Recent advances in hyaluronic acid hydrogels for biomedical applications Christopher B Highley 1 , Glenn D Prestwich 2 and Jason A Burdick 1 Hyaluronic acid (HA) is widely used in the design of engineered hydrogels, due to its biofunctionality, as well as numerous sites for modification with reactive groups. There are now widespread examples of modified HA macromers that form either covalent or physical hydrogels through crosslinking reactions such as with click chemistry or supramolecular assemblies of guest-host pairs. HA hydrogels range from relatively static matrices to those that exhibit spatiotemporally dynamic properties through external triggers like light. Such hydrogels are being explored for the culture of cells in vitro, as carriers for cells in vivo, or to deliver therapeutics, including in an environmentally responsive manner. The future will bring new examples of HA hydrogels due to the synthetic diversity of HA. Addresses 1 Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Medicinal Chemistry, University of Utah, Salt Lake City, UT, USA Corresponding author: Burdick, Jason A (burdick2@seas.upenn.edu) Current Opinion in Biotechnology 2016, 40:35–40 This review comes from a themed issue on Tissue, cell and pathway engineering Edited by April Kloxin and Kyongbum Lee For a complete overview see the Issue and the Editorial Available online 27th February 2016 http://dx.doi.org/10.1016/j.copbio.2016.02.008 0958-1669/# 2016 Elsevier Ltd. All rights reserved. Introduction Hydrogels are hydrated polymeric networks with diverse properties that have, in recent years, seen continued advancement and creativity in their design, fabrication, and application. Areas of use range from cell and thera- peutic delivery to in vitro platforms for creating and controlling cellular environments. Hyaluronic acid or hyaluronan (HA) represents one biopolymer that can be modified and processed to form hydrogels for biomed- ical applications [1]. Owing to their biocompatibility, tunable properties, and native biofunctionality, hydrogels built from HA are increasingly versatile for a myriad of applications [1]. HA has inherent biological importance due to its binding to receptors such as CD44, ability to degrade via oxidative species and hyaluronidases, and relevance during development, wound healing, and in the function and structure of adult tissues [2]. With these features in mind, several HA hydrogel systems have already advanced to clinical use in human and veterinary patients, particularly as dermal fillers, as intra-articular viscosupplements, for corneal and dermal wound repair, and for post-surgical adhesion prevention, among other uses. HA hydrogels are now evolving in their design to be responsive to a range of cues, to present dynamic envir- onments, and to possess multiple functionalities such as sophisticated structures and biochemical signals. Our goal with this report is to highlight recent advances in the development of HA hydrogels and their continued appli- cation to numerous biomedical conditions. Indeed, since our review on this topic in 2011 [1], significant new research advances have occurred. We aim to further explore the advantages of HA-based hydrogels for con- tinued development of versatile, biocompatible materials based on a growing diversity of chemical modifications and processing techniques available. HA gelation via covalent crosslinking Scientists and engineers working with HA continue to expand upon and refine existing chemistries for synthe- sizing and crosslinking HA macromers (see Figure 1). Many of the specific, orthogonal ‘click’ chemistries have been used to produce hydrogels from HA-derivatives. For example, strain-promoted [3 + 2] cycloaddition crosslink- ing between HA modified with either azide or cyclooc- tyne groups formed biocompatible hydrogels [3]. Selective Diels-Alder reactions have also been used to crosslink furan-functionalized HA with either maleimide- functionalized HA [4] or maleimide-poly(ethylene glycol) (PEG) crosslinkers [5,6] and maleimide-modified HA has been directly crosslinked via Michael addition reactions with dithiol crosslinkers, such as peptides containing cysteines [7]. HA modified with a tetrazine derivative was crosslinked with bis-trans-cyclooctene molecules [8], and norbornene-modified HA supports thiol-ene click crosslinking using spatially controlled photoinitiation [9]. These crosslinking approaches can provide direct functionality to the hydrogel (e.g., enzymatically degrad- able peptide crosslinkers) and specific, orthogonal reac- tions may enable the engineering of spatiotemporal control into hydrogel platforms. Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Biotechnology 2016, 40:35–40