Angiogenesis Promotion by Combined Administration of DFO and Vein Endothelial Cells Using Injectable, Biodegradable, Nanocomposite Hydrogel Scaffolds

Abstract

Desferrioxamine (DFO) upregulates HIF-1α and stimulates expression of vascular endothelial growth factor (VEGF), thereby accelerating neovascularization. As DFO acts primarily upon surrounding vein endothelial cells to stimulate angiogenesis, the angiogenic efficacy of DFO could be reduced in severely injured tissues lacking a sufficient number of vein endothelial cells. We hypothesized that combined administration of DFO and vein endothelial cells is a promising tissue engineering approach for promoting neovascularization. In this study, we evaluated the applicability of this approach using injectable, biocompatible, biodegradable nanocomposite gels consisting of poly­(d l-lactide-co-glycolide)-b-polyethylene glycol-b-poly­(d l-lactide-co-glycolide) (PLGA-PEG-PLGA) copolymers and clay nanoparticle LAPONITE. The nanocomposites exhibited irreversible thermo-gelation in the presence of DFO, and the mechanical strength was strongly affected by the amount of DFO. The storage moduli of the gels increased with increasing amount of DFO. These results indicate that the interaction between DFO and LAPONITE works as physical cross-linking points and facilitates the formation of the gel network. The nanocomposite gels achieved sustained slow release of DFO due to interactions between DFO and LAPONITE. Human umbilical vein endothelial cells (HUVECs) cultured on DFO-loaded nanocomposite gels exhibited a higher degree of vascular tube formation than cells cultured on nanocomposite gels without DFO. Moreover, the number of branching points and the diameter of the blood vessels regenerated in the gels significantly increased with increasing DFO amount, indicating that DFO released from the gels facilitates vascular tube-forming capacity. As a proof of concept, we demonstrate that the combined administration of DFO and vein endothelial cells using nanocomposite gels promotes greater angiogenesis than DFO administration alone using the same gels by in vivo experiments, confirming the validity of our hypothesis. Considering the multiple advantages of nanocomposite gels with regard to potential vascularization capacity, certain biocompatibility, biodegradability, and injectable cell- and drug-delivery capacity, we concluded that the nanocomposite gels have potential utility as scaffolding biomaterials for vascularization in tissue engineering applications.

Remodeling the hepatic fibrotic microenvironment with emerging nanotherapeutics: a comprehensive review

“…Anionic HA-containing NPs LSECs, Tregs Suppressing antigen-specific immune responses [29] AB diblock copolymers NPs LSECs, KCs Leading to immune inflammation [33] Stab2-containing NPs LSECs, Tregs Clearing of lipoproteins [30] Mannose-modified albumin NPs Macrophages TGFβ-siRNA to CD206 + as an anti-fibrotic strategy [37] CMC-containing NPs Macrophages Reducing host immune response [40] PS-containing NPs Macrophages Reducing collagen fiber deposition [42] silk or silicon-containing NPs Macrophages Pro-inflammatory phenotype [69] hydrogel particles M2-polarized macrophages Improving immunocompromised and impaired angiogenesis [108,109] DEX/HA-TK-ART PMs M2-polarized macrophages HIF-1α/NF-κB signaling cascade [90] mLNP-siHMGB1 Macrophages, HSCs Inhibiting the activation of HSCs [38] DSPE-PEG-CeO2 NPs Macrophages, HSCs Reducing inflammation [86] CNF HSCs, macrophages Increasing glycolysis and reprogramming and reducing initiated inflammatory [70] VA-SLNs HSCs Reducing PPARγ/SREBPs-mediated lipid accumulation [61] CS sulfate PMs HSCs Anti-fibrotic strategy [63] CS-coated green silver NPs HSCs Bounding to the fibrogenic protein TGF-β [65] hydrogels HSCs Blocking the TGF-β1/Smad pathway [66] RGD HSCs Inhibiting the proliferation of HSCs [82] Chol-PCX/miRNA NPs HSCs, T cells Disrupting the lipid metabolic network [73,74] GQD HSCs Inhibiting lipid peroxidation, apoptosis, and autophagy [87] CeO2 NPs HSCs Antioxidant effect [85] FPL HSCs Antioxidant effect [88] ChiBil carrying losartan HSCs attenuating iron death [89] PEG-PLGA-containing NPs LSECs, hepatocytes and HSCs Constricting abnormal blood vessels, reducing MVD [99] Self-assembled PMs LSECs, hepatocytes and HSCs Avoiding the hepatotoxicity and side effects [96] NPs laponite HUVECs enhancing HIF-1α and VEGF expression, accelerating neovascularization [110] and mannose receptors (MR) that produce inhibitory acquired immune responses. LSECs regulate adaptive immune responses directly by presenting antigens to T cells and also regulate natural killer T cells (NKT cells) by expressing CXCL16, and the cell surface ligand for CXCR6…”

Advances in Biodegradable Soft Robots

“…However, PEGDA degrades slowly in vivo, so it is not suitable for long-term implantable applications [ 81 ]. Lately, PEG- or PEGDA-based soft robots have been extensively utilized as biodegradable microrobots [ 82 , 97 , 98 ], as micro-swimmers [ 82 , 99 ] for targeted therapeutic healthcare applications and tissue engineering [ 80 ].…”

“…Another scaffold loaded with stem cells and drugs is shown in Figure 6 C [ 80 ]. Specifically, desferrioxamine (DFO) and human umbilical vein endothelial cells (HUVECs) were combined with biodegradable poly(DL-lactide-co-glycolide)-b-polyethylene glycol-b-poly(DL-lactide-co-glycolide) (PLGA-PEG-PLGA) to create smart scaffolds to promote vascularization in in vivo tissue engineering applications [ 80 ].…”

“…Another scaffold loaded with stem cells and drugs is shown in Figure 6 C [ 80 ]. Specifically, desferrioxamine (DFO) and human umbilical vein endothelial cells (HUVECs) were combined with biodegradable poly(DL-lactide-co-glycolide)-b-polyethylene glycol-b-poly(DL-lactide-co-glycolide) (PLGA-PEG-PLGA) to create smart scaffolds to promote vascularization in in vivo tissue engineering applications [ 80 ]. Additionally, Figure 6 D describes another human umbilical arterial smooth muscle cells (vSMCs)-loaded, biodegradable, hydrogel-based scaffold, which can be utilized to effectively repair tissue defects via tissue engineering [ 153 ].…”

“…( C ) Representative CLSM images of DFO (0.1%) and HUVEC (5 × 10 5 , 1 × 10 6 , and 3 × 10 6 )-laden P5L1.1 gels (nanocomposite gels containing 5.0% ( w / v ) PLGA-PEG-PLGA and 1.1% ( w / v ) laponite), formed in the subcutaneous tissue of mice. Reproduced with permission [ 80 ]. Copyright 2022, The American Chemical Society.…”