Control of gelation, degradation and physical properties of polyethylene glycol hydrogels through chemical and physical identity of crosslinker

Significance Statement

Hydrogels are of particular interest for a number of medical applications such as tissue engineering and drug delivery. This is owing to their highly hydrated tissue-like environment, superior biocompatibility, and excellent mechanical and physical attributes. Most of these applications demand hydrogels that can degrade under physiological attributes in a predetermined period. Previous work has indicated that by precisely controlling the polymeric chain network chemical structure and physical properties, degradation can be implemented to temporally tune drug release and to regulate cell growth and differentiation.

Several polymers as well as chemistries can be implemented to produce degradable hydrogels and tune their mechanical, biochemical, and degradation properties. Suitable selection of the macromolecular hydrogel precursors allows for tailor-made initial hydrogel attributes as well as the hydrogel degradation attributes to match a preferred application.

Polyethylene glycol is majorly studied for designing degradable hydrogels owing to its bio-inertness, excellent versatility, and biocompatibility. Unfortunately, polyethylene glycol lacks reactive functional groups, and hydrolytic and enzymatic degradation sites. Thus, end-functionalized polyethylene glycol derivatives with thiol, malemide, acrylate, and vinyl sulfone have been developed to allow for the formation of insoluble polyethylene glycol networks. These hydrogel networks can be further rendered degradable in physiologically relevant environments by the incorporation of various hydrolytically or enzymatically degradable sites, such as ester moieties or peptide-based crosslinkers.

Dr. Era Jain and colleagues at Saint Louis University investigated hydrolytically degradable polyethylene glycol hydrogels, and the function of the chemical structure as well as physical attributes of thiol-functionalized crosslinkers on polyethylene glycol hydrogel gelation and degradation. The main motivation of their research was that by selecting α, β, or γ-substituents of the thiol or ester moiety of the crosslinker, one could tune degradation or gelation of the resulting hydrogel. Their work is published in Journal of Materials Chemistry B.

The authors analyzed the relationship between the dithiol crosslinker chemical and physical structure and the resultant attributes of polyethylene glycol hydrogels produced through Michael-type addition reaction. Precisely, the authors correlated the dithiol crosslinker characteristics and chemical structure with gelation time, reaction rate constant, hydrolytic degradation rate, crosslink density, and storage modulus of polyethylene glycol hydrogels.

Through a vigilant selection of the dithiol crosslinker structure as well as physical attributes, the authors were able to generate an array of degradable hydrogels of different gelation, degradation rates and preceding hydrogel attributes. They realized that the hydrogel degradation times were related to gelation times, which indicated that degradation and hydrogel formation were dictated by the same attributes of the chemical structure of the dithiol crosslinkers.

The research team observed that dithiol crosslinkers with pKa<9 exhibited faster gelation and degradation times, while crosslinkers with pKa>9 had slower gelation and degradation times. In addition, they were able to tune the hydrogel modulus independent of degradation times. This was possible by choosing crosslinkers with varying physical properties.

This detailed evaluation of dithiol crosslinkers presented in the study can enable the design of dithiol crosslinkers, which can be implemented to realize hydrogels with tuned degradation rates, moduli, and swelling. This would also guide their implementation for numerous biomedical applications.

Control of gelation, degradation and physical properties of polyethylene glycol hydrogels through the chemical and physical identity of the crosslinker- Advances in Engineering

About The Author

Era Jain, Ph.D. is a research scientist at Washington University at St Louis. Prior to this she worked as postdoctoral associate at Biomedical Engineering at Saint Louis University, where she worked on developing biodegradable polyethylene glycol hydrogels for biomedical applications. She obtained a Bachelor’s degree in Pharmacy from India in 2004 and a Ph.D. in Bioengineering from Indian Institute of Technology of Kanpur (IITK), India in 2011. During her doctoral studies, she worked on developing macroporous scaffolds, namely cryogels, as bioreactor matrices for antibody production and as a bioartifical liver. Her primary research interests include development of novel biomaterial for drug delivery and for tissue engineering applications. Her work till date has produced 18 publications, 7 book chapters and 1 patent.

About The Author

Erin Canning graduated from Saint Louis University (SLU) in May 2016 with a Bachelor of Science degree in Biomedical Engineering and a Minor in Spanish. While a student at SLU, Erin completed a summer research internship at Illinois Institute for Technology through the NSF funded Research Experience for Undergraduates (REU) program in the summer of 2014.

Her research with the synthesis and characterization of hydrogels was selected to be presented at the 2014 Annual BMES Conference in San Antonio. Erin continued gaining experience with hydrogel characteristics in Dr. Silviya Zustiak’s lab in the Department of Biomedical Engineering at SLU. In addition to lab experience, Erin participated in a variety of organizations including the Society of Women Engineers, the Biomedical Engineering Society, Christian Life Communities and the Micah Program.

She joined peers in starting the Engineering Health Collaborative (EHC) at SLU, an organization that develops student leaders and interdisciplinary cooperation to improve global health through engineering. As the Vice President of Education for EHC, Erin organized events such as participation in Engineer’s Week at the St. Louis Science Center and “Under Pressure”, a blood pressure testing and education event during midterms and finals weeks. After graduating, Erin completed a year of service with the Jesuit Volunteer Corps, where she lived in a community and worked for and with the Dolores Mission community in East Los Angeles.

About The Author

Lindsay Hill is a Ph.D. student in the Department of Biomedical Engineering at Saint Louis University. She is currently working in Dr. Zustiak’s soft tissue engineering laboratory. She received her B.S. degree in Mathematics and Physics from Baker University in 2014. In 2012, she was a research intern in the Department of Mathematics at the University of Hawaii-Hilo. Her main research interests include cancer research and developing 3D in vitro cancer models as drug screening platforms.

About The Author

Scott A. Sell, Ph.D. is currently an Associate Professor of Biomedical Engineering in Parks College of Engineering, Aviation, and Technology at Saint Louis University. Prior to joining SLU in August of 2012, Dr. Sell received his education from Virginia Commonwealth University (BS in BME ’03; MS in BME ’06; and Ph.D. in BME in ’09), and spent three years conducting clinical tissue engineering research as a Polytrauma Research Fellow at the Hunter Holmes McGuire VA Medical Center in Richmond, VA.

Dr. Sell’s Tissue Engineering Scaffold Fabrication Lab focuses on the fabrication and evaluation of tissue engineering scaffolds capable of replicating both the form and function of the native extracellular matrix (ECM). Of principal interest is the fabrication of scaffolds capable of promoting wound healing and the filling of large tissue defects, as well as orthopaedic applications such as bone and intervertebral disc repair. Dr. Sell is also heavily interested in engineering and entrepreneurship education; having worked closely with both the Kern Entrepreneurship Education Network (KEEN) and the Coleman Foundation, and been selected to participate in the National Academy of Engineering’s Frontiers of Engineering Education Symposium in 2016.

Dr. Sell has over 65 peer reviewed publications, over 150 conference abstracts, and 3150+ citations of his work. He has also been the recipient of several prestigious awards during his time at SLU: the Association of Parks College Students Outstanding Faculty of the Year Award, Saint Louis University’s Junior Faculty Grantwinner Award for Excellence in Research, the Outstanding Graduate Faculty Award for Parks College, and Saint Louis University’s Outstanding Faculty Mentorship Award.

About The Author

Silviya Petrova Zustiak is an Assistant Professor in the Biomedical Engineering Department at Saint Louis University. She obtained a Bachelor’s and a Master’s degree in Bioelectrical Engineering from Technical University, Sofia, Bulgaria in 2002 and a doctoral degree in Chemical and Biochemical Engineering from the University of Maryland Baltimore County 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.

Reference

Era Jain, Lindsay Hill, Erin Canning, Scott A. Sell and Silviya P. Zustiak. Control of gelation, degradation and physical properties of polyethylene glycol hydrogels through the chemical and physical identity of the crosslinker. J. Mater. Chem. B, 2017, 5, 2679–2691

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