Three-dimensional printed polymeric system to encapsulate human mesenchymal stem cells differentiated into islet-like insulin-producing aggregates for diabetes treatment

Abstract

Diabetes is one of the most prevalent, costly, and debilitating diseases in the world. Pancreas and islet transplants have shown success in re-establishing glucose control and reversing diabetic complications. However, both are limited by donor availability, need for continuous immunosuppression, loss of transplanted tissue due to dispersion, and lack of vascularization. To overcome the limitations of poor islet availability, here, we investigate the potential of bone marrow–derived mesenchymal stem cells differentiated into islet-like insulin-producing aggregates. Islet-like insulin-producing aggregates, characterized by gene expression, are shown to be similar to pancreatic islets and display positive immunostaining for insulin and glucagon. To address the limits of current encapsulation systems, we developed a novel three-dimensional printed, scalable, and potentially refillable polymeric construct (nanogland) to support islet-like insulin-producing aggregates’ survival and function in the host body. In vitro studies showed that encapsulated islet-like insulin-producing aggregates maintained viability and function, producing steady levels of insulin for at least 4 weeks. Nanogland—islet-like insulin-producing aggregate technology here investigated as a proof of concept holds potential as an effective and innovative approach for diabetes cell therapy.

3D Printed Vascularized Device for Subcutaneous Transplantation of Human Islets

“…Transplantation of islets on porous biomaterials has emerged as a promising strategy for long‐term islet function facilitating rapid tissue ingrowth, vascularization and innervation providing oxygen, nutrition, and waste removal . Recognizing such needs for an islet and cell encapsulation system, we are working on new strategies to deliver cells subcutaneously . The architecture of the proposed device is designed to maintain pancreatic islets close to blood vessels in a growth factor enriched environment, but separated from each other to mimic the physiological architecture in the pancreas and avoid cell crowding.…”

“…The nanopattering of the device surfaces was evaluated before and after treatment by scanning electron microscopy (SEM) (Nova NanoSEM, FEI) for channel quality and size (Figure b and c). Hydrophilicity was evaluated by measuring the water contact angle and surface roughness was evaluated by atomic‐force microscopy set in tapping mode (BioScope Catalyst, Bruker Instruments, TX) …”

Mesenchymal Stromal Cell-Seeded Biomimetic Scaffolds as a Factory of Soluble RANKL in Rankl-Deficient Osteopetrosis

“…More substantial modifications of the protocol, than those used in the present study, would be necessary to improve the outcome of this approach. For example, we might consider increasing hsRL production by transduced cells, by using a higher MOI; using telomerase overexpression in LVhsRL‐transduced Rankl −/− MSCs to augment their proliferation ; implanting a higher number of scaffolds or larger scaffolds (as far as this is technically feasible in these small mice); using a biomimetic smart scaffold functionalized to enhance MSC attachment ; isolating the system from the host cells by means of newly developed cell encapsulation systems, thus preventing its disruption . The optimization of these aspects might be pursued, for example, by exploiting the emerging technology of rechargeable devices containing 3D printed cell‐seeded functionalized scaffolds , which has already achieved promising results in other fields.…”

Integration of nano‐ and biotechnology for beta‐cell and islet transplantation in type‐1 diabetes treatment

“…Inadequate oxygen supply causes the gradual loss of cell mass and function, and this effect can be aggravated with encapsulation, thus pose one of the challenges in BAP development . To overcome this problem, several different experimental approaches have been tested such as the stimulation of vascularization growth prior to cell transplantation, the use of a hypoxia‐resistant cell line from Tilapia, microencapsulation, increased oxygen permeability of the encapsulating material . Incorporated refillable oxygen reservoir in the βAir device has already been tested in small and large animal models, and recently, in a clinical phase I study (Clinicaltrials.gov: NCT02064309) has been conducted to evaluate its safety .…”