{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:01:47Z","timestamp":1790128907773,"version":"4.0.1"},"reference-count":88,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T00:00:00Z","timestamp":1641772800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Key R&D Program of China","award":["2017YFA0104702"],"award-info":[{"award-number":["2017YFA0104702"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31771052"],"award-info":[{"award-number":["31771052"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32171356"],"award-info":[{"award-number":["32171356"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Military Medical Research and Development Projects","award":["AWS17J005"],"award-info":[{"award-number":["AWS17J005"]}]},{"name":"Youth Training Project of Chinese PLA General Hospital","award":["QNC19012"],"award-info":[{"award-number":["QNC19012"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Stem Cell Res Ther"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Peripheral nerve injury (PNI) is one of the essential causes of physical disability with a high incidence rate. The traditional tissue engineering strategy, Top-Down strategy, has some limitations. A new tissue-engineered strategy, Bottom-Up strategy (tissue-engineered microtissue strategy), has emerged and made significant research progress in recent years. However, to the best of our knowledge, microtissues are rarely used in neural tissue engineering; thus, we intended to use microtissues to repair PNI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We used a low-adhesion cell culture plate to construct adipose-derived mesenchymal stem cells (ASCs) into microtissues in vitro, explored the physicochemical properties and microtissues components, compared the expression of cytokines related to nerve regeneration between microtissues and the same amount of two-dimension (2D)-cultured cells, co-cultured directly microtissues with dorsal root ganglion (DRG) or Schwann cells (SCs) to observe the interaction between them using immunocytochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA). We used grafts constructed by microtissues and polycaprolactone (PCL) nerve conduit to repair sciatic nerve defects in rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The present study results indicated that compared with the same number of 2D-cultured cells, microtissue could secrete more nerve regeneration related cytokines to promote SCs proliferation and axons growth. Moreover, in the direct co-culture system of microtissue and DRG or SCs, axons of DRG grown in the direction of microtissue, and there seems to be a cytoplasmic exchange between SCs and ASCs around microtissue. Furthermore, microtissues could repair sciatic nerve defects in rat models more effectively than traditional 2D-cultured ASCs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tissue-engineered microtissue is an effective strategy for stem cell culture and therapy in nerve tissue engineering.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13287-021-02676-0","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T06:03:16Z","timestamp":1641794596000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Functional tissue-engineered microtissue formed by self-aggregation of cells for peripheral nerve regeneration"],"prefix":"10.1186","volume":"13","author":[{"given":"Jian","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaochao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanqi","family":"Meng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tieyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiqi","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuzhi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinjuan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,10]]},"reference":[{"key":"2676_CR1","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jmbbm.2014.10.002","volume":"41","author":"R Sridharan","year":"2015","unstructured":"Sridharan R, Reilly RB, Buckley CT. Decellularized grafts with axially aligned channels for peripheral nerve regeneration. J Mech Behav Biomed Mater. 2015;41:124\u201335.","journal-title":"J Mech Behav Biomed Mater"},{"issue":"3","key":"2676_CR2","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1042\/BST20140004","volume":"42","author":"MK Kolar","year":"2014","unstructured":"Kolar MK, Kingham PJ. Regenerative effects of adipose-tissue-derived stem cells for treatment of peripheral nerve injuries. Biochem Soc Trans. 2014;42(3):697\u2013701.","journal-title":"Biochem Soc Trans"},{"issue":"1","key":"2676_CR3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1097\/00005373-199807000-00025","volume":"45","author":"J Noble","year":"1998","unstructured":"Noble J, Munro CA, Prasad VS, et al. Analysis of upper and lower extremity peripheral nerve injuries in a population of patients with multiple injuries. J Trauma. 1998;45(1):116\u201322.","journal-title":"J Trauma"},{"key":"2676_CR4","doi-asserted-by":"crossref","first-page":"23828","DOI":"10.1038\/srep23828","volume":"6","author":"W Weng","year":"2016","unstructured":"Weng W, Zhao B, Lin D, et al. Significance of alpha smooth muscle actin expression in traumatic painful neuromas: a pilot study in rats. Sci Rep. 2016;6:23828.","journal-title":"Sci Rep"},{"issue":"17","key":"2676_CR5","doi-asserted-by":"crossref","first-page":"e1800276","DOI":"10.1002\/adhm.201800276","volume":"7","author":"X Sun","year":"2018","unstructured":"Sun X, Wang Y, Guo Z, et al. Acellular cauda equina allograft as main material combined with biodegradable chitin conduit for regeneration of long-distance sciatic nerve defect in rats. Adv Healthc Mater. 2018;7(17):e1800276.","journal-title":"Adv Healthc Mater."},{"issue":"1","key":"2676_CR6","doi-asserted-by":"crossref","first-page":"143","DOI":"10.4103\/1673-5374.286954","volume":"16","author":"J Wang","year":"2021","unstructured":"Wang J, Zhu YQ, Wang Y, et al. A novel tissue engineered nerve graft constructed with autologous vein and nerve microtissue repairs a long-segment sciatic nerve defect. Neural Regen Res. 2021;16(1):143\u20139.","journal-title":"Neural Regen Res"},{"issue":"10","key":"2676_CR7","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.4103\/1673-5374.280322","volume":"15","author":"Y Zhang","year":"2020","unstructured":"Zhang Y, Wang WT, Gong CR, et al. Combination of olfactory ensheathing cells and human umbilical cord mesenchymal stem cell-derived exosomes promotes sciatic nerve regeneration. Neural Regen Res. 2020;15(10):1903\u201311.","journal-title":"Neural Regen Res"},{"issue":"19\u201320","key":"2676_CR8","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1089\/ten.tea.2018.0279","volume":"25","author":"K Ramli","year":"2019","unstructured":"Ramli K, Gasim AI, Ahmad AA, et al. Efficacy of human cell-seeded muscle-stuffed vein conduit in rat sciatic nerve repair. Tissue Eng Part A. 2019;25(19\u201320):1438\u201355.","journal-title":"Tissue Eng Part A"},{"key":"2676_CR9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3389\/fbioe.2019.00337","volume":"7","author":"CR Carvalho","year":"2019","unstructured":"Carvalho CR, Oliveira JM, Reis RL. Modern trends for peripheral nerve repair and regeneration: beyond the hollow nerve guidance conduit. Front Bioeng Biotechnol. 2019;7:337.","journal-title":"Front Bioeng Biotechnol"},{"key":"2676_CR10","doi-asserted-by":"crossref","first-page":"980353","DOI":"10.1155\/2012\/980353","volume":"2012","author":"E Zomorodian","year":"2012","unstructured":"Zomorodian E, Baghaban Eslaminejad M. Mesenchymal stem cells as a potent cell source for bone regeneration. Stem Cells Int. 2012;2012:980353.","journal-title":"Stem Cells Int"},{"issue":"2","key":"2676_CR11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/term.1","volume":"1","author":"GA Silva","year":"2007","unstructured":"Silva GA, Coutinho OP, Ducheyne P, et al. Materials in particulate form for tissue engineering. 2. Applications in bone. J Tissue Eng Regen Med. 2007;1(2):97\u2013109.","journal-title":"J Tissue Eng Regen Med"},{"issue":"5","key":"2676_CR12","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1002\/term.1529","volume":"8","author":"T Cordonnier","year":"2014","unstructured":"Cordonnier T, Langonn\u00e9 A, Corre P, et al. Osteoblastic differentiation and potent osteogenicity of three-dimensional hBMSC-BCP particle constructs. J Tissue Eng Regen Med. 2014;8(5):364\u201376.","journal-title":"J Tissue Eng Regen Med"},{"issue":"6","key":"2676_CR13","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1089\/scd.2010.0348","volume":"20","author":"D Ma","year":"2011","unstructured":"Ma D, Zhong C, Yao H, et al. Engineering injectable bone using bone marrow stromal cell aggregates. Stem Cells Dev. 2011;20(6):989\u201399.","journal-title":"Stem Cells Dev"},{"issue":"2","key":"2676_CR14","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1089\/biores.2013.0001","volume":"2","author":"TK Goh","year":"2013","unstructured":"Goh TK, Zhang ZY, Chen AK, et al. Microcarrier culture for efficient expansion and osteogenic differentiation of human fetal mesenchymal stem cells. BioResearch Open Access. 2013;2(2):84\u201397.","journal-title":"BioResearch Open Access"},{"issue":"7","key":"2676_CR15","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.2106\/00004623-200407000-00029","volume":"86","author":"GF Muschler","year":"2004","unstructured":"Muschler GF, Nakamoto C, Griffith LG. Engineering principles of clinical cell-based tissue engineering. J Bone Joint Surg. 2004;86(7):1541\u201358.","journal-title":"J Bone Joint Surg"},{"issue":"3","key":"2676_CR16","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1002\/jbm.a.36587","volume":"107","author":"C Luo","year":"2019","unstructured":"Luo C, Fang H, Li J, et al. An in vivo comparative study of the gelatin microtissue-based bottom-up strategy and top-down strategy in bone tissue engineering application. J Biomed Mater Res A. 2019;107(3):678\u201388.","journal-title":"J Biomed Mater Res A"},{"issue":"1","key":"2676_CR17","first-page":"63","volume":"130","author":"J Eyckmans","year":"2017","unstructured":"Eyckmans J, Chen CS. 3D culture models of tissues under tension. J Cell Sci. 2017;130(1):63\u201370.","journal-title":"J Cell Sci"},{"key":"2676_CR18","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.actbio.2015.07.042","volume":"25","author":"Y Zeng","year":"2015","unstructured":"Zeng Y, Zhu L, Han Q, et al. Preformed gelatin microcryogels as injectable cell carriers for enhanced skin wound healing. Acta Biomater. 2015;25:291\u2013303.","journal-title":"Acta Biomater"},{"key":"2676_CR19","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.actbio.2016.01.024","volume":"33","author":"H Yin","year":"2016","unstructured":"Yin H, Wang Y, Sun Z, et al. Induction of mesenchymal stem cell chondrogenic differentiation and functional cartilage microtissue formation for in vivo cartilage regeneration by cartilage extracellular matrix-derived particles. Acta Biomater. 2016;33:96\u2013109.","journal-title":"Acta Biomater"},{"key":"2676_CR20","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201906539:e1906539-e1906539","author":"Q He","year":"2020","unstructured":"He Q, Liao Y, Zhang J, et al. \u201cAll-in-One\u201d gel system for whole procedure of stem-cell amplification and tissue engineering. Small. 2020. https:\/\/doi.org\/10.1002\/smll.201906539:e1906539-e1906539.","journal-title":"Small"},{"key":"2676_CR21","doi-asserted-by":"crossref","first-page":"110399","DOI":"10.1016\/j.msec.2019.110399","volume":"108","author":"C Fan","year":"2020","unstructured":"Fan C, Zhan S-H, Dong Z-X, et al. Cross-linked gelatin microsphere-based scaffolds as a delivery vehicle of MC3T3-E1 cells: in vitro and in vivo evaluation. Mater Sci Eng C Mater Biol Appl. 2020;108:110399\u2013110399.","journal-title":"Mater Sci Eng C Mater Biol Appl"},{"issue":"15\u201316","key":"2676_CR22","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1089\/ten.tea.2019.0206","volume":"26","author":"C Hoefner","year":"2020","unstructured":"Hoefner C, Muhr C, Horder H, et al. Human adipose-derived mesenchymal stromal\/stem cell spheroids possess high adipogenic capacity and acquire an adipose tissue-like extracellular matrix pattern. Tissue Eng Part A. 2020;26(15\u201316):915\u201326.","journal-title":"Tissue Eng Part A"},{"issue":"5","key":"2676_CR23","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1089\/ten.tec.2020.0039","volume":"26","author":"X Yan","year":"2020","unstructured":"Yan X, Zhang K, Yang Y, et al. Dispersible and dissolvable porous microcarrier tablets enable efficient large-scale human mesenchymal stem cell expansion. Tissue Eng Part C Methods. 2020;26(5):263\u201375.","journal-title":"Tissue Eng Part C Methods"},{"key":"2676_CR24","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.actbio.2018.07.031","volume":"77","author":"H Yin","year":"2018","unstructured":"Yin H, Wang Y, Sun X, et al. Functional tissue-engineered microtissue derived from cartilage extracellular matrix for articular cartilage regeneration. Acta Biomater. 2018;77:127\u201341.","journal-title":"Acta Biomater"},{"key":"2676_CR25","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.biomaterials.2018.04.033","volume":"171","author":"Y Wang","year":"2018","unstructured":"Wang Y, Yuan X, Yu K, et al. Fabrication of nanofibrous microcarriers mimicking extracellular matrix for functional microtissue formation and cartilage regeneration. Biomaterials. 2018;171:118\u201332.","journal-title":"Biomaterials"},{"issue":"1","key":"2676_CR26","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/s13287-018-1064-1","volume":"9","author":"D Wu","year":"2018","unstructured":"Wu D, Wang Z, Wang J, et al. Development of a micro-tissue-mediated injectable bone tissue engineering strategy for large segmental bone defect treatment. Stem Cell Res Ther. 2018;9(1):331.","journal-title":"Stem Cell Res Ther"},{"key":"2676_CR27","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3389\/fphys.2017.00534","volume":"8","author":"J Yipeng","year":"2017","unstructured":"Yipeng J, Yongde X, Yuanyi W, et al. Microtissues enhance smooth muscle differentiation and cell viability of hADSCs for three dimensional bioprinting. Front Physiol. 2017;8:534.","journal-title":"Front Physiol"},{"issue":"4","key":"2676_CR28","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1007\/s10856-020-06374-w","volume":"31","author":"J Colle","year":"2020","unstructured":"Colle J, Blondeel P, De Bruyne A, et al. Bioprinting predifferentiated adipose-derived mesenchymal stem cell spheroids with methacrylated gelatin ink for adipose tissue engineering. J Mater Sci Mater Med. 2020;31(4):36.","journal-title":"J Mater Sci Mater Med"},{"issue":"1","key":"2676_CR29","doi-asserted-by":"crossref","first-page":"015021","DOI":"10.1088\/1758-5090\/ab51ae","volume":"12","author":"I Zarkesh","year":"2019","unstructured":"Zarkesh I, Halvaei M, Ghanian MH, et al. Scalable and cost-effective generation of osteogenic micro-tissues through the incorporation of inorganic microparticles within mesenchymal stem cell spheroids. Biofabrication. 2019;12(1):015021.","journal-title":"Biofabrication"},{"issue":"16","key":"2676_CR30","doi-asserted-by":"crossref","first-page":"4663","DOI":"10.7150\/thno.34464","volume":"9","author":"C Luo","year":"2019","unstructured":"Luo C, Fang H, Zhou M, et al. Biomimetic open porous structured core-shell microtissue with enhanced mechanical properties for bottom-up bone tissue engineering. Theranostics. 2019;9(16):4663\u201377.","journal-title":"Theranostics"},{"issue":"31","key":"2676_CR31","doi-asserted-by":"crossref","first-page":"e1802273","DOI":"10.1002\/adma.201802273","volume":"30","author":"DX Wei","year":"2018","unstructured":"Wei DX, Dao JW, Chen GQ. A micro-ark for cells: highly open porous polyhydroxyalkanoate microspheres as injectable scaffolds for tissue regeneration. Adv Mater. 2018;30(31):e1802273.","journal-title":"Adv Mater."},{"issue":"6","key":"2676_CR32","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1002\/term.2084","volume":"11","author":"A Totaro","year":"2017","unstructured":"Totaro A, Salerno A, Imparato G, et al. PCL-HA microscaffolds for in vitro modular bone tissue engineering. J Tissue Eng Regen Med. 2017;11(6):1865\u201375.","journal-title":"J Tissue Eng Regen Med"},{"issue":"8","key":"2676_CR33","doi-asserted-by":"crossref","first-page":"1700008","DOI":"10.1002\/biot.201700008","volume":"12","author":"S Zhang","year":"2017","unstructured":"Zhang S, Zhou M, Ye Z, et al. Fabrication of viable and functional pre-vascularized modular bone tissues by coculturing MSCs and HUVECs on microcarriers in spinner flasks. Biotechnol J. 2017;12(8):1700008.","journal-title":"Biotechnol J"},{"issue":"1","key":"2676_CR34","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1039\/C5NR06876B","volume":"8","author":"Y Zhou","year":"2016","unstructured":"Zhou Y, Gao H-L, Shen L-L, et al. Chitosan microspheres with an extracellular matrix-mimicking nanofibrous structure as cell-carrier building blocks for bottom-up cartilage tissue engineering. Nanoscale. 2016;8(1):309\u201317.","journal-title":"Nanoscale"},{"key":"2676_CR35","first-page":"128","volume":"18","author":"Y Xu","year":"2019","unstructured":"Xu Y, Peng J, Richards G, et al. Optimization of electrospray fabrication of stem cell-embedded alginate-gelatin microspheres and their assembly in 3D-printed poly(\u03b5-caprolactone) scaffold for cartilage tissue engineering. J Orthop Transl. 2019;18:128\u201341.","journal-title":"J Orthop Transl"},{"issue":"2","key":"2676_CR36","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jcyt.2015.10.015","volume":"18","author":"R Tiruvannamalai Annamalai","year":"2016","unstructured":"Tiruvannamalai Annamalai R, Mertz DR, Daley EL, et al. Collagen Type II enhances chondrogenic differentiation in agarose-based modular microtissues. Cytotherapy. 2016;18(2):263\u201377.","journal-title":"Cytotherapy"},{"issue":"1","key":"2676_CR37","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1159\/000486813","volume":"45","author":"X Hong","year":"2018","unstructured":"Hong X, Yuan Y, Sun X, et al. Skeletal extracellular matrix supports cardiac differentiation of embryonic stem cells: a potential scaffold for engineered cardiac tissue. Cell Physiol Biochem. 2018;45(1):319\u201331.","journal-title":"Cell Physiol Biochem."},{"issue":"8","key":"2676_CR38","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1089\/ten.tec.2014.0376","volume":"21","author":"P Beauchamp","year":"2015","unstructured":"Beauchamp P, Moritz W, Kelm JM, et al. Development and characterization of a scaffold-free 3D spheroid model of induced pluripotent stem cell-derived human cardiomyocytes. Tissue Eng Part C Methods. 2015;21(8):852\u201361.","journal-title":"Tissue Eng Part C Methods"},{"issue":"5","key":"2676_CR39","doi-asserted-by":"crossref","first-page":"2765","DOI":"10.1021\/nl502227a","volume":"15","author":"Y Tan","year":"2015","unstructured":"Tan Y, Richards D, Xu R, et al. Silicon nanowire-induced maturation of cardiomyocytes derived from human induced pluripotent stem cells. Nano Lett. 2015;15(5):2765\u201372.","journal-title":"Nano Lett"},{"issue":"8","key":"2676_CR40","doi-asserted-by":"crossref","first-page":"e1904806","DOI":"10.1002\/smll.201904806","volume":"16","author":"I Gal","year":"2020","unstructured":"Gal I, Edri R, Noor N, et al. Injectable cardiac cell microdroplets for tissue regeneration. Small. 2020;16(8):e1904806.","journal-title":"Small"},{"key":"2676_CR41","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.colsurfb.2017.12.056","volume":"163","author":"R Narayan","year":"2018","unstructured":"Narayan R, Agarwal T, Mishra D, et al. Goat tendon collagen-human fibrin hydrogel for comprehensive parametric evaluation of HUVEC microtissue-based angiogenesis. Colloids Surf B Biointerfaces. 2018;163:291\u2013300.","journal-title":"Colloids Surf B Biointerfaces"},{"issue":"3","key":"2676_CR42","doi-asserted-by":"crossref","first-page":"035009","DOI":"10.1088\/1758-5090\/aac7e6","volume":"10","author":"L De Moor","year":"2018","unstructured":"De Moor L, Merovci I, Baetens S, et al. High-throughput fabrication of vascularized spheroids for bioprinting. Biofabrication. 2018;10(3):035009.","journal-title":"Biofabrication"},{"key":"2676_CR43","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.biomaterials.2016.10.052","volume":"115","author":"S Pradhan","year":"2017","unstructured":"Pradhan S, Clary JM, Seliktar D, et al. A three-dimensional spheroidal cancer model based on PEG-fibrinogen hydrogel microspheres. Biomaterials. 2017;115:141\u201354.","journal-title":"Biomaterials"},{"issue":"2","key":"2676_CR44","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jss.2014.12.036","volume":"194","author":"HL Bumpers","year":"2015","unstructured":"Bumpers HL, Janagama DG, Manne U, et al. Nanomagnetic levitation three-dimensional cultures of breast and colorectal cancers. J Surg Res. 2015;194(2):319\u201326.","journal-title":"J Surg Res"},{"issue":"7","key":"2676_CR45","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S1474-4422(11)70121-1","volume":"10","author":"A Uccelli","year":"2011","unstructured":"Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10(7):649\u201356.","journal-title":"Lancet Neurol"},{"issue":"1","key":"2676_CR46","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1186\/s13287-019-1474-8","volume":"10","author":"S Yu","year":"2019","unstructured":"Yu S, Cheng Y, Zhang L, et al. Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res Ther. 2019;10(1):333.","journal-title":"Stem Cell Res Ther"},{"issue":"1","key":"2676_CR47","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s13287-018-0884-3","volume":"9","author":"X Sun","year":"2018","unstructured":"Sun X, Zhu Y, Yin HY, et al. Differentiation of adipose-derived stem cells into Schwann cell-like cells through intermittent induction: potential advantage of cellular transient memory function. Stem Cell Res Ther. 2018;9(1):133.","journal-title":"Stem Cell Res Ther"},{"issue":"5","key":"2676_CR48","doi-asserted-by":"crossref","first-page":"903","DOI":"10.4103\/1673-5374.249239","volume":"14","author":"Q Quan","year":"2019","unstructured":"Quan Q, Meng HY, Chang B, et al. Aligned fibers enhance nerve guide conduits when bridging peripheral nerve defects focused on early repair stage. Neural Regen Res. 2019;14(5):903\u201312.","journal-title":"Neural Regen Res"},{"issue":"6","key":"2676_CR49","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1002\/term.2084","volume":"11","author":"A Totaro","year":"2017","unstructured":"Totaro A, Salerno A, Imparato G, et al. PCL-HA microscaffolds for in vitro modular bone tissue engineering. J Tissue Eng Regen Med. 2017;11(6):1865\u201375.","journal-title":"J Tissue Eng Regen Med"},{"key":"2676_CR50","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.biomaterials.2018.04.033","volume":"171","author":"Y Wang","year":"2018","unstructured":"Wang Y, Yuan X, Yu K, et al. Fabrication of nanofibrous microcarriers mimicking extracellular matrix for functional microtissue formation and cartilage regeneration. Biomaterials. 2018;171:118\u201332.","journal-title":"Biomaterials"},{"issue":"8","key":"2676_CR51","doi-asserted-by":"crossref","first-page":"e1904806","DOI":"10.1002\/smll.201904806","volume":"16","author":"I Gal","year":"2020","unstructured":"Gal I, Edri R, Noor N, et al. Injectable cardiac cell microdroplets for tissue regeneration. Small. 2020;16(8):e1904806.","journal-title":"Small."},{"issue":"4","key":"2676_CR52","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1097\/CM9.0000000000000654","volume":"133","author":"YP Jin","year":"2020","unstructured":"Jin YP, Shi C, Wu YY, et al. Encapsulated three-dimensional bioprinted structure seeded with urothelial cells: a new construction technique for tissue-engineered urinary tract patch. Chin Med J (Engl). 2020;133(4):424\u201334.","journal-title":"Chin Med J (Engl)"},{"key":"2676_CR53","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.actbio.2018.05.035","volume":"74","author":"T Ahmad","year":"2018","unstructured":"Ahmad T, Shin HJ, Lee J, et al. Fabrication of in vitro 3D mineralized tissue by fusion of composite spheroids incorporating biomineral-coated nanofibers and human adipose-derived stem cells. Acta Biomater. 2018;74:464\u201377.","journal-title":"Acta Biomater"},{"issue":"5411","key":"2676_CR54","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1126\/science.284.5411.143","volume":"284","author":"MF Pittenger","year":"1999","unstructured":"Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143\u20137.","journal-title":"Science"},{"issue":"4","key":"2676_CR55","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/term.83","volume":"2","author":"S Bajada","year":"2008","unstructured":"Bajada S, Mazakova I, Richardson JB, et al. Updates on stem cells and their applications in regenerative medicine. J Tissue Eng Regen Med. 2008;2(4):169\u201383.","journal-title":"J Tissue Eng Regen Med"},{"issue":"7","key":"2676_CR56","doi-asserted-by":"crossref","first-page":"e743","DOI":"10.1038\/cddis.2013.268","volume":"4","author":"A Faroni","year":"2013","unstructured":"Faroni A, Rothwell SW, Grolla AA, et al. Differentiation of adipose-derived stem cells into Schwann cell phenotype induces expression of P2X receptors that control cell death. Cell Death Dis. 2013;4(7):e743.","journal-title":"Cell Death Dis."},{"issue":"4","key":"2676_CR57","first-page":"592","volume":"7","author":"GB Liu","year":"2011","unstructured":"Liu GB, Cheng YX, Feng YK, et al. Adipose-derived stem cells promote peripheral nerve repair. Arch Med Sci. 2011;7(4):592\u20136.","journal-title":"Arch Med Sci"},{"key":"2676_CR58","first-page":"139085","volume":"2014","author":"S Gao","year":"2014","unstructured":"Gao S, Zheng Y, Cai Q, et al. Combination of acellular nerve graft and schwann cells-like cells for rat sciatic nerve regeneration. Neural Plast. 2014;2014:139085.","journal-title":"Neural Plast."},{"issue":"1\u20132","key":"2676_CR59","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1089\/ten.tea.2013.0565","volume":"21","author":"H Luo","year":"2015","unstructured":"Luo H, Zhu B, Zhang Y, et al. Tissue-engineered nerve constructs under a microgravity system for peripheral nerve regeneration. Tissue Eng Part A. 2015;21(1\u20132):267\u201376.","journal-title":"Tissue Eng Part A"},{"issue":"1","key":"2676_CR60","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.neulet.2012.02.066","volume":"514","author":"Y Wang","year":"2012","unstructured":"Wang Y, Zhao Z, Ren Z, et al. Recellularized nerve allografts with differentiated mesenchymal stem cells promote peripheral nerve regeneration. Neurosci Lett. 2012;514(1):96\u2013101.","journal-title":"Neurosci Lett"},{"key":"2676_CR61","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.biomaterials.2017.07.022","volume":"142","author":"T Ozdemir","year":"2017","unstructured":"Ozdemir T, Srinivasan PP, Zakheim DR, et al. Bottom-up assembly of salivary gland microtissues for assessing myoepithelial cell function. Biomaterials. 2017;142:124\u201335.","journal-title":"Biomaterials"},{"issue":"1","key":"2676_CR62","doi-asserted-by":"crossref","first-page":"015021","DOI":"10.1088\/1758-5090\/ab51ae","volume":"12","author":"I Zarkesh","year":"2019","unstructured":"Zarkesh I, Halvaei M, Ghanian MH, et al. Scalable and cost-effective generation of osteogenic micro-tissues through the incorporation of inorganic microparticles within mesenchymal stem cell spheroids. Biofabrication. 2019;12(1):015021.","journal-title":"Biofabrication."},{"key":"2676_CR63","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.addr.2015.11.001","volume":"97","author":"AD Theocharis","year":"2016","unstructured":"Theocharis AD, Skandalis SS, Gialeli C, et al. Extracellular matrix structure. Adv Drug Deliv Rev. 2016;97:4\u201327.","journal-title":"Adv Drug Deliv Rev"},{"issue":"4","key":"2676_CR64","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1242\/dev.119.4.1079","volume":"119","author":"EL George","year":"1993","unstructured":"George EL, Georges-Labouesse EN, Patel-King RS, et al. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development. 1993;119(4):1079\u201391.","journal-title":"Development"},{"issue":"1","key":"2676_CR65","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0092-8674(81)90236-1","volume":"25","author":"Z Avnur","year":"1981","unstructured":"Avnur Z, Geiger B. The removal of extracellular fibronectin from areas of cell-substrate contact. Cell. 1981;25(1):121\u201332.","journal-title":"Cell"},{"issue":"1","key":"2676_CR66","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00441-009-0838-2","volume":"339","author":"M Durbeej","year":"2010","unstructured":"Durbeej M. Laminins. Cell Tissue Res. 2010;339(1):259\u201368.","journal-title":"Cell Tissue Res."},{"key":"2676_CR67","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev.cellbio.20.010403.094555","volume":"20","author":"JH Miner","year":"2004","unstructured":"Miner JH, Yurchenco PD. Laminin functions in tissue morphogenesis. Annu Rev Cell Dev Biol. 2004;20:255\u201384.","journal-title":"Annu Rev Cell Dev Biol"},{"key":"2676_CR68","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1038\/srep00183","volume":"1","author":"F Difato","year":"2011","unstructured":"Difato F, Tsushima H, Pesce M, et al. The formation of actin waves during regeneration after axonal lesion is enhanced by BDNF. Sci Rep. 2011;1:183.","journal-title":"Sci Rep"},{"key":"2676_CR69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.neulet.2016.04.006","volume":"621","author":"J Zheng","year":"2016","unstructured":"Zheng J, Sun J, Lu X, et al. BDNF promotes the axonal regrowth after sciatic nerve crush through intrinsic neuronal capability upregulation and distal portion protection. Neurosci Lett. 2016;621:1\u20138.","journal-title":"Neurosci Lett"},{"issue":"7\u20138","key":"2676_CR70","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1089\/ten.tea.2014.0416","volume":"21","author":"L Huang","year":"2015","unstructured":"Huang L, Quan X, Liu Z, et al. c-Jun gene-modified Schwann cells: upregulating multiple neurotrophic factors and promoting neurite outgrowth. Tissue Eng Part A. 2015;21(7\u20138):1409\u201321.","journal-title":"Tissue Eng Part A"},{"issue":"1","key":"2676_CR71","doi-asserted-by":"crossref","first-page":"111937","DOI":"10.1016\/j.yexcr.2020.111937","volume":"390","author":"G Wu","year":"2020","unstructured":"Wu G, Li X, Li M, et al. Long non-coding RNA MALAT1 promotes the proliferation and migration of Schwann cells by elevating BDNF through sponging miR-129-5p. Exp Cell Res. 2020;390(1):111937.","journal-title":"Exp Cell Res."},{"issue":"2","key":"2676_CR72","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1152\/physrev.00031.2008","volume":"89","author":"C Ruiz de Almodovar","year":"2009","unstructured":"Ruiz de Almodovar C, Lambrechts D, Mazzone M, et al. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009;89(2):607\u201348.","journal-title":"Physiol Rev."},{"issue":"5","key":"2676_CR73","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/aja.2011.197","volume":"14","author":"E Darrington","year":"2012","unstructured":"Darrington E, Zhong M, Vo BH, et al. Vascular endothelial growth factor A, secreted in response to transforming growth factor-\u03b21 under hypoxic conditions, induces autocrine effects on migration of prostate cancer cells. Asian J Androl. 2012;14(5):745\u201351.","journal-title":"Asian J Androl"},{"issue":"3","key":"2676_CR74","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.ajpath.2013.05.031","volume":"183","author":"N Beazley-Long","year":"2013","unstructured":"Beazley-Long N, Hua J, Jehle T, et al. VEGF-A165b is an endogenous neuroprotective splice isoform of vascular endothelial growth factor A in vivo and in vitro. Am J Pathol. 2013;183(3):918\u201329.","journal-title":"Am J Pathol"},{"issue":"12","key":"2676_CR75","doi-asserted-by":"crossref","first-page":"4243","DOI":"10.1046\/j.0953-816X.2000.01326.x","volume":"12","author":"M Sondell","year":"2000","unstructured":"Sondell M, Sundler F, Kanje M. Vascular endothelial growth factor is a neurotrophic factor which stimulates axonal outgrowth through the flk-1 receptor. Eur J Neurosci. 2000;12(12):4243\u201354.","journal-title":"Eur J Neurosci"},{"issue":"3","key":"2676_CR76","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000334600","volume":"196","author":"D Foehring","year":"2012","unstructured":"Foehring D, Brand-Saberi B, Theiss C. VEGF-induced growth cone enhancement is diminished by inhibiting tyrosine-residue 1214 of VEGFR-2. Cells Tissues Organs. 2012;196(3):195\u2013205.","journal-title":"Cells Tissues Organs"},{"issue":"5","key":"2676_CR77","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.neuron.2011.04.014","volume":"70","author":"C Ruiz de Almodovar","year":"2011","unstructured":"Ruiz de Almodovar C, Fabre PJ, Knevels E, et al. VEGF mediates commissural axon chemoattraction through its receptor Flk1. Neuron. 2011;70(5):966\u201378.","journal-title":"Neuron."},{"key":"2676_CR78","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.brainres.2014.12.045","volume":"1619","author":"JC Gensel","year":"2015","unstructured":"Gensel JC, Zhang B. Macrophage activation and its role in repair and pathology after spinal cord injury. Brain Res. 2015;1619:1\u201311.","journal-title":"Brain Res"},{"issue":"1","key":"2676_CR79","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2012.08.008","volume":"24","author":"PM Vidal","year":"2013","unstructured":"Vidal PM, Lemmens E, Dooley D, et al. The role of \u201canti-inflammatory\u201d cytokines in axon regeneration. Cytokine Growth Factor Rev. 2013;24(1):1\u201312.","journal-title":"Cytokine Growth Factor Rev"},{"issue":"4","key":"2676_CR80","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.7150\/thno.40919","volume":"10","author":"R Li","year":"2020","unstructured":"Li R, Li D, Wu C, et al. Nerve growth factor activates autophagy in Schwann cells to enhance myelin debris clearance and to expedite nerve regeneration. Theranostics. 2020;10(4):1649\u201377.","journal-title":"Theranostics"},{"issue":"2","key":"2676_CR81","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10571-013-0013-x","volume":"34","author":"A Kaselis","year":"2014","unstructured":"Kaselis A, Treinys R, Vosyli\u016bt\u0117 R, et al. DRG axon elongation and growth cone collapse rate induced by Sema3A are differently dependent on NGF concentration. Cell Mol Neurobiol. 2014;34(2):289\u201396.","journal-title":"Cell Mol Neurobiol"},{"issue":"1","key":"2676_CR82","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/0304-3940(92)90762-V","volume":"147","author":"LB Laudiero","year":"1992","unstructured":"Laudiero LB, Aloe L, Levi-Montalcini R, et al. Multiple sclerosis patients express increased levels of beta-nerve growth factor in cerebrospinal fluid. Neurosci Lett. 1992;147(1):9\u201312.","journal-title":"Neurosci Lett"},{"issue":"8","key":"2676_CR83","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.2174\/18715273113129990087","volume":"12","author":"CM Acosta","year":"2013","unstructured":"Acosta CM, Cortes C, MacPhee H, et al. Exploring the role of nerve growth factor in multiple sclerosis: implications in myelin repair. CNS Neurol Disord Drug Targets. 2013;12(8):1242\u201356.","journal-title":"CNS Neurol Disord Drug Targets"},{"issue":"6","key":"2676_CR84","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nmat3980","volume":"13","author":"MJ Dalby","year":"2014","unstructured":"Dalby MJ, Gadegaard N, Oreffo RO. Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate. Nat Mater. 2014;13(6):558\u201369.","journal-title":"Nat Mater"},{"issue":"6","key":"2676_CR85","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1111\/jcmm.12946","volume":"21","author":"Y Zhou","year":"2017","unstructured":"Zhou Y, Chen H, Li H, et al. 3D culture increases pluripotent gene expression in mesenchymal stem cells through relaxation of cytoskeleton tension. J Cell Mol Med. 2017;21(6):1073\u201384.","journal-title":"J Cell Mol Med"},{"issue":"7280","key":"2676_CR86","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/nature08908","volume":"463","author":"DA Fletcher","year":"2010","unstructured":"Fletcher DA, Mullins RD. Cell mechanics and the cytoskeleton. Nature. 2010;463(7280):485\u201392.","journal-title":"Nature"},{"issue":"10","key":"2676_CR87","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1111\/jcmm.12336","volume":"18","author":"L Guo","year":"2014","unstructured":"Guo L, Zhou Y, Wang S, et al. Epigenetic changes of mesenchymal stem cells in three-dimensional (3D) spheroids. J Cell Mol Med. 2014;18(10):2009\u201319.","journal-title":"J Cell Mol Med"},{"issue":"1","key":"2676_CR88","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.arr.2005.10.001","volume":"5","author":"S Sethe","year":"2006","unstructured":"Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006;5(1):91\u2013116.","journal-title":"Ageing Res Rev"}],"container-title":["Stem Cell Research &amp; Therapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-021-02676-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13287-021-02676-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13287-021-02676-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T06:07:19Z","timestamp":1641794839000},"score":1,"resource":{"primary":{"URL":"https:\/\/stemcellres.biomedcentral.com\/articles\/10.1186\/s13287-021-02676-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,10]]},"references-count":88,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2022,12]]}},"alternative-id":["2676"],"URL":"https:\/\/doi.org\/10.1186\/s13287-021-02676-0","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-868547\/v1","asserted-by":"object"}]},"ISSN":["1757-6512"],"issn-type":[{"value":"1757-6512","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,10]]},"assertion":[{"value":"1 September 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 January 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The animal experiments were approved by the Institutional Animal Care and Use Committee of the Chinese PLA General Hospital and were performed in accordance with Guides for the Care and Use of Laboratory Animals from the Chinese Ministry of Public Health. All efforts were made to minimize animal suffering.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}