Hollow fiber-combined glucose-responsive gel technology as an in vivo electronics-free insulin delivery system

Akira Matsumoto,Hirohito Kuwata,Shinichiro Kimura,Kozue Ochi,Taiki Miyazawa,Hitoshi Ishii,Siyuan Chen,Akiko Watanabe,Hiroko Matsumoto,Miyako Tanaka,Hiroshi Inoue,Yuki Moro-Oka,Takayoshi Suganami,Taichi Nakamura,Toshiaki Baba,Yuji Miyahara,Yoshihiro Ogawa,Hiroshi Yoshida,Hironori Yamada

doi:10.1038/s42003-020-1026-x

Abstract

Accumulating evidence demonstrates that not only sustained elevation of blood glucose levels but also the glucose fluctuation represents key determinants for diabetic complications and mortality. Current closed-loop insulin therapy option is limited to the use of electronics-based systems, although it poses some technical issues with high cost. Here we demonstrate an electronics-free, synthetic boronate gel-based insulin-diffusion-control device technology that can cope with glucose fluctuations and potentially address the electronics-derived issues. The gel was combined with hemodialysis hollow fibers and scaled suitable for rats, serving as a subcutaneously implantable, insulin-diffusion-active site in a manner dependent on the subcutaneous glucose. Continuous glucose monitoring tests revealed that our device not only normalizes average glucose level of rats, but also markedly ameliorates the fluctuations over timescale of a day without inducing hypoglycemia. With inherent stability, diffusion-dependent scalability, and week-long & acute glucose-responsiveness, our technology may offer a low-cost alternative to current electronics-based approaches.

Highlights

Accumulating evidence demonstrates that sustained elevation of blood glucose levels and the glucose fluctuation represents key determinants for diabetic complications and mortality
An electronics-based “closed-loop” system represents so far the only accessible option for the patients, it poses a number of technical issues; high cost, burdensome sensor calibration, risk of electronic failures, and so on[8,9]
Our previous studies have shown that the boronate gel-based insulindiffusion control mechanism is weekly sustainable while being acutely glucose-responsive on a timescale of tens of seconds[14,15,19], features potentially meeting the current unmet needs in insulin therapy, including the management of glucose spikes

Summary

Introduction

Accumulating evidence demonstrates that sustained elevation of blood glucose levels and the glucose fluctuation represents key determinants for diabetic complications and mortality. A large-scale clinical study has shown that M-value, an indicator of blood glucose fluctuations, is highly correlated with microalbuminuria, an early symptom of diabetic nephropathy in type 1 diabetic patients[7] These findings came to develop a consensus that care must be taken to evaluate the daily blood glucose fluctuations, so-called “glucose spikes”, as much as the commonly used fasted blood glucose levels and HbA1c, in order to maximize the efficacy of the treatment. Despite this knowledge, an electronics-based “closed-loop” system (or artificial pancreas) represents so far the only accessible option for the patients, it poses a number of technical issues; high cost, burdensome sensor calibration, risk of electronic failures, and so on[8,9]. We could demonstrate in vivo a marked benefit of our device in coping with the glucose spike-like symptom over a timescale of day, to our knowledge, for the first time using an electronics-free system

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