Hyaluronic acid (HAc) hydrogel exhibits excellent biocompatibility, but it has limited biomedical application due to its poor biomechanical properties as well as too-fast enzymatic degradation. In this study, we have developed an in situ precipitation process for the fabrication of a HAc-calcium phosphate nanocomposite hydrogel, after the formation of the glycidyl methacrylate-conjugated HAc (GMHA) hydrogels via photo-cross-linking, to improve the mechanical and biological properties under physiological conditions. In particular, our process facilitates the rapid incorporation of calcium phosphate (CaP) nanoparticles of uniform size and with minimal agglomeration into a polymer matrix, homogeneously. Compared with pure HAc, the nanocomposite hydrogels exhibit improved mechanical behavior. Specifically, the shear modulus is improved by a factor of 4. The biostability of the nanocomposite hydrogel was also significantly improved compared with that of pure HAc hydrogels under both in vitro and in vivo conditions.

For hydrogel injection applications, it is important to improve the strength and biostability of the hydrogel as well as its injectability to pass easily through the needle. Making gel microspheres is one approach to achieve these improvements. Granulization of a bulk hydrogel is a common procedure used to form microsized particles; however, the nonuniform size and shape cause an uneven force during injection, damaging the surrounding tissue and causing pain to the patients. In this study, injectable hyaluronic acid (HA)-based hybrid hydrogel microspheres were fabricated using a water-in-oil emulsion process. The injectability was significantly enhanced because of the relatively uniform size and spherical shape of the hydrogel formulates. In addition, the biostability and mechanical strength were also increased owing to the increased cross-linking density compared with that of conventionally fabricated gel microparticles. This tendency was further improved after in situ calcium phosphate precipitation. Our findings demonstrate the great potential of HA-based hydrogel microspheres for various clinical demands requiring injectable biomaterials.

Patients with diabetes experience delayed wound healing because of the uncontrolled glucose level in their bloodstream, which leads to impaired function of white blood cells, poor circulation, decreased production and repair of new blood vessels. Treatment using polydeoxyribonucleotide (PDRN), which is a DNA extracted from the sperm cells of salmon, has been introduced to accelerate the healing process of diabetic wounds. To accelerate the wound-healing process, sustained delivery of PDRN is critical. In this study, taking advantage of the non-invasive gelation property of alginate, PDRN was loaded inside the hydrogel (Alg-PDRN). The release behavior of PDRN was altered by controlling the crosslinking density of the Alg hydrogel. The amount of PDRN was the greatest inside the hydrogel with the highest crosslinking density because of the decreased diffusion. However, there was an optimal degree of crosslinking for the effective release of PDRN. In vitro studies using human dermal fibroblasts and diabetes mellitus fibroblasts and an in ovo chorioallantoic membrane assay confirmed that the Alg-PDRN hydrogel effectively induced cell proliferation and expression of angiogenic growth factors and promoted new blood vessel formation. Its effectiveness for accelerated diabetic wound healing was also confirmed in an in-vivo animal experiment using a diabetic mouse model.

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In this study, we evaluated the surface characterization of a novel chitosan-silica hybridized membrane and highlighted the substantial role of silica in the wound environment. The chemical coupling of chitosan and silica resulted in a more condensed network compared with pure chitosan, which was eventually able to stably maintain its framework, particularly in the wet state. In addition, we closely observed the wound-healing process along with the surface interaction between chitosan-silica and the wound site using large-surface-area wounds in a porcine model. Our evidence indicates that chitosan-silica exerts a synergetic effect of both materials to promote a remarkable wound-healing process. In particular, the silica in chitosan-silica accelerated wound closure including wound contraction, and re-epithelialization via enhancement of cell recruitment, epidermal maturity, neovascularization, and granulation tissue formation compared with pure chitosan and other commercial dressing materials. This advanced wound dressing material may lead to effective treatment for problematic cutaneous wounds and can be further applied for human skin regeneration.