In-situ forming adhesive hydrogels for tissue regeneration

Abstract

Hydrogels have been widely used for various biomedical applications due to their similarity to extracellular matrix and biocompatibility. In particular, adhesive hydrogels, which strongly adhere to tissues, have recently emerged in tissue regeneration fields, such as wound closure, sealing, hemostasis, and a tissue engineering scaffold. However, conventional adhesive hydrogels have several limitations, including cytotoxicity, low mechanical stability, and limited wet adhesion. To overcome these limitations, novel adhesive hydrogels with good biocompatibility and reliable adhesion to a wet tissue are highly desired. In this thesis, the natural polymer-based biocompatible adhesive hydrogels were synthesized and utilized for the effective regeneration of several tissues, such as cardiac tissue after myocardial infarction and skeletal muscle after volumetric muscle loss (VML). Specifically, natural polymers (dextran aldehyde (dex-ald) and gelatin) were formulated as the basal matrix materials for the adhesive hydrogel. Upon mixing in aqueous solution, these two polymers undergo spontaneous gelation via the Schiff base reaction, allowing for painting, in situ gelation, and strong adhesion to tissue via Schiff base formation and hydrogen bonding. This adhesive polymer hydrogel was further used to embed functional components, such therapeutic substance and conductive materials, for fabrication of sustained drug releasing hydrogel patch and electrically conductive hydrogels. First, a paintable and adhesive hydrogel was developed by incorporating the anti-inflammatory protein ANGPTL4 into dex-ald/gelatin hydrogel as a cardiac hydrogel patch capable of mechanical support of infarcted heart and sustained release of ANGPLT4 at the epicardium of heart repair. A paintable and adhesive hydrogel containing 10% gelatin and 5% dex-ald showed in-situ gelation within 135 s, cardiac tissue-like modulus (40.5 kPa), adequate tissue adhesion (4.3 kPa), and excellent mechanical stability. ANGPTL4 was released continuously from the adhesive hydrogel without significant burst release. The adhesive hydrogel could be conveniently painted onto the beating heart and degraded in vivo. In vivo studies with acute myocardial infarction animal demonstrated that our ANGPTL4-containing hydrogel cardiac patch significantly improved cardiac tissue repair. Second, a conductive and adhesive hydrogel (CAH) as a paintable cardiac patch was developed by combining the two-dimensional titanium carbide (Ti3C2Tx) MXene for infarcted heart repair. The hydrogel containing 3.0 mg/mL MXene exhibited material properties suitable for cardiac patch applications, such as high electrical conductivity (18.3 mS/cm). This CAH was cytocompatible and induced cardiomyocytes to mature and beat faster in vitro. In vivo animal studies showed that CAH patch treatment significantly improved cardiac function and attenuated infarct pathological remodeling. Finally, a wet tissue-adhesive powder hydrogel was developed for muscle regeneration after VML. A powder was formulated as a blend of dex-ald and gelatin. The powder applied to a wound site, absorbed interfacial water and was further hydrated with additional treatment with phosphate buffered saline, eventually forming intact hydrogels and firmly adhering to the tissue via a Schiff base reaction. A reasonable gelation time (258 s), strong tissue adhesion (14.5 kPa), and stability were obtained for the powder hydrogel composed of a 1:4 ratio of dex-ald and gelatin. In comparison to other wet hydrogels and fibrin glue, the powder hydrogels adhered strongly to various organs and exhibited excellent hemostasis. In animal studies using the mouse VML injury model, the powder hydrogel significantly improved skeletal muscle regeneration of VML. In conclusion, this thesis has elaborated to develop natural polymer-based biocompatible adhesive hydrogel that endows new properties through the incorporation of functional components. Multifunctional adhesive hydrogels will be beneficial to develop biomaterial-based tissue regeneration applications.