Nanotechnology and Tissue Engineering: Hope or Hype?

NEW HORIZON WORKSHOP Nanotechnology and Tissue Engineering: Hope or Hype? Organizer: Elizabeth Loboa, PhD Speakers: Elizabeth Loboa, PhD Molly Stevens, PhD Joachim Kohn, PhD

NEW HORIZON WORKSHOP: Nanotechnology and Tissue Engineering: Hope or Hype? Educational Goals: The use of electrospun, nanofibrous, biomimetic scaffolds for tissue engineering applicationshas skyrocketed in the last decade. This workshop will focus on tissue engineering advancements as a result of this technology with specific discussion on the benefits and challenges for clinical implementation of these biomaterials. Results and Outcomes: Advanced understanding of how nanotechnological approaches can enhance and advance musculoskeletal tissue engineering; active discussion by speakers and participants on state of the art in this area; critical evaluation of challenges. Benefit to meeting attendees for this workshop: Biomimetic, nanofibrous materials have been touted in many publications as key to successful musculoskeletal tissue engineering. Understanding and critical evaluation of the creation and implementation of these materials in vitro and in vivo will benefit both scientists and clinicians interested in using such materials for musculoskeletal tissue engineering applications. Moderator and Speaker: Elizabeth G. Loboa, Ph.D. Nanofibrous Scaffolds for Tissue Engineering and Drug Delivery: Advancements and Challenges The extracellular matrix is an intricate material comprised of protein fibers that range in size from 10 to several hundred nanometers. This nanofibrous protein mesh provides binding sites for cell adhesion and has also been shown to regulate cell shape, migration, growth, and differentiation. Due to increased understanding of the critical roles that nanofiber morphology and functionalization play in regulating cell response, the development and use of biomimetic nanofibrous scaffolds for drug delivery and tissue engineering have skyrocketed in the last decade. The Loboa lab has created and evaluated biocompatible, biodegradable, electrospun nanofibrous scaffolds for tissue engineering, regenerative medicine, and wound healing applications (e.g., 1-6). The importance of biomimetic, three dimensional, nanofibrous scaffolds for tissue engineering has been shown. However, significant challenges remain with these materials including their reduced material properties, pore sizes, and challenges with commercial scaleup. This workshop and Dr. Loboa s presentation will focus on advancements, and challenges, associated with creation and use of biomimetic nanofibrous materials for musculoskeletal tissue engineering applications. Speaker: Joachim Kohn, Ph.D. Nanoparticular Drug Carriers for the Delivery of Actives Out of the huge universe of nanoparticulate drug carriers, the following approaches are particularly relevant to bone tissue engineering or bone healing in the clinic: 1. Ceramic nanocomposites, usually nanoparticles of HA; 2. Growth factor delivery using polymeric carriers, in particular delivery of BMP-2; and 3. The newest area, DNA or RNA

vehicles to enhance osteogenesis at the injury site. Finally, there is the challenge of combining nanostructured scaffolds (such as electrospun fiber mats) with the delivery of actives. Very often, the biologically active molecule is entrapped in nanoparticles, and that formulation is then mixed into the scaffold to create some scaffold - particle hybrid. The approach used in the Kohn laboratory is to chemically link (tether) BMP-2 or other bioactive peptides and proteins to the polymer surface after the nanostructured scaffold has been fabricated. In this presentation, Dr. Kohn will present and discuss nanofibrous biomaterials created using these approaches with particular focus on opportunities, and challenges, with clinical translation. Speaker: Molly Stevens, Ph.D. New Materials-based Approaches for Regenerative Medicine Bio-responsive nanomaterials are of growing importance with potential applications including drug delivery, diagnostics and tissue engineering (7). A disagreeable side effect of longer lifespans is the failure of one part of the body the knees, for example before the body as a whole is ready to surrender. The search for replacement body parts has fuelled the highly interdisciplinary field of tissue engineering and regenerative medicine. This talk will describe our research on the design of new materials to direct stem cell differentiation for regenerative medicine (8). This talk will also cover progress in state of the art materials analysis to better understand regenerated and native tissue properties. By applying multivariate analysis techniques to micro-raman spectra of mineralized nodules, we reveal cell-source-dependent differences in interactions between multiple bone-like mineral environments (9). Understanding the biological mechanisms of bone formation that contribute to cell-source-specific materials differences may facilitate the development of clinically successful engineered bone. I will also discuss the application of nano-analytical electron microscopy techniques to bone and mineralisation in tissues to yield unique insights into these tissues (10).

Speaker Biographies Dr. Elizabeth Loboa is an Associate Professor and the Associate Chair of the Joint Department of Biomedical Engineering at the University of North Carolina at Chapel Hill and North Carolina State University. She is also an Associate Professor in the Department of Materials Science and Engineering at NC State University and holds adjunct faculty positions in the Departments of Fiber and Polymer Science (NCSU), Physiology (NCSU), Biotechnology (NCSU), Curriculum in Oral Biology (UNC-CH), and Orthopaedics (UNC-CH). Dr. Loboa is also the founding and current Director of the Cell Mechanics Laboratory at North Carolina State University. Research in her group predominantly focuses on two areas: 1) Elucidation and application of biomimetic mechanical and material stimuli for functional tissue engineering of musculoskeletal tissues using human stem cells; and, 2) nanofibrous scaffolds as controlled release systems for wound healing and tissue regeneration applications requiring stem cell lineage specification, antimicrobial, antibacterial, and/or anti-inflammatory treatment(s). This work is supported with funding from the National Institutes of Health, North Carolina Biotechnology Center, various industry sponsors, and the National Science Foundation. Dr. Loboa serves on the Board of Directors for the North Carolina Tissue Engineering and Regenerative Medicine Society (NCTERMS), 2015 Conference Chair for the Biomedical Engineering Society (BMES) Special Interest Group in Cellular and Molecular Bioengineering (CMBE), Endorsement Committee for the Tissue Engineering and Regenerative Medicine International Society (TERMIS), and Editorial Board and Chair of the Young Investigator Council for the journal Tissue Engineering, Parts A, B, and C. She is a recipient of the Ralph E. Powe Junior Faculty Award (2005), Sigma Xi Faculty Research Award (2009), UK-US Stem Cell Collaboration Development Award (2009), Stanford University Distinguished Alumni Scholar Award (2010), the NCSU Chancellor s Innovation Award (2011), and the NCSU Faculty Scholar Award (2012). Professor Joachim Kohn is the Board of Governors Professor of Chemistry and Chemical Biology at Rutgers University. He has served as Director of the New Jersey Center for Biomaterials since its establishment in 1997. He is a Fellow of the American Institute for Medical and Biological Engineering (AIMBE) and of the International Union of Societies for Biomaterials Science and Engineering (IUSBSE). He is the principal investigator of several leading federally-funded R&D programs: NIH-funded postdoctoral training program in Tissue Engineering, NSF-funded Partnership for Innovation designed to explore new plant-synthetic hybrid biomaterials, NIH-funded National Resource for Polymeric Biomaterials (RESBIO), and the DoD-funded Center for Military Biomaterials Research (CeMBR). As one of two principal investigators of the Armed Forces Institute of Regenerative Medicine (AFIRM), he guides the efforts of more than one hundred scientists and clinicians located in 15 institutions across the nation. Professor Kohn's research interests focus on the development of new biomaterials. He pioneered the use of combinatorial and computational methods for the optimization of biomaterials for specific medical applications. He is mostly known for his seminal work on "pseudo-poly(amino acid)s"- a new class of polymers that combine the nontoxicity of individual amino acids with the strength and process ability of high-quality engineering plastics. Medical devices using these materials have been implanted in more than 20,000 patients. Molly Stevens is currently Professor of Biomedical Materials and Regenerative Medicine and the Research Director for Biomedical Material Sciences in the Institute of Biomedical Engineering at Imperial College. She joined Imperial in 2004 after a Postdoctoral training in the laboratory of Professor Robert Langer in the Chemical Engineering Department at the

Massachusetts Institute of Technology (MIT). Prior to this she graduated from Bath University with a First Class Honours degree in Pharmaceutical Sciences and was then awarded a PhD in biophysical investigations of specific biomolecular interactions and single biomolecule mechanics from the Laboratory of Biophysics and Surface Analysis at the University of Nottingham (2000). In 2010 she was recognised by The Times as one of the top ten scientists under the age of 40 and also received the Polymer International-IUPAC award for creativity in polymer science, the Rosenhain medal and the Norman Heatley Prize for Interdisciplinary research from the Royal Society of Chemistry. In 2009 she was awarded the Jean Leray Award from the European Society for Biomaterials, in 2007 the prestigious Conference Science Medal from the Royal Pharmaceutical Society and in 2005 the Philip Leverhulme Prize for Engineering. She has also recently been recognised by the TR100, a compilation of the top innovators, under the age of 35, who are transforming technology - and the world with their work. Her previous awards include the Ronald Belcher Memorial Lecture Award from the Royal Society of Chemistry (2000) and both the Janssen Prize and the UpJohn Prize for academic excellence and research. In 2010 Molly was awarded the RSC Norman Heatley Prize and the IOM3 Rosenhain Medal and Prize, In 2012 Molly was awarded the Griffith Prize and medal from IOM3. In 2012 she presented the Royal Society Clifford Patterson Lecture and in 2013 she was elected Fellow of the Royal Academy of Engineering.

References 1. Mohiti-Asli M, Pourdeyhimi B, Loboa EG. Novel, silver-ion-releasing nanofibrous scaffolds exhibit excellent antibacterial efficacy without the use of silver nanoparticles. Acta Biomaterialia 2013 Dec 21. pii: S1742-7061(13)00626-0. doi: 10.1016/j.actbio.2013.12.024. [Epub ahead of print] PubMed PMID: 24365706. 2. Asli MM, Pourdeyhimi B, Loboa EG. Release profiles of tricalcium phosphate nanoparticles from poly(l-lactic acid) electrospun scaffolds with single component, core-sheath, or porous fiber morphologies: effects on hasc viability and osteogenic differentiation. Macromol Biosci. 2012 Jul;12(7):893-900. 3. McCullen SD, Gittard SD, Miller PR, Pourdeyhimi B, Narayan RJ, Loboa EG. Laser ablation imparts controlled micro-scale pores in electrospun scaffolds for tissue engineering applications. Ann Biomed Eng. 2011Dec;39(12):3021-30. 4. Haslauer CM, Moghe AK, Osborne JA, Gupta BS, Loboa EG. Collagen-PCL sheath-core bicomponent electrospun scaffolds increase osteogenic differentiation and calcium accretion of human adipose-derived stem cells. J Biomater Sci Polym Ed. 2011;22(13):1695-712. 5. McCullen SD, Miller PR, Gittard SD, Gorga RE, Pourdeyhimi B, Narayan RJ, Loboa EG. In situ collagen polymerization of layered cell-seeded electrospun scaffolds for bone tissue engineering applications. Tissue Eng Part C Methods. 2010 Oct;16(5):1095-105 6. McCullen SD, Zhu Y, Bernacki SH, Narayan RJ, Pourdeyhimi B, Gorga RE, Loboa EG. Electrospun composite poly(l-lactic acid)/tricalcium phosphate scaffolds induce proliferation and osteogenic differentiation of human adipose-derived stem cells. Biomed Mater. 2009 Jun;4(3):035002. 7. Stevens MM, George JH, Exploring and engineering the cell surface interface., Science, 2005, Vol:310, Pages:1135-1138. 8. Place ES, Evans ND, Stevens MM, Complexity in biomaterials for tissue engineering., Nature Materials, 2009, Vol:8, Pages:457 470 9. Bertazzo S, Gentleman E, Cloyd KL, Chester AH, Yacoub MH, Stevens MM. Nature Materials12, 576-583, 2013. 10. Gentleman E, Swain RJ, Evans ND, Boonrungsiman S, Jell G, Ball MD, Shean TA, Oyen ML, Porter A, Stevens MM. Nature Materials 8, 763-770, 2009