以透明質酸水膠作為長效釋放藥物載體進行慢性肌腱病變治療

The Preparation and Evaluation of Hyaluronate-Based Hydrogel as Sustained Release Drug Carrier for Tendinopathy

蕭名彥(Ming-Yen Hsiao)

指導教授 ： 林峯輝

共同指導教授 ： 陳文翔

國立臺灣大學/工學院/醫學工程學研究所/博士(2019年)

https://doi.org/10.6342/NTU201901791

摘要

肌腱病變 ( Tendinopathy) 是臨床上最常見的退化性疾病之一，占了接近三分之一的肌肉骨骼系統疾患，常造成慢性疼痛，影響病患之日常生活功能及生活品質甚劇。一般認為造成肌腱病變成的病因為過度使用造成反覆微小創傷(accumulative microtraumas)、癒合不良(impaired healing)以及氧化壓力(oxidative stress)等。由於對其病理機轉未能完全了解，肌腱病變目前的處置上多以症狀控制、休息及活動調整為主，並無好的特異性根本治療；許多治療需要冗長的療程及重複注射，並且很少能真正改變疾病的惡化。
本研究以合成氧化透明質酸(hyaluronic acid, HA)與己二酸醯肼 ( Adipic dihydrazide, ADH)的交聯水膠(oxi-HA/ADH)作為本身對於肌腱病變即具有治療效用的藥物載體，並結合其他治療藥物，達到藥物緩釋的作用。目的是由疾病的病生理學進行特異性治療，同時減少氧化壓力及促進肌腱癒合過程，以早期阻斷肌腱病變的產生。
細胞實驗中，本研究創新設計一差別形變週期拉伸裝置(differential uniaxial tensile strain bioreactor)，可以使用同一機具、在同一群培養細胞同時進行不同形變量的拉伸，以模擬細胞在正常生理及過度受力之病理狀態。本裝置將使實驗變因更嚴格控制。在大鼠肌腱病變細胞模型結果發現，具抗氧化作用的兒茶素 (epigallocatechin gallate, EGCG)以及細胞保護作用的藥物吡拉西坦 (piracetam)可以減少肌腱細胞在週期性高拉伸應力下的異常分化基因表現，顯示抑制氧化壓力可能是治療肌腱病變的有效方法之一。
以水膠做為兒茶素的藥物載體具有緩釋的藥物釋放特性。水膠本身在大鼠肌腱病變細胞模型(週期性高拉伸應力)及活體模型(膠原蛋白酶注射)都具有治療效果；水膠結合兒茶素後對於肌腱病變有更好的抑制效果，在活體模型中有效減少了膠原蛋白酶注射後造成的肌腱病變現象，如膠原蛋白結構散亂、細胞增生及血管新生等，也抑制了肌腱細胞的異常分化基因表現。
本研究結果指出，在肌腱病變的早期以不同藥物分別阻斷不同病生理路徑可能是未來治療肌腱病變的方向，特別是減少氧化壓力及促進癒合過程，提供了有效解決肌腱病變治療的可能策略。本研究建立的肌腱病變實驗模組及藥物載體未來將可應用於肌腱病變病生理學的基礎研究，以及開發潛在的疾病治療標的。

關鍵字

肌腱病變 ； 透明質酸 ； 水膠 ； 緩釋 ； 藥物載體 ； 抗氧化

並列摘要

Resulting from accumulative microtraumas, impaired healing and oxidative stress, tendinopathy is a debilitating and relentlessly deteriorating disease that greatly affects daily function and quality of life. Current therapy usually provides symptomatic relief only, partly because of incomplete understanding of the pathophysiology of the disease. Sufferers undergo repetitive and protracted treatment courses that rarely alter the disease process.
We developed a sustained-release regimen with an intrinsic therapeutic effect in tendinopathy treatment, using oxidised hyaluronic acid/adipic acid dihydrazide hydrogel (oxi-HA/ADH) as both the drug carrier and a mitigating agent of symptoms. By facilitating the healing process and mitigating oxidative stress, we attempt to halt tendinopathy early in the disease course.
A novel bioreactor that can exert different ranges of cyclic uniaxial tensile strain on the cultured cells simultaneously was fabricated, which enables the simulation of both physiological and pathological (mechanical overloaded) status with otherwise identical experimental conditions. The results showed that the potent antioxidative (epigallocatechin gallate, EGCG) and the cytoprotecitve medication (piracetam) could diminish the expression of genes representing aberrant tenocyte differentiation in the rat cell model of tendinopathy induced by cyclic uniaxial stretching, indicating that eliminating oxidative stress could be a potential strategy in the treatment of tendinopathy.
EGCG incorporated into oxi-HA/ADH showed sustained-release properties. Oxi-HA/ADH itself could mitigate tendinopathy changes both in vitro (cyclic stretching induced tendinopathy model) and in vivo (collagenase injection-induced tendinopathy model). In addition, EGCG-loaded oxi-HA/ADH conferred an additional protective effect in both models, including alleviating disorganisation of the collagen fibres, hypercellularity and hypervascularity, and decreasing the expression of genes representing aberrant tenocyte differentiation.
The regimen opens a new window of tendinopathy treatment, in which the relentlessly degenerative process of tendinopathy is arrested at an early stage by inducing multiple pathways, including the healing process and oxidative stress mitigation. The established experimental model and drug carrier system provide a platform for exploring pathophysiology of tendinopathy as well as new therapeutics against this debilitating disease.

並列關鍵字

tendinopathy ； hyaluronic acid ； hydrogel ； sustained-release ； drug carrier ； antioxidative

參考文獻

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