Healthcare Technology Brochure

Saving Lives, Cutting Costs HEALTHCARE TECHNOLOGY RESEARCH

ENGINEERING HEALTHCARE From drug-coated stents that keep hearts beating to ultrafast CT scans that catch tumors early, high-tech innovations are enabling dramatic improvements in the quality of healthcare across the globe. Deployed correctly, advanced medical technology not only improves health outcomes but also makes healthcare more affordable in both developed and resource-limited countries. For example, a labelfree, chip-scale, point-of-care biosensor could enable medical personnel to diagnose infectious diseases rapidly on-site, avoiding expensive, centralized lab processing and delays in treatment.

This is but one of dozens of higher-quality, lower-cost healthcare solutions emerging from Boston University’s College of Engineering. Others include faster, cheaper DNA sequencing that could revolutionize personalized medicine; targeted cancer treatments designed to minimize potentially lethal side effects and treatment time; new devices to detect and monitor cardiovascular disease noninvasively; and sophisticated biomaterials for bone healing and injury repair.

A Multi-Disciplinary, Multi-Scale Endeavor Anchored by its top-10-ranked Biomedical Engineering department, BU College of Engineering healthcare technology research often involves collaborations that span multiple departments and divisions and leverage the expertise of physicians and medical researchers from the BU School of Medicine, the BU Goldman School of Dental Medicine and other Boston-area medical research institutions. Projects are funded by major federal agencies such as the National Institutes of Health, National Science Foundation, and Department of Defense, as well as by private foundations such as the Wallace H. Coulter Foundation.

In their efforts to advance our fundamental understanding of biology and physiology in health and disease and translate these principles into highly effective and affordable clinical technologies, our researchers are not only crossing departmental boundaries, but also working at every scale of biology—from molecule to cell to tissue to patient.

Saving Lives and Money Whether designed to prevent, diagnose, treat or manage disease, healthcare technologies emerging from the BU College of Engineering promise to improve patients’ well-being, saving them money, and, quite possibly, their lives. As you’ll see on the following pages, our researchers are facing—and overcoming—formidable challenges to deliver on that promise.

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RESEARCH AT-A-GLANCE

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Lighting the Way On-Chip Pathogen Detection with Plasmonics Assistant Professor Hatice Altug (ECE, MSE)

High-Res Checkup Tracking Single Molecules in Cells Assistant Professor Sean Andersson (ME)

Managing Obesity Boosting Immune Response, Reducing Complications Associate Professor Calin Belta (ME, SE)

Beyond the Eye Chart Tracking Retinal Disease with Adaptive Optics Professor Thomas Bifano (ME, MSE); Director of the Boston University Photonics Center

Scattered Light Noninvasive, Early Cancer Detection Professor Irving Bigio (BME)

Making the Medicine Work Targeting Recurring Bacterial Infections with Sugar-Coated Antibiotics Professor James Collins (BME, MSE, SE)

Hybrid Biosensors Combining Optical Nanostructures and Silicon Technology for Pathogen Detection Associate Professor Luca Dal Negro (ECE, MSE)

Closing the Loop A Bionic Pancreas for Low-Maintenance Diabetes Professor Edward Damiano (BME)

Brainteaser Systems Biology Platform Helps Pinpoint Genetic Predisposition for Glioma Professor Charles DeLisi (BME); Dean Emeritus, College of Engineering

Reconfigurable Biology Synthetic Biology Tools Probe DNA “Circuitry� Behind TB Assistant Professor Douglas Densmore (ECE)

Saving Lives, Cutting Costs BU College of Engineering

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Exotic and Deadly Monitoring Potentially Malignant Rare Cells Research Professor Daniel Ehrlich (BME)

No Swimming Allowed Nanoscale Diving Boards that Detect Pathogens Associate Professor Kamil Ekinci (ME, MSE)

A First Responder’s Dream Portable, Noninvasive Imaging of Brain Injuries Lecturer Caleb Farny (ME)

Deconstructing TB Honing in on Potential Drug Targets Associate Professor James Galagan (BME)

Nipped in the Bud Targeted Chemotherapy for Lung Cancer Patients Professor Mark Grinstaff (BME, MSE)

Mind Altering Optical Neurotechnologies to Probe and Correct Brain Disorders Professor Xue Han (BME)

Catching the Wave A Faster, Cheaper Way to Grow Tissue Associate Professor Glynn Holt (ME)

No Needles, Please An Electrostatic Method for Pain-Free Inoculation Professor Mark Horenstein (ECE)

Sharper Image A Blur-Free Scanning Method for Improved Heart Monitoring Professor W. Clem Karl (ECE, SE)

Tipping Points Lung Cancer Biomarkers Present New Drug Targets Professor Simon Kasif (BME)

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Point-of-Care Infectious Disease Diagnostics on a Chip Associate Professor Catherine Klapperich (BME, MSE)

Tree Work Probing the Lung’s Branching Airways to Improve Asthma Treatment Professor Kenneth R. Lutchen (BME); Dean, College of Engineering

Getting the Right Dose Engineering More Effective Drugs for Lung Disease Research Professor Malay Mazumder (ECE)

The $100 Genome Faster, Better, Cheaper Personalized Medicine Professor Amit Meller (BME, MSE)

Look Inside Low-Cost, High-Res, Deep Imaging of Bodily Organs Associate Professor Jerome Mertz (BME)

All in the Cartilage Imaging Diagnostics for Bone Fracture Healing Associate Professor Elise Morgan (ME, MSE)

Of Lasers and LEDs Fighting Pathogens with UV Technology Professor Theodore Moustakas (ECE, MSE)

Data-Driven Algorithms for Better, Cheaper Healthcare Professor Ioannis Paschalidis (ECE, SE)

Sounding Out Tumors Ultrasound Techniques for Targeted Cancer Drug Delivery Assistant Professor Tyrone Porter (ME)

At the Turn of a Dial Nanoparticle-Assisted Ultrasound for Tumor Imaging and Therapy Professor Ronald Roy (ME); Chair, Department of Mechanical Engineering

Going with the Flow Sound Wave-Driven, Microfluidic Biochips for Cancer Drug Discovery Assistant Professor Matthias Schneider (ME)

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Vaccines On-Demand High-Production Factory Extracts Medicines from Tobacco Plants Professor Andre Sharon (ME)

Can you Repeat That?

Advancing Better Hearing Diagnostics and Aids Professor Barbara Shinn-Cunningham (BME)

Shape Matters A New Pathway to Anti-Cancer Drugs and Tissue Engineering Assistant Professor Michael Smith (BME)

Breathing Free New and Improved Mechanical Ventilators Professor Bela Suki (BME)

Lifelines, Literally Engineered Blood Vessels for Reconstructive Surgery AssociateProfessor Joe Tien (BME)

Label-Free On-Chip Pathogen Detection with Interferometry Professor Selim Ünlü (ECE, MSE)

Missed Signals Finding New Cancer Drug Targets Where Proteins Combine Professor Sandor Vajda (BME, SE)

High Contrast Nanoparticle-Enhanced Imaging for Heart Disease Detection Associate Professor Joyce Wong (BME, MSE)

Simple, Cheap and Durable Medical Technologies for Resource-Limited Countries Associate Professor Muhammad Zaman (BME)

Breaking Down the Walls Biomechanical Model to Probe Cardiovascular Disease Mechanisms and Potential Therapies Assistant Professor Katherine Yanhang Zhang (ME, MSE)

Color-Coded Precisely Engineered Magnetic Resonance Imaging (MRI) Contrast Agents Using a Top-Down Approach Professor Xin Zhang (ME, MSE)

College of Engineering faculty affiliations that appear in this brochure include home departments— Biomedical Engineering (BME), Electrical Engineering & Computer Science (ECE) and Mechanical Engineering (ME), and divisions—Materials Science & Engineering (MSE) and Systems Engineering (SE). bu.edu/eng

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LIGHTING THE WAY On-Chip Pathogen Detection with Plasmonics

Assistant Professor

HATICE ALTUG (ECE, MSE)

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We’re developing a label-free, real-time, multiplexed detection system with unprecedented sensing capabilities. This labon-a-chip platform could be used in pointof-care disease diagnostics and drug discovery applications.

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Rapid, chip-scale, low-cost detection of viruses and other pathogens is critical in treating infectious diseases and curbing the spread of pandemics, but today’s biodetection technology falls short. Most diagnostic tests for bacterial and viral diseases are too expensive, time- and labor-intensive to be completed at point of care, leading many physicians to overprescribe antibiotics and miss opportunities to contain viral outbreaks.

But Assistant Professor Hatice Altug (ECE, MSE) has introduced an optical biosensor platform that could change all that. Developed in collaboration with Boston University School of Medicine

microbiologist John Connor, this highly sensitive, on-chip biosensor rapidly detects live viruses from biological media with minimal sample preparation.

It’s the first to detect intact viruses by exploiting plasmonic nanohole arrays— 250-350 nanometer-wide apertures on metallic films that transmit light more strongly at certain wavelengths. When a live virus binds to the sensor surface, it triggers a detectable shift in the resonance frequency of the light transmitted through the nanoholes. The magnitude of that shift reveals the presence and concentration of the virus in the solution.

When a live virus (blue) binds to an immobilized antibody (green) on the sensor surface, the effective refractive index in the close vicinity of the sensor changes, causing a detectable shift in the resonance frequency of the light transmitted through the nanoholes.

Saving Lives, Cutting Costs BU College of Engineering

HIGH-RES CHECKUP Tracking Single Molecules in Cells

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Our research centers on developing and applying new instrumentation for studying dynamics in systems with nanoscale features, especially proteins and other biomolecules. These tools could help improve our understanding of biological processes at the molecular level and lead to new insights and even new treatments for a variety of cardiac, brain, neuroinflammatory and other disorders related to changes in the dynamics at this scale.

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Two well-known biological imaging techniques—atomic force microscopy (AFM) and confocal fluorescence microscopy (CFM)—use a point-like sensor which moves back and forth in a raster scan, sampling point-by-point to build an image, pixel-by-pixel. The techniques perform well in capturing static phenomena, but are far too slow to image dynamic biological processes.

Custom-built tracking confocal microscope. By actuating the relative position of the focal point of the microscope and the sample (achieved here by moving the sample with a nanopositioning stage), a single fluorescing molecule is followed over seconds to minutes. This approach allows for existing single molecule techniques to be applied over a much broader time range, thereby providing significantly more information, as well as a direct approach to understand the motion of that molecule.

Assistant Professor SEAN ANDERSSON (ME, SE)

Now Assistant Professor Sean Andersson (ME, SE) is reconfiguring AFM and CFM with new software algorithms to perform high-speed, high-resolution dynamic imaging in order to track the behavior of single molecules in solution, and, eventually, living cells.

To accelerate AFM, Andersson focuses only on dynamic processes occurring along string-like biopolymers.

Using AFM measurements of biomolecules to direct the instrument’s sharp tip close to the string, he’s minimizing data collection and time needed to build an image. To accelerate CFM and effectively obtain a wide field of view of a dynamic process, Andersson moves the instrument’s detection volume through a feedback process. Based on the measurements he gets from the fluorescence of what’s moving, he advances the detection volume to follow the action.

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MANAGING OBESITY Boosting Immune Response, Reducing Complications

Associate Professor CALIN BELTA (ME, SE)

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Our goal is to determine how obesity affects the response to infection— knowledge that could be used to develop targeted diagnostics and drugs for infections in obese patients.

Experiments by Boston University Goldman School of Dental Medicine Professor Salomon Amar indicate that obese organisms have a deficient immune response to infection, leading to significantly longer-lasting illnesses. To better understand how body mass index impacts the immune response—and to try to reverse the process, Amar is collaborating with an expert in computational modeling of gene and other networks, Associate Professor Calin Belta (ME, SE).

Amar and Belta are developing a genome-scale mathematical model of metabolism, signaling and gene networks in the immune system cells of lean and fat strains of mice infected with the microorganism P. gingivalis.

The researchers obtain gene

expression data, computationally predict which genes are restricting the immune response, and knock out or over-express those genes to see if they provoke sharp differences in immune response in the two strains.

The effort could lead to a medication rendering obese individuals less prone to infectious diseases and better equipped to mount an effective immune response, thereby reducing the complications and costs—about $150 billion annually in the U.S.—of obesity.

” Macrophages from lean and obese mice are exposed to P. gingivalis infection. The corresponding gene expression data is fed into the researchers’ computational tools to predict genes that are essential to this response.

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Saving Lives, Cutting Costs BU College of Engineering

BEYOND THE EYE CHART Tracking Retinal Disease with Adaptive Optics

Developed at Boston University over the past decade, Professor Thomas Bifano’s (ME, MSE) deformable mirrors are widely used to compensate for optical aberrations in telescopes and microscopes. His “adaptive optics” technique uses MEMS technology—electrostatic actuators and flexible layers of silicon—to shape the mirrors precisely and to bring images of everything from cells to planets into sharper focus. And now the technique has found its way into the clinic.

A research consortium has produced a prototype of a scanning laser ophthalmoscope (SLO) that uses Bifano’s deformable mirrors to compensate for optical

aberrations of the eye, yielding cell-scale, in vivo images of the retina.

Clinicians at the Joslin Diabetes Center are expected to use the integrated SLO to study the progression of selected diabetes-related retinal diseases and to assess the effectiveness of clinical treatments.

The technology may ultimately enhance routine eye exams. “Upon detecting signs of an abnormality using low-resolution diagnostics, an ophthalmologist could use this instrument to obtain very high-resolution scans over the entire retina, and to track disease progression,” says Bifano.

Photograph of MEMS Deformable Mirror used in the new ophthalmoscope. The 4mm square mirror membrane can be reshaped using an underlying array of 140 actuators to compensate for optical imperfections in the eye, allowing sharper retinal images.

High resolution image of a portion of the retina made at Joslin Diabetes Center with the ophthalmoscope. Cone photoreceptor cells are clearly resolved, as is blood flow through traversing vessels.

Imaging these structures in vivo will advance the study of eye disease.

Professor

THOMAS BIFANO (ME, MSE) Director, Boston University Photonics Center

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With colleagues from Indiana University and Boston Micromachines Corporation, I developed a high-resolution retinal imaging system. Used by Joslin Diabetes Center researchers to study molecular mechanisms of retinal disease in diabetes, this instrument provides the highest resolution ever attained in a clinical setting, and enables the first direct imaging of cell-sized structures in the retinas of patients with eye disease.

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SCATTERED LIGHT Noninvasive, Early Cancer Detection

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We’ve developed an optical method to detect subcellular structural changes in the epithelial layer of hollow organs associated with pre-cancer conditions or the onset of cancer. The method could be used not only in noninvasive diagnosis of selected early stage cancers, but also in guided cancer treatment.

Professor

IRVING J. BIGIO (BME)

In the 1990s, Professor Irving J. Bigio (BME) pioneered a noninvasive early cancer detection method called elastic scattering spectroscopy (ESS), in which a fiber-optic probe is passed through an endoscope or catheter, or integrated into a surgical tool. When the probe’s tip is in gentle contact with the tissue, an optical fiber shines white light into the tissue, and an adjacent optical fiber collects light scattered back from the tissue. Software then analyzes the spectrum scattered from the tissue with a stored diagnostic algorithm to pinpoint early signs of cancer.

Based on clinical studies with hundreds of patients, ESS shows great promise as a lowcost, low-maintenance, user-friendly clinical tool for diagnosing early stage colon, esophageal and other hollow organ cancers, but recent research shows that the method could also provide timely, critical information to cancer surgeons.

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One example is to assess the resection margins during breast cancer surgery, to assure that no cancer is left behind. Another example, in collaboration with Boston University School of Medicine specialists, is the clinical testing of a new device that integrates ESS into the fine needle aspiration diagnostic tool typically used to probe the thyroid gland. Delivering additional diagnostic information, the enhanced tool could prevent many unnecessary thyroidectomies.

Optical fibers integrated into the biopsy forceps used during colonoscopy can shine light on the tissue, and the ESS system can provide instantaneous diagnostic information to the endoscopist about the risk potential of the tissue.

Saving Lives, Cutting Costs BU College of Engineering

MAKING THE MEDICINE WORK Targeting Recurring Bacterial Infections with Sugar-Coated Antibiotics

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Adding certain sugars to first-line antibiotics can dramatically boost their effectiveness, and may lead to better treatments for recurring bacterial infections and TB.

Professor JAMES COLLINS (BME, MSE, SE)

A discovery by Professor James Collins (BME, MSE, SE) and PhD student Kyle Allison (BME’11) may deliver a new weapon in the daunting battle against recurring, potentially lethal bacterial infections such as staphylococcus and streptococcus. And the weapon—a modified form of sugar—is as widely available and cheap as it is effective, says Collins.

“A spoonful of sugar makes the medicine work,” says the MacArthur genius award recipient. It does that, he says, by “waking up” stealthy, dormant bacteria that can lie in a state of metabolic hibernation for weeks or months.

The researchers found that sugar dramatically boosts the effectiveness of first-line

antibiotics such as gentamicin. A sugar-antibiotics combination could be used to obliterate recurring, often debilitating infections such as those of the ear, throat, lungs and urinary tract, all of which can spread to the kidneys and other vital organs if left unchecked.

Collins and Allison are now investigating the impact of sugar additives on the efficacy of drugs for tuberculosis, which kills approximately two million people worldwide each year.

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HYBRID BIOSENSORS Combining Optical Nanostructures and Silicon Technology for Pathogen Detection

Associate Professor

LUCA DAL NEGRO (ECE, MSE)

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We’re developing efficient, nanoscale, metallic and semiconducting nanoparticles on planar silicon-based chips for the engineering of superior light sources, optical sensors and laser structures boosted by optical fields confined at the nanoscale. Our research could result in novel and more sensitive optical biosensors fully integrated with widespread silicon technology.

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Using precisely-engineered arrays of metallic and silicon nanoparticles to boost the intensity of optical fields localized on two-dimensional surfaces, Associate Professor Luca Dal Negro (ECE, MSE) is developing a new platform for nanoscale optical sensing that could be used to detect disease-causing pathogens with superior accuracy and dependability.

“We envision optics and electronics components on high-density silicon chips on a silicon-based materials platform,” says Dal Negro. “This leads to inexpensive, highperforming, mass-producible, electrical and optical devices with superior performances resulting from engineered electric fields at the nanoscale.

This vision can enable an inexpensive, integrated silicon chip with thousands of waveguides, modulators, detectors and other optical components interacting with controllable nanoscale fields, all within the standard microelectronics circuitry.”

By engineering the shape and size and arrangement of nanoparticles to scatter light on two-dimensional surfaces, Dal Negro aims to boost the performance of current optical biosensors, photo-detectors and other active photonic devices. Potential applications include biosensors capable of detecting harmful bacteria, viruses and food and water contaminants with greater reliability and lower error rates than current technology.

Figure shows (a) white light microscope image of an aperiodic surface of gold nanoparticles; (b) electron microscope picture of fabricated arrays of gold nanoparticles on silicon (the pattern shows detail of aperiodic twodimensional surface); (c) white light microscope image of an aperiodic spiral of gold nanoparticles on silicon; and (d) electromagnetic simulation of a localized optical wave trapped on the two dimensional surface referenced in (b).

Saving Lives, Cutting Costs BU College of Engineering

CLOSING THE LOOP A Bionic Pancreas for Low-Maintenance Diabetes

Working with endocrinologists Steven Russell and David Nathan at Massachusetts General Hospital (MGH), Associate Professor Edward Damiano and Senior Research Associate Firas El-Khatib (both BME) have conducted successful clinical trials at MGH in adults and children with type 1 diabetes, testing prototypes of the bionic endocrine pancreas that they developed. Aimed at people with type 1 diabetes who must monitor their blood glucose levels throughout the day and continuously receive insulin, the system uses automated decision-making software to pump insulin (a blood-glucose lowering hormone) and glucagon (a blood-glucose

raising hormone) just below the skin using FDA-approved infusion pumps based on measurements obtained every five minutes from a commercially available continuous glucose monitor.

The device emulates the endocrine pancreas, which continually secretes these two hormones to regulate blood glucose.

“Our automated system will not only reduce the decision-making burden on people with type 1 diabetes and their caregivers, but will also keep blood glucose levels within a much healthier range than what’s achievable for most people with today’s therapies,” says Damiano.

Professor

EDWARD DAMIANO (BME)

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We’re developing a software-controlled, bionic endocrine pancreas to enable people living with type 1 diabetes to maintain much safer and better blood glucose control with far less effort than can be achieved with conventional therapies.

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In an ongoing clinical trial at MGH, adults and children with type 1 diabetes are connected to an experimental version of the software-controlled, automated bionic pancreas for 51 hours and provided with six carbohydrate-rich meals. The system responds to glucose readings streamed online every five minutes from a continuous glucose monitor, and commands insulin and glucagon doses wirelessly using infusion pumps. Intravenous blood glucose is also monitored every 15 minutes to test the system, but this information is not provided to the bionic pancreas.

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BRAINTEASER Systems Biology Platform Helps Pinpoint Genetic Predisposition for Glioma

“ ” We have identified 29 genes that predispose to glioma, a tumor typically found in the brain, optic nerve or spinal cord. Some of these genes could serve as drug targets.

OUT OF FOCUS

Professor

CHARLES DELISI (BME)

Dean Emeritus, College of Engineering

Depending on its location, a high-grade glioma can cause seizures, vision loss, numbness or other symptoms. This relatively uncommon disease, which tends to arise between the ages of 45 and 70 and caused the death of the late Senator Edward M. Kennedy, is rarely curable, but research

by Professor Charlers DeLisi (BME) could lead to new therapies designed to prevent its onset.

Using a large systems biology platform he and colleagues developed over the past decade to map the relationships among cellular networks of genes and proteins involved in cancer and other

biological processes, DeLisi and Department of Mathematics & Statistics Professor Mark Kon and postdoctoral fellow Tun-Hsiang Yang conducted a study to identify genetic predispositions.

“We used blood cells from a group of people with and without glioma, and compared up to one million sites in their genomes,” says DeLisi.

“As a result, we identified 29 genes unique to individuals with the disease, 12 of which are already known to be cancer related. Some of the 29 could be potential drug targets.”

Regions on chromosomes 1 and 9 that contain some of the cancer related genes that appear to predispose to glioma. For example, CDKN2 is known to regulate cell division; its loss diminishes growth regulation and predisposes to cancer.

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Saving Lives, Cutting Costs BU College of Engineering

RECONFIGURABLE BIOLOGY Synthetic Biology Tools Probe DNA “Circuitry” Behind TB

Assistant Professor Douglas Densmore’s (ECE) research focuses on the development of tools for the specification, design and assembly of synthetic biological systems, which can be used to model how natural biological systems function. He’s currently applying these tools to help accelerate Associate Professor James Galagan’s (BME) efforts (see p. 19) to reverse engineer the process by which selected genes turn on and off in “circuits” (collections of DNA segments) within Mycobacterium tuberculosis and thereby enable the bacterium to become pathogenic.

“Our software lets you make a reconfigurable DNA circuit—

producing it once and reconfiguring it for multiple experiments, either in computer simulations or in the lab,” says Densmore. “By isolating genes suspected of transforming the TB bacterium to a pathogenic state and studying their interactions, we hope to better understand this process and how to inhibit it.”

There’s a pressing need to get a handle on this process: Approximately one-third of the world’s population is infected with TB (about 1.7 million died from the disease in 2009), and the threat from multi-drug resistant strains is growing.

Reconfigurable circuits are designed using computer software and then introduced into bacteria. These circuits then “reconfigure” themselves with the introduction of specific enzymes into configurations to test gene interaction.

Assistant Professor

DOUGLAS DENSMORE (ECE)

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Using computational tools, we can create synthetic gene networks—collections of engineered DNA segments—which can be reconfigured to examine how bacterial systems develop. We are applying these tools to support Associate Professor James Galagan’s (BME) efforts to model gene regulatory networks in the bacterium that causes tuberculosis, and thereby uncover new drug targets.

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EXOTIC AND DEADLY Monitoring Potentially Malignant Rare Cells

Research Professor

DANIEL EHRLICH (BME)

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Our laboratory is developing the new methods and instruments needed to gather detailed molecular snapshots from rare cells that can trigger cancer and other diseases—for both drug development and clinical diagnosis.

An emerging view likens cancer to contagious disease.

Under the body’s systemic control or ongoing drug treatment, a balance is maintained between healthy and potentially malignant rare cell types, such as early cancer cells. It is when these cells proliferate and subvert this balance that disease emerges. To monitor the development of rare cells would require molecular-level detection capability, but current genomics technology provides too blunt an instrument.

Research Professor Daniel Ehrlich (BME) is now assembling a more precise rare cell detection technology

that combines elements of high-speed microscopy (to image cells at the molecular level) and flow cytometry (to analyze cells suspended in a stream of fluid). The new technology enables highthroughput detection and analysis of the cells, greatly expanding the number of samples that can be investigated per unit time.

“We’re building a secondgeneration prototype of what we call a parallel microfluidics cytometer,” says Ehrlich. “It’s a disposable, plastic cartridge that automates the standard instrument lab techs use to analyze blood samples, and can also be adapted for highthroughput drug discovery.”

What is a Parallel Microfluidic Cytometer (PMC)?

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Microfluidic devices used for high-content cell cytometry. A 16-test disposable device for clinical applications and a larger 384-channel device, suitable for high-throughput drug development, are shown. A typical cytometry trace is shown on right.

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Saving Lives, Cutting Costs BU College of Engineering

NO SWIMMING ALLOWED Nanoscale Diving Boards that Detect Pathogens

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We are designing diving-board-like cantilevers to detect trace amounts of pathogens in a fluid.

The textured surfaces of these special cantilevers mitigate the inherent stickiness of water and other fluids, thus optimizing signals received from any pathogens onboard.

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Associate Professor KAMIL EKINCI (ME, MSE)

When a pathogen attaches to one of Associate Professor Kamil Ekinci’s (ME, MSE) vibrating, nanoscale diving boards, the board becomes heavier and its resonant frequency decreases. By bouncing light or radio waves off these boards, one can measure this reduced frequency and detect the pathogen.

After showing that the diving boards worked in a vacuum and in air, Ekinci’s next challenge was to enable them to detect a biomolecule in a fluid such as a blood sample—all while preventing the fluid from sticking to the board and dampening its vibrational motion. He subsequently

designed super-hydrophobic structures on the cantilevers to mitigate the inherent stickiness of water and other fluids, thereby optimizing signals received from any pathogens onboard.

“We have engineered the cantilever so that when we submerge it in water, air is trapped on it; it effectively moves as if in air, so the damping effect is minimized and the source becomes easier to detect,” he explains. The highly-sensitive cantilevers may ultimately be used to detect proteins, viruses, bacteria, DNA and other biomolecules.

Ekinci’s lab is developing diving-board-like cantilevers to detect trace amounts of pathogens in water. The textured surfaces are designed to overcome water’s inherent stickiness, which inhibits the devices’ sensitivity.

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A FIRST RESPONDER’S DREAM Portable, Noninvasive Imaging of Brain Injuries

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We’re working to improve imaging techniques of soft tissue in the brain through the skull using ultrasound.

The goal is to develop a portable transcranial imaging modality that allows the skull layer to remain intact.

Lecturer

CALEB FARNY (ME)

In collaboration with researchers at Brigham & Women’s Hospital, Lecturer Caleb Farny (ME) is developing an unprecedented, ultrasound-based imaging technology for the U.S. Army that could detect foreign objects that penetrate the skull, or identify regions of blood pooling or hemorrhaging that result. Ultrasound offers a low-cost, lowpower, portable, radiation-free solution that’s easily deployable in the field, but getting it to perform as specified is no easy task.

“It’s difficult to image soft tissue through the skull, and high-frequency ultrasound doesn’t pass well through thick bone layers,” says Farny. “We’re

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developing imaging methods that correct for signal distortion coming from two different types of sound wave propagation—longitudinal and shear mode—that the skull introduces.”

Longitudinal waves travel and oscillate in the same direction, whereas shear mode waves oscillate perpendicular to the direction of travel.

Like noise-cancelling headphones, Farny’s ultrasound device cancels out sound coming through the shear mode wave, yielding a sharper image of soft tissue beneath the skull— and could add a new imaging modality beyond MRI and CT-scans.

Saving Lives, Cutting Costs BU College of Engineering

DECONSTRUCTING TB Honing in on Potential Drug Targets

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We’re attempting to reverse-engineer regulatory and metabolic networks in the tuberculosis bacterium to determine which proteins and genes trigger the disease. By pinpointing these proteins and genes, we hope to pave the way for simpler, faster, more targeted diagnostics and drugs for TB.

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Associate Professor JAMES GALAGAN (BME)

Associate Professor James Galagan’s (BME) group and four collaborating research teams are building molecular maps of the regulatory and metabolic networks of the bacterium that causes tuberculosis, all to determine which proteins and genes in these networks trigger the disease. This knowledge could yield simpler, faster, more targeted diagnostics and drugs for TB, which causes about two million deaths each year.

To map the bacterium’s regulatory network, the researchers apply genome sequencing technology to obtain a “circuit diagram” of the network’s 180 known transcription factors, interconnected proteins

that activate or deactivate the approximately 4,000 genes controlling the cell.

Applying a synthetic biology technique, they next activate the transcription factors— individually and in groups, or “subcircuits”—to see which genes get turned on or off as a result.

Finally, they integrate the data into a predictive computer model, which they use to pinpoint promising gene and protein subcircuits to knock out.

“What’s unique about our approach to TB is that we’re trying to map out the terrain in a systematic, unbiased and comprehensive way,” says Galagan.

Myobacterium tuberculosis bacteria. Associate Professor James Galagan (BME) is taking a systematic approach to pinpointing the genes and proteins in the TB bacterium that trigger the disease. (Image courtesy of Centers for Disease Control and Prevention)

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NIPPED IN THE BUD Targeted Chemotherapy for Lung Cancer Patients

Professor

MARK GRINSTAFF (BME, MSE)

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We’re exploring the use of nanoparticles and flexible films for the delivery of anticancer agents to treat lung cancer. The idea is to take advantage of unique material properties offered by these technologies to increase the efficiency of drug delivery.

The leading cause of cancer mortality in the U.S., lung cancer is remarkably difficult to cure. Standard practice for early stage lung cancer is to surgically remove, or resect, lung tissue tumors, but nearly 30 percent of patients receiving such treatment develop recurrent disease, and only 60 percent survive after five years. Systematic injection of paclitaxel, the standard chemotherapy agent for lung cancer, delivers inadequate concentrations of the drug to diseased lung tissue and damages healthy organs, but Professor Mark Grinstaff’s (BME, MSE) approach overcomes these drawbacks.

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Saving Lives, Cutting Costs BU College of Engineering

Developed with collaborator Dr. Yolanda Colson, a cardiothoracic surgeon at Boston’s Brigham and Women’s Hospital, Grinstaff’s idea is to resect the tumor and apply paclitaxel via polymeric nanoparticles or films at the margin during surgery. The nanoparticles expand and release the drug upon entering tumor cells; the flexible, conformal films can be stapled directly to the resection margin and elute the drug over several weeks.

Tests show that cancerous mice treated with the nanoparticles or films performed significantly better at killing tumors that those receiving conventional chemotherapy treatment.

Upper panel shows scanning electron micrographs of particles before (left) and after (right) swelling; lower panel shows flexibility of a wet polymer film (scale bar: 5 mm). (Source: Annals of Surgical Oncology)

MIND ALTERING Optical Neurotechnologies to Probe and Correct Brain Disorders

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Our research focuses on developing radical new genetic, molecular, optical and electrical neurotechnologies to understand and treat brain disorders. Toward that end, we have pioneered several technologies for optically controlling specific brain cells using pulses of light.

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Assistant Professor XUE HAN (BME)

Brain disorders constitute a major unmet medical need; most are currently untreatable, and available treatments often involve serious side effects. But Assistant Professor Xue Han (BME) is confronting this challenge head-on. She has developed novel technologies to control the brain’s neural network and identify neurons within the network that go awry in neurological and psychiatric disorders.

“With technology we’ve developed to optically control specific brain cells using pulses of light, we can simultaneously monitor and control neuronal activity within the brain,” says Han. “Our challenge is to use this technology to establish causal links between neural dynamics and behavioral phenomena, from memory loss to abnormal movements.”

Han is currently using the technology to investigate the neural circuit principles of neurological and psychiatric diseases, with an ultimate goal of developing circuit-based biomarkers for brain disorders.

Shown is a neuron in the brain genetically altered to express light-activated protein channelrhodopsin. This neuron can be precisely controlled with pulses of light.

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21

CATCHING THE WAVE A Faster, Cheaper Way to Grow Tissue

Associate Professor

GLYNN HOLT (ME)

“

Our research seeks to freeze, on the nanosecond time scale, wave patterns created by acoustics on suitable polymer materials. This wavefreezing technique can potentially produce micro-patterned solid materials much more quickly and inexpensively than current techniques, and could be used as an alternative method for engineering scaffold structures for tissue cell growth.

” 22

In collaboration with researchers from Clemson University and Riverside Research Institute, Associate Professor Glynn Holt (ME) and Associate Professor Catherine Klapperich (BME, MSE) are advancing a novel acoustic method to form a micro-patterned scaffold to grow artificial skin or other biological tissue. The method exploits Faraday waves, which, in a thin liquid film, exhibit a variety of patterns and pattern spacings that can be frozen instantaneously.

Through simple adjustments in the acoustic method or scaffold material, the

researchers can alter these patterns and spacings to achieve desired specifications.

Compared to traditional methods such as photolithography, freezing Faraday waves offer a faster, cheaper, less complex and more reliable way to produce the small pore size (100 microns) that enable epithelial cells—which form the ultrathin surface layer of the skin and other organs—to adhere to tissue-engineering scaffolds.

By transmitting sound waves at the right frequency, the researchers are able to achieve the desired pore size. Using a transducer set at 30 kilohertz, they have reliably produced approximately 100-micron pores across a large surface.

Associate Professors Glynn Holt (ME) and Catherine Klapperich (BME, MSE) are advancing a novel acoustic method that exploits Faraday waves (shown here in water) to form a micro-patterned scaffold for use in the growth of artificial skin or other biological tissue.

Saving Lives, Cutting Costs BU College of Engineering

NO NEEDLES, PLEASE An Electrostatic Method for Pain-Free Inoculation

All methods aimed at systematically delivering drugs beneath the skin either require using micro-needles or dose very slowly, but Professors Mark Horenstein (ECE) and David Sherr (School of Public Health) are advancing an approach that avoids these drawbacks and may ultimately permit the rapid inoculation of large populations.

To inoculate someone rapidly, one must direct a vaccine into the stratum corteum, the system of cells lying just under the outer skin layer that has a direct pipeline to the immune system. With

that goal in mind, the researchers are working to use electrostatic force to drive drug-encapsulated nanoparticles about 10 microns below the outer layer of the skin, where the stratum corneum resides, and track their pathway to the immune system.

Ultimately, they hope to develop a portable field instrument that can be used in a doctor’s office or by an emergency medical technician for the painless and rapid inoculation of large populations in the event of a bioterror attack.

Professor

MARK HORENSTEIN (ECE)

“

We are developing a method for transdermal, needle-free drug delivery in which drug-laden nanoparticles are forced into the skin using an electrostatic pulse. If successful, the technique could be used for the rapid inoculation of mass populations, or as a preferable alternative to ordinary drug delivery.

”

Professors Mark Horenstein (ECE), left, and David Sherr (School of Public Health) examine a prototype of their nano-pulse patch, which would deliver drug-laden nanoparticles through the skin. Fluorescent dye helps track the movement of nanoparticles through the body.

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23

SHARPER IMAGE A Blur-Free Scanning Method for Improved Heart Monitoring

“

We’re working to enable high-resolution, high signal-to-noise imaging of coronary artery inflammation through PET-CT scans. The technology could be used to monitor plaque development in high-risk patients and to validate the effectiveness of potential drugs designed to reduce arterial inflammation.

Professor

W. CLEM KARL (ECE, SE)

The leading cause of mortality in industrialized nations, coronary artery disease is characterized by chronic inflammation and plaque formation in the arterial walls, which, if not properly diagnosed and treated, can lead to a heart attack. Accurate detection of the degree of inflammation could help prevent heart attacks, but current diagnostic techniques, some quite invasive, fall short. Even positron emission tomography (PET), which can noninvasively image arterial inflammation, is compromised by severe blurring induced by cardiac and respiratory motion during lengthy PET acquisitions.

Now Professor W. Clem Karl (ECE, SE), graduate student Sonal Ambwani (ECE, PhD’11)

”

and physicians from Massachusetts General Hospital have joined forces to develop an advanced technique that combines PET and CT scanning to eliminate that blurring and, for the first time, provides noninvasive, direct, sharp in vivo images of developing coronary plaques.

Combining image processing and motion estimation techniques to allow direct visualization of inflamed arteries, the new PET-CT coronary artery inflammation detection method compensates for cardiac and respiratory motion and boosts image resolution in computer simulations. Next step: clinical studies.

College of Engineering researchers have developed a new high-resolution PET reconstruction method that compensates for motion allowing direct non-invasive monitoring of coronary.

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Saving Lives, Cutting Costs BU College of Engineering

TIPPING POINTS Lung Cancer Biomarkers Present New Drug Targets

Much of the cellular machinery behind biological processes unique to cancer cells is run by a command and control system called signal transduction, which itself is partly controlled by a process called phosphorylation. When a protein is phosphorylated, it either becomes active or repressed, depending on its special function. Identifying the phosphorylation status of proteins in cancer cells versus normal cells provides a unique ability to understand and possibly intervene with the command and control center of cancer cells.

Professor Simon Kasif (BME), Assistant Professor Martin Steffen (BME, Boston University School of Medicine) and their collaborators have

identified several proteins whose activation signature—which indicates their phosphorylation status—enables scientists to distinguish between lung cancer and normal lung tissue cells with almost 97 percent accuracy. They have also developed a new computational strategy to analyze this data and identify specific subnetworks of biological pathways, or molecular circuits, which are active in cancer and dormant in normal cells.

The researchers’ findings may ultimately lead to the development of drugs designed to inhibit these proteins, particularly in lung cancer patients.

Professor

SIMON KASIF (BME)

“

We have identified proteins that distinguish lung cancer cells from normal lung tissue cells.

Collections of these proteins may serve as targets for future anticancer drugs.

”

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25

POINT-OF-CARE: Infectious Disease Diagnostics on a Chip

“

We’re developing robust, inexpensive, handheld plastic chips and devices that extract nucleic acids from complex human samples—technologies that could enable rapid, point-of-care diagnostics for infectious diseases and cancer without the need for electricity or refrigeration. These minimally instrumented systems could be a major step forward in facilitating molecular diagnostics in developing countries.

Associate Professor

”

CATHERINE KLAPPERICH (BME, MSE)

The robust, inexpensive, easy-to-manufacture microfluidic chips, cartridges and “instruments” that Associate Professor Catherine Klapperich (BME, MSE) is developing integrate sample preparation, amplification and detection using micron-sized, “micro solid phase extraction columns” to grab and concentrate nucleic acids from a few hundred microliters of blood or other bodily fluid. The instruments used to run these extractions require no electricity to power and will be built from locally available materials.

Associate Professor Catherine Klapperich (BME, MSE) and ME PhD student Jacob Trueb have developed a compact, inexpensive, bicycle-pump-powered, disease diagnostic device that extracts and analyzes DNA and viral particles obtained from blood samples.

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Saving Lives, Cutting Costs BU College of Engineering

The columns and chips could ultimately be used to collect and store nucleic acids from samples of blood, urine or other body fluids potentially infected with bacteria, a flu virus or another pathogen. The technology is also capable of isolating biomarkers necessary to diagnose, stage and monitor malignant tumors. It’s especially suitable for use in resourcelimited communities because the extracted genetic material does not require expensive refrigeration or electricity and the devices are portable and easy to use.

TREE WORK Probing the Lung’s Branching Airways to Improve Asthma Treatment

“

We are trying to understand how different structures throughout the airways change so that individual airways are capable of asthmatic hyper-constriction, and further which airways throughout the branching airway tree constrict most during an asthmatic attack. Through this understanding, we hope to identify potential therapeutic drug targets.

”

Professor KENNETH R. LUTCHEN (BME) Dean, College of Engineering

Affecting an estimated 20 million Americans and 300 million people worldwide, asthma remains an enigma. It is well-known that when the smooth muscle coating an asthmatic’s lung airways is exposed to an allergen, it “hyperconstricts” and makes breathing difficult. But scientists lack a complete understanding of the integrated mechanisms underlying this process.

To learn more about these mechanisms at the individual airway level, Professor Kenneth R. Lutchen (BME) uses ultrasound imaging to examine how isolated airway wall structures and simulated breathing forces modulate the ability of the airway smooth muscle to create sufficient force to hyper-constrict the airway. He then uses PET and Hyperpolarized MRI imaging to investigate how a real lung, comprised of hundreds of airways in a complex branching structure, constricts in asthmatic versus healthy subjects.

“By matching images of airways with a three-dimensional computer model of the lung, we determined that the smallest of airways contribute the most to constriction, and the worse constrictions tend to occur in localized clusters,” Lutchen says.

“Our next step is to use these findings to establish how asthma at the single-airway level leads to emergent clusters of very poorly ventilated clusters of airways during an attack.”

Three-dimensional computer rendering of the human airway tree. Colors represent distinct lobes.

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27

GETTING THE RIGHT DOSE Engineering More Effective Drugs for Lung Disease

Research Professor

MALAY MAZUMDER (ECE)

“

Dry powder inhalers administer drugs to treat diseases from asthma to lung cancer, but current inhalers suffer from many problems such as nonuniform blending, dose-to-dose variability and inefficient delivery of active ingredients.

We are developing new methods for formulating drug particles with an improved delivery system to meet critical clinical needs.

Designed to administer drugs to the lungs in the form of dry powder particles, dry powder inhalers require patients to inhale deeply, hold their breath and exhale at a prescribed rate. As a result, many respiratory disease patients—from very young children suffering from asthma or cystic fibrosis, to octogenarians with emphysema—end up with insufficient doses of medication.

In collaboration with Professor Mark Horenstein (ECE) and researchers at the BU Biomedical Engineering Department, Boston Medical Center and Harvard School of

Laser-based instrument used to analyze the therapeutic aerosol produced by dry powder inhalers

” 28

Public Health, Research Professor Malay Mazumder (ECE) aims to overcome this drawback. “Our goal is to develop a formulation so that despite a wide variation in inhalation flow rates, we can administer the drug successfully,” he says.

Toward that end, the researchers are engineering drug particles with diameters of one to three micrometers— the ideal size to reach the lung—and lactose “carrier” particles that prevent the drug particles from sticking together.

They expect the new formulation will lead to easier, more effective drug delivery for a wide range of patients.

Saving Lives, Cutting Costs BU College of Engineering

THE $100 GENOME Faster, Better, Cheaper Personalized Medicine

When it comes to genetic testing, today’s DNA sequencing technology is not ready for prime time. Because this technology typically relies on time-consuming, expensive, error-prone DNA replication tools, sequencing a human genome can take over one week and cost well over $5,000.

But a new DNA sequencing method advanced by Associate Professor Amit Meller (BME, MSE) that exploits solid-state nanopores—tiny, nearly cylindrical, silicon nitride sensors that optically detect DNA molecules as they pass through the pore—requires far fewer DNA molecules than conventional technologies, achieves greater accuracy, and may ultimately enable clinicians

to sequence an individual’s entire genome for as little as $100 in a matter of hours.

Combining optical detection capability with the ability to analyze extremely long DNA molecules with superior sensitivity, the team’s solid state nanopores are uniquely positioned to compete with the most advanced DNA sequencing methods for accuracy, cost and speed. Meller is collaborating with researchers from the University of Massachusetts Medical School in Worcester to refine his method, and founded NobleGen Biosciences in 2010 to commercialize the technology.

Professor

AMIT MELLER (BME, MSE)

“

We’re advancing rapid, accurate, inexpensive methods for amplification-free detection and sequencing of individual DNA molecules. Our research could vastly improve clinicians’ capability to diagnose patients’ susceptibility to certain diseases and tolerance for selected drugs.

”

Professor Amit Meller (BME, MSE) is advancing an ultra-fast, low-cost DNA sequencing method that uses electrically-based nanoscale sensors with optical readout.

bu.edu/eng

29

LOOK INSIDE Low-Cost, High-Res, Deep Imaging of Bodily Organs

Associate Professor

JEROME MERTZ (BME)

“

We’re developing new low-cost, highresolution imaging techniques using light to image inside tissue in the brain, colon and other organs.

”

30

A problem with using light to image inside tissue is that tissue is basically opaque, either absorbing or scattering most of the incoming light. To address this problem, Associate Professor Jerome Mertz (BME) has devised a number of strategies.

One technique he’s developed called HiLo microscopy “numerically rejects” out-of-focus haze that appears alongside what’s in focus in an image of tissue, resulting in a higher-contrast image. Using a normal image and one made noisy by using structured illumination, one can infer what is out of focus in the normal image, and then

numerically subtract it out.

Boston Medical Center gastroenterologist Satish K. Singh is now using a HiLoenhanced endoscope to examine fluorescently-labeled structures in colon tissue in search of signs of disease.

Mertz is also developing two label-free strategies to help clinicians pinpoint signs of pathology inside tissue.

One uses light to locally heat absorbing structures so they become easier to image; the other couples ultrasound with light to enhance highresolution imaging in thick tissue, with potential applications in imaging the colon and other organs.

Frame from video of chick embryo vasculature acquired with a fiber bundle endomicroscope. Left: Raw image through fibers. Middle: Sampling-corrected image. Right: HiLo image with out-of-focus background removed.

Saving Lives, Cutting Costs BU College of Engineering

ALL IN THE CARTILAGE Imaging Diagnostics for Bone Fracture Healing

“

We are developing a minimally invasive diagnostic technique to track the progress of healing of bone fractures.

The technique could help clinicians identify complications early and take measures to accelerate fracture repair.

”

Associate Professor ELISE MORGAN (ME, MSE)

Most bone fractures heal by forming cartilage at the fracture site. The cartilage becomes mineralized, eventually transforming into new bone tissue. Until bone forms at the facture site, however, fracture healing cannot be monitored in vivo using standard imaging technology.

“If we could see cartilage with an X-ray or CT scan, we could see much earlier than is currently possible whether or not the healing process is on track,” says Associate Professor Elise Morgan (ME, MSE). As a result, clinicians could apply early interventions when needed and better predict when a patient could resume weight-bearing activities.

To enable early assessment of bone fracture healing, Morgan has developed a CT-scanning technique that uses a contrast agent developed by Associate Professor Mark Grinstaff (BME, MSE) to label cartilage at the fracture site. “The technique provides a three-dimensional, time-evolving map of cartilage and bone that offers much more real-time feedback on treatment progress,” says Morgan, who is now testing the technique with researchers in orthopedic surgery through animal studies at Boston University Medical Center.

The new CT scanning technique allows researchers to see where and how much cartilage (shown in blue) has formed relative to the bone shaft (red). The new technique also identifies other soft tissue (yellow) that surrounds the bone fracture.

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31

OF LASERS AND LEDS Fighting Pathogens with UV Technology

Professor

THEODORE MOUSTAKAS (ECE, MSE)

“ ”

We’re developing handheld, deep ultraviolet (UV) lasers that could be used to analyze a patient’s blood at the point of care, and UV-LEDs that could immobilize certain viruses, including the avian flu virus, and thus be used to sterilize medical instruments.

32

Professor Theodore Moustakas (ECE, MSE) is developing two UV light technologies with applications ranging from military communication to biodefense. Made from aluminum gallium nitride alloys, they could collectively identify and neutralize potential pathogens.

The first, a handheld, electron-beam pumped semiconductor laser, is expected to be the first to operate within the deep UV region of the electromagnetic spectrum. Because of its ultra-low emission wavelength (below 250 nanometers) and compact size, such a laser could provide point-of-care

chemical analyses of blood or other bodily fluids. In collaboration with Associate Professors Roberto Paiella and Luca Dal Negro (both ECE, MSE) and industrial partners, Moustakas is developing a prototype sized below one cubic inch.

The second, highly energyefficient LEDs that emit light in the UV-C range (200-290 nanometers), may not only detect pathogens but also damage microorganisms’ DNA—and therefore be used for surface decontamination in hospitals. Nucleic acids in DNA and RNA absorb UV radiation within this range; a UV light source at 266 nm prevents an organism’s DNA and RNA from replicating, thereby killing it.

Professor Theodore Moustakas (ECE, MSE) inspecting the growth of nitride-based semiconductor materials.

Saving Lives, Cutting Costs BU College of Engineering

DATA-DRIVEN Algorithms for Better, Cheaper Healthcare

Despite spending about $2 trillion annually on healthcare, the U.S. recently ranked lowest among 19 industrialized countries in its rate of “preventable” deaths. But medical experts believe that a more proactive, data-driven healthcare management strategy could yield dramatic improvements in health outcomes and significantly lower costs.

To that end, Professor Ioannis Paschalidis (ECE, SE), Daniel Newman, Boston Medical Center (BMC) Chief Medical Information Officer Daniel Newman, and Shiby Thomas, BMC director of enterprise analytics, are pursuing a comprehensive and systematic approach to intelligently processing electronic health records (EHRs) and wireless

body sensor data, and directing physician attention to preventing serious medical conditions.

Paschalidis plans to apply data mining and optimization techniques to electronic, clinical practice data from the Boston Medical Center, associated insurance claims and information from wireless, wearable sensors to Professor produce algorithms that KENNETH R. LUTCHEN (BME) place Dean, patients in different College of Engineering risk-based clusters Professor (reclassifying them when IOANNIS PASCHALIDIS indicated by new data), (ECE, SE) provide a predictive model and physician-recommended actions specific to each We’re applying data cluster, and indicate optimum healthcare management mining and optimization approaches for specific techniques to electronic chronic conditions like health records and diabetes and heart disease.

“

wearable sensor data to produce algorithms that assess patients’ health risks and predict future healthcare needs. The automated, dynamic system that we’re developing could enable more effective preventative care and reduce overall healthcare costs.

”

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33

SOUNDING OUT TUMORS Combining Nanomedicine and Ultrasound for Targeted Cancer Therapy

Assistant Professor

TYRONE PORTER (ME)

“

My group combines nanotechnology and ultrasound to target solid tumors more precisely, both through novel drug delivery and thermal ablation techniques.

Treatment options for solid, cancerous tumors include surgery, which is invasive and often requires a lengthy recovery, and chemotherapy, which is damaging to healthy tissue, can compromise the immune system and produce other debilitating side effects.

Assistant Professor Tyrone Porter (ME) has developed two far less toxic techniques that combine nanotechnology and focused ultrasound to kill localized malignancies rapidly without damaging surrounding cells and tissues.

Developed with Boston University School of Medicine oncologist David C. Seldin, the first technique uses pressure-sensitive liquid nanodroplets loaded with cancer therapeutics. Small enough to leak through tiny openings in blood vessels

within solid tumors and accumulate in the interstitial space between cancer cells, the nanodroplets are vaporized with focused ultrasound, releasing their payload at the tumor site.

Porter’s second technique, developed in collaboration with Nathan McDannold, research director of the Brigham and Women’s Hospital/ Harvard Medical School Focused Ultrasound Laboratory, is to produce liquid perfluorocarbon nanodroplets that accumulate within solid tumors after being injected into the bloodstream.

Upon reaching the tumor site, the nanodroplets are vaporized noninvasively with highintensity focused ultrasound pulses, yielding bubbles that increase ultrasound absorption, producing sufficient heat to kill the cancer.

” Nanodroplets for delivery of therapeutic agents—a research collaboration between Assistant Professor Tyrone Porter (ME) and BU School of Medicine Professor David Seldin. (Image by of Aysegul Yonet)

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Saving Lives, Cutting Costs BU College of Engineering

AT THE TURN OF A DIAL Nanoparticle-Assisted Ultrasound for Tumor Imaging and Therapy

“

We combine nanoparticles with laser light and focused ultrasound to image tissue structures and/or thermally lesion tumors and other diseased tissue more precisely and reliably. These nanoparticles can be designed to adhere to specific tissue types, such as tumor cells, enabling tissue-specific targeted imaging and therapy.

”

Professor RONALD A. ROY (ME)

High-intensity focused ultrasound (HIFU) can project acoustical energy into tissue and generate localized heating at depth—literally “cooking” the region of exposed tissue. A key challenge in HIFU therapy is to accurately heat targeted tissue volume with minimal damage to surrounding tissue.

A solution devised by Professor Ronald Roy (ME) uses laser irradiated nanoparticles to promote small amounts of

acoustic cavitation, which helps convert acoustical energy into heat.

A single flash of laser light heats the particles, forming nanoscale vapor cavities that evolve into a cavitation bubble field when exposed to HIFU. The heated nanoparticles promote controlled cavitation production with greater precision and less ultrasonic energy. Laser irradiated nanoparticles can also be used in conjunction with short-pulse ultrasound to achieve photoacoustic imaging at depth.

“The advantage of cavitation is not to generate bulk heating, but an acoustic emission—which occurs when the bubble collapses,” says Roy. “We’ve shown that gold nanoparticles increase the acoustic emission response 100-fold over conventional photoacoustics, enabling much deeper imaging.”

Roy envisions an apparatus that switches from imaging (short acoustic pulses) to therapy (long pulses) mode at the turn of a dial.

Laser-irradiated nanoparticles can nucleate cavitation activity in the presence of high-intensity focused ultrasound, resulting in a substantial enhancement of acoustic emissions levels.

bu.edu/eng

35

GOING WITH THE FLOW Sound Wave-Driven, Microfluidic Biochips for Cancer Drug Discovery

“

Using the principles of sound, we create nano-earthquakes to mimic blood flow along the surface of microfluidic biochips. These chips are used in fundamental and applied research to advance novel approaches to treating cancer and other diseases.

Assistant Professor

MATTHIAS SCHNEIDER (ME)

Today’s cancer drugs target not only cancerous cells, but also many other fast-growing cells throughout the body, leading to weakened immune systems and other side effects in patients undergoing radiation and chemotherapy. But a new thumbnail-sized, acousticsdriven, microfluidic biochip developed by Assistant Professor Matthias Schneider (ME) and collaborators in Austria and Germany could help uncover new strategies for identifying more effective therapies.

Using surface acoustic waves (SAW) with amplitudes spanning a few molecules, the researchers pump minute amounts of liquid containing protein-coated microand nanoparticles toward cancer cells on the chip’s surface. Similar to pumping blood through arteries, the waves creates a flow in which the particles, designed to adhere exclusively to the cancer cells, are dispersed toward their targets.

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”

“These biochips will allow us to critically and objectively evaluate the efficiency of micro- and nanoparticle-based drug delivery vehicles,” says Schneider. “This is crucial, since identifying ineffective strategies is sometimes more important than finding new ones.”

Microfluidic SAW chips could be used in high-throughput experiments to critically evaluate old and new approaches to treating cancer and other diseases. (Source: Lab on a Chip)

Saving Lives, Cutting Costs BU College of Engineering

VACCINES ON-DEMAND High-Production Factory Extracts Medicines from Tobacco Plants

“ ” We have developed a tobacco plantbased vaccine factory that could be used for high-volume vaccine production to address pandemics and other time-critical public health needs.

Professor

ANDRE SHARON (ME)

When a future pandemic breaks out, public health officials may have a high-production vaccine factory at their disposal, thanks to researchers at the Fraunhofer USA Center for Manufacturing Innovation at Boston University.

Working with the Fraunhofer USA Center for Molecular Biology in Delaware and the biopharmaceutical company iBio, Inc., they’ve developed a fully automated “factory” that uses tobacco plants to produce large quantities of biological medicines within weeks.

This first-ever, plant-based vaccine factory exploits the tobacco plant’s well-understood, genetically engineered mechanisms for producing specific proteins within the leaves and stalks. The factory consists of a series of robotically tended machines that plant seeds, nurture growing plants, insert genetic instructions on what to produce, and harvest plants at maturity.

“Even though the process of making vaccines from plants is almost like farming, we treat it like an automated manufacturing process,” says Professor Andre Sharon (ME), director of the Fraunhofer Center at BU. “That’s how we can cost effectively scale it up from a few milligrams in laboratory demonstrations to many kilograms in case of a pandemic.”

Plant-based vaccine factory, developed by Fraunhofer/BU College of Engineering, consists of robotically tended machines that plant seeds, nurture growing plants, insert genetic instructions on what to produce and harvest plants at maturity. (Image courtesy of Fraunhofer USA Center for Manufacturing Innovation at Boston University)

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37

CAN YOU REPEAT THAT? Advancing Better Hearing Diagnostics and Aids

“

Our research introduces more precise measures of auditory processing impairments than are in use in today’s audiologists’ offices—measures that could lead to improved hearing diagnostics and hearing aid technology.

Professor

”

BARBARA SHINN-CUNNINGHAM (BME)

Overexposure to loud music is known to cause permanent hearing loss, but new research suggests that even before a typical audiological exam can detect the damage, such exposure may interfere with everyday communication.

An individual may have “normal hearing” based on standard tests that measure the quietest sound a person can hear, yet still have trouble understanding what her best friend is telling her at a crowded bar.

A study led by Professor Barbara ShinnCunningham (BME) indicates that the problem may lie in the “firstresponder” portion of the auditory system, which encodes the detailed structure of incoming sounds before the brain processes them further.

38

Until now, scientists didn’t know if this problem was due to impairments in the cortex, where decision-making and language processing occur, or earlier in the auditory system, where basic sensory information is first encoded. “Our results suggest that the fidelity of early sensory encoding in the subcortical brain determines the ability to communicate in challenging settings,” ShinnCunningham explains.

The study’s findings could lead to more effective hearing diagnostics and hearing aids.

In a recent study published in PNAS, Professor Barbara Shinn-Cunningham (BME) and her coauthors explored why some people with normal hearing have difficulty understanding conversations in complex auditory environments such as bars.

Saving Lives, Cutting Costs BU College of Engineering

SHAPE MATTERS A New Pathway to Anti-Cancer Drugs and Tissue Engineering

To interrogate its surroundings, a cell relies on twonanometer-wide receptors on its surface. These receptors are configured to bind to a fibrous protein matrix in the local microenvironment, but external forces can stretch this fiber, adversely impacting the receptors’ ability to latch onto it. As a result, the cell may miss out on vital information, such as instructions to cancer cells to stop proliferating.

To better understand the mechanisms behind this process, Assistant Professor Michael Smith (BME) is probing “nonequilibrium binding sites”—those perturbed by force—with a spectroscopic device called

FRET and an atomic force microscope (AFM). FRET is a nanoscale ruler that can determine if a protein has been stretched; the AFM is used to image the cell’s surroundings at nanometer resolution and detect binding sites that get exposed when the protein gets stretched.

By uncovering nonequilibrium protein conformations in the local cellular environment and their impact on cell signaling, Smith aims to identify new drug targets and approaches to stem cell-based therapeutics for regenerative medicine and tissue engineering.

Assistant Professor

MICHAEL SMITH (BME)

“

I’m interested in how forces change the shape, or conformation, of proteins that cells use to interrogate their surroundings—fibrous proteins that may ultimately be manipulated to grow desired stem cells or halt the spread of cancer. My main goal is to use advanced tools to investigate the impact of forces on these proteins at the nanoscale level.

”

The image illustrates how microfabricated surfaces and a spectroscopic tool can be used to understand protein behavior in a 1 micrometer diameter extracellular matrix fiber of fibronectin. Fiber stretching with the tip of a MEMS device is accommodated by unfolding of fibronectin molecules into nonequilibrium protein conformations. After release from the tip, the fiber relaxes back to its initial length through a process that involves molecular refolding into its equilibrium state. The green color in the fiber results from a nanometer scale spectroscopic label on the fibronectin molecules that provides information about the molecular conformation within the fiber.

bu.edu/eng

39

BREATHING FREE New and Improved Mechanical Ventilators

Professor

BELA SUKI (BME)

“

We are developing a technology to ventilate people in the ICU in an optimal manner so that they recover from acute lung injury faster. The technique has been tested in small and large animals, and it works very efficiently.

A potentially life threatening lung condition leading to low blood oxygen levels, acute respiratory distress syndrome (ARDS) requires admission to an intensive care unit and mechanical ventilation. But of the approximately 100,000 ARDS patients admitted to ICUs each year, only about 60 percent survive.

One reason is that the volume of air that conventional ventilators periodically deliver to the lung is fixed. “People don’t breathe that way,” says Professor Bela Suki (BME). “A biologically variable ventilator that mimics natural breathing and is optimized for presenting conditions— from pneumonia to organ

failure—would provide better oxygenation and lung function.”

In the past 10 years, Suki’s research group determined that variable ventilation improves oxygenation and stimulates lung cells to secrete surfactant, a lipidprotein mixture that’s critical for breathing. In collaboration with Boston (University) Medical Center pulmonary medicine specialist George O’Connor, Suki has modified existing human ventilators to deliver variable ventilation, conducted hundreds of animal tests in his laboratory and patented the technology. The next step is to obtain FDA approval and start a small clinical trial.

” Ventilator modified by Suki’s group to deliver variable ventilation.

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Saving Lives, Cutting Costs BU College of Engineering

LIFELINES, LITERALLY Engineered Blood Vessels for Reconstructive Surgery

One of the biggest problems in tissue engineering is the vascularization of engineered tissue. While skin grafts for a burn victim can wait long enough for blood vessels to grow into them, larger structures such as muscle and heart tissue need immediate access to blood vessels or they will die from lack of oxygen and nutrients.

To avoid this problem, Associate Professor Joe Tien (BME) is developing materials with engineered blood vessels already inside. Starting with a gel or polymer, he applies lithographic patterning methods from the integrated

circuit industry to carve out microfluidic networks in the materials that mimic the shape and size of real blood vessels.

Among other things, the technology could be a boon to blast victims in military theaters worldwide.

“Reconstructive surgery is quite advanced, but usually a surgeon takes tissue from one part of the body and transfers it to the other,” says Tien. “In severe cases, you need to replace a large volume of muscle or other tissue, and that’s where the biomaterials we’re developing could help.”

Associate Professor

JOE TIEN (BME)

“

We build biomaterials that contain internal channels that resemble the human vascular (blood vessel) system in scale and shape. Our objective is to provide reconstructive surgeons with new tools for forming complex threedimensional tissues that require immediate perfusion with blood.

”

Image of a collagen-based biomaterial that contains internal channels to guide the flow of blood. The pairs of “ports” shown at the top and bottom could, in principle, be surgically connected to the vascular system of a recipient in which the biomaterial is implanted.

bu.edu/eng

41

LABEL-FREE On-Chip Pathogen Detection with Interferometry

“

We are developing a nanoparticle detection technique/device with high sensitivity and specificity that provides rapid, chip-scale, low-cost detection of viruses and other pathogens. The technology could be used in infectious disease diagnostics and detection of potential bioterror agents.

Professor

SELIM ÜNLÜ (ECE, MSE)

Rapid, chip-scale, low-cost detection of viruses and other pathogens is key to containing outbreaks, but today’s biosensor technologies, which typically rely on fluorescent labels, are expensive and cumbersome. Labelfree biosensing devices avoid these drawbacks through advanced photonics technology, but often lack sufficient sensitivity to detect nanoscale viral particles.

Now a new, highly sensitive nanoparticle detection technique and device called Interferometric Reflectance Imaging Sensor (IRIS) developed by Professor Selim Ünlü’s (ECE, MSE) research

42

”

group in collaboration with Professor Bennett Goldberg (ECE, MSE) and Boston University School of Medicine microbiologist John Connor, promises to pinpoint single virus and other pathogen particles with greater speed, accuracy and affordability than existing label-free techniques.

To detect and size up to a million potential pathogens in parallel, IRIS shines light from multi-color LED sources sequentially on nanoparticles bound to the vast sensor surface, which consists of a silicon dioxide layer atop a silicon substrate. Light reflected from the sensor surface is modified by the presence of particles, producing a distinct signal revealing the size of each particle.

Conceptual representation of H1N1 viruses (blue) captured by antibodies (orange) on the IRIS surface. (Image courtesy of Aysegul Yonet)

Saving Lives, Cutting Costs BU College of Engineering

MISSED SIGNALS Finding New Cancer Drug Targets Where Proteins Combine

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We have developed algorithms to predict the structure of complexes formed by proteinprotein interactions involved in metabolic control, signal transduction, gene regulation and other critical processes. These algorithms could uncover new targets for drugs that combat cancer and inflammatory diseases.

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Professor SANDOR VAJDA (BME, SE)

An interdisciplinary team of College of Engineering faculty members—Professor Sandor Vajda (BME, SE), Research Assistant Professor Dima Kozakov (BME), Professor Ioannis Paschalidis (ECE, SE) and Associate Professor Pirooz Vakili (ME, SE)—are developing powerful optimization algorithms for predicting the structures of complexes that form when two cell proteins bond together— structures that, in some cases, generate erroneous cell signaling pathways that can trigger cancer and inflammatory diseases.

“Protein-protein interactions represent an increasingly important class of targets for the development of drugs,” says Vajda.

“Understanding the atomic details of the complex frequently provides a good starting point for finding small molecules capable of modulating biological function. Another important application is to biotechnology, where the accurate prediction of interactions between biologics such as engineered antibodies and their cellular receptors offers the basis for rational design.”

Many biologically important proteinprotein interactions produce fragile complexes that do not remain intact long enough to permit direct experimental analysis, but optimization algorithms such as those developed by the College of Engineering team

can determine the structure of these complexes with great accuracy based on the structures of the component proteins.

An interdisciplinary College of Engineering team has developed computational methods to predict the structures that form when two cellular proteins interact.

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HIGH CONTRAST Nanoparticle-Enhanced Imaging for Heart Disease Detection

Associate Professor

JOYCE WONG (BME, MSE)

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We are developing iron oxide nanoparticles as imaging contrast agents to facilitate the early detection of heart disease.

Vulnerable plaques are unstable structures in an arterial wall that could rupture in minutes to hours, leading to stroke, heart attack or pulmonary embolism. Associate Professor Joyce Wong’s (BME, MSE) goal is to develop magnetic resonance contrast agents—using 20nanometer-diameter iron oxide nanoparticles—to detect vulnerable plaques before they rupture. Aided by these nanoparticles, a physician could determine whether a plaque is likely to rupture and needs immediate treatment.

One of Wong’s collaborators, James Hamilton, professor of physiology and biophysics at

the Boston University School of Medicine and an affiliated faculty member in the Biomedical Engineering Department, developed a unique animal model for the study of triggered plaque rupture—a model that closely resembles the progression of disease in humans. By injecting imageenhancing nanoparticles into the arteries in these regions, physicians could examine plaques and determine potential rupture sites.

“Based on our research, we envision a noninvasive, diagnostic kit that a doctor could use to determine if a patient needs treatment for vulnerable plaques and subsequently monitor that treatment,” says Wong.

” By adding a marker to iron oxide particles, Wong aims to develop a noninvasive method for differentiating between stable and unstable arterial plaques in MRIs.

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Saving Lives, Cutting Costs BU College of Engineering

SIMPLE, CHEAP AND DURABLE Medical Technologies for Resource-Limited Countries

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We are creating computational and experimental tools to improve the quality of life and the practice of medicine in resource-limited countries. In this regard, we are working closely with the Center for Global Health and Development and various medical schools and engineering institutions around the globe to develop cheap, robust and easy-to-use solutions for improved diagnostics and health data analysis.

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Assistant Professor MUHAMMAD ZAMAN (BME)

For Assistant Professor Muhammad Zaman (BME), the effectiveness of a medical device depends not only on the technology but also its implementation. “Engineers need to be aware of who is going to use the technology they design and where it is going to be used,” he says. “A lot of technologies fail because they’re brilliant ideas but not context-specific.”

Informed by that perspective, Zaman and students in his Lab for Engineering Education & Development are advancing several fielddeployable medical technologies for resource-limited countries. They include a portable, microfluidic system that uses fluorescence-based

Design of a microfluidic system for counterfeit detection in the field.

sensors to detect counterfeit and substandard prescription drugs; a $20 cell phonepowered pulse oximeter that can measure blood oxygenation and screen for early signs of acute respiratory infection; and a simple technique that uses selected gels and other inexpensive materials to extend the shelf life of proteins, antibodies and other biological components needed for HIV and other medical tests.

“These devices are affordable, durable and easy to use, and address the particular needs of specific countries from Pakistan to Zambia,” says Zaman.

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BREAKING DOWN THE WALLS Biomechanical Model to Probe Cardiovascular Disease Mechanisms and Potential Therapies

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We’re developing and validating a biomechanical model of the vascular extracellular matrix, in order to probe basic mechanisms behind cardiovascular diseases and other vascular diseases, and design new therapies.

Assistant Professor

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KATHERINE YANHANG ZHANG (ME, MSE)

The leading cause of death in industrialized countries, cardiovascular diseases (CVDs) account for 40 percent of all U.S. deaths, more than all forms of cancer combined.

Many CVDs involve arteriosclerosis, or hardening of the arteries due to structural changes in blood vessel walls. To better understand the underlying physics of arterial stiffness associated with CVDs, Assistant Professor Katherine Yanhang Zhang (ME, MSE) aims to pinpoint the mechanisms that control structural and functional changes in blood vessel walls.

Toward that end, she is developing a biomechanical model of the vascular extracellular matrix, specialized proteins that provide structural support to blood vessels and the development of cells. Coupling molecular-level structural protein mechanics to tissue-level behavior, this multi-scale model could enable researchers and clinicians to probe basic mechanisms behind CVDs and other

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vascular diseases, and eventually design new therapies.

Ultimately, Zhang seeks to enable patient-specific clinical studies combining the multi-scale model and three-dimensional vascular anatomy imaging capabilities. “This should be useful in following disease progression, especially regarding the initiation and effects of arterial remodeling in CVDs,” she explains.

Saving Lives, Cutting Costs BU College of Engineering

COLOR-CODED Precisely Engineered Magnetic Resonance Imaging (MRI) Contrast Agents Using a Top-Down Approach

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We’re developing next generation, fabricated contrast agents for magnetic resonance imaging (MRI) which offer the potential of labeling and differentiating particular cells or tissues simultaneously using MRI. This capability could enhance cancer detection and characterization and improve monitoring of cell-based therapies.

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XIN ZHANG

Using a top-down, engineering approach to the fabrication of nano- and microparticles yields precise control of critical features such as size and shape.

Recently, this approach has been applied to optimizing drug delivery as well as developing novel MRI contrast agents.

Now a research team led by Professors Xin Zhang (ME, MSE) and Stephan Anderson, a radiologist at Boston University Medical Center, is further developing these approaches in the design of unique MRI contrast agents using biocompatible materials.

Professor (ME, MSE)

In collaboration with Anderson, Zhang and two students—graduate student Xiaoning “Travis” Wang and post-doctoral student Congshun Wang—have developed fabrication techniques using photo- and electron beam lithography employing biocompatible iron oxides to yield precisely engineered, magnetic nano- and microparticles. The precision engineering affords unique, tunable MRI “signatures” based on particle size and shape as well as the particular iron oxide used in fabrication.

The tunability of these MRI signatures offers the possibility of distinguishing various contrast particles simultaneously using MRI, and color-coding particular cells or tissues of interest.

Scanning electron micrograph images of arrays of microparticles of double-disk geometry (left) and nanoparticles of cylindrical geometry (right). These precisely engineered magnetic particles can serve as MRI contrast agents.

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RESEARCH CENTERS AND EDUCATIONAL PROGRAMS Healthcare technology is a major focus of several College of Engineering and Boston University-wide research organizations and College of Engineering educational programs.

Research Centers and Initiatives > Biomolecular Engineering Research Center bmerc-www.bu.edu > Boston (University) Medical Center bmc.org > Boston University Photonics Center bu.edu/photonics > Center for BioDynamics cbd.bu.edu > Center for Biophotonic Sensors and Systems bu.edu/cbss > Center for Global Health & Development/Global Health Initiative bu.edu/cghd > Center for Information and Systems Engineering bu.edu/systems > Center for Memory and Brain bu.edu/cmb > Center for Nanoscience & Nanobiotechnology nanoscience.bu.edu > Center for Neuroscience bu.edu/neuro/research/cfn > Computational Genomics Laboratory bu.edu/bme/research/labs/cg > Hearing Research Center bu.edu/hrc > Nanomedicine Initiative nanoscience.bu.edu/nanomedicine > Neuromuscular Research Center bu.edu/nmrc > NSF Smart Lighting Engineering Research Center at BU bu.edu/smartlighting > Wallace H. Coulter Translational Research Partnership bu.edu/bme/research/coulter/ Student Training and Research Programs > Global Health Initiative bu.edu/eng/links/ghi > CIMIT Healthcare Technology Prize cimit.org > Cross-disciplinary Training Program in Nanomedicine for Cancer (XTNC) nano-cancer.bu.edu > Engineers Without Borders http://blogs.bu.edu/ewbexec > GAANN Fellowship bu.edu/eng/links/gaann > Laboratory for Engineering Education & Development bu.edu/leed > Translational Research in Biotechnology Program bu.edu/eng/links/trbp

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Saving Lives, Cutting Costs BU College of Engineering

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Nanodroplets for delivery of therapeutic agents—a research collaboration between College of Engineering Assistant Professor Tyrone Porter (ME) and School of Medicine Professor David Seldin. (Image by Aysegul Yonet)