BIOMED PhD Thesis Defense

Title: 
Improving Liver Cancer Radiotherapy using Ultrasound-triggered Microbubble Destruction

Speaker:
Corinne Wessner, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisors:
Margaret Wheatley, PhD
John M. Reid Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University 

John Eisenbrey, PhD
Professor of Radiology
Sidney Kimmel Medical College 
Thomas Jefferson University 

Details:
Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) account for roughly 70% and 15% of all primary liver cancers, respectively. Additionally, metastatic disease to the liver (MDL) is cancer originating elsewhere in the body and traveling to the liver. The preferred curative treatment for these tumors is surgical resection or liver transplantation. Unfortunately, most patients are not eligible for these treatment options due to tumor burden, extrahepatic disease, or poor medical conditions. Locoregional therapies such as transarterial radioembolization (TARE) are essential in managing disease in patients with liver tumors. TARE is comprised of small glass beads encapsulating the radioisotope yttrium-90 (Y90). These glass beads are delivered to the liver tumor. Although Y90-TARE has been proven effective for downstaging disease, the treatment response after Y90-TARE is between 30-70% using standard criteria, highlighting the need for improvements in treatment response.  

Traditionally, treatment efficacy for Y90-TARE is determined by a CT or MRI scan 2-6 months post-treatment. Patients often have to wait 4-6 months to conclusively determine if the treatment is effective. An imaging technique that could be performed earlier than a CT or MRI is contrast-enhanced ultrasound (CEUS). CEUS uses small gas filled ultrasound contrast agents (UCA) (1-10 µm in diameter) that enhance ultrasound signals in the vascular system and has the capability to image in real time without ionizing radiation.  

A unique characteristic of a UCA is its ability to generate nonlinear responses at sufficient pressures. UCAs undergo oscillations, and at higher pressures produce bioeffects via inertial or stable cavitation. Cavitation-related bioeffects have been shown to produce endothelial cell apoptosis via a ceramide-mediated pathway. Endothelial cells are susceptible to stress, and when activated by inertial cavitation (i.e., ultrasound-triggered microbubble destructions (UTMD)), this destruction can mechanically perturb cell membranes of the tumor endothelial cells. This stress within the tumor vasculature leads to the upregulation of ceramide, leading to endothelial cell apoptosis. Consequently, one way to improve the therapeutic response in patients that receive Y90-TARE is to perform UTMD to increase the ceramide-induced endothelial cell apoptosis. 

The first aim of this thesis characterizes the safety and treatment response of localized UTMD to improve HCC response to Y90-TARE in a randomized clinical trial in 98 participants. The second aspect of this thesis focuses on translating microbubble-based radiosensitization into ICC and MDL participants that received 2D and 3D UTMD to evaluate feasibility, safety, and treatment response compared to historical controls. In this thesis, I found that UTMD is feasible and safe. Additionally, the patients that received Y90-TARE with UTMD had improved response rates compared to the patients who received Y90-TARE alone. Additionally, in the HCC cohort, the patients that received Y90-TARE with UTMD had prolonged survival compared to Y90-TARE alone patients. The last aim of this thesis was an analysis of quantitative CEUS to predict HCC response to Y90-TARE. CEUS could predict response in HCC as early as two weeks post Y90-TARE. Fractional tumor vascularity (FTV) showed a difference between nonviable and viable tumors at 2 weeks post-Y90-TARE. These findings have the potential to change clinical management and allow participants to potentially get retreated earlier. 

BIOMED PhD Research Proposal 

Title: 
A Graph Learning Framework To Identify Shared Genetic Drivers of Congenital Heart Defects (CHD) and Neuroblastoma

Speaker:
Benjamin Stear, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisors:
Deanne Taylor, PhD
Research Associate Professor of Pediatrics
Department of Biomedical and Health Informatics
Perelman School of Medicine
University of Pennsylvania 
Director, Bioinformatics Group
Children's Hospital of Philadelphia (CHOP)

Ahmet Sacan, PhD
Teaching Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University 

Details:
Congenital heart defects (CHDs) and neuroblastoma (NBL) are major contributors to pediatric morbidity and mortality, yet their genetic etiologies remain poorly understood. Converging evidence suggests a shared developmental origin rooted in neural crest biology, in which perturbations to early cell fate decisions and regulatory programs may give rise to both structural birth defects and pediatric malignancy. However, conventional approaches such as single-trait genome-wide association studies are limited in their ability to capture the complex, pleiotropic, and network-driven nature of these diseases.

This work develops an integrative framework to identify and characterize shared genetic mechanisms underlying CHD and NBL by combining whole-genome sequencing data with biological interaction networks and single-cell transcriptomic trajectories. Graph neural networks are used to prioritize disease-associated variants and genes within an interactome context, while network propagation and enrichment analyses map genetic burden onto neural crest gene regulatory networks to identify functionally relevant modules. To resolve temporal and cell state–specific effects, single-cell trajectory data are incorporated into a state-resolved graph, enabling the application of temporal graph attention models to infer how genetic perturbations influence developmental progression.

Together, this approach provides a systems-level view of pleiotropy by linking genetic variation to dynamic regulatory processes across development. The results are expected to uncover previously unrecognized disease-associated genes, identify critical developmental windows of vulnerability, and provide mechanistic insight into how disruptions in neural crest development give rise to divergent pediatric phenotypes. This framework offers a generalizable strategy for studying complex developmental diseases and advancing precision medicine in pediatric populations.

BIOMED PhD Thesis Defense

Title: 
Avidity-Controlled Biotherapeutic Delivery Systems for the Treatment of Acute Kidney Injury

Speaker: 
Arielle D'Elia, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisor:
Chris Rodell, PhD
Assistant Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Kidney disease affects over 800 million people worldwide and represents a major and growing global health burden. Acute kidney injury (AKI), which occurs in over 50% of critically ill patients and affects more than 13 million individuals annually, is a significant predictor of in-hospital mortality and a major driver of progression to chronic kidney disease (CKD). The progression from AKI-to-CKD is driven by persistent inflammation and immune dysregulation, including impaired recruitment and differentiation of regulatory T cells (Tregs), which are essential for resolving inflammation and promoting tissue repair. While therapeutic proteins such as cytokines and chemokines offer high specificity and biocompatibility for immune modulation, their clinical utility is limited by rapid clearance, burst release, and a lack of spatiotemporal control over signaling. These challenges motivate the development of biomaterial-based delivery systems capable of sustained and localized presentation of immunoregulatory cues.

To address these limitations, this work develops an injectable hydrogel platform for the avidity-based control of sustained biomolecule delivery. Supramolecular host–guest interactions between β-cyclodextrin-based hydrogels and adamantane-modified proteins were leveraged to control biomolecule retention and release through synthetically tunable avidity. Methacrylated β-cyclodextrin and dextran were co-polymerized to form mechanically robust hydrogels (G’ ~15 kPa), which were processed into injectable granular hydrogels exhibiting shear-thinning (>90% reduction in storage modulus under strain) and rapid self-healing (>95% recovery within seconds). This platform enabled precise control over release kinetics, where increasing guest modification (up to 10 Ad per protein) attenuated burst release and extended biomolecule delivery for greater than one month.

Building upon this delivery system, a dual-delivery immunomodulatory strategy was developed to recruit and program T cells in vivo. The chemokine CCL21 was selected for its ability to rapidly recruit CD4⁺ T cells, while adamantane-modified interleukin-2 (Ad-IL2) enabled sustained cytokine presentation to promote Treg differentiation and expansion. In vitro studies demonstrated that unmodified IL-2 exhibited rapid burst release (>90% release within 24 hours), whereas Ad-IL2 sustained release over 28 days while maintaining bioactivity. In vivo, subcutaneous delivery of CCL21 significantly increased CD4⁺ T cell recruitment within the first week, while Ad-IL2 increased Treg populations without inducing cytotoxic CD8⁺ T cell responses. Combination delivery of CCL21 and Ad-IL2 resulted in sustained expansion of Tregs within the hydrogel depot over 28 days, demonstrating the ability to coordinate immune cell recruitment and differentiation through temporally controlled signaling.

This system was applied in a murine model of bilateral ischemia–reperfusion injury, which recapitulates key features of AKI-to-CKD progression. Hydrogel-mediated delivery of combined CCL21 and Ad-IL2 significantly improved renal function, as evidenced by increased transdermal glomerular filtration rate (tGFR) and decreased neutrophil gelatinase-associated lipocalin (NGAL), indicating reduced kidney injury. Immunofluorescence analysis further demonstrated over a 20-fold increase in FOXP3⁺ regulatory T cells and more than a 3-fold increase in CD206⁺ reparative macrophages in the combination treatment group, consistent with a shift toward a pro-regenerative immune microenvironment. 

In conclusion, this work establishes a modular, supramolecular hydrogel platform capable of avidity-controlled biomolecule delivery to tune the release rate of multiple included biotherapeutics. In the context of kidney injury, this platform was applied for localized immune modulation to assuage kidney disease. By enabling the sequential recruitment and programming of T cells, this system promotes sustained Treg enrichment and mitigates inflammation-driven disease progression. More broadly, this approach provides a generalizable framework for the spatiotemporal control of therapeutic proteins, with potential applications across a wide range of inflammatory and regenerative medicine contexts.

BIOMED PhD Thesis Defense

Title: 
Altered Intrinsic Thalamic and Subcortical Functional Connectivity in Temporal Lobe Epilepsy with Focal-to-Bilateral Tonic-Clonic Seizures

Speaker: 
Stacy N. Hudgins, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Advisor:
Hasan Ayaz, PhD
Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Details:
Epilepsy is a debilitating neurological disorder affecting over 50 million people worldwide. In temporal lobe epilepsy (TLE), seizures typically arise from a mesial temporal epileptogenic zone and remain focal, yet a substantial subgroup develops focal-to-bilateral tonic-clonic seizures (FBTCS), which confer heightened risk for sudden unexpected death in epilepsy (SUDEP), cognitive decline, and poor surgical outcomes. The intrinsic thalamic and subcortical network mechanisms that support seizure generalization—particularly their dependence on seizure onset laterality and clinical utility as biomarkers—remain poorly defined.

This dissertation tested the hypothesis that TLE patients exhibit laterality-dependent disruptions in intrinsic thalamic and broader subcortical functional organization that distinguish FBTCS+ from FBTCS− patients and index seizure generalization propensity. Resting-state functional MRI data were acquired from 166 TLE patients (120 FBTCS+, 46 FBTCS−; 71 right TLE, 95 left TLE) and 119 healthy controls. Functional network connectivity (FNC) and graph-theoretic analyses quantified clustering coefficient (segregation), degree centrality (hubness), local efficiency (integration), and intrinsic connectivity contrast (ICC; cross-hemispheric balance) across 16 bilateral thalamic regions (Aim 1) and 27 bilateral regions per hemisphere spanning 7 subcortical structures (54 total ROIs) encompassing thalamus, hippocampus, amygdala, caudate, putamen, globus pallidus, and nucleus accumbens (Aim 2). Support vector machine (SVM) classification evaluated the discriminative value of connectivity features versus clinical features (age, sex, seizure onset age, duration, education) for FBTCS status prediction (Aim 3).

Aim 1 (intrathalamic network reorganization) revealed reduced cross-hemispheric ventral anterior (VA) thalamic connectivity in TLE versus controls, with more pronounced ipsilateral VA dysfunction in right compared to left TLE. FBTCS+ patients demonstrated reduced right dorsal posterior local efficiency. Critically, only right-TLE FBTCS+ patients exhibited impaired cross-hemispheric connectivity from ipsilateral VA that worsened with illness duration, implicating a laterality-specific mechanism of thalamic disruption in seizure generalization.

Aim 2 (subcortical network topology) identified six bilateral subcortical subnetworks in TLE, with right TLE exhibiting more extensive topological alterations than left TLE. FBTCS+ patients showed reduced clustering coefficient (CC; segregation) in the left ventroposterior lateral thalamus, left ventral anterior caudate, and right ventroposterior putamen (β ≤ −0.087, p ≤ .036), consistent with thalamo-striatal desegregation. Right TLE patients with FBTCS history presented with more pronounced subnetwork derangements that included increased intrinsic connectivity contrast (ICC; cross-hemispheric connectivity) in bilateral nucleus accumbens, a pattern heightened with recent FBTCS and absent in left TLE. Temporal stratification of FBTCS+ patients into current (≤1 year) versus remote (>1 year) subgroups revealed that nucleus accumbens cross-hemispheric abnormalities tracked with recent seizure burden (state-dependent marker), while thalamo-striatal segregation reductions persisted regardless of FBTCS recency (trait-like marker).

Aim 3 (machine learning classification) provided proof-of-concept evidence that SVM classification using subcortical connectivity features captured complimentary FBTCS-related variance partially independent of standard clinical features, with cross-validated AUC values ranging from 0.519 to 0.769 across models. Overall discrimination was modest and laterality dependent. In left TLE, connectivity features outperformed clinical features (AUC 0.648 vs. 0.519); in right TLE, clinical features significantly outperformed connectivity (AUC 0.769 vs. 0.685; DeLong Z = 2.48, p = .013), and combined models did not improve upon clinical features alone (combined vs. clinical, RTLE: Z = 4.14, p < .001). Ventroposterior thalamus and nucleus accumbens emerged as top connectivity discriminators. Because connectivity features were pre-selected from full-sample rmMANOVA contrasts and z-score normalization was applied to the pooled SVM cohort prior to fold partitioning, reported AUCs reflect apparent rather than fully held-out performance and may overestimate generalization. The classification analysis is therefore presented as exploratory.

Taken together, subcortical connectivity abnormalities in TLE involved organized limbic-thalamo-striatal subnetworks rather than isolated regional effects, with state-dependent Nucleus Accumbens effects dissociable from trait-like thalamo-striatal markers. Connectivity features provided complementary, proof-of-concept discriminative information with laterality-dependent performance: connectivity outperformed clinical features in left TLE, while clinical features outperformed connectivity in right TLE, and combined models did not uniformly improve classification beyond clinical variables. These intrinsic brain signatures motivate continued investigation as candidate FBTCS risk-stratification biomarkers and implicate targets for personalized medical treatment, pending nested-cross-validation replication and prospective external validation. 

The School of Biomedical Engineering, Science and Health Systems is pleased to announce its 8th Annual Immune Modulation & Engineering Symposium (IMES).