Vascular Endothelial Growth Factor–Releasing Microspheres Based on Poly(ε-Caprolactone-PEG-ε-Caprolactone)-b-Poly(L-Lactide) Multiblock Copolymers Incorporated in a Three-Dimensional Printed Poly(Dimethylsiloxane) Cell Macroencapsulation Device

Abstract

Pancreatic islet transplantation is a promising advanced therapy that has been used to treat patients suffering from diabetes type 1. Traditionally, pancreatic islets are infused via the portal vein, which is subsequently intended to engraft in the liver. Severe immunosuppressive treatments are necessary, however, to prevent rejection of the transplanted islets. Novel approaches therefore have focused on encapsulation of the islets in biomaterial implants which can protect the islets and offer an organ-like environment. Vascularization of the device's surface is a prerequisite for the survival and proper functioning of transplanted pancreatic islets. We are pursuing a prevascularization strategy by incorporation of vascular endothelial growth factor (VEGF)-loaded microspheres in 3-dimensional printed poly(dimethylsiloxane)-based devices prior to their prospective loading with transplanted cells. Microspheres (~50 mm) were based on poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymers and were loaded with 10 mg VEGF/mg microspheres, and subsequently dispersed in a hyaluronic acid carrier liquid. In vitro release studies at 37 C demonstrated continuous release of fully bioactive VEGF for 4 weeks. In conclusion, our results demonstrate that incorporation of VEGF-releasing microspheres ensures adequate release of VEGF for a time window of 4 weeks, which is attractive in view of the vascularization of artificial pancreas implants.

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device

“…However, Nakatsu et al found the process to be dose dependant. Lower concentrations of VEGF 165 promoted growth of long, thinner blood vessels, whereas higher concentrations of VEGF, which correlate with the dosage chosen for the present study [29,30], remarkably enhance the vessel diameter [52].…”

“…In the presence of water, the polymer matrix swelled, enabling the diffusion of VEGF from the microspheres. A detailed documentation on the fabrication of these microspheres and their VEGF release properties is reported by Scheiner et al [29,30]. The membranes were formed by spraying 8 layers of a custom silicone ink on to a hot plate set to 90 °C, and each layer was 8 μm thick.…”

“…This timeframe was selected as the literature indicated that a constant dose of VEGF for approximately 4 weeks can result in sufficient vascularization in rodent models [32,33]. This timeframe was also previously utilized in our in vitro work for optimizing release of VEGF from the multiblock copolymer microspheres in preparation for preclinical studies [29,30]. Previous studies demonstrating prevascularization strategies using devices alone have also chosen an implantation period of 4 weeks [8,9,11,12].…”

“…Transplanted islets will eventually release VEGF in response to reduced blood supply, however, premature delivery of VEGF within encapsulation systems has demonstrated improved engraftment and islet efficacy [18,[26][27][28]. Our previous in vitro release studies demonstrated that VEGF-releasing microspheres ensure satisfactory VEGF release for 4 weeks, and could prove to be valuable when used as a prevascularization strategy for artificial pancreas implants [29,30].…”

Prevascularized Micro-/Nano-Sized Spheroid/Bead Aggregates for Vascular Tissue Engineering

“…Native-like tissue microenvironment usually is not facilitated due to the limited cell–cell and cell–ECM interactions. It can be attained by the growth of cells in an isolated fashion such as cell-laden hydrogels or cells in monolayers [ 146 ]. To address the issue, novel bioprinting technologies have been introduced.…”