Nano Engineering for Cross Tolerance (NEXT)

Diabetes is caused by insufficient or lack of insulin secretion by the specialised B cells of the pancreas and, if not treated adequately, evolves into complications which alter patients integrity and wellness.

Treatment is based on lifetime drugs administration for blood glucose control or parenteral infusion of insulin to better control glucose levels and glycosylation of haemoglobin.

Artificial pancreases are in development but still dependent by external energy sources and need permanent transcutaneous access to release the hormone.

Pancreatic whole organ transplantation is a major intervention requiring selected recipient and matched cadaveric donor which keep numbers down.

Islet of Langerhans transplantation is a non-invasive method for the treatment of type 1 diabetes but several questions remain and several issues have to be addressed in order to improve the method since islet engraftment is clearly suboptimal, as a result of pro-apoptotic and pro-inflammatory stimuli sustained during islet isolation and at the site of implantation, the long-term islet graft function drops to 15 per cent with time, and the current systemic immunosuppressive regimen has several drawbacks in terms of side effects.

The solution should be to increase transplantation efficiency with an higher number of islet, eventually from animals, induce tolerance toward the graft, avoiding systemic, lifetime immunosuppression and, lowering a specific inflammatory reaction and enhancing graft micro vasculogenesis to improve islet nesting.

NEXT is an EC project (overall value € 6,189,750) that started on 1 October 2013 to provide a 360° solution to the pitfalls of current methodology for pancreatic islet transplantation:

Biomimetic nanostructured biomaterials are under development that can be used to engineer donor cell surfaces in order to derange recognition by the immune system and suppress their rejection. These biomaterials form a thin coating around single pancreatic beta cells and expose immune-stealth molecules able to protect the islet in a highly-localised manner.

Advanced tissue engineering methods, to assemble bio-synthetic islet, enriched by chimeric microvasculature. The same biomimetic biomaterials have been designed to drive the organization of the engineered pancreatic beta cells into 3D constructs capable of integrating in a biospecific manner microvasculature deriving from the host to form a bioengineered islet.

This unique class of biomaterials have so far shown a very promising clinical potential and they can achieve a double immune-suppressive strategy where the initial biomaterial immune-stealth properties are combined with the intrinsic immune-compatibility provided by the microvasculature of the host that will not allow extravasion of immunocompetent cells into the bioengineered islet.
The project has a strong translational basis in its partnership that includes three companies, AvantiCell (UK), Explora (Italy), Cellon (Luxembourg) and a centre for organ transplantation, ISMETT (Italy).

The biomaterials developed by the project are an important breakthrough: they can drive the formation of pseudo-islets through the assembly of pancreatic beta cells and vascular endothelial cells. In previous approaches, biomaterials were solely used to encapsulate isolated pancreatic islets. This resulted in limited protection of the islets from the host response, and poor integration with surrounding host tissue. NEXT solves both problems at the same time.

Unlike the disordered cell aggregates formed with other methods, our biomaterial makes the biochip respond to hyperglycaemic stimuli with an enhanced production of insulin. Also, it offers an anchorage point for the coupling of the biochip with immunosuppressant proteins. Thanks to such coupling, specific biochemical pathways of the immune/host response that would lead to pancreatic islet death under the current treatment can be inhibited, making the use of immunosuppressant drugs known to cause adverse effect to the patient unnecessary.

Initially, the project team aimed to deliver an immunosuppressant peptide directly integrated into their biomaterial. As the results were unsatisfying, a recombinant protein was produced instead, but its relatively large size makes it unfit for integration into the biochip. The protein will need to be scaled up at industrially-feasible amounts, and the procedure optimised in dedicated in vivo models.

The optimisation will need to ascertain the size and number of biochips optimal to reverse diabetes conditions in the chosen animal models and to be expanded to xenogeneic protocols proving that the technology can perform when immune-protected biochips made from other animal species are transplanted.


In the meantime, the partners were able to develop novel methodologies and equipment enabling the successful clinical transplantation of the tissue-engineered biochips: an in vitro model of fibrosis by AvantiCells Science to test pancreatic islets for their propensity to be encapsulated in an unwanted fibrous capsule; a battery-sourced bioreactor by Cellon that can be easily accommodated in ambulances; a comprehensive set of recombinant immunosuppressant proteins; as well as a novel toolkit for DNA modular assembly now marketed as Doulix by Explora.

NEXT technology could also expand the current clinical procedure of pancreatic islet transplantation to the use of animal tissues and not only cadaveric specimens. The technology will enable the establishment of cell banks to be used for the production of immunoprotected biochips, thus solving the problem of donor shortage and immune reactions upon transplantation.