Synthesis and characterization of sensitive hydrogels based on semi-interpenetrated networks of poly[2-ethyl-(2-pyrrolidone) methacrylate] and hyaluronic acid Joana Magalha ˜ es, 1 Rui A. Sousa, 2 Joa ˜ o F. Mano, 2 Rui L. Reis, 2 Francisco J. Blanco, 1 Julio San Rom an 3 1 Rheumatology Division, CIBER-BBN/ISCIII, Tissue Engineering and Cellular Therapy Group (CBTTC-CHUAC), INIBIC-Hospital Universitario A Coru~ na, C/As Xubias, S/N 15006 A Coru~ na, Spain 2 3B’s Research Group Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, 4806-909 Taipas, Guimara ˜ es, Portugal 3 Polymer Science and Technology Institute, CSIC and CIBER-BBN, C/Juan de la Cierva, 3, 28006 Madrid, Spain Received 1 December 2011; revised 15 May 2012; accepted 25 May 2012 Published online 25 July 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/jbm.a.34312 Abstract: Sensitive hydrogels attract interest due to their soft wet appearance and shape response to environmental varia- tions. The synthesis and characterization of semi-interpene- trated hydrogels obtained by radical-induced polymerization of 2-ethyl-(2-pyrrolidone)methacrylate (EPM) in the presence of different concentrations of hyaluronic acid (HA) using N,N 0 -methylene-bisacrylamide or triethylene glycol dimetha- crylate as crosslinker, followed by freeze-drying, are described. Polymeric systems were characterized by NMR, FTIR, SEM, TGA, and DMA. PEPMHA hydrogels’ mechanical properties and swelling were found to be intimately related to HA concentration and crosslinker. The swelling response was assessed for temperature and pH variation in order to study the behavior of the hydrogels. We found that the pres- ence of HA in PEPM polymeric systems induced a sensitivity to pH variation rather than temperature. Finally, the biocom- patibility profile of the hydrogels was evaluated, using mes- enchymal stem cells. Cell adhesion and proliferation results revealed the non-cytotoxicity of the systems. We estimate that PEPMHA hydrogels can be used for applications in tissue engineering and for the controlled release of bioactive com- pounds. V C 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 101A: 157–166, 2013. Key Words: hyaluronic acid, vinyl pyrrolidone, hydrogels, hydrophilic polymers, stimuli-sensitive polymers How to cite this article: Magalha ˜ es J, Sousa RA, Mano JF, Reis RL, Blanco FJ, Rom an JS. 2013. Synthesis and characterization of sensitive hydrogels based on semi-interpenetrated networks of poly[2-ethyl-(2-pyrrolidone) methacrylate] and hyaluronic acid. J Biomed Mater Res Part A 2013:101A:157–166. INTRODUCTION Hydrogels are crosslinked polymer networks that can swell up to 99% water, which renders them with better lubricat- ing properties, low coefficients of friction, and high mechan- ical strength, making them ideal for transmitting loads. 1 These materials are of especially useful for the controlled release of drugs, and these are currently being used in the field of tissue engineering (TE) as three-dimensional scaf- folds, cell delivery agents, and cell carriers. 2,3 The development of appropriate hydrogel matrices is critical for the success of any approach. If we consider bone and cartilage TE applications, the hydrogel matrix should be composed of biocompatible and biodegradable materials and should exhibit mechanical properties that can sustain load bearing. 4–6 Hydrogel matrices have been fabricated widely from polymers of both natural and synthetic origin. 5 Even though naturally derived materials are intrinsically biocompatible and physiologically degradable, several limitations are encountered; for instance, they are generally weak and lack batch-to-batch consistency. 7 On the other hand, hydrogels based on synthetic polymers that lack cell recognition sites offer a range of easily tailored properties that are advantageous for a reproducible fabrication. 8 Therefore, sev- eral groups have been investigating the utility of biosyn- thetic composite hydrogels composed of both synthetic and naturally occurring extracellular matrix (ECM) components so as to exploit the advantages of both polymer types. 9–11 One approach of creating composite hydrogels is the fab- rication of an interpenetrating network (IPN) or semi-IPN (sIPN) of polymers. A sIPN consists of a polymer network containing a molecularly entangled second polymer. 12 Although IPN can achieve significant improvement in strength and stiffness, they are often nondegradable and not Correspondence to: J. Magalha ˜ es; e-mail: joana.cristina.silva.magalhaes@sergas.es Contract grant sponsor: Marie Curie Early Stage Training Alea Jacta Est; contract grant number: MEST-CT-2004-8104 V C 2012 WILEY PERIODICALS, INC. 157