{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T11:51:56Z","timestamp":1791892316301,"version":"4.3.4"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"the National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11802096"],"award-info":[{"award-number":["11802096"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Fundamental Research Funds for the Central Universities","award":["ZQN-715"],"award-info":[{"award-number":["ZQN-715"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exceeded mechanical stress leads to a sublethal injury to anterior cruciate ligament (ACL) fibroblasts, and it will hinder cell mobility and ACL regeneration, and even induce osteoarthritis. The mechano growth factor (MGF) could be responsible for mechanical stress and weakening its negative effects on cell physiological behaviors. In this study, effects of MGF on cell mobility and relevant molecules expression in injured ACL fibroblasts were detected. After an injurious mechanical stretch, the analysis carried out, at 0 and 24 h, respectively, showed that the cell area, roundness, migration, and adhesion of ACL fibroblasts were reduced. MGF (10, 100 ng\/mL) treatment could improve cell area, roundness and promote cell migration and adhesion capacity compared with the injured group without MGF. Further study indicated that cell mobility-relevant molecules (PAK1\/2, Cdc42, Rac1, RhoA, and ROCK1) expression in ACL fibroblasts was down-regulated at 0 or 24 h after injurious stretch (except Rac1 and RhoA at 0 h). Similarly, MGF improved cell mobility-relevant molecule expression, especially the ROCK1 expression level in ACL fibroblasts at 0 or 24 h after injurious stretch. Protein expression of ROCK1 in injured ACL fibroblasts was also reduced and could be recovered by MGF treatment. In a rabbit partial ACL transection (ACLT) model, ACL exhibited poor regenerative capacity in collagen and extracellular matrix (ECM) synthesis after partial ACLT for 2 or 4 weeks, and MGF remarkably accelerated ACL regeneration and restored its mechanical loading capacity after partial ACLT for four weeks. Our findings suggest that MGF weakens the effects of pathological stress on cell mobility of ACL fibroblasts and accelerates ACL repair, and might be applied as a future treatment approach to ACL rupture in the clinic.<\/jats:p>","DOI":"10.3390\/ijms23084331","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T21:44:06Z","timestamp":1649972646000},"page":"4331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Mechano Growth Factor Accelerates ACL Repair and Improves Cell Mobility of Mechanically Injured Human ACL Fibroblasts by Targeting Rac1-PAK1\/2 and RhoA-ROCK1 Pathways"],"prefix":"10.3390","volume":"23","author":[{"given":"Yongqiang","family":"Sha","sequence":"first","affiliation":[{"name":"Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China"},{"name":"National Innovation and Attracting Talents \u201c111\u201d Base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huhai","family":"Hong","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingjia","family":"Chi","sequence":"additional","affiliation":[{"name":"National Innovation and Attracting Talents \u201c111\u201d Base, Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China"},{"name":"Department of Mechanics and Engineering Structure, Hubei Key Laboratory of Theory and Application of Advanced Materials Mechanics, Wuhan University of Technology, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1177\/0363546517700882","article-title":"Analysis of 2019 patients undergoing anterior cruciate ligament reconstruction from a community-based registry","volume":"45","author":"Arianjam","year":"2017","journal-title":"Am. J. Sports Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhang, J., Pan, T., Im, H.J., Fu, F.H., and Wang, J.H. (2011). Differential properties of human ACL and MCL stem cells may be responsible for their differential healing capacity. BMC Med., 9.","DOI":"10.1186\/1741-7015-9-68"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/jor.20981","article-title":"GDF-5\/7 and bFGF activate intergrin alpha2-mediated cellular migration in rabbit ligament fibroblasts","volume":"28","author":"Date","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1007\/s11010-011-1061-5","article-title":"Differential response to CoCl2-stimulated hypoxia on HIF-1a, VEGF, and MMP-2 expression in ligament cells","volume":"360","author":"Wang","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1002\/jor.21349","article-title":"Combined effects of TNF-a, IL-1b, and HIF-1a on MMP-2 production in ACL fibroblasts under mechanical stretch: An in vitro study","volume":"20","author":"Wang","year":"2011","journal-title":"J. Orthop. Res."},{"key":"ref_6","first-page":"149","article-title":"Arterial supply to the human anterior cruciate ligament","volume":"30","author":"Toy","year":"1995","journal-title":"J. Athl. Train."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1177\/0363546503262179","article-title":"The effect of estrogen on ovine anterior cruciate ligament fibroblasts: Cell proliferation and collagen synthesis","volume":"32","author":"Seneviratne","year":"2004","journal-title":"Am. J. Sports Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1302\/2046-3758.98.BJR-2019-0365.R1","article-title":"Extracorporeal shock wave promotes activation of anterior cruciate ligament remnant cells and their paracrine regulation of bone marrow stromal cells\u2019 proliferation, migration, collagen synthesis, and differentiation","volume":"9","author":"Lu","year":"2020","journal-title":"Bone Jt. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/S0736-0266(01)00115-2","article-title":"Chronic anterior cruciate ligament deficiency is associated with increased anterior translation of the tibia during the transition from nonweightbearing to weightbearing","volume":"20","author":"Beynnon","year":"2002","journal-title":"J. Orthop. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1056\/NEJMcp1805931","article-title":"Anterior cruciate ligament tear","volume":"380","author":"Musahl","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1016\/S0021-9290(00)00073-7","article-title":"Three-dimensional deformation and stress distribution in an analytical\/computational model of the anterior cruciate ligament","volume":"33","author":"Hirokawa","year":"2000","journal-title":"J. Biomech."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"120117","DOI":"10.1115\/1.4000167","article-title":"A study on construction three-dimensional nonlinear finite element model and stress distribution analysis of anterior cruciate ligament","volume":"131","author":"Xie","year":"2009","journal-title":"J. Biomech. Eng."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1177\/0363546508323644","article-title":"Incidence of anterior cruciate ligament injuries among elite ballet and modern dancer: A 5-year prospective study","volume":"36","author":"Liederbach","year":"2008","journal-title":"Am. J. Sports Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1177\/0363546514524525","article-title":"Comparison of landing biomechanics between male and female dancers and athletes, part 2: Influence of fatigue and implications for anterior cruciate ligament injury","volume":"42","author":"Liderbach","year":"2014","journal-title":"Am. J. Sports Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1113\/jphysiol.2002.035832","article-title":"Expression and splicing of the insulin-like growth factor gene in rodent muscle is associated with muscle satellite (stem) cell activation following local tissue damage","volume":"549","author":"Hill","year":"2003","journal-title":"J. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1210\/en.2009-1217","article-title":"Minireview: Mechano-growth factor: A putative product of IGF-1 gene expression involved in tissue repair and regeneration","volume":"151","author":"Matheny","year":"2010","journal-title":"Endocrinology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.abb.2011.04.016","article-title":"A novel mechanical loading model for studying the distributions of strain and mechano-growth factor expression","volume":"511","author":"Peng","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.hlc.2007.04.013","article-title":"Mechano-growth factor reduces loss of cardiac function in acute myocardial infraction","volume":"17","author":"Carpenter","year":"2008","journal-title":"Heart Lung Circ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.ijdevneu.2009.09.002","article-title":"Changes in the expression of insulin-like growth factor 1 variants in the postnatal brain development and in neonatal hypoxia-ischaemia","volume":"28","author":"Beresewicz","year":"2010","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8846","DOI":"10.1002\/jcp.27546","article-title":"MGF E peptide improves anterior cruciate ligament repair by inhibiting hypoxia-induced cell apoptosis and accelerating angiogenesis","volume":"234","author":"Sha","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.lfs.2017.09.017","article-title":"MGF E peptide pretreatment improves the proliferation and osteogenic differentiation of BMSCs via MEK-ERK1\/2 and PI3K-Akt pathway under severe hypoxia","volume":"189","author":"Sha","year":"2017","journal-title":"Life Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107628","DOI":"10.1016\/j.intimp.2021.107628","article-title":"pretreatment with mechano growth factor E peptide attenuates osteoarthritis through improving cell proliferation and extracellular matrix synthesis in chondrocytes under severe hypoxia","volume":"97","author":"Sha","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.ghir.2010.03.005","article-title":"IGF-IEc expression, regulation and biological function in different tissues","volume":"20","author":"Dai","year":"2010","journal-title":"Growth Horm. IGF Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/BF00123364","article-title":"Cloning and characterization of an IGF-1 isoform expressed in skeletal muscle subjected to stretch","volume":"17","author":"Yang","year":"1996","journal-title":"J. Muscle Res. Cell Motil."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2559","DOI":"10.1007\/s10529-014-1625-z","article-title":"Pretreatment with mechano-growth factor E peptide protects bone marrow mesenchymal cells against damage by fluid shear stress","volume":"36","author":"Lv","year":"2014","journal-title":"Biotechnol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1242\/dev.01162","article-title":"Distincet roles of Rac1\/Cdc42 and Rho\/RocK for axon outgrowth and nucleokinesis of precerebellar neurons toward netrin 1","volume":"131","author":"Causeret","year":"2004","journal-title":"Development"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod.111.094698","article-title":"Role of Rho GTPases in human tropblast migration induced by IGFBP1","volume":"86","author":"Saso","year":"2012","journal-title":"Biol. Reprod."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1002\/jor.1100170521","article-title":"Adhesion strength of differential of human ligament fibroblasts to collagen types I and III","volume":"17","author":"Yang","year":"1999","journal-title":"J. Orthop. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5502","DOI":"10.1016\/j.actbio.2012.11.024","article-title":"The influence and interactions of substrate thickness, organization and dimensionality on cell morphology and migration","volume":"9","author":"Feng","year":"2013","journal-title":"Acta Biomater."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1002\/jor.22215","article-title":"\u03b12\u03b21 integrin and RhoA mediates electric field-induced ligament fibroblasts migration directionality","volume":"31","author":"Tsai","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.eng.2020.02.010","article-title":"Enhancing the surface properties of a bioengineered anterior cruciate ligament matrix for use with point-of-care stem cell therapy","volume":"7","author":"Yu","year":"2021","journal-title":"Engineering"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Marmura, H., Tremblay, P.F., Getgood, A.M.J., and Bryant, D.M. (2022). The knee injury and osteoarthritis outcome score does not have adequate structural validity for use with young, active patients with ACL tears. Clin. Orthop. Relat. Res.","DOI":"10.1097\/CORR.0000000000002158"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jacquet, C., Mouton, C., Magosch, A., Komnos, G.A., Menetrey, J., Ollivier, M., and Seil, R. (2021). The aspiration test reveals an instability of the posterior horn of the lateral meniscus in almost one-third of ACL-injured patients. Knee Surg. Sports Traumatol. Arthrosc.","DOI":"10.1007\/s00167-021-06806-2"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s10439-022-02903-6","article-title":"Post-traumatic osteoarthritis in rabbits following traumatic injury and surgical reconstruction of the knee","volume":"50","author":"Wei","year":"2022","journal-title":"Ann. Biomed. Eng."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"246","DOI":"10.3109\/03008207.2011.632828","article-title":"Comparative study of normal and rheumatoid arthritis fibroblast-like synoviocytes proliferation under cyclic mechanical stretch: Role of prostaglandin E2","volume":"53","author":"Yan","year":"2012","journal-title":"Connect. Tissue Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1038\/s41467-017-00543-2","article-title":"A 3D magnetic tissue stretcher for remote mechanical control of embryonic stem cell differentiation","volume":"8","author":"Du","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1016\/j.orthres.2005.01.022","article-title":"Differential MMP-2 activity of ligament cells under mechanical stretch injury: An in vitro study on human ACL and MCL fibroblasts","volume":"23","author":"Zhou","year":"2005","journal-title":"J. Orthop. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/03008207.2018.1512978","article-title":"Bay11-7082 facilitates wound healing by antagonizing mechanical injury- and TNF-\u03b1-induced expression of MMPs in posterior cruciate ligament","volume":"60","author":"Xu","year":"2019","journal-title":"Connect. Tissue Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1080\/08977194.2017.1327856","article-title":"MGF E peptide pretreatment improves collagen synthesis and cell proliferation of injured human ACL fibroblasts via MEK-ERK1\/2 signaling pathway","volume":"35","author":"Sha","year":"2017","journal-title":"Growth Factors"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.2106\/00004623-200010000-00004","article-title":"Histological changes in the human anterior cruciate ligament after rupture","volume":"82","author":"Murray","year":"2000","journal-title":"J. Bone Jt. Surg. Am."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7442289","DOI":"10.1155\/2022\/7442289","article-title":"Clinical-like cryotherapy in acute knee arthritis protects neuromuscular junctions of quadriceps and reduces joint inflammation in mice","volume":"2022","author":"Castro","year":"2022","journal-title":"Biomed. Res. Int."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1186\/s13075-021-02661-1","article-title":"Immune cell profiles in synovial fluid after anterior cruciate ligament and meniscus injuries","volume":"23","author":"Holt","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1177\/08853282211039179","article-title":"The use of gold nanoparticles in improving ACL graft performance in an ovine model","volume":"36","author":"Bellririchard","year":"2022","journal-title":"J. Biomater. Appl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1053\/jars.2001.28979","article-title":"Donor-site morbidity and anterior knee problems after anterior cruciate ligament reconstruction using autografts","volume":"17","author":"Kartus","year":"2001","journal-title":"Arthroscopy"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1002\/jbm.a.30578","article-title":"Biomaterials and scaffolds for ligament tissue engineering","volume":"77","author":"Ge","year":"2006","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1614","DOI":"10.1002\/jbm.a.34820","article-title":"Current tissue engineering strategies in anterior cruciate ligament reconstruction","volume":"102","author":"Leong","year":"2014","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1177\/0363546515587713","article-title":"Effects of remnant tissue preservation on clinical and arthroscopic results after anatomic double-bundle anterior cruciate ligament reconstruction","volume":"43","author":"Kondo","year":"2015","journal-title":"Am. J. Sports Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1016\/S0142-9612(00)00426-9","article-title":"The migration of cells from the ruptured human anterior cruciate ligament into collagen-glycosaminoglycan regeneration templates in vitro","volume":"22","author":"Murray","year":"2001","journal-title":"Biomaterials"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"8386","DOI":"10.1096\/fj.201802281R","article-title":"Distinct expression pattern of periostin splice variants in chondrocytes and ligament progenitor cells","volume":"33","author":"Cai","year":"2019","journal-title":"FASEB J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"23094990211061249","DOI":"10.1177\/23094990211061249","article-title":"Does remnant tissue preservation in anterior cruciate ligament reconstruction influence the creation of the rectangular femoral tunnel?","volume":"29","author":"Asai","year":"2021","journal-title":"J. Orthop. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"G\u00f6gele, C., Konrad, J., Hahn, J., Breier, A., Schr\u00f6pfer, M., Meyer, M., Merkel, R., Hoffmann, B., and Schulze-Tanzil, G. (2021). Maintenance of ligament homeostasis of spheroid-colonized embroidered and functionalized scaffolds after 3D stretch. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22158204"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1055\/s-0036-1581135","article-title":"Influences of tumor necrosis factor-\u03b1 on lysyl oxidases and matrix metalloproteinases of injured anterior cruciate ligament and medial collateral ligament fibroblasts","volume":"30","author":"Cai","year":"2017","journal-title":"J. Knee Surg."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1007\/s10529-020-02870-9","article-title":"Mechanical inury and IL-1\u03b2 regulated LOXs and MMP-1, 2, 3 expression in ACL fibroblasts co-cultured with synoviocytes","volume":"42","author":"Wang","year":"2020","journal-title":"Biotechnol. Lett."},{"key":"ref_54","first-page":"230","article-title":"LncRNA uc.48+ regulates immune and inflammatory reactions mediated by the P2X7 receptor in type 2 diabetic mice","volume":"20","author":"Hong","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1002\/jor.20367","article-title":"Enhanced histologic repair in a central wound in the anterior cruciate ligament with a collagen-platelet-rich plasma scaffold","volume":"25","author":"Murray","year":"2007","journal-title":"J. Orthop. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4331\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:53:43Z","timestamp":1760136823000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/8\/4331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,14]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["ijms23084331"],"URL":"https:\/\/doi.org\/10.3390\/ijms23084331","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,14]]}}}