Clinical islet transplantation for treatment of type 1 diabetes (T1D) is limited by the shortage of pancreas donors and need for lifelong immunosuppressive therapy. A convection-driven intravascular bioartificial pancreas (iBAP) based on highly permeable, yet immunologically protective, silicon nanopore membranes (SNM) holds promise to sustain islet function without the need for immunosuppressants. Here, we investigate short-term functionality of encapsulated human islets in an iBAP prototype. Using the finite element method (FEM), we calculated predicted oxygen profiles within islet scaffolds at normalized perifusion rates of 14-200 nl/min/IEQ. The modeling showed the need for minimum in vitro and in vivo islet perifusion rates of 28 and 100 nl/min/IEQ, respectively to support metabolic insulin production requirements in the iBAP. In vitro glucose-stimulated insulin secretion (GSIS) profiles revealed a first-phase response time of <15 min and comparable insulin production rates to standard perifusion systems (~10 pg/min/IEQ) for perifusion rates of 100-200 nl/min/IEQ. An intravenous glucose tolerance test (IVGTT), performed at a perifusion rate of 100-170 nl/min/IEQ in a non-diabetic pig, demonstrated a clinically relevant C-peptide production rate (1.0-2.8 pg/min/IEQ) with a response time of <5 min.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m² and 140-165 mL/min/m², respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain >90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage, and recipient cytokine levels are not suggestive of hyperacute rejection. These initial data confirm the potential feasibility of an implantable bioreactor for renal cell therapy utilizing silicon nanopore membranes.