BIOE: Hydrogels for drug screening and protein delivery applications
(sign-up)Dr. Silviya P. Zustiak, Assistant Professor, Department of Biomedical Engineering, Saint Louis University, St. Louis, MO
|Time:||11 a.m. - 12 p.m.|
2240 Digital Computer Lab, 1304 W Springfield Ave, Urbana, IL
|Event Contact:||Lisa Leininger
Department of Bioengineering
"Hydrogels for drug screening and protein delivery applications"
Hydrogels are soft crosslinked polymer networks that can contain as much as 99% water by weight. Because of their hydrophilicity, viscoelasticity, and low mechanical strength, they are ideal mimics of all soft tissues in the body. Furthermore, hydrogel matrices are capable of delivering protein drugs in a controlled manner, while preserving their structure and bioactivity. This presentation will focus on two main applications of hydrogels pursued by our laboratory - developing tumor spheroid models for drug screening applications and designing injectable hydrogels for protein delivery.
We focus on multicellular tumor spheroids to model avascular tumors with the goal providing a means for predictive high-throughput drug screening to enable breakthrough cancer therapies. Most commonly, spheroids are grown scaffold-free; while such spheroids mimic many morphological, functional, and mass transport features of naturally occurring tumors, they exist in an attachment-free microenvironment which does not resemble the mechanical, physical and biochemical properties of the native tumor extracellular matrix (ECM). To more faithfully mimic the native microenvironment, growth of tumor spheroids in a hydrogel matrix would be critical. Here, we developed a novel in vitro hydrogel-based tumor spheroid model by encapsulating cancer cells in uniform polyethylene glycol (PEG) microspheres produced by electrospraying. PEG hydrogels were prepared by Michael-type addition of 4-arm PEG-Ac and various dithiol crosslinkers. RGD-functionalized 4-arm PEG-Ac was also added to elicit cell attachment. Microspheres in size ranges of 70-400 µm with a low percent coefficient of variance of 6-18% were produced by manipulating electrospraying parameters. We were able to encapsulate various cell types at various cell densities (106-109) with high cell viability (>90%), pinpointing the broad utility of our fabrication method. In a subsequent step, cells encapsulated in biodegradable microspheres were encapsulated in a PEG hydrogel slab to create a templated hydrogel seeded with multicellular spheroids upon microsphere degradation. Current research is aimed at comparing the cell transcriptome of scaffold-grown and scaffold-free spheroids as well as the differences in spheroid behaviors and drug responses as a function of hydrogel encapsulation and hydrogel properties.
A similar PEG hydrogel chemistry and an electrospraying technology were used to fabricate degradable and injectable PEG microspheres for a multicomponent protein mixture delivery. Specifically, we focused on the sustained delivery of platelet-rich plasma (PRP), which is a concentrated assortment of growth factors and cytokines derived from the patient’s own platelets, for the treatment of knee osteoarthritis (OA). OA is caused by chronic inflammation and wearing of articular cartilage and affects over 50 million Americans. PRP therapy is already used as a direct injection in the clinic, because it has shown the potential to slow, reverse or halt OA progression. However, such bolus injections have shown mixed results due to a rapid clearance of the growth factors, a problem, which we believe would be greatly alleviated by a sustained-release PRP device. To develop such device, we first designed a library of dithiol crosslinkers, which allowed us to control hydrogel degradation between 10 hours and 32 days, while preserving its nanoporous mesh size of 9-14 nm. This enabled us to achieve a degradation- and diffusion-controlled release. Importantly, while PRP showed a burst bulk protein release, individual PRP proteins were released in a sustained fashion until complete gel degradation as shown by multiplex analysis. Sustained release was attributed to anomalous diffusion, possibly caused by interactions and obstruction by the gel, as determined by fluorescence correlation spectroscopy. Lastly, we evaluated the therapeutic effects of sustained PRP release from PEG hydrogels on primary articular chondrocytes. PRP released from hydrogels promoted chondrocyte growth in vitro and led to a significant reduction in gene expression for genes related to matrix degradation and upregulation of anti-inflammatory genes. Current work on this project focuses on the evaluation of the developed PRP-delivery device in cartilage explants and an in vivo osteoarthritis mouse model.
About the speaker:
Silviya Petrova Zustiak, Ph.D. joined the Biomedical Engineering Department at Saint Louis University as an Assistant Professor in spring 2013. She obtained a BS/MS degree in Bioelectrical Engineering from Technical University, Sofia, Bulgaria in 2002 and a Ph.D. in Chemical and Biochemical Engineering from the University of Maryland Baltimore County, MD in 2009. She conducted postdoctoral research in the Laboratory of Integrative and Medical Biophysics at the National Institutes of Health in Bethesda, MD. Dr. Zustiak’s primary research interests are in hydrogel biomaterials and soft tissue engineering, with emphasis on developing novel biomaterials as cell scaffolds and drug screening platforms, and elucidating matrix structure-property relationships as well as cell-matrix interactions. Her research is highly multidisciplinary, merging the fields of engineering, materials science, biophysics, and biology.
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