201710090108Diabetic Retinopathy)非侵入式光電快速濃縮晶片[:篩檢;糖尿病視網膜病變];之發展與研究 FY2012

非侵入式光電快速濃縮晶片篩檢糖尿病視網膜病變之發展與研究 FY2012~

Conventionally the examination of the early-stage diabetic retinopathy heavily relies on the ophthalmologist’s clinical experience. However, the diagnosis per se is usually very biasing according to every doctor’s professional knowledge and subjective opinion. The uncertainty   may defer the patient’s “golden time” to undergo an appropriate treatment. As reported, diabetes has become one of the top 10 modern diseases, which accounts for a population of 82 million blind people in the world. Taking this into consideration, establishing a quantitative and objective diagnosis to this disease will not only improve the human health but also mitigate the needs for medical care imposed on the society.

Since tears directly contact with eye balls, they are regarded as one of the ideal sample sources from patients for non-invasive diagnoses. Multiple proteins in the tears have been identified as the biomarkers in the initial formation of diabetic retinopathy. Although other sources, such as blood and saliva, may contain the same biomarkers, complex preprocessing, cross-contamination, varying composition, and invasive sampling make them inferior to tears. In contrast, tears have a relatively simple composition of filtered proteins, increasing their reliability. However, the actual practice remains difficult due to insufficient samples and low volume of a tear drop. To concentrate the samples to a level that can be detected, we therefore aim to develop a screening tool for rapid concentration and sensing based on the optoelectric effect in this project. With the tool, several protein biomarkers can be concentrated and detected in a minute without off-chip preprocessing. The prior study has proven that the simultaneous surges of some proteins, such as Lipocalin I, lactotransferrin, lacritin, and Ig lambda, have potential connections to the specific diabetic retinopathy. Consequently this unique indication can be utilized to assist ophthalmologists to diagnose their patients with the disease in the early stage more precisely.

The rapid concentration and sensing microchip is based on a self-developed optoelectric manipulation technique. After a tear drop is added into the microchip, it will be moved to the central reaction region by means of optoelectrowetting (OEW). Similarly, modified latex particles suspended in the buffer will be moved to the same region and mix with the samples. In this phase, mixing is achieved by the rapid electrokinetic patterning (REP) induced toroidal vortices. When the target proteins are concentrated and bound to the particles, fluorescence will be measured. By quantifying all of the protein biomarkers, a reliable diagnosis and a subsequent treatment can be made by a doctor accordingly. 

Specifically the optoelectrically-enabled microchip developed in this project will be an efficient tool in the clinical diagnosis of the diabetic retinopathy. Furthermore, the same technique with different modified particles can be used to diagnose other diseases with very low-dose samples as well. The success of this research may lead to a commercialized product and diversified developments. This project is a joint international collaboration between the Biomedical Engineering at National Cheng Kung University and the Mechanical Engineering at Pusan National University in Korea. The research team (Prof. Chuang, Prof. Shieh, and MD. Chiu) in Taiwan will be working on optoelectronics, chip design, and disease diagnosis; the research team in Korea (Prof. Kim) will focus on chip characterization and model simulations. We believe that the integration of the expertise in both sides will strengthen the project. It is also expected that the collaboration will facilitate the final product to enter the markets of medical devices in both countries eventually.

 

傳統上糖尿病引起的先期視網膜病變(Diabetic Retinopathy)主要依賴眼科醫師的臨床經驗來診斷是否需要治療。然而這當中涉及醫師本身的專業素養與主觀意識,因此往往無法達到客觀的判斷,造成病患可能延誤治療的時機。隨著現代人飲食習慣的快速改變,糖尿病已成為排名前十大的主要文明病,並造成全世界8200萬失明人口。若能快速、有效且客觀地早期診斷糖尿病視網膜病變,將有助於提升國民生活健康,降低社會成本。

淚液由於直接接觸眼球,因此成為非侵入式視網膜檢測最佳的活體生物樣本來源。藉由分析其中的成分,可發現多種指標性的蛋白(Biomarkers)在視網膜病變初期所產生的起伏變化。其他的取樣來源,包括血液與唾液等,由於涉及侵入式行為、樣本交互汙染或前處理程序過度複雜,因此除了必須動用更多的分離手段外,檢驗結果也不甚可靠。淚液相對便顯得簡化許多。然而淚液本身雖已預先排除相當多的背景雜質,產生相對純化的樣本,但是其樣本濃度與可收集的淚液量卻相當低,造成實際檢測困難。為有效提升局部可檢測的濃度,本計畫擬提出一種新型的濃縮檢測裝置。以額外增加處裡樣本的條件下,濃縮欲檢測的指標性蛋白。預期可在短時間內(<1分鐘)完成檢定並產生預測結果。先前研究已顯示Lipocalin ILactotransferrinLacritinIg lambda等蛋白在淚液中升高對於糖尿病視網膜病變具有關連性。我們因此欲同時檢測Lipocalin ILacritin希望對該疾病的預測可以提供更高的專一性,便於有效、快速地協助臨床醫師在現場立即診斷且不會與其他眼部病變產生混淆。

本計畫中所使用的快速濃縮檢測晶片是採用我們過去所開發的光電操控技術。在淚液樣本加入晶片後,利用光電濕潤法(Optoelectrowetting, OEW)將樣本移動到晶片中心的處理區。另外再將表面修飾過的乳膠粒子加入另外準備的緩衝液(Buffer)中,同樣利用OEW將液珠移動到中心與樣本混合。混合時利用光所誘發之電熱梯度形成三維環狀渦流快速攪拌動作,將樣本與乳膠粒子帶到中心區域反應。與樣本反應後的乳膠粒子受到電場誘發偶極,因此被吸引聚集在中心區域。藉由樣本濃縮後反應在粒子上所產生的螢光,可以測定目標蛋白的實際含量進而預測眼角膜因糖尿病產生病變的可能性。量化結果可做為醫師接下來應行治療手段的重要依據。

具體來說,本研究中所開發的光電式快速濃縮檢測晶片預期可成為臨床上診斷糖尿病引發視網膜病變的一項有效利器。不僅如此,在同樣技術的基礎下,該晶片也可以藉由改變不同表面修飾的乳膠粒子來檢測其他微含量的疾病蛋白。因此該晶片的成功開發將具有商業化的價值與多樣性的發展。本計畫聯合成大工系莊漢聲助理教授、成大口醫所所長謝達斌教授、新營署立醫院眼科醫師邱含菁與韓國釜山國立大學機械系Prof. K.C. Kim實驗室團隊共同開發此項快速濃縮檢測晶片,分別由台灣方面負責光電技術、晶片設計與疾病檢測;而韓國方面負責晶片特性測試與理論模擬分析。藉由結合兩方面的專長,預期可以提升本計畫的成功機率。最終規劃將本產品逐步導入兩國醫材市場。

功能:檢眼鏡主要用來檢查視網膜之黃斑部及視神經有無病變。
眼底鏡:直接眼底鏡眼底檢查,不需散曈,是一項簡單,快速,準確,便宜的檢查。除了可以

診斷腦瘤之外,一些眼底的病變如青光眼,視神經炎,黃斑部病變,也可經由直接眼底鏡眼底檢查發現。
如果我們將光線照射到眼珠裡面,我們就可看到眼底,包括視網膜和血管。1851年,赫姆霍茲(Helmholtz)發明了一個半透鏡,能將外來的光反射至病人的眼睛內,加上校正度數的鏡片,醫生經由半透鏡中3mm直徑的洞,就可以看到病人的眼底。後來半透鏡換成銀色的鏡子,中間也有個洞,就明亮多了。  
由於血管能夠直接看到的就是在眼底,因此眼底鏡一個很重要的用途就是看糖尿病視網膜病變,作為糖尿病視網膜病變併發症的篩檢工具。

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