Effect of prevascularization on in vivo vascularization of poly(propylene fumarate)/fibrin scaffolds

Mishra, Ruchi; Roux, Brianna M.; Posukonis, Megan; Bodamer, Emily; Brey, Eric M.; Fisher, John P.; Dean, David

doi:10.1016/j.biomaterials.2015.10.026

Cited by 79 publications

(73 citation statements)

References 56 publications

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“…Proper tissue function requires a cell to be located within 150-200 μm of the nearest capillary [1] and it is without surprise therefore that most tissue engineering approaches rely on the presence of a functional vascular network [2-4]. The use of biomaterials in tissue engineering have focused on two major strategies: as a tool to control and prolong the release of angiogenic factors [5-7], or alternatively as a scaffold to enhance the growth of vascular cells supplied [3, 4, 8, 9]. …”

Section: Introductionmentioning

confidence: 99%

“…Such impaired vascular regeneration is implicated in highly prevalent diseases including stroke, liver cirrhosis, muscle atrophy, Alzheimer's disease as well as cardiac and kidney failure. The potential to use biomaterials to enhance vascularization of ischemic tissues [11, 34, 35], as well as for vascular tissue engineering applications [2, 4, 11] hold great promise. However, it should be noted that not all vascular beds respond similarly to angiogenic factors.…”

Section: Introductionmentioning

confidence: 99%

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Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury

et al. 2017

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Loss of the microvascular (MV) network results in tissue ischemia, loss of tissue function, and is a hallmark of chronic diseases. The incorporation of a functional vascular network with that of the host remains a challenge to utilizing engineered tissues in clinically relevant therapies. We showed that vascular-bed-specific endothelial cells (ECs) exhibit differing angiogenic capacities, with kidney microvascular endothelial cells (MVECs) being the most deficient, and sought to explore the underlying mechanism. Constitutive activation of the phosphatase PTEN in kidney MVECs resulted in impaired PI3K/AKT activity in response to vascular endothelial growth factor (VEGF). Suppression of PTEN in vivo resulted in microvascular regeneration, but was insufficient to improve tissue function. Promoter analysis of the differentially regulated genes in KMVECs suggests that the transcription factor FOXO1 is highly active and RNAseq analysis revealed that hyperactive FOXO1 inhibits VEGF-Notch-dependent tip-cell formation by direct and indirect inhibition of DLL4 expression in response to VEGF. Inhibition of FOXO1 enhanced angiogenesis in human bio-engineered capillaries, and resulted in microvascular regeneration and improved function in mouse models of injury-repair.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury

et al. 2017

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“…6,12–18 The most impressive of these studies demonstrate that implantation of pre-cultured human microvessels in immune-compromised mice can result in inosculation with the host vasculature and perfusion of the human microvessels. 13,14,17 However, these studies were carried out in the healthy subcutaneous environment, and no study has implanted pre-cultured human microvessels in the especially challenging myocardial infarct environment. With the ultimate goal of treating myocardial infarctions and heart disease with a perfusable, beating cardiac patch containing both microvessels and cardiomyocytes, the only fair way to assess the vascularization potential of a precursor patch containing only microvessels would be to implant it at the site of a myocardial infarction.…”

Section: Introductionmentioning

confidence: 99%

Inosculation and perfusion of pre-vascularized tissue patches containing aligned human microvessels after myocardial infarction

et al. 2016

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A major goal of tissue engineering is the creation of pre-vascularized tissues that have a high density of organized microvessels that can be rapidly perfused following implantation. This is especially critical for highly metabolic tissues like myocardium, where a thick myocardial engineered tissue would require rapid perfusion within the first several days to survive transplantation. In the present work, tissue patches containing human microvessels that were either randomly oriented or aligned were placed acutely on rat hearts post-infarction and for each case it was determined whether rapid inosculation could occur and perfusion of the patch could be maintained for 6 days in an infarct environment. Patches containing self-assembled microvessels were formed by co-entrapment of human blood outgrowth endothelial cells and human pericytes in fibrin gel. Cell-induced gel contraction was mechanically-constrained resulting in samples with high densities of microvessels that were either randomly oriented (with 420±140 lumens/mm2) or uniaxially aligned (with 940±240 lumens/mm2) at the time of implantation. These patches were sutured onto the epicardial surface of the hearts of athymic rats following permanent ligation of the left anterior descending artery. In both aligned and randomly oriented microvessel patches, inosculation occurred and perfusion of the transplanted human microvessels was maintained, proving the in vivo vascularization potential of these engineered tissues. No difference was found in the number of human microvessels that were perfused in the randomly oriented (111±75 perfused lumens/mm2) and aligned (173±97 perfused lumens/mm2) patches. Our results demonstrate that tissue patches containing a high density of either aligned or randomly oriented human pre-formed microvessels achieve rapid perfusion in the myocardial infarct environment - a necessary first-step toward the creation of a thick, perfusable heart patch.

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“…The two cell types studied here, HUVECs and MSCs, are widely used as model cells in the evaluation of biomaterials and tissue engineering products . Results of the DNA comet assays indicate that PLGA concentrations of 2 and 6 mg/mL induce DNA damage in both types of cells when exposed for 4 days or more.…”

Section: Discussionmentioning

confidence: 89%

“…The two cell types studied here, HUVECs and MSCs, are widely used as model cells in the evaluation of biomaterials and tissue engineering products. 26,27 Results of the DNA comet assays indicate that PLGA concentrations of 2 and 6 mg/mL induce DNA damage in both types of cells when exposed for 4 days or more. PLGA degradation requires a time period of 1-5 weeks; 15 it appears that after 4 days the levels of degradation products are high enough to induce damage.…”

Section: Genotoxicitymentioning

confidence: 99%

Investigation of DNA damage in cells exposed to poly (lactic‐co‐glycolic acid) microspheres

Živković

Akar

Roux

et al. 2016

J Biomedical Materials Res

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Poly (lactic-co-glycolic acid) (PLGA)-based materials are widely investigated for drug delivery and tissue engineering applications. Despite their popularity the genotoxic potential of PLGA has not been investigated. In this study, the comet assay, a sensitive assay for DNA damage, was used to evaluate potential genotoxicity in model cell types exposed to PLGA microspheres. Human umbilical vein endothelial cells (HUVECs) and mesenchymal stem cells (MSCs) cells were exposed to PLGA microspheres (0.4-6 mg/mL) and DNA damage assessed at 24 h, 4 days, and 7 days. DNA damage was not identified after 24 h. However, after 4 and 7 days of exposure to 2 and 6 mg/mL of PLGA microspheres a significant elevation of DNA damage in both cell types was observed. The PLGA microspheres did not exhibit any cytotoxic effects on the cells under the conditions tested. Our results suggest that PLGA may have a genotoxic effect on cells. A broader investigation of the PLGA genotoxic profile in biological systems is needed. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 284-291, 2017.

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Effect of prevascularization on in vivo vascularization of poly(propylene fumarate)/fibrin scaffolds

Cited by 79 publications

References 56 publications

Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury

Hyperactive FOXO1 results in lack of tip stalk identity and deficient microvascular regeneration during kidney injury

Inosculation and perfusion of pre-vascularized tissue patches containing aligned human microvessels after myocardial infarction

Investigation of DNA damage in cells exposed to poly (lactic‐co‐glycolic acid) microspheres

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