{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T04:06:58Z","timestamp":1784002018180,"version":"3.55.0"},"reference-count":45,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PVAMU\u2019s RISE Undergraduate Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomimetics"],"abstract":"<jats:p>Vascularization remains a fundamental bottleneck in tissue engineering, as the absence of functional vascular networks limits oxygen and nutrient delivery, resulting in necrotic cores and poor host integration. While structural scaffold design and cell sourcing have advanced considerably, emerging evidence indicates that paracrine signaling, rather than direct cell contact or scaffold architecture alone, is the primary driver of angiogenesis and vasculogenesis within engineered constructs. Key cell types, including endothelial cells (ECs) and mesenchymal stem cells (MSCs), engage in bidirectional paracrine crosstalk through the secretion of vascular endothelial growth factor (VEGF), angiopoietins, hepatocyte growth factor, and platelet-derived growth factor, among other mediators. While researchers have long focused on improving scaffold structure and cell selection, growing evidence shows that the chemical messages cells send to one another play a far more important role in driving blood vessel formation than previously appreciated. This review explores how cells embedded within engineered scaffolds communicate through secreted signals to coordinate the growth of new blood vessels. Two cell types, MSCs and ECs, are central to this process: cells that line blood vessels and bone marrow-derived stem cells. These cells exchange a variety of chemical messages that instruct neighboring cells to multiply, move, and organize into vessel-like structures. Importantly, the material properties of the scaffold itself, including its stiffness, surface texture, and degradation over time, influence the signals cells produce and how those signals spread through the tissue. Strategies to amplify paracrine signaling include growth factor-loaded delivery systems, hypoxic and genetic preconditioning of MSCs, and perfusion bioreactor culture. In vitro and in vivo evidence consistently demonstrates that coculture systems leveraging paracrine interactions produce superior vascular outcomes compared to single-cell or acellular constructs. Despite this progress, challenges related to signaling complexity, reproducibility, and clinical translation persist. Integration of transcriptomic and proteomic profiling, computational modeling, and machine learning approaches offers a path toward rationally designed scaffolds that recapitulate the spatiotemporal dynamics of native vascular signaling and ultimately support functional tissue regeneration.<\/jats:p>","DOI":"10.3390\/biomimetics11070492","type":"journal-article","created":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T03:28:47Z","timestamp":1783999727000},"page":"492","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Paracrine Signaling in Cell\u2013Biomaterial Interactions in Scaffold Vascularization: A Mini Review"],"prefix":"10.3390","volume":"11","author":[{"given":"Anisa","family":"Cole","sequence":"first","affiliation":[{"name":"Texas Undergraduate Medical Academy, School of Public and Allied Health, Prairie View A&M University, Prairie View, TX 77446, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6036-7865","authenticated-orcid":false,"given":"Naznin","family":"Sultana","sequence":"additional","affiliation":[{"name":"Texas Undergraduate Medical Academy, School of Public and Allied Health, Prairie View A&M University, Prairie View, TX 77446, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.addr.2011.03.004","article-title":"Vascularization is the key challenge in tissue engineering","volume":"63","author":"Novosel","year":"2011","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1016\/j.tibtech.2016.03.002","article-title":"Vascularization and angiogenesis in tissue engineering: Beyond creating static networks","volume":"34","author":"Rouwkema","year":"2016","journal-title":"Trends Biotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"121818","DOI":"10.1016\/j.biomaterials.2022.121818","article-title":"Scalable macroporous hydrogels enhance stem cell treatment of volumetric muscle loss","volume":"290","author":"Eugenis","year":"2022","journal-title":"Biomaterials"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1177\/0963689718782452","article-title":"Vascularization of Natural and Synthetic Bone Scaffolds","volume":"27","author":"Liu","year":"2018","journal-title":"Cell Transplant."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"012002","DOI":"10.1088\/2516-1091\/ab5637","article-title":"Vascularization in tissue engineering: Fundamentals and state-of-the-art","volume":"2","author":"Yang","year":"2020","journal-title":"Prog. Biomed. Eng."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.biomaterials.2017.11.041","article-title":"Crosstalk between developing vasculature and optogenetically engineered skeletal muscle improves muscle contraction and angiogenesis","volume":"156","author":"Osaki","year":"2018","journal-title":"Biomaterials"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Abdulghani, S., and Mitchell, G.R. (2019). Biomaterials for In Situ Tissue Regeneration: A Review. Biomolecules, 9.","DOI":"10.3390\/biom9110750"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1007\/s11033-020-06108-9","article-title":"Understanding angiogenesis and the role of angiogenic growth factors in the vascularisation of engineered tissues","volume":"48","author":"Omorphos","year":"2021","journal-title":"Mol. Biol. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8837654","DOI":"10.1155\/2020\/8837654","article-title":"Mesenchymal Stem\/Progenitor Cells: The Prospect of Human Clinical Translation","volume":"2020","author":"Rady","year":"2020","journal-title":"Stem Cells Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.brainresbull.2019.03.004","article-title":"The influence of microenvironment and extracellular matrix molecules in driving neural stem cell fate within biomaterials","volume":"148","author":"Wilems","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrm3620","article-title":"Role of the extracellular matrix in regulating stem cell fate","volume":"14","author":"Watt","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sultana, N. (2026). Bone Tissue Engineering: Scaffold Design Principles, Biomaterial Advances, and Strategies for Functional Regeneration and Clinical Translation. Bioengineering, 13.","DOI":"10.3390\/bioengineering13050514"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12","DOI":"10.2302\/kjm.ABSTRACT_73_1-1","article-title":"Molecular Basis of Angiogenesis and its Application","volume":"73","author":"Ferrara","year":"2024","journal-title":"Keio J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.stem.2011.06.008","article-title":"The MSC: An injury drugstore","volume":"9","author":"Caplan","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_15","first-page":"e51312","article-title":"Endothelial cell tube formation assay for the in vitro study of angiogenesis","volume":"91","author":"Henry","year":"2014","journal-title":"J. Vis. Exp."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.jcyt.2024.06.007","article-title":"The Mesenchymal Stromal Cell Secretome Promotes Tissue Regeneration and Increases Macrophage Infiltration in Acute and Methicillin-Resistant Staphylococcus aureus-Infected Skin Wounds In Vivo","volume":"26","author":"Rajesh","year":"2024","journal-title":"Cytotherapy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1002\/term.1617","article-title":"Review of vascularised bone tissue-engineering strategies with a focus on coculture systems","volume":"9","author":"Liu","year":"2015","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.actbio.2024.08.034","article-title":"Formation and Biological Activities of Foreign Body Giant Cells in Response to Biomaterials","volume":"188","author":"Cai","year":"2024","journal-title":"Acta Biomater."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature10137","article-title":"Role of YAP\/TAZ in mechanotransduction","volume":"474","author":"Dupont","year":"2011","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"558","DOI":"10.1038\/nmat3980","article-title":"Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate","volume":"13","author":"Dalby","year":"2014","journal-title":"Nat. Mater."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1002\/wdev.176","article-title":"The fibroblast growth factor signaling pathway","volume":"4","author":"Ornitz","year":"2015","journal-title":"Wiley Interdiscip. Rev. Dev. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.mam.2017.10.001","article-title":"PDGFs and Their Receptors in Vascular Stem\/Progenitor Cells: Functions and Therapeutic Potential in Retinal Vasculopathy","volume":"62","author":"Lu","year":"2018","journal-title":"Mol. Asp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.freeradbiomed.2009.09.026","article-title":"Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis","volume":"48","author":"Liu","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"878","DOI":"10.1016\/j.bbamcr.2011.01.034","article-title":"The pro- and anti-inflammatory properties of the cytokine interleukin-6","volume":"1813","author":"Scheller","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1172\/JCI59643","article-title":"Macrophage plasticity and polarization: In vivo veritas","volume":"122","author":"Sica","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hohmann, N., Xia, N., Steinkamp-Fenske, K., F\u00f6rstermann, U., and Li, H. (2016). Estrogen Receptor Signaling and the PI3K\/Akt Pathway Are Involved in Betulinic Acid-Induced eNOS Activation. Molecules, 21.","DOI":"10.3390\/molecules21080973"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nimlamool, W., Potikanond, S., Ruttanapattanakul, J., Wikan, N., Okonogi, S., Jantrapirom, S., Pitchakarn, P., and Karinchai, J. (2021). Curcuma amarissima Extract Activates Growth and Survival Signal Transduction Networks to Stimulate Proliferation of Human Keratinocyte. Biology, 10.","DOI":"10.3390\/biology10040289"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Yoshitomi, Y., Ikeda, T., Saito-Takatsuji, H., and Yonekura, H. (2021). Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22062804"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5418","DOI":"10.1038\/s41598-021-84123-x","article-title":"3D-Microtissue Derived Secretome as a Cell-Free Approach for Enhanced Mineralization of Scaffolds in the Chorioallantoic Membrane Model","volume":"11","author":"Otto","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Abdelrazik, H., Giordano, E., Barbanti Brodano, G., Griffoni, C., De Falco, E., and Pelagalli, A. (2019). Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20215386"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1186\/s12967-014-0260-8","article-title":"A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods","volume":"12","author":"Madrigal","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.cell.2006.06.044","article-title":"Matrix elasticity directs stem cell lineage specification","volume":"126","author":"Engler","year":"2006","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2011.08.039","article-title":"Basic and therapeutic aspects of angiogenesis","volume":"146","author":"Potente","year":"2011","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41440-020-0524-z","article-title":"Cell Seeding Accelerates the Vascularization of Tissue Engineering Constructs in Hypertensive Mice","volume":"44","author":"Wagner","year":"2021","journal-title":"Hypertens. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1098\/rsif.2010.0223","article-title":"Growth factor delivery-based tissue engineering: General approaches and a review of recent developments","volume":"8","author":"Lee","year":"2011","journal-title":"J. R. Soc. Interface"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1089\/ten.teb.2021.0145","article-title":"Hypoxia-Conditioned Mesenchymal Stem Cells in Tissue Regeneration Application","volume":"28","author":"Yang","year":"2022","journal-title":"Tissue Eng. Part B Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.vph.2014.06.004","article-title":"Multiple paracrine factors secreted by mesenchymal stem cells contribute to angiogenesis","volume":"63","author":"Kwon","year":"2014","journal-title":"Vasc. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Marassi, V., Giordani, S., Kurevija, A., Panetta, E., Roda, B., Zhang, N., Azzolini, A., Dolzani, S., Manko, D., and Reschiglian, P. (2022). The Challenges of O2 Detection in Biological Fluids: Classical Methods and Translation to Clinical Applications. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232415971"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kim, B.C., Kwack, K.H., Chun, J., and Lee, J.H. (2021). Comparative Transcriptome Analysis of Human Adipose-Derived Stem Cells Undergoing Osteogenesis in 2D and 3D Culture Conditions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157939"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"100464","DOI":"10.1016\/j.mtbio.2022.100464","article-title":"Effect of Coculture of Mesenchymal Stem Cell and Glomerulus Endothelial Cell to Promote Endothelialization Under Optimized Perfusion Flow Rate in Whole Renal ECM Scaffold","volume":"17","author":"Choi","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1002\/jbm.a.37580","article-title":"Pre-Cultured, Cell-Encapsulating Fibrin Microbeads for the Vascularization of Ischemic Tissues","volume":"112","author":"Friend","year":"2024","journal-title":"J. Biomed. Mater. Res. A"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"218","DOI":"10.20517\/evcna.2023.19","article-title":"Bioprinting Extracellular Vesicles as a \u201cCell-Free\u201d Regenerative Medicine Approach","volume":"4","author":"Jiao","year":"2023","journal-title":"Extracell. Vesicles Circ. Nucleic Acids"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Hayes, C.N., Nakahara, H., Ono, A., Tsuge, M., and Oka, S. (2024). From Omics to Multi-Omics: A Review of Advantages and Tradeoffs. Genes, 15.","DOI":"10.20944\/preprints202411.0882.v1"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5552","DOI":"10.1021\/acsabm.0c00791","article-title":"3D bioprinting of tumor models for cancer research","volume":"3","author":"Kang","year":"2020","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20417314251376104","DOI":"10.1177\/20417314251376104","article-title":"Angiogenesis Induction Using Organoid-Tissue Modules: A Platform for Modular Vessel Construction","volume":"16","author":"Park","year":"2025","journal-title":"J. Tissue Eng."}],"container-title":["Biomimetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2313-7673\/11\/7\/492\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T03:31:36Z","timestamp":1783999896000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2313-7673\/11\/7\/492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,14]]},"references-count":45,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["biomimetics11070492"],"URL":"https:\/\/doi.org\/10.3390\/biomimetics11070492","relation":{},"ISSN":["2313-7673"],"issn-type":[{"value":"2313-7673","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,14]]}}}