Complex Coacervate-Based Materials for Biomedicine: Recent Advancements and Future Prospects

Abstract

Complex coacervation, a specific type of associative phase separation that happens when oppositely charged macro-ions (or polyelectrolytes) are mixed, is the formation of a dense macro-ion-rich phase (the coacervate) in equilibrium with a dilute macro-ion-poor phase (the continuous phase or supernatant). Since Bungenberg de Jong and colleagues' ground-breaking work on the gelatin−acacia gum complex coacervation in the 1920s and 1940s, coacervates have drawn increasing research attention because they are essential to a wide range of established and developing technologies. Charge complexation in solution may play a role in this association. Unfortunately, misconceptions about the theoretical foundations of complex coacervation are common, and conceptual errors have persisted in the literature. This Review is an attempt to provide a concise and comprehensive overview of the main research streams pursued in this field regarding the parameters influencing the formation of complex coacervates, encompassing various technological aspects enabling the investigation of complex coacervates in industrial applications. Coacervate complex formation is a well-known and widely used, but poorly understood, phenomenon in physical polymer science. Finally, a critical assessment of perspectives and anticipated difficulties in the further development and improvement of next-generation materials is suggested, and insights into the field's future prospects are explored.

Mixing order asymmetry in nanoparticle-polymer complexation and precipitation revealed by isothermal titration calorimetry

“…1 In recent years, complex coacervation has undergone a renewed interest thanks to combined efforts to obtain precise experimental and theoretical accounts of the phenomenon, describing in details the phase diagrams, the role of ionic strength, the surface tension or the rheology of the coacervate phase. [2][3][4][5][6][7][8][9][10][11][12][13] A variant of the coacervation transition has also been noted in select systems that show liquid-solid phase coexistence instead, with the solid phase referred to as a complex precipitate. [14][15][16][17] In other well-studied cases, when one of the chains is replaced by a charge-neutral block copolymer, the electrostatic association leads to a microphase separation, and to the spontaneous formation of complex coacervate core micelles .…”

“…In the field of complex coacervation, the most extensively studied systems involve oppositely charged synthetic polymers with matching degrees of polymerization and charge. 3,6,8,18 Far from charge stoichiometry however, co-assembly also takes place, giving rise to colloids made of entangled and loosely bound polymers, known as polyelectrolyte complexes (PECs). 3,18,[33][34][35] Because their formation depends on physicochemical conditions such as concentration, pH and ionic strength and also the mixing mode, it is assumed that PECs are out of equilibrium, and in a metastable state.…”

“…Despite the extensive research on NP functionalization, there has been however limited investigation into the polymer-induced coacervation or precipitation of inorganic NPs to date. 2,6 In this work, we study the phase behavior and thermodynamics of the electrostatic complexation of sub-10 nm cerium (CeO2) and iron (𝛾-Fe2O3) oxide NPs with oppositely charged polymers. Both NPs are coated with negatively charged, low-molecular-weight poly(acrylic) acid chains.…”

Mixing Order Asymmetry in Nanoparticle-Polymer Complexation and Precipitation Revealed by Isothermal Titration Calorimetry

“…This phenomenon was initially identified more than a century ago and later examined in details in mixtures of proteins and polysaccharides by Bungenberg de Jong . In recent years, complex coacervation has undergone a renewed interest thanks to combined efforts to obtain precise experimental and theoretical accounts of the phenomenon, describing in details the phase diagrams, the role of ionic strength, the surface tension or the rheology of the coacervate phase. − A variant of the coacervation transition has also been noted in select systems that show liquid–solid phase coexistence instead, with the solid phase referred to as a complex precipitate. − In other well-studied cases, when polyelectrolytes are replaced by charge-neutral block copolymers, the electrostatic association leads to a microphase separation, and to the spontaneous formation of complex coacervate core micelles. ,− The driving force for association has been found to be of enthalpic and entropic origin, as revealed by isothermal titration calorimetry (ITC). ,− The enthalpic part of the association free energy is linked to the pairing of opposite charges, while the entropic contribution comes from the release of counterions that are originally condensed on the colloid surface or along the polymer backbone.…”

“…In the field of complex coacervation, the most extensively studied systems involve oppositely charged synthetic polymers with matching degrees of polymerization and charge. ,,, Far from charge stoichiometry, however, coassembly also takes place, giving rise to colloids made of entangled and loosely bound polymers, known as polyelectrolyte complexes (PECs). ,,− Because their formation depends on physicochemical conditions such as concentration, pH and ionic strength and also the mixing mode, it is assumed that PECs are out of equilibrium, and in a metastable state. , Apart from the species mentioned above – polymers, surfactants and proteins, most charged molecular and colloidal systems, including multivalent ions, ,, lipids assemblies, , biological polymers, ,,− nanoparticles, , cellulose nanofibers , nanoplastics, form electrostatic complexes by association with oppositely charged macromolecules, by analogy with PECs. In many of the previous instances, coassembled structures exhibit endothermic signatures similar to those of coacervation and precipitation, and are typically characterized by entropy-driven mechanisms. ,,,, …”