(158e) Engineering Advanced Bio-Interfaces for Stem Cell-Based Tissue Regeneration

My research interests lie in the fields of polymeric membranes, drug/gene delivery, tissue engineering and regenerative medicine. The main goal of my research program is to address the challenges in life sciences and medicine by using engineered materials-centered approaches and elucidating the mechanisms underlying material structure-property relationships, material-cell and cell-cell interactions. This presentation will particularly concentrate on the development of functional biomaterials-based 3D platforms and biodegradable electronic interfaces for stem cell-based regenerative therapies. We will initially discuss stem cell-based strategies to enhance peripheral nerve regeneration and will continue with the application of these strategies for central nervous system problems and muscle and skin regeneration.

The multipotent adult stem cells, obtained from various tissue resources, have demonstrated the ability to differentiate into specific cell lineages.¹ Because of the accessibility and multipotency, transdifferentiation of mesenchymal stem cells (MSCs) into Schwann cell (SC)-like phenotypes (the glial cells of the peripheral nervous system providing myelination and axonal regeneration) has recently been considered as a promising approach for peripheral nerve regeneration.¹ However, this approach has not widely transitioned into clinical use due to three main challenges: (i) non-scalable and reversible transdifferentiation protocols; (ii) lack of reliability in controlling the final fate of the implanted cell population; and (iii) challenges in designing a multifunctional conduit/scaffold platform that mimics the complex extracellular matrix microenvironment.¹ We have developed different strategies to overcome these challenges and make stem cell-laden functional biomaterials-based platforms/bio-interfaces a viable solution not only for peripheral nerve injury repair but also for other tissue regeneration applications. In the first part of my presentation, I will highlight a unique biomaterials-based approach to combine different functionalities into a single conduit system that enables cellular alignment, directional growth and mimicry of native SCs’ paracrine activity.^2-3 Then, I will proceed with discussing chemical stimuli-based MSCs to SCs transdifferentiation and emphasize the influence of 3D microstructural/mechanical properties of conduit platforms on MSCs behavior.⁴ As an alternative, I will introduce a novel, chemical or growth factor free, electrical stimuli-based method to transdifferentiate MSCs into SCs via inkjet or 3D printed conductive graphene-based microcircuit platforms.^5-7 Following this, we will discuss my current research efforts focusing on two novel electronic interface fabrication methods that allow room temperature processing and enable the use of various biodegradable substrate materials with controlled 3D microstructural/mechanical properties.^8-9 With these methods we can fabricate high resolution and low feature size microcircuit integrated, 3D microstructured and stem cell-laden hydrogels or biodegradable electronic interfaces to provide in situ and local control on stem cell transdifferentiation and fate commitment for both in vitro and potentially complex in vivo conditions through the synergistic effect of microstructural/mechanical and electrical cues. In the second part, we will discuss my future research plans focusing on the development of biodegradable electronic platforms and understanding cellular mechanisms behind the electrical stimuli-based stem cell differentiation and tissue regeneration. We will put a particular emphasis on the use of these platforms for muscle and skin regeneration along with nerve/skin and nerve/muscle reinnervation and interaction as well as the central nervous system problems such as spinal cord injuries, neurodegenerative diseases or retinal regeneration. These platforms have demonstrated promising results in controlling the conversion of adult stem cells into specific cell lineages and the potential to pave the way for different tissue engineering applications.

References:

1. Uz, M.; Das, S. R.; Ding, S.; Sakaguchi, D. S.; Claussen, J. C.; Mallapragada, S. K., Advances in Controlling Differentiation of Adult Stem Cells for Peripheral Nerve Regeneration. Advanced Healthcare Materials 2018, 7 (14), 1701046.
2. Sharma, A. D.; Wiederin, J.; Uz, M.; Ciborowski, P.; Mallapragada, S. K.; Gendelman, H. E.; Sakaguchi, D. S., Proteomic analysis of mesenchymal to Schwann cell transdifferentiation. Journal of Proteomics 2017, 165, 93-101.
3. Uz, M.; Sharma, A. D.; Adhikari, P.; Sakaguchi, D. S.; Mallapragada, S. K., Development of multifunctional films for peripheral nerve regeneration. Acta Biomaterialia 2017, 56, 141-152.
4. Uz, M.; Buyukoz, M.; Sharma, A. D.; Sakaguchi, D. S.; Altinkaya, S. A.; Mallapragada, S. K., Gelatin-based 3D conduits for transdifferentiation of mesenchymal stem cells into Schwann cell-like phenotypes. Acta Biomaterialia 2017, 53, 293-306.
5. Das, S. R.; Uz, M.; Ding, S.; Lentner, M. T.; Hondred, J. A.; Cargill, A. A.; Sakaguchi, D. S.; Mallapragada, S.; Claussen, J. C., Electrical Differentiation of Mesenchymal Stem Cells into Schwann-Cell-Like Phenotypes Using Inkjet-Printed Graphene Circuits. Advanced Healthcare Materials 2017, 6 (7).
6. Uz, M.; Donta, M.; Mededovic, M.; Sakaguchi, D. S.; Mallapragada, S. K., Development of Gelatin and Graphene-Based Nerve Regeneration Conduits Using Three-Dimensional (3D) Printing Strategies for Electrical Transdifferentiation of Mesenchymal Stem Cells. Industrial & Engineering Chemistry Research 2019, 58 (18), 7421-7427.
7. Uz, M.; Hondred, J. A.; Donta, M.; Jung, J.; Kozik, E.; Green, J.; Sandquist, E. J.; Sakaguchi, D. S.; Claussen, J. C.; Mallapragada, S., Determination of Electrical Stimuli Parameters To Transdifferentiate Genetically Engineered Mesenchymal Stem Cells into Neuronal or Glial Lineages. Regenerative Engineering and Translational Medicine 2019.
8. Uz, M.; Jackson, K.; Donta, M. S.; Jung, J.; Lentner, M. T.; Hondred, J. A.; Claussen, J. C.; Mallapragada, S. K., Fabrication of High-resolution Graphene-based Flexible Electronics via Polymer Casting. Scientific Reports 2019, 9 (1), 10595.
9. Uz, M.; Lentner, M. T.; Jackson, K.; Donta, M. S.; Jung, J.; Hondred, J.; Mach, E.; Claussen, J.; Mallapragada, S. K., Fabrication of Two-Dimensional and Three-Dimensional High-Resolution Binder-Free Graphene Circuits Using a Microfluidic Approach for Sensor Applications. ACS Applied Materials & Interfaces 2020, 12 (11), 13529-13539.