4503, 2011.
Creixell, et al., ACS Nano, 5(9), 7124-7129, 2011.
Lee, et al., Journal of Nanoscience and Nanotechnology,
11:4153-4157, 2011.
Rodriguez-Luccioni, et al., International Journal of Nanomedicine, 6:373-380, 2011.
15
CHRISTINE E. SCHMIDT
J. Crayton Pruitt Family Professor &
Department Chair (as of January 2013)
Ph.D. , 1995 University of Illinois
Spinal Cord Injury
Biomimetic Conducting Polymers
Natural-Based Biomaterials
Cell-Materials Interactions
THERAPIES FOR NERVE REGENERATION
D
amage to spinal cord and peripheral nerve tissue
can have a devastating impact on the quality of life
for individuals suffering from nerve injuries. Our
research is focused on analyzing and designing biomaterials
that can stimulate and interface with regenerating neurons
and nerves. We take a unique approach to this problem – we
are using electrically conducting polymers and naturallyderived materials (e.g., hyaluronic acid-based biomaterials
and chemically processed nerve tissue) to create therapies
that can electrically, chemically, biologically, and mechanically
trigger neurons to re-grow damaged axons.
BIOMIMETIC CONDUCTING POLYMERS
We are working with electroactive polymers with inherent
properties that can stimulate electrically responsive cell types
such as neurons. Using these polymers, our group has created
new biomimetic, electronic materials by processing electrically
conducting polymer composites (e.g., polypyrrole-PLGA) into
3D fiber matrices for enhanced topographical guidance. We
have incorporated biological moieties using novel peptides
that directly bind to conducting polymers. Ultimately, these
materials can be used to interface with neurons for electronic
communication or as internal “pathways” to stimulate neurons
to grow and physically guide axon extension.
NATURAL-BASED MATERIALS
Our research group is designing tissue scaffolds that can
facilitate the growth of peripheral and spinal cord axons.
In this work, we are using hyaluronan, a naturally-derived
biopolymer found throughout mammalian tissues. Hyaluronan
16
is non-immunogenic (i.e., not rejected by the body’s immune
system) and plays a major role in wound healing and embryo
development. Our group has devised novel techniques
to process hyaluronan into materials that can be used in
therapeutic applications. For example, we are using gels
of hyaluronan to treat spinal cord lesions in rats. The gels
attenuate the inflammation characteristic of spinal cord injury
and provide a scaffold for regenerating axons.
We have also developed “acellular tissue grafts” created from
human cadaver nerves that have been chemically processed
so as not to provoke an immune response in patients. These
grafts have been optimized to maintain the natural intricate
architecture of the nerve pathways, and thus, they are ideal
for promoting the re-growth of damaged axons across lesions.
These engineered nerve grafts have been translated to clinical
use and are an example of how our research is promoting the
development of biomedical products that can improve human
health.
CELL-MATERIALS INTERACTIONS
Our group is also interested in the cellular mechanisms of
axon extension and neuron decision making. In particular,
we have created microfabricated devices for testing how
neurons respond to physical and chemical environmental
cues. We found that neurons favor physical cues over
chemical cues when forming axons. This information
has steered our research group to focus on therapeutic
devices that provide topographical features to enhance
regeneration of peripheral and spinal cord nerve tissue.
In a parallel approach we are using advanced laser-based
processes to create complex topographical patterns of cellsignaling proteins within hyaluronan materials to provide
physical and chemical guidance for re-growing axons.
Ranganatha Sitaram
Assistant Professor
Ph.D., 2008, University of Tuebingen
Neural Engineering & Neuroimaging
Multimodal Brain-Computer Interfaces
Functional & Structural Connectomics
Brain State Decoding
with Pattern Recognition
Neurorehabilitation of
Perception, Action & Emotion
INTERDISCIPLINARY APPROACH TO NEUROSCIENCE
M
y research is at the intersection of neuroscience,
imaging and computational intelligence. It is
based on the pivotal question: can modulation of
brain activity in selected regions and networks lead to specific
changes in sensation, perception, cognition and action, and if
so what are they and how can they be used in neuroscience
research and clinical treatment of neuropsychological
disorders? Conceptually, my work is based on the fundamental
neuropsychological paradigms of learning, namely, operant
conditioning, classical conditioning and associative learning,
to induce changes in the brain and behavior; combining it
with innovative developments in functional and structural
brain imaging, physiological measurement technology, and
computational algorithms.
an independent variable and recording the brain responses
as dependent variables. Novel approaches incorporate
a complementary philosophy where brain activity is
noninvasively manipulated as an independent variable to
observe the causal effects on behavior. In achieving these
aims, I have applied state-of-the-art techniques in brain
signal acquisition, including, real-time versions of fMRI,
fNIRS, EEG/MEG, and also stimulation techniques such as
transcranial magnetic stimulation (TMS) and functional
electrical stimulation (FES): combining these with advanced
experimental paradigms of experimental neuroscience and
neuropsychology. I’m interested in applying these methods
in: 1) communication and control in paralysis, 2) clinical
rehabilitation of neuropsychological disorders, such as stroke,
psychopathy and schizophrenia, and 3) scientific investigations
in neuroscience, of emotion, cognition, motor function, and
distinction between conscious and non-conscious perception.
RESEARCH & TREATMENT OF EMOTIONAL
DISORDERS
MULTIMODAL IMAGING & BRAIN-COMPUTER
INTERFACES
Brain imaging in neuroscience adopts experimental
paradigms correlating a particular behavioral manipulation as
Another topic of research focus is the development of
Functional near infrared spectroscopy (fNIRS) as a more
portable and flexible imaging approach for movement
research. Recent studies in my laboratory have demonstrated
that fMRI and fNIRS BCIs could be used for rapid imaging and
rehabilitation of stroke patients.
Figure 3. (Left) Application of FES-BCI for stroke rehabilitation. (Right)
Changes in functional connectivity after neuromodulation in stroke.
BRAIN CONNECTOMICS
Figure 2. Brain activation in a participant during volitional control of the left
anterior insula, a region involved in emotion processing
Figure 1. FMRI Brain-Computer Interface for neural self-regulation.
NEUROREHABILITATION OF MOVEMENT
DISORDERS
Traditional approaches to diagnosing and treating
neuropsychological and psychiatry disorders, such as
depression, schizophrenia and other psychopathologies,
have largely relied on subjective reports and behavioral
observations of the patients, followed by pharmocological
and cognitive-behavioral therapeuric interventions, with
mixed results. Recent studies, applying innovative techniques
in neural self-regulation and control, in clinical populations
are beginning to demonstrate that patients can be trained
to modulate and correct their abnormal brain leading to
symptom improvements and behavioral changes.
Connectomics is an emerging and exciting application of
brain imaging to increase the speed, efficiency, and resolution
of maps of the multitude of neural connections in the brain. My
group has been focusing on the graph theoretic representation
of brain’s functional and structural connectivity, integrating it
with behavioral and psychological measures to study brainbehavior relationships in the healthy brain as well as in
dementia, Alzheimer’s, stroke, schizophrenia and other brain
“disconnections” where abnormal development and old age
affect brain connectivity and hence its function.
Figure 4. Graph representation of fibre connectivity, obtained from diffuse
tensor imaging (DTI), and its quantification in healthy and diseased brains.
17
Johannes (Hans) van Oostrom
Associate Professor and Associate Chair
Ph.D., 1993, Eindhoven University of Technology,
The Netherlands
Simulation of Human Physiology
Instrumentation
BME Education
al information to be gathered from existing sensors by utilizing
more advanced signal processing, to enhance measurements
by combining various signal sources, and by combining sensor
measurements with models of human physiology to do parameter estimations that cannot otherwise be done.
In one recent project, we utilized a pressure measurement
mat to measure interface pressure for patients that are bedridden. Pressure ulcers are formed by too much pressure on
the same location for a prolonged period of time. The standard of practice is to regularly turn the patients. Our measurements have now shown that this has limited effect, as there
continue to be areas of the skin that are never unloaded.
Simulation of Human Physiology
P
hysiology describes the processes of the human body.
From the time we have understood how the human
body works, we have described the physiology with
mathematical equations. This can now be done at different
levels, ranging from the cellular level to the organ system level.
My interest in physiology simulation is at the system/organ
level. Many different models describing physiology exist, but
the challenge is to combine them in a cohesive fashion, and to
BME Education
Duration (hrs) of time interface pressures exceeded 32 mmHg (up to 5.5 hrs
for one ICU patient)
have a clear, open source, open model architecture that can be
utilized by others. To that goal, we have been starting meetings with other international experts in the field to define a
structure with which physiological models can be described. A
recent project includes a model of the coronary circulation, in
which we modeled the circulation of the endo- and epi-cardium, with oxygen supply and demand, modulated by the work
of the heart. A graphical representation of the model allows
integration into a medical school or biomedical engineering
curriculum.
Instrumentation
Left and right myocardium. Due to an obstruction in the coronary vessel feeding the left side, the oxygen buffer is being depleted.
18
Measurements on the human body are essential for making a diagnosis of disease. Invasive measurements allow for
the greatest signal fidelity, but more and more, the associated
risk has reduced the frequency of these measurements. Noninvasive measurements have increased, and due to advances
in signal processing, their accuracy has improved. My research
focuses on new non-invasive measurements to allow addition-
Biomedical engineering education is ever evolving. While
degree programs have been defined for decades, to date, it
is still unclear exactly what the skills of a biomedical engineer should include. In our program, we are evolving from a
classroom knowledge-based setting to a truly integrative educational program in collaboration with other colleges on our
campus. This includes close interactions with the Biology department and the College of Medicine. Biomedical engineers
will need to understand the clinical environment very well by
understanding the language clinicians speak. In addition, they
need to work collaboratively with clinicians, and be comfortable in the clinical setting. To achieve this goal, we have several opportunities for our students to be immerged into the
clinical arena, and our new location as part of the Health Sciences Center will make that even easier.
One of my interests is to bring more collaborative learning
techniques to many of our courses. Techniques such as Process Oriented Guided Inquiry Learning (POGIL) have shown
that by involving the student in teams, they will learn more,
and they will get the practical skill needed to work in teams
and to collaborate with others.
Bruce C. Wheeler
Professor and Interim Chair
Ph.D., 1981, Cornell University
Neural Engineering
Microfabrication
Signal Processing
Biomedical Engineering
Education and Leadership
BRAIN ON A CHIP
T
he confluence of neural cell culture and
electronic microfabfication technologies enables
the development of “brain on chip” technologies,
where neurons are cultured on microelectrode arrays.
The Wheeler laboratory has long been a leader in the
development of cellular lithographic (micropatterning),
electrode array and signal processing approaches to
enable this work. In collaboration with Dr. Gregory
Brewer of the Southern Illinois University School of
Medicine, the team has been a world leader in showing
how to control the growth patterns of neurons in culture.
The general goal of the work is the development of
technologies that enable new investigations that assist
basic neuroscience researchers in understanding how
networks of neurons encode information in spatiotemporal patterns. Further use of the technology is
likely in areas including detecting and drug screening
for neurotoxicity, as well as for applied science studies
in the areas of learning, memory, development, stroke,
and epilepsy.
The microtunnel technology illustrated here enables
us to recreate circuits from the brain.
CELLULAR LITHOGRAPHY
A major enabling technology is the ability to alter
the chemical composition of a cell culture surface. This
is achieved through stamping bioactive molecules to
at¬tract or repel cells or to provide ligands to bind to
specific functional receptors on the cell surfaces. This lab
was an early pioneer in the development of microstamping
for neural control. The precision of the cellular growth
patterns is unmatched worldwide. The lab also pioneered
laser ablation techniques to accomplish the same and is able
to use microfluidics for similar purposes.
Illinois, starting the B.S., M.S. and Ph.D. programs, serving as
interim department head from 2004 to 2008.
Microfabrication and Electrode Arrays
The laboratory has been a long time contributor to the
development of planar electrode array recording technology,
originating their successful use with brain slices. Novel devices,
including perforated, flexible arrays have been developed.
Current work includes enhanced recording from narrow
tunnels in which isolated axons grow. An unusual feature
is the very large signals acquired from axons in the tunnels,
enabling us to monitor the communications between discrete
islands of brain tissue in adjacent wells.
Signal Processing
One of the great challenges in this work is the acquisition,
analysis and understanding of the flood of data. Commonly, 60
channels of signals, sampled at 25 kHz, are recorded, often in
trials lasting nearly a second, with up to hundreds of trials. It is
desirable to be able to record continuously for periods of days.
A very fundamental signal processing problem is how to analyze
the data, whose complexity grows with the combinatorics of
large numbers of channels and interaction times that vary from
milliseconds to seconds, with experimentally relevant changes
occurring in days or weeks. Current work aims to take general
signal processing techniques and to focus them narrowly on
relevant biological hypotheses
Brain on a Chip. The brain circuit from cortex to striatum to substantia nigra
is recreated in cell culture in three wells separated by two sets of tunnels,
superposed over a microelectrode array. To the right are recorded action
potentials showing communication among the three region. Courtesy Dr.
Kucku Varghese, Mr. Sankar Alagapan.
Close up of green stained neurons extending axons into the microtunnels . Close up
of electrodes in microtunnels and large
amplitude signals showing propagation
of action potentials. Courtesy Dr. Liangbin
Pan.
Biomedical Engineering
Education and Leadership
Dr. Wheeler is the incoming President of the IEEE Engineering in Medicine and Biology Society (EMBS), the world’s largest
BME society. He has served (2007-2012) as the Editor in Chief
of its flagship journal, the IEEE Transactions on Biomedical Engineering.
At UF he has helped lead the effort, with Dr. van Oostrom,
to establish the B.S. BME degree program. Dr. Wheeler was on
the faculty of the University of Illinois from 1980 to 2008. He
founded the Bioengineering Department at the University of
Statistical analysis of spike patterns shows how the neural
network is connected. Courtesy: Dr. Thomas DeMarse.
19
J. Crayton Pruitt Family
Department of Biomedical Engineering
BIOMEDICAL SCIENCES BUILDING | ROOM JG56
P.O. BOX 116131
GAINESVILLE, FL 32611-6131