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

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.

Take a deep breath and digest the material: organoids and biomaterials of the respiratory and digestive systems

“…Microporous scaffolds have been widely employed for islet transplantation, [62][63][64][67][68][69][70] primarily in rodent models, though studies have begun transplantation into non-human primates. [71,72] Reports are beginning to emerge with the transplantation of hPSC-derived immature beta cells on microporous PLGA and PLLA scaffolds, but thus far have only reported some beta cell maturation in vivo and a short rescue of normoglycemia in diabetic mice. [70,73,74] Acinar and ductal organoids…”

Clinical Islet Cell Transplantation – Recent Advances

“…The islets transplanted in the omentum showed granulated, vascularized, insulin-positive islets encompassed by T-cell subsets and macrophages. Compared to portal vein, the islets transplanted in the omentum showed delayed engraftment but similar levels of C-peptide production were eventually achieved 30,31 .…”

“…The omentum has numerous blood vessel pedicles, various lymphatic vessels, exclusive portal drainage, high vascular density and neoangiogenesis capability 27 . In rodents, enough evidence is available for better function of islets transplanted in the omentum [28][29][30] . Recently, the omental pouch has been used as islet transplantation site in diabetic cynomolgus monkey, a nonhuman primate model.…”

Islet Cell Transplantion: Update on Current Clinical Trials

“…While it has been widely presumed that the Liver is a suboptimal transplantation site, an alternative site with better engraftment and function has yet to be identified in preclinical and clinical studies. However, recent reports using the omentum[33], bone marrow[34] and an extracorporeal, oxygenated device[35] in patients are promising.…”

“…However, thus far no alternative site has conclusively shown to be superior to the liver for islet transplantation. Most recently, a minimally invasive approach to implant islets laparoscopically into an omental pouch and immobilizing them with coagulated serum has been successfully performed in a single patient[33]. Another group used the Bone marrow as an immunoprivileged site for islet transplantation[34].…”