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TOULOUSE, France — Pancreatic islet transplants have been offered at about 10 certified centers in France since 2020, but a number of limitations have forced scientists to turn to cell and tissue bioengineering.
Amid all the feats, hopes and disappointments of micro-, nano- and macroencapsulation, we will experience a historic moment in 2024, Sandrine Labranche, MD, diabetologist and endocrinologist at the University of Grenoble Medicine in France, said at a meeting of the French-speaking Diabetes Association.
Islet transplants of insulin-producing Langerhans cells were approved by French health authorities in 2020 to treat type 1 diabetes (T1D). “You no longer need to demonstrate a metabolic effect,” says Labranche. “You improve blood sugar balance, reduce blood sugar fluctuations, prevent severe hypoglycemia, and make a certain number of patients insulin independent, albeit temporarily. There is room for improvement.”
Currently, several limitations remain, especially regarding the cell source, making it a resource-intensive technique, requiring two to three infusions of islets from multiple donors per patient.
Furthermore, the essential long-term immunosuppression causes direct toxicity both to the islets (e.g. the impact of calcineurin inhibitors on beta-cell secretory capacity and viability) and to the transplant patient (weight gain, insulin resistance, metabolic disorders, hypertension, nephrotoxicity, dyslipidemia, cardiovascular risk, infection and neoplastic risk).
Multifactorial loss of islet function is also inevitable and is related to matrix loss, acute and chronic hypoxia, inflammatory phenomena, and also occurs due to recurrence of T1D in islets after transplantation, subjecting them to allogeneic rejection.
In other words, the cost-benefit balance with respect to glycemic stability does not currently favor islet transplantation in patients with well-controlled type 1 diabetes.
This has led to attention being focused on bioartificial pancreases that must meet many requirements, including an unlimited source of beta cells, the ability to provide long-term, and potentially lifelong, endogenous insulin delivery, revascularization or prevascularization to ensure optimal oxygen and nutrient supply, and maximum biocompatibility to prevent inflammatory responses and device fibrosis. The bioartificial pancreas must also ensure islet function.
Since the mid-1990s, solutions such as pancreatic islet microencapsulation have been developed, a technology that has demonstrated metabolic benefits in animals and one proof-of-concept study in humans. experimentThis study, which achieved insulin independence for nine months, has never been replicated.
In the mid-2000s, Some small series Using this technique, positive results have been observed in terms of immunological protection, but mixed results have been seen in terms of metabolic outcomes.
The research Four patients A patient who received intraperitoneal transplantation of human islet microcapsules. Three years later, the patient was again secreting endogenous C-peptide at rest and after stimulation, and severe hypoglycemia was prevented. The patient's glycated hemoglobin improved from 1% to 1.5%, insulin dosage was reduced by 10 IU, and vaccinations were no longer necessary.
To increase beta cell survival and functionality, the researchers Reconstruction of the microenvironment The capsules are enriched with extracellular matrix (ECM) (a hydrogel obtained from decellularized human pancreas) and then transplanted into the islets.
a Animal Publications It was shown that decellularized ECM (a hydrogel-like freeze-dried ECM) can be used to encapsulate pancreatic islets, and this technique improved the metabolic status of mice, with more subjects who received this technique achieving normoglycemia compared to subjects who received islet transplants with alginate capsules alone.
Other innovations in microencapsulation include coating the microcapsules with a layer of polyethylene glycol (PEG) or enriching them with oxygen carriers (e.g., perfluorinated nanoparticles).
Publication From the second half of 2023, both technologies will be combined to inhibit capsular fibrosis and pericapsular inflammatory cytokine production.
According to the authors, this solution combines the “stealth” effect of PEG chains with the high oxygen transport performance of fluorinated nanoparticles. Cationic poly(L-lysine)-grafted poly(ethylene glycol) is coated onto alginate microcapsules through electrostatic interactions, preventing fibrinogen adhesion and excessive fibrosis around the microcapsules and isolating the host's immune system. This is the “stealth effect” of the microencapsulated islet cells.
Furthermore, simultaneous loading of fluoride-based “nanocarriers” improved oxygen transport capacity and oxygen supply, prolonging islet cell survival. The islet cells within the capsules showed similar cell viability and normal insulin release even in long-term culture under hypoxic conditions.
“The results were promising, as we observed a reduction in macrophage activation and cytokine production,” LaBranche said, “and the perfluorinated nanoparticles improved cell survival in a hypoxic environment and improved insulin release in response to glucose.”
In parallel with this study, Nanoencapsulation Technology The idea is to create layers as close as possible to or in contact with the islets, reducing the volume inside the capsule. These monolayers can be functionalized with, for example, pro-angiogenic or immunomodulatory factors to promote islet vascularization.
In vitro and in vivo studies have Isolated human isletsIt is coated with multi-layer nanocapsules using differently charged polymers (chitosan and poly).[sulfonate] Nanoencapsulated islets were able to maintain stimulated physiological insulin release, and one positive point was that the toxicity caused by palmitic acid or cytokines in the coated islets was reduced.
of The most promising concept According to LaBranche, the difference with macroencapsulation is that rather than being individually encapsulated in a gel capsule, the islets are contained together in a macrochamber that traps the graft. Proof of concept and metabolic effects have been established in animals, and proof of concept in humans has also been established, although the data is somewhat sparse at this stage.
The ViaCyte device (Vertex) is perhaps the most advanced, with clinical studies utilizing embryonic stem cell derived pancreatic progenitor cell transplants. Initial Clinical Study The ViaCyte VC-01 device (2014) was shown to be safe without immunosuppression, but extensive fibrosis of the device and cellular necrosis of its contents were observed. Endogenous insulin secretion (or C-peptide) was not measured in recipients.
The second study (VC-02) used the same concept, but larger pores were created in the macrochambers to allow vascularization of the cellular contents and required immunosuppression of the recipients.
Preliminary data from an ongoing human phase 1/2 open-label study showed that 6 of 17 (35%) patients with type 1 diabetes had positive C-peptide levels when stimulated as early as 6 months after implantation, without significant differences in metabolic criteria. Upon explantation, 63% of explants expressed C-peptide and secreted endogenous insulin 3-12 months after implantation. The contents were vascularized.
“At this stage of research, certain macroencapsulation devices, including the latter, have reached a sufficient level of maturity to allow for phase 1 and 2 clinical trials,” Labranche said.
LaBranche reported financial ties to Abbott.
This story is Medscape French version As part of our process, we use multiple editing tools, including AI, and a human editor reviewed this content before publishing.