{"paper_id":"c8377da6-bc12-477e-9aba-282ba9c299c3","body_text":"Abstract\nUterine disorders, such as thin endometrium and intrauterine adhesions, remain significant challenges in reproductive medicine, often leading to infertility and poor pregnancy outcomes. Recent advances in regenerative medicine and tissue engineering have led to the development of innovative therapeutic strategies aimed at restoring endometrial structure and function. Biomaterials play a central role in these advancements, serving not only as structural scaffolds and delivery vehicles for stem/progenitor cells and bioactive molecules but also as modulators of the tissue microenvironment by promoting angiogenesis and regulating immune responses. Mesenchymal stem cells from various sources, including female reproductive tissues, along with their extracellular vesicles, have demonstrated potential in promoting angiogenesis, reducing fibrosis, and modulating immune responses for endometrial repair. Additionally, platelet-rich plasma and a range of pharmacological agents—often with advanced drug delivery systems, such as nanocarriers—further contribute to endometrial regeneration. Engineered scaffolds, particularly those derived from decellularized extracellular matrix or fabricated using three-dimensional bioprinting technologies, closely mimic the biomechanical and biochemical properties of native endometrium. These scaffolds facilitate cellular engraftment and provide valuable platforms for in vitro modeling of endometrial physiology. The development of uterus-derived extracellular matrix scaffolds with immunologically compatible biomaterials and organoids marks a pivotal step toward reducing immune rejection and improving clinical applicability. This review highlights recent progress in biomaterial-based therapeutics for uterine regeneration and discusses the remaining challenges in shifting therapeutic paradigms of personalized and tissue-specific regenerative strategies.\nSimilar content being viewed by others\nData availability\nData sharing does not apply to this article as no datasets were generated or analyzed during the current study.\nReferences\nSalamonsen LA, Hutchison JC, Gargett CE (2021) Cyclical endometrial repair and regeneration. Development 148(17):dev199577\nHong IS (2023) Endometrial stem/progenitor cells: properties, origins, and functions. Genes Dis 10(3):931–947\nLee JY, Lee M, Lee SK (2011) Role of endometrial immune cells in implantation. Clin Exp Reprod Med 38(3):119–125\nWang Y, Tang Z, Teng X (2024) New advances in the treatment of thin endometrium. Front Endocrinol (Lausanne) 15:1269382\nLv H, Zhao G, Jiang P, Wang H, Wang Z, Yao S, Zhou Z, Wang L, Liu D, Deng W, Dai J, Hu Y (2022) Deciphering the endometrial niche of human thin endometrium at single-cell resolution. Proc Natl Acad Sci USA 119(8):e2115912119\nXu L, Fan Y, Wang J, Shi R (2022) Dysfunctional intercellular communication and metabolic signaling pathways in thin endometrium. Front Physiol 13:1050690\nKoo HS, Park CW, Cha SH, Yang KM (2018) Serial evaluation of endometrial blood flow for prediction of pregnancy outcomes in patients who underwent controlled ovarian hyperstimulation and in vitro fertilization and embryo transfer. J Ultrasound Med 37(4):851–857\nMiwa I, Tamura H, Takasaki A, Yamagata Y, Shimamura K, Sugino N (2009) Pathophysiologic features of thin endometrium. Fertil Steril 91(4):998–1004\nYu D, Wong YM, Cheong Y, Xia E, Li TC (2008) Asherman syndrome–one century later. Fertil Steril 89(4):759–779\nEvans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE, Dimitriadis E (2016) Fertile ground: human endometrial programming and lessons in health and disease. Nat Rev Endocrinol 12(11):654–667\nYao S, Zhou Z, Wang L, Lv H, Liu D, Zhu Q, Zhang X, Zhao G, Hu Y (2023) Targeting endometrial inflammation in intrauterine adhesion ameliorates endometrial fibrosis by priming MSCs to secrete C1INH. iScience 26(7):107201\nDi Guardo F, Della Corte L, Vilos GA, Carugno J, Torok P, Giampaolino P, Manchanda R, Vitale SG (2020) Evaluation and treatment of infertile women with Asherman syndrome: an updated review focusing on the role of hysteroscopy. Reprod Biomed Online 41(1):55–61\nConforti A, Alviggi C, Mollo A, De Placido G, Magos A (2013) The management of Asherman syndrome: a review of literature. Reprod Biol Endocrinol 11:118\nUllah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells - current trends and future prospective. Biosci Rep 35(2):e00191\nEl-Jawhari JJ, Ganguly P, Jones E, Giannoudis PV (2021) Bone marrow multipotent mesenchymal stromal cells as autologous therapy for osteonecrosis: effects of age and underlying causes. Bioeng (Basel) 8(5):69\nTaylor HS (2004) Endometrial cells derived from donor stem cells in bone marrow transplant recipients. JAMA 292(1):81–5\nCervello I, Gil-Sanchis C, Mas A, Faus A, Sanz J, Moscardo F, Higueras G, Sanz MA, Pellicer A, Simon C (2012) Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient. PLoS ONE 7(1):e30260\nIkoma T, Kyo S, Maida Y, Ozaki S, Takakura M, Nakao S, Inoue M (2009) Bone marrow-derived cells from male donors can compose endometrial glands in female transplant recipients. Am J Obstet Gynecol 201(6):608e1–608e8\nDu H, Taylor HS (2007) Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells 25(8):2082–2086\nBratincsak A, Brownstein MJ, Cassiani-Ingoni R, Pastorino S, Szalayova I, Toth ZE, Key S, Nemeth K, Pickel J, Mezey E (2007) CD45-positive blood cells give rise to uterine epithelial cells in mice. Stem Cells 25(11):2820–2826\nYang Y, Wang Y, Huang Y, Song J, Ma X (2024) Interceed combined with bone marrow mesenchymal stem cells improves endometrial receptivity of intrauterine adhesion. Regen Ther 27:445–454\nZhou T, Yuan Z, Weng J, Pei D, Du X, He C, Lai P (2021) Challenges and advances in clinical applications of mesenchymal stromal cells. J Hematol Oncol 14(1):24\nDeuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, Phan TT, Volk HD, Reichenspurner H, Robbins RC, Schrepfer S (2011) Immunogenicity and Immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell Transpl 20(5):655–667\nUccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8(9):726–736\nXu L, Ding L, Wang L, Cao Y, Zhu H, Lu J, Li X, Song T, Hu Y, Dai J (2017) Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars. Stem Cell Res Ther 8(1):84\nZhang L, Li Y, Dong YC, Guan CY, Tian S, Lv XD, Li JH, Su X, Xia HF, Ma X (2022) Transplantation of umbilical cord-derived mesenchymal stem cells promotes the recovery of thin endometrium in rats. Sci Rep 12(1):412\nHua Q, Zhang Y, Li H, Li H, Jin R, Li L, Xiang Y, Tian M, Wang J, Sun L, Wang Y (2022) Human umbilical cord blood-derived MSCs trans-differentiate into endometrial cells and regulate Th17/Treg balance through NF-kappaB signaling in rabbit intrauterine adhesions endometrium. Stem Cell Res Ther 13(1):301\nBenor A, Gay S, DeCherney A (2020) An update on stem cell therapy for Asherman syndrome. J Assist Reprod Genet 37(7):1511–1529\nSi Z, Wang X, Sun C, Kang Y, Xu J, Wang X, Hui Y (2019) Adipose-derived stem cells: sources, potency, and implications for regenerative therapies. Biomed Pharmacother 114:108765\nDong L, Li X, Leng W, Guo Z, Cai T, Ji X, Xu C, Zhu Z, Lin J (2023) Adipose stem cells in tissue regeneration and repair: from bench to bedside. Regen Ther 24:547–560\nDai Y, Xin L, Hu S, Xu S, Huang D, Jin X, Chen J, Chan RWS, Ng EHY, Yeung WSB, Ma L, Zhang S (2023) A construct of adipose-derived mesenchymal stem cells-laden collagen scaffold for fertility restoration by inhibiting fibrosis in a rat model of endometrial injury. Regen Biomater 10:rbad080\nYotsumoto F, Iwaguro H, Harada Y, Sobajima S, Suwabe T, Miyamoto S (2020) Adipose tissue-derived regenerative cells improve implantation of fertilized eggs in thin endometrium. Regen Med 15(7):1891–1904\nPark M, Kim YS, Song H (2025) Macrophages: a double-edged sword in female reproduction and disorders. Exp Mol Med 57(2):285–297\nSterodimas A, de Faria J, Nicaretta B, Pitanguy I (2010) Tissue engineering with adipose-derived stem cells (ADSCs): current and future applications. J Plast Reconstr Aesthet Surg 63(11):1886–1892\nGe X, Wang IN, Toma I, Sebastiano V, Liu J, Butte MJ, Reijo Pera RA, Yang PC (2012) Human amniotic mesenchymal stem cell-derived induced pluripotent stem cells May generate a universal source of cardiac cells. Stem Cells Dev 21(15):2798–2808\nHuang X, Yang X, Huang J, Wei L, Mao Y, Li C, Zhang Y, Chen Q, Wu S, Xie L, Sun C, Zhang W, Wang J (2024) Human Amnion mesenchymal stem cells promote endometrial repair via paracrine, preferentially than transdifferentiation. Cell Commun Signal 22(1):301\nGan L, Duan H, Xu Q, Tang YQ, Li JJ, Sun FQ, Wang S (2017) Human amniotic mesenchymal stromal cell transplantation improves endometrial regeneration in rodent models of intrauterine adhesions. Cytotherapy 19(5):603–616\nRahnama M, Ghasemzadeh N, Latifi Z, Kheradmand F, Koukia FA, Sharun K, Golchin A (2025) Menstrual blood and endometrial mesenchymal stem/stromal cells: A frontier in regenerative medicine and cancer therapy. Eur J Pharmacol 1000:177726\nZhu H, Jiang Y, Pan Y, Shi L, Zhang S (2018) Human menstrual blood-derived stem cells promote the repair of impaired endometrial stromal cells by activating the p38 MAPK and AKT signaling pathways. Reprod Biol 18(3):274–281\nTan J, Li P, Wang Q, Li Y, Li X, Zhao D, Xu X, Kong L (2016) Autologous menstrual blood-derived stromal cells transplantation for severe asherman’s syndrome. Hum Reprod 31(12):2723–2729\nMa H, Liu M, Li Y, Wang W, Yang K, Lu L, He M, Deng T, Li M, Wu D (2020) Intrauterine transplantation of autologous menstrual blood stem cells increases endometrial thickness and pregnancy potential in patients with refractory intrauterine adhesion. J Obstet Gynaecol Res 46(11):2347–2355\nSun B, Cheng X, Wu Q (2024) The endometrial stem/progenitor cells and their niches. Stem Cell Rev Rep 20(5):1273–1284\nChan RW, Schwab KE, Gargett CE (2004) Clonogenicity of human endometrial epithelial and stromal cells. Biol Reprod 70(6):1738–1750\nWang X, Bao H, Liu X, Wang C, Hao C (2018) Effects of endometrial stem cell transplantation combined with Estrogen in the repair of endometrial injury. Oncol Lett 16(1):1115–1122\nBausyte R, Vaigauskaite-Mazeikiene B, Borutinskaite V, Valatkaite E, Besusparis J, Valkiuniene RB, Kazenaite E, Ramasauskaite D, Navakauskiene R (2023) Human endometrium-derived mesenchymal stem/stromal cells application in endometrial-factor induced infertility. Front Cell Dev Biol 11:1227487\nHwang SY, Lee D, Lee G, Ahn J, Lee YG, Koo HS, Kang YJ (2024) Endometrial organoids: a reservoir of functional mitochondria for uterine repair. Theranostics 14(3):954–972\nTurco MY, Gardner L, Hughes J, Cindrova-Davies T, Gomez MJ, Farrell L, Hollinshead M, Marsh SGE, Brosens JJ, Critchley HO, Simons BD, Hemberger M, Koo BK, Moffett A, Burton GJ (2017) Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat Cell Biol 19(5):568–577\nHur YH, Cerione RA, Antonyak MA (2020) Extracellular vesicles and their roles in stem cell biology. Stem Cells 38(4):469–476\nWiklander OPB, Brennan MA, Lotvall J, Breakefield XO, Andaloussi SE (2019) Advances in therapeutic applications of extracellular vesicles. Sci Transl Med 11(492):eaav8521\nTabeeva G, Silachev D, Vishnyakova P, Asaturova A, Fatkhudinov T, Smetnik A, Dumanovskaya M (2023) The therapeutic potential of multipotent mesenchymal stromal Cell-Derived extracellular vesicles in endometrial regeneration. Int J Mol Sci 24(11):9431\nLin Y, Li Y, Chen P, Zhang Y, Sun J, Sun X, Li J, Jin J, Xue J, Zheng J, Jiang XC, Chen C, Li X, Wu Y, Zhao W, Liu J, Ye X, Zhang R, Gao J, Zhang D (2023) Exosome-Based regimen rescues endometrial fibrosis in intrauterine adhesions via targeting clinical fibrosis biomarkers. Stem Cells Transl Med 12(3):154–168\nYao Y, Chen R, Wang G, Zhang Y, Liu F (2019) Exosomes derived from mesenchymal stem cells reverse EMT via TGF-beta1/Smad pathway and promote repair of damaged endometrium. Stem Cell Res Ther 10(1):225\nYin S, Zhou S, Ren D, Zhang J, Xin H, He X, Gao H, Hou J, Zeng F, Lu Y, Zhang X, Fan M (2022) Mesenchymal stem Cell-Derived exosomes attenuate Epithelial-Mesenchymal transition of HK-2 cells. Tissue Eng Part A 28(13–14):651–659\nZhu Q, Tang S, Zhu Y, Chen D, Huang J, Lin J (2022) Exosomes derived from CTF1-Modified bone marrow stem cells promote endometrial regeneration and restore fertility. Front Bioeng Biotechnol 10:868734\nLi J, Pan Y, Yang J, Wang J, Jiang Q, Dou H, Hou Y (2022) Tumor necrosis factor-alpha-primed mesenchymal stem cell-derived exosomes promote M2 macrophage polarization via Galectin-1 and modify intrauterine adhesion on a novel murine model. Front Immunol 13:945234\nJin X, Dai Y, Xin L, Ye Z, Chen J, He Q, Chen X, Xu X, Song G, Yu X, Zhang S (2023) ADSC-derived exosomes-coupled decellularized matrix for endometrial regeneration and fertility restoration. Mater Today Bio 23:100857\nSun H, Dong J, Fu Z, Lu X, Chen X, Lei H, Xiao X, Chen S, Lu J, Su D, Xiong Y, Fang Z, Mao J, Chen L, Wang X (2024) TSG6-Exo@CS/GP attenuates endometrium fibrosis by inhibiting macrophage activation in a murine IUA model. Adv Mater 36(21):e2308921\nPoon IK, Lucas CD, Rossi AG, Ravichandran KS (2014) Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol 14(3):166–180\nBattistelli M, Falcieri E (2020) Apoptotic bodies: particular extracellular vesicles involved in intercellular communication. Biology (Basel) 9(1):21\nHoseinzadeh A, Esmaeili SA, Sahebi R, Melak AM, Mahmoudi M, Hasannia M, Baharlou R (2025) Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights. Stem Cell Res Ther 16(1):33\nXu X, Lai Y, Hua ZC (2019) Apoptosis and apoptotic body: disease message and therapeutic target potentials. Biosci Rep 39(1):BSR20180992\nVaskivuo TE, Stenback F, Karhumaa P, Risteli J, Dunkel L, Tapanainen JS (2000) Apoptosis and apoptosis-related proteins in human endometrium. Mol Cell Endocrinol 165(1–2):75–83\nYu L, Zhu G, Zhang Z, Yu Y, Zeng L, Xu Z, Weng J, Xia J, Li J, Pathak JL (2023) Apoptotic bodies: bioactive treasure left behind by the dying cells with robust diagnostic and therapeutic application potentials. J Nanobiotechnol 21(1):218\nXin L, Wei C, Tong X, Dai Y, Huang D, Chen J, Ma L, Zhang S (2022) In situ delivery of apoptotic bodies derived from mesenchymal stem cells via a hyaluronic acid hydrogel: A therapy for intrauterine adhesions. Bioact Mater 12:107–119\nVerma R, Kumar S, Garg P, Verma YK (2023) Platelet-rich plasma: a comparative and economical therapy for wound healing and tissue regeneration. Cell Tissue Bank 24(2):285–306\nKim MK, Yoon JA, Yoon SY, Park M, Lee WS, Lyu SW, Song H (2022) Human platelet-rich plasma facilitates angiogenesis to restore impaired uterine environments with asherman’s syndrome for embryo implantation and following pregnancy in mice. Cells 11(9):1549\nKim JH, Park M, Paek JY, Lee WS, Song H, Lyu SW (2020) Intrauterine infusion of human Platelet-Rich plasma improves endometrial regeneration and pregnancy outcomes in a murine model of asherman’s syndrome. Front Physiol 11:105\nChang Y, Li J, Chen Y, Wei L, Yang X, Shi Y, Liang X (2015) Autologous platelet-rich plasma promotes endometrial growth and improves pregnancy outcome during in vitro fertilization. Int J Clin Exp Med 8(1):1286–1290\nFrantz N, Ferreira M, Kulmann MI, Frantz G, Bos-Mikich A, Oliveira R (2020) Platelet-Rich plasma as an effective alternative approach for improving endometrial receptivity - a clinical retrospective study. JBRA Assist Reprod 24(4):442–446\nZeng J, Quan J, Liu H, Geng W, Qiu F, Liu J (2025) Comprehensive single-cell transcriptome analysis of autologous platelet-rich plasma therapy on human thin endometrium. Sci Rep 15(1):14637\nKatsika ET, Venetis CA, Bosdou JK, Kolibianakis EM (2025) Is it justified to offer intrauterine infusion of autologous PRP in women with repeated implantation failure? Hum Reprod 40(5):771–784\nZhou Y, Shen H, Wu Y, Zhao X, Pei J, Mou Z, Dong J, Hua X (2020) Platelet-Rich plasma therapy enhances the beneficial effect of bone marrow stem cell transplant on endometrial regeneration. Front Cell Dev Biol 8:52\nYuan G, Yu C, Du X, Li D, Dou H, Lu P, Wu T, Hao C, Wang Y (2024) Injectable GelMA hydrogel microspheres with sustained release of Platelet-Rich plasma for the treatment of thin endometrium. Small 20(47):e2403890\nZheng X, Huang R, Yin L, Yao M, Chu J, Yang F, Dong Y, Zhao M, Ma T (2025) Injectable antioxidant hyaluronan/chitosan hydrogel as a platelet-rich plasma and stem cell carrier to promote endometrial regeneration and fertility restoration. Acta Biomater 195:201–215\nGleicher N, Kim A, Michaeli T, Lee HJ, Shohat-Tal A, Lazzaroni E, Barad DH (2013) A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies. Hum Reprod 28(1):172–177\nJain S, Mahey R, Malhotra N, Kalaivani M, Sangeeta P, Bhatt A, Singh N, Kriplani A (2018) Effect of intrauterine perfusion of granulocyte Colony-stimulating factor on endometrial parameters and in vitro fertilization outcome in women undergoing in vitro fertilization/Intracytoplasmic sperm injection cycles: A randomized controlled trial. J Hum Reprod Sci 11(3):254–260\nRezaee D, Bandehpour M, Kazemi B, Salehi M (2020) Role of intrauterine administration of transfected peripheral blood mononuclear cells by GM-CSF on embryo implantation and pregnancy rate in mice. Mol Hum Reprod 26(2):101–110\nWei W, Wang N, Zhu Y, Liao M, Wang B, Du T, Zhang J, Mao X (2024) GM-CSF improves endometrial receptivity in a thin endometrium rat model by upregulating HOXA10. Mol Hum Reprod 30(1):gaad042\nLi L, Liu L, Kou Z, Huo M, An J, Zhang X (2022) GnRH agonist treatment regulates IL-6 and IL-11 expression in endometrial stromal cells for patients with HRT regiment in frozen embryo transfer cycles. Reprod Biol 22(2):100608\nWang P, Yang H, Chen Z, Chen Y, Jin C, Yu R, Lin J, Chen Q, Huang X (2023) Agonist long protocol improves outcomes of vitrified-warmed embryo transfer in repeatedly thin endometrium. Reprod Biomed Online 46(3):527–535\nLee D, Ahn J, Koo HS, Kang YJ (2023) Intrauterine botulinum toxin A administration promotes endometrial regeneration mediated by IGFBP3-dependent OPN proteolytic cleavage in thin endometrium. Cell Mol Life Sci 80(1):26\nMa XL, Ding Y, Wu LM, Wang YX, Yao Y, Wang YX, Zhang YG, Niu JQ, He XX, Wang YQ (2021) The glucagon-like peptide-1 (GLP-1) analog exenatide ameliorates intrauterine adhesions in mice. Peptides 137:170481\nQin J, Sun M, Cheng J, Jiang H, Lv M, Jing J, Chen R, Fan Z, Du J (2024) Ultrasound-Responsive hydrogel incorporated with TGF-beta mimetic peptides for endometrium recovery to restore fertility. ACS Appl Mater Interfaces 16(43):57963–57971\nvan Staden D, Gerber M, Lemmer HJR (2024) The application of nano drug delivery systems in female upper genital tract disorders. Pharmaceutics 16(11):1475\nQu L, Chen Z, Chen J, Gan Y, Tan X, Wang Y, Zhang C, Chen B, Dai J, Chen J, Shi C (2023) Collagen biomaterials promote the regenerative repair of abdominal wall defects in Bama miniature pigs. Biomater Sci 11(24):7926–7937\nWu B, Li X, Wang R, Liu L, Huang D, Ye L, Wang Z (2025) Biomimetic mineralized collagen scaffolds for bone tissue engineering: strategies on elaborate fabrication for bioactivity improvement. Small 21(3):e2406441\nLiu F, Hu S, Yang H, Li Z, Huang K, Su T, Wang S, Cheng K (2019) Hyaluronic acid hydrogel integrated with mesenchymal stem Cell-Secretome to treat endometrial injury in a rat model of asherman’s syndrome. Adv Healthc Mater 8(14):e1900411\nPlamadiala I, Croitoru C, Pop MA, Roata IC, Filaments (2025). Polym (Basel) 17(2):191\nZhou L, Wang H, Shen D, Xiang J, Yu N, He X, Zhao W, Wang R, Wang H, Yu H, Ding X, Liu Z, He Y (2023) Stem cells implanted with nanofibrous Mats for injured endometrial regeneration and immune-microenvironment remodeling. Mater Today Bio 23:100855\nLitwiniuk M, Grzela T (2014) Amniotic membrane: new concepts for an old dressing. Wound Repair Regen 22(4):451–456\nChen X, Zhou Y, Sun Y, Ji T, Dai H (2021) Transplantation of decellularized and lyophilized amniotic membrane inhibits endometrial fibrosis by regulating connective tissue growth factor and tissue inhibitor of matrix metalloproteinase-2. Exp Ther Med 22(3):968\nLi X, Li P, Wang C, Shang T, Han H, Tong Y, Kang Y, Fang J, Cui L (2022) A thermo-sensitive and injectable hydrogel derived from a decellularized amniotic membrane to prevent intrauterine adhesion by accelerating endometrium regeneration. Biomater Sci 10(9):2275–2286\nWang S, Shi C, Cai X, Wang Y, Chen X, Han H, Shen H (2021) Human acellular amniotic matrix with previously seeded umbilical cord mesenchymal stem cells restores endometrial function in a rat model of injury. Mediators Inflamm 2021:5573594\nYoshimasa Y, Takao T, Katakura S, Tomisato S, Masuda H, Tanaka M, Maruyama T (2023) A decellularized uterine endometrial scaffold enhances regeneration of the endometrium in rats. Int J Mol Sci 24(8):7605\nAhn J, Sen T, Lee DB, Kim H, Lee JY, Koo HS, Kim JY, Kim J, Jang J, Kang YJ, Cho DW (2023) Uterus-Derived decellularized extracellular Matrix-Mediated endometrial regeneration and fertility enhancement. Adv Funct Mater 33(34):2214291\nFeng D, Li Y, Zheng H, Wang Y, Deng J, Liu T, Liao W, Shen F (2024) IL-4-induced M2 macrophages inhibit fibrosis of endometrial stromal cells. Reprod Biol 24(2):100852\nLv H, Sun H, Wang L, Yao S, Liu D, Zhang X, Pei Z, Zhou J, Wang H, Dai J, Yan G, Ding L, Wang Z, Cao C, Zhao G, Hu Y (2023) Targeting CD301(+) macrophages inhibits endometrial fibrosis and improves pregnancy outcome. EMBO Mol Med 15(9):e17601\nPark M, Oh HJ, Han J, Hong SH, Park W, Song H (2022) Liposome-mediated small RNA delivery to convert the macrophage polarity: A novel therapeutic approach to treat inflammatory uterine disease. Mol Ther Nucleic Acids 30:663–676\nWon JE, Park M, Hong SH, Kim YS, Song H (2025) Quantum Dots as biocompatible small RNA nanocarriers modulating macrophage polarization to treat asherman’s syndrome. NPJ Regen Med 10(1):15\nLin JY, Lin J, Zhu QQ, Yan X, Wu FL, Wang B, Du T, Huang JY, Li B (2024) Semiconducting polymer nanoparticles laden with platelet-rich plasma for endometrium regeneration via regulating macrophage M1/M2 type polarization. Appl Mater Today 40:102409\nClevers H (2016) Modeling development and disease with organoids. Cell 165(7):1586–1597\nLouie SM, Moye AL, Wong IG, Lu E, Shehaj A, Garcia-de-Alba C, Ararat E, Raby BA, Lu B, Paschini M, Bronson RT, Kim CF (2022) Progenitor potential of lung epithelial organoid cells in a transplantation model. Cell Rep 39(2):110662\nTadokoro T, Murata S, Kato M, Ueno Y, Tsuchida T, Okumura A, Kuse Y, Konno T, Uchida Y, Yamakawa Y, Zushi M, Yajima M, Kobayashi T, Hasegawa S, Kawakatsu-Hatada Y, Hayashi Y, Osakabe S, Maeda T, Kimura K, Mori A, Tanaka M, Kamishibahara Y, Matsuo M, Nie YZ, Okamoto S, Oba T, Tanimizu N, Taniguchi H (2024) Human iPSC-liver organoid transplantation reduces fibrosis through Immunomodulation. Sci Transl Med 16(757):eadg0338\nJiang X, Li X, Fei X, Shen J, Chen J, Guo M, Li Y (2021) Endometrial membrane organoids from human embryonic stem cell combined with the 3D matrigel for endometrium regeneration in Asherman syndrome. Bioact Mater 6(11):3935–3946\nXu Y, Cai S, Wang Q, Cheng M, Hui X, Dzakah EE, Zhao B, Chen X (2023) Multi-Lineage human endometrial organoids on acellular amniotic membrane for endometrium regeneration. Cell Transpl 32:9636897231218408\nQin X, Hu KL, Li Q, Sun Y, Peng T, Liu X, Li J, Nan W, Yu Y, Qi X, Li R (2025) Situ sprayed hydrogel delivers extracellular vesicles derived from human endometrial organoids for uterine function preservation and fertility restoration. Adv Healthc Mater 14(2):e2403604\nNie N, Gong L, Jiang D, Liu Y, Zhang J, Xu J, Yao X, Wu B, Li Y (2023) Zou, 3D bio-printed endometrial construct restores the full-thickness morphology and fertility of injured uterine endometrium. Acta Biomater 157:187–199\nZhao LM, Da LC, Wang R, Wang L, Jiang YL, Zhang XZ, Li YX, Lei XX, Song YT,Zou CY, Huang LP, Zhang WQ, Zhang QY, Li QJ, Nie R, Zhang Y, Liang Y, Li-Ling J,Xie HQ (2023) Promotion of uterine reconstruction by a tissue-engineered uterus withbiomimetic structure and extracellular matrix microenvironment. Sci Adv 9(46):eadi6488\nSubbiah R, Hipfinger C, Tahayeri A, Athirasala A, Horsophonphong S, ThrivikramanG, Franca CM, Cunha DA, Mansoorifar A, Zahariev A, Jones JM, Coelho PG, WitekL, Xie H, Guldberg RE (2020) Bertassoni, 3D printing of Microgel-Loaded modularmicrocages as instructive scaffolds for tissue engineering. Adv Mater 32(36):e2001736\nPark SR, Kook MG, Kim SR, Lee JW, Park CH, Oh BC, Jung Y, Hong IS (2023) Development of cell-laden multimodular Lego-like customizable endometrial tissueassembly for successful tissue regeneration. Biomater Res 27(1):33\nAcknowledgements\nAll figures were created with Biorender.com.\nFunding\nThis work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIT) (RS-2024-00338274 to YJK and RS-2025-00517458 to HS), by Korean Fund for Regenerative Medicine (KFRM) funded by Ministry of Science and ICT, and Ministry of Health and Welfare, Republic of Korea (22A0106L1 to YJK and RS-2025-02223118 to HS), by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2025-02215684 to HS), and by Basic Science Research Program through the NRF funded by the Ministry of Education (RS-2019-NR40073 to HS).\nAuthor information\nAuthors and Affiliations\nContributions\nYJK and HS conceived the initial concept of the article; DL and YJK performed the literature search; DBL, YSK, and HS drafted and/or critically revised the work. All authors read and approved the final manuscript.\nCorresponding authors\nEthics declarations\nCompeting interests\nAuthors declare no other financial or non-financial interests related to this work except for the funding acknowledged.\nAdditional information\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nLee, D., Kang, YJ. & Song, H. Regenerating the uterus: translational advances in endometrial bioengineering and immunotherapeutics. Semin Immunopathol 47, 36 (2025). https://doi.org/10.1007/s00281-025-01063-8\nReceived:\nAccepted:\nPublished:\nVersion of record:\nDOI: https://doi.org/10.1007/s00281-025-01063-8","source_license":"CC0","license_restricted":false}