Objective
Based on our previous published work, the main goal of Bio-ACT proposal is to bioengineer an ex vivo Vascularized Islet Organ (Bio-VIO) in a concept ready for future clinical translation that recapitulates integrated human vascular and endocrine compartments. Additional objectives of the study are the assessment of Bio-VIOs function in an preclinical model (small and large) of diabetes. The demonstration that Bio-VIO may be successful as an ex vivo and an in vivo new technology for the treatment of T1D, holds the potential to revolutionize the field and deliver the technology in future clinical translation.
Background Rationale
Islet transplantation for patient affected by severe T1D is able to temporary restore insulin independence. This is caused by several complications including the initial difficulty of transplanted islet to engraft, which dramatically reduces their number, eventually destroyed by inflammatory and immunological events. Here, we decide to overcome those limitations proposing an alternative strategy based on organ decellularization-recellularization technology adopting human endocrine cell. Organ decellularization enables to obtain acellular organ scaffold only composed by extracellular matrix. Decellularized products preserve the empty organ structure, vascular architecture and spatial hierarchical organization. We select the decellularized pig lung left lobe as scaffold because of constituted by millions of independent units (alveoli) connected by an extensive capillary network. This organ structure mimics the pancreatic endocrine niche structure. Due to this similarity, in the Bio-ACT project, we plan to bioengineer, in a design close to clinical setting, the first ex vivo Vascularized Islet Organ (Bio-VIO) based on decellularized lung left lobe as scaffold seeded with human endothelial cells and pancreatic islet (HI). In this scenario, thanks to our customized bioreactor, we will seed endothelial and HI in the scaffold structure allowing the integration of functional islet in the organ within seven days of culture. This engineering process will be used to generate a new class of engineered bio-artificial endocrine organ for the treatment of T1D. In this context, prior implantation, we will i) evaluate ex vivo islet engraftment and ii) test Bio-VIO function and the ability of islet to survive in a transplant setting closed to clinical application. This ex vivo multistep process will confirm the Bio-VIOs readiness for clinical translation.
Description of Project
In patient affected by Type 1 Diabetes (T1D) the body become unable to produce insulin, the hormone secreted by pancreatic islet, that helps to turn glucose into energy. This is caused by an immune system dysfunction that, for a still unknown reason, reacts and destroys the pancreatic cells devoted to the insulin production. As of now, exogenous insulin administration is an available therapeutic option able to restore the normal glucose levels in most of the affected patients. In case of severe and frequent hypoglycemic conditions, islet transplantation is a valid option to replace the pancreatic cells able to sense the glucose body concentration. Actually, we are not able to replace donor islet in their original pancreatic environment for surgical limitations. Islet for transplantation are firstly isolated from the pancreas of organ donor and, once purified, transplanted in a heterotopic site: the liver. This procedure, known as intrahepatic islet transplantation, represents the gold standard for brittle T1D and is a valuable treatment option and pioneer application for cell therapy but limits linked to the procedure and limited source of endocrine cells are still present and do not permit to extend this application for all T1D patients. Indeed, transplantation of islet requires their disassociation from the original pancreatic environment, which is composed by a special matrix, the so-called extracellular matrix, and a dense capillary network. Once in the liver, islet have to engraft in a non-self-tissue and need to regenerate the original vascular network. This process takes time and makes islet vulnerable to several process (i.e. surgical damage and inflammation) leading the loss of more than 50-75% of the overall transplanted islets. To overcome this limitation, the goal of BIO-ACT study is to generate a new technology, set up in a version close to clinical application, named Bioengineering of a Vascularized Islet Organ (Bio-VIO), which would facilitate and improves the outcome of the transplantation. Bio-VIOs will be based on a pulmonary-derived scaffold deprived of its original cells and repopulated with human endocrine cells prior implantation. The Bio-VIO will be cultured in laboratory in a customized bioreactor to allow endocrine organ function maturation. The Bio-VIO prototype will be: 1) tested in laboratory to evaluate the function and 2) implanted to test its ability to cure diabetes small and large preclinical models. We expect that the ex vivo engraftment of the pancreatic islet in scaffold, will improve islet function and immediately restore the normoglycemia in diabetic recipients. The goal of this study is to generate the first vascularized islet organ that will represent a valuable alternative to the classical intraportal islet transplantation designed with a dedicated focus for future clinical translation.
Anticipated Outcome
The proposed Bio-ACT project will generate the first bioengineered device (Bio-VIO) aimed to treat T1D. This scaffold technology based on decellularized pig lung left lobe will be directly self-assembly with human islet with or without human endothelial cells. Based on our published successful rodent VIO results, we aim to scale up this technology for the future therapeutic use in clinical application. Cell repopulation of Bio-VIOs will be performed in a bioreactor system that will allow to test vascularized islet organ readiness for implantation and the close proximity of the engineering setting for a future clinical translation. On the basis of the rodent data, we expect to confirm that the generation of Bio-VIO represents a successful strategy to overcome the current limitations in islet transplantation showing superiority over current state of the art. This system will allow us to generate the most advanced biocompatible endocrine organ technology for the in vivo treatment of T1D. From a scientific viewpoint, if successful, here we will engineer a novel bio-technology for hosting islets in a suitable environment that offers many advantages over currently available technologies. This concept could serve as a platform for bio-artificial endocrine organs.
Relevance to T1D
Using our previous experience in beta cell replacement and organ regeneration, we will engineer an innovative biotechnology that will represent clinical compliant bio-artificial vascularized islet organ. We believe that the generation of Bio-VIO in laboratory will represent the first step to validate its readiness prior to the in vivo implantation. Moreover, thanks to the ex vivo engineering process, we will eliminate the in vivo phase during which islet are devoid of an appropriate vascular environment, and we will improve cell engraftment prior implantation, two classical troubles of the intrahepatic islet transplantation. These unique features will open a new possible scenario in the field of beta cell replacement. Indeed, due to the initial lack of engraftment, a single islet transplantation required at least two pancreas to allow the achievement of insulin independence. Thus, the possibility to efficiently control pancreatic islet engraftment, may reduce the number of islets necessary for single infusion and reduce the number of pancreas used for patients. Moreover, if successful in preclinical model of T1D, this new platform could start the road map for clinical translation.