A benchtop closed-loop system controlled by a bio-inspired silicon implementation of the pancreatic beta cell

Abstract

The normal pancreatic beta-cell membrane depolarizes in response to increasing concentrations of glucose in a bursting pattern. At <7 mM (126 mg/dl), the cell is electrically silent. The bursting pulse width increases as glucose rises >7 mM (126 mg/dl) until a continuous train of bursting is seen at >25 mM (450 mg/dl). A bio-inspired silicon device has been developed using analogue electronics to implement membrane depolarization of the beta cell. The device is ultralow powered, miniaturized (5 x 5 mm), and produces a bursting output identical to that characterized in electrophysiological studies.

Objective: The goal of this study was to demonstrate the ability of silicon implementation of beta-cell electrophysiology to respond to a simulated glucose input and to drive an infusion pump in vitro.

Method: The silicon device response to a current source was recorded at varying simulated glucose concentrations. Subsequently, the bursting response to a changing analyte concentration measured by an amperometric enzyme electrode was converted to a voltage, driving a syringe pump loaded with a 50-ml syringe containing water.

Results: Bursting responses are comparable to those recorded in electrophysiology. Silicon beta-cell implementation bursts with a pulse width proportional to concentration and is able to drive an infusion pump.

Conclusion: This is the first in vitro demonstration of closed loop insulin delivery utilizing miniaturized silicon implementation of beta-cell physiology in analogue electronics.

Figures

Figure 1.

β-cell electrophysiology. GLUT2, glucose transporter 2; KATP, potassium ATP channel; K, potassium; Ca, calcium; gCa, voltage-gated calcium channel; gK, voltage-gated potassium channel.

Figure 2.

β-cell electrophysiology bursting behavior.

Figure 3.

(A) Phospholipid bilayer with ion channel with (B) nonlinear resistor circuit overlaid.

Figure 4.

Ion channels as resistors in serial in a circuit provide a membrane potential in silicon implementation of the β cell. gCa, gK, and gS, where S is a slow time variable, are nonlinear resistors. ICa, IK, and IS are current inputs, and summation of their voltages, VCa + VK + VS, produces an overall membrane potential, Cm.

Figure 5.

MATLAB simulation of glycemic excursion to 16 mmol/liter (288 mg/dl).

Figure 6.

Experimental results from silicon implementation of the β cell showing increasing burst pulse width with increasing current (simulated glucose concentration input).

Figure 7.

Benchtop closed loop schematic. CE, counter electrode; WE, working electrode; RE, reference electrode.