Heparin and heparin analogue based biomaterials for tissue regeneration

Abstract

Heparin, a negatively charged glycosaminoglycan, possesses various biological activities, such as anticoagulation, growth factor binding, anti-inflammation, and protein stabilization, as well as biocompatibility and biodegradability. Heparin has been extensively utilized in biomedical applications with these characteristics. To replicate the biological activities of heparin in other biomaterials, sulfate groups, which are key components for the activities of heparin, have been introduced to diverse polymers and biomaterials to mimic heparin and replicate these functions. Heparin and heparin analogue-based biomaterials have been studied for tissue regeneration in this thesis. In chapter Ⅱ, injectable sulfated cellulose nanocrystal (CNC) hydrogels efficiently delivered vascular endothelial growth factor (VEGF). Sulfated CNC, a heparin analogue, featuring sulfate groups, exhibited an affinity for VEGF, achieving sustained release of loaded VEGF with maintained bioactivity. Excellent biocompatibility, host tissue responses, and angiogenesis were demonstrated after subcutaneous injection of CNC hydrogels into mice. Chapter Ⅲ presented a literature study of various drug delivery systems (DDSs) for inflammatory diseases. It described the background of inflammation and DDSs and introduced traditional and emerging DDSs for inflammatory diseases. Strategies for targeting and controlled drug release were explored to maximize the therapeutic effects of DDSs while minimizing their side effects. Hemin, an FDA-approved heme-derived metalloorganic porphyrin, is a nanozyme with catalase and peroxidase-mimetic activities. While the catalytic activities of hemin were well-known, its poor bioavailability and rapid clearance in vivo limited their clinical applications. In Chapter Ⅳ, superoxide dismutase-mimetic activity of hemin was newly reported. Hemin was conjugated to heparin to form self-assembled structures with a nano-size and exhibited enhanced enzymatic activities and stabilities compared to free hemin. Hemin-conjugated heparin protected renal proximal tubular cells against external reactive oxygen species (ROS) in vitro. The anti-inflammatory and tissue regenerative effects of polymer-based nanozyme systems were evaluated using a glycerol-induced acute kidney injury model. Chapter Ⅴ developed hemin-incorporated heparin/hyaluronic acid hydrogels, providing a favorable stem cell niche for 3D encapsulation of stem cells with excellent cytoprotective effects against external ROS, maintaining viability and activities and lowering the intracellular ROS levels of the encapsulated stem cells. The therapeutic efficacy of encapsulated the stem cells in hemin-incorporated hydrogels was evaluated in a diabetic wound model. The hemin-incorporated hydrogels reduced tissue ROS levels and inflammation, accelerating the wound healing process with angiogenesis. In conclusion, various heparin and heparin analogue-based biomaterials have been developed for tissue engineering. This thesis extensively covers from the preparation and characterizations of these materials, to their functional evaluation in in vitro and in vivo. Heparin and heparin analogue-based biomaterials can be considered as promising and effective candidates for tissue engineering and other biomedical applications.