Stromal Cell-Derived Factor-1α (SDF-1α)-Gene Activated Scaffold and Angiogenesis Process in Tissue Engineering: A Systematic Review and Meta-Analysis of in Vitro Studies

Abstract

Stromal cell-derived factor-1α (SDF-1α) is a potent stem cell recruitment chemokine that can promote angiogenesis, particularly when delivered via gene-activated scaffolds (GAS). This systematic review and meta-analysis synthesized in vitro evidence on the angiogenic potential of SDF-1α GAS. Four databases were utilized to search for eligible studies, comprising investigations that examined the in vitro effects of SDF-1α GAS on angiogenesis-related outcomes compared with gene-free scaffolds. Data on gene expression, protein levels, and endothelial formation were extracted. Meta-analyses were conducted using random or fixed-effect models, expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). Risk of bias was assessed using the Quality Assessment Tool for In Vitro Studies (QUIN) tool. Eight studies were included. Pooled analysis demonstrated SDF-1α GAS efficacy to significantly increase SDF-1α gene expression (SMD = 1.20; 95% CI = 0.13–2.27; p = .03), fold-change of the gene (MD = 12.48; 95% CI = 10.33–14.64; p < .0001), and protein production (MD = 0.29 ng/mL; 95% CI = 0.14–0.43 ng/mL; p = .0001). Most studies showed a moderate risk of bias. Based on in vitro studies, SDF-1α GAS activity is associated with significant elevation of SDF-1α gene expression and protein quantity, although it did not exhibit significant enhancement of VEGF expression or functional endothelial morphogenesis under the studied conditions.

Keywords

angiogenesis / meta-analysis / scaffold / wound healing

References

[1] B. I. Sukmana, R. Margiana, Y. Q. Almajidi, et al., “Supporting Wound Healing by Mesenchymal Stem Cells (MSCs) Therapy in Combination With Scaffold, Hydrogel, and Matrix; State of the Art,” Pathology—Research and Practice 248 (2023): 154575.

[2] M. Kremer and N. Burkemper, “Aging Skin and Wound Healing,” Clinics in Geriatric Medicine 40, no. 1 (2024): 1–10.

[3] H. Sorg and C. G. G. Sorg, “Skin Wound Healing: Of Players, Patterns, and Processes,” European Surgical Research 64, no. 2 (2023): 141–157.

[4] M. S. Sangha, F. Deroide, and R. Meys, “Wound Healing, Scarring and Management,” Clinical and Experimental Dermatology 49, no. 4 (2024): 325–336.

[5] D. Nasiry, A. R. Khalatbary, M. A. Abdollahifar, et al., “SDF-1α Loaded Bioengineered Human Amniotic Membrane-Derived Scaffold Transplantation in Combination With Hyperbaric Oxygen Improved Diabetic Wound Healing,” Journal of Bioscience and Bioengineering 133, no. 5 (2022): 489–501.

[6] S. Yuge, T. Ishii, C. Noishiki, and S. Fukuhara, “Novel Regulatory Mechanisms Underlying Angiogenesis During Wound Healing Revealed by Fluorescence-Based Live-Imaging in Zebrafish,” Journal of Biochemistry 174, no. 1 (2023): 5–12.

[7] M. Wang, C. Xu, D. Wang, J. Lu, A. Wang, and Q. Zhou, “Analysis of Current Trends in Angiogenesis Research for Wound Healing: A Bibliometric Study From 2013 to 2023,” Heliyon 10, no. 12 (2024): e32311.

[8] X. Wang, R. Li, and H. Zhao, “Enhancing Angiogenesis: Innovative Drug Delivery Systems to Facilitate Diabetic Wound Healing,” Biomedicine & Pharmacotherapy 170 (2024): 116035.

[9] K. Sindhi, R. B. Pingili, V. Beldar, S. Bhattacharya, J. Rahaman, and D. Mukherjee, “The Role of Biomaterials-Based Scaffolds in Advancing Skin Tissue Construct,” Journal of Tissue Viability 34, no. 2 (2025): 100858.

[10] J. Qin, F. Chen, P. Wu, and G. Sun, “Recent Advances in Bioengineered Scaffolds for Cutaneous Wound Healing,” Frontiers in Bioengineering and Biotechnology 10 (2022): 841583.

[11] A. L. Laiva, F. J. O'Brien, and M. B. Keogh, “SDF-1α Gene-Activated Collagen Scaffold Enhances Provasculogenic Response in a Coculture of Human Endothelial Cells With Human Adipose-Derived Stromal Cells,” Journal of Materials Science: Materials in Medicine 32, no. 3 (2021): 26.

[12] W. Zhao, K. Jin, J. Li, X. Qiu, and S. Li, “Delivery of Stromal Cell-Derived Factor 1α for in Situ Tissue Regeneration,” Journal of Biological Engineering 11, no. 1 (2017): 22.

[13] S. Su, J. Bai, R. Wang, S. Gao, R. Zhou, and F. Zhou, “A Novel Strategy for Bone Defect Repair: Stromal Cell-Derived Factor 1α Sustained-Release Acellular Fish Scale Scaffolds Combined With Injection of Bone Marrow Mesenchymal Stem Cells Promote Bone Regeneration,” Materials Today Bio 32 (2025): 101759.

[14] A. L. Laiva, F. J. O'Brien, and M. B. Keogh, “Dual Delivery Gene-Activated Scaffold Directs Fibroblast Activity and Keratinocyte Epithelization,” APL Bioengineering 8, no. 1 (2024): 16104.

[15] R. N. Power, B. L. Cavanagh, J. E. Dixon, C. M. Curtin, and F. J. O'Brien, “Development of a Gene-Activated Scaffold Incorporating Multifunctional Cell-Penetrating Peptides for pSDF-1α Delivery for Enhanced Angiogenesis in Tissue Engineering Applications,” International Journal of Molecular Sciences 23, no. 3 (2022): 1460.

[16] R. M. Raftery, A. G. Gonzalez Vazquez, D. P. Walsh, et al., “Mobilizing Endogenous Progenitor Cells Using pSDF1α-Activated Scaffolds Accelerates Angiogenesis and Bone Repair in Critical-Sized Bone Defects,” Advanced Healthcare Materials 13, no. 23 (2024): 1–15.

[17] A. L. Laiva, F. J. O'Brien, and M. B. Keogh, “SDF-1α Gene-Activated Collagen Scaffold Drives Functional Differentiation of Human Schwann Cells for Wound Healing Applications,” Biotechnology and Bioengineering 118, no. 2 (2021): 725–736.

[18] A. L. Laiva, R. M. Raftery, M. B. Keogh, and F. J. O'Brien, “Pro-Angiogenic Impact of SDF-1α Gene-Activated Collagen-Based Scaffolds in Stem Cell Driven Angiogenesis,” International Journal of Pharmaceutics 544, no. 2 (2018): 372–379.

[19] A. L. Laiva, F. J. O'Brien, and M. B. Keogh, “SDF-1α Gene-Activated Collagen Scaffold Restores Pro-Angiogenic Wound Healing Features in Human Diabetic Adipose-Derived Stem Cells,” Biomedicines 9, no. 2 (2021): 160.

[20] P. Das, M. Maresch, N. Dey, et al., “Programmed Wound Healing in Aged Skin May Be Enhanced by Mesenchymal Cell Loaded Gene-Activated Scaffolds,” APL Bioengineering 9, no. 2 (2025): 1–13.

[21] F. Moccia, S. Negri, M. Shekha, P. Faris, and G. Guerra, “Endothelial Ca(2+) Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel,” International Journal of Molecular Sciences 20, no. 16 (2019): 3962.

[22] F. Sadri, Z. Rezaei, H. Safarpour, et al., “SDF-1α Loaded Lipid Liquid Crystalline Hydrogel Accelerates Diabetic Wound Healing in in Vitro and In Vivo Models,” Scientific Reports 15, no. 1 (2025): 26188.

[23] L. Pawig, C. Klasen, C. Weber, J. Bernhagen, and H. Noels, “Diversity and Inter-Connections in the CXCR4 Chemokine Receptor/Ligand Family: Molecular Perspectives,” Frontiers in immunology 6 (2015): 429.

[24] F. Sadri, Z. Rezaei, and M. Fereidouni, “The Significance of the SDF-1/CXCR4 Signaling Pathway in the Normal Development,” Molecular Biology Reports 49, no. 4 (2022): 3307–3320.

[25] E. Shaabani, M. Sharifiaghdam, R. Faridi-Majidi, S. C. De Smedt, K. Braeckmans, and J. C. Fraire, “Gene Therapy to Enhance Angiogenesis in Chronic Wounds,” Molecular Therapy - Nucleic Acids 29 (2022): 871–899.

[26] L. Porosk, J. Nebogatova, H. H. Härk, et al., “Predicting Transiently Expressed Protein Yields: Comparison of Transfection Methods in CHO and HEK293,” Pharmaceutics 14, no. 9 (2022): 1949.

[27] J. E. Yoon, Y. Kim, S. Kwon, et al., “Senescent Fibroblasts Drive Ageing Pigmentation: A Potential Therapeutic Target for Senile Lentigo,” Theranostics 8 (2018): 4620–4632.

[28] Y. I. Lee, S. Choi, W. S. Roh, J. H. Lee, and T. G. Kim, “Cellular Senescence and Inflammaging in the Skin Microenvironment,” International Journal of Molecular Sciences 22, no. 8 (2021): 3849.

[29] S. Rafii, Z. Cao, R. Lis, et al., “Platelet-Derived SDF-1 Primes the Pulmonary Capillary Vascular Niche to Drive Lung Alveolar Regeneration,” Nature Cell Biology 17, no. 2 (2015): 123–136.

[30] Z. Liang, J. Brooks, M. Willard, et al., “CXCR4/CXCL12 Axis Promotes Vegf-Mediated Tumor Angiogenesis Through Akt Signaling Pathway,” Biochemical and Biophysical Research Communications 359, no. 3 (2007): 716–722.

[31] D. M. Ma, D. X. Luo, and J. Zhang, “SDF-1/CXCR7 Axis Regulates the Proliferation, Invasion, Adhesion, and Angiogenesis of Gastric Cancer Cells,” World Journal of Surgical Oncology 14, no. 1 (2016): 256.

[32] F. de Nigris, V. Crudele, A. Giovane, et al., “CXCR4/YY1 Inhibition Impairs Vegf Network and Angiogenesis During Malignancy,” Proceedings of the National Academy of Sciences 107, no. 32 (2010): 14484–14489.

[33] F. Jin, N. Hagemann, S. T. Schäfer, U. Brockmeier, A. Zechariah, and D. M. Hermann, “SDF-1 Restores Angiogenesis Synergistically With VEGF Upon LDL Exposure Despite CXCR4 Internalization and Degradation,” Cardiovascular Research 100, no. 3 (2013): 481–491.

[34] H. Shokrani, A. Shokrani, S. M. Sajadi, et al., “Cell-Seeded Biomaterial Scaffolds: The Urgent Need for Unanswered Accelerated Angiogenesis,” International Journal of Nanomedicine 17, no. null (2022): 1035–1068.

[35] X. Yuan, H. Wu, X. Li, et al., “SDF-1α/CXCR4 Signaling Promotes Capillary Tube Formation of Human Retinal Vascular Endothelial Cells by Activating ERK1/2 and PI3K Pathways in Vitro,” Molecular Medicine Reports 26, no. 4 (2022): 305.

[36] Q. Liu, G. Ying, C. Hu, et al., “Engineering in Vitro Vascular Microsystems,” Microsystems & Nanoengineering 11, no. 1 (2025): 100.

[37] E. Gordon, L. Schimmel, and M. Frye, “The Importance of Mechanical Forces for in Vitro Endothelial Cell Biology,” Frontiers in Physiology 11 (2020): 684.

[38] C. A. Dessalles, C. Leclech, A. Castagnino, and A. I. Barakat, “Integration of Substrate- and Flow-Derived Stresses in Endothelial Cell Mechanobiology,” Communications Biology 4, no. 1 (2021): 764.

[39] B. C. Heng, X. Li, Y. Guo, et al., “Biophysical Stimuli for Promoting Angiogenesis and Vascularization in Regenerative Medicine and Dentistry,” EngMedicine 2, no. 3 (2025): 100078.

[40] T. Waritani, J. Chang, B. McKinney, and K. Terato, “An Elisa Protocol to Improve the Accuracy and Reliability of Serological Antibody Assays,” MethodsX 4 (2017): 153–165.

[41] C. Zhong, S. He, Y. Huang, et al., “Scaffold-Based Non-Viral Crispr Delivery Platform for Efficient and Prolonged Gene Activation to Accelerate Tissue Regeneration,” Acta Biomaterialia 173 (2024): 283–297.

[42] M. J. Page, J. E. McKenzie, P. M. Bossuyt, et al., “The PRISMA 2020 Statement: An Updated Guideline for Reporting Systematic Reviews,” BMJ 372 (2021): n71.

[43] T. P. Umar, M. G. Samudra, K. M. N. Nashor, D. Agustini, and R. A. Syakurah, “Health Professional Student's Volunteering Activities During the COVID-19 Pandemic: A Systematic Literature Review,” Frontiers in Medicine 9 (2022): 797153.

[44] M. Ouzzani, H. Hammady, Z. Fedorowicz, and A. Elmagarmid, “Rayyan—A Web and Mobile App for Systematic Reviews,” Systematic Reviews 5, no. 1 (2016): 210.

[45] V. H. Sheth, N. P. Shah, R. Jain, N. Bhanushali, and V. Bhatnagar, “Development and Validation of a Risk-of-Bias Tool for Assessing in Vitro Studies Conducted in Dentistry: The QUIN,” Journal of Prosthetic Dentistry 131, no. 6 (2024): 1038–1042.

[46] L. A. McGuinness and J. P. T. Higgins, “Risk-of-Bias Visualization (robvis): An R Package and Shiny Web App for Visualizing Risk-of-Bias Assessments,” Research Synthesis Methods 12, no. 1 (2021): 55–61.

Rights & permissions

2026 The Author(s). MedComm – Biomaterials and Applications published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).