An implantable MEMS micropump system for drug delivery in small animals

Abstract

We present the first implantable drug delivery system for controlled timing and location of dosing in small animals. Current implantable drug delivery devices do not provide control over these factors nor are they feasible for implantation in research animals as small as mice. Our system utilizes an integrated electrolysis micropump, is refillable, has an inert drug reservoir for broad drug compatibility, and is capable of adjustment to the delivery regimen while implanted. Electrochemical impedance spectroscopy (EIS) was used for characterization of electrodes on glass substrate and a flexible Parylene substrate. Benchtop testing of the electrolysis actuator resulted in flow rates from 1 μL/min to 34 μL/min on glass substrate and up to 6.8 μL/min on Parylene substrate. The fully integrated system generated a flow rate of 4.72 ± 0.35 μL/min under applied constant current of 1.0 mA while maintaining a power consumption of only ~3 mW. Finally, we demonstrated in vivo application of the system for anti-cancer drug delivery in mice.

Fig. 1

Illustrations and photograph of the refillable implantable micropump system (RIMS) a) The main features are an electrochemical bellows actuator, refill port, and check valve b) Current applied to a pair of interdigitated electrodes splits water (electrolyte) into hydrogen and oxygen gases. The phase change induces a pressure increase within the bellows and drives fluid out of the reservoir and through the catheter c) The reservoir can be refilled through the built-in refill port d) Photograph of the RIMS

Fig. 2

The dual-layer photoresist process for electrode fabrication on glass (left) or Parylene C (right, photograph taken prior to detachment from silicon support)

Fig. 3

A sourcemeter provides current to the electrodes for electrolysis in a testing fixture, then dispense into a) a weigh boat for volumes >100 μL or b) a calibrated micropipette for volumes <100 μL

Fig. 4

a) Fabrication of the bellows consisted of molding a PEG form using PDMS, deposition of Parylene C over the PEG mold, and removal of the sacrificial PEG b) Photograph of the 2 convolution Parylene C bellows after removal of PEG

Fig. 5

Side view of the check valve packaged in FEP tubing

Fig. 6

Commercial one-way disc valve (left) and in-line check valve (right) used for comparison to the fabricated check valve

Fig. 7

Assembly of the RIMS. The bellows actuator is inserted into the cast silicone rubber reservoir, then PDMS is used to seal the slit and adhere a lid to the reservoir. Photograph (bottom) of the MEMS check valve integrated with the fully packaged micropump system (left) and a miniature prototype (right).

Fig. 8

EIS results of electrodes on glass show an overall decrease in impedance with increasing frequency, as expected for two metals electrodes (reference and working) in solution

Fig. 9

EIS results of electrodes on Parylene show an overall decrease in impedance with increasing frequency, as expected for an electrochemical cell. Delamination was seen above 1 mA for Pt-Ti electrodes deposited on a Parylene C substrate. As fabricated (top right) and delaminated (bottom right) electrodes.

Fig. 10

Flow rates (mean ± SE, n=4) for Pt/Ti electrodes on a Parylene C substrate show higher variability than those on glass and exhibit delamination, particularly at currents above 1.0 mA

Fig. 11

Load-deflection results for a 2 convolution, 13.5 μm wall thickness bellows under applied pressure

Fig. 12

Constant current of 1.0 mA was applied for 15 minutes and turned off for 45 minutes for 4 cycles in a RIMS with no valve. After current was removed, and without a valve, a significant portion of the delivered volume flows in reverse during recombination (inset).

Fig. 13

Constant current of 1.0 mA was applied for 15 minutes and turned off for 45 minutes in a RIMS with no valve (n=4 consecutive runs), a commercial one-way disc valve (n=4 consecutive runs), a commercial in-line check valve (n=1), and a MEMS check valve (n=1).