Page 116 - Glucose Monitoring Devices

Glucose transduction technologies 117

reaction of glucose oxidase (coated onto the sensor tips) with glucose. In a clinical
study by Cass and coworkers, microneedles were shown to consistently penetrate
into the epidermis when applied using manual pressure and sensor readings tracked
with blood glucose readings [35]. In a second approach previously under develop-
ment by Arkal Medical (Fremont, CA), the microneedles are hollow and designed
to draw dermal interstitial fluid to the proximal, glucose oxidase-coated electrode.
A clinical study of a hollow-needle microsensor array by Arkal demonstrated a
good correlation with blood glucose readings over a 72-h wear period [21]. Biolinq
(San Diego, CA) is developing a patch sensor the size of nickel using GOx coated
onto microneedle arrays.
Profusa, Inc. (South San Francisco, CA) is developing tissue-integrating sensors
using fluorescent hydrogels that can be injected under the skin and fluorescence
intensity measured through the skin using an externally worn device. The small
size, soft (flexible) nature, and unique porous structure minimizes the foreign
body response, thus enabling long-term in vivo use time; sensors have been reported
to function 4 years after implant [31]. A sensor for oxygen (LumeeÔ) is currently
counter electrode (CE) marked and available in the EU and a glucose sensor has
been reported to be under development. The glucose sensor hydrogel technology
can conceivably be designed via either incorporation of glucose-sensing enzymes
(such as glucose oxidase) that consume oxygen, or through the incorporation of a
glucose-sensing dye in place of an oxygen-sensing dye.
Fluorescent glucose sensors that make use of the equilibrium binding between
glucose and glucose/galactose-binding protein (GGBP) have been clinically evalu-
ated by researchers at BD Technologies (Research Triangle Park, NC) [57]. The
GGBP was modified by site-specific mutagenesis to improve stability and binding
properties and was labeled with the fluorescent dye acrylodan. Reversible glucose
binding to the protein changes the protein conformation that results in a change in
the local environment around the dye and a corresponding shift in the peak fluores-
cent wavelength. The acrylodan-modified GGBP was attached to the tip of a fiber
optic that was then placed either intradermally (<1 mm) or subcutaneously
(>3 mm) through the skin. Fluorescent signals traveled through the fiber optics to
the external reader and signals were shown to correlate with blood glucose measure-
ments during the 12-h wear period.

Tissue interface for transcutaneous and subcutaneous transduction

All CGMs approved for use in the United States and the European Union are
implanted through the skin and reside within the dermal subcutaneous tissue. Conse-
quently, their functionality is dependent upon the extent by which the surrounding
human tissue reacts with the sensor. A foreign body reaction (FBR) is initiated
upon the creation of the wound during sensor insertion and may persist for the dura-
tion of the implant [1]. Short duration (acute) responses that may affect sensor per-
formance include fouling of the sensor surface by proteins, reduction in glucose and/
or oxygen in the tissue surrounding the sensor, localized decrease in pH, and