TY - JOUR
T1 - Prolonging Endothelial Cell Survival with Thermoresponsive Peptide-Functionalized Hydrogels Improves Ischemic Limb Tissue Regeneration and Function
AU - Wang, Huifeng
AU - Dang, Caitlyn
AU - Rivera-Bolanos, Nancy
AU - Tong, Ophelia
AU - Wang, Xinlong
AU - Chen, Guo
AU - Riter, Rebecca L.
AU - Chin, Yuan-Ho
AU - Duan, Chongwen
AU - Zhang, Xiaomin
AU - Haney, Chad R.
AU - Ameer, Guillermo
AU - Jiang, Bin
PY - 2024/10/23
Y1 - 2024/10/23
N2 - Abstract Critical limb ischemia (CLI) presents a significant clinical challenge, leading to tissue ischemia and potentially resulting in limb necrosis or amputation. Cell-based regenerative therapies offer promise for improving outcomes in CLI, but their effectiveness is often limited by poor cell survival and engraftment. This study hypothesized that a thermo-responsive polymer, poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN), combined with pro-survival bioactive peptides, can create a protective microenvironment to improve endothelial cell survival and function after their delivery. Through in vitro and in vivo experiments, laminin-derived peptide A5G81 and vascular endothelial growth factor (VEGF)-derived peptide QK are identified as effective in promoting endothelial cell spreading, proliferation, and prolonged survival. PPCN's viscoelastic properties protected against shear stress during injection, while the peptides supported endothelial cell behavior through distinct molecular pathways. Importantly, delivery of endothelial cells with PPCN-A5G81 and PPCN-QK in a murine hindlimb ischemia model resulted in significant improvements in limb perfusion, tissue preservation, and functional outcomes compared to controls. Additionally, this approach enhanced skeletal muscle remodeling following ischemic injury. This innovative biomaterial platform represents a versatile solution for addressing cell survival challenges and advancing regenerative therapies in CLI and other ischemic conditions.
AB - Abstract Critical limb ischemia (CLI) presents a significant clinical challenge, leading to tissue ischemia and potentially resulting in limb necrosis or amputation. Cell-based regenerative therapies offer promise for improving outcomes in CLI, but their effectiveness is often limited by poor cell survival and engraftment. This study hypothesized that a thermo-responsive polymer, poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN), combined with pro-survival bioactive peptides, can create a protective microenvironment to improve endothelial cell survival and function after their delivery. Through in vitro and in vivo experiments, laminin-derived peptide A5G81 and vascular endothelial growth factor (VEGF)-derived peptide QK are identified as effective in promoting endothelial cell spreading, proliferation, and prolonged survival. PPCN's viscoelastic properties protected against shear stress during injection, while the peptides supported endothelial cell behavior through distinct molecular pathways. Importantly, delivery of endothelial cells with PPCN-A5G81 and PPCN-QK in a murine hindlimb ischemia model resulted in significant improvements in limb perfusion, tissue preservation, and functional outcomes compared to controls. Additionally, this approach enhanced skeletal muscle remodeling following ischemic injury. This innovative biomaterial platform represents a versatile solution for addressing cell survival challenges and advancing regenerative therapies in CLI and other ischemic conditions.
KW - bioactive peptide
KW - cell-based therapies
KW - citrate-based hydrogel
KW - critical limb ischemia
KW - endothelial cells
KW - tissue regeneration
U2 - 10.1002/adfm.202416553
DO - 10.1002/adfm.202416553
M3 - Article
SN - 1616-301X
VL - 35
JO - Advanced Functional Materials
JF - Advanced Functional Materials
IS - 10
ER -