Clinical Accuracy Evaluation of Sencil for Chronic Glucose Monitoring in vivo

Abstract

Objective of the study is to investigate the clinical accuracy of SencilTM for glucose monitoring in vivo. Sencilsare a family of fiber-optic sensors, providing analytes monitoring in vivo for several weeks [1-3]. The technology canbenefit not only the clinical application, but also the veterinary medicine and basic research in molecular biology.Preliminary animal implantation studies have demonstrated good chronic biocompatibility and durability [2]. Its firstapplication is to measure the interstitial glucose based on changes in fluorescence resonance energy transfer (FRET)between fluorophores bound to betacyclodextrin and concanavalin A (Con A) in a polyethylene glycol (PEG) matrix. Invitro experiments demonstrated a rapid and precise relationship between the ratio of the two fluorescent emissions andconcentration of glucose in saline for the physiological range of concentrations (0-500mg/dl) over seven weeks [1].The performance of the glucose sensor will be studied in the following two aspects:1. To characterize the coefficients of in vivo sensor based on the two-compartment model to indicate bloodglucose by measuring ISF glucose in both hyperglycemic and hypoglycemic studies.2. To test in vivo sensor response time by quantifying any delay in ISF glucose equilibration and if gradient isaffected by insulin changes (hyperglycemic and hypoglycemic studies).The steady-state precision (point accuracy) of measures in vivo (in rabbit model with glucose clamp/infusion) willbe evaluated by applying “original Clarke error grid analysis” between detection values and reference blood glucosereadings from conventional in vitro methods. The dynamic accuracy (rate accuracy) will be quantified by “continuousglucose - Clarke error grid analysis” for verifying temporal precision.In the first year, the main task will be focused on the mass production of sensor probes, and design and test therabbit jacket (customized jacket was applied on rats in reference [1]) for the in vivo studies. The physiologicalcondition of rabbit will be more realistic to the clinical simulation with certain pool of blood circulation for glucoseclamp studies and effect of skin structures) for chronic implantation studies. In the second year, the in vivocharacterization of sensor performance based on glucose clamp/infusion will be conducted on rabbits. If preliminaryresults met the clinical criteria (A+B readings > 95% in Clarke error grid analysis), a clinical trial involving 9diabetes-dog (criteria of veterinary clinical trial) will be investigated in the third year. It will be the key information toverify the clinical and marketing potential of the platform technology. Most of all, it will verify the feasibility of theglucose sensor to be the foundation for building an “artificial pancreas / beta cell”, consisting of a chronic implantablesensor, an insulin pump and a close-loop algorithm to adjust dosage continuously.

本計畫將以動物模式及活體內葡萄糖恆定技術(glucose clamp / infusion)，來探討以SencilTM 感測器長期監測活體內葡萄糖濃度的臨床精準度。Sencil 是一項光纖感測器的平台[1-3]，可用來持續偵測活體內特定生化標的物於數周間的變化情形。這項科技發展除了能應用於臨床醫療用途外，也能讓動物診療及分子生物學的基礎研究受惠。此光纖感測器在初步動物植入實驗中呈現良性的生物相容性及長期處於活體中的完整性[2]。它的第一項應用是以偵測螢光物質間因共振能量轉移產生的變化，來判讀細胞間質內的葡萄糖濃度。在模仿生理條件的活體外實驗中，它能快速及準確地以兩個不同波長的螢光強度比值來表示生理環境中的葡萄糖濃度(0-500mg/dl)。感測器的動態表現則由以下兩方面來鑑定:1. 藉由兩區間模型(two-compartment model)來確認以測得細胞間質濃度代表血醣濃度之間的相關係數。2. 在葡萄糖恆定實驗中，改變恆定濃度來探討測得細胞間質濃度與血醣濃度之間變化的時間延遲。此偵測的點精確性(point accuracy)將以偵測值與血醣參考值(由標準檢測法)之間的原始Clarke 誤差表分析(original Clarke error grid analysis)來評估。此偵測的動態精確性(rate accuracy)將由連續式葡萄糖Clarke 誤差表分析(continuous glucose - Clarke error grid analysis)來定量。本研究第一年將以大量生產實驗所需的感測器及設計測試實驗用兔子的防護衣(參考資料[1]簡述小鼠防護衣的設計和功用；對本次研究而言，兔子的體型及生理條件較符合臨床上的需求，如體循環量供葡萄醣恆定實驗與皮膚結構厚度……等)為主要任務。第二年以兔子為對象探討此感測器的準確性及動態表現。若初步結果符合臨床準確性的標準(Clarke 誤差表分析中，偵測值位於準確與良性區間達95%)，第三年將以九隻(動物用藥臨床測試標準)患糖尿病的狗為對象進行臨床測試，它將是此感測器平台能否因應臨床需求與商品化的主要指標。更重要的是它能驗證此葡萄醣感測器是否能為組成人工胰臟(內含一個長期植入式的感測器、一個胰島素幫浦和一個封閉迴路控制來調整劑量)的基礎。