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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

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Front. Med.    2019, Vol. 13 Issue (2) : 160-188    https://doi.org/10.1007/s11684-018-0629-9
REVIEW
Current advances for bone regeneration based on tissue engineering strategies
Rui Shi1, Yuelong Huang2, Chi Ma1, Chengai Wu1, Wei Tian1,2()
1. Institute of Traumatology and Orthopaedics, Beijing Laboratory of Biomedical Materials, Beijing Jishuitan Hospital, Beijing 100035, China
2. Department of Spine Surgery of Beijing Jishuitan Hospital, The Fourth Clinical Medical College of Peking University, Beijing 100035, China
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Abstract

Bone tissue engineering (BTE) is a rapidly developing strategy for repairing critical-sized bone defects to address the unmet need for bone augmentation and skeletal repair. Effective therapies for bone regeneration primarily require the coordinated combination of innovative scaffolds, seed cells, and biological factors. However, current techniques in bone tissue engineering have not yet reached valid translation into clinical applications because of several limitations, such as weaker osteogenic differentiation, inadequate vascularization of scaffolds, and inefficient growth factor delivery. Therefore, further standardized protocols and innovative measures are required to overcome these shortcomings and facilitate the clinical application of these techniques to enhance bone regeneration. Given the deficiency of comprehensive studies in the development in BTE, our review systematically introduces the new types of biomimetic and bifunctional scaffolds. We describe the cell sources, biology of seed cells, growth factors, vascular development, and the interactions of relevant molecules. Furthermore, we discuss the challenges and perspectives that may propel the direction of future clinical delivery in bone regeneration.
Keywords bone tissue engineering      stem cell      bone scaffold      growth factor      bone regeneration     
Corresponding Author(s): Wei Tian   
Just Accepted Date: 29 May 2018   Online First Date: 26 July 2018    Issue Date: 28 March 2019
 Cite this article:   
Rui Shi,Yuelong Huang,Chi Ma, et al. Current advances for bone regeneration based on tissue engineering strategies[J]. Front. Med., 2019, 13(2): 160-188.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0629-9
https://academic.hep.com.cn/fmd/EN/Y2019/V13/I2/160
Fig.1  Main methods and essential procedures that compose bone tissue engineering (BTE). The BTE involves stem cells, biological growth factors, and biocompatible scaffolds that are transplanted to the bone defect area. Three different patterns are used in BTE as follows: (A) cells and factors directly blended with scaffolds; (B) scaffolds combined with factors first and then cocultured with stem cells; and (C) osteogenic culture and 3D culture with scaffolds and factors.
AM technologies Printing materials Main achievements in BTE References
Powder-based:
3DP
SLS
SLM/SEBM		 Powder of ceramic, mental, polymer, and their composites Several in vivo studies have demonstrated its validity and potential in clinical practice [26, 29−35]
Photosensitivity-based:
SLA		 Polymers, hydrogels with good photopolymerization capabilities (PPF, gelatin, and TCM-based) PDLLA composites and PPF/ diethyl fumarate scaffolds were fabricated and cultured with hMSC and MC3T3-E1 osteoblasts [36–38]
Melt-extrusion-based:
FDM		 Biodegradable polymers and their composites (PCL, PLGA, PDL, PCL/ tricalcium phosphate, PLGA/TCP/HA) PCL composite-based scaffolds were fabricated and tested in vitro; PCL/HA bones enhanced the new bone formation in long load-bearing goat femur bone segmental defect model [39,42]
Tab.1  Additive manufacturing (AM) techniques for the production of cell-free bone tissue engineering (BTE) scaffolds
Cell sources Origin Differentiation medium Main markers
Adult stem cells
BMSCs Bone marrow 10–100 nmol/L DEX, 0.1–0. 5 mmol/L ACS, 10 mmol/L β-GP CD105, CD106, CD73, CD90, CD45−, CD34−
ADSCs Adipose tissue 10–100 nmol/L DEX, 10 mmol/L β-GP, 50 μmol/L ASP CD29, CD34, CD73, CD90, CD105, CD106−
MDSCs Skeletal muscle 0. 5 mmol/L ACS, 5 mmol/L β-GP, 10 nmol/L DEX CD44, CD73, CD90, CD105, Sca-1
SDSCs Synovium 10 nmol/L DEX, 20 mmol/L β-GP, 50 μmol/L ASP CD44, CD73, CD105, CD166, CD14−
DPSCs Pulps 100 nmol/L DEX, 0.5 mmol/L ACS, 10 mmol/L β-GP CD44, CD90, CD34, CD166
USCs Urine 100 nmol/L DEX, 10 mmol/L β-GP, 50 μmol/L ASP CD44, CD73, CD90, CD105, CD133, CD45−, HLA-DR−
ESCs Embryo 100 nmol/L DEX, 10 mmol/L β-GP, 0.5?mmol/L ACS CD9, Oct-4, SOX2, SSEA3/4 and NANOG, TRA-1-60/81, SSEA1−
Extra-embryonic stem cells
UCBSCs Umbilical cord blood 100 nmol/LDEX, 10 mmol/L β-GP, 0.5 mmol/L ACS CD29, CD44, CD54, CD73, CD90, CD105, CD49d
Wharton’s Jelly SCs Umbilical cord 2 mmol/L L-glutamine, 100 nmol/L DEX, 10 mmol/L β-GP, 0.2 mmol/L ACS CD34, CD45, CD44, CD73, CD90, CD105, HLA-DR−, CD18−
AFSCs Amniotic fluid 100 nmol/L DEX, 10 mmol/L β-GP, 0.5 mmol/L ACS CD31, CD44 CD45, CD90
PDSCs Placenta 100 nmol/L DEX, 10 mmol/L β-GP, 20 μmol/L ASP CD29, CD73, CD166, CD34−, CD45−, SSEA-1/4, Oct-4, Sox2
AMSCs Amnion 100 nmol/L DEX, 10 mmol/L β-GP, 100 μmmol/LASC Oct-4, Nanog, CD34, CD90, CD105
IPSCs Somatic cells 100 nmol/L DEX, 10 mmol/L β-GP, 100 μmol/L ASP CD29, CD34, CD44, CD73, CD90, CD105, Sox2, TRA-1-81, Oct3/4
Tab.2  Characteristics of the different stem cells
Fig.2  Extraction processes and osteogenic differentiation of stem cells in the BTE. The tissues are first dissociated from the patients and digested with enzymes. The primary cells are cultured and followed by magnetic activated cell sorting (MACS). Those stem cells are differentiated into osteocytes with the help of growth factors.
Fig.3  Classifications and action patterns of bioactive factors in BTE. Bioactive factors can be divided into four parts, namely, growth factors, peptides, chemical molecules, and other small molecules, according to their characteristics. These factors present distinct actions on the cytoplasmic and nuclear components, such as receptors, diffusion, and drug delivery systems.
Peptide Cells Effects References
OGP Rat mesenchymal stem cell Increase of osteogenic markers in osteoinductive medium and new bone formation in vivo [195]
PTH MC3T3-E1 Increased hydrazine-bisphosphonates affinity to bone and improved hydrazine bisphosphonates interaction with osteoblastic cells in basal medium [196]
Heparin-binding peptide Human mesenchymal cells Increase of mineralization in osteoinductive medium [197]
Tab.3  Peptides types in BTE
Small molecule Drug delivery system In vitro/in vivo osteogenesis References
Phenamil 2D/3D scaffold Enhanced proliferation of MC3T3 cells, increased ALP expression and enhanced mineralization [202]
Oxysterols Hydrogel/sponge/3D scaffold Oxysterol-21 promoted bone formation in the callus and increased mechanical stability of lumber vertebral segments [216]
Purmorphamine Bone adhesive composite beads Activation of Hh pathway [222]
FTY720 Bone autografts/ 3D scaffold Coated allografts promoted new bone formation with significant increases in mechanical properties when compared to the controls [221]
Simvastatin 3D scaffold/porous bone
Cement/ hydrogel		 New bone formation was observed after scaffold implantation in tibial defect model. In vivo osteogenesis were observed when loaded scaffolds were combined with MSCs cell sheet [223,224]
TH (helioxanthin derivative) Tetrapod-shaped granules Promote osteoblastic differentiation in mouse MC3T3-E1 cells [225]
FK506 3D scaffold Evidenced by the ectopic bone formation in subcutaneous location [226]
Tab.4  Different kinds of small osteoinductive molecules
Gene of interest Delivery system Cell/animal model Function References
Gucocorticoid receptor (GR) Polymer Human bone marrow Successful siRNA delivery and release for up to 40 days [228]
RANK Polymer Murine osteoclast precursor cells Inhibition of bone resorption due to RANK expression knockdown [229]
Semaphorin 4d Polymeric nanoparticles Ovriaectomy in mice Decreased bone loss resulted from osteoporosis [231]
Tab.5  Different types of other small molecules for BTE
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