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TOULOUSE, FRANCE — Pancreatic islet transplantation has been offered since 2020 in about 10 certified French centers, but its numerous limitations are compelling scientists to turn to cellular and tissue bioengineering.

Between the feats, promises, and disappointments of micro-, nano-, and macroencapsulation, we are experiencing historic moments in 2024, said Sandrine Lablanche, MD, PhD, a diabetologist and endocrinologist at CHU Grenoble in France, at the congress of the Francophone Diabetes Society.

Islet Transplantation Limitations

Islet transplantation of insulin-producing Langerhans cells received approval from the French Health Authority in 2020 for treating type 1 diabetes (T1D). "Its metabolic results no longer need to be demonstrated," said Lablanche. "It improves glycemic balance, reduces glycemic variability, protects against severe hypoglycemia, and renders a certain number of patients insulin-independent, albeit transiently and still improvable."

Several limitations persist today, particularly regarding the cell source, making it a resource-intensive technique. It requires two to three infusions of islets from multiple donors per patient.

Moreover, the indispensable long-term immunosuppression causes direct toxicity to both the islets (eg, from calcineurin inhibitors' effect on beta cells' secretory capacity and viability) and the recipient (through weight gain, insulin resistance, metabolic disorders, hypertension, renal toxicity, dyslipidemia, cardiovascular risks, infections, and neoplastic risks).

The multifactorial loss of islet functionality is also unavoidable, being linked to matrix loss, acute and chronic hypoxia, as well as inflammatory phenomena. It also results from the recurrence of T1D on the islet after transplantation and is exposed to allogeneic rejection.

In other words, the cost-benefit balance, with regard to glycemic stability, at this stage does not favor islet transplantation in a patient with well-controlled T1D.

Microencapsulation

Thus, attention turned to the bioartificial pancreas, which must fulfill many requirements. These requirements include an unlimited beta cell source, the ability to provide prolonged, even lifelong endogenous insulin delivery, revascularization or prevascularization to ensure optimal oxygen and nutrient supply, and maximum biocompatibility to prevent any inflammatory reaction and device fibrosis. The bioartificial pancreas also must ensure islet functionality.

Since the mid-1990s, solutions such as islet microencapsulation have been developed. The technique demonstrated metabolic efficacy in animals, and a single proof-of-concept study was conducted in humans. The experiment, which achieved insulin dependence for 9 months, has never been replicated.

In the mid-2000s, several small series using this technique observed positive results concerning immunologic protection but mixed results for metabolic outcomes.

A study was conducted on four patients who received intraperitoneal transplantation of human islet microcapsules. After 3 years, patients again secreted endogenous C-peptide at rest and after stimulation, and severe hypoglycemia was prevented. The patients had improvement in glycated hemoglobin between 1% and 1.5%, a 10 IU reduction in insulin doses, and no immunization.

Creating a Microenvironment 

To enhance beta cell viability and functionality, researchers pursued the goal of reconstructing a microenvironment for the islet by enriching the capsule with extracellular matrix (ECM), a hydrogel obtained from decellularized human pancreas.

A publication in animals showed that it was possible to use decellularized ECM (lyophilized ECM in hydrogel form) to encapsulate islets. The technique improved metabolic state in mice, and a larger number of subjects who underwent it achieved normoglycemia compared with those who underwent islet grafting in alginate capsules alone.

Other innovations in microencapsulation have emerged, such as coating microcapsules with layers of polyethylene glycol (PEG) and enriching them with oxygen carriers (eg, perfluorinated nanoparticles).

A publication from late 2023 combined both technologies to limit capsule fibrosis and proinflammatory cytokine production around the capsule.

According to the authors, this solution integrates the "stealth" effect on PEG chains and the high oxygen transport performance of fluorinated nanoparticles. The cationic poly(l-lysine)-grafted-poly(ethylene glycol) is coated on alginate microcapsules by electrostatic interaction to prevent fibrinogen adhesion and excessive fibrosis around microcapsules and to isolate the host's immune system, hence the "stealth effect" of microencapsulated islet cells.

Moreover, concomitant loading of fluoride-based "nanocarriers" confers improved oxygen transport capacity and oxygen supply, thus prolonging islet cell survival. Intracapsular islet cells showed similar cell viability and normal insulin release even in long-term culture under hypoxic conditions.

"The results are promising, with a reduction observed in macrophage activation and cytokine production," said Lablanche, "along with improved cellular survival in hypoxic environments due to perfluorinated nanoparticles, resulting in better insulin release in response to glucose."

Parallel to this research, nanoencapsulation technology has developed. The idea is to create a layer as close as possible to or in contact with the islet, thus reducing the volume within the capsule. These monolayers can be functionalized with, for example, proangiogenic factors to promote islet vascularization or immunomodulatory factors.

In vitro and in vivo studies have been conducted with isolated human pancreatic islets, coated with a multilayered nanoencapsulation using polymers with different charges (chitosan and poly[sulfonate] sodium). Nanoencapsulated islets were able to maintain stimulated physiologic insulin release. One positive aspect was the reduced toxicity induced by palmitate or cytokines in the coated islets.

Macroencapsulation

The most promising concept is that in macroencapsulation, islets are no longer individually encapsulated in a gel capsule but enclosed together in a macro-chamber that confines the graft, according to Lablanche. Proof of concept and metabolic efficacy have been established in animals, as well as a proof of concept in humans, but the data are somewhat sparse at this stage.

ViaCyte devices (Vertex) are probably the most advanced, with clinical studies exploiting pancreatic progenitor grafts derived from embryonic stem cells. The first clinical study with a ViaCyte VC-01 device (2014), without immunosuppression, showed safety but observed massive device fibrosis and cellular necrosis of its content. No endogenous insulin secretion (or C-peptide) was measured in the recipient.

A second study (VC-02) used the same concept but created large pores in the macro-chamber to allow cell content vascularization, necessitating recipient immunosuppression.

According to preliminary data from an ongoing human phase 1/2 open-label study, six out of 17 patients with T1D, or 35%, showed a positive C-peptide level upon stimulation as early as 6 months post-implantation, with no significant difference in metabolic criteria. When explanted, 63% of explants expressed C-peptide, and endogenous insulin was secreted at 3-12 months post-implantation. The content was vascularized.

"At this stage of research," said Lablanche, "certain macroencapsulation devices, including the latter, have reached sufficiently high maturity levels to undergo phase 1 and 2 clinical trials."

Lablanche reported a financial relationship with Abbott.

This story was translated from the Medscape French edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.