3D bioprinting is a powerful fabrication technique in biomedical engineering, which is currently limited by the number of available materials that meet all physicochemical and cytocompatibility requirements for biomaterial inks. Inspired by the key role of coacervation in the extrusion and spinning of many natural materials, hyaluronic acid–chitosan complex coacervates are proposed here as tunable biomaterial inks. Complex coacervates are obtained through an associative liquid–liquid phase separation driven by electrostatic attraction between oppositely charged macromolecules. They offer bioactive properties and facile modulation of their mechanical properties through mild physicochemical changes in the environment, making them attractive for 3D bioprinting. Fine‐tuning the salt concentration, pH, and molecular weight of the constituent polymers results in biomaterial inks that are printable in air and water. The biomaterial ink, initially a viscoelastic fluid, transitions into a viscoelastic solid upon printing due to dehydration (for printing in air) or due to a change in pH and ionic composition (for printing in solution). Consequently, scaffolds printed using the complex coacervate inks are stable without the need for post‐printing processing. Fabricated cell culture scaffolds are cytocompatible and show long‐term topological stability. These results pave the way to a new class of easy‐to‐handle tunable biomaterials for biofabrication.

It is well-known that the phase behavior and physicochemical and adhesive properties of complex coacervates are readily tuneable with the salt concentration of the medium. For toxicity reasons, however, the maximum applicable salt concentration in biomedical applications is typically low. Consequently, other strategies must be implemented in order to optimize the properties of the resulting complex coacervates. In this work, the effect of the charge density of a strong polyanion on the properties of complex coacervates was studied. To control this charge density, statistical anionic/charge-neutral hydrophilic copolymers were synthesized by means of an elegant protection/deprotection strategy and subsequently complexed with a strong polycation. The resulting complexes were observed to have an increasing water content as well as faster relaxation dynamics, with either increasing salt concentration or decreasing charge density. Time-salt and time-salt-charge density superpositions could be performed and showed that the relaxation mechanism of the complex coacervates remained unchanged. When the charge density was decreased, lower salt concentration complexes became suitable for viscoelastic adhesion with improved injectability. Such complex coacervates are promising candidates for injectable biomedical adhesives.

3D printing of hydrogels usually relies on a combination of fine‐tuned material chemistry and polymer chain architecture to obtain an ink with adequate yield‐stress flow, shear‐thinning, and self‐healing behavior. Recent approaches in hydrogel ink design include introduction of reversible covalent or supramolecular bonds or jamming of microparticles into a granular hydrogel. However, the dimensional stability of such systems is typically afforded by a post‐printing covalent cross‐linking step that impedes further on‐demand degradation of the scaffolds. Here, a jammed micro‐gels ink made of thermosensitive poly(N‐isopropylacrylamide) micro‐gels incorporating terpyridine ligand linkers are proposed as a 3D printable ink that is cured post‐printing by iron (II) cations for long‐term stabilization. The uncross‐linked micro‐gels ink exhibits the rheological characteristics of granular materials, meaning yield‐stress, shear‐thinning and fast recovery. Upon curing, iron (II)‐bis‐terpyridine coordination complexes between neighboring micro‐gels are formed. The supramolecular bonds are sufficiently strong and long‐lived to maintain scaffold integrity during manual handling or immersion in liquid medium for over two months. The thermosensitivity of the micro‐gels endows the printed construct with reversible and cyclable temperature‐induced resolution enhancement, while the supramolecular cross‐linking provides an asset of disintegration on‐demand. The proposed micro‐gel scaffolds are biocompatible, revealing the potential for biomedical applications and 4D bioprinting.

Complex coacervates make up a class of versatile materials formed as a result of the electrostatic associations between oppositely charged polyelectrolytes. It is well-known that the viscoelastic properties of these materials can be easily altered with the ionic strength of the medium, resulting in a range of materials from free-flowing liquids to gel-like solids. However, in addition to electrostatics, several other noncovalent interactions could influence the formation of the coacervate phase depending on the chemical nature of the polymers involved. Here, the importance of intermolecular hydrogen bonds on the phase behavior, microstructure, and viscoelasticity of hyaluronic acid (HA)-chitosan (CHI) complex coacervates is revealed. The density of intermolecular hydrogen bonds between CHI units increases with increasing pH of coacervation, which results in dynamically arrested regions within the complex coacervate, leading to elastic gel-like behavior. This pH-dependent behavior may be very relevant for the controlled solidification of complex coacervates and thus for polyelectrolyte material design.

Tissue adhesives are used for various medical applications, including wound closure, bleeding control, and bone healing. Currently available options often show weak adhesion or cause adverse effects. Recently, there has been an increasing interest in complex coacervates as medical adhesives. Complex coacervates are formed by mixing oppositely charged macromolecules that associate and undergo liquid‐liquid phase separation, in which the dense bottom phase is the complex coacervate. Complex coacervates are strong and often biocompatible, and show strong underwater adhesion. The properties of the resulting materials are tunable by intrinsic factors such as polymer chemistry, molecular weight, charge density, and topology of the macromolecules, as well as extrinsic factors such as temperature, pH, and salt concentration. Therefore, complex coacervates are interesting new candidates for medical adhesives. In this review, it is described how complex coacervates form and how different factors influence their behavior. Next, an overview of recent studies on complex coacervates in the context of medical adhesives is presented. The application of complex coacervates as hemostatic or embolic agents, skin or bone repair adhesives, and soft tissue sealants is discussed. Lastly, additional possibilities for utilizing these materials in the future are discussed.