北京大学学报(医学版) ›› 2026, Vol. 58 ›› Issue (2): 272-277. doi: 10.19723/j.issn.1671-167X.2026.02.008

• 工作综述 • 上一篇    下一篇

基于干细胞和生物材料调控的口腔颅颌面骨再生的研究进展

李峥1,2, 吕珑薇1,2, 张晓1,2, 夏丹丹1,2,3, 张萍1,2, 刘云松1,2, 周永胜1,2,*()   

  1. 1. 北京大学口腔医学院·口腔医院修复科, 国家口腔医学中心, 国家口腔疾病临床医学研究中心, 口腔生物材料和数字诊疗装备国家工程研究中心, 颅颌面组织生物智造与修复再生北京市重点实验室, 国家卫生健康委员会口腔数字医学重点实验室, 北京 100081
    2. 北京大学口腔医院三亚医院(三亚口腔医学中心), 海南三亚 572013
    3. 北京大学口腔医学院·口腔医院材料研究室, 北京 100081
  • 收稿日期:2025-11-05 出版日期:2026-04-18 发布日期:2026-01-13
  • 通讯作者: 周永胜
  • 基金资助:
    国家自然科学基金重点项目(82530030); 国家自然科学基金重点项目(82270954); 国家自然科学基金重点项目(81930026); 国家重点研发计划(2023YFB4605400); 国家重点研发计划(2018YFB1106900); 北京市自然科学基金委员会-海淀原始创新联合基金重点研究专题项目(L222030); 海南省自然科学基金优秀青年基金(825YXQN603)

Advances in oral and craniofacial bone regeneration modulated by stem cells and biomaterials

Zheng LI1,2, Longwei LV1,2, Xiao ZHANG1,2, Dandan XIA1,2,3, Ping ZHANG1,2, Yunsong LIU1,2, Yongsheng ZHOU1,2,*()   

  1. 1. Department of Prosthodontics, Peking University School and Hospital of Stomatology & National Center for Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory for Intelligent Biomanufacturing and Regeneration of Craniofacial Tissues & NHC Key Laboratory of Digital Stomatology, Beijing 100081, China
    2. Peking University Hospital of Stomatology Sanya Division(Sanya Stomatology Center), Sanya 572013, Hainan, China
    3. Department of Dental Materials, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2025-11-05 Online:2026-04-18 Published:2026-01-13
  • Contact: Yongsheng ZHOU
  • Supported by:
    the National Natural Science Foundation of China(82530030); the National Natural Science Foundation of China(82270954); the National Natural Science Foundation of China(81930026); the National Key Research and Development Program of China(2023YFB4605400); the National Key Research and Development Program of China(2018YFB1106900); Haidian Original Innovation Joint Fund Key Research Program of the Beijing Natural Science Foundation(L222030); Hainan Provincial Natural Science Foundation of China(825YXQN603)

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摘要:

口腔颅颌面骨缺损由创伤、肿瘤、感染及先天畸形等多种因素引起,严重影响患者生理功能与生活质量。传统的骨修复方法(如自体或异体移植)在复杂、大范围缺损修复中仍面临供区损伤、免疫排斥及远期吸收等局限,其内在原因是缺乏对骨组织再生过程中复杂的细胞行为、信号网络及材料-宿主相互作用的深入解析,导致现有治疗策略难以精准调控修复进程。因此,发展基于机制探索的新理论、新技术和新材料,是目前口腔颅颌面骨再生研究的重要战略方向。本文系统综述了本课题组围绕“调控细胞命运-构建智能材料-实现功能重建”这一核心理念,在口腔颅颌面骨再生领域取得的系列原创性研究进展。从骨骼干细胞命运调控机制入手,阐明了表观遗传修饰、泛素化系统和单细胞水平下功能性干细胞亚群在骨再生中的关键作用,提出了凋亡囊泡作为新型无细胞治疗载体的再生机制及其工程化增强策略;在材料层面,发展了可降解镁、锌金属的生物功能化设计和增材制造技术,并构建了形态与功能双重动态可调的4D打印智能支架,同时引入人工智能,实现精准设计和数字化制造,构建了从机制到转化的系统性创新体系。

关键词: 干细胞, 生物材料, 颅颌面骨缺损, 骨再生

Abstract:

Cranio-maxillofacial bone defects resulting from trauma, tumors, infection, or congenital malformations not only severely impair patients' physiological functions, but also impose a profound psychological burden, constituting a major public health issue that affects overall health and quality of life. Conventional reconstructive approaches, including autologous grafting and allogeneic implantation, can partially restore tissue morphology; however, limitations, such as donor-site morbidity, immune rejection, and long-term resorption prevent the achievement of true biological functional reconstruction. These challenges are particularly pronounced in the repair of complex and large-scale bone defects. The underlying cause lies in the insufficient understanding of the complex cellular behaviors, signaling networks, and material-host interactions involved in bone regeneration, which hampers precise regulation of the repair process. Therefore, the development of new theories, technologies, and materials grounded in mechanistic insights has become a key strategic direction in cranio-maxillofacial bone regeneration research. Supported by the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and National and Provincial Major Talent Programs, our research group has addressed critical clinical challenges in cranio-maxillofacial bone defect repair by proposing an innovative concept of "regulating cell fate, designing intelligent biomaterials, and achieving functional reconstruction". Centered on this key scientific question, we have systematically carried out a full-chain research strategy spanning "fundamental theory-technological breakthroughs-product translation", overcoming multiple bottlenecks and achieving a series of original outcomes. (1) At the level of fundamental theory, we elucidated the epigenetic and ubiquitination regulatory networks governing skeletal stem cell fate determination, and precisely defined functional stem cell subpopulations using single-cell technologies. We also pioneered apoptotic vesicles as a new paradigm for cell-free therapy and clarified their functional diversity. (2) In terms of technological breakthroughs, we established 4D printing technologies with dynamically tunable morphology and function, developed metal surface engineering strategies that integrate controllable degradation with biofunctional regulation, and built artificial intelligence-driven intelligent design and manufacturing platforms. (3) Regarding translational applications, we developed a series of apoptotic vesicle-based biotherapeutics, smart responsive bone-repair scaffolds, and next-generation biofunctionalized biodegradable metal implants. Collectively, these achievements have advanced the fundamental theory of regenerative medicine, overcome key technological barriers, established new clinical strategies for cranio-maxillofacial tissue defect repair, and significantly enhanced core competitiveness in this field.

Key words: Stem cells, Bioactive materials, Cranio-maxillofacial bone defects, Bone regeneration

中图分类号: 

  • R782.2
1
Lv L , Ge W , Liu Y , et al. Lysine-specific demethylase 1 inhibitor rescues the osteogenic ability of mesenchymal stem cells under osteoporotic conditions by modulating H3K4 methylation[J]. Bone Res, 2016, 4, 16037.

doi: 10.1038/boneres.2016.37
2
Ge W , Shi L , Zhou Y , et al. Inhibition of osteogenic differentiation of human adipose-derived stromal cells by retinoblastoma binding protein 2 repression of RUNX2-activated transcription[J]. Stem Cells, 2011, 29 (7): 1112- 1125.

doi: 10.1002/stem.663
3
Zhang P , Liu Y , Jin C , et al. Histone H3K9 acetyltransferase PCAF is essential for osteogenic differentiation through bone morphogenetic protein signaling and may be involved in osteoporosis[J]. Stem Cells, 2016, 34 (9): 2332- 2341.

doi: 10.1002/stem.2424
4
Zhang P , Liu Y , Jin C , et al. Histone acetyltransferase GCN5 regulates osteogenic differentiation of mesenchymal stem cells by inhibiting NF-κB[J]. J Bone Miner Res, 2016, 31 (2): 391- 402.

doi: 10.1002/jbmr.2704
5
Zhang M , Liu X , Li Z , et al. Asymmetrical methyltransferase PRMT3 regulates human mesenchymal stem cell osteogenesis via miR-3648[J]. Cell Death Dis, 2019, 10 (8): 581.

doi: 10.1038/s41419-019-1815-7
6
Zhang Y , Qing J , Li Y , et al. PRMT7-mediated PTEN activation enhances bone regeneration in female mice[J]. Int J Mol Sci, 2025, 26 (7): 2981.

doi: 10.3390/ijms26072981
7
Lv L , Liu Y , Zhang P , et al. The nanoscale geometry of TiO2 nanotubes influences the osteogenic differentiation of human adipose-derived stem cells by modulating H3K4 trimethylation[J]. Biomaterials, 2015, 39, 193- 205.

doi: 10.1016/j.biomaterials.2014.11.002
8
Ge W , Liu Y , Chen T , et al. The epigenetic promotion of osteogenic differentiation of human adipose-derived stem cells by the genetic and chemical blockade of histone demethylase LSD1[J]. Biomaterials, 2014, 35 (23): 6015- 6025.

doi: 10.1016/j.biomaterials.2014.04.055
9
Fan C , Jia L , Zheng Y , et al. miR-34a promotes osteogenic differentiation of human adipose-derived stem cells via the RBP2/NOTCH1/CYCLIN D1 coregulatory network[J]. Stem Cell Reports, 2016, 7 (2): 236- 248.

doi: 10.1016/j.stemcr.2016.06.010
10
Chen S , Zheng Y , Zhang S , et al. Promotion effects of miR-375 on the osteogenic differentiation of human adipose-derived mesenchymal stem cells[J]. Stem Cell Reports, 2017, 8 (3): 773- 786.

doi: 10.1016/j.stemcr.2017.01.028
11
Jin C , Jia L , Huang Y , et al. Inhibition of lncRNA MIR31HG promotes osteogenic differentiation of human adipose-derived stem cells[J]. Stem Cells, 2016, 34 (11): 2707- 2720.

doi: 10.1002/stem.2439
12
Li Z , Jin C , Chen S , et al. Long non-coding RNA MEG3 inhibits adipogenesis and promotes osteogenesis of human adipose-derived mesenchymal stem cells via miR-140-5p[J]. Mol Cell Biochem, 2017, 433 (1/2): 51- 60.
13
Du Y , Zhang M , Liu X , et al. CDC20 promotes bone formation via APC/C dependent ubiquitination and degradation of p65[J]. EMBO Rep, 2021, 22 (9): e52576.

doi: 10.15252/embr.202152576
14
Du Y , Liu Y , Zhou Y , et al. Knockdown of CDC20 promotes adipogenesis of bone marrow-derived stem cells by modulating β-catenin[J]. Stem Cell Res Ther, 2022, 13 (1): 443.

doi: 10.1186/s13287-022-03062-0
15
Zhang H , Du Y , Lu D , et al. UBE2C orchestrates bone formation through stabilization of SMAD1/5[J]. Bone, 2024, 187, 117175.

doi: 10.1016/j.bone.2024.117175
16
Liu X , Liu X , Du Y , et al. DUSP5 promotes osteogenic differentiation through SCP1/2-dependent phosphorylation of SMAD1[J]. Stem Cells, 2021, 39 (10): 1395- 1409.

doi: 10.1002/stem.3428
17
Jin C , Zhang P , Zhang M , et al. Inhibition of SLC7A11 by sulfasalazine enhances osteogenic differentiation of mesenchymal stem cells by modulating BMP2/4 expression and suppresses bone loss in ovariectomized mice[J]. J Bone Miner Res, 2017, 32 (3): 508- 521.

doi: 10.1002/jbmr.3009
18
Wang Y , Liu Y , Zhang M , et al. Inhibition of PTGS1 promotes osteogenic differentiation of adipose-derived stem cells by suppres-sing NF-κB signaling[J]. Stem Cell Res Ther, 2019, 10 (1): 57.

doi: 10.1186/s13287-019-1167-3
19
Liu X , Li Z , Liu H , et al. Low concentration flufenamic acid enhances osteogenic differentiation of mesenchymal stem cells and suppresses bone loss by inhibition of the NF-κB signaling pathway[J]. Stem Cell Res Ther, 2019, 10 (1): 213.

doi: 10.1186/s13287-019-1321-y
20
Zhang P , Dong J , Fan X , et al. Characterization of mesenchymal stem cells in human fetal bone marrow by single-cell transcriptomic and functional analysis[J]. Signal Transduct Target Ther, 2023, 8 (1): 126.

doi: 10.1038/s41392-023-01338-2
21
Li Y , Lu D , Xu F , et al. EGR1 promotes craniofacial bone rege-neration via activation of ALPL+ PDGFD+ periosteal stem cells[J]. Adv Sci (Weinh), 2025, 12 (30): e10243.

doi: 10.1002/advs.202410243
22
Li W , Liu Y , 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.

doi: 10.1021/acsami.7b17620
23
Chen S , Tang Y , Liu Y , et al. Exosomes derived from miR-375-overexpressing human adipose mesenchymal stem cells promote bone regeneration[J]. Cell Prolif, 2019, 52 (5): e12669.

doi: 10.1111/cpr.12669
24
Zhang X , Tang J , Kou X , et al. Proteomic analysis of MSC-derived apoptotic vesicles identifies Fas inheritance to ameliorate haemophilia a via activating platelet functions[J]. J Extracell Vesicles, 2022, 11 (7): e12240.

doi: 10.1002/jev2.12240
25
Zhu Y , Yang K , Cheng Y , et al. Apoptotic vesicles regulate bone metabolism via the miR1324/SNX14/SMAD1/5 signaling axis[J]. Small, 2023, 19 (16): e2205813.

doi: 10.1002/smll.202205813
26
Yang K , Zhu Y , Shao Y , et al. Apoptotic vesicles derived from dental pulp stem cells promote bone formation through the ERK1/2 signaling pathway[J]. Biomedicines, 2024, 12 (4): 730.

doi: 10.3390/biomedicines12040730
27
Jiang Y , Zhu Y , Shao Y , et al. Platelet-derived apoptotic vesicles promote bone regeneration via Golgi phosphoprotein 2 (GOLPH2)-AKT signaling axis[J]. ACS Nano, 2023, 17 (24): 25070- 25090.

doi: 10.1021/acsnano.3c07717
28
Shao Y , Jiang Y , Yang K , et al. Apoptotic vesicles derived from human red blood cells promote bone regeneration via carbonic anhydrase 1[J]. Cell Prolif, 2024, 57 (2): e13547.

doi: 10.1111/cpr.13547
29
Cheng Y , Zhu Y , Liu Y , et al. Tailored apoptotic vesicles promote bone regeneration by releasing the osteoinductive brake[J]. Int J Oral Sci, 2024, 16 (1): 31.

doi: 10.1038/s41368-024-00293-0
30
Liu Y , Zhu Y , Ding Y , et al. Poly (lactic-co-glycolic) acid porous microspheres for the sequential delivery of apoptotic vesicles and strontium in maxillofacial bone regeneration[J]. Chem Eng J, 2025, 513, 162902.

doi: 10.1016/j.cej.2025.162902
31
Xia D , Liu Y , Wang S , et al. In vitro and in vivo investigation on biodegradable Mg-Li-Ca alloys for bone implant application[J]. Sci China Mater, 2019, 62 (2): 256- 272.

doi: 10.1007/s40843-018-9293-8
32
Xia D , Jia Z , Shen Y , et al. pH stimuli-responsive, rapidly self-healable coatings enhanced the corrosion resistance and osteogenic differentiation of Mg-1Ca osteoimplant[J]. Small, 2022, 18 (36): 2106056.

doi: 10.1002/smll.202106056
33
Du S , Shen Y , Zheng Y , et al. Systematic in vitro and in vivo study on biodegradable binary Zn-0.2 at% Rare Earth alloys (Zn-RE: Sc, Y, La-Nd, Sm-Lu)[J]. Bioact Mater, 2023, 24, 507- 523.
34
Liang S , Du S , Zheng Y , et al. Biodegradable Zn-xY alloys with enhanced osteogenesis and angiogenesis effects for bone implant applications[J]. Acta Biomater, 2025, 201, 684- 702.

doi: 10.1016/j.actbio.2025.05.048
35
Yuan W , Xia D , Zheng Y , et al. Controllable biodegradation and enhanced osseointegration of ZrO2-nanofilm coated Zn-Li alloy: In vitro and in vivo studies[J]. Acta Biomater, 2020, 105, 290- 303.

doi: 10.1016/j.actbio.2020.01.022
36
Hsu Y , He Y , Zhao X , et al. Photothermal coating on zinc alloy for controlled biodegradation and improved osseointegration[J]. Adv Sci (Weinh), 2025, 12 (9): e2409051.

doi: 10.1002/advs.202409051
37
Guo H , Xia D , Zheng Y , et al. A pure zinc membrane with degradability and osteogenesis promotion for guided bone regeneration: In vitro and in vivo studies[J]. Acta Biomater, 2020, 106, 396- 409.

doi: 10.1016/j.actbio.2020.02.024
38
Yan F , Yu M , He Y , et al. Hierarchical mineralized collagen coated Zn membrane to tailor cell microenvironment for guided bone regeneration[J]. Adv Funct Mater, 2025, 35 (7): 2412695.

doi: 10.1002/adfm.202412695
39
Xia D , Qin Y , Guo H , et al. Additively manufactured pure zinc porous scaffolds for critical-sized bone defects of rabbit femur[J]. Bioact Mater, 2022, 19, 12- 23.
40
Lu Y , Liu A , Jin S , et al. Additively manufactured biodegradable Zn-based porous scaffolds to suppress osteosarcoma and promote osteogenesis[J]. Adv Mater, 2025, 37 (3): e2410589.

doi: 10.1002/adma.202410589
41
Qin Y , Liu A , Guo H , et al. Additive manufacturing of Zn-Mg alloy porous scaffolds with enhanced osseointegration: In vitro and in vivo studies[J]. Acta Biomater, 2022, 145, 403- 415.

doi: 10.1016/j.actbio.2022.03.055
42
Xia D , Yang F , Zheng Y , et al. Research status of biodegradable metals designed for oral and maxillofacial applications: A review[J]. Bioact Mater, 2021, 6 (11): 4186- 4208.
43
Wan Z , Bai X , Wang X , et al. Mgp high-expressing MSCs orchestrate the osteoimmune microenvironment of collagen/nanohydroxyapatite- mediated bone regeneration[J]. Adv Sci (Weinh), 2024, 11 (23): e2308986.

doi: 10.1002/advs.202308986
44
Guo X , Yi J , Wan Z , et al. Morphology and function dual-adjustable biomimetic 4D-printed scaffold for the regenerative restoration of complex bone defects[J]. Adv Funct Mater, 2025, 35 (45): 2509961.

doi: 10.1002/adfm.202509961
45
Wan Z , Dong Q , Liu Y , et al. Programmed biomolecule delivery orchestrate bone tissue regeneration via MSC recruitment and epigenetic modulation[J]. Chem Eng J, 2022, 438, 135518.

doi: 10.1016/j.cej.2022.135518
46
Wan Z , Zhang P , Lv L , et al. NIR light-assisted phototherapies for bone-related diseases and bone tissue regeneration: A systema-tic review[J]. Theranostics, 2020, 10 (25): 11837- 11861.

doi: 10.7150/thno.49784
47
Wan Z , Dong Q , Guo X , et al. A dual-responsive polydopamine-modified hydroxybutyl chitosan hydrogel for sequential regulation of bone regeneration[J]. Carbohydr Polym, 2022, 297, 120027.

doi: 10.1016/j.carbpol.2022.120027
48
Zhai M , Xianyu B , Zhang H , et al. Se polyurethane-coated titanium for improved osteogenesis and immune response[J]. Adv Funct Mater, 2026, 36 (3): e14534.

doi: 10.1002/adfm.202514534
49
Zhai M , Huang Z , Xianyu B , et al. Selenium-containing polyurethane thermo-sensitive hydrogel accelerates diabetic wound healing by activating unfolded protein response[J]. Aggregate, 2025, 6 (7): e70074.

doi: 10.1002/agt2.70074
50
Yuan Z , Bai X , Li S , et al. Multimaterial and multidimensional bioprinting in regenerative medicine: Advances, limitations, and future directions[J]. Adv Healthc Mater, 2025, 14 (18): e2500475.

doi: 10.1002/adhm.202500475
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