Zwitterionic fusion in hydrogels and spontaneous and time-independent self-healing under physiological conditions Tao Bai a , Sijun Liu b , Fang Sun a , Andrew Sinclair a , Lei Zhang a , Qing Shao a , Shaoyi Jiang a, b, * a Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA b Department of Bioengineering, University of Washington, Seattle, WA 98195, USA article info Article history: Received 5 December 2013 Accepted 31 January 2014 Available online 20 February 2014 Keywords: Zwitterionic materials Self-healing materials Time-independent behavior Zwitterionic Fusion abstract The biomedical applications of current self-healing materials are largely impeded by their healing conditions, which usually require heating, UV exposure or harsh pH environments. At the same time, for very few existing spontaneously self-healing materials, healing can only be achieved immediately after rupture occurs. Here, we developed a spontaneously healing material, driven by a new mechanism, “zwitterionic fusion”, which is repairable independent of time after damage under physiological con- ditions. We also tested the anti-fatigue property of this zwitterionic hydrogel. Furthermore, we utilized this zwitterionic fusion to link different cell-hydrogel constructs together. Ó 2014 Elsevier Ltd. All rights reserved. 1. Introduction Self-healing materials can eliminate damage or fatigue during normal utilization, thus holding promise for enhanced lifetimes and enduring strength [1e4]. They have been demonstrated by exploiting polymereclay interactions [5], phase segregation [6], redox reactions [7], photo-reactive groups [8,9], and microvascular networks [10e12]. Currently, few materials have been reported to effectively and spontaneously repair themselves under physiolog- ical conditions after damage. For these scarce existing spontane- ously self-healing materials, healing can only be achieved either immediately after rupture occurs [5,13e16] (e.g. in less than 1 min) or at low pH values [17,18]. Materials capable of spontaneous self- healing are typically constructed from either single-charged or non-ionic amphiphilic components. Their healing abilities rely on hydrogen-bond donors/acceptors [5,13,17] or hydrophobic in- teractions [14]. For example, Phadke et al. [17] recently developed a self-healing single-charged hydrogel. However, the driving force for this reconstruction is superseded by electrostatic repulsion among the ionized carboxyl groups under physiological pH conditions: this problem is depicted in Fig. 1a. As a result, these single-charged hydrogels cannot undergo healing unless the pH is reduced to as low as 3, which limits their applications in biologically relevant systems. Another type of self-healing material is non-ionic and amphiphilic, with an outermost layer assembled from hydrophobic components in contact with air. When damage occurs, hydrophilic healable functional groups are initially exposed to air. In order to minimize the surface free energy of the system, hydrophobic components then move to the surface and bury the hydrophilic groups inside over timedthe so-called “hydrophobic regeneration” process [19,20] (Fig. 1a). However, interactions among these hy- drophobic components are not strong enough to mediate the movement of polymer chains across a rupture junction for further healing. Consequently, the newly formed hydrophobic outer layer prevents broken pieces from fusing. For example, Wang et al. [5] designed a spontaneously self-healing hydrogel based on amphi- philic polyethylene glycol (PEG) dendrimers. As they pointed out, deposited water droplets spread over a cut surface immediately but beaded on an uncut surface. Therefore, fusion did not take place unless the blocks were cut to obtain fresh surfaces. Moreover, if the blocks were cut but left alone for more than a minute, they also lost their adhering ability. This time-dependent self-healing behavior is attributed to surface reconstruction resulting from the amphiphilic nature of current self-healing materials. In order to achieve time- independent self-healing, this surface reconstruction must be avoided. In sharp contrast to the amphiphilic character of most materials, the superhydrophilic nature of zwitterionic materials has made them uniquely suited for protein protection [21], nanoparticle * Corresponding author. Department of Chemical Engineering, University of Washington, Seattle, WA 98195, USA. Fax: þ1 206 543 3778. E-mail address: sjiang@uw.edu (S. Jiang). Contents lists available at ScienceDirect Biomaterials journal homepage: www.elsevier.com/locate/biomaterials http://dx.doi.org/10.1016/j.biomaterials.2014.01.077 0142-9612/Ó 2014 Elsevier Ltd. All rights reserved. Biomaterials 35 (2014) 3926e3933