title: 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.
abstract: 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 in vivo 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.
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Jason
authors: J
authors: Li
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Michael K L
authors: MK
authors: Chu
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Claudia R
authors: CR
authors: Gordijo
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Azhar Z
authors: AZ
authors: Abbasi
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors: Kuan
authors: K
authors: Chen
authors: Physiology & Experimental Medicine Research Program, The Hospital for Sick Children, Toronto, Ontario M5T 3H7, Canada.
authors: Hibret A
authors: HA
authors: Adissu
authors: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Hesse 65926, Germany.
authors: Matthias
authors: M
authors: Löhn
authors: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors: Adria
authors: A
authors: Giacca
authors: Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Hesse 65926, Germany.
authors: Oliver
authors: O
authors: Plettenburg
authors: Department of Pharmaceutical Science, Leslie L. Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada. Electronic address: xywu@phm.utoronto.ca.
authors: Xiao Yu
authors: XY
authors: Wu
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D001786:Blood Glucose / Q000032:analysis; D002374:Catalase / Q000737:chemistry; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015195:Drug Design; D005355:Fibrosis; D005947:Glucose / Q000737:chemistry; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000008:administration & dosage*; D007332:Insulin Infusion Systems; D008297:Male; D055616:Microtechnology / Q000379:methods*; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin / Q000737:chemistry
chemical_list: D001672:Biocompatible Materials; D001786:Blood Glucose; D007328:Insulin; D011108:Polymers; D013311:Streptozocin; D002374:Catalase; D005947:Glucose
keywords: Biocompatibility; Closed-loop insulin delivery implant; Diabetes; Drug delivery implant; Microfabrication; Microporous membrane