(6l) Rational Fabrication of Biomaterial-Based Scaffolds, Devices and Films for Tissue Engineering, Drug/Gene Delivery, Biomedical Processes and Flexible Electronics

Biodegradable Polymer-based Functional Scaffolds for Stem Cell Therapies and Tissue Regeneration:

Mimicking the complex 3D microenvironment of natural extracellular matrix is crucial to provide an available environment for cellular attachment, growth, proliferation, spreading, migration and differentiation.(1,2) Our research is concentrated on biomaterial design for stem cell-laden implantable scaffolds-based cellular therapies with a particular interest in stem cell differentiation targeting neuroregeneration. We uniquely integrated various physical and chemical cues on porous polymeric films, which possess longitudinal surface micropatterns and surface concentration gradient of neurotropic factors providing directed nerve growth as well as neurotropic factors loaded microparticles throughout the film matrix providing controlled release properties.(3) In addition, we demonstrated that the 3D microstructural and mechanical properties of the scaffolds has profound effect on stem cell differentiation.(4) Our results suggested that the scaffolds with larger pore size and higher porosity and possessing less stiff structure are providing the most favorable environment for differentiation of mesenchymal stem cells (MSCs) into Schwann cell-like phenotypes (SCs) via chemical induction. Recently, we have shown that the electrical stimuli applied through conductive graphene circuits developed on 2D substrates can be used as an alternative strategy for differentiation of MSCs into SCs.(5) This study selected as cover art for Advanced Healthcare Materials Journal, received Star Award from the Society for Biomaterials and resulted in provisional patent filing. Recently, we identified significantly regulated proteins and related cellular pathways upon transdifferentiation of MSCs into SCs via chemical stimuli.(6) This comparative proteomics analysis provided valuable information about specific proteins and pathways that play significant roles in myelination, axonal guidance, cytokine and growth factor secretion. Based on this background, we will focus on designing stem cell-laden, implantable, 3D bioprinted scaffolds to investigate material-cell and cell-cell interactions and in vitro and in vivo stem cell differentiation and neural regeneration. The future directions will be to serve the ultimate goal of making realistic 3D tissue models that mimic the actual cellular arrangement of a neural tissue using 3D bioprinting.

Nanoscale Drug/Gene Delivery System Design for Cancer Treatment and Theranostics:

Currently applied treatments for cancer, involving surgical cytoreduction followed by systemic cytotoxic agent chemotherapy, have not provided desired outcomes and resulted in chemo-resistance and tumor relapse.(7) As an alternative, RNA based therapies (microRNAs (miRNAs) and small interfering RNAs (siRNAs)) that influence major driver pathways in cancer development by directing sequence-specific degradation of target messenger RNAs (mRNA), have been proposed as a potential therapeutic for cancer treatment.(8) However, the potential clinical application of RNA therapy is limited by challenges related to delivery, stability, transport, diffusion, cellular entry, endosomal escape, efficient release and activity in the cytoplasm as well as the co-incorporation of drug molecules and RNAs in a single nano delivery device.(7,8) We have developed stimuli responsive polymer, peptide and inorganic nanoparticle based small interfering RNA (siRNA) delivery systems for cancer treatment. Our works have demonstrated that the pH and temperature responsive, cationic, amphiphilic and biocompatible multi-block copolymer-base systems are able to electrostatically condense and protect siRNA as well as providing enhanced cellular uptake and endosomal escape due to their temperature and pH responsive micellization enhancing the biological siRNA activity.(8) The cell penetrating and fusogenic peptide based peptideplex and conjugate systems are also alternative platforms for effective siRNA delivery.(9) We have also showed an efficient use of gold nanoparticles for theranostics and siRNA delivery applications.(8,10) The gold nanoparticle based multicomponent systems developed through subsequent layer-by-layer addition of siRNA and stimuli responsive polymer or cell penetrating and fusogenic peptide layers resulted in enhanced siRNA delivery and activity.(8,9,10) We have recently concentrated on developing nanoscale delivery platforms for co-delivery of siRNA and/or miRNA with chemotherapeutic drugs to target various intracellular pathways to reduce drug resistance and increase drug activity for ovarian and pancreatic cancer treatment.(11) As future direction, we will focus on the development of functional nanoscale delivery systems for efficient delivery of genome editing tools (Crispr-Cas9-sgRNA), along with chemotherapeutic agents for cancer treatment.

Design of Biomimetic, Polymer based Films for Biomedical Applications and Development of Biodegradable Flexible Electronic Films:

The objective of my research is to develop biomimetic synthetic membranes that are responsive to multiple external stimuli and exhibit selective transport capabilities, anti-fouling and self-cleaning features as in biological cell membranes. These bioinspired synthetic membranes are potentially promising for various biomedical applications including cell sorting, cell transfer, protein separation, hemodialysis and so on. We developed various polymer based membranes using dry or dry-wet phase inversion techniques and further carried out surface modification via layer-by-layer approach or surface chemistry. We developed nano/ultrafiltration membranes with enhanced surface properties to prevent chemical or biological fouling for waste water treatment applications.(12,13) We developed active agent incorporated polymeric membranes and developed different controlled release strategies (i.e. changing the membrane structure, incorporating nanoparticles in membrane matrix etc.) to provide sustained release, antibacterial activity and increase the shelf life of foods.(14,15) Recently, we have proposed bioinspired, biomimetic membranes functionalized through surface initiated atom transfer radical polymerization and protein localization to mimic selective separation, anti-fouling and self-cleaning properties of natural cell membranes for biomedical applications. This study received the Baxter Young Investigator Award. We will work on the development of functional polymeric films for biosensor and microfluidics applications. In alignment with these studies, another aspect of my current research is focused on developing biodegradable polymer based, 3D microstructured, flexible electronic devices/films using a novel approach coupled with 3D origami as an easy, fast, cost effective and green fabrication method. Our efforts for this study have resulted in submission of an invention disclosure and together with 3D bioprinting, it will be the main foundation of my future research endeavors. These flexible electronic devices hold promising potential to be used in various biomedical, tissue engineering and robotics applications. Thus, we investigate the biointerface of these devices for the purpose of microfluidics and organ/lab-on-a-chip applications for neural regeneration, which will be the main future directions.

Teaching Interests:

I am interested in teaching fundamental chemical and biological engineering principles and helping students understand how to use these principles in current technological problems. My teaching philosophy is based on embracing diversity/inclusion and using various learning methods such as, flipped classroom, problem, team and project-based learning, along with technological and online teaching tools in the class. I served as a teaching assistant for various chemical engineering undergraduate core courses and recently taught 3 credit chemical engineering undergraduate course “CHE 160: Chemical Engineering Problems with Computer Applications Laboratory” at Iowa State during 2015 Fall Semester. In addition to teaching core courses of chemical and biological engineering, I am also interested in curriculum development.

References:

1. Uz, M, and Mallapragada, S.K.; Smart Materials for Nerve Regeneration and Neural Tissue Engineering. Smart Materials for Tissue Engineering: Applications, Qun Wang (Ed.), Royal Society of Chemistry, 2017, pp.382-408. (Print ISBN: 978-1-78262-484-4)
2. J. Sandquist, M. Uz, A.D. Sharma, B.B. Patel, S.K. Mallapragada, D.S. Sakaguchi, Stem Cells, Bioengineering, and 3-D Scaffolds for Nervous System Repair and Regeneration: G.L. Zhang and L.D. Kaplan (Eds.), Neural Engineering: From Advanced Biomaterials to 3D Fabrication Techniques, Springer International Publishing 2016, pp. 25-81.
3. Uz, M., Sharma, A., Adhikari, P., Sakaguchi, D., and Mallapragada, S.K., “Development of Multifunctional Films for Peripheral Nerve Regeneration Conduits, Acta Biomat. (2017). Available online. https://doi.org/10.1016/j.actbio.2016.09.039
4. Uz, M., Buyukoz, M., Sharma, A., Sakaguchi, D., Altinkaya, S., and Mallapragada, S.K., “Gelatin-Based 3D Conduits for Transdifferentiation of Mesenchymal Stem Cells into Schwann-cell Like Phenotypes”, Acta Biomat., 53, 293-306 (2017).
5. Das, S.,^#Uz, M.,^# Ding, S., Lentner, M., Hondred, J., Cargill, A., Sakaguchi, D.S., Mallapragada, S., and Claussen, J., “Electrical Differentiation of Mesenchymal Stem Cells into Schwann Cell-Like Phenotypes using Inkjet Printed Graphene Circuits”, Healthcare Mater., 6(7), 1601087 (2017). Journal cover image. doi: 10.1002/adhm.201601087. (^# These authors put equal contribution)
6. Anup D. Sharma, Jayme Horning, Metin Uz, Pawel Ciborowski, Surya K. Mallapragada, Howard E. Gendelman, and Donald S. Sakaguchi; “Proteomics Analysis of Mesenchymal to Schwann Cell Transdifferentiation.”, Journal of Proteomics, June 2017, In Press, https://doi.org/10.1016/j.jprot.2017.06.011
7. Uz, M.; Altinkaya, S. A.; and Mallapragada, S. K.; Stimuli responsive polymer-based strategies for polynucleotide delivery. Journal of Materials Research, April 2017. (DOI: https://doi.org/10.1557/jmr.2017.116)
8. Uz, M.; Mallapragada, S. K.; Altinkaya, S. A., Responsive Pentablock Copolymers for siRNA Delivery. RSC Advances 2015, 5 (54), 43515-43527.
9. Metin Uz, Volga Bulmus and Sacide Alsoy Altinkaya; Evaluation of Cell Penetrating and Fusogenic TAT-HA2 Peptide Performance in Peptideplex, Multicomponent and Conjugate siRNA Delivery Systems. (Under review, draft manuscript available upon request)
10. Uz, M.; Bulmus, V.; Alsoy Altinkaya, S., Effect of PEG Grafting Density and Hydrodynamic Volume on Gold Nanoparticle–Cell Interactions: An Investigation on Cell Cycle, Apoptosis, and DNA Damage. Langmuir 2016, 32 (23), 5997-6009.
11. Metin Uz, Satyanarayana Rachagani, Surinder K. Batra and Surya K. Mallapragada; Dual Delivery Nanoscale Device for miR-345 and Gemcitabine Co-Delivery to Treat Pancreatic Cancer. (Under review, draft manuscript available upon request)
12. Uz, M.; Mahlicli, F. Y.; Polat, M.; Altinkaya, S. A., Characterization of Polysulfone Based Hemodialysis Membranes by AFM. Procedia Engineering 2012, 44, 1166-1167.
13. Metin Uz, Filiz Yasar Mahlicli, Erol Seker, Sacide Alsoy Altinkaya; Silver Release from TiO₂-nAgCl Xerogels Incorporated Mixed Matrix Ultrafiltration PAN Membranes in the Presence of Excess Chloride Ions: Long-term Silver Retaining, Biofouling Resistance and Antibacterial Activity. (Under review, draft manuscript available upon request)
14. Ozer P.B.B. ^‡; Uz M. ^‡; Oymaci P.; Altinkaya S.A, Development of a Novel Strategy for Controlled Release of Lysozyme from Whey Protein Isolate Based Active Food Packaging Films. Food Hydrocolloids 2016, 61, 877–886. (^‡These authors contributed equally to this work.)
15. Uz, M.; Altınkaya, S. A., Development of Mono and Multilayer Antimicrobial Food Packaging Materials for Controlled Release of Potassium Sorbate. LWT - Food Science and Technology 2011, 44 (10), 2302-2309.