# Toward Long-Term Implantable Glucose Biosensors for Clinical Use
## 2 Materials and Methods
### Calibration
#### 2.3.2 Factory Calibration  
CGMS sensor technology of Abbot FreeStyle Libre and Dexcom G6(r) has reached factory calibration through consistent sensor manufacturing, high sensor stability, and consistent blood/subcutaneous-interstitial-fluid glucose relationship. Factory-calibrated CGM sensors remove burden of user in vivo calibration and include calibration-factor (i.e., sensor sensitivity) preprocessing into the sensor electronics during sensor manufacturing process. The first step of the factory calibration is  
\begin{table}
\begin{tabular}{c c c c} \hline \hline
**Overall Range** & **\textless{}70 mg/dL** & **70–180 mg/dL** & **\textgreater{}180 mg/dL** \\ \hline \multirow{8}{*}{within \(\pm 20\%\) error in the lower one-sided \(95\%\), in the lower one-sided \(95\%\), must exceed \(85\%\)} & within \(\pm 15\%\) error in the \(95\%\), must exceed \(85\%\) & within \(\pm 15\%\) error in the \(95\%\), must exceed \(70\%\) & within \(\pm 10\%\) error in the \(95\%\), must exceed \(80\%\) \\ \cline{1-1} \cline{2-4}  & within \(\pm 40\%\)/dL error in the lower one-sided \(95\%\), must exceed \(98\%\) & within \(\pm 40\%\) error in the \(95\%\), must exceed \(99\%\) & within \(\pm 40\%\) error in the \(95\%\), lower one-sided \(95\%\), must exceed \(99\%\) \\ \cline{1-1} \cline{2-4}  & no corresponding blood \(\phantom{\textless{}}\)glucose value shall read \(\phantom{\textless{}}\)above \(180\) mg/dL. & no corresponding blood \(\phantom{\textless{}}\)glucose value shall read \(\phantom{\textless{}}\)less than \(70\) mg/dL. \\ \hline \hline \end{tabular}
\end{table}
Table 1: Performance requirements of integrated continuous glucose monitoring system (iCGM).  
manufacturing sensor lots with low sensor-to-sensor variation. The consistent sensor manufacturing process is crucial to such quality manufacturing. The consistency is able to obtain from reproducibility of glucose-oxidase (sensor) deposition on working electrode and uniformity of glucose-limiting membrane coating. Second, laboratory-based calibration to determine the in vitro sensor sensitivity is carried out using a number of sensors from each sensor lot. The in vitro calibration is conducted at the end of sensor manufacturing process. Then, the sensor manufacturer converts the lot glucose sensitivity into a sensor code and preprograms the sensor code into the sensor electronics memory. Since the sensors are not used soon after production, the sensor sensitivity should be consistent during shelf storage. Abbott FreeStyle Libre immobilizes the enzyme in a crosslinked polymer matrix to optimize enzyme stability that determines the sensor stability. The sensor sensitivity during wear is significantly affected from sensor biocompatibility. Since subcutaneous sensors breaks skin barrier, the foreign body responses can interfere sensor signal. If sensor biocompatibility is sufficiently high to minimize the interference, the sensor sensitivity can show small variation even during long-term wear time. Abbott FreeStyle Libre, the first factory-calibrated CGM sensor, shows 14 days of the consistent sensor sensitivity. Dexcom G6(r) guarantees 10 days of the sensor stability. The last requirement of the factory calibration is the consistent relationship of glucose concentration between blood and subcutaneous-interstitial-fluid. The manufacturers assume that relationship of glucose concentration between two compartments is not different within a person at different body sites [29].