Injectable Multifunctional Drug Delivery System for Hard Tissue Regeneration under Inflammatory Microenvironments

Abstract

Engineering multifunctional hydrogel systems capable of amplifying the regenerative capacity of endogenous progenitor cells via localized presentation of therapeutics under tissue inflammation is central to the translation of effective strategies for hard tissue regeneration. Here, we loaded dexamethasone (DEX), a pleotropic drug with anti-inflammatory and mineralizing abilities, into aluminosilicate clay nanotubes (halloysite clay nanotubes (HNTs)) to engineer an injectable multifunctional drug delivery system based on photo-cross-linkable gelatin methacryloyl (GelMA) hydrogel. In detail, a series of hydrogels based on GelMA formulations containing distinct amounts of DEX-loaded nanotubes was analyzed for physicochemical and mechanical properties and kinetics of DEX release as well as compatibility with mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs). The anti-inflammatory response and mineralization potential of the engineered hydrogels were determined in vitro and in vivo. DEX conjugation with HNTs was confirmed by FTIR analysis. The incorporation of DEX-loaded nanotubes enhanced the mechanical strength of GelMA with no effect on its degradation and swelling ratio. Scanning electron microscopy (SEM) images demonstrated the porous architecture of GelMA, which was not significantly altered by DEX-loaded nanotubes' (HNTs/DEX) incorporation. All GelMA formulations showed cytocompatibility with SHEDs (p < 0.05) regardless of the presence of HNTs or HNTs/DEX. However, the highest osteogenic cell differentiation was noticed with the addition of HNT/DEX 10% in GelMA formulations (p < 0.01). The controlled release of DEX over 7 days restored the expression of alkaline phosphatase and mineralization (p < 0.0001) in lipopolysaccharide (LPS)-stimulated SHEDs in vitro. Importantly, in vivo data revealed that DEX-loaded nanotube-modified GelMA (5.0% HNT/DEX 10%) led to enhanced bone formation after 6 weeks (p < 0.0001) compared to DEX-free formulations with a minimum localized inflammatory response after 7 days. Altogether, our findings show that the engineered DEX-loaded nanotube-modified hydrogel may possess great potential to trigger in situ mineralized tissue regeneration under inflammatory conditions.

Chitosan-Based Smart Biomaterials for Biomedical Applications: Progress and Perspectives

“…A regenerative dental procedure including dentine-pulp complex regeneration is an alternative approach for treating severe pulp exposure to pulp capping and various pulpotomy procedures . Hoveizi et al encapsulated human endometrial stem cells in chitosan hydrogel containing titanium oxide nanoparticles for dental pulp repair .…”

“…A regenerative dental procedure including dentine-pulp complex regeneration is an alternative approach for treating severe pulp exposure to pulp capping and various pulpotomy procedures. 177 Hoveizi et al encapsulated human endometrial stem cells in chitosan hydrogel containing titanium oxide nanoparticles for dental pulp repair. 178 Results show the combination of stem cells with chitosan/TiO 2 exhibited a synergistic effect on each other and increased the speed and quality of dentine repair.…”

Nanomaterials: A Review about Halloysite Nanotubes, Properties, and Application in the Biological Field

“…The DEX-loaded nanotube modified GelMA hydrogel (GelMA + 5.0%HNT-DEX10%) showed relevant properties from a mechanical point of view, but also biodegradability and cytocompatibility with mesenchymal stem cells from human exfoliated deciduous teeth (SHEDs). Moreover, the system had in vivo biocompatibility, and it also supported bone regeneration in vivo [ 145 ]. Phototherapy is described as a safe and secure way to destroy cancer cells when light waves of a particular wavelength are used with appropriate activating agents.…”

Liquid Metal–Hydrogel Biosensor for Behavior and Sweat Monitoring

“…With their unique biocompatibility, gelatin methacryloyl (GelMA) has been extensively used in biological fields, including drug delivery, 15,16 tissue repair, 17,18 and bioengineering. 19,20 However, GelMA hydrogels also have fatal defects in their poor mechanical properties and antidrying ability, which severely limit the range of their application.…”

“…With their unique biocompatibility, gelatin methacryloyl (GelMA) has been extensively used in biological fields, including drug delivery, , tissue repair, , and bioengineering. , However, GelMA hydrogels also have fatal defects in their poor mechanical properties and antidrying ability, which severely limit the range of their application. Therefore, it is urgent to develop a simple and effective method to greatly improve its mechanical properties without changing its high biocompatibility.…”