基于组织工程新技术构建理想体外瘢痕模型的研究进展

朱冬振; 姚斌; 闫自强; 黄沙; 付小兵

doi:10.3760/cma.j.cn501120-20210723-00257

基于组织工程新技术构建理想体外瘢痕模型的研究进展

doi: 10.3760/cma.j.cn501120-20210723-00257

1.
解放军总医院医学创新研究部创伤修复与组织再生研究中心，北京　　100048
2.
天津大学医学工程与转化医学研究院，天津　　300072
3.
解放军69213部队，喀什　　844900

基金项目:

国家重点研发计划 2017YFC1103303

国家自然科学基金青年科学基金项目 32000969

上海王正国创伤医学发展基金会生长因子复兴计划 SZYZ-TR-03

详细信息

通讯作者:
黄沙，Email：stellarahuang@sina.com

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出版历程
- 收稿日期: 2021-07-23
- 网络出版日期: 2022-10-24

Research advances on the construction of an ideal scar model in vitro based on innovative tissue engineering technology

1.
Research Center for Wound Repair and Tissue Regeneration, Medical Innovation Research Department, the PLA General Hospital, Beijing 100048, China
2.
Institute of Medical Engineering and Translational Medicine, Tianjin University, Tianjin 300072, China
3.
Unit 69213 of PLA, Kashgar 844900, China

Funds:

National Key Research and Development Program of China 2017YFC1103303

Youth Science Foundation of National Natural Science Foundation of China 32000969

Shanghai Wang Zhengguo Foundation for Traumatic Medicine Growth Factor Rejuvenation Plan SZYZ-TR-03

More Information

Corresponding author: Huang Sha, Email: stellarahuang@sina.com

摘要

摘要: 瘢痕的形成给患者造成巨大的经济负担和严重的心理阴影。尽管目前用于瘢痕治疗的手段趋于多样化，但是能够真正实现人体皮肤损伤后的“完美愈合”或是“无瘢痕愈合”的治疗方法相当匮乏。随着组织工程技术在医学研究中的广泛应用，诸如生物三维打印、类器官培养和器官芯片技术等新技术不断涌现，基于这些新技术构建的体外疾病模型也展现出比以往传统动物疾病模型更大的优势。该文介绍了类器官培养、生物三维打印、器官芯片技术等目前在皮肤组织工程中应用的热点技术，重点总结了构建理想的体外瘢痕模型需把握的3个关键要素，并结合该研究团队长期从事皮肤组织修复与再生研究的经验，对未来构建理想体外瘢痕模型进行展望。
- 瘢痕 /
- 组织工程 /
- 皮肤 /
- 疾病模型
Abstract: The scar brings a huge economic burden and creates a serious psychological shadow for patients. Although the current methods for scar treatment tend to be diversified, the treatment method that can truly achieve the goal of "perfect healing" or "scarless healing" after human skin injury is quite scarce. With the wide application of tissue engineering technologies in medicine research, technologies such as three-dimensional bioprinting, organoid culture, and organ chip technologies are constantly emerging. Disease models in vitro based on these innovative technologies showed more advantages than traditional animal disease models. The article introduces the current hotspot technologies in skin tissue engineering such as organoid culture, three-dimensional bioprinting, and organ chip technologies, focuses on summarizing the three key elements to be mastered for constructing an ideal scar model in vitro, and puts forward the future prospect of constructing an ideal scar model in vitro based on our research team's long-term experience in skin tissue repair and regeneration research.
- Cicatrix /
- Tissue engineering /
- Skin /
- Disease model
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参考文献(47)

[1]	RahimnejadM,DerakhshanfarS,ZhongW.Biomaterials and tissue engineering for scar management in wound care[J/OL].Burns Trauma,2017,5:4[2022-09-21].https://pubmed.ncbi.nlm.nih.gov/28127573/. DOI: 10.1186/s41038-017-0069-9.
[2]	中国整形美容协会瘢痕医学分会. 瘢痕早期治疗全国专家共识(2020版) [J]. 中华烧伤杂志, 2021, 37(2):113-125. DOI: 10.3760/cma.j.cn501120-20200609-00300.
[3]	SharmaJR,LebekoM,KidzeruEB,et al.In vitro and ex vivo models for functional testing of therapeutic anti-scarring drug targets in keloids[J].Adv Wound Care (New Rochelle),2019,8(12):655-670.DOI: 10.1089/wound.2019.1040.
[4]	SeokJ,WarrenHS,CuencaAG,et al.Genomic responses in mouse models poorly mimic human inflammatory diseases[J].Proc Natl Acad Sci U S A,2013,110(9):3507-3512.DOI: 10.1073/pnas.1222878110.
[5]	DiegelmannRF,CohenIK,McCoyBJ.Growth kinetics and collagen synthesis of normal skin, normal scar and keloid fibroblasts in vitro[J].J Cell Physiol,1979,98(2):341-346.DOI: 10.1002/jcp.1040980210.
[6]	GarretaE,KammRD,Chuva de Sousa LopesSM,et al.Rethinking organoid technology through bioengineering[J].Nat Mater,2021,20(2):145-155.DOI: 10.1038/s41563-020-00804-4.
[7]	BagabirR,SyedF,PausR,et al.Long-term organ culture of keloid disease tissue[J].Exp Dermatol,2012,21(5):376-381.DOI: 10.1111/j.1600-0625.2012.01476.x.
[8]	KischerCW,PindurJ,ShetlarMR,et al.Implants of hypertrophic scars and keloids into the nude (athymic) mouse: viability and morphology[J].J Trauma,1989,29(5):672-677.DOI: 10.1097/00005373-198905000-00023.
[9]	JacobF, SalinasRD, ZhangDY, et al. A patient-derived glioblastoma organoid model and biobank recapitulates inter- and intra-tumoral heterogeneity[J]. Cell,2020,180(1):188-204.e22. DOI: 10.1016/j.cell.2019.11.036.
[10]	SunW,StarlyB,DalyAC,et al.The bioprinting roadmap[J].Biofabrication,2020,12(2):022002.DOI: 10.1088/1758-5090/ab5158.
[11]	BinderKW, ZhaoW, AboushwarebT, et al. In situ bioprinting of the skin for burns[J]. Journal of the American College of Surgeons, 2010, 211(3-supp-S):S76. DOI: 10.1016/j.jamcollsurg.2010.06.198.
[12]	HuangS,YaoB,XieJ,et al.3D bioprinted extracellular matrix mimics facilitate directed differentiation of epithelial progenitors for sweat gland regeneration[J].Acta Biomater,2016,32:170-177.DOI: 10.1016/j.actbio.2015.12.039.
[13]	RimannM,BonoE,AnnaheimH,et al.Standardized 3D bioprinting of soft tissue models with human primary cells[J].J Lab Autom,2016,21(4):496-509.DOI: 10.1177/2211068214567146.
[14]	KochL,DeiwickA,SchlieS,et al.Skin tissue generation by laser cell printing[J].Biotechnol Bioeng,2012,109(7):1855-1863.DOI: 10.1002/bit.24455.
[15]	ZhouF,HongY,LiangR,et al.Rapid printing of bio-inspired 3D tissue constructs for skin regeneration[J].Biomaterials,2020,258:120287.DOI: 10.1016/j.biomaterials.2020.120287.
[16]	KimBS,LeeJS,GaoG,et al.Direct 3D cell-printing of human skin with functional transwell system[J].Biofabrication,2017,9(2):025034.DOI: 10.1088/1758-5090/aa71c8.
[17]	YaoB,HuT,CuiX,et al.Enzymatically degradable alginate/gelatin bioink promotes cellular behavior and degradation in vitro and in vivo[J].Biofabrication,2019,11(4):045020.DOI: 10.1088/1758-5090/ab38ef.
[18]	LiJ,ZhangY,EnheJ,et al.Bioactive nanoparticle reinforced alginate/gelatin bioink for the maintenance of stem cell stemness[J].Mater Sci Eng C Mater Biol Appl,2021,126:112193.DOI: 10.1016/j.msec.2021.112193.
[19]	YaoB,WangR,WangY,et al.Biochemical and structural cues of 3D-printed matrix synergistically direct MSC differentiation for functional sweat gland regeneration[J].Sci Adv,2020,6(10):eaaz1094.DOI: 10.1126/sciadv.aaz1094.
[20]	SinghNK,HanW,NamSA,et al.Three-dimensional cell-printing of advanced renal tubular tissue analogue[J].Biomaterials,2020,232:119734.DOI: 10.1016/j.biomaterials.2019.119734.
[21]	KimBS,AhnM,ChoWW,et al.Engineering of diseased human skin equivalent using 3D cell printing for representing pathophysiological hallmarks of type 2 diabetes in vitro[J].Biomaterials,2021,272:120776.DOI: 10.1016/j.biomaterials.2021.120776.
[22]	YaoB, ZhuDZ, CuiXL, et al.Modeling human hypertrophic scars with 3D preformed cellular aggregates bioprinting[J].Bioact Mater,2022,10:247-254.DOI: 10.1016/j.bioactmat.2021.09.004.
[23]	PeddeRD,MiraniB,NavaeiA,et al.Emerging biofabrication strategies for engineering complex tissue constructs[J].Adv Mater,2017,29(19). DOI: 10.1002/adma.201606061.
[24]	BhatiaSN,IngberDE.Microfluidic organs-on-chips[J].Nat Biotechnol,2014,32(8):760-772.DOI: 10.1038/nbt.2989.
[25]	AtaçB,WagnerI,HorlandR,et al.Skin and hair on-a-chip: in vitro skin models versus ex vivo tissue maintenance with dynamic perfusion[J].Lab Chip,2013,13(18):3555-3561.DOI: 10.1039/c3lc50227a.
[26]	MoriN,MorimotoY,TakeuchiS.Skin integrated with perfusable vascular channels on a chip[J].Biomaterials,2017,116:48-56.DOI: 10.1016/j.biomaterials.2016.11.031.
[27]	AbaciHE,GledhillK,GuoZ,et al.Pumpless microfluidic platform for drug testing on human skin equivalents[J].Lab Chip,2015,15(3):882-888.DOI: 10.1039/c4lc00999a.
[28]	MomeniF, SeyedM, XunL, et al. A review of 4D printing[J]. Materials & design, 2017, 122:42-79. DOI: 10.1016/j.matdes.2017.02.068.
[29]	ChuH,YangW,SunL,et al.4D printing: a review on recent progresses[J].Micromachines (Basel),2020,11(9):796.DOI: 10.3390/mi11090796.
[30]	王蕴璋, 苏晨, 付思祺, 等. 瘢痕疙瘩中的成纤维细胞特性研究进展[J]. 中华烧伤与创面修复杂志, 2022, 38(6):590-594. DOI: 10.3760/cma.j.cn501120-20210510-00176.
[31]	BuechlerMB,PradhanRN,KrishnamurtyAT,et al.Cross-tissue organization of the fibroblast lineage[J].Nature,2021,593(7860):575-579.DOI: 10.1038/s41586-021-03549-5.
[32]	MascharakS,desJardins-ParkHE,DavittMF,et al.Preventing Engrailed-1 activation in fibroblasts yields wound regeneration without scarring[J].Science,2021,372(6540):eaba2374.DOI: 10.1126/science.aba2374.
[33]	WangZC,ZhaoWY,CaoY,et al.The roles of inflammation in keloid and hypertrophic scars[J].Front Immunol,2020,11:603187.DOI: 10.3389/fimmu.2020.603187.
[34]	ShookBA,WaskoRR,Rivera-GonzalezGC,et al.Myofibroblast proliferation and heterogeneity are supported by macrophages during skin repair[J].Science,2018,362(6417):eaar2971.DOI: 10.1126/science.aar2971.
[35]	ChenCZ,RaghunathM.Focus on collagen: in vitro systems to study fibrogenesis and antifibrosis state of the art[J].Fibrogenesis Tissue Repair,2009,2:7.DOI: 10.1186/1755-1536-2-7.
[36]	VeithAP,HendersonK,SpencerA,et al.Therapeutic strategies for enhancing angiogenesis in wound healing[J].Adv Drug Deliv Rev,2019,146:97-125.DOI: 10.1016/j.addr.2018.09.010.
[37]	KorntnerS,LehnerC,GehwolfR,et al.Limiting angiogenesis to modulate scar formation[J].Adv Drug Deliv Rev,2019,146:170-189.DOI: 10.1016/j.addr.2018.02.010.
[38]	HsuCK,LinHH,HarnHI,et al.Mechanical forces in skin disorders[J].J Dermatol Sci,2018,90(3):232-240.DOI: 10.1016/j.jdermsci.2018.03.004.
[39]	GeorgesPC,HuiJJ,GombosZ,et al.Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis[J].Am J Physiol Gastrointest Liver Physiol,2007,293(6):G1147-1154.DOI: 10.1152/ajpgi.00032.2007.
[40]	Viji BabuPK,RiannaC,BelgeG,et al.Mechanical and migratory properties of normal, scar, and Dupuytren's fibroblasts[J].J Mol Recognit,2018,31(9):e2719.DOI: 10.1002/jmr.2719.
[41]	SantosA,LagaresD.Matrix stiffness: the conductor of organ fibrosis[J].Curr Rheumatol Rep,2018,20(1):2.DOI: 10.1007/s11926-018-0710-z.
[42]	ZhuY,CaoY,PanJ,et al.Macro-alignment of electrospun fibers for vascular tissue engineering[J].J Biomed Mater Res B Appl Biomater,2010,92(2):508-516.DOI: 10.1002/jbm.b.31544.
[43]	SeoBR,ChenX,LingL,et al.Collagen microarchitecture mechanically controls myofibroblast differentiation[J].Proc Natl Acad Sci U S A,2020,117(21):11387-11398.DOI: 10.1073/pnas.1919394117.
[44]	BermanB.Biological agents for controlling excessive scarring[J].Am J Clin Dermatol,2010,11 Suppl 1:S31-34.DOI: 10.2165/1153419-S0-000000000-00000.
[45]	SylakowskiK,WellsA.ECM-regulation of autophagy: the yin and the yang of autophagy during wound healing[J].Matrix Biol,2021,100-101:197-206.DOI: 10.1016/j.matbio.2020.12.006.
[46]	McCormackA,HighleyCB,LeslieNR,et al.3D printing in suspension baths: keeping the promises of bioprinting afloat[J].Trends Biotechnol,2020,38(6):584-593.DOI: 10.1016/j.tibtech.2019.12.020.
[47]	RamezaniH, ZhouLY, ShaoL, et al. Coaxial 3D bioprinting of organ prototyps from nutrients delivery to vascularization[J]. J Zhejiang Univ Sci A, 2020,21:859-875. DOI: 10.1631/jzus.A2000261.

表 1 皮肤组织工程常用的生物三维打印方法的优点和不足

打印方法	优点	不足
喷墨式打印	（1）打印速度快	（1）需采用有一定黏滞性的材料
	（2）可采用多种聚合机制	（2）不能打印厚度较高的模型
	（3）低成本、可商业化	（3）打印材料中细胞密度较低
		（4）打印过程影响细胞活性
微挤出式打印	（1）可采用高黏滞性和高细胞密度溶液打印	（1）喷头易阻塞
	（2）可打印较厚的垂直结构	（2）高精度打印影响细胞活性
	（3）可采用多种聚合机制	（3）各层连接松散
激光辅助式打印	（1）打印材料中细胞活性高	（1）需采用有一定黏滞性的材料
	（2）高细胞密度打印	（2）不能打印厚度较高的模型
	（3）适用于低黏滞性材料	（3）单一聚合机制
	（4）打印精度高	（4）过程复杂、费用高
立体光刻式打印	（1）打印速度快	（1）打印墨水只能用光交联聚合物
	（2）打印精度高	（2）需采用有一定黏滞性的材料
	（3）可打印较厚的垂直结构	（3）紫外线可影响细胞活性
	（4）打印材料内部连接较为紧密