Table 1.
Selected list of mediators involved in resolution of inflammation used as therapeutics for bone regeneration
| Class | Molecule | Biomaterial | Injury model | Treatment outcome | References |
|---|---|---|---|---|---|
| Cytokines | IL-4+IL-13 | Collagen sponge | Mouse (C57BL/6N); femoral osteotomy (0.7 mm) | Enhanced bone formation (microCT); increased M2 macrophages | Claudia Schlundt, 2018 |
| IL-4+SDF-1 | Gelatin | Rat (Sprague-Dawley); periodontal defect (2×2 mm) | Improved periodontal regeneration (histology, microCT); decreased M1 macrophages; increased M2 macrophages; increased MSCs | He, 2019 | |
| IL-4 | Nanofibrous gelatin microspheres | Rat (Sprague-Dawley), diabetic; mandibular periodontal defect (3×2×1 mm) | Restored bone regeneration (histology, microCT); recovered M2/M1 macrophage ratio; reduced TNF-alpha | Hu, 2018 | |
| IL-4 | Decellularized bone matrix reservoir | Rat (Sprague Dawley); cranial defect (5 mm) | decreased TNF-α levels | Zheng, 2018 | |
| Anti TNF-alpha antibody (Infliximab) | Systemic (free molecule) delivery | Mouse (Tg197); femoral fracture (closed) | Benefited fracture healing (histology, biomechanical test) | Timmen, 2014 | |
| TGF-beta1 | Cellulose | Rabbit; cranial defect (15 mm) | Enhanced bone formation (histology and X-ray) | McKinney, 1996 | |
| TGF-beta1 | Chitosan/collagen microgranules | Rabbit (New Zealand); cranial defect (8 mm) | Enhanced bone regeneration (histology) | Lee, 2006 | |
| TGF-beta1 | Porous oly(propylene fumarate) scaffold | Rabbit (New Zealand); cranial defect (6.3 mm) | Adequately induced bone formation (histology) | Vehof, 2002 | |
| TGF-beta1 | CaP/Gelain microparticles | Rabbit (New Zealand); femoral | Enhanced bone remodeling (histology, biomechanical | Link, 2008 | |
| IGF-1 | Poly(lactide-co-glycolide) microspheres (PLGA MS) | Ovine; methaphyseal drill hole (8-mm) and segmental tibia defect (10-mm) | New bone formation and bridging, reduced inflammation | Meinel, 2003 | |
| IGF-1/IGF-2 | ColI gel | Rat (Sprague-Dawley); facial critical-sized defect (5×15 mm) |
Osseous healing, IGF-2<IGF-1/IGF/2<IGF-1 | Toung, 1999 | |
| Lipids | Resolvin E1 | Local injection, no scaffold | Mouse (FVB and chemR23tg); cranial defect (1 mm) | Accelerated bone healing (histology) | Gao, 2013 |
| Maresin1 | Systemic (free molecule) delivery | Mouse (C57BL/6J), aged; transverse tibial fracture | Improved fracture healing (histology, microCT, biomechanical testing); decreased local pro-inflammatory macrophages; decreased circulating IL-6, IL-10, TNF-alpha, KC, IL-1beta, MCP-1 | Huang, 2020 | |
| Resolvin D1 | Chitosan scaffold | Rat (Wistar); femoral defect (3 mm) | Improved bone repair (histology, micrCT) | Vasconcelos, 2018 | |
| Resolvin D1 | Macrophage cell membrane-coated gold nanocage in boron-containing mesoporous bioactive glass scaffold | Mouse (C57BL/6); femoral defect (1 mm) | Enhance bone regeneration (histology); increased M2 macrophages | Yin, 2020 | |
| 15-Deoxy-prostaglandin J2 | Collagen sponge/PLGA nanoparticle | Rat (Wistar); femoral defect (5 mm) | Increased bone formation (histology); decreased IL-6, IL-1beta, TNF-alpha; increased BMP-6 and PDGF-B | Tang, 2017 | |
| 15-Deoxy-prostaglandin J2 | Collagen sponge | Rat (Sprague Dawley); fibula segmental defect (7 mm) | Small improvement in bone formation (X-ray, histology, microCT) | Nam, 2019 | |
| PGI2 analog (Iloprost) | Biphasic fibrin | Mouse (C56BL/6N); femoral osteotomy (0.7 mm) | Improved fracture healing (Histology, microCT); decreased CD8+IFNγ+ T cells; decreased M1 macrophages; increased M2 macrophages | Wendler, 2019 | |
| Lipoxin A4 analog (Benzo-lipoxin A4) | Neutrophil microparticles | Miniature swine; chronic periodontal defect | Improved bone formation (histology, microCT); decreased inflammatory cell infiltration; increased lipoxins and resolvins; decreased PGE2 and PGD2 | Van Dyke, 2015 | |
| Oleic acid | Porous PCL scaffold | Rat (Wistar); tibial defect (3 mm) | Improved bone formation (histology) | Cardoso, 2017 | |
| Purine (Adenosine) | Adenosine | Layered MgFe hydroxide nanocarriers/gelatin gel | Rat (Sprague-Dawley); tibial defect (4 mm) | Increased bone healing (histology, microCT) | Kang, 2017 |
| Adenosine | PEG-PBA macroporous scaffold | Mouse (C57BL/6J); transverse tibial fracture | Improved bone healing (histology, microCT); increased angiogenesis | Zeng, 2020 | |
| A2A receptor agonist (CGS 21680) | Collagen sponge | Mouse (C57BL/6 and A2A KO); cranial defect (3 mm) | Enhanced bone regeneration (histology, microCT) | Mediero, 2015 | |
| ENT inhibitor (Dipyridamole) | Collagen sponge | Mouse (C57BL/6 and A2A KO); cranial defect (3 mm) | Enhanced bone formation (histology, microCT) | Mediero, 2015 | |
| ENT inhibitor (Dipyridamole) | HAp/beta-TCP scaffold | Mouse (C57BL/6); cranial defect (3 | Enhanced bone regeneration (histology, microCT) | Ishack, 2017 | |
| A2A receptor agonist (CGS 21680) | Fibrin gel | Rat (Sprague-Dawley); transverse tibial fracture, burnt periosteum | Accelerated bone healing (histology, X-ray, microCT) | Zheng, 2020 | |
| ENT inhibitor (Dipyridamole) | Beta-TCP scaffold | Sheep (Dorset/Finn); cranial defect (11 mm) | Improved bone regeneration (histology, microCT) | Bekisz, 2018 |