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

Ruth E Levey,Eoin O’Cearbhaill,Rob Steendam,Mark Canney,Stefano Deotti,Wim E Hennink,Karina C Scheiner,Liam P Burke,Robert Wylie,Thanh T Nguyen,Giulio Ghersi,Scott T Robinson,Fergal B Coulter,Peter Dockery,Helena M Kelly,Liam Mcdonough,Robbert J Kok,Eimear B Dolan,Garry P Duffy

doi:10.3390/pharmaceutics13122077

Abstract

Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. −VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR.

Highlights

The islets of Langerhans are highly metabolic multi-cell structures, which require large quantities of oxygen and glucose to operate normally
In this study we describe a 4-week prevascularization approach, which consisted of VEGF microspheres macroencapsulated within an additive manufactured multi-scale porosity macroencapsulation device, implanted sub-muscularly in a rodent model
(** p = 0.004) percentage of mature vessels surrounding the VEGF loaded devices. This finding suggested that the addition of VEGF may promote the development of more stable and mature blood vessels

Summary

Introduction

The islets of Langerhans are highly metabolic multi-cell structures, which require large quantities of oxygen and glucose to operate normally Islet isolation procedures can often destroy the native islet vascular networks, causing prolonged hypoxic stress, contributing to a 60% loss in transplanted cells within 48 h post-transplantation [5,6] For these reasons, the development and distribution of blood vessels surrounding macroencapsulation devices is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previous studies by Padera and Colton examining the ideal time course of microarchitecture-driven vascularization demonstrated a time-frame comparable to the typical wound healing cascade of 7–21 days and diminishing by day 329 They found that the number of stable vascular structures plateaued on day 21 and remained unchanged on day 329. This study found that the degree of tissue integration and vascularity in proximity to the implant is shown to increase 2.5-fold with precisely controlled surface structural complexity [17]

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Results

Conclusion