TY - JOUR

T1 - Microfabricated microporous membranes reduce the host immune response and prolong the functional lifetime of a closed-loop insulin delivery implant in a type 1 diabetic rat model

AU - Li, Jason

AU - Chu, Michael K.L.

AU - Gordijo, Claudia R.

AU - Abbasi, Azhar Z.

AU - Chen, Kuan

AU - Adissu, Hibret A.

AU - Löhn, Matthias

AU - Giacca, Adria

AU - Plettenburg, Oliver

AU - Wu, Xiao Yu

N1 - Funding Information: This work was supported financially by the MaRS Innovation POP grant (No. 308147 ), the Ontario Research Fund: Research Excellence (ORF-RE) Nanomaterials grant (No. RE03-058 ) in collaboration with Sanofi Aventis; and the CIHR Equipment Grant. The NSERC CGS scholarship to J. Li, and the OGS scholarship and Ben Cohen top-up award to both J. Li and M. Chu are also acknowledged. The authors also acknowledge Dr. Barry Elkind at the MaRS Innovation for his stimulating discussion and Lily Morikawa for her excellent histology analysis at the Pathology Core of the Centre for Modeling Human Disease, at The Lunenfeld-Tanenbaum Research Institute ( www.cmhd.ca ).

PY - 2015/4

Y1 - 2015/4

N2 - Implantation of a medical implant within the body inevitably triggers a host inflammatory response that negatively impacts its function and longevity. Nevertheless, the degree and severity of this response may be reduced by selecting appropriate materials, implant geometry, surface topography and surface treatment. Here we demonstrate a strategy to improve the biocompatibility of a chemically-driven closed-loop insulin delivery implant. A microfabricated microporous, poly(ethylene glycol)-grafted polydimethylsiloxane membrane was placed on top of the glucose-responsive insulin release plug of the implant. Implant biocompatibility was assessed in healthy rats while implant function was evaluated in a type 1 diabetic rat model. The microporous membrane with a small distance to the plug provided a geometric barrier to inflammatory cell migration and prevented leukocyte-mediated degradation of the plug for at least 30 days. Membrane-protected devices elicited a significantly milder inflammatory response and formation of a well-defined fibrous capsule at the device opening compared to unprotected devices. The device's glucose-responsiveness was nearly unchanged, although the insulin release rate decreased with decreasing pore size. The microporous membrane improved biocompatibility and prolonged invivo efficacy of the implant by ~3-fold. This work suggests the importance of implant design in modulating inflammatory response and thereby extending the functional duration of the implant.

AB - Implantation of a medical implant within the body inevitably triggers a host inflammatory response that negatively impacts its function and longevity. Nevertheless, the degree and severity of this response may be reduced by selecting appropriate materials, implant geometry, surface topography and surface treatment. Here we demonstrate a strategy to improve the biocompatibility of a chemically-driven closed-loop insulin delivery implant. A microfabricated microporous, poly(ethylene glycol)-grafted polydimethylsiloxane membrane was placed on top of the glucose-responsive insulin release plug of the implant. Implant biocompatibility was assessed in healthy rats while implant function was evaluated in a type 1 diabetic rat model. The microporous membrane with a small distance to the plug provided a geometric barrier to inflammatory cell migration and prevented leukocyte-mediated degradation of the plug for at least 30 days. Membrane-protected devices elicited a significantly milder inflammatory response and formation of a well-defined fibrous capsule at the device opening compared to unprotected devices. The device's glucose-responsiveness was nearly unchanged, although the insulin release rate decreased with decreasing pore size. The microporous membrane improved biocompatibility and prolonged invivo efficacy of the implant by ~3-fold. This work suggests the importance of implant design in modulating inflammatory response and thereby extending the functional duration of the implant.

KW - Biocompatibility

KW - Closed-loop insulin delivery implant

KW - Diabetes

KW - Drug delivery implant

KW - Microfabrication

KW - Microporous membrane

UR - http://www.scopus.com/inward/record.url?scp=84922784007&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2015.01.005

DO - 10.1016/j.biomaterials.2015.01.005

M3 - Article

C2 - 25682160

AN - SCOPUS:84922784007

VL - 47

SP - 51

EP - 61

JO - BIOMATERIALS

JF - BIOMATERIALS

SN - 0142-9612

ER -