Long-lasting and bioactive hyaluronic acid-hydroxyapatite composite hydrogels for injectable dermal fillers: Physical properties and in vivo durability

Abstract

Hyaluronic acid (HAc)-hydroxyapatite (HAp) composite hydrogels were developed to improve the biostability and bioactivity of HAc for dermal filler applications. Two kinds of HAc-HAp composite fillers were generated: HAcmicroHAp and HAc-nanoHAp composites. HAc-microHAp was fabricated by mixing HAp microspheres with HAc hydrogels, and HAc-nanoHAp was made by in situ precipitation of nano-sized HAp particles in HAc hydrogels. Emphasis was placed on the effect of HAp on the durability and bioactivity of the fillers. Compared with the pure HAc filler, all of the HAc-HAp composite fillers exhibited significant improvements in volumetric maintenance based on in vivo tests owing to their reduced water content and higher degree of biointegration between the filler and surrounding tissues. HAc-HAp composite fillers also showed noticeable enhancement in dermis recovery, promoting collagen and elastic fiber formation. Based on their long-lasting durability and bioactivity, HAc-HAp composite fillers have great potential for soft tissue augmentation with multifunctionality.

Hyaluronic acid‐hydroxyapatite nanocomposite hydrogels for enhanced biophysical and biological performance in a dermal matrix

“…6,24,25 In particular, it can be inferred how long wrinkle improvement would maintain according to gel persistence with biostability. 15 According to our previous study, HAc-nanoHAp filler maintained 60% in volume after 4-week injection into nude mouse skin, whereas pure HAc drastically degraded away, retaining only 40%. 15 It is indicated that HAp nanoparticles in HAc-nanoHAp imposed a physical barrier to enzymatic breakdown, which contributing to high resistance.…”

“…15 According to our previous study, HAc-nanoHAp filler maintained 60% in volume after 4-week injection into nude mouse skin, whereas pure HAc drastically degraded away, retaining only 40%. 15 It is indicated that HAp nanoparticles in HAc-nanoHAp imposed a physical barrier to enzymatic breakdown, which contributing to high resistance. Thus the incorporation of HAp nanoparticles made the gel more durable under physiological condition rather than pure HAc.…”

“…This structural support of dermal ECM by HAp nanoparticles generated a tightening effect on the collagen fiber network in accordance with the stretched fibroblasts. 9,15,32 Thus, it improved firmness of the dermal tissue, as increasing the thickness of dermal tissue. In conclusion, it can be explained that HAp nanoparticles in HAc-nanoHAp contribute to the modulation of fibroblast's biological function as promoting the production of growth factor, stimulating of vimentin filament in proliferated fibroblasts, and finally synthesis of ECM matrix such as collagens through molecular pathway related to TGF-b mediated SMAD pathway.…”

“…HAc-nanoHAp hydrogel was fabricated following in situ precipitation process introduced in previous research. 14,15 Briefly, pure HAc hydrogel was prepared after crosslinking by 1,4-butanediol diglycidyl ether and was immersed in the solution of calcium chloride (CaCl 2 ) and phosphoric acid (H 3 PO 4 ). Subsequently, it was dipped in 15% ammonium hydroxide (NH 4 OH) solution for 30 min to precipitate HAp nanoparticles within the hydrogel.…”

“…13 With a more extensible approach for fabricating nanocomposite hydrogels, the in situ precipitation process has been established in our previous study to fabricate HAc-hydroxyapatite (HAp) nanocomposite hydrogels (HAc-nanoHAp) that possess high mechanical strength and enzymatic resistance. 14,15 In this system, in situ precipitation expedited a strong reaction between HAc and HAp, regulating the uniform mineralization of HAp nanoparticles in HAc chains, and these homogeneous structures greatly enhanced the mechanical properties of hydrogels. 16 In addition, HAp nanoparticles provided a supportive environment for cell functions, increasing the bioactivity of the gels.…”