傷口癒合的過程是由一連串複雜的生理機制所構成，可大致分為止血期、發炎期、增生期及重塑期等四個階段，而未在三個月內癒合的傷口即為慢性傷口。在傷口的癒合過程中，需要生長因子的協助，近期研究指出，新穎血管新生因子，rhTM (recombinant human thrombomodulin, rhTM)，具有EGF-like domain，可以刺激keratinocyte、fibroblast等細胞的增生、移動及誘導血管新生作用，因此具有促進慢性傷口癒合的臨床應用潛力。
蛋白質藥物的半衰期短、安定性低，因此不利於臨床使用，若是要將rhTM應用於慢性傷口的治療，需要緩慢且穩定釋出的劑型以配合傷口護理頻次。奈米結構脂質載體 (nanostructured lipid carrier, NLC) 具有保護蛋白質藥物，減緩代謝、降低劑量及持續釋放的作用。先前的研究已製成包載 rhTM 的奈米結構脂質載體 (rhTM NLC) 劑型，並證實具有促進傷口癒合的療效。本研究擬進一步添加增稠劑至rhTM NLC中，製備成rhTM NLC-gel，使藥品易於塗抹於傷口處並延長停留時間以促進藥物局部作用，增加臨床使用的便利性。
本研究首先篩選適合的增稠劑，製成rhTM NLC的凝膠劑型，並評估其粒徑大小、分布情形、介面電位、pH值、藥物釋出及安定性等。接著使用 STZ 誘導糖尿病小鼠模式，觀察給予rhTM NLC-gel後傷口癒合的情形，並透過組織切片染色評估傷口癒合的階段與完整性，同時利用人類角質細胞移行實驗評估不同劑型的細胞活性。給予不同劑型的藥物後，藉著不同採血時間rhTM的血中濃度變化，來評估不同劑型的全身暴露情形。
研究結果顯示，以0.085% Carbopol製備而成的rhTM NLC-gel仍保持原有之粒子形態、具有物理安定性以、緩釋特性，和6週內的釋出安定性。rhTM NLC及rhTM NLC-gel顯著促進 HaCaT 細胞移行和糖尿病小鼠傷口癒合，加速肉芽組織增生、表皮新生、膠原蛋白沉積和血管新生。rhTM血中濃度低而持久，可能減少 rhTM 的全身暴露而改善臨床使用的安全性。
綜合言之，包載1.2g rhTM 的 NLC與 NLC-gel 皆能顯著促進糖尿病小鼠傷口癒合，且具有較平穩的血中濃度。rhTM NLC-gel製備簡易、塗抹方便、安全性佳，具有開發為臨床應用劑型之潛力，幫助慢性傷口患者之照護。

Previous studies have demonstrated that recombinant human TM (rhTM) loaded in nanostructured lipid carrier (NLC) accelerated chronic wound healing in streptozotocin-induced diabetic mice. To further improve the clinical applications of rhTM-NLC, the study was aimed to incorporate NLC into gel form to prolong drug retention on the wound and enhance localized action for wound healing. By incorportating 0.085% Carbopol into rhTM NLC, the NLC-gel presented similar particle characteristics, and demonstrated physical stability and sustained release property. The release stability was maintained within 6 weeks. Both rhTM NLC (1.2g) and rhTM NLC-gel (1.2g) improved wound healing of diabetic mice and cell migration of HaCaT significantly. In comparison with rhTM solution, plasma concentrations of rhTM post applications of NLC and NLC-gel formulations were lower and more sustained in 24 hours. In conclusion, rhTM NLC-gel formulation is easy to prepare, convenient to apply to the wound with reduced systemic exposure, which may warrant a potential delivery system for the care of chronic wound patients.

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