Exploring Insulin Production Following Alveolar Islet Transplantation (AIT).

Recent studies have demonstrated the feasibility of islet implantation into the alveoli. However, until today, there are no data on islet behavior and morphology at their transplant site. This study is the first to investigate islet distribution as well insulin production at the implant site. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized into the lung using an endoscopic spray-catheter. Lung tissue was explanted and bronchial airways were surgically isolated and connected to a perfusor. Correct implantation was confirmed via histology. The purpose of using this new lung perfusion model was to measure static as well as dynamic insulin excretions following glucose stimulation. Alveolar islet implantation was confirmed after aerosolization. Over 82% of islets were correctly implanted into the intra-alveolar space. The medium contact area to the alveolar surface was estimated at 60 +/- 3% of the total islet surface. The new constructed lung perfusion model was technically feasible. Following static glucose stimulation, insulin secretion was detected, and dynamic glucose stimulation revealed a biphasic insulin secretion capacity during perfusion. Our data indicate that islets secrete insulin following implantation into the alveoli and display an adapted response to dynamic changes in glucose. These preliminary results are encouraging and mark a first step toward endoscopically assisted islet implantation in the lung.

Islet Transplantation in the Lung via Endoscopic Aerosolization: Investigation of Feasibility, Islet Cluster Cell Vitality, and Structural Integrity.

Aerosolized drug delivery has recently attracted much attention as a possible new tool for the delivery of complex nanoparticles. This study aims to investigate whether catheter-based aerosolization of islets via endobronchial systems is a feasible option in islet transplantation. Besides investigating the feasibility of islet aerosolization, we also examined cluster cell vitality and structural integrity of the islets following aerosolization. Using an ex vivo postmortem swine model, porcine pancreatic islets were isolated and aerosolized with an endoscopic spray catheter. Following aerosolization, islet cell vitality and function were assessed via Calcein AM and propidium iodide as well as insulin production after glucose exposure. In the final step, the overall feasibility of the procedure and structural integrity of cells were analyzed and evaluated with respect to clinical applicability. No significant difference was detected in the viability of control islets (90.67 ± 2.19) vs aerosolized islets (90.68 ± 1.20). Similarly, there was no significant difference in control islets (1.62 ± 0.086) vs aerosolized islets (1.42 ± 0.11) regarding insulin release after stimulation. Indocyanine green marked islets were transplanted into the lung without major difficulty. Histological analysis confirmed retained structural integrity and predominant location in the alveolar cavity. Our ex vivo data suggest that catheter-based aerosolized islet cell delivery is a promising tool for the application of cell clusters. According to our data, islet cell clusters delivery is feasible from a mechanical and physical perspective. Moreover, cell vitality and structural integrity remain largely unaffected following aerosolization. These preliminary results are encouraging and represent a first step toward endoscopically assisted islet cell implantation in the lung.

Approaches in Immunotherapy, Regenerative Medicine, and Bioengineering for Type 1 Diabetes.

Recent advances on using immune and stem cells as two-pronged approaches for type 1 diabetes mellitus (T1DM) treatment show promise for advancement into clinical practice. As T1DM is thought to arise from autoimmune attack destroying pancreatic ß-cells, increasing treatments that use biologics and cells to manipulate the immune system are achieving better results in pre-clinical and clinical studies. Increasingly, focus has shifted from small molecule drugs that suppress the immune system nonspecifically to more complex biologics that show enhanced efficacy due to their selectivity for specific types of immune cells. Approaches that seek to inhibit only autoreactive effector T cells or enhance the suppressive regulatory T cell subset are showing remarkable promise. These modern immune interventions are also enabling the transplantation of pancreatic islets or ß-like cells derived from stem cells. While complete immune tolerance and body acceptance of grafted islets and cells is still challenging, bioengineering approaches that shield the implanted cells are also advancing. Integrating immunotherapy, stem cell-mediated ß-cell or islet production and bioengineering to interface with the patient is expected to lead to a durable cure or pave the way for a clinical solution for T1DM.