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Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold

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ABSTRACT

Transplantation of pancreatic islets is a therapeutic option to preserve or restore β-cell function. Our study was aimed at developing a clinically applicable protocol for extrahepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ–generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and nonhuman primate (NHP) models. Intraomental islet engraftment in the biologic scaffold was confirmed by achievement of improved metabolic function and preservation of islet cytoarchitecture, with reconstitution of rich intrainsular vascular networks in both species. Long-term nonfasting normoglycemia and adequate glucose clearance (tolerance tests) were achieved in both intrahepatic and intraomental sites in rats. Intraomental graft recipients displayed lower levels of serum biomarkers of islet distress (e.g., acute serum insulin) and inflammation (e.g., leptin and α2-macroglobulin). Importantly, low-purity (30:70% endocrine:exocrine) syngeneic rat islet preparations displayed function equivalent to that of pure (>95% endocrine) preparations after intraomental biologic scaffold implantation. Moreover, the biologic scaffold sustained allogeneic islet engraftment in immunosuppressed recipients. Collectively, our feasibility/efficacy data, along with the simplicity of the procedure and the safety of the biologic scaffold components, represented sufficient preclinical testing to proceed to a pilot phase I/II clinical trial.

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Biomarkers detected in the serum of rat recipients of intraomental biologic scaffold and intrahepatic syngeneic islets. Aliquots of 1,300 IEQ from the same syngeneic donor rat islet batch were transplanted in parallel either within the intraomental biologic scaffold (omentum [○]) or the intrahepatic site (liver [●]). Blood samples were collected from indwelling JVC for detection of biomarker levels in circulation. Data presented are mean ± SEM (n = 4–7 per time point). A and B: Metabolic markers assessed at 1 h posttransplant. A: Insulin in μg/mL (*P = 0.018). B: C-peptide in μg/mL. Inflammation markers assessed 24 h posttransplant: MCP-1/CCL2 in pg/mL (C), IL-6 in pg/mL (D), leptin in pg/mL (*P = 0.013) (E), haptoglobin in μg/mL (F), and α2-macroglobulin in μg/mL (**P < 0.03) (G).
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Figure 5: Biomarkers detected in the serum of rat recipients of intraomental biologic scaffold and intrahepatic syngeneic islets. Aliquots of 1,300 IEQ from the same syngeneic donor rat islet batch were transplanted in parallel either within the intraomental biologic scaffold (omentum [○]) or the intrahepatic site (liver [●]). Blood samples were collected from indwelling JVC for detection of biomarker levels in circulation. Data presented are mean ± SEM (n = 4–7 per time point). A and B: Metabolic markers assessed at 1 h posttransplant. A: Insulin in μg/mL (*P = 0.018). B: C-peptide in μg/mL. Inflammation markers assessed 24 h posttransplant: MCP-1/CCL2 in pg/mL (C), IL-6 in pg/mL (D), leptin in pg/mL (*P = 0.013) (E), haptoglobin in μg/mL (F), and α2-macroglobulin in μg/mL (**P < 0.03) (G).

Mentions: Selected biomarkers associated with islet distress and inflammation elicited by the transplantation procedure were evaluated. Blood samples were collected from JVC at different time points after transplantation. A spike in insulin and C-peptide levels, likely a result of insulin dumping from distressed islet cells (5,37,38), was observed 1 h posttransplant in both experimental groups. The insulin peak was significantly higher in the intrahepatic compared with the intraomental group (2.841 ± 0.338 vs. 1.405 ± 0.352 μg/mL, respectively; P = 0.018) (Fig. 5A), with comparable levels in both groups at subsequent time points (data not shown). No statistically significant differences were observed in C-peptide levels (2.565 ± 0.25 vs. 2.941 ± 0.303 μg/mL, respectively) (Fig. 5B).


Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold
Biomarkers detected in the serum of rat recipients of intraomental biologic scaffold and intrahepatic syngeneic islets. Aliquots of 1,300 IEQ from the same syngeneic donor rat islet batch were transplanted in parallel either within the intraomental biologic scaffold (omentum [○]) or the intrahepatic site (liver [●]). Blood samples were collected from indwelling JVC for detection of biomarker levels in circulation. Data presented are mean ± SEM (n = 4–7 per time point). A and B: Metabolic markers assessed at 1 h posttransplant. A: Insulin in μg/mL (*P = 0.018). B: C-peptide in μg/mL. Inflammation markers assessed 24 h posttransplant: MCP-1/CCL2 in pg/mL (C), IL-6 in pg/mL (D), leptin in pg/mL (*P = 0.013) (E), haptoglobin in μg/mL (F), and α2-macroglobulin in μg/mL (**P < 0.03) (G).
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Figure 5: Biomarkers detected in the serum of rat recipients of intraomental biologic scaffold and intrahepatic syngeneic islets. Aliquots of 1,300 IEQ from the same syngeneic donor rat islet batch were transplanted in parallel either within the intraomental biologic scaffold (omentum [○]) or the intrahepatic site (liver [●]). Blood samples were collected from indwelling JVC for detection of biomarker levels in circulation. Data presented are mean ± SEM (n = 4–7 per time point). A and B: Metabolic markers assessed at 1 h posttransplant. A: Insulin in μg/mL (*P = 0.018). B: C-peptide in μg/mL. Inflammation markers assessed 24 h posttransplant: MCP-1/CCL2 in pg/mL (C), IL-6 in pg/mL (D), leptin in pg/mL (*P = 0.013) (E), haptoglobin in μg/mL (F), and α2-macroglobulin in μg/mL (**P < 0.03) (G).
Mentions: Selected biomarkers associated with islet distress and inflammation elicited by the transplantation procedure were evaluated. Blood samples were collected from JVC at different time points after transplantation. A spike in insulin and C-peptide levels, likely a result of insulin dumping from distressed islet cells (5,37,38), was observed 1 h posttransplant in both experimental groups. The insulin peak was significantly higher in the intrahepatic compared with the intraomental group (2.841 ± 0.338 vs. 1.405 ± 0.352 μg/mL, respectively; P = 0.018) (Fig. 5A), with comparable levels in both groups at subsequent time points (data not shown). No statistically significant differences were observed in C-peptide levels (2.565 ± 0.25 vs. 2.941 ± 0.303 μg/mL, respectively) (Fig. 5B).

View Article: PubMed Central - PubMed

ABSTRACT

Transplantation of pancreatic islets is a therapeutic option to preserve or restore &beta;-cell function. Our study was aimed at developing a clinically applicable protocol for extrahepatic transplantation of pancreatic islets. The potency of islets implanted onto the omentum, using an in situ&ndash;generated adherent, resorbable plasma-thrombin biologic scaffold, was evaluated in diabetic rat and nonhuman primate (NHP) models. Intraomental islet engraftment in the biologic scaffold was confirmed by achievement of improved metabolic function and preservation of islet cytoarchitecture, with reconstitution of rich intrainsular vascular networks in both species. Long-term nonfasting normoglycemia and adequate glucose clearance (tolerance tests) were achieved in both intrahepatic and intraomental sites in rats. Intraomental graft recipients displayed lower levels of serum biomarkers of islet distress (e.g., acute serum insulin) and inflammation (e.g., leptin and &alpha;2-macroglobulin). Importantly, low-purity (30:70% endocrine:exocrine) syngeneic rat islet preparations displayed function equivalent to that of pure (&gt;95% endocrine) preparations after intraomental biologic scaffold implantation. Moreover, the biologic scaffold sustained allogeneic islet engraftment in immunosuppressed recipients. Collectively, our feasibility/efficacy data, along with the simplicity of the procedure and the safety of the biologic scaffold components, represented sufficient preclinical testing to proceed to a pilot phase I/II clinical trial.

No MeSH data available.


Related in: MedlinePlus