# Bioactivity and Delivery Strategies of Phytochemical Compounds in Bone Tissue Regeneration
## 5 Phytochemical-Delivery Vehicles in Bone Tissue Regeneration
### Scaffolds  
Since the scaffold surface functionalization with polyphenols increases the bone regeneration capacity, the use of enriched scaffolds is considered a promising tool for bone bioengineering [129; 130; 131]. Ideally, a scaffold should mimic the extracellular matrix characteristics of the organ of interest to form cell/tissue-specific combination, pattern/topology, and mechanical properties able to support tissue formation [131]. The combination of scaffolds and phytochemicals is used to improve adhesion, growth, or differentiation of cells through the action of the bioactive compound for which the release can be controlled through three methods. When drugs are incorporated into the matrix of the scaffold, the release kinetics are regulated by the degradation of the polymer. Similarly, when scaffold surfaces are coated with a polymer/drug layer, the release is controlled by diffusion and degradation of the coating polymer. Conversely, the integration of micro-nano spheres into scaffolds offers a third mechanism of release based on the degradation of the scaffold and the consequent diffusion of the particle [132]. For example, [PERSON] et al. used biodegradable antioxidant scaffolds based on soybean (SB), as bone filler. This material showed an in vitro block of osteoclast activation succeeding incubation with SB, with a parallel inhibitory effect on monocyte/macrophage activity and an improved ability to induce mineralization in osteoblasts [133]. In another study, the SB granules implanted in rabbits led to bone repair with distinctive morphology from non-treated defects [134]. [PERSON] et al. produced scaffolds loaded with resveratrol by grafting the polyphenol to polyacrylic acid (PAA) and integrating this molecular drug into atelocolagen (Coll) hydrogels (Coll/PAA-RSV) [135]. These scaffolds supported the growth of chondrocytes and BMSCs protecting cells against reactive oxygen species. Moreover, the in vivo implantation on rabbits led to the disappearance of osteochondral defects and the integration of the newly formed tissue with surrounding tissue and subchondoral bone. [PERSON] et al. functionalized a poly-\(\varepsilon\)-caprolactone (PCL) surface with resveratrol, obtaining an osteogenic porous material. The presence of polyphenol on a scaffold surface increases the mineralization in stromal cells with an improvement in bone regenerating capacity [136]. [PERSON] et al. formulated a porous composite scaffold integrating PLC with resveratrol-loaded albumin nanoparticles. This 3D material produced a significant increment in cell proliferation, ALP activity, and mineralization imparting osteogenic properties to PCL scaffold [137]. [PERSON] et al. synthesized a PLA electrospinning membrane able to release resveratrol in a tunable manner for the preservation of the alveolar socket after tooth extraction. The controlled release of resveratrol influenced in vitro osteoblast and osteoclast differentiation [138]. In another work, the resveratrol released form PLA membrane presents a significant antibacterial and antibiofilm activity versus _Pseudomonas aeruginosa_ and _Streptococcus mutans_, becoming a promising solution for the prevention of implant-associated infections [51]. For cranio-facial tissue-engineering applications, [PERSON] et al. combine a collagen scaffold loaded with resveratrol with human adipose stem cells (hASCs). This composite promotes epidermal wound healing and bone mineralization [139]. [PERSON] et al. introduced dopamine (D) onto strontium-doped calcium polyphosphate (SCPP) scaffolds with silk fibroin (SF). SCPP/D/SF stimulated angiogenic factor secretion, osteogenesis, and had great biocompatibility (Figure 3). Then, SCPP/D/SF could fulfill a role as a potential scaffold for bone tissue engineering with the ability to speed up bone regeneration and vascularization. (Figure 4) [140]. [PERSON] et al. reported the synthesis by electrospinning of bone-like composite structures containing catecholamines and Ca(2+).