Table 1 A list of polyphenols and their in vitro and in vivo experimental outcomes in bone tissue engineering

Curcumin

Beijing Solarbio Science & Technology, China

In vitro: Isolated bone marrow mesenchymal stem cells (BMSCs) from 5 to 6-week male BALB/c mice (15–21 g bw)

Mouse embryonic fibroblasts (MEFs) isolated from pregnant C57/BL female mice (23–26 g bw) at 13 days of post-coitum

1) OM group: Cells in osteogenic medium

2) CR group: Cells in osteogenic medium containing 15 μM curcumin

3) ATRA group: Cells in osteogenic medium containing 1 μM all-trans retinoic acid

CR group showed an increase in the osteogenic differentiation capacity of BMSCs compared to OM and ATRA groups, as identified by the mineralization assay and RT-PCR analysis of bone markers and OCN expression.

CR group augmented the osteogenic differentiation of MEFs, reprogrammed with the osteogenic factor hLMP-3. Further, it significantly increased the expression of the bone markers Runx2, BMP, and osterix at 1, 2, and 3 weeks of post-transduction.

Ahmed et al. (2019) [59]

Curcumin

Sigma-Aldrich, Germany

In vivo: Male Wistar albino rats (170–210 g bw); n = 10 curcumin group and n = 6 control group; transverse femur shaft fracture model

Control and curcumin groups (histological, biomechanical, and radiological assessment); 14 and 28 days; 200 mg/ kg oral dose in saline

The curcumin group showed no significant difference in histological, biomechanical, and radiological treatment on 14 days.

No significant difference between control and curcumin-treated groups was observed on 28 days.

Safali et al. (2019) [60]

Green tea extract (GTE)

GTE Sunphenon 90LB, Taiyo International, Germany

In vitro: Primary human osteoblasts isolated from the femur heads of patients undergoing total hip replacement; 2.0 × 10⁴ cells/cm²

1) Control: Unstimulated cells

2) Cells stimulated six times with/without 50 μM H₂O₂ and 0.01, 0.1, and 1 μg/ml of GTE

Low doses of GTE improved mineralization in stimulated osteoblasts with H₂O₂ over 21 days. The combined effects of GTE and H₂O₂ led to a higher level of gene expression (osteocalcin and collagen1α1) during osteoblasts differentiation. High doses of GTE protected osteoblasts against oxidative stress by reducing intracellular free radicals and LDH leakage.

Vester et al. (2014) [61]

Green tea polyphenols (GTP)

Shili Natural

Product Company, China (purity > 80%)

In vivo: Virgin 14-month-old female F344 × BFN1/NIA rats; n = 10/group; postmenopausal bone loss model

1) Baseline group: No surgical treatment

2) Estrogen adequate sham group (SH): SH control, SH-L (sham+ 0.1% GTP (w/v) in drinking water), and SH-H (SH + 0.5% GTP)

3) Estrogen deficient OVX group: OVX ovariectomy control, OVX-L (OVX + 0.1%), and OVX-H (OVX + 0.5%)

OVX group showed a dose-dependent increase in periosteal parameters such as mineralized bone surface and bone formation rate. However, the OVX-H group demonstrated a significant difference (p < 0.05) compared to other OVX groups, SH groups, and baseline group.

Shen et al. (2009) [62]

Pomace polyphenolic extract adsorbed Synergoss Red

Pomace extract: Croatina grape, Alemat, Italy

Synergoss Red: Synthesized from HA, β-TCP powders, and poly (vinyl alcohol)

In vitro: Human osteoblast-like SAOS2 cells; 8.5 × 10⁴ cells/ml

0.2 g /well; 3, 5, and 7 days

The compound improved early-stage bone matrix deposition and downregulated inflammation. Further, it regulated osteoclastogenesis by the action of anti-inflammatory and antioxidant properties.

Iviglia et al. (2021) [63]

Naringin

Sigma-Aldrich, USA (purity > 95%)

In vitro: BMSCs isolated from lateral tibial tubercle of 4–8 weeks old New Zealand white rabbit (2.0 ± 0.5 kg bw)

0.1, 1, and 10 μM; 48 h

1 μM; 3, 7, 14, and 21 days

Naringin stimulated BMSCs differentiation into osteoblasts via the upregulation of miR-20a and the downregulation of PPARγ, which was significant compared to control.

1 μM of naringin significantly increased ALP expression after 3 days and showed a higher OC and Col I expression level in 21 days.

Fan et al. (2015) [64]

Apigenin

Institute of Traditional Chinese Medicine, Nanjing, China

Human fetal bone marrow-derived from the stem cells (hMSCs), Prince of Wales Hospital

Control: Osteogenic induced medium (OIM)

OIM + apigenin: 0.1,1, and 5 μM; 3, 7, and 14 days.

Apigenin promoted the osteogenesis of hMSCs by stimulating JNK and p38 MAPK signaling pathways. The effect of apigenin on mRNA expression (Runx2 and OPN) in hMSCs was significantly more significant than control on 7 days (p < 0.01).

Zhang et al. (2015) [65]

Icariin

Tauto Biotech, Shanghai, China

In vivo:

1) 8-week-old male C57BL/6 N mice (20–25 g bw), Oriental Kobo, Japan; n = 5; calvarial defect model

2) 14-week-old male mice (28–33 g bw); n = 5; senescence-accelerated mouse (SAM) model

Control group: Calcium phosphate cement (CPC) tablet alone,

Icariin-CPC group: CPC containing 1 mg of icariin; 4 and 6 weeks.

SAM P1-control, SAMP1-icariin, SAM P6-control, and SAM P6-icariin; intraperitoneal injection; 0.2 mg/kg/day for 6 weeks.

Icariin-CPC group improved angiogenesis and accelerated bone tissue regeneration after transplantation (p < 0.05 compared to the control group).

Among the groups, SAM P6-icariin treated mice significantly increased the trabecular bone thickness and showed a higher new bone formation rate than the control group.

Zhao et al. (2010) [66]