wileyonlinelibrary.com Macromolecular Rapid Communications Review 598 DOI: 10.1002/marc.201300818 1. Introduction Hydrogels are 3D, water-swollen polymer networks formed as a result of physical or chemical cross-linking between water-soluble polymer chains. [1] Given their high water content, controllable porosity, and mechanical and (poten- tially) compositional similarities between hydrogels and native soft tissues in the body, [2] hydrogels have been widely investigated for tissue engineering, bioadhesive, wound healing, space filling, cell encapsulation, and controlled release applications. [3–6] The design of these soft materials has benefited greatly from recent developments in polymer science that have enabled the synthesis of poly- mers with unprecedented control over molecular weight, composition, topology, and functionality. [7] Imparting this control on a linear polymer level to a hydrogel network has resulted in the design of novel hydrogels that can change their water content in response to one or more environ- mental stimuli, [8] have more uniform networks, [9,10] or can dynamically rearrange their structure. [11–13] Successful biomedical application of conventional hydrogels, however, remains somewhat limited given that the inherent elasticity of hydrogels limits their ability to be delivered via an injection or any other minimally-inva- sive (i.e., non-surgical) route. Most synthetic hydrogels are prepared using free radical chemistry and/or functional group condensation chemistry, which is generally incom- patible with in vivo conditions. [14] One clinical exception to this rule is in situ photopolymerization of hydrogels, which has found significant applications in conjunc- tion with surgical interventions as adhesion prevention materials. [15] However, the need for a small molecule pho- toinitator as well as UV irradiation over (in most cases) several minutes to induce gelation both pose potential safety concerns with this technique, as does the highly Hydrogels that can form spontaneously via covalent bond formation upon injection in vivo have recently attracted significant attention for their potential to address a variety of biomed- ical challenges. This review discusses the design rules for the effective engineering of such materials, and the major chem- istries used to form injectable, in situ gelling hydrogels in the context of these design guidelines are outlined (with exam- ples). Directions for future research in the area are addressed, noting the outstanding challenges associated with the use of this class of hydrogels in vivo. Designing Injectable, Covalently Cross-Linked Hydrogels for Biomedical Applications Mathew Patenaude, Niels M. B. Smeets, Todd Hoare* M. Patenaude Department of Chemical Engineering McMaster University 1280 Main St. W., Hamilton, Ontario, Canada L8S 4L7 N. M. B. Smeets Department of Chemical Engineering, McMaster University 1280 Main St. W., Hamilton, Ontario, Canada L8S 4L7 Prof. T. Hoare Associate Professor Department of Chemical Engineering, McMaster University, 1280 Main St. W., Hamilton, Ontario, Canada L8S 4L7 E-mail: hoaretr@mcmaster.ca Macromol. Rapid Commun. 2014, 35, 598−617 © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim