Objective
This project aims to advance the clinical translation of a bioactive, multilayered islet delivery device with localized drug delivery to promote engraftment and maintainance of long term beta cell function. The proposed innovations have the potential to transform cell-based therapies for type 1 diabetes, offering a viable alternative to insulin therapy and improving patient outcomes.
Background Rationale
Immunoprotective cell encapsulation was first proposed almost nine decades ago, however, despite its potential, the technology has yet to deliver its clinical promise. The few clinical trials based on microencapsulation have not led to any licensed therapies. Up till now device strategies use synthetic biomaterials for micro or macroencapsulation, yet despite biocompatibility, implantation triggers a foreign body reaction, causing inflammation, cell stress, and fibrotic capsule formation. This initial suboptimal condition hinders revascularization, leading to impaired nutrient exchange and cell death. Recent developments in the field of stem cell biology have led to the creation of functional so-called stem cell islets, especially interesting is the use of induced pluripotent stem cells (iPSCs) as unlimited renewable source for the creation of beta cells. Currently in development are now strategies to genetically modify primary or stem cell islets to evade the immune system, or use the patient's own stem cells to create islets. Although clinical results regarding the application of these cells are limited available, preliminary results seem promising and they open the doors for using so-called open cell delivery devices.
We have developed an open-device delivery strategy for extrahepatic sites, funded partially by JDRF, which utilizes a macroporous thin-film microwell array delivery device. The device consists of ~30 µm-thick polymer sheets fabricated through solvent casting, femtosecond laser micromachining, and microthermoforming to create 400 µm diameter microwells. Islets are seeded between two macroporous layers. Initial in vitro and in vivo studies demonstrated successful islet engraftment and functionality. However, challenges remain in optimizing device design, improving engraftment, and mitigating the foreign body response for clinical translation.
Objectives
This project aims to address these challenges by using knowledge aquired in these previous studies:
1. Developing a multilayered microwell device: Increasing islet density in a compact macroporous design while supporting revascularization.
2. Optimizing islet dosing: Determining the relationship between cell density, glycemic control, and device efficacy.
3. Incorporating a drug delivery depot: Tailoring local release of inflammatory response-mitigating drugs to improve engraftment.
4. Computational modeling: Simulating drug diffusion around the device to optimize dosage and placement.
5. Evaluating immune response and engraftment: Assessing immune cell activity, FBR, and islet survival in preclinical models.
6. Identifying optimal implantation sites: Testing various sites in large preclinical models to maximize efficacy and safety.
Description of Project
In the last twenty years, scientists have been trying different ways to transplant islets and beta cells into people with severe type 1 diabetes. They're aiming to help these patients control their blood sugar levels without needing insulin injections. One common idea is to use a special device to deliver these cells, keeping them safe inside the body and replacing them if needed. Right now, these devices usually use man-made materials, but they often cause problems like inflammation and cell death. This projects aim to improve the efficiency of transplantation of donor islets and stem cell islet therapy with a tailormade implant. The implant consist of mutiple porous layers to retain islets surrounded by a support ring which is used to deliver a specific drugs to enhance the survival of beta cells by mitigating the tissue response. The open porous nature of the device allows for quick revascularisation after implantation which further supports beta cell function and survival. In this project specific attention is payed to future clinical implementation.
Anticipated Outcome
Expected Outcomes
1. A validated multilayered islet delivery device design capable of holding a clinically relevant number of islets in relative compact and small implant
2. Optimized drug delivery strategy in close vicinity of the implant to mitigate inflammation and support revascularization of the transplanted cells.
3. Identification of the most effective implantation site for future clinical application in a large preclinical animal model.
4. Comprehensive preclinical data supporting future regulatory submissions and clinical trials.
Relevance to T1D
This project is an important first step toward developing a new device for transplanting insulin-producing cells in people with type 1 diabetes. The goal is to create a multi-layered, open-structured device that not only protects these cells but also delivers supportive drugs to help them function better in the body.
Right now, we are preparing for an initial safety trial using a simpler, single-layer version of the device, which will be tested with donated human islets under hospital exemption. The production of this device follows strict quality control procedures in a cleanroom environment to ensure safety and consistency. If the trial is successful, the lessons learned will help us move forward with the more advanced multi-layered device with built-in drug delivery.
Currently, donated human islets are the main option for achieving insulin independence in type 1 diabetes, aside from pancreas transplants. However, stem cell-derived islets are emerging as a promising alternative. As more clinical trials provide safety and performance data on these stem cell islets, it will be crucial to develop a delivery method that ensures their survival and function, especially in the early stages after transplantation. Cell delivery devices offer a key advantage—they can be tailored to meet the specific needs of beta cells, providing a better environment for long-term survival. Our ultimate goal is to refine and scale up this multi-layered device so that it can be mass-produced according to strict medical standards. This will help bring the technology closer to clinical use.
We have a strong partnership with the Dutch clinical islet transplantation center at Leiden University Medical Hospital, led by Prof. de Koning. Together, we are working on a stem cell-based islet therapy using this device. If successful, this approach could pave the way for a new generation of cell transplantation strategies to improve beta cell therapy treatment options for people with type 1 diabetes.