Intracranial aneurysms often remain stable over years; however, a ruptured aneurysm may cause subarachnoid hemorrhage and stroke. Clinical management of incidentally discovered unruptured intracranial aneurysms (UIA) is challenging because risk of rupture must be weighed against the risk of intervention. In current clinical practice, guidelines for assessing risk of an UIA rupture are based on its morphology and patient’s clinical history. While numerous studies indicate local blood flow forces can affect aneurysm growth and rupture, the translational value of these studies remains controversial. The Rayz Lab is funded by an NIH R01 award to develop a comprehensive methodology for UIA risk stratification, with a multidisciplinary team that includes Purdue biomedical and mechanical engineers, neurosurgeons from Barrow Neurological Center, and radiologists and MR imaging scientists from U.C. San Francisco and Northwestern. They work on developing a novel approach to enhance in vivo MRI flow measurements to obtain reliable patient-specific hemodynamic metrics related to vessel remodeling and aneurysm growth (Fig. 3). The methodology combines morphological, clinical, and flow-related risk factors; thus, improving accuracy of predicted aneurysm stability or growth. This project will result in quantitative analyses and data that can improve clinical management of cerebral aneurysms; thereby, bridging the gap between engineering and clinical communities. MR imaging data acquired by collaborators at medical institutions will be used to generate patient-specific computational and experimental models of intra-aneurysmal flow. Angiographic images are used to construct patient-specific vascular geometries to be used for computational fluid dynamics (CFD) modeling or in vitro measurements in 3D-printed flow phantoms. Measured or computed flow metrics are correlated to observed aneurysm progression. Fellows will help with processing MR images and constructing patient-specific flow models. They will be involved in image segmentation, 3D modeling and printing of the geometries, and basic numerical simulations of the flow with the open-source modeling platform SimVascular. Fellows will gain research skills related to 1) basic principles of MR imaging, image-processing and computational modeling, and 3) fundamentals of flow physics and biomedical transport.

Cardiovascular Disease Research

• Biomedical Engineering

Biomedical Engineering

Vitaliy Rayz

Lower-extremity peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis that affects more than 236 million individuals worldwide. Patients with PAD have a worse quality of life (QOL) than their healthy counterparts, due in part to the marked decline in physical functioning. Few non-invasive therapies currently exist to improve functional performance and restore QOL in people with PAD. Dr. Roseguini and his team are currently examining the benefits of home-based leg heat therapy (HT) on lower-extremity functioning and QOL in patients with PAD (Fig. 2). This novel approach consists of custom engineered trousers and a portable water pump. Hot water is circulated through the trousers, evenly heating the buttocks, thighs, and calf. This system is safe and convenient for application in a home setting without supervision. In a randomized, double-blind, sham-controlled clinical trial, PAD patients will be randomly assigned to one of two groups that either receive leg HT or a sham intervention. Participants randomized to the leg HT group will be asked to apply the treatment daily for 90 min using water-circulating trousers perfused with water heated to 42ºC. In the sham group, water at 33ºC will be circulated through the trousers. The primary study outcome is the change in 6-minute walk distance between baseline and the 12-week follow up. Performance on the 6-min walk test correlates closely with physical activity levels in the community and is linked to cardiovascular and all-cause mortality risk and the rate of mobility loss in patients with PAD. Secondary outcomes include performance on the short physical performance battery; handgrip strength; QOL (SF-36 and WIQ); and the morphology, fat content, maximal strength, and bioenergetics of the calf muscles as assessed using magnetic resonance imaging and phosphorus-31 magnetic resonance spectroscopy. Students will work in a multidisciplinary team composed of research coordinators, nurses, vascular surgeons, physicists, and biostatisticians. Fellows will be exposed to state-of-the-art techniques for assessment of walking performance, skeletal muscle function, and metabolism in PAD patients.

Cardiovascular Disease Research

• Biomedical Engineering
• Health Science PreProfessional
• Kinesiology

Health and Kinesiology

Bruno Roseguini

The Harbin Lab has identified a liquid, fibril-forming type I collagen polymer (oligomer) that under physiologic conditions forms collagen-fibril scaffolds with features of collagen scaffolds found naturally in tissues, namely D-banded ultrastructure, high mechanical stability, and slow turnover in vivo (high resistance to proteolytic degradation). This low-cost biologic can be formulated as an injectable, in situ scaffold-forming product with applications as a regenerative soft tissue filler [3, 11]. As purified collagen liquid that self-assembles, it is also amenable to scalable biomanufacturing where geometry, fibril architecture, and mechanical properties can be controlled and therapeutic cells and drugs readily encapsulated [12-16]. Driven by collagen-cell mechanochemical signaling, these materials show site-appropriate tissue regeneration by a paradigm shifting mechanism of action in which they persist, integrate, and support vascularization and site-appropriate tissue formation without evoking an inflammatory-mediated foreign body response. Collectively, these characteristics uniquely position oligomer as an enabling biopolymer for engineering advanced regenerative tissue replacements, including heart valves and vascular grafts that adapt and grow with patients.
The Harbin Lab aims to apply an integrative multi-disciplinary approach to the design, fabrication, and evaluation of functional and regenerative blood vessel and heart valve replacements. Students will apply and scale innovative collagen polymer device biofabrication methods informed by computational modeling, non-clinical performance testing (e.g., hierarchical structural analysis, multi-scale biomechanical and biotransport properties), and preclinical animal testing. Notably, previous undergraduate mentees have been integral to development and validation of this biomaterial platform. Alexis Yrineo, working under the co-mentorship of Drs. Goergen and Harbin, performed early preclinical studies demonstrating the potential of in situ scaffold-forming collagen to limit abdominal aortic aneurysm expansion, which led to a first-author publication, and an undergraduate design team won Best Senior Design Project for development of an early-stage prototype regenerative heart valve replacement for children with tetralogy of Fallot. Fellows will gain research skills related to 1) innovative fabrication of replacement tissues, including prioritization of multi-scale design specifications based on cardiovascular surgeon and patient needs; 2) biomechanical and in-flow performance testing using standard methods for material characterization; and 3) use of animal models and non-invasive imaging modalities for preclinical evaluation and testing.

Cardiovascular Disease Research

• Biomedical Engineering

Biomedical Engineering

Sherry Voytik-Harbin

Currently, clinical care for cardiac patients employs traditional tests that lack sensitivity, require hours to complete, or are invasive. While cardiac ultrasound can be used to visualize anatomical structures and heart dynamics [1, 2], it does not provide compositional or oxygenation information of tissue. Multispectral vibrational photoacoustic tomography (VPAT) imaging has the potential to quantify a variety of biological components, including lipids and both oxygenated and deoxygenated blood due to their unique wavelength-dependent excitations [3]. However, its utility for cardiac imaging has yet to be explored, largely due to temporal resolution being limited by the laser pulse repetition frequency. Fellows will assist in a multidisciplinary project to develop a retrospective gating imaging technique to overcome limitations in sampling rate by reordering VPAT and ultrasound images based on the appropriate cardiac time point (Fig. 1). The objective is to create a technique capable of acquiring 4D cardiac datasets to assess changes in tissue oxygenation and composition. The central hypothesis is that changes in cardiac oxygenation and lipid accumulation due to disease initiation and progression can be identified with a combined multispectral 4D VPAT/ultrasound technique well before any changes are observed with traditional ultrasound. Development of this multimodal imaging approach will provide a holistic view of the complex interplay between changes in cardiovascular morphology, hemodynamics, kinematics, and composition. Students will 1) work with graduate mentors to optimize the imaging system by quantifying signal-to-noise ratio, 2) analyze results via advanced image processing techniques, and 3) assess use of this approach using murine cardiac disease models. Fellows will gain research skills in multiple areas related to 1) medical imaging theory, 2) animal surgery, and 3) clinical treatments for myocardial infarction.

Cardiovascular Disease Research

• Biomedical Engineering

Small animal handling, image processing, coding

Biomedical Engineering

Craig Goergen

While angiography is typically performed using imaging techniques such as computed tomography or MRI, ultrasound provides an alternative means for cardiovascular imaging and is the fastest medical imaging modality. Ultrasound contrast agents (UCSAs) enhance the signal in a region by introducing pockets of significantly different impedance relative to the surrounding matrix. Most commercially available contrast agents create these impedance pockets by encapsulating air [17-20]. These agents create a large echogenic signal [17-20] because air has both reduced density and significantly different propagation properties than water. UCSAs are typically made by encapsulating a hydrophobic gas in a lipid monolayer [17, 21]. They can also be created via emulsification of a high density, hydrophobic liquid. One limitation of the emulsion-based agents is that they have lower contrast than gas filled agents and typically do not provide sufficient contrast for use in cardiovascular applications. Dr. Solorio’s lab has focused on developing liquid emulsion contrast agents composed of a protein shell that becomes highly echogenic after a thermocycling process in which the emulsion is heated and then cooled. After thermal cycling, they provide sufficient signal to allow detection in circulation and have shown enhanced echogenecity for at least 12 hours. Due to the stable nature of the nanoemulsion, the echogenic particles can be modified with targeting ligands to accumulate in inflamed tissues. These USCAs can be designed to deliver therapeutics in response to an external stimulus such as focused low frequency ultrasound. The research objective is to apply the novel contrast agents to study vascular pathology. USCAs will be used to 1) detect superficial plaque abnormalities such as ulcerations, 2) measure neovascularization of plaques, and 3) detect aneurysms. Fellows will gain research skills related to 1) understanding basic principles of ultrasound, 2) developing an understanding of the current limitations of contrast agents, 3) learning how to apply physical theory to clinically relevant systems, and 4) developing an understanding of contrast agent design.

Cardiovascular Disease Research

• Biomedical Engineering

Biomedical Engineering

Luis Solorio