ArticleProceedings of the National Academy of Sciences of the United States of America2014
Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed.
- Shock wave treatment enhances cell proliferation and improves wound healing by ATP release-coupled extracellular signal-regulated kinase (ERK) activation.The Journal of biological chemistry · 2014Trial
- Programmable Paracrine-Mimetic Microneedle System for Temporal Regulation of Cardiac Repair.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Fibrin scaffolds for angiogenesis in soft tissue models: a systematic review.Bioactive materials · 2026Review
- Tinkering with Blood: Optimizing the Coagulation System for Therapeutic Purposes.Bioengineering (Basel, Switzerland) · 2025Review
- Enhanced safety and potency in local angiogenic growth factor delivery via aptamer functionalization of hydrogels.Journal of controlled release : official journal of the Controlled Release Society · 2025Article
- Advanced biomaterial strategies for overcoming age-associated wound healing impairments.APL bioengineering · 2025Review
- Getting Blood out of a Stone: Vascularization via Spheroids and Organoids in 3D Bioprinting.Cells · 2025Review
- Toward Origami-Inspired In Vitro Cardiac Tissue Models.ACS biomaterials science & engineering · 2025Article
- Growth factors and growth factor gene therapies for treating chronic wounds.Bioengineering & translational medicine · 2024Review
- Semaphorin 3A promotes the long-term persistence of human SVF-derived microvascular networks in engineered grafts.Frontiers in bioengineering and biotechnology · 2024Article
- Growth factor free, peptide-functionalized gelatin hydrogel promotes arteriogenesis and attenuates tissue damage in a murine model of critical limb ischemia.Biomaterials · 2023Article
- Mimicking Molecular Pathways in the Design of Smart Hydrogels for the Design of Vascularized Engineered Tissues.International journal of molecular sciences · 2023Review
- Therapeutic role of growth factors in treating diabetic wound.World journal of diabetes · 2023Review
- VEGF-Encoding, Gene-Activated Collagen-Based Matrices Promote Blood Vessel Formation and Improved Wound Repair.ACS applied materials & interfaces · 2023Article
- Ischemia Impaired Wound Healing Model in the Rat-Demonstrating Its Ability to Test Proangiogenic Factors.Biomedicines · 2023Article
- VEGF dose controls the coupling of angiogenesis and osteogenesis in engineered bone.NPJ Regenerative medicine · 2023Article
- Growth Factor and Cytokine Delivery Systems for Wound Healing.Cold Spring Harbor perspectives in biology · 2022Review
- Advances in Fibrin-Based Materials in Wound Repair: A Review.Molecules (Basel, Switzerland) · 2022Review
- Static and Dynamic Biomaterial Engineering for Cell Modulation.Nanomaterials (Basel, Switzerland) · 2022Review
- Engineered Molecular Therapeutics Targeting Fibrin and the Coagulation System: a Biophysical Perspective.Biophysical reviews · 2022Review
7 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 μg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 μg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.
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