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J Diabetes Sci Technol. 2016 September; 10(5): 1192–1194.
Published online 2016 March 17. doi:  10.1177/1932296816640542
PMCID: PMC5032950

Preliminary Evaluation of a Long-Term Intraperitoneal Glucose Sensor With Flushing Mechanism

Lauren M. Huyett, BS,1, Rowena Mittal, PhD,2, Howard C. Zisser, MD,1 Evan S. Luxon, MS,2 Alex Yee, MS,2 Eyal Dassau, PhD,1,3 Francis J. Doyle, III, PhD,1,3 and Daniel R. Burnett, MD, MBA2

Encapsulation is known to deteriorate the performance of subcutaneous (SQ) continuous glucose monitors (CGMs), preventing these devices from meeting the long-term functionality requirements for widespread use and creating a bottleneck in artificial pancreas (AP) development.1,2 While recent studies of implanted SQ sensors have shown promising results, there is still much room for improvement, including the reduction of encapsulation-induced sensor lag.3,4 We present a proof-of-concept study of a novel flushing assembly to routinely clean the sensor surface, thereby prolonging its lifetime. Placing the sensor in the intraperitoneal (IP) space allows flushing with saline that would not be possible in the restricted SQ space.

Fluorescent glucose sensors were implanted in the SQ or IP space of sheep. Sensors were provided by the manufacturer in a lengthened, tethered format. The IP sensors were modified with silicone tubing, flush port, Dacron cuff, and adaptors to allow flushing with saline solution. Experiments were conducted under an IACUC-approved protocol by BioSurg, Inc (Davis, CA). After preliminary testing to optimize the flushing procedure, long-term responsiveness was evaluated with an IP sensor placed in 1 sheep and an SQ sensor placed in a second sheep. The IP sensor was flushed weekly with saline. Glucose response challenges were performed periodically over 3 months by infusing 0.5 g/kg dextrose through an ear vein over 60 s (13 challenges over 114 days for IP, 9 challenges over 91 days for SQ). The results are summarized in Figure 1.

Figure. 1.
Demonstration of the sensor signal response to intravenous glucose challenge. (A) Representative signal response curves to intravenous glucose challenge from sensor in the IP space, which was flushed. The solid, dashed, and dash-dot lines represent days ...

The IP sensor demonstrated anomalously slow response during the first challenge (day 8) due to tissue trauma following implantation, which is known to cause inflammatory response.3 Excluding day 8, the IP sensor maintained consistent responsiveness throughout the 114-day period, with time to half-maximum (t1/2) between 2.7 and 4.7 min and time to maximum (tmax) between 11.6 and 17.2 min. Conversely, the nonflushed sensor in the SQ space gradually lost responsiveness, with t1/2 between 2.6 and 13.5 min and tmax between 9.7 and 72 min. By 91 days following implantation, the SQ sensor signal did not peak within the 60-min testing period (see Figure 1B).

The development of long-term implantable CGMs is a key step toward making this technology more practical; however, CGM performance is hindered by diffusion lag and loss of sensitivity caused by encapsulation driven by the foreign body response.2,3 The IP space has already been shown to be valuable to AP applications, with experimental evidence showing both faster insulin action and faster glucose sensing in this space.5,6 The performance of the flushed IP sensor presented here far exceeded that of the conventional SQ sensor after long implantation periods, showing promise for further investigation of the flushing method.

This proof-of-concept study introduces the use of a flushing mechanism to allow CGM in the IP space with consistent responsiveness during 3 months in vivo. Future iterations of this system will utilize automated flushing of the sensing element with small volumes of fluid drawn from the patient’s bodily fluids. Data generated from this study will guide the development of an IP CGM to enable an implantable AP and improve practicality of CGM use for day-to-day diabetes therapy.

Acknowledgments

We would like to thank Dr Brett D. Mensh for helpful discussions in early stages of this work and Marcie Hamilton for operational management at Theranova. DRB is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

Abbreviations: AP, artificial pancreas; CGM, continuous glucose monitor; IP, intraperitoneal; SQ, subcutaneous.

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DRB is a founder and CEO of Theranova, LLC. He is a coinventor of patents related to the device reported here. Theranova, LLC is the owner and developer of an intraperitoneal artificial pancreas and holds multiple patents related to this product. ESL and AY are employees of Theranova, LLC and co-inventor of patents related to the device. HCZ is a paid consultant to Theranova. DRB, ESL, and AY have equity interests in the artificial pancreas technology. LMH from UCSB, and ED and FJD from UCSB and Harvard do not have any competing financial interests in this work that could be perceived as a conflict of interest.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Helmsley Charitable Trust Foundation grant 2014PG-T1D008. The work by the team at UCSB and Harvard was supported by the National Institutes of Health (NIH) grant DP3DK101068.

References

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3. Wang Y, Vaddiraju S, Gu B, Papadimitrakopoulos F, Burgess DJ. Foreign body reaction to implantable biosensors: effects of tissue trauma and implant size. J Diabetes Sci Technol. 2015;9(5):966-977. [PMC free article] [PubMed]
4. Dehennis A, Mortellaro MA, Ioacara S. Multisite study of an implanted continuous glucose sensor over 90 days in patients with diabetes mellitus. J Diabetes Sci Technol. 2015;9(5):951-956. [PMC free article] [PubMed]
5. van Dijk PR, Logtenberg SJJ, Gans ROB, Bilo HJG, Kleefstra N. Intraperitoneal insulin infusion: treatment option for type 1 diabetes resulting in beneficial endocrine effects beyond glycaemia. Clin Endocrinol (Oxf). 2014;81(4):488-497. [PubMed]
6. Burnett DR, Huyett LM, Zisser HC, Doyle FJ, III, Mensh BD. Glucose sensing in the peritoneal space offers faster kinetics than sensing in the subcutaneous space. Diabetes. 2014;63(7):2498-2505. [PMC free article] [PubMed]

Articles from Journal of Diabetes Science and Technology are provided here courtesy of Diabetes Technology Society