An Artificial Liquid–Liquid Phase Separation-Driven Silk Fibroin-Based Adhesive for Rapid Hemostasis and Wound Sealing

Underwater bioadhesive systems in native aquatic organisms provide an inspiration for the design and fabrication of functional protein-based adhesive materials [[1], [2], [3]]. For example, to mimic the catecholic amino acids of mussels, numerous research works have been conducted to synthesize catechol-containing polymers as adhesive materials for clinical applications [[4], [5], [6]], yet it remains challenging to reconstruct the hierarchical organization of mussel foot proteins in byssal threads. More recently, there has been increasing evidence that liquid–liquid phase separation (LLPS) also plays a critical role in the strong underwater adhesion of mussel foot proteins. Marine mussels utilize the LLPS strategy to induce the supramolecular assembly of mussel foot proteins, which form a protein coacervate phase with coexisting droplets, followed by liquid-to-solid maturation for robust interfacial adhesion under seawater conditions [[7], [8], [9]]. In another example, sandcastle worms secrete two oppositely charged protein polyelectrolytes to form dense complex coacervates via LLPS rather than directly secreting protein polyelectrolytes into seawater [[10], [11], [12]]. This LLPS-mediated coacervation mechanism facilitates the efficient deposition and coagulation of protein polyelectrolytes on the surface of underwater mineral substrates for robust adhesion, preventing their dissolution into the ocean. Therefore, exploiting LLPS-mediated coacervation to generate robust underwater adhesion provides a new approach for designing artificial protein-based bioadhesives.

Following this argument, marine organism-inspired LLPS-driven underwater adhesion has attracted considerable attention for the construction of artificial bioadhesives. Zhao et al. demonstrated an interesting approach by mixing cationic quaternized chitosan with anionic catechol-functionalized poly(acrylic acid) in dimethyl-sulfoxide (DMSO) [13]. During the water–DMSO solvent exchange, polyelectrolyte coacervates were formed to achieve underwater adhesion. Ma et al. reported a biocompatible protein-based adhesive composed of genetically engineered cationic polypeptides and anionic aromatic surfactants [14]. Coacervates were immediately formed after mixing the two components via LLPS, resulting in wet tissue adhesion and wound hemostasis as biomedical glues. In addition to the above mentioned two-component co-assembly systems, LLPS-mediated coacervation behavior based on a single component is a powerful tool for adhesive applications. Cui et al. created a genetic fusion protein containing mussel foot protein-5 and a mammalian low-complexity domain [15]. The genetic fusion protein underwent LLPS to form liquid-like condensates and eventually matured into an amyloid nanofiber coating, exhibiting strong underwater adhesion. Despite remarkable advances, these material fabrication methods often need time-consuming processing steps and the use of harsh solvents, which limits the suitability of these artificial bioadhesives in biomedical applications. Therefore, it is highly desirable to establish a simple and feasible strategy for constructing artificial protein-based adhesives by adopting LLPS-mediated coacervation.

Herein, inspired by the LLPS behavior of mussels, we introduce a new generation of robust underwater protein-based adhesives driven by LLPS-mediated coacervation (Figure 1). This underwater adhesive comprises the natural protein silk fibroin (SF) and the anionic surfactant sodium dodecylbenzene sulfonate (SDBS). SF, derived from Bombyx mori silkworm silk, has shown great potential for biomedical applications because of its good biocompatibility and biodegradability [[16], [17], [18], [19], [20]]. SDBS is a non-toxic surfactant approved by the U.S. Food and Drug Administration (FDA) for use in biomedical devices and cosmetic products [[21], [22], [23]]. The hydrophobic interactions between SF and SDBS led to LLPS of the complexes to form an SF-based adhesive coacervate (SFG). The SFG coacervates were effectively deposited on various wet substrate surfaces with irregularities, allowing tight contact with the substrates underwater. The spontaneous coacervate-hydrogel transition in situ enhanced the cohesion of SFG, resulting in robust bulk adhesion on various wet substrates without any additional stimuli. In vivo animal experiments suggested that SFG exhibited tight tissue adhesion and rapid hemostatic performance in bleeding tissues. The advantages of SFG include good biocompatibility, robust wet adhesion, adaptability to irregular tissue surfaces, and ease of operation, making it a promising protein-based adhesive for facilitating wound healing and tissue regeneration.

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