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  • Periodic Report Summary 2 - NEXT (Nano Engineering for Cross Tolerance: new approach for bioengineered, vascularised, chimeric islet transplantation in non-immunosuppressed hosts.)

Periodic Report Summary 2 - NEXT (Nano Engineering for Cross Tolerance: new approach for bioengineered, vascularised, chimeric islet transplantation in non-immunosuppressed hosts.)

Project Context and Objectives:
NEXT is an interdisciplinary, Pan-European consortium with a majority representation of SMEs and integrated research institutions aiming at developing a revolutionary method for the treatment of type 1 diabetes. The ultimate objective of the NEXT project is to engineer artificial pancreatic islets with immuno-stealth properties suitable for transplantation in diabetic patients non-responsive to insulin and suffering asymptomatic hypoglycemia. A revolutionary project that aims at engineering chimeric pancreatic islets capable to escape patient immune response, hence reducing organ rejection following islets transplantation.
Type 1 diabetes results from the autoimmune destruction of the insulin-producing beta cells in the pancreas. The subsequent lack of insulin leads to increased blood and urine glucose, when untreated type 1 diabetes is ultimately fatal; however, the disease can be controlled with supplemental insulin (insulin therapy).
Insulin therapy and dietary management are the most common Type 1 diabetes management strategy today, although effective insulin therapy impairs patient quality of life and may lead to severe psychological distress.
Alternative treatments such as pancreas transplantation or islet cell transplantation aim at restoring proper glucose regulation targeting the cause of diabetes. Despite progresses, these this kind of interventions require aggressive immunosuppression treatment in order to prevent the immunologic response of the patient which leads to rejection of the donor cells/organ.
The goal of NEXT project is to development chimeric pancreatic islets encapsulated into nanoengineered scaffold capable to shield islets from patient immune response substantially reducing the risk of rejection.

Project Results:
During the 2nd report period the partners have made substantial progress towards the optimisation of bioengineered pancreatic islets, called biochips, that have been derived by the substrate-driven organisation of pancreatic beta cells into spheroids to be implanted in vivo as a therapeutically alternative to traditional islet transplantation. Indeed, a thorough cytotoxicity study by AvantiCell well-established testing methods has allowed the identification of a candidate biomaterial substrate developed by the University of Brighton. This is an innovative biomaterial where FDA-approved gelatine structure and biofunctionality has been transformed through the functionalisation of the linear biopolymer with hyperbranched macromolecules able to expose ligands for beta cell receptors and immunosuppressant agents in a spacely- and density-ordered manner. Hence, the final product uniquely combine the properties of: (i) mimicking the extracellular matrix present in the pancreatic islets and encouraging the assembly of the beta cells and endothelial cells into structures similar to natural pancreatic islets. (ii) presenting peptides able to induce localised immunosuppression and hence protection from the host response during the early phases of transplantation. The testing performed by AvantiCell also showed the safety of a recombinant protein developed by EXPLORA that is now a candidate agent to generate localised immunosuppression of the biochips.
The immunosuppressant activity of this recombinant protein has been proved by ISMETT through their in vitro testing based on the evaluation of the suppression of specific immunocompetent cells relevant to the host response to pancreatic islets transplantation. A clinically-suitable procedure for the final assembly and transportation of the biochips has been developed by the University of Brighton and CELLON. While the University of Brighton has identified the optimal ratio between beta cells able to produce insulin and vascular cells able to form blood vessel in the biochip, CELLON has integrated this protocol in their microgravity bioreactor where various physicochemical parameters have been optimised to the final clinical application. Indeed, the use of the CELLON bioreactor has been proven a key step in ensuring the formation, survival and functions of the bioengineered islets. Capitalising on the results so far achieved, the project Steering Committee has identified intermediate products and clear commercial benefits for the industrial partners: (i) AvantiCell has demonstrated the suitability of their tests to measure in a reliable manner the viability of beta cells and pancreatic islets prior to transplantation. (ii) Explora has developed an immunosuppressant recombinant protein that has the potential of being used in clinical applications beyond islet transplantation. (iii) CELLON has proven the efficacy and adaptability of their bioreactor in assembling bioengineered islets as well as in ensuring the survival and functionality of islets upon a clinicallyrelevant period of time.
The partnership has also contributed to dissemination by presenting non-confidential results at international conferences and more recently submitting a paper on the use of one of the developed substrates for the anchorage of bioengineered beta cells that is based on chitosan beads functionalised by the same class of hyperbranched macromolecules used for the functionalisation of gelatine. This alternative substrate also provides future commercial opportunities in the field of application under investigation in this project as well as in the broader field of cell-based therapy.

Potential Impact:
This project will have an enormous social and economic impact in the field of Type I diabetes, and the market for biomaterials. The results of the project represent a new treatment of non-complicated diabetes by means of functional transplantation of pancreatic islets without requiring solid organic transplantation of kidney and corresponding immune-suppression treatment.
The potential output product could improve survival and efficiency of PITX that could be translated to artificial organ construction, eliminating the need for donated transplant organs and allowing avoidance of the lifelong immunosuppression currently required following islet transplantation.
In addition, the development of immune-stealth biopolymer may be translated to alleviate immunoreaction for other solid organ transplantation paving the way for a new strategy to manage allo- and xeno-transplantation.

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United Kingdom


Life Sciences
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