Self-assembling in situ gel based on lyotropic liquid crystals containing VEGF for tissue regeneration

Current tissue-regenerative biomaterials confront two critical issues: the uncontrollable delivery capacity of vascular endothelial growth factor (VEGF) for adequate vascularization and the poor mechanical properties of the system for tissue regeneration. To overcome these two issues, a self-assembling in situ gel based on lyotropic liquid crystals (LLC) was developed. VEGF-LLC was administrated as a precursor solution that would self-assemble into an in situ gel with well-defined internal inverse bicontinuous cubic phases when exposed to physiological fluid at a defect site. The inverse cubic phase with a 3D bicontinuous water channel enabled a 7-day sustained release of VEGF. The release profile of VEGF-LLC was controlled using octyl glucoside (OG) as a hydration-modulating agent, which could enlarge the water channel, yielding a 2-fold increase in water channel size and a 7-fold increase in VEGF release. For the mechanical properties, the elastic modulus was found to decrease from ∼100 kPa to ∼1.2 kPa, which might be more favorable for angiogenesis. Furthermore, the self-recovery ability of the VEGF-LLC gel was confirmed by quick recovery of the inner network in step-strain measurements. In vitro, VEGF-LLC considerably promoted the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) as compared to free VEGF (p < 0.05). Furthermore, angiogenesis was successfully induced in rats after subcutaneous injection of VEGF-LLC. The self-assembling LLC gel showed satisfactory degradability and mild inflammatory response with little impact on the surrounding tissue. The controllable release profile and unique mechanical properties of VEGF-LLC offer a new approach for tissue regeneration. STATEMENT OF SIGNIFICANCE: The potential clinical use of currently available biomaterials in tissue regeneration is limited by their uncontrollable drug delivery capacity and poor mechanical properties. Herein, a self-assembling in situ gel based on lyotropic liquid crystals (LLC) for induced angiogenesis was developed. The results showed that the addition of octyl glucoside (OG) could change the water channel size of LLC, which enabled the LLC system to release VEGF in a sustained manner and to possess a suitable modulus to favor angiogenesis simultaneously. Moreover, the self-recovery capability allowed the gel to match the deformation of surrounding tissues during body motion to maintain its properties and reduce discomfort. In vivo, angiogenesis was induced by VEGF-LLC 14 days after administering subcutaneous injection. These results highlight the potential of LLC as a promising sustained protein drug delivery system for vascular formation and tissue regeneration.