Transport in Engineering and Medicine (TEM) Research Areas

Two American Heart Association grants awarded to Dr. Banerjee focus on the important area of coronary stenoses (Figure 1) diagnostics, which, at present, is primarily dependent on angiographic evidence of stenosis rather than the more deterministic hemodynamic endpoints. This research is aimed towards improving the cardiovascular diagnostics using guidewires during heart attacks.

Pulmonary Valve Insufficiency (PI) as the name suggests is the malfunctioning of the pulmonary valve (PV). It is one of the long-term sequelae of surgical procedure to rectify Tetralogy of Fallot (TOF). TOF, also called blue-baby syndrome, is one of the most common congenital heart defects in children after infancy and is estimated to account for 10% of all congenital heart defects. TOF consists of four interrelated defects: i) Ventricular septal defect (VSD) which is the hole between right and the left ventricle, ii) Pulmonary stenosis which is the result of the stiffening of the pulmonary arteries, iii) Right ventricular hypertrophy which results in enlarged right ventricle as it takes the mail function to pump blood and (iv) Overriding Aorta, as the aorta is almost connected to right ventricle. Tetralogy of Fallot, has been successfully repaired for several decades and here are now an estimated 100,000 adult “repaired TOF” patients in the United States alone. As a result, long-term sequels of the disease and repair have become important clinical issue. Specifically, residual pulmonary valve insufficiency is one such accepted and often unavoidable sequel. Chronic pulmonary valve insufficiency (PI), when severe, abnormally alters the RV loading conditions, thereby triggering RV hypertrophy and dilatation. 

Hemodialysis vascular access dysfunction is one of the major causes of morbidity and hospitalization among the population undergoing hemodialysis procedure. Vascular access has three major types that include PTFE grafts, arteriovenous fistula (AVF), and catheters among which the AVF is the most preferred form due to its lower infection rate, lower risk of thrombosis, and higher patency rate. These advantages have made the AVF the first choice of the vascular access. However, failure of AVF to mature and formation of thrombosis in matured fistulas have been the major causes of morbidity and mortality in hemodialysis patients. Progression of stenosis, which occurs due to adverse remodeling in AVFs, is one of the major underlying factors under both scenarios. 

Aortic stenosis is a type of valvular heart disease that results from abnormal narrowing of the aortic valve opening. In the United States, the most common cause is degenerative calcification of the aortic valve. The occurrence of calcific aortic valve disease increases with age. A narrow aortic valve opening causes an increase in resistance to the flow of blood exiting the left ventricle of the heart. With the introduction of minimally invasive procedures like Transcatheter aortic valve implantation (TAVI), treatment options are now available for patients who have aortic stenosis and are considered to have high surgical risk. Therefore, accurate assessment of the severity of aortic stenosis is critical. The ambiguities and imprecisions of the current diagnostic parameters can result in sub-optimal clinical decisions. The figure below shows a normal aortic valve that fully opens and has normal thickness and a diseased aortic valve with a narrow opening and increased thickness.

We, at the TEM Laboratory, have a proposed a new diagnostic parameter called aortic valve coefficient (AVC) to improve the accuracy of the non-invasive diagnosis of aortic stenosis using Doppler echocardiography. The AVC is a non-dimensional parameter and is expected to better differentiate between the different grades of severity of aortic stenosis by simultaneously accounting for the variation in pressure drop and flow. An initial retrospective clinical study was conducted to test the feasibility of using AVC to diagnose aortic stenosis. The results of this initial study demonstrated the potential of AVC to improve the diagnostic accuracy of aortic stenosis. The TEM Laboratory is currently developing a methodology to accurately calculate the flow dynamics and the associated deformations of the aortic valve and aorta using computational models. The computational models will be used for detailed evaluations of AVC before proceeding to pre-clinical and clinical studies.

Abdominal aortic aneurysm (AAA) is the abnormal enlargement of the abdominal aorta. If left untreated, an AAA continues to expand until it ruptures. The rupture of an AAA can lead to severe internal bleeding. In the past open repair was the only available treatment which results in traumatic and stressful experience. In the recent years an alternative procedure has been developed where the stent-graft is introduced, via iliac vessels into the AAA site. If placed correctly, blood will flow through the stent-graft and relieve the stress on the AAA walls, which eventually heals in the due course of time.

In this Lab, computational fluid (blood)-structure (arterial wall) interaction technique for compliant arteries and grafts is used to investigate the pulsatile displacement forces on a stent-graft within an artery. This allows the determination of displacement forces translate into motion of the stent-graft. The velocity from the particle image velocimeter and pressure data can be used as the input boundary conditions for the blood flow-arterial wall computation. The forces from the computation are then compared with the experimental forces as recorded in-vitro model. Several different variations of stent-graft geometries are being studied. This research has being conducted in collaboration with Cleveland clinic foundation and Case Western Reserve University.

Figure shows the 3D geometry obtained from MRI images using image reconstruction. Figure shows the reconstructed geometry in an isometric view. Figure shows the speed and temperature contour plots for different arterial velocities. Increasing the blood flow rate from no flow to hyperemic flow (velocity = 41.4 cm/s) not only reduced the maximum temperature rise but also shifted the location of the maximum temperature rise. While the presence of blood perfusion is responsible for the reduction in maximum temperature rise, the large blood vessel is responsible for the shift in the location of the maximum temperature from the center. Thus, both blood perfusion in microvessels and proximity of blood vessels influence the temperature rise.

A 2D axi-symmetric model of the TLM with a pancreas tissue surrogate and container modeled as co-axial cylinders is as shown in the figure. A multi-phase heat transfer model is employed to solve for natural convection. The velocity vectors near interface section at the 5th minute of preservation obtained by numerical computation are as shown in the figure.

Whole body thermal modeling is a computational analysis technique to determine the temperature changes occurring within the human body under different environmental and physiologic conditions. Differences in the environment can include scenarios of extreme heat stress such as a fire fighting condition inside a building, or being immersed in cold water. Changes in the physiologic conditions can be caused by variable physical loads on the human body, including exercise scenarios, firefighting activities, skydiving (gravity effects), or deep sea diving (water pressure at increased depths of water). Being able to predict the temperature changes enables one to design or modify the appropriate clothing gear, determine the safe duration for each activity, and provide insights on the need and frequency for food or water replenishments.

The human body can be divided into multiple sub-domains such as the head, the muscle, and the internal organs. Each of these sub domains is assigned with their respective metabolism rate that generates body heat and blood perfusion. The blood perfusion assists in distributing the heat within the body. The interactions of these subdomains, their physiological parameters, and the immediate surroundings results in a complex interplay of heat transfer from the human body to the environment or vice versa.

Severe vision loss from vitreoretinal (VR) diseases such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), intraocular lymphoma (IOL), uveitis and proliferative retinopathy (PVR ) accounts for most cases of irreversible ocular diseases world-wide. Existing therapeutic procedures for treatment of VR diseases are limited as: 1) systemic drug therapy administered through mouth or injected into the bloodstream, and topical administration such as eye drops, fail to penetrate the physiological barriers; 2) intravitreal injections can lead to uneven drug distribution causing increased toxicity for non-target ocular tissues; and 3) in comparison to lipophilic (not water soluble) drugs, sustained release devices for hydrophilic (water soluble) drugs for treating VR diseases are difficult to fabricate, as these hydrophilic drugs do not bind well with existing FDA approved lipophilic materials.

At present, research is being conducted in developing a novel polymer-based biodegradable intravitreal micro-implant platform (Figure. 1) which administers therapeutic release of hydrophilic drug such as Methotrexate (MTX) over a period of more than 1 month. This study involves formulation and fabrication of the micro-implant drug delivery platform along with the in-vitro material characterization and pharmacokinetics analysis. The micro-implant has been further evaluated in vivo, in a limited number of rabbit eyes where it showed therapeutic release of the drug for > 1 month without any evidence of toxicity.

Oxygen is supplied to the avascular region of arterial wall by diffusion from the luminal blood and from the vasa vasorum. The abnormalities in this supply of oxygen are linked with the conditions of hypoxia or hyperoxia, which accelerates the human atherosclerosis by initiating a chain reaction of self sustaining metabolic abnormalities. The changes in the supply of the oxygen to the avascular arterial wall have always been a subject of research over the period of past few decades. This research aims at finding the oxygen concentration distribution in normal artery as well as its pathophysiologic counterpart. This includes i) various degrees of area occlusion representing a wide range of stenoses for ii) flow rates varying from basal to hyperemic conditions, and iii) effect of the viscosity changes due to hematocrit (Hct) variations. The coupled flow and oxygen transport equations in luminal blood flow and oxygen consuming arterial wall are solved and validated with previous studies. 

We have developed a pharmacokinetic model for monoclonal antibodies (mAb) to aid in investigating protocols for targeting small primary tumors or sites of metastatic disease. The model describes the uptake of systemically-administered antibody by a prevascular spherical tumor nodule embedded in normal tissue. The model incorporates plasma kinetics, transcapillary transport, interstitial diffusion, binding reactions, and lymphatic clearance. Antigen internalization can easily be incorporated. Simulations obtained from a three-dimensional finite element analysis are used to assess errors in predictions from earlier models in which the influence of the normal tissue was collapsed into a boundary condition at the tumor surface. The model employing a Dirichlet boundary condition substantially over predicted the mean total tumor mAb concentration at all times. Although the model with a concentration-dependent flux (composite) boundary condition under predicted mAb concentration, the discrepancy with finite element results is only notable at early times. Sensitivity analyses were performed on mAb dose and on the coefficients for mAb diffusion in the tissue regions, since reported antibody diffusivity values have varied over 30-fold. The results of the study suggest that mAb diffusivity and mAb binding site density in tumors should have major influences on optimizing doses and scheduling of mAb administration in tumor targeting protocols.

• Oxygen-dependent gene expression in microgravity
  • The bio-transport research under simulated microgravity conditions, such as those that would apply during a long-duration spaceflight, has the potential to improve understanding of the oxygen transport process, which becomes more complex as the arterial wall structure, e.g. endothelial cells and its biochemical compositions are altered. Earlier reports have documented physiological changes such as reduction in red blood cell (RBC) count, reduced pulsatile blood ejection rate from the heart, changes in blood volume and distribution within the components of the cardiovascular systems, and bone loss as the duration of spaceflight increases. These changes are adaptive processes, which were formerly attributed to reduced levels of metabolic activities and less demand for oxygen by the astronauts during long-duration spaceflights. Evaluation of the effect of simulated microgravity on altered demand for oxygen and metabolic activities has been limited. Even for terrestrial gravity (~1 g) condition, few data are available for oxygen transport in cells in conjunction with microcirculation. Cellular mechanics and oxygen-sensitive gene expression under simulated microgravity have been investigated and correlated to the patho-physiological changes that occur at the cellular and molecular (DNA, RNA, and Protein) level.
    
• Protein Study
  • Based on the microarray study, the present study is in the process of analyzing the activation of typical oxygen-dependent proteins, and to further identify the regulatory pathways and effector molecules using EMSA, Western blotting and ELISA. The results are now being analyzed and prepared to be submitted to a related journal.
• Computational Analysis of O2 Transport in RWV
  • The present study is to determine the appropriate suspension conditions for the microcarrier beads/cell distribution and evaluate oxygen transport and to validate the physio-chemical changes in the RWV bioreactor. The results are submitted to a related journal and now under review. This research is partially funded by NASA-Glenn: Microgravity Division.

Traditionally, fluid pumping techniques have been mainly based on using mechanical pumps that have different types and operation principles. Due to increased development in MEMs and Lap-on-chip (LOC) devices, there is a need to develop small-scale, reliable, and low-cost pump. One of the most promising pumping techniques is to use the electro-hydrodynamic (EHD) fluid pumping principle. This pumping technique is based on the fact that when an aqueous solution is brought into contact with a surface such as a channel wall, the surface will acquire a negative charge. The positively-charged ions in the solution will be attracted to the surface leading to a higher concentration of positive ions in its vicinity. The concentration of positive ions in the fluid bulk will be lower. When an electric field is applied between two points in the fluid, a bulk motion of the fluid occurs. This is known as electro-osmotic flow (EOF).

EOF has a unique feature that can suitable for LOC applications. EOF has a plug flow profile that can reduce sample dispersion. Also, for heat transfer in micro-channels, plug profile increases the amount of heat transfer due to the increase in the heat transfer coefficient.

I. Sample transport and micro-reactions control:  Research investigated controlled sample transport to micro-reactors where pinching and switching techniques were implemented. The research was conducted experimentally and was verified using numerical calculations. Nano-liter discrete samples were transported to a micro-reactor using EOF. The samples were allowed to react for a specific amount of time while their concentrations were monitored in the reactor. Sample pinching process is shown in Fig. 2. The lab is in the process of developing diagnostic devices for immunoassays that help detect biomolecules, cells, and pathogens in throughput screening. One such method of immunoassay is magnetophoretic separation that uses magnetic microbeads conjugated with antibodies against specific cell surface epitopes (antigens) and are used to tag cells of interest.

Analysis of liquid samples for pathogens and toxins is a crucial step to determining the quality of liquid, e.g. water, and how to most efficiently treat a particular water supply. Currently, analysis of liquid supplies for particular toxins is both expensive and time consuming. The analytical methods require the transport of samples to fully stocked labs where lengthy assays have to be performed to determine the concentration of a pathogen in the sample. However, through the use of functionalized magnetic microbeads, an electro-osmotic driven system, and an external magnetic field, it is possible to quickly analyze liquid samples for pathogen content.

We in the TEM Lab at the University of Cincinnati are working on developing an easy to use, portable, and efficient lab-on-chip device that can be used in the field to analyze liquid samples. We have developed a novel approach that a magnet and an electro-osmotic flow field to enhance the capture of microbeads in the channel. We ran experimental tests (Figure 1) to analyze the capture efficiency of the magnetic microbeads that confirmed our predictions regarding the effectiveness of flow switching. Through the use of microfluidic channels, we are able to efficiently capture targeted microbeads, and therefore the pathogens of interest, using an inexpensive, portable, and self-contained system. 

Hand arm vibration syndrome (HAVS) is a debilitating disorder which causes vasospasticity and vibration white finger (VWF) in the finger tissue of industrial workers who use hand held powered tools like chippers and grinders, repeatedly. Even though, HAVS is a mélange of musculoskeletal, vascular and sensorineural disorders, the vascular disorder has remained a subject of avid research in recent years and the knowledge of its early pathophysiology is still underappreciated. The ‘frequency weighting’ proposed by current ISO 2001 guidelines on vibration exposures, which places lower risk for vibration frequencies >100 Hz, has been criticized by researchers who have documented that high frequencies > 100 Hz, can potentially cause damage to vascular tissue. This has been validated using a rat tail model of vibration injury which exhibits a biodynamic response at these frequencies similar to that observed in a human finger tissue.

The principle investigator for the heat transfer research in bio-crystal is Professor Michael J. Kazmierczak (Ph: (513) 556-0259; e-mail: mike.kazmierczak@uc.edu).  The BioFHM lab is assisting in this effort and is a resource to this study. For further information, please contact Professor Kazmierczak.  

In this ongoing research a laser or an x-ray beam is used to heat a bio-crystal that is immersed in uniform external flow. Temperature distributions as well as local and average convective heat transfer coefficients are being calculated in order to evaluate the efficacy of cooling the bio-crystal.  This research extend previous studies by: applying unique heat sources imposed by irradiating the bio-crystal with an intense x-ray energy beam; performing the conjugate heat transfer analysis in fluid and solid domain; and calculating the internal and surface temperature distribution. Absorption of the irradiation results in non-uniform heat generation, having an exponential spatial distribution of heat source. The limiting cases of heat source distribution are localized surface “laser” heating and a near uniform heat generation throughout the bio-crystal.  Results that are being investigated are: the maximum internal temperature, the local and average Nusselt numbers (Nu). The diameter of the source beam striking the bio-crystal is varied (small and large) without altering the incident power.  This results in a significant change in the magnitude of the maximum temperature and an increased variation in the internal local temperature distribution within the bio-crystal. A bio-crystal having a high thermal conductivity maintains itself at a near uniform temperature resulting in a nearly constant average Nu over the range of heat source variation. However as the thermal conductivity decreases, the temperature distribution becomes more distinctive resulting in larger variations in local and surface integrated heat transfer rate, Nu and maximum temperatures.

The field of bioengineering is relatively new and complex including multiple disciplines encompassing areas in science and engineering. Efforts including the National Science Foundation (NSF) sponsored Integrative Graduate Education and Research Traineeship (IGERT) and VaNTH Engineering Research Center in Bioengineering Educational Technologies have been made to establish and disseminate knowledge and proven methods for teaching bioengineering concepts. Further, the summer bioengineering conference (SBC), sponsored by the American Society of Mechanical Engineers’ (ASME) Bioengineering Division, was established to provide a meeting place for engineering educators and students having common interests in biological systems. Of the many sub-disciplines of bioengineering, biotransport is a key subject that has wide applicability to many issues in engineering, biology, medicine, pharmacology, and environmental science, among others. The absence of standard content, guidelines, and texts needed for teaching biotransport courses to students motivated the Biotransport committee of ASME’s Bioengineering Division to establish a biotransport education initiative. Biotransport education workshop sessions were conducted during the SBC 2011, 2012, and 2013 as part of this initiative. The workshop sessions included presentations from experienced faculty covering a spectrum of information from general descriptions of undergraduate biotransport courses to very detailed outlines of graduate courses to successful teaching techniques. A list of texts and references available for teaching biotransport courses at undergraduate and graduate levels has been collated and documented based on the workshop presentations. Further, based on individual teaching experiences and methodologies shared by the presenters, it was noted that active learning techniques, including cooperative and collaborative learning, can be useful for teaching undergraduate courses while problem based learning (PBL) can be a beneficial method for graduate courses. The outcomes of the education initiative will help produce students who are knowledgeable in thesubject of biotransport, facile in applying biotransport concepts for solving problems in various application areas, and comfortable with their own abilities as life-long learners.