Table 2.

Significant results on natural polymer-HAp scaffolds and their remarks

Composite scaffolds	Fabrication method	Pore size and structure	Mechanical strength	Mode of study	Remarks	Ref
Quercetin-Col-HAp	Freeze-drying	~ 70% porosity and uniform	Compression strength  > 0.178 ± 0.02 MPa	In vitro (BMSC cells) and in vivo (rat calvarial bone defect)	Inclusion of Qtn mildly reduced the compressive strength, conversely porosity increased with increment of Qtn concentration. Osteoconductive and osteoinductive features exhibited	136
HAp/Col-coated PLGA	Electrospinning followed by biomimetic and adsorption	Interconnected porous structure	-	In vitro (MSC cells)	Accelerated cell spreading, elevated level of ALP activity, and improved expression of osteogenic marker genes (Runx2, ALP, and OCN) on HAp/Col coating when compared with HAp coating	137
Fe-Col/HAp	Biomimetic and freeze-drying route	Micro-macroporosity	-	In vitro (MG-63 cells)	In vitro biocompatibility study revealed good ability to support cell adhesion and proliferation. The final microstructures of the scaffold in terms of open porosity and the degradation rate seem to have great influence on the cell behavior in vitro	138
Col/HAp	“Layer by layer” freeze-drying route	Pore diameter of upper (~ 132 μm), intermediate (~ 86 μm), and lower (~ 36 μm) layers	-	In vitro (BMSC cells)	The scaffold offered a suitable environment for BMSC cell proliferation owing to its impeccably integrated layer structure, higher levels of porosity, homogeneous pore structure, and high degree of pore interconnectivity achieved	139
Col/HAp	Gradient scaffolds by freeze-drying route	Open and interconnected porosity	Compressive modulus  ~ 8–18 kPa	In vitro (hBMSC cells) and in vivo (rat model)	hBMSC signifies the ability of cells to be directed by the chondrogenic or osteogenic environment created by the gradient material composition and stiffness in the different regions of the gradient scaffold. The in vivo biocompatibility was confirmed by the subcutaneous implantation in rats, with minimal inflammatory response observed and cellular differentiation	140
CS-HAp	Sol–gel with freeze-drying technique	-	-	In vitro (hMSC cells)	At higher concentration of HAp (60 and 70%) showed a notable effect on osteogenic differentiation of hMSC towards mature osteoblast phenotype and were able to prevent, on in vitro cell culture model, pro-inflammatory events. A good effect on the expression of anti-inflammatory cytokines (IL-10 and IL-4), meanwhile it was able to decrease pro-inflammatory cytokine (TGF-β) levels	141
CS-HAp films	Solultion casting	-	Tensile strength -  ~ 69 MPa	-	CS/HAp nanocomposites containing 10 and 20% by weight HAp showed intercalated morphologies, layered 3D porous structures. Uniform and stable nanoscale dispersions obtained using formic acid solvent	142
Copper-CS/Sr-HAp scaffolds	Freeze-drying	~ 90% porosity 10 – 100 μm in size with interconnected porosity	Compressive modulus 2–3 MPa	In vitro (MG-63 cells)	CS complexed with copper and strontium substituted HAp for effective loading and release of ions in order to obtain therapeutic effect. The composites headed to tailored biological effects, from antibacterial activity, to osteogenesis and angiogenesis	143
Alg/PVA/HAp	3D printing	-	Compressive modulus 8.6 to 10.3 kPa	In vitro (MC3T3-E1 cells)	3D printed scaffolds composed of optimal formulations displayed sufficient integrity and mechanical properties over a 14-day incubation period in cell culture media, suggesting potential to offer a suitable environment for cells for in vitro culture	144
Alg-HAp	3D printing	Pore size 200 μm	1215 kPa	In vitro (mBMSC cells)	Porous scaffolds had high porosity and adjustable hierarchical porous structure. The mBMSCs could be adhered and proliferated well on the pore wall surface of the porous scaffolds, representing that the porous scaffolds had superior biocompatibility	145
Alg/Mg-HAp hydrogels	Freeze-drying	Pore size 200–700 μm	-	In vitro (MC3T3-E1 cells)	Diels–Alder click chemistry is an efficient and non-toxic cross-linking approach to fabricate biocomposite scaffolds with high porosity after freeze-drying. The addition of 5 wt% MgHAp in the scaffold composition ensures the best development for a biocomposite with a suitable porosity and dimensional hierarchy with good cell–material interactions	146
Gel/HAp	Sol–gel and Freeze-drying	Pore size ranges 90–190 μm and 100–200 μm for top and cross-sectional views respectively	Compressive modulus  ~ 18.99–581.06 kPa	In vitro (hMSC cells)	The electrostatic interactions between Ca2+ ions and COO groups regulate the alignment of nHAp crystals along the gelatin matrix. Especially, at a lower amount of inorganic phase, a homogeneous distribution was obtained; meanwhile, the formation of a gradient was achieved by increasing the inorganic phase at 30wt%, which has reduced compressive modulus, but showed better results than other fillers used to repair bone defects	147
SF/HAp	In situ mineralization and 3D printing	~ 70% porosity, ~ 400 μm in size with interconnected pores	Compressive strength > 6 MPa	In vitro (hBMSC cells) and in vivo (rat model)	By using SA as printing glue, the SF/HA-SA composite scaffolds possessed a relatively high compressive strength combined with high interconnectivity and high porosity. The pore structure complexity was feasible to be adjusted via 3D printing technology. Furthermore, the scaffolds allowed hBMSC penetration and spread all over the scaffold network and were found promoting hBMSC proliferation and osteogenic differentiation	148
Hyal/HAp hydrogels	Freeze-drying	< 90% porosity, pore size ranges 30–300 μm with open pore structure	-	-	All the sponges were highly porous and the porosity decreased with increase of mineralization time. Maximum porosity of 95.83% was observed for 3-h immersion and the minimum porosity of 81.42% was shown for the 18-h immersion. This decrease in the porosity might be due to the increase in the deposition of the hydroxyapatite minerals on the walls of the sponges	149
PVA-Hyal/HAp hydrogels	Freeze-thawing	-	-	In vitro (MG-63 cells)	Hydrogel based on mixtures of PVA and Hyal enriched by HAp using a freezing–thawing method of physical crosslinking. Hyal significantly increased the primary adhesion of cells and HAp improved the cell spreading and proliferation but only to a certain extent. A further increase in HAp content caused a decrease in cell proliferation	150
Silk fibroin/collagen/HAp	Low-temperature 3D printing	Highly porous	Improved mechanical properties	In vitro (MC3T3-E1 cells) In vivo (reconstruction of mandibular defects)	Optimized scaffolds are loaded with recombinant human erythropoietin for the reconstruction of bone defects, on which MC3T3-E1 cells were well adhered and proliferated. Proliferation and formation of osteoblasts and collagen fibrils respectively encouraged the reconstruction of mandibular defects	151