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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Comparable function of intrahepatic and intraomental islets transplanted into biologic scaffolds. Nonfasting blood glucose levels in diabetic rats receiving a clinically relevant syngeneic islet mass of 1,300 IEQ (∼8,200 IEQ/kg body wt) within an intraomental biologic scaffold (A) (●, n = 7) or into the liver (via the portal vein) (B) (○, n = 5) with islets from the same batch isolation. The groups had an identical time course for reversal of diabetes, and removal of the intraomental biologic scaffold on day 80 posttransplant resulted in return to hyperglycemia (arrowhead in A). Glycemic profile during OGTT performed in all transplanted animals 5 (C) or 11 weeks (D) after transplantation. Inset shows AUC (mg × min × dL−1) during the glucose challenge for each group. wks, weeks.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC5384628&req=5

Figure 4: Comparable function of intrahepatic and intraomental islets transplanted into biologic scaffolds. Nonfasting blood glucose levels in diabetic rats receiving a clinically relevant syngeneic islet mass of 1,300 IEQ (∼8,200 IEQ/kg body wt) within an intraomental biologic scaffold (A) (●, n = 7) or into the liver (via the portal vein) (B) (○, n = 5) with islets from the same batch isolation. The groups had an identical time course for reversal of diabetes, and removal of the intraomental biologic scaffold on day 80 posttransplant resulted in return to hyperglycemia (arrowhead in A). Glycemic profile during OGTT performed in all transplanted animals 5 (C) or 11 weeks (D) after transplantation. Inset shows AUC (mg × min × dL−1) during the glucose challenge for each group. wks, weeks.

Mentions: We compared the performance of syngeneic islets implanted within the intraomental biologic scaffold to that of intrahepatic grafts. Aliquots of 1,300 IEQ (∼8,200 IEQ/kg body wt [a “clinically relevant” mass]) from the same batch of islets were transplanted in parallel either within an intraomental biologic scaffold (n = 7; 160.3 ± 6.4 g body wt [8,122 ± 334 IEQ/kg]) (Fig. 4A) or in the intrahepatic site (n = 5; 155.4 ± 7.3 g body wt [8,380 ± 396 IEQ/kg]) (Fig. 4B). All recipients in both groups achieved euglycemia within 1 week and maintained good metabolic control during the 82-day (∼12 weeks) follow-up period. Omental graft removal resulted in a prompt return to hyperglycemia (n = 4) (Fig. 4A). At 5 (Fig. 4C) and 11 weeks posttransplant (Fig. 4D), OGTT showed comparable metabolic function in both transplant sites (AUC at 5 weeks, 18,393 ± 571 and 18,036 ± 598.5 mg × min × dL−1, and AUC at 11 weeks, 21,987 ± 2,580 and 21,149 ± 1,456 mg × min × dL−1, for intraomental biologic scaffold recipients or intrahepatic islet recipients, respectively) (Fig. 4C and D).


Bioengineering the Endocrine Pancreas: Intraomental Islet Transplantation Within a Biologic Resorbable Scaffold
Comparable function of intrahepatic and intraomental islets transplanted into biologic scaffolds. Nonfasting blood glucose levels in diabetic rats receiving a clinically relevant syngeneic islet mass of 1,300 IEQ (∼8,200 IEQ/kg body wt) within an intraomental biologic scaffold (A) (●, n = 7) or into the liver (via the portal vein) (B) (○, n = 5) with islets from the same batch isolation. The groups had an identical time course for reversal of diabetes, and removal of the intraomental biologic scaffold on day 80 posttransplant resulted in return to hyperglycemia (arrowhead in A). Glycemic profile during OGTT performed in all transplanted animals 5 (C) or 11 weeks (D) after transplantation. Inset shows AUC (mg × min × dL−1) during the glucose challenge for each group. wks, weeks.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5384628&req=5

Figure 4: Comparable function of intrahepatic and intraomental islets transplanted into biologic scaffolds. Nonfasting blood glucose levels in diabetic rats receiving a clinically relevant syngeneic islet mass of 1,300 IEQ (∼8,200 IEQ/kg body wt) within an intraomental biologic scaffold (A) (●, n = 7) or into the liver (via the portal vein) (B) (○, n = 5) with islets from the same batch isolation. The groups had an identical time course for reversal of diabetes, and removal of the intraomental biologic scaffold on day 80 posttransplant resulted in return to hyperglycemia (arrowhead in A). Glycemic profile during OGTT performed in all transplanted animals 5 (C) or 11 weeks (D) after transplantation. Inset shows AUC (mg × min × dL−1) during the glucose challenge for each group. wks, weeks.
Mentions: We compared the performance of syngeneic islets implanted within the intraomental biologic scaffold to that of intrahepatic grafts. Aliquots of 1,300 IEQ (∼8,200 IEQ/kg body wt [a “clinically relevant” mass]) from the same batch of islets were transplanted in parallel either within an intraomental biologic scaffold (n = 7; 160.3 ± 6.4 g body wt [8,122 ± 334 IEQ/kg]) (Fig. 4A) or in the intrahepatic site (n = 5; 155.4 ± 7.3 g body wt [8,380 ± 396 IEQ/kg]) (Fig. 4B). All recipients in both groups achieved euglycemia within 1 week and maintained good metabolic control during the 82-day (∼12 weeks) follow-up period. Omental graft removal resulted in a prompt return to hyperglycemia (n = 4) (Fig. 4A). At 5 (Fig. 4C) and 11 weeks posttransplant (Fig. 4D), OGTT showed comparable metabolic function in both transplant sites (AUC at 5 weeks, 18,393 ± 571 and 18,036 ± 598.5 mg × min × dL−1, and AUC at 11 weeks, 21,987 ± 2,580 and 21,149 ± 1,456 mg × min × dL−1, for intraomental biologic scaffold recipients or intrahepatic islet recipients, respectively) (Fig. 4C and D).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus