Browsing by Author "Khan, Zerin Mahzabin"

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    Bubble cloud behavior and ablation capacity for histotripsy generated from intrinsic or artificial cavitation nuclei
    Edsall, Connor; Khan, Zerin Mahzabin; Mancia, Lauren; Hall, Sarah; Mustafa, Waleed; Johnsen, Eric; Klibanov, Alexander L.; Durmaz, Yasemin Yuksel; Vlaisavljevich, Eli (2021-03)
    The study described here examined the effects of cavitation nuclei characteristics on histotripsy. High-speed optical imaging was used to compare bubble cloud behavior and ablation capacity for histotripsy generated from intrinsic and artificial cavitation nuclei (gas-filled microbubbles, fluid-filled nanocones). Results showed a significant decrease in the cavitation threshold for microbubbles and nanocones compared with intrinsic-nuclei controls, with predictable and well-defined bubble clouds generated in all cases. Red blood cell experiments showed complete ablations for intrinsic and nanocone phantoms, but only partial ablation in microbubble phantoms. Results also revealed a lower rate of ablation in artificial-nuclei phantoms because of reduced bubble expansion (and corresponding decreases in stress and strain). Overall, this study demonstrates the potential of using artificial nuclei to reduce the histotripsy cavitation threshold while highlighting differences in the bubble cloud behavior and ablation capacity that need to be considered in the future development of these approaches. (E-mail: cwedsall@vt.edu) (C) 2020 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.
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    Characterization and structure-property relationships of an injectable thiol-Michael addition hydrogel toward compatibility with glioblastoma therapy
    Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Elsevier, 2022-05-01)
    Glioblastoma multiforme (GBM) is an aggressive primary brain cancer and although patients undergo surgery and chemoradiotherapy, residual cancer cells still migrate to healthy brain tissue and lead to tumor relapse after treatment. New therapeutic strategies are therefore urgently needed to better mitigate this tumor recurrence. To address this need, we envision after surgical removal of the tumor, implantable biomaterials in the resection cavity can treat or collect residual GBM cells for their subsequent eradication. To this end, we systematically characterized a poly(ethylene glycol)-based injectable hydrogel crosslinked via a thiol-Michael addition reaction by tuning its hydration level and aqueous NaHCO3 concentration. The physical and chemical properties of the different formulations were investigated by assessing the strength and stability of the polymer networks and their swelling behavior. The hydrogel biocompatibility was assessed by performing in vitro cytotoxicity assays, immunoassays, and immunocytochemistry to monitor the reactivity of astrocytes cultured on the hydrogel surface over time. These characterization studies revealed key structure-property relationships. Furthermore, the results indicated hydrogels synthesized with 0.175 M NaHCO3 and 50 wt% water content swelled the least, possessed a storage modulus that can withstand high intracranial pressures while avoiding a mechanical mismatch, had a sufficiently crosslinked polymer network, and did not degrade rapidly. This formulation was not cytotoxic to astrocytes and produced minimal immunogenic responses in vitro. These properties suggest this hydrogel formulation is the most optimal for implantation in the resection cavity and compatible toward GBM therapy. Statement of significance: Survival times for glioblastoma patients have not improved significantly over the last several decades, as cancer cells remain after conventional therapies and form secondary tumors. We characterized a biodegradable, injectable hydrogel to reveal structure-property relationships that can be tuned to conform the hydrogel toward glioblastoma therapy. Nine formulations were systematically characterized to optimize the hydrogel based on physical, chemical, and biological compatibility with the glioblastoma microenvironment. This hydrogel can potentially be used for adjuvant therapy to glioblastoma treatment, such as by providing a source of molecular release for therapeutic agents, which will be investigated in future work. The optimized formulation will be developed further to capture and eradicate glioblastoma cells with chemical and physical stimuli in future research.
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    Development of a Synthetic, Injectable Hydrogel to Capture Residual Glioblastoma and Glioblastoma Stem-Like Cells with CXCL12-Mediated Chemotaxis
    Khan, Zerin Mahzabin; Munson, Jennifer M.; Long, Timothy E.; Vlaisavljevich, Eli; Verbridge, Scott S. (Wiley, 2023-06)
    Glioblastoma (GBM), characterized by high infiltrative capacity, is the most common and deadly type of primary brain tumor in adults. GBM cells, including therapy-resistant glioblastoma stem-like cells (GSCs), invade the healthy brain parenchyma to form secondary tumors even after patients undergo surgical resection and chemoradiotherapy. New techniques are therefore urgently needed to eradicate these residual tumor cells. A thiol-Michael addition injectable hydrogel for compatibility with GBM therapy is previously characterized and optimized. This study aims to develop the hydrogel further to capture GBM/GSCs through CXCL12-mediated chemotaxis. The release kinetics of hydrogel payloads are investigated, migration and invasion assays in response to chemoattractants are performed, and the GBM-hydrogel interactions in vitro are studied. With a novel dual-layer hydrogel platform, it is demonstrated that CXCL12 released from the synthetic hydrogel can induce the migration of U251 GBM cells and GSCs from the extracellular matrix microenvironment and promote invasion into the synthetic hydrogel via amoeboid migration. The survival of GBM cells entrapped deep into the synthetic hydrogel is limited, while live cells near the surface reinforce the hydrogel through fibronectin deposition. This synthetic hydrogel, therefore, demonstrates a promising method to attract and capture migratory GBM cells and GSCs responsive to CXCL12 chemotaxis.
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    Development of an Injectable Hydrogel Platform to Capture and Eradicate Glioblastoma Cells with Chemical and Physical Stimuli
    Khan, Zerin Mahzabin (Virginia Tech, 2023-05-15)
    Glioblastoma multiforme (GBM) is the most aggressive type of primary brain tumor. Even after patients undergo maximum and safe surgical resection followed by adjuvant chemotherapy and radiation therapy, residual GBM cells form secondary tumors which lead to poor survival times and prognoses for patients. This tumor recurrence can be attributed to the inherent GBM heterogeneity that makes it difficult to eradicate the therapy-resistant and tumorigenic subpopulation of GBM cells with stem cell-like properties, referred to as glioma stem cells (GSCs). Additionally, the migratory nature of GBM/GSCs enable them to invade into the healthy brain parenchyma beyond the resection cavity to generate new tumors. In an effort to address these challenges of GBM recurrence, this research aimed to develop a biomaterials-based approach to attract, capture, and eradicate GBM cells and GSCs with chemical and physical stimuli. Specifically, it is proposed that after surgical removal of the primary GBM tumor mass, an injectable hydrogel can be dispensed into the resection cavity for crosslinking in situ. A combination of chemical and physical cues can then induce the migration of the residual GBM/GSCs into the injectable hydrogel to localize and concentrate the malignant cells prior to non-invasively abating them. In order to develop this proposed treatment, this dissertation focused on 1) characterizing and optimizing the thiol-Michael addition injectable hydrogel, 2) attracting and entrapping GBM/GSCs into the hydrogel with CXCL12-mediated chemotaxis, and 3) assessing the feasibility of utilizing histotripsy to mechanically and non-invasively ablate cells entrapped in the hydrogel. The results revealed that hydrogel formulations comprising 0.175 M NaHCO3(aq) and 50 wt% water content were the most optimal for physical, chemical, and biological compatibility with the GBM microenvironment on the basis of their swelling characteristics, sufficiently crosslinked polymer networks, degradation rates, viscoelastic properties, and interactions with normal human astrocytes. Loading the hydrogel with 5 µg/mL of CXCL12 was optimal for the slow, sustained release of the chemokine payload. A dual layer hydrogel platform demonstrated in vitro that the resulting chemotactic gradient induced the invasion of GBM cells and GSCs from the extracellular matrix and into the synthetic hydrogel with ameboid migration and myosin IIA activation. This injectable hydrogel also demonstrated direct therapeutic benefits by passively eradicating entrapped GBM cells through matrix diffusion limitations as well as decreasing the GBM malignancy and GSC stemness upon cancer cell-hydrogel interactions. Research findings revealed the hydrogels can be synthesized under clinically relevant conditions mimicking GBM resection in vitro, and hydrogels were distinguishable with ultrasound imaging. Furthermore, the synthetic hydrogel was acoustically active to generate a stable cavitation bubble cloud with histotripsy treatment for ablation of entrapped red blood cells with well-defined, uniform lesion areas. Overall, the results from this research demonstrate this injectable hydrogel is a promising platform to attract and entrap malignant GBM/GSCs for subsequent eradication with chemical and physical stimuli. Further development of this platform, such as by integrating electric cues for electrotaxis-directed cell migration, may help to improve the cancer cell trapping capabilities and thereby mitigate GBM tumor recurrences in patients.
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    Electroresponsive Hydrogels for Therapeutic Applications in the Brain
    Khan, Zerin Mahzabin; Wilts, Emily; Vlaisavljevich, Eli; Long, Timothy E.; Verbridge, Scott S. (Wiley, 2021-12-01)
    Electroresponsive hydrogels possess a conducting material component and respond to electric stimulation through reversible absorption and expulsion of water. The high level of hydration, soft elastomeric compliance, biocompatibility, and enhanced electrochemical properties render these hydrogels suitable for implantation in the brain to enhance the transmission of neural electric signals and ion transport. This review provides an overview of critical electroresponsive hydrogel properties for augmenting electric stimulation in the brain. A background on electric stimulation in the brain through electroresponsive hydrogels is provided. Common conducting materials and general techniques to integrate them into hydrogels are briefly discussed. This review focuses on and summarizes advances in electric stimulation of electroconductive hydrogels for therapeutic applications in the brain, such as for controlling delivery of drugs, directing neural stem cell differentiation and neurogenesis, improving neural biosensor capabilities, and enhancing neural electrode-tissue interfaces. The key challenges in each of these applications are discussed and recommendations for future research are also provided.