Cellular infiltration in an injectable sulfated cellulose nanocrystal hydrogel and efficient angiogenesis by VEGF loading

Abstract

Background Cellular infiltration and angiogenesis into implanted biomaterial scaffolds are crucial for successful host tissue integration and tissue regeneration. Cellulose nanocrystal (CNC) is a nano-sized cellulose derivative, which can form an injectable physical gel with salts. Sulfate groups of sulfated CNC (CNC-S) can act as a binding domain to various growth factors and cytokines with a heparin-binding domain for sustained release of them. Vascular endothelial growth factor (VEGF) can promote the proliferation of endothelial cells and angiogenesis. In this study, VEGF-loaded CNC-S hydrogel was evaluated as an injectable scaffold that can induce cellular infiltration and angiogenesis. Methods CNC-S was hydrolyzed to get desulfated CNC (CNC-DS), which was used as a negative control group against CNC-S. Both CNC-S and CNC-DS hydrogels were prepared and compared in terms of biocompatibility and VEGF release. The hydrogels with or without VEGF loading were subcutaneously injected into mice to evaluate the biocompatibility, cellular infiltration, and angiogenesis induction of the hydrogels. Results Both hydrogels possessed similar stability and shear-thinning behavior to be applicable as injectable hydrogels. However, CNC-S hydrogel showed sustained release (until 8 weeks) of VEGF whereas CNC-DS showed a very fast release of VEGF with a large burst. Subcutaneously injected CNC-S hydrogel showed much enhanced cellular infiltration as well as better biocompatibility with milder foreign body response than CNC-DS hydrogel. Furthermore, VEGF-loaded CNC-S hydrogel induced significant angiogenesis inside the hydrogel whereas VEGF-loaded CNC-DS did not. Conclusion CNC-S possesses good properties as a biomaterial including injectability, biocompatibility, and allowing cellular infiltration and sustained release of growth factors. VEGF-loaded CNC-S hydrogel exhibited efficient angiogenesis inside the hydrogel. The sulfate group of CNC-S was a key for good biocompatibility and the biological activities of VEGF-loaded CNC hydrogel.

Hydrogels in Gene Delivery Techniques for Regenerative Medicine and Tissue Engineering

“…[ 72 ] Thus, chemically cross‐linked hydrogels are more stable to resist degradation and have better mechanical characteristics. [ 73 ] Usually, chemical cross‐linking requires introducing a cross‐linking agent and takes longer. [ 74 ] The presence of cross‐linking agents contributes to the antimicrobial activity of hydrogels, while there is a risk of toxicity problems and lower biocompatibility posed by the chemical cross‐linkers.…”

“…[ 79 ] Physically cross‐linked hydrogels are less stable against degradation and are biodegradable and cell‐compatible. [ 73,80 ] Moreover, physical cross‐linking is also known as self‐assembling hydrogels, generally carried out by straightforward and convenient methods to avoid any cross‐linking agents, [ 81 ] leading to low cytotoxicity and low cost. [ 74 ]…”

Potential Role of Hydrogels in Stem Cell Culture and Hepatocyte Differentiation

“…They utilized tyraminesubstituted silk or gelatin to crosslink regenerated silk, which can improve the gelation kinetics and mechanical properties of silk hydrogels by increasing the number of phenol groups available for enzymatic crosslinking. Generally, there are three types of cellular encapsulation in 3D hydrogels: porous structure [47], fibrous structure [48] and microencapsulation [49]. Many protein-based hydrogels have been reported to have a porous structure that may provide a favorable niche loaded with growth factors and valuable cells for tissue formation and growth.…”

Advancements and Applications of Injectable Hydrogel Composites in Biomedical Research and Therapy

“…For example, a sulfated cellulose nanocrystal (CNC-S) hydrogel loaded with vascular endothelial growth factor (VEGF) has been developed to facilitate tissue regeneration by promoting cellular infiltration and angiogenesis. This innovative hydrogel-based approach offers a potential solution for promoting tissue regeneration in various clinical scenarios [43].…”

“…In addition to their aforementioned applications, injectable hydrogel systems hold great potential in several other areas of biomedical research. These include ischemic brain injury, tissue regeneration, cardiovascular diseases, and personalized cancer immunotherapy [42][43][44][45]. Notably, in the treatment of ischemic brain injury, injectable hydrogels have demonstrated the ability to facilitate neuronal proliferation, angiogenesis, and tissue regeneration, offering promising therapeutic prospects [42].…”