In article number 2000305 by Ellen T. Roche, Eimear B. Dolan, and co‐workers, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models that are easily translated to human studies, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation, and filling/refilling with a therapeutic cargo.

IntroductionDrug-based treatment regimens for cancer are often associated with off-target toxic side effects and low penetration of the drug at the tumor site leading to patient morbidity and limited efficacy. Locoregional drug delivery has the potential to increase efficacy while concomitantly reducing toxicity. Areas coveredClinical applications using loco-regional delivery include intra-arterial drug delivery in retinoblastoma, direct intra-tumoral (IT) injection of ethanol for ablation in hepatocellular carcinoma (HCC) and the use of HIPEC in peritoneal carcinomas. In recent years, there has been a significant increase in both approved products and clinical trials, with a particular emphasis on drug delivery platforms such as drug eluting beads for HCC and hydrogel platforms for intravesical delivery in bladder cancer. Expert opinionDevelopment of loco-regional drug delivery systems has been slow, limited by weak clinical data for early applications and challenges relating to dosing, delivery and retention of drugs at the site of action. However, there is increasing focus on the potential of loco-regional drug delivery when combined with bespoke drug delivery platforms. With the growth in immunotherapies, the use of IT delivery to drive priming of the anti-tumor response has opened up a new field of opportunity for locoregional drug delivery.

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.

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Islet encapsulation devices can induce a Foreign Body Response (FBR) and the formation of a dense avascular fibrotic capsule. This FBR is heightened when the device has a smooth surface as fibrous tissue is unable to adhere, instigating a substantial immunological reaction, islet death and ultimately implant failure. In this study, we examine whether additive manufactured multiscale porous devices promote optimal tissue integration and vascularisation for long-term functional islet encapsulation. Furthermore, we examine the potential for this method to be scaled for functional use in a large diabetic animal model. Silicone devices exhibiting progressively more complex surface architectures (quantity of macro- and micro-pores), were implanted submuscularly in rodents. Upon explant, analysis of fibrous capsule, angiogenic and macrophage response were performed. To determine its potential as an encapsulation device, multiscale porosity devices were used for intra-peritoneal syngeneic islet transplantation in 8 diabetic rats. Circulating blood glucose levels were monitored for 8 weeks. To validate scalability and functionality, devices were implanted submuscularly in an STZ-induced diabetes pig model for 2 weeks before blood glucose levels were measured in response to the infusion of insulin through the device. Degree of tissue integration and vascularity in proximity to the implant was shown to increase 2.5 fold with precisely controlled multiscale device topography. Moreover, encapsulated islets maintain glucose responsiveness and function for 8 weeks. Bioavailability was equal when the same dose of insulin is delivered via the device vs. subcutaneously in diabetic pig model. The use of additive manufactured multiscale porous coatings on macroencapsulation devices can increase tissue integration and vascularity. These findings demonstrate functionality, scalability and could help to resolve the immunological and diffusion limitations of current encapsulation devices. Disclosure R.E. Levey: None. F.B. Coulter: None. S.T. Robinson: None. L. McDonough: None. S. Deotti: None. E.B. Dolan: None. P. Dockery: None. H. Kelly: None. E.D. OCearbhaill: None. G.P. Duffy: None. Funding European Union (645991)