Past Projects

The University of Illinois at Chicago (UIC) has a substantial NIH-funded basic science and translational research mission focused on inflammatory as well as obstructive and restrictive pulmonary pathologies. This involves program (P01), project (R01), and training grants (T32) from NHLBI, NCI, NIBIB, and NIEHS related to diagnosis, treatment and mechanisms of lung cancer, radiation-induced lung injury, acute respiratory distress syndrome, sickle cell-linked acute chest syndrome, acute lung injury and transplant obliterative bronchiolitis. In this context, scientists are conducting animal and human subject studies leading to improved understanding of the mechanisms and methods for regulation of lung vascular and alveolar permeability and wound healing and repair as well as the lung’s interaction with innate immunity, and how these are affected by regional ventilatory changes and challenges. While much of this research benefits from advances in imaging at microscopic and macroscopic scales, in vivo and in vitro, current in vivo imaging tools are a limiting factor, particularly in terms of their inability to provide quantitative functional imaging of ventilation and gas exchange at the endothelial barrier with meaningful resolution. UIC also has significant expertise and shared instrumentation facilities for developing and conducting research utilizing magnetic resonance imaging (MRI) including a 30 cm bore 9.4 Tesla MRI for small animal studies and clinical (1.5 and 3 Tesla) MRI systems for large animal and human subject studies. Most MRI measurements are conducted based on proton (hydrogen atom 1H) imaging. Unfortunately, the lungs are the one soft tissue region in the body where 1H imaging suffers from such bad noise due to lack of signal that it is not considered of value in all but a few types of lung imaging protocols.  Over the past few decades hyperpolarized noble gas MR imaging, specifically 3He(lium) and 129Xe(non), has been shown to provide an attractive alternative for imaging of the structure of the airways. 129Xe has the added benefit that it dissolves within the blood stream and biological tissue with distinct chemical shift values relative to the gas phase and each other that are approximately 40 times higher than in proton based MRI. Therefore, the state of 129Xe, dissolved (in tissue or blood) or free, can be quantitatively differentiated with high resolution. This is invaluable in quantifying regional gas exchange, vascular permeability and transmembrane diffusion.  Recent technological advances have resulted in the availability of easily operated commercial systems for providing hyperpolarized 129Xe. We propose to acquire such a system, which will be used first and foremost to expedite and improve the outcomes of our ongoing NIH-funded animal-based pulmonary research described herein. Additionally, this device will be a resource available to other NIH-funded researchers at UIC, as well as at neighboring Rush University Medical Center, Jesse Brown VA, Northwestern University, Loyola University Medical School, and University of Chicago. Existing agreements between these institutions and UIC facilitate shared usage of core instrumentation.

https://projectreporter.nih.gov/project_info_description.cfm?aid=9274663&icde=45153341&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&pball=

It is believed that more than 300,000 people are born throughout the world each year with sickle cell disease (SCD). In the US alone, approximately 100,000 people, mostly of African background, are afflicted. While in many low-income countries, the majority die before five years of age, for those born in the US, 90% live to their late teens. Distressingly, this is followed by an increase in death rate for those in their early 20’s; overall, in the US, 50% of those with SCD die before they are 50 years of age.

While pain is the most common symptom of SCD and the leading cause of hospital admission, the acute chest syndrome (ACS), first described in 1979, is the second most common cause for hospitalization and a leading cause of death for those with SCD. ACS is an acute lung injury syndrome, classically defined by the development of a new pulmonary infiltrate on chest x-ray, with fever, and respiratory symptoms. About half of those with SCD will have at least one episode of ACS in their lifetime. For adults, it generally occurs 1 to 3 days after admission to the hospital for a severe painful vaso-occlusive episode, suggesting that the process may have already started while the patient was at home, but before there are sufficient indications for a positive diagnosis of ACS upon admission. Efforts have been made to apply various technologies in the hospital setting to diagnosis ACS or predict it sooner than an x-ray, but they are expensive, increase radiation exposure to the patient, require labs, and are not technologies that can be easily transferrable for home use to help with early diagnosis.

Acoustic crepitations have been noted when performing chest auscultation during ACS. Frequent severe wheezing episodes have also been correlated with SCD and ACS, and are considered a marker of the severity of the disease progression. It was thus hypothesized by our group that acoustical measurements recorded quantitatively with contact sensors, such as an electronic stethoscope, and analyzed using computational analysis methods amenable to mobile devices, such as a smart phone or simple wireless transmit/receive technology, may provide an earlier diagnostic indicator of the onset of ACS than is currently available. “Training” of computational algorithms building upon patient-specific baseline measurements may be a necessary pre-phase that could be developed as part of routine care and checkups at a SC clinic.

Our hypothesis therefore is that new acoustic analysis technology that will be inexpensive, portable, and able to give real time results, will detect pulmonary changes associated with the development of ACS in adults with SCD earlier than current methods. These findings would then form the basis for interventional trials to decrease the morbidity and mortality of ACS. Preliminary measurements and computational signal analysis to test the diagnostic hypothesis were performed by our group in the latter half of 2016. Initial results, summarized herein, support but do not rigorously validate our hypothesis and therefore motivate us to pursue the following aim.

The Specific Aim of this project is to rigorously test the hypothesis that the onset of the acute chest syndrome (ACS) in sickle cell (SC) patients can be detected sooner than current clinical practice allows by using a combination of routine vital sign measurements combined with advanced computational analysis of noninvasive acoustic (auscultative) measurements. If the hypothesis can be validated a comprehensive strategy for early diagnosis and monitoring of SC patients to identify ACS earlier could be developed. In this project we hope to refine and establish sensitivity and specificity of a simple point-of-care acoustic method, usable at home or in health care settings, and in low or no-resource settings, as well as high resource settings, to track the wellness of SC patients and to predict the potential development of ACS when it is early in or even prior to the prodromal phase in order to minimize pain, permanent damage and death.

Tissue engineering and regenerative medicine (TE/RM) is an evolving interdisciplinary field that integrates engineering with biology and medicine for the development of functional tissues and organs. Monitoring of tissues in vitro prior to implantation and assessment of tissues in vivo during development are both essential in order to optimize the regeneration of tissue and the restoration of organ function. Since direct visualization of developing tissues, i.e., tissue sampling via sacrifice or biopsy, is invasive and wasteful, one challenge in TE/RM is establishing non-invasive tools to monitor the development of the constructs in vitro and in vivo. In addition, visualization of the transitional region between the tissue implant and the surrounding tissues is critical to the establishment of the overall success of the procedure.MRI is increasingly being used in TE/RM to monitor the remodeling and regeneration of engineered tissues. Bioengineers can now generate spatial maps of MR relaxation times, diffusion coefficients, magnetization transfer ratios, and the shear modulus to monitor, for example, new bone growth for prosthetic therapy in TE/RM. We hypothesize that MR can be extended to monitor quantitatively the growth of engineered tissues including bone, fat, and cartilage. By its periodic application in vitro and in vivo MR can enable the much anticipated successes in TE/RM. Our preliminary data demonstrate that quantitative MR methods can be applied to characterize non-invasively the changes associated with adipogenesis, osteogenesis, and chondrogenesis in tissue-engineered MSC-based constructs. This in vitro work established that MR acquired data can be directly correlated with the underlying tissue composition and structure as measured by biochemical and histological techniques. Our long term goal is to extend these methods to assess the structure and function of developing, engineered tissues in vivo. In order to achieve this goal we have assembled an interdisciplinary team of imaging scientists, tissue engineers and clinicians. The proposed work forms a 4-year plan to establish useful clinical MR tools for the optimization of TE/RM specifically for chondrogenic tissues. The focus of the AVL team is to develop microscopic MR elastography for monitoring the development of engineered tissues, in vitro and in vivo.

Magnetic resonance elastography (MRE) is a phase contrast-based MR imaging technique for observing acoustic strain waves propagating in soft materials (e.g., biological tissues: brain, liver, kidney, muscle, as well as gels, polymers and composites). Mechanical shear waves, typically with amplitudes of less than 100 µm and frequencies of 100-500 Hz, are induced using either a piezoelectric or speaker coil oscillator directly coupled to the region of interest. By using multiple phase offsets and motion encoding gradients we acquire data that allows the generation of images that depict shear wave motion and the calculation of local values of the tissue viscoelastic properties. Current MRE studies using 1.5 T MRI systems are directed at establishing techniques for quantifying changes in the mechanical properties of tissues associated with developing disease: malignant tumors appear to be stiffer than benign tumors; fibrosis and cirrhosis tend to increase liver stiffness; and articular cartilage softens in developing osteoarthritis. Work to date suggests that MRE may in fact be able to detect both early stage and diffuse disease well before it can be visualized by conventional MRI, ultrasound or X-ray/CT techniques. Current MRE techniques may advance the understanding of soft tissue mechanobiology if the system spatial resolution is improved. Such micro MR elastography (µMRE) studies require stronger static fields, higher performance RF coils and gradients, and more compact, higher frequency mechanical actuators. The goal of the proposed exploratory/development project is to design, develop and validate a new high field (11.74 T) µMRE system (2 cm FOV), 5 kHz maximum shear wave frequency that will provide high spatial resolution (less than 100 µm3 voxel) for the measurement of shear moduli up to 2.5 MPa. These capabilities should allow µMRE to be used to evaluate the microstructure of complex materials and tissues, such as articular cartilage, and the micromechanical properties of tissue engineered constructs. The specific aims are: 1) Design and build a high resolution µMRE system that operates in the 10 mm diameter clear imaging bore available in an 11.74 T NMR spectrometer (500 MHz for proton); 2) Design, construct and evaluate new mechanical actuators suitable for higher frequency (up to 5 kHz) and multi-frequency shear wave excitation; and 3) Apply µMRE to investigate biological, polymer and composite materials at high spatial resolution.

The objective of this project is to develop an improved means of remotely monitoring changes in blood pressure on individuals engaged in strenuous ambulatory activity, such as fire fighters and combat personnel. This will be accomplished by developing and testing a superior sensor system that noninvasively measures blood pulse wave velocity.

The primary focus of the current application is to develop a new device for pneumothorax detection using computerized analysis of breath sounds. Pilot animal studies suggested that this approach may have high diagnostic power. The proposed human, animal, and mechanical experiments will utilize acoustic measurements and analyses that are designed to test feasibility, optimize the technique, and study audible-frequency acoustic wave behavior in the pulmonary system. Devices resulting from this technology are expected to be accurate, easy-to-use, radiation-free, inexpensive, rapid, portable, and safe. The long-term objective of this project is to develop techniques for the diagnosis of medical conditions using computer-assisted auscultation of body sounds. While the use of stethoscopes for medical diagnosis is common, this approach is skill dependent, can only provide qualitative information, and may suffer from inherent limitations of human ability to discern certain acoustic differences. The innovative nature of the proposed work is the implementation of simultaneous multi-sensor acquisition of body sounds combined with state of the art digital processing algorithms. The accumulated knowledge base and experience from the proposed work may be useful in developing a broad range of diagnostic technologies including cardiovascular, gastrointestinal, muscle, and joint applications. For example, earlier studies have suggested potential utility for diagnosis of such conditions as small bowel obstruction, pneumoperitoneum, vascular access compromise, coronary occlusions, and osteoporosis.

We will improve ultrasound (US) medical imaging technology by integrating a simultaneous noninvasive audible frequency measurement of biological sounds indicative of pathology. This multimode sonic / US imaging technique will advance diagnostic capabilities beyond the state-of-the-art and will be ideal for retrofit on existing systems. Measurement of naturally-occurring biological acoustic phenomena can augment conventional imaging technology by providing unique information about material structure and system function. Sonic phenomena of diagnostic value are associated with a wide range of biological functions, such as breath sounds, bowel sounds and vascular bruits. The initial focus of the technology and of this proposal would be to provide an improved diagnostic tool for common peripheral vascular complications associated with arteriovenous (AV) grafts. The specific aim of this R21 application is to develop and evaluate the capability of the proposed sonic / US diagnostic technology to track and predict AV graft failure.

The objective of the proposed research is to determine the role of fluid and solid stresses in the failure of ateriovenous (AV) dialysis grafts. The insights gained in this study will lead to significant improvements in the durability of AV grafts that are commonly used as a vascular access site for hemodialysis patients. Increased durability would reduce patient morbidity, pain and discomfort as well as reduce the cost of AV graft surgical procedures, currently one billion dollars per year in the United States alone. AV grafts often fail due to a flow limiting stenosis at the venous anastomosis caused by venous anastomotic intimal hyperplasia (VAIH). The AV circuit represents a unique hemodynamic environment in which transition to turbulence often occurs. High flow velocity and pressure fluctuations at the venous anastomosis induce vein-wall vibration. The level of vein-wall vibration has been correlated with VAIH in an animal model by previous researchers. However, the molecular and cellular cascade of events underlying VAIH and the importance of tensile stress and wall shear stress have not yet been examined. Our preliminary work shows that activity of mitogen-activated protein kinases (MAPKs) is increased in areas of elevated vein-wall vibration. MAPKs have been shown to be part of the complex cascade of intracellular signaling events that respond to shear stress stimulation in vascular smooth muscle cells (VSMC). This proposal is based on the hypothesis that biomechanical stimuli modulate VSMC proliferation and VAIH. The proposed research will determine the spatial distribution of biomechanical stimuli, VAIH, and the degree to which MAPKs are expressed.

This project, conducted in collaboration with researchers at Rush-Presbyterian-St. Luke’s Academic Medical Center, is for basic research to better understand how mechanical waves propagate in biological tissues in the audible (sonic) frequency range. In spite of the wealth of information present in this frequency range that can be of great diagnostic value, fundamental aspects of sonic frequency wave propagation in biological tissue are poorly understood. In this frequency range, compression, shear, surface and interlayer surface wave propagation can all be significant and highly dependent on tissue properties. Recent preliminary research by us has led to an improved understanding of this vibro-acoustic problem. Continued research will catalyze advancements in diagnostic procedures that are based on passive monitoring of biologically generated sounds as well as other procedures that involve actively exciting biological tissue and monitoring its response.

Our objective is to establish a new method for diagnosis and monitoring of bone injury, with particular application to the mandible. This new method will satisfy the constraints of portability, immediate results, ease of use (and training), and specificity. It is based on the use of vibro-acoustic wave propagation as a noninvasive, nondestructive measurement methodology. The essential hypothesis is that vibratory waves propagating through bone structure, such as the mandible, will undergo diagnostic changes that can be related to the amount of coupling or healing occurring across a fracture as well as the effective material properties of the non-fractured bone regions.

Vibratory signature analysis is utilized as an effective nondestructive evaluation technique for a ceramic composite bladed disk assembly (blisk). The blisk typically operates in a high-pressure LOX environment and experiences high dynamic loading; as such effective health monitoring is desired. Multiple blade-dominant vibration modes are examined to determine both blade frequency and damping parameters. From these parameters, correlations have been found with both manufacturing anomalies and accumulated environmental effects. Current interest is in quantitating accumulated environmental effects and extending this capability to accurate component life prediction.

Pneumothorax refers to air accumulation in the space between the lung and the chest wall. The many potential causes include spontaneous rupture of small alveoli or blebs, progression of inflammatory diseases, complications of diagnostic or therapeutic procedures, plus penetrating (e.g., knife or bullet) or blunt chest trauma (e.g., motor vehicle accidents). It is estimated that over 50,000 cases occur each year. Morbidity and mortality would be reduced with improved diagnosis of pneumothorax. We are developing an innovative technology for immediate and accurate detection of this condition using (audible frequency) sound waves. (This is not ultrasound, nor an imagining technology.) The essential hypothesis is that sound travels through chest structures differently when a pneumothorax is present, and that these changes are diagnostic. A diagnostic device based on this concept would be portable, inexpensive, safe, and easy to use.

The focus of basic research in this area is to finesse nonlinearity in transduction mechanisms used in adaptive, hybrid and active structural vibration control problems. Such transduction mechanisms are typically based on piezoelectric, electrostrictive or magnetostrictive principles. Specific issues being investigated include: a) developing accurate dielectric hysteresis models in piezoelectrics that can be employed in adaptive feedforward control schemes; b) investigating passive electrical shunting techniques for hysteresis compensation or augmentation for improved energy dissipation / vibration control; and c) investigating distributed, nonlinear tuned dynamic vibration absorption for improved structural vibration control.

This project is to develop an ultrasonic dental scaler with improved performance over existing technology at lower cost and with increased portability. Current ultrasonic scaler systems are too large, require plumbing and electrical utilities, and are a noise hazard to the dentist and patient. The quantum leap in technology will be achieved via one primary and several secondary innovations. The primary innovation is to replace the current nickel alloy ultrasonic motor with the most efficient and durable transducer material commercially available, Terfenol-D.

The focus of basic research in this area is to understand nonlinearity in transduction mechanisms used in adaptive, hybrid and active structural vibration control problems. Such transduction mechanisms are typically based on piezoelectric, electrostrictive or magnetostrictive principles. Specific issues being investigated include: a) developing accurate dielectric hysteresis models in piezoelectrics that can be employed in adaptive feedforward control schemes; and b) developing a fundamental understanding of vibratory energy generation, transmission and dissipation in complex smart structural systems with integrated transduction elements.

The general objective of this project is to develop an innovative technique for the immediate, painless, safe and low-cost diagnosis of patients with gastrointestinal perforation. The central hypotheses are that low frequency vibro-acoustic properties of the abdomen depend on abdominal contents and that free (extraluminal) air produces measurable differences in the vibro-acoustic response. Therefore, if known excitations are applied to the abdomens of perforated patients, response differences should be detectable by a vibro-acoustic sensor.

The soundboard of a harp must be highly flexible in order to convert vibratory energy in the strings to radiated sound energy. Yet, it must maintain its strength and static position over time under significant tension loads from the numerous taught strings. To meet these conflicting needs, harp soundboards are made by combining specific woods in a complex laminate structure. Nonetheless, soundboard warpage and fracture are still the primary failure modes of the harp. Advanced engineering composite materials for soundboard construction are being investigated as an improved alternative.

At the Advanced Photon Source (APS), a state of the art synchrotron radiation facility at Argonne National Laboratory (ANL), high precision, custom-designed positioning systems are needed to conduct a wide range of experiments utilizing the high brilliance x-ray beam. Precision and stability may be compromised by, for example, hysteresis in actuation mechanisms, vibrations from flow-structure interactions in cooling systems and from facility-based disturbances propagating through the floor. An ongoing project is to develop accurate computational design tools that predict the positioning precision and vibratory stability of proposed custom configurations and help the designer improve his/her design.