TABLE 2.
Small molecular agents examined in vivo.
| Molecule | Classification | Molecular Weight | Working Concentrations | Bone Defect/Surgical Model | Delivery Methods | Primary Osteogenic Effect(s) | References |
|---|---|---|---|---|---|---|---|
| SB431542 | Benzamides | 384.4 g/mol | 0.1 μM, 1.0 μM | Guangxi Bama minipigs with maxillary bone defects (12 mm x 5 mm - Diameter x Depth) produced using a trephine | Minipig GMSC grafts treated with SB431542 were implanted into the maxillary defect | Downregulates TGF-β signaling; prevents Smad3 gene phosphorylation; induces activation of BMP signaling in minipigs | Shi et al. (2019) |
| . | . | . | 26 mM | CD-1 immunodeficient mice with parietal bone defects (2 mm in diameter) produced using a trephine | Collagen sponges treated with SB431542 were implanted into the parietal bone defect | Enhanced parietal bone regeneration within the calvarium; reduced Smad2 and Smad3 expression | Senarath-Yapa et al. (2016) |
| Phenamil | Amiloride derivative | 305.7 g/mol | 300 μM | Sprague Dawley rats with critical-sized mandibular defects (5 x 5 x 2.5 mm3) produced using a drill burr | Appropriately-sized scaffolds with phenamil were placed onto the mandibular defect with a resorbable suture, followed by skin closure with nonresorbable suture | Inhibition of Smurf1 in rats | Fan et al. (2017b) |
| Resveratrol | Stilbenes | 228.2 g/mol | 1.0 mg/ml | Sprague Dawley rats with critical-sized mandibular defects (circular, full-thickness 4-mm) produced using a trephine | RSV-SrRn scaffolds were impalnted into the mandibular defect before being closed | Higher bone volume to total volume (BV/TV) ratios; peripheral and central bone regeneration inrats with large mandibular defects | Zhang et al. (2020) |
| Strontium ranelate | Tetracarboxylic acids | 513.5 g/mol | 1.0 mg/ml | Sprague Dawley rats with critical-sized mandibular defects (circular, full-thickness 4-mm) produced using a trephine | RSV-SrRn scaffolds were implanted into the mandibular defect before closure of defect | Higher bone volume to total volume (BV/TV) ratios; peripheral and central bone regeneration in rats with large mandibular defects | Zhang et al. (2020) |
| Simvastatin | Statins | 418.6 g/mol | Not reported | Wistar rats with exposed tooth socket after extraction of mandibular right central incisor | PLGA scaffolds with simvastatin were implanted in the tooth sockets before suturing of the gingiva | Induced BMP2 gene expression; anti-resorption elements to impede osteoclast proliferation in rats | Wu et al. (2008) |
| Dimethyloxalylglycine | Glycine derivative | 175.1 g/mol | 1% w/w of PLGA | Wistar rats with mandibular buccal bone defects (5 × 4 × 1 mm3) produced using a drill burr | Fibrous membranes containing DMOG were implanted into mandibular defect, then the defect was closed | Stimulation of PDLSC osteogenic differentiation; modulation of deleterious inflammatory responses in rats | Shang et al. (2021) |
| Tideglusib | Naphthalenes | 334.4 g/mol | 50 nM | Axin2 and GPR177(Wntless) mice with exposed dentin or pulp on maxillary first molars produced using a drill burr | Exposed dentin on maxillary first molars were capped with tideglusib | Tertiary dentin formation; Wnt/β-catenin pathways upregulation in odontoblastic pulp cells of mouse molars | Neves & Sharpe (2018); Neves et al. (2017) |
| CHIR99021 | Aminopyrimidines | 465.3 g/mol | Different concentrations between 0 μM and 10 μM | Severe combined immunodeficient (SCID) mice | Tooth slices/scaffolds containing DPSCs, treated with CHIR99021, were transplanted into the subcutaneous space of the dorsum of SCID mice | Wnt/β-catenin signaling upregulation; increased VEGFR2, VE-Cadherin, CD31, Tie-2 for vasculogenic differentiation of DSPCs in mice | Zhang et al. (2016) |
| JW67 | - | 394.4 g/mol | Different concentrations between 0 μM and 10 μM | Severe combined immunodeficient (SCID) mice | Tooth slices/scaffolds containing DPSCs, treated with JW67, were transplanted into the subcutaneous space of the dorsum of SCID mice | Enhanced odontoblast and osteoblast differentiation of DPSCs in mice | Zhang et al. (2016) |
| HA-1077 (Fasudil) | Isoquinoline derivative | 291.4 g/mol | 0.5 μM | Sprague Dawley rats with parietal bone defects (circular, 5mm in diameter) produced using a trephine | Atelocollagen sponges containing HA-1077 were implanted into the parietal bone defect, then the flap was sutured. | Enhanced parietal bone regeneration within the calvarium | Nakata et al. (2020) |
| Y-27632 | N-arylamides | 247.3 g/mol | 0.5 μM, 5 μM | Sprague Dawley rats with parietal bone defects (circular, 5 mm in diameter) produced using a trephine | Atelocollagen sponges containing Y-27632 were implanted into the parietal bone defect, then the flap was sutured. | Enhanced parietal bone regeneration within the calvarium; upregulated VEGF-A mRNA expression | Nakata et al. (2020) |
| Dexamethasone | Hydroxysteroids | 392.5 g/mol | 2.18 μg/mg of chi-MSNs | Sprague Dawley rats with skull defects (5 mm in diameter), tools used not reported | Gelfoam implants containing DEX-embedded silica nanoparicles were transplanted to the defect site | Higher bone volume to total volume (BV/TV) ratios; enhanced skull bone regeneration | Sun et al. (2019) |
| Hydroxycholesterol mixture* | Oxysterols | see footnote | 5 μM | Sprague Dawley rats with alveolar clefts from zygomatic arch to the ipsilateral maxillary incisor (7 × 4 × 3 mm3), produced using a hand-held drill and silicone molds for accuracy | Collagen sponges containing hydroxycholesterols were implanted into the alveolar defect, then the gingival flap was sutured. | Enhanced alveolar cleft regeneration; absence of adverse infiltration by inflammatory cells | Bakshi et al. (2019) |
| WAY-262611 | Naphthalenes | 318.4 g/mol | 12.5 mg/kg, 25 mg/kg per mouse body weight | Pax9 -/- Dkk1 f/+ ;Wnt1Cre compound mutant mice embryos (generated through serial matings) displaying cleft palates | Doses of WAY-262611 were injected daily into the tail veins of pregnant Pax9 +/- mice | Increased Wnt signaling; enhanced cell proliferation; palatal shelf outgrowth and fusion; upregulation in Col1a1 expression in postnatal palatal mesenchyme | Jia et al. (2017) |
| IIIc3a | - | 570.1 g/mol | 12.5 mg/kg, 25 mg/kg per mouse body weight | Pax9 -/- Dkk1 f/+ ;Wnt1Cre compound mutant mice embryos (generated through serial matings) displaying cleft palates | Doses of WAY-262611 were injected daily into the tail veins of pregnant Pax9 +/- mice | Increased Wnt signaling; enhanced cell proliferation; palatal shelf outgrowth and fusion; upregulation in Col1a1 expression in postnatal palatal mesenchyme | Jia et al. (2017) |
*20(S)-hydroxycholesterol (402.7 g/mol) and 22(R)-hydroxycholesterol (402.7 g/mol).