@article{22a7070dc7be4bf59abd1526d7eafe2c,
title = "Adhesive protein-based angiogenesis-mimicking spatiotemporal sequential release of angiogenic factors for functional regenerative medicine",
abstract = "Damaged vascular structures after critical diseases are difficult to completely restore to their original conditions without specific treatments. Thus, therapeutic angiogenesis has been spotlighted as an attractive strategy. However, effective strategies for mimicking angiogenic processes in the body have not yet been developed. In the present work, we developed a bioengineered mussel adhesive protein (MAP)-based novel therapeutic angiogenesis platform capable of spatiotemporally releasing angiogenic growth factors to target disease sites with high viscosity and strong adhesiveness in a mucus-containing environment with curvature. Polycationic MAP formed complex coacervate liquid microdroplets with polyanionic hyaluronic acid and subsequently gelated into microparticles. Platelet-derived growth factor (PDGF), which is a late-phase angiogenic factor, was efficiently encapsulated during the process of coacervate microparticle formation. These PDGF-loaded microparticles were blended with vascular endothelial growth factor (VEGF), which is the initial-phase angiogenic factor, in MAP-based pregel solution and finally crosslinked in situ into a hydrogel at the desired site. The microparticle-based angiogenic-molecule spatiotemporal sequential (MASS) release platform showed good adhesion and underwater durability, and its elasticity was close to that of target tissue. Using two in vivo critical models, i.e., full-thickness excisional wound and myocardial infarction models, the MASS release platform was evaluated for its in vivo feasibility as an angiogenesis-inducing platform and demonstrated effective angiogenesis as well as functional regenerative efficacy. Based on these superior physicochemical characteristics, the developed MASS release platform could be successfully applied in many biomedical practices as a waterproof bioadhesive with the capability for the spatiotemporal delivery of angiogenic molecules in the treatment of ischemic diseases.",
keywords = "Angiogenesis, Hydrogels, Microparticles, Mussel adhesive protein, Myocardial infarction, Spatiotemporal sequential release",
author = "Park, {Tae Yoon} and Maeng, {Seong Woo} and Jeon, {Eun Young} and Joo, {Kye Il} and Cha, {Hyung Joon}",
note = "Funding Information: Based on the many advantages of MAP, we developed a MAP-based effective angiogenesis-inducing platform that combines the strategies of spatially separating angiogenic GF molecules according to the release features of the material fabrications and providing physical support by attaching materials possessing similar mechanical properties to surrounding tissue. Through the developed platform, we could expect improved in vitro and in vivo angiogenesis-inducing capabilities. To spatiotemporally distribute and sequentially release two angiogenic factors, VEGF and PDGF, MAP-based hydrogels and coacervate microparticles with different biophysical features were employed together. PDGF, necessary for the late phase of angiogenesis, was encapsulated rapidly and simultaneously with the formation of catechol-containing MAP-hyaluronic acid (HA) coacervate liquid microdroplets, which were subsequently gelated into microparticles by oxidative crosslinking. Then, the PDGF-loaded microparticles were included in a MAP-based pregel solution already containing VEGF, which is necessary for the initial phase of angiogenesis. The MAP pregel solution with PDGF-loaded microparticles and VEGF rapidly formed a hydrogel in situ by di-tyrosine crosslinking. To evaluate the in vivo angiogenesis-inducing feasibility of our developed microparticle-based angiogenic molecule spatiotemporal sequential (MASS) release platform (Fig. 1A), two critical models, i.e., a full-thickness excisional wound model (Fig. 1B, left) and an MI model (Fig. 1B, right), were used.We acknowledge the financial support by the Korea Health Technology R&D Project (grant number: HI20C0090) through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare, Korea and the National Research Foundation (grant number: NRF-2020M3H4A1A03082879) funded by the Ministry of Science and ICT, Korea. Funding Information: We acknowledge the financial support by the Korea Health Technology R&D Project (grant number: HI20C0090 ) through the Korea Health Industry Development Institute funded by the Ministry of Health and Welfare , Korea and the National Research Foundation (grant number: NRF-2020M3H4A1A03082879 ) funded by the Ministry of Science and ICT , Korea. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
month = may,
doi = "10.1016/j.biomaterials.2021.120774",
language = "English",
volume = "272",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier BV",
}