Bio-inspired Nanoparticulate Medical Glues for Minimally Invasive Tissue Repair

摘要

Methods to seal tissue leaks, attach devices, and to join tissues together during minimally invasive surgeries represents a significant challenge. Tissue adhesives and sealants used in clinic include fibrin sealants, cyanoacry-late-based glues, and protein/peptide-based glues, however their use in minimally invasive procedures is limited due to suboptimal usability/controllability by surgeons as they are generally applied in a low viscosity state, are hydrophilic and can dilute in blood or other fluids, and it is typically difficult to control their adhesive activation.1'5 In addition, the viscosity can present challenges when delivery is required through small-bore needles, especially, during procedures such as endoscopic and laparoscopic surgeries and surgeries on fragile tissues within confined space (e.g. ophthalmic applications). Inspired by the viscous glue secretion mechanism of the sandcastle worm (Phragmato-poma californica) using granule-packaged glues, we demonstrate a nano-encapsulated viscous glue that can easily be injected through small-bore needles for application during minimally invasive procedures (Figure 1). The sandcastle worms secrete glues into the surrounding environment without clogging their secretory ducts to build a tube-shaped house that makes use of accessible particu-lates including sand particles. To achieve this, high concentrations of proteinaceous glues are packaged into micrometer-size granules and stored in secretory cells (Figure la). When they are signaled to release the glues via a "burst" response, these granules are quickly delivered through secretory ducts into seawater that contains rich electrolytes and high pH (＞8.0). The electrolytes in sea-water trigger the granule membranes to rupture to release their glue contents resulting in viscous bulk glue mass that further cures to bond surrounding objects (e.g. sand particles). Inspired by the granule-based controlled glue transportation/activation system of sandcastle worms, we demonstrate a strategy to formulate viscous glues into wa-ter-dispersible injectable glue nanoparticles that can be assembled into the native viscous glue state following injection and can be cured in response to on-demand external stimuli (Figure 1b).