Hyaluronic acid colloidal gels as self-assembling elastic biomaterials Amir Fakhari, 1 Quang Phan, 2 Cory Berkland 1,3,4 1 Bioengineering Graduate Program, University of Kansas, Lawrence, Kansas 2 College of Pharmacy and Health Sciences, Drake University, Des Moines, Iowa 3 Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 4 Departemant of Chemical and Petroleum Engineering, University of Kansas, Lawrence, Kansas Received 21 April 2013; revised 20 August 2013; accepted 28 August 2013 Published online 7 October 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.b.33041 Abstract: Hyaluronic acid (HA) is a naturally occurring bio- degradable polymer with a variety of applications in medi- cine. The use of HA as a filler or scaffold for regenerating tissues often requires improving the elastic properties of HA. This is conventionally accomplished via chemical cross- linking, which might require the generation of toxic free radicals. Although the mechanical properties of the result- ing gel material can be tuned, these types of materials are static and susceptible to mechanical failure. The aim of this study was to develop a colloidal system for scaffold fabrica- tion that is held together by physical interactions between HA nanoparticles. HA nanoparticles composed of 17 kDa HA suspended in water at different concentrations (15%, 30%, and 45% w/v, respectively) formed a stable three- dimensional (3D) colloidal gel as a result of physical entan- glement of free polymer chains on the surfaces of nanopar- ticles. The swelling ratio, shear moduli (G), compressive failure properties, and viscosity of colloidal gels were con- centration dependent. The colloidal gels also were found to exhibit dynamic and recoverable properties, thus suggest- ing that these “self-associating colloids” offer characteris- tics distinct arising from crosslinked polymers or high concentration colloids. V C 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 102B: 612–618, 2014. Key Words: hyaluronic acid, nanoparticle, colloidal gel How to cite this article: Fakhari A, Phan Q, Berkland C. 2014. Hyaluronic acid colloidal gels as self-assembling elastic biomate- rials. J Biomed Mater Res Part B 2014:102B:612–618. INTRODUCTION Colloidal gels are materials made from particles that interact to form three-dimensional (3D) networks. Such materials have been pursued as tissue engineering scaffolds, drug delivery systems, and biosensors. 1 Colloidal gels often exhibit dynamic viscoelastic properties, which has led to exploration as injectable biomaterials for tissue engineering. 2–5 The dynamic properties of colloidal gels allow the material to flow during injection and recover elasticity after placement. Many researchers have utilized chemical crosslinking (e.g., in situ) to improve the elasticity of colloidal gel materials. Non- covalent interactions between colloids, however, may also be able achieve the properties of native tissue in applications such as dermal filling and tissue replacement. Prior work to stabilize the structure of colloid- containing materials has often relied on chemical reactions such as in situ crosslinking; however, the applications of these reactions are sometimes limited due to toxicity. 6–11 Advanced techniques should either yield the desired termi- nal mechanical properties (e.g., elasticity) or enhance dynamic properties (e.g., shear effects on viscoelasticity) of colloidal gels while maintaining compatibility with tissues. Electrostatic interactions have been explored as a mecha- nism to assemble colloids into dynamic materials. 3–5,12–14 As expected, charge interactions between nanoparticles are disruptable by shear and provide a promising approach to injectable tissue filling. Less work has been done on other phenomena to drive nanoparticle association such as entan- glement of surface chains on colloids. 3–5,15 Hyaluronic acid (HA), also named hyaluronan, is a naturally occurring biodegradable glycosaminoglycan (GAG). 1,11,16,17 HA is one of the major elements in the extracellular matrix (ECM) of vertebrate tissues. It is found in many body fluids and tissues, such as the synovial fluid, the vitreous humor of the eye, and hyaline cartilage. 1,18–21 HA is also a self-associating polymer. Here, a novel colloidal gel assembled from HA nanoparticles was explored as a means to form stable 3D networks. As an alternative to chemical crosslinking or electrostatic assembly of colloids, association of surface chains on was explored as a means to assemble colloidal gels. Surprisingly, these “self-associating” HA nanoparticles can form robust, colloidal gels with excep- tional elastic recoverability. MATERIALS AND METHODS Materials HA with different molecular weights (17 and 1500 kDa) was purchased from Lifecore Biomedical (Chaska, MN). Correspondence to: C. Berkland (e-mail: berkland@ku.edu) 612 V C 2013 WILEY PERIODICALS, INC.