Orientation of microvascular blood flow in pancreatic islet isografts.

Menger, Michael D.; Vajkoczy, Peter; Beger, Carmela; Meßmer, K.

doi:10.1172/jci117228

Cited by 101 publications

(79 citation statements)

References 22 publications

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“…15,17,35 A biosynthetic collagen/polyester material showed a higher FVD as compared with polytetrafluorethylene synthetic material. It should be noted that the scaffold dimensions in that study (1 ϫ 1 ϫ 1 mm) differed from the dimensions used in our study.…”

Section: Discussionmentioning

confidence: 99%

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Druecke

Langer

Lamme³

et al. 2003

J Biomedical Materials Res

169

138

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Poly(ether ester) block-copolymer scaffolds of different pore size were implanted into the dorsal skinfold chamber of balb/c mice. Using intravital fluorescent microscopy, the temporal course of neovascularization into these scaffolds was quantitatively analyzed. Three scaffold groups (diameter, 5 mm; 220 -260 thickness, m; n ϭ 30) were implanted. Different pore sizes were evaluated: small (20 -75 m), medium (75-212 m) and large pores (250 -300 m). Measurements were performed on days 8, 12, 16, and 20 in the surrounding normal tissue, in the border zone, and in the center of the scaffold. Standard microcirculatory parameters were assessed (plasma leakage, vessel diameter, red blood cell velocity, and functional vessel density). The largepored scaffolds showed significantly higher functional vessel density in the border zone and in the center (days 8 and 12) compared with the scaffold with the small and mediumsized pores. These data correlated with a larger vessel diameter and a higher red blood cell velocity in the largepored scaffold group. Interestingly, during the evaluation period the microcirculatory parameters on the edge of the scaffolds returned to values similar to those found in the surrounding tissue. In the center of the scaffold, however, neovascularization was still active 20 days after implantation. Plasma leakage and vessel diameter were higher in the center of the scaffold. Red blood cell velocity and functional vessel density were 50% lower than in the surrounding tissue. In conclusion, the dorsal skinfold chamber model in mice allows long-term study of blood vessel growth and remodeling in porous biomedical materials. The rate of vessel ingrowth into poly(ether ester) block-copolymer scaffolds is influenced by pore size and was highest in the scaffold with the largest pores. The data generated with this model contribute to knowledge about the development of functional vessels and tissue ingrowth into biomaterials.

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Section: Discussionmentioning

confidence: 99%

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Druecke

Langer

Lamme³

et al. 2003

J Biomedical Materials Res

169

138

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show abstract

“…It is noteworthy that we limited the administration of sirolimus to the first 14 days posttransplantation, based on previous findings that islet engraftment initiates as early as on day 2 posttransplantation and concludes with the reestablishment of blood flow to islets grafts within 2-3 weeks in rodent models of diabetes (9,32). Strikingly, we found that sirolimus-mediated impairment in islet graft function was irreversible, as hyperglycemia, glucose intolerance, and hyperlipidemia persisted after discontinuation of sirolimus treatment at day 15 posttransplantation.…”

Section: Discussionmentioning

confidence: 99%

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

et al. 2006

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Successful islet transplantation depends on the infusion of sufficiently large quantities of islets, but only a fraction of transplanted islets can survive and become engrafted, and yet the underlying mechanism remains unclear. In this study, we examined the effect of sirolimus, a key component of the immunosuppressive regimen in clinical islet transplantation, on islet engraftment and function. To distinguish the effect of sirolimus on immune rejection from its effect on islet engraftment, we used a syngeneic model. Diabetic mice were transplanted with 250 islets under the renal capsule, followed by treatment with sirolimus or vehicle for 14 days. Thirty days posttransplantation, islet grafts were retrieved for the determination of insulin content and vascular density. Compared with mocktreated controls, diabetic recipient mice receiving sirolimus exhibited impaired blood glucose profiles and reduced glucose-stimulated insulin secretion, correlating with reduced intragraft insulin content and decreased vascular density. Islets exposed to sirolimus for 24 h in culture displayed significantly diminished glucose-stimulated insulin release, coinciding with decreased pancreas duodenum homeobox-1 and GLUT2 expression in cultured islets. Furthermore, sirolimus-treated diabetic recipient mice, as opposed to mock-treated controls, were associated with dyslipidemia. These data suggest that sirolimus, administered in the early posttransplantation phase, is a confounding factor for reduced islet engraftment and impaired ␤-cell function in transplants. Diabetes 55:2429 -2436, 2006 T he Edmonton protocol for islet transplantation depends on the infusion of ϳ10,000 IE (islet equivalents)/kg body wt, requiring multiple cadaver pancreata per diabetic recipient (1-4). Despite the implantation of such a large quantity of islets, Ͻ30% of transplanted islets can survive the procedure and gain stable engraftment, and yet the mechanism underlying the loss of a vast majority of islet mass in the early posttransplantation phase remains elusive (4,5). Unlike whole-organ transplantation, by which grafts are implanted as vascularized tissue, islets are transplanted as single islets or islet clusters that are considered avascular following collagenase digestion and isolation. Although residual endothelial cells in isolated islets may contribute to islet revascularization (6,7), adequate intraislet blood flow requires the formation of a functional microvascular network that links engrafted islets to surrounding tissues. These data suggest that microvascular perfusion to newly transplanted islets does not resume immediately after transplantation and can take up to 2 weeks before the reestablishment of a functional microvasculature in islet grafts (8,9). This delay in islet revascularization can potentially deprive islets of oxygen and nutrients, resulting in islet cell death, particularly within the core of engrafted islets. There is mounting evidence that impaired islet revascularization is an independent factor that limits the success rate...

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“…Hence, unlike whole pancreas transplantation, islet grafts require the process of revascularization to establish adequate microvascular blood supply. 14,15 Isolated islets are reported to revascularize within 10-14 days after transplantation. 16 Vascular endothelial growth factor (VEGF) is a homodimeric protein comprised of four isoforms of 206, 189, 165 and 121 amino acids resulting from differential splicing.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-based vascular endothelial growth factor gene delivery to human pancreatic islets

et al. 2004

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Islet transplantation is limited by islet graft failure due to poor revascularization, host immune rejection and nonspecific inflammatory response. Delivery of human vascular endothelial growth factor (hVEGF) gene to the islets is likely to promote islet revascularization and survival. We used a bicistronic adenoviral vector encoding hVEGF and CpG-free allele of green fluorescent protein (Adv-GFP-hVEGF) and introduced into human pancreatic islets by transfection. We found that transfection efficiency and apoptosis were dependent on the multiplicity of infection (MOI). Compared to Adv-GFP transfected and nontransfected islets, the levels of hVEGF secreted from Adv-GFP-hVEGF transfected islets were higher and exhibit a linear relationship between hVEGF expression and MOI (10-5000). Persistent, but low level expression of hVEGF from nontransfected islets was also observed. This may be due to expression of the endogenous hVEGF gene under hypoxic conditions. The levels of DNA fragmentation determined by ELISA of islet lysates were dependent on the MOI of Adv-GFP-hVEGF. On glucose challenge, insulin release from transfected islets was comparable to nontransfected islets. Immunohistochemical staining for hVEGF was very high in Adv-GFP-hVEGF transfected islets. Weak staining was also observed for hCD31 in both transfected and nontransfected islets. These findings suggest that Adv-GFP-hVEGF is a potential candidate for promoting islet revascularization.

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Orientation of microvascular blood flow in pancreatic islet isografts.

Cited by 101 publications

References 22 publications

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Neovascularization of poly(ether ester) block‐copolymer scaffolds in vivo: Long‐term investigations using intravital fluorescent microscopy

Sirolimus Is Associated With Reduced Islet Engraftment and Impaired β-Cell Function

Adenovirus-based vascular endothelial growth factor gene delivery to human pancreatic islets

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