© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.advhealthmat.de www.MaterialsViews.com wileyonlinelibrary.com 1 PROGRESS REPORT Microfluidic Strategies for Design and Assembly of Microfibers and Nanofibers with Tissue Engineering and Regenerative Medicine Applications Michael A. Daniele,* Darryl A. Boyd, André A. Adams, and Frances S. Ligler DOI: 10.1002/adhm.201400144 1. Introduction The practice of mechanically spinning fibers has been in existence for more than 10 000 years, with the earliest known example of hand-twisted natural threads dating before 30 000 BCE. [1,2] Through the millennia, the technologies related to fiber production drove the textile industry and were a hall- mark of industrial society. It was not until the early 20th cen- tury, coinciding with the academic and industrial boom in polymer science, that new materials and processes were devel- oped for high-throughput manufacturing of synthetic fibers, and by mid-century the use of synthetic fibers pervaded eve- ryday life. In 1940, 64 million pairs of nylon stockings were sold, by 1970 every man was in polyester-blend leisure suit, and in 2012 the world production of synthetic and natural fibers was approximately 80 million tons with a global market exceeding $50 billion. [3] Fiber-based materials provide critical capabilities for biomedical applications. Microfluidic fiber fabrication has recently emerged as a very promising route to the synthesis of polymeric fibers at the micro and nanoscale, providing fine control over fiber shape, size, chemical anisotropy, and biological activity. This Progress Report summarizes advanced microfluidic methods for the fab- rication of both microscale and nanoscale fibers and illustrates how different methods are enabling new biomedical applications. Microfluidic fabrication methods and resultant materials are explained from the perspective of their microfluidic device principles, including co-flow, cross-flow, and flow-shaping designs. It is then detailed how the microchannel design and flow parameters influence the variety of synthesis chemistries that can be utilized. Finally, the integration of biomaterials and microfluidic strategies is discussed to manu- facture unique fiber-based systems, including cell scaffolds, cell encapsula- tion, and woven tissue matrices. Dr. M. A. Daniele, D. A. Boyd, A. A. Adams Center for Bio/Molecular Science and Engineering Naval Research Laboratory 4555 Overlook Ave. SW, Washington D.C. 20375, USA E-mail: michael.daniele.ctr@nrl.navy.mil Prof. F. S. Ligler Department of Biomedical Engineering University of North Carolina Chapel Hill and North Carolina State University Mail Stop 7115, Raleigh, NC 27965–7115, USA A majority of mass-produced synthetic fibers are made by one of the industrial- ized spinning techniques: wet, dry, melt, gel, and electrospinning. Standard wet, dry, and melt spinning involve physi- cally forcing a liquid through a spinneret to form continuous filaments of a solid polymer. The fiber-forming polymers must be converted into a fluid for extrusion. This is usually achieved by melting if the polymers are thermoplastics or by dis- solving the polymers in a suitable solvent if they are thermosets. For wet spinning, the spinnerets are submerged in a chem- ical bath, and as the filaments emerge, they precipitate from solution and solidify. Acrylic, rayon, and spandex can be pro- duced by this process. For dry spinning, solidification is achieved by evaporating the solvent in a stream of air or inert gas. This process may be used for the production of acetate, triac- etate, acrylic, and vinyl. For gel and melt spinning, the fiber- forming material is a high-viscosity fluid extruded through the spinneret and then directly solidified by cooling in a dry or wet bath. Olefins and aramids are made by gel spinning, while nylon, high-molecular weight olefins, and polyesters are more commonly produced by melt spinning. Unique from these approaches is electrospinning, in which a polymer jet is drawn from a needle by the application of high voltage between the tip of the syringe and a collector plate. As prevalent and popular as these fabrication methods are, they are limited by the materials compatible with the process, high production costs of complex spinnerets, extreme process parameters (e.g., high shear, melt temperatures, rapid evaporation/solidification, high voltage) and nonuniformity arising from surface tension and rapid evaporation. Ultimately, the conventional spinning processes limit the choice of materials, which curtails the utilization of fiber-based systems in 21st century biomedical technologies. Nonetheless, fiber-based systems are an ideal platform for mimicking biological materials and tissue constructs, and cur- rent research has begun to exploit fiber matrices for these bio- medical applications. [4,5] The geometry of micro and nanofibers better replicates the interconnected networks of native tissue, and fine-tuned fiber geometry holds the promise of replicating the immense tubule network of the cardiovascular system and even the direct fibrous constructs of the musculoskeletal system. In such applications, the fiber fabrication process must be compatible with the next generation of biological Adv. Healthcare Mater. 2014, DOI: 10.1002/adhm.201400144