3D打印水凝胶支架在宫腔粘连防治中的应用

doi:10.12280/gjfckx.20231104

国际妇产科学杂志 ›› 2024, Vol. 51 ›› Issue (3): 290-296.doi: 10.12280/gjfckx.20231104

• 普通妇科疾病及相关研究:综述 • 上一篇下一篇

3D打印水凝胶支架在宫腔粘连防治中的应用

史明, 孙铭辉, 杨微微, 黄慧华, 张昌林, 邓宇斌^△()

518107 广东省深圳市，中山大学附属第七医院科研中心（史明，邓宇斌）;中山大学医学院（孙铭辉，杨微微，黄慧华）;中山大学附属第七医院妇产科，深圳市中药活性物质筛选与转化研究重点实验室（张昌林）

收稿日期:2023-12-28 出版日期:2024-06-15 发布日期:2024-06-25
通讯作者: 邓宇斌 E-mail:dengyub@mail.sysu.edu.cn
作者简介:^△审校者
基金资助:
深圳市科技计划项目(JCYJ20210324123001003)

Application of 3D Printed Hydrogel Stents in Prevention and Treatment of Intrauterine Adhesion

SHI Ming, SUN Ming-hui, YANG Wei-wei, HUANG Hui-hua, ZHANG Chang-lin, David YB Deng^△()

Department of Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China (SHI Ming, David YB Deng); School of Medicine, Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China (SUN Ming-hui, YANG Wei-wei, HUANG Hui-hua); Department of Obstetrics and Gynecology, Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China (ZHANG Chang-lin)

Received:2023-12-28 Published:2024-06-15 Online:2024-06-25
Contact: David YB Deng E-mail:dengyub@mail.sysu.edu.cn

摘要/Abstract

摘要：

宫腔粘连（intrauterine adhesion，IUA）常易引发停经、不孕和复发性流产等问题，严重影响女性身心健康。临床上，对IUA的治疗主要采用手术分离方式，术后易复发，治疗效果欠佳。3D生物打印支架成为治疗IUA的前沿领域，可分隔受损区域防止粘连形成，体内可控降解无需手术取出。该支架可用于药物负载、干细胞移植及外泌体的递送，可将药物或生长因子释放到损伤区域，促进组织修复与再生。将负载干细胞或干细胞外泌体的3D打印水凝胶移植到损伤区域，可有效促进IUA的修复并改善妊娠率。3D生物打印可为患者提供个体化治疗方案，联合干细胞或干细胞外泌体的治疗策略有望成为治疗IUA的有力工具。

关键词: 宫腔粘连, 打印, 三维, 干细胞, 治疗, 子宫内膜修复

Abstract:

Intrauterine adhesion (IUA) often leads to amenorrhea, infertility, and recurrent miscarriage, seriously affecting the physical and mental health of women. Clinically, surgical separation is the main treatment for IUA, but this approach frequently results in postoperative recurrence and has poor treatment efficacy. 3D bioprinted scaffolds have emerged as a cutting-edge approach in the treatment of IUA, capable of separating damaged areas to prevent adhesion formation and undergoing controllable in vivo degradation without the need for surgical removal. These scaffolds can be used for drug loading, stem cell transplantation, and exosome delivery, enabling the release of drugs or growth factors to the injured area to promote tissue repair and regeneration. Transplanting 3D bioprinted hydrogels loaded with stem cells or stem cell-derived exosomes to the damaged area can effectively promote the repair of IUA and improve pregnancy rates. 3D bioprinting can provide personalized treatment plans for patients, and the combined treatment strategy with stem cells or stem cell-derived exosomes holds promise as a powerful tool for treating IUA.

Key words: Intrauterine adhesion, Printing, three-dimensional, Stem cells, Therapy, Endometrial repair

史明, 孙铭辉, 杨微微, 黄慧华, 张昌林, 邓宇斌. 3D打印水凝胶支架在宫腔粘连防治中的应用[J]. 国际妇产科学杂志, 2024, 51(3): 290-296.

SHI Ming, SUN Ming-hui, YANG Wei-wei, HUANG Hui-hua, ZHANG Chang-lin, David YB Deng. Application of 3D Printed Hydrogel Stents in Prevention and Treatment of Intrauterine Adhesion[J]. Journal of International Obstetrics and Gynecology, 2024, 51(3): 290-296.

图/表 3

表1 水凝胶材料参数及其优缺点

序号	水凝胶材料	参数	优点	缺点
1	GelMA、SA^[9]	10%GelMA，2%SA，1%光引发剂	多孔性、可压缩性高、生物相容性高	GelMA体内降解较慢、单独支架促修复效果有限
2	Gel、SA^[10]	20%Gel和4%SA，2∶1体积比，4度打印，10%氯化钙交联	可在体外体内长期支持负载细胞的活性，体内可自然降解，生物相容性高	人的诱导性多能干细胞移植到大鼠存在免疫反应，子宫内膜修复疗效有限
3	自交联HA^[11]	5 mg/mL	为UC-MSCs移植提供载体，防止细胞流出，提供物理支持	单独支架移植未改善恒河猴的宫腔形态及月经周期
5	Ⅰ型胶原蛋白^[12]	0.5%胶原冻干，105 ℃热脱水15 h	具有细胞外基质同样的纤维结构、具有多孔结构，适合MSCs的负载黏附和营养支持	需要和干细胞联合使用才能达到促修复和改善妊娠效果
6	壳聚糖^[13]	2%壳聚糖/乙酸溶液3 mL加入1.5 mL交联液，搅拌15 min，37 ℃交联形成水凝胶	生物相容性高，具备抗菌性能，稳定性高	制备过程较为复杂，氨基成分易被化学修饰，机械强度弱

图1 3D打印水凝胶支架缓释G-CSF体内促大鼠IUA模型修复的示意图[17] 注：G-CSF粒细胞集落刺激因子；PLGA聚乳酸-羟基乙酸共聚物；Gelatin Alginate明胶海藻酸钠；3D Bioprinter 3D生物打印机；3D printed scaffold 3D打印支架；Scaffold implanted支架移植；IUA model宫腔粘连模型；Endometrial regeneration子宫内膜再生；Uterus子宫；Basal layer 子宫基底层；Functional layer子宫功能层；Endometrium子宫内膜层；Myometrium子宫肌层。

图2 应用MSCs修复受损子宫内膜的方法及机制[5] 注：Bone Marrow骨髓；BMSCs骨髓间充质干细胞；Adipose Tissue脂肪组织；ADSCs脂肪间充质干细胞；Uterus子宫；EnSCs（Endometrial stem/progenitor cells）子宫内膜干细胞/祖细胞；embryo胚胎；UC-MSCs脐带间充质干细胞；ESCs （Embryonic stem cells）胚胎干细胞；ASCs（Amniotic membrane stem cells）羊膜干细胞；Stem cells干细胞；isolate分离；Injection注射；EV/Exo囊泡/外泌体；Scaffold materials支架材料；Intravenous injection静脉注射；Intrauterine injection子宫内注射；Intrauterine adhesion宫腔粘连；Orthotopic biomaterial transplantation原位生物材料移植；Inhibitory effect抑制作用；Enhancement effect促进作用；Inflammation炎症；Endometrial fibrosis子宫内膜纤维化；Gland regeneration腺体再生；Revascularization血管再生；Re-epithelization再上皮化；Restore normal uterine 恢复正常子宫。

参考文献 34

[1]	Hooker AB, de Leeuw RA, Twisk J, et al. Reproductive performance of women with and without intrauterine adhesions following recurrent dilatation and curettage for miscarriage: long-term follow-up of a randomized controlled trial[J]. Hum Reprod, 2021, 36(1):70-81. doi: 10.1093/humrep/deaa289.
[2]	Lee WL, Liu CH, Cheng M, et al. Focus on the Primary Prevention of Intrauterine Adhesions: Current Concept and Vision[J]. Int J Mol Sci, 2021, 22(10):5175. doi: 10.3390/ijms22105175.
[3]	Qiao J, Wang Y, Li X, et al. A Lancet Commission on 70 years of women′s reproductive, maternal, newborn, child, and adolescent health in China[J]. Lancet, 2021, 397(10293):2497-2536. doi: 10.1016/S0140-6736(20)32708-2. pmid: 34043953
[4]	Trinh TT, Nguyen KD, Pham HV, et al. Effectiveness of Hyaluronic Acid Gel and Intrauterine Devices in Prevention of Intrauterine Adhesions after Hysteroscopic Adhesiolysis in Infertile Women[J]. J Minim Invasive Gynecol, 2022, 29(2):284-290. doi: 10.1016/j.jmig.2021.08.010.
[5]	Song YT, Liu PC, Tan J, et al. Stem cell-based therapy for ameliorating intrauterine adhesion and endometrium injury[J]. Stem Cell Res Ther, 2021, 12(1):556. doi: 10.1186/s13287-021-02620-2.
[6]	Abudukeyoumu A, Li MQ, Xie F. Transforming growth factor-β1 in intrauterine adhesion[J]. Am J Reprod Immunol, 2020, 84(2):e13262. doi: 10.1111/aji.13262.
[7]	Rajabi N, Rezaei A, Kharaziha M, et al. Recent Advances on Bioprinted Gelatin Methacrylate-Based Hydrogels for Tissue Repair[J]. Tissue Eng Part A, 2021, 27(11/12):679-702. doi: 10.1089/ten.TEA.2020.0350.
[8]	Janarthanan G, Kim JH, Kim I, et al. Manufacturing of self-standing multi-layered 3D-bioprinted alginate-hyaluronate constructs by controlling the cross-linking mechanisms for tissue engineering applications[J]. Biofabrication, 2022 May 31;14(3). doi: 10.1088/1758-5090/ac6c4c.
[9]	Cai Y, Wu F, Yu Y, et al. Porous scaffolds from droplet microfluidics for prevention of intrauterine adhesion[J]. Acta Biomater, 2019, 84:222-230. doi: 10.1016/j.actbio.2018.11.016. pmid: 30476581
[10]	Ji W, Hou B, Lin W, et al. 3D Bioprinting a human iPSC-derived MSC-loaded scaffold for repair of the uterine endometrium[J]. Acta Biomater, 2020, 116:268-284. doi: 10.1016/j.actbio.2020.09.012. pmid: 32911103
[11]	Wang L, Yu C, Chang T, et al. In situ repair abilities of human umbilical cord-derived mesenchymal stem cells and autocrosslinked hyaluronic acid gel complex in rhesus monkeys with intrauterine adhesion[J]. Sci Adv, 2020, 6(21):eaba6357. doi: 10.1126/sciadv.aba6357.
[12]	Xin L, Lin X, Pan Y, et al. A collagen scaffold loaded with human umbilical cord-derived mesenchymal stem cells facilitates endometrial regeneration and restores fertility[J]. Acta Biomater, 2019, 92:160-171. doi: 10.1016/j.actbio.2019.05.012. pmid: 31075515
[13]	Wenbo Q, Lijian X, Shuangdan Z, et al. Controlled releasing of SDF-1α in chitosan-heparin hydrogel for endometrium injury healing in rat model[J]. Int J Biol Macromol, 2020, 143:163-172. doi: 10.1016/j.ijbiomac.2019.11.184. pmid: 31765745
[14]	Xu T, Jin J, Gregory C, et al. Inkjet printing of viable mammalian cells[J]. Biomaterials, 2005, 26(1):93-99. doi: 10.1016/j.biomaterials.2004.04.011. pmid: 15193884
[15]	Matai I, Kaur G, Seyedsalehi A, et al. Progress in 3D bioprinting technology for tissue/organ regenerative engineering[J]. Biomaterials, 2020,226:119536. doi: 10.1016/j.biomaterials.2019.119536.
[16]	Melchels FP, Feijen J, Grijpma DW. A review on stereolithography and its applications in biomedical engineering[J]. Biomaterials, 2010, 31(24):6121-6130. doi: 10.1016/j.biomaterials.2010.04.050. pmid: 20478613
[17]	Wen J, Hou B, Lin W, et al. 3D-printed hydrogel scaffold-loaded granulocyte colony-stimulating factor sustained-release microspheres and their effect on endometrial regeneration[J]. Biomater Sci, 2022, 10(12):3346-3358. doi: 10.1039/d2bm00109h.
[18]	Min J, Lu N, Huang S, et al. Phenotype and biological characteristics of endometrial mesenchymal stem/stromal cells: A comparison between intrauterine adhesion patients and healthy women[J]. Am J Reprod Immunol, 2021, 85(6):e13379. doi: 10.1111/aji.13379.
[19]	Xiang E, Han B, Zhang Q, et al. Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis[J]. Stem Cell Res Ther, 2020, 11(1):336. doi: 10.1186/s13287-020-01852-y. pmid: 32746936
[20]	Gargett CE, Ye L. Endometrial reconstruction from stem cells[J]. Fertil Steril, 2012, 98(1):11-20. doi: 10.1016/j.fertnstert.2012.05.004. pmid: 22657248
[21]	Zheng JH, Zhang JK, Kong DS, et al. Quantification of the CM-Dil-labeled human umbilical cord mesenchymal stem cells migrated to the dual injured uterus in SD rat[J]. Stem Cell Res Ther, 2020, 11(1):280. doi: 10.1186/s13287-020-01806-4.
[22]	Xu L, Ding L, Wang L, et al. Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars[J]. Stem Cell Res Ther, 2017, 8(1):84. doi: 10.1186/s13287-017-0535-0. pmid: 28420433
[23]	Cao Y, Sun H, Zhu H, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phaseⅠclinical trial[J]. Stem Cell Res Ther, 2018, 9(1):192. doi: 10.1186/s13287-018-0904-3.
[24]	Wei X, Liu F, Zhang S, et al. Human Umbilical Cord Mesenchymal Stem Cell-Derived Conditioned Medium Promotes Human Endometrial Cell Proliferation through Wnt/β-Catenin Signaling[J]. Biomed Res Int, 2022,2022:8796093. doi: 10.1155/2022/8796093.
[25]	Zhao YX, Chen SR, Huang QY, et al. Repair abilities of mouse autologous adipose-derived stem cells and ShakeGel^TM3D complex local injection with intrauterine adhesion by BMP7-Smad5 signaling pathway activation[J]. Stem Cell Res Ther, 2021, 12(1):191. doi: 10.1186/s13287-021-02258-0.
[26]	Fonseca AC, Melchels F, Ferreira M, et al. Emulating Human Tissues and Organs: A Bioprinting Perspective Toward Personalized Medicine[J]. Chem Rev, 2020, 120(19):11128-11174. doi: 10.1021/acs.chemrev.0c00342.
[27]	Feng M, Hu S, Qin W, et al. Bioprinting of a Blue Light-Cross-Linked Biodegradable Hydrogel Encapsulating Amniotic Mesenchymal Stem Cells for Intrauterine Adhesion Prevention[J]. ACS Omega, 2021, 6(36):23067-23075. doi: 10.1021/acsomega.1c02117. pmid: 34549107
[28]	Lu S, Wang XC, Li WZ, et al. Injectable 3D-Printed Porous Scaffolds for Adipose Stem Cell Delivery and Endometrial Regeneration[J]. Adv Funct Mater, 2023, 33(34):2303368. doi: 10.1002/adfm.202303368.
[29]	Ma T, Fu B, Yang X, et al. Adipose mesenchymal stem cell-derived exosomes promote cell proliferation, migration, and inhibit cell apoptosis via Wnt/β-catenin signaling in cutaneous wound healing[J]. J Cell Biochem, 2019, 120(6):10847-10854. doi: 10.1002/jcb.28376. pmid: 30681184
[30]	Chang CL, Sung PH, Chen KH, et al. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome[J]. Am J Transl Res, 2018, 10(4):1053-1070.
[31]	Li J, Du S, Sheng X, et al. MicroRNA-29b Inhibits Endometrial Fibrosis by Regulating the Sp1-TGF-β1/Smad-CTGF Axis in a Rat Model[J]. Reprod Sci, 2016, 23(3):386-394. doi: 10.1177/1933719115602768. pmid: 26392347
[32]	Liu Y, Zhang S, Xue Z, et al. Bone mesenchymal stem cells-derived miR-223-3p-containing exosomes ameliorate lipopolysaccharide-induced acute uterine injury via interacting with endothelial progenitor cells[J]. Bioengineered, 2021, 12(2):10654-10665. doi: 10.1080/21655979.2021.2001185. pmid: 34738867
[33]	Zhao S, Qi W, Zheng J, et al. Exosomes Derived from Adipose Mesenchymal Stem Cells Restore Functional Endometrium in a Rat Model of Intrauterine Adhesions[J]. Reprod Sci, 2020, 27(6):1266-1275. doi: 10.1007/s43032-019-00112-6. pmid: 31933162
[34]	Ebrahim N, Mostafa O, El Dosoky RE, et al. Human mesenchymal stem cell-derived extracellular vesicles/estrogen combined therapy safely ameliorates experimentally induced intrauterine adhesions in a female rat model[J]. Stem Cell Res Ther, 2018, 9(1):175. doi: 10.1186/s13287-018-0924-z. pmid: 29954457

3D打印水凝胶支架在宫腔粘连防治中的应用

Application of 3D Printed Hydrogel Stents in Prevention and Treatment of Intrauterine Adhesion

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 3

参考文献 34

相关文章 15

编辑推荐

Metrics

本文评价

[1]	陈晓娟, 张艳馨. 妊娠合并血友病A患者足月分娩一例[J]. 国际妇产科学杂志, 2025, 52(2): 158-160.
[2]	张昊晟, 魏芳. Nectin-4在妇科恶性肿瘤中的研究进展[J]. 国际妇产科学杂志, 2025, 52(2): 165-168.
[3]	林环宇, 邵小光, 路旭宏, 王秋月, 魏巍, 佟春艳. Web of Science核心数据库2004—2024年女性恶性肿瘤患者生育力保存的研究现状及热点[J]. 国际妇产科学杂志, 2025, 52(2): 180-186.
[4]	江爱美, 张信美. 腹壁子宫内膜异位症的治疗进展[J]. 国际妇产科学杂志, 2025, 52(2): 211-216.
[5]	白耀俊, 王思瑶, 令菲菲, 张森淮, 李红丽, 刘畅. Trop-2及靶向Trop-2抗体偶联药物在妇科恶性肿瘤中的应用进展[J]. 国际妇产科学杂志, 2025, 52(1): 1-7.
[6]	侯春艳, 杜秀萍. 妊娠中晚期自发性子宫破裂二例[J]. 国际妇产科学杂志, 2025, 52(1): 110-113.
[7]	钟佩蕖, 招丽坚, 邹欣欣. 残角子宫妊娠行期待治疗至妊娠晚期一例[J]. 国际妇产科学杂志, 2025, 52(1): 114-116.
[8]	潘琪, 冯同富, 金晶, 吴莺, 杜欣. 腹腔镜切除成人腹膜后巨大成熟性畸胎瘤一例[J]. 国际妇产科学杂志, 2025, 52(1): 28-31.
[9]	贾炎峰, 吴珍珍, 王维红, 王玥元, 李娟. 原发性卵巢腺鳞癌一例[J]. 国际妇产科学杂志, 2025, 52(1): 32-36.
[10]	宋丽芳, 吴珍珍, 毛宝宏, 赵小丽, 刘青. 卵巢癌腹股沟淋巴结孤立转移一例[J]. 国际妇产科学杂志, 2025, 52(1): 37-41.
[11]	石百超, 王宇, 常惠, 卢凤娟, 关木馨, 余健楠, 吴效科. 中药及天然产物改善子宫内膜异位症的作用机制[J]. 国际妇产科学杂志, 2025, 52(1): 66-71.
[12]	李恒兵, 袁海宁, 张云洁, 张江琳, 郭子珍, 孙振高. 外泌体通过调控免疫微环境治疗慢性子宫内膜炎的研究进展[J]. 国际妇产科学杂志, 2025, 52(1): 72-78.
[13]	张野, 陈巧云, 赵佳怡, 陈璐, 刘建荣. 纳米微球在宫颈癌预防与治疗中的应用进展[J]. 国际妇产科学杂志, 2025, 52(1): 8-12.
[14]	刘思敏, 李红丽, 郭希, 胡雅莉, 杨永秀. 妊娠晚期合并卵巢浆液性囊腺瘤蒂扭转一例[J]. 国际妇产科学杂志, 2024, 51(6): 632-635.
[15]	黄楚冰, 郭淳, 郑佳依, 刘伟. 妊娠合并急性高脂血症性胰腺炎一例[J]. 国际妇产科学杂志, 2024, 51(6): 636-640.