Int J Stomatol ›› 2022, Vol. 49 ›› Issue (4): 489-496.doi: 10.7518/gjkq.2022060

• Reviews • Previous Articles    

Research progress on exosome composite scaffolds in oral tissue engineering

Cai Chaoying1(),Chen Xuepeng1,Hu Ji’an2()   

  1. 1.Dept. of Orthodontics, The Affiliated Hospital of Stomatology, Zhejiang University School of Medicine, School of Stomatology, Zhejiang University, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, China
    2.Dept. of Pathology, The Affiliated Hospital of Stomatology, Zhejiang University School of Medicine, School of Stomatology, Zhejiang University, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou 310006, China
  • Received:2021-09-25 Revised:2022-03-24 Online:2022-07-01 Published:2022-06-28
  • Contact: Ji’an Hu;
  • Supported by:
    National Nature Science Foundation of Zhejiang Province(LY18H140001)


Defects in various oral and maxillofacial tissues will seriously affect the appearance and function of patients, and effective repair of the defects is the focus of current clinical work. Oral tissue engineering achieves tissue regeneration and functional reconstruction through the application of scaffolds, growth factors and stem cells. The composite materials of stem cells and scaffolds are widely used in the regeneration of oral tissues due to their good regeneration performance. However, the stem cells have poor biocompatibility and low availability, inducing a bottleneck in clinical application. Compared with stem cells, exosomes have lower immunogenicity and higher yield, and are expected to replace stem cells in clinical application. Increasingly abundant scaffold materials can effectively protect and deliver exosomes to target tissues. At present, researches on the application of exosome composite scaffolds have covered the regeneration of jaw bone, articular cartilage, pulp and periodontal tissues. This article reviews the researches upon exosome composite scaffolds in the regeneration of oral and maxillofacial tissues.

Key words: oral tissue engineering, exosome, scaffold, bone regeneration, cartilage regeneration, pulp regeneration, periodontal regeneration

CLC Number: 

  • Q 254

1 Langer R, Vacanti JP. Tissue engineering[J]. Scien-ce, 1993, 260(5110): 920-926.
2 Soteriou D, Fuchs Y. A matter of life and death: stem cell survival in tissue regeneration and tumour formation[J]. Nat Rev Cancer, 2018, 18(3): 187-201.
3 Volarevic V, Markovic BS, Gazdic M, et al. Ethical and safety issues of stem cell-based therapy[J]. Int J Med Sci, 2018, 15(1): 36-45.
4 Kim HJ, Park JS. Usage of human mesenchymal stem cells in cell-based therapy: advantages and disadvantages[J]. Dev Reprod, 2017, 21(1): 1-10.
5 Zheng CX, Chen J, Liu SY, et al. Stem cell-based bone and dental regeneration: a view of microenvironmental modulation[J]. Int J Oral Sci, 2019, 11(3): 23.
6 Ratajczak J, Wysoczynski M, Hayek F, et al. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communication[J]. Leukemia, 2006, 20(9): 1487-1495.
7 刘士博, 刘显. 不同源性外泌体在骨缺损修复中的研究进展[J]. 华西口腔医学杂志, 2020, 38(2): 193-197.
Liu SB, Liu X. Review for different sources of exosomes in bone tissue engineering research[J]. West China J Stomatol, 2020, 38(2): 193-197.
8 Haraszti RA, Miller R, Stoppato M, et al. Exosomes produced from 3D cultures of MSCs by tangential flow filtration show higher yield and improved activity[J]. Mol Ther, 2018, 26(12): 2838-2847.
9 Ludwig N, Whiteside TL, Reichert TE. Challenges in exosome isolation and analysis in health and di-sease[J]. Int J Mol Sci, 2019, 20(19): E4684.
10 Yang Y, Knight R, Stephens P, et al. Three-dimensional culture of oral progenitor cells: effects on small extracellular vesicles production and proliferative function[J]. J Oral Pathol Med, 2020, 49(4): 342-349.
11 Konoshenko MY, Lekchnov EA, Vlassov AV, et al. Isolation of extracellular vesicles: general methodo-logies and latest trends[J]. Biomed Res Int, 2018, 2018: 8545347.
12 Gardiner C, Di Vizio D, Sahoo S, et al. Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey[J]. J Extracell Vesicles, 2016, 5: 32945.
13 Yang DB, Zhang WH, Zhang HY, et al. Progress, opportunity, and perspective on exosome isolation-efforts for efficient exosome-based theranostics[J]. Theranostics, 2020, 10(8): 3684-3707.
14 Huang JH, Xiong JY, Yang L, et al. Cell-free exosome-laden scaffolds for tissue repair[J]. Nanoscale, 2021, 13(19): 8740-8750.
15 Cheng YR, Zeng QY, Han Q, et al. Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes[J]. Protein Cell, 2019, 10(4): 295-299.
16 Wu JY, Li YJ, Hu XB, et al. Preservation of small extracellular vesicles for functional analysis and the-rapeutic applications: a comparative evaluation of storage conditions[J]. Drug Deliv, 2021, 28(1): 162-170.
17 Trubiani O, Marconi GD, Pierdomenico SD, et al. Human oral stem cells, biomaterials and extracellular vesicles: a promising tool in bone tissue repair[J]. Int J Mol Sci, 2019, 20(20): E4987.
18 Elahi FM, Farwell DG, Nolta JA, et al. Preclinical translation of exosomes derived from mesenchymal stem/stromal cells[J]. Stem Cells, 2020, 38(1): 15-21.
19 Komaki M, Numata Y, Morioka C, et al. Exosomes of human placenta-derived mesenchymal stem cells stimulate angiogenesis[J]. Stem Cell Res Ther, 2017, 8(1): 219.
20 Zhou H, Li X, Yin Y, et al. The proangiogenic effects of extracellular vesicles secreted by dental pulp stem cells derived from periodontally compromised teeth[J]. Stem Cell Res Ther, 2020, 11(1): 110.
21 Zhang SP, Teo KYW, Chuah SJ, et al. MSC exosomes alleviate temporomandibular joint osteoarthritis by attenuating inflammation and restoring matrix homeostasis[J]. Biomaterials, 2019, 200: 35-47.
22 Hiraki T, Kunimatsu R, Nakajima K, et al. Stem cell-derived conditioned media from human exfolia-ted deciduous teeth promote bone regeneration[J]. Oral Dis, 2020, 26(2): 381-390.
23 Wang MH, Li J, Ye YY, et al. SHED-derived conditioned exosomes enhance the osteogenic differentiation of PDLSCs via Wnt and BMP signaling in vitro [J]. Differentiation, 2020, 111: 1-11.
24 Zhuang XY, Ji LL, Jiang H, et al. Exosomes derived from stem cells from the apical papilla promote dentine-pulp complex regeneration by inducing specific dentinogenesis[J]. Stem Cells Int, 2020, 2020: 581-6723.
25 Stanko P, Altanerova U, Jakubechova J, et al. Dental mesenchymal stem/stromal cells and their exosomes[J]. Stem Cells Int, 2018, 2018: 8973613.
26 Imai T, Takahashi Y, Nishikawa M, et al. Macrophage-dependent clearance of systemically administered B16BL6-derived exosomes from the blood circulation in mice[J]. J Extracell Vesicles, 2015, 4: 26238.
27 Yan HC, Yu TT, Li J, et al. The delivery of extracellular vesicles loaded in biomaterial scaffolds for bone regeneration[J]. Front Bioeng Biotechnol, 2020, 8: 1015.
28 Cheng A, Schwartz Z, Kahn A, et al. Advances in porous scaffold design for bone and cartilage tissue engineering and regeneration[J]. Tissue Eng Part B Rev, 2019, 25(1): 14-29.
29 Perić Kačarević Ž, Rider P, Alkildani S, et al. An introduction to bone tissue engineering[J]. Int J Artif Organs, 2020, 43(2): 69-86.
30 Jazayeri HE, Lee SM, Kuhn L, et al. Polymeric scaffolds for dental pulp tissue engineering: a review[J]. Dent Mater, 2020, 36(2): e47-e58.
31 Wei W, Dai H. Articular cartilage and osteochondral tissue engineering techniques: recent advances and challenges[J]. Bioact Mater, 2021, 6(12): 4830-4855.
32 Eggli PS, Müller W, Schenk RK. Porous hydroxya-patite and tricalcium phosphate cylinders with two different pore size ranges implanted in the cancellous bone of rabbits. A comparative histomorphometric and histologic study of bony ingrowth and implant substitution[J]. Clin Orthop Relat Res, 1988(232): 127-138.
33 Pishavar E, Luo HR, Naserifar M, et al. Advanced hydrogels as exosome delivery systems for osteogenic differentiation of MSCs: application in bone regeneration[J]. Int J Mol Sci, 2021, 22(12): 6203.
34 Huang QT, Zou YJ, Arno MC, et al. Hydrogel scaffolds for differentiation of adipose-derived stem cells[J]. Chem Soc Rev, 2017, 46(20): 6255-6275.
35 Hu HX, Dong LL, Bu ZH, et al. miR-23a-3p-abundant small extracellular vesicles released from Gelma/nanoclay hydrogel for cartilage regeneration[J]. J Extracell Vesicles, 2020, 9(1): 1778883.
36 Yang S, Zhu B, Yin P, et al. Integration of human umbilical cord mesenchymal stem cells-derived exosomes with hydroxyapatite-embedded hyaluronic acid-alginate hydrogel for bone regeneration[J]. ACS Biomater Sci Eng, 2020, 6(3): 1590-1602.
37 Jiang SP, Tian GZ, Yang Z, et al. Enhancement of acellular cartilage matrix scaffold by Wharton's jelly mesenchymal stem cell-derived exosomes to promote osteochondral regeneration[J]. Bioact Mater, 2021, 6(9): 2711-2728.
38 Karageorgiou V, Kaplan D. Porosity of 3D biomaterial scaffolds and osteogenesis[J]. Biomaterials, 2005, 26(27): 5474-5491.
39 Loh QL, Choong C. Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size[J]. Tissue Eng Part B Rev, 2013, 19(6): 485-502.
40 Marques A, Miranda G, Silva F, et al. Review on current limits and potentialities of technologies for biomedical ceramic scaffolds production[J]. J Biomed Mater Res B Appl Biomater, 2021, 109(3): 377-393.
41 Jeon JE, Vaquette C, Klein TJ, et al. Perspectives in multiphasic osteochondral tissue engineering[J]. Anat Rec (Hoboken), 2014, 297(1): 26-35.
42 Zhang JY, Liu XL, Li HY, et al. Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signa-ling pathway[J]. Stem Cell Res Ther, 2016, 7(1): 136.
43 Li WY, Liu YS, Zhang P, et al. Tissue-engineered bone immobilized with human adipose stem cells-derived exosomes promotes bone regeneration[J]. ACS Appl Mater Interfaces, 2018, 10(6): 5240-5254.
44 Shafei S, Khanmohammadi M, Heidari R, et al. Exosome loaded alginate hydrogel promotes tissue regeneration in full-thickness skin wounds: an in vivo study[J]. J Biomed Mater Res A, 2020, 108(3): 545-556.
45 Liu XL, Yang YL, Li Y, et al. Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage rege-neration[J]. Nanoscale, 2017, 9(13): 4430-4438.
46 Zha Y, Li YW, Lin TY, et al. Progenitor cell-derived exosomes endowed with VEGF plasmids enhance osteogenic induction and vascular remodeling in large segmental bone defects[J]. Theranostics, 2021, 11(1): 397-409.
47 Zhang LL, Fan CX, Hao WP, et al. NSCs migration promoted and drug delivered exosomes-collagen scaffold via a bio-specific peptide for one-step spinal cord injury repair[J]. Adv Healthc Mater, 2021, 10(8): e2001896.
48 Liu AQ, Lin D, Zhao HJ, et al. Optimized BMSC-derived osteoinductive exosomes immobilized in hierarchical scaffold via lyophilization for bone repair through Bmpr2/Acvr2b competitive receptor-activated Smad pathway[J]. Biomaterials, 2021, 272: 120718.
49 Qi X, Zhang JY, Yuan H, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats[J]. Int J Biol Sci, 2016, 12(7): 836-849.
50 Chen PF, Zheng L, Wang YY, et al. Desktop-stereolithography 3D printing of a radially oriented extracellular matrix/mesenchymal stem cell exosome bioink for osteochondral defect regeneration[J]. Thera-nostics, 2019, 9(9): 2439-2459.
51 Su N, Hao YY, Wang F, et al. Mesenchymal stromal exosome-functionalized scaffolds induce innate and adaptive immunomodulatory responses toward tissue repair[J]. Sci Adv, 2021, 7(20): eabf7207.
52 Qin YH, Sun RX, Wu CL, et al. Exosome: a novel approach to stimulate bone regeneration through regulation of osteogenesis and angiogenesis[J]. Int J Mol Sci, 2016, 17(5): E712.
53 Diomede F, Gugliandolo A, Cardelli P, et al. Three-dimensional printed PLA scaffold and human gingival stem cell-derived extracellular vesicles: a new tool for bone defect repair[J]. Stem Cell Res Ther, 2018, 9(1): 104.
54 Xing X, Han S, Li Z, et al. Emerging role of exosomes in craniofacial and dental applications[J]. Theranostics, 2020, 10(19): 8648-8664.
55 Wu JY, Chen LL, Wang RF, et al. Exosomes secre-ted by stem cells from human exfoliated deciduous teeth promote alveolar bone defect repair through the regulation of angiogenesis and osteogenesis[J]. ACS Biomater Sci Eng, 2019, 5(7): 3561-3571.
56 Chen S, Tang YM, Liu YS, et al. Exosomes derived from miR-375-overexpressing human adipose me-senchymal stem cells promote bone regeneration[J]. Cell Prolif, 2019, 52(5): e12669.
57 Li WY, Zheng YF, Zhao XH, et al. Osteoinductive effects of free and immobilized bone forming peptide-1 on human adipose-derived stem cells[J]. PLoS One, 2016, 11(3): e0150294.
58 Swanson WB, Zhang Z, Xiu KM, et al. Scaffolds with controlled release of pro-mineralization exosomes to promote craniofacial bone healing without cell transplantation[J]. Acta Biomater, 2020, 118: 215-232.
59 Zhang R, Ma J, Han J, et al. Mesenchymal stem cell related therapies for cartilage lesions and osteoarthritis[J]. Am J Transl Res, 2019, 11(10): 6275-6289.
60 de Jong OG, van Balkom BW, Schiffelers RM, et al. Extracellular vesicles: potential roles in regenerative medicine[J]. Front Immunol, 2014, 5: 608.
61 Bielajew BJ, Donahue RP, Espinosa MG, et al. Knee orthopedics as a template for the temporomandibular joint[J]. Cell Rep Med, 2021, 2(5): 100241.
62 Jiang SP, Guo WM, Tian GZ, et al. Clinical application status of articular cartilage regeneration techniques: tissue-engineered cartilage brings new hope[J]. Stem Cells Int, 2020, 2020: 5690252.
63 Huang JH, Huang ZW, Liang YJ, et al. 3D printed gelatin/hydroxyapatite scaffolds for stem cell chondrogenic differentiation and articular cartilage repair[J]. Biomater Sci, 2021, 9(7): 2620-2630.
64 Zhou QF, Cai YZ, Lin XJ. The dual character of exosomes in osteoarthritis: antagonists and therapeutic agents[J]. Acta Biomater, 2020, 105: 15-25.
65 Yu SJ, Chen H, Gao B. Potential therapeutic effects of exosomes in regenerative endodontics[J]. Arch Oral Biol, 2020, 120: 104946.
66 Kim SG, Malek M, Sigurdsson A, et al. Regenerative endodontics: a comprehensive review[J]. Int Endod J, 2018, 51(12): 1367-1388.
67 Ivica A, Ghayor C, Zehnder M, et al. Pulp-derived exosomes in a fibrin-based regenerative root filling material[J]. J Clin Med, 2020, 9(2): E491.
68 Galler KM, Brandl FP, Kirchhof S, et al. Suitability of different natural and synthetic biomaterials for dental pulp tissue engineering[J]. Tissue Eng Part A, 2018, 24(3/4): 234-244.
69 Huang CC, Narayanan R, Alapati S, et al. Exosomes as biomimetic tools for stem cell differentiation: applications in dental pulp tissue regeneration[J]. Biomaterials, 2016, 111: 103-115.
70 Zhang SY, Thiebes AL, Kreimendahl F, et al. Extracellular vesicles-loaded fibrin gel supports rapid neovascularization for dental pulp regeneration[J]. Int J Mol Sci, 2020, 21(12): E4226.
71 Swanson WB, Gong T, Zhang Z, et al. Controlled release of odontogenic exosomes from a biodegra-dable vehicle mediates dentinogenesis as a novel biomimetic pulp capping therapy[J]. J Control Release, 2020, 324: 679-694.
72 Ivica A, Zehnder M, Weber FE. Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles in regenerative endodontics[J]. Eur Cell Mater, 2021, 41: 233-244.
73 Cortellini P, Tonetti MS. Clinical concepts for rege-nerative therapy in intrabony defects[J]. Periodontol 2000, 2015, 68(1): 282-307.
74 Yi GZ, Ma Y, Chen Y, et al. A review of the functions of matrix vesicles in periodontal tissues[J]. Stem Cells Dev, 2021, 30(4): 165-176.
75 Rosen PS, Reynolds MA, Bowers GM. The treatment of intrabony defects with bone grafts[J]. Perio-dontol 2000, 2000, 22: 88-103.
76 杨雪婷, 杨波, 田卫东. 牙周组织工程新技术的研究进展[J]. 中华口腔医学杂志, 2018, 53(7): 490-494.
Yang XT, Yang B, Tian WD. Development of new technology in periodontal tissue engineering[J]. Chin J Stomatol, 2018, 53(7): 490-494.
77 Dissaux C, Wagner D, George D, et al. Mechanical impairment on alveolar bone graft: a literature review[J]. J Craniomaxillofac Surg, 2019, 47(1): 149-157.
78 Chew JRJ, Chuah SJ, Teo KYW, et al. Mesenchymal stem cell exosomes enhance periodontal ligament cell functions and promote periodontal rege-neration[J]. Acta Biomater, 2019, 89: 252-264.
79 Liu L, Guo SJ, Shi WW, et al. Bone marrow mesenchymal stem cell-derived small extracellular vesicles promote periodontal regeneration[J]. Tissue Eng Part A, 2021, 27(13/14): 962-976.
80 Shen ZS, Kuang SH, Zhang Y, et al. Chitosan hydrogel incorporated with dental pulp stem cell-derived exosomes alleviates periodontitis in mice via a ma-crophage-dependent mechanism[J]. Bioact Mater, 2020, 5(4): 1113-1126.
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[1] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
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[3] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
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[5] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[6] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[7] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[8] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[9] . [J]. Foreign Med Sci: Stomatol, 2004, 31(02): 126 -128 .
[10] . [J]. Inter J Stomatol, 2008, 35(S1): .