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系統識別號 U0026-0812200911514835
論文名稱(中文) 光動力療法條件培養液對傷口癒合之研究
論文名稱(英文) Study of Conditioned Medium from Photodynamic Therapy on Wound Healing
校院名稱 成功大學
系所名稱(中) 臨床藥學研究所
系所名稱(英) Institute of Clinical Pharmacy
學年度 94
學期 2
出版年 95
研究生(中文) 陳泰宇
研究生(英文) Tai-Yu Chen
學號 s6692107
學位類別 碩士
語文別 中文
論文頁數 98頁
口試委員 指導教授-王德華
口試委員-許漢銘
指導教授-蔡瑞真
中文關鍵字 傷口癒合  光動力療法  介白素6 
英文關鍵字 wound healing  photodynamic therapy  interleukin-6 
學科別分類
中文摘要   傷口癒合是一種複雜性的生理反應修復過程,會受到許多細胞激素和胞外基質間協調控制,當生理狀況改變如糖尿病、老年、感染等會使得傷口癒合表現延緩,甚至形成慢性傷口致使組織壞死。光動力療法是在組織外加光感物質再經過特定波長光照射激發後,和組織細胞內的氧分子作用產生活性氧分子,達到選擇性消滅腫瘤細胞。近年來有文獻研究指出光動力療法能減少傷口感染且促進癒合,但目前尚未完全清楚光動力療法是透過何種機制去影響傷口癒合。由於在光動力治療過程中會刺激細胞分泌產生介白素6表達,而介白素6為傷口修復初期時所需的一種前發炎細胞激素,能加強發炎反應和活化免疫功能,促使表皮細胞移動覆蓋傷口組織,加快上皮再生形成。

  本研究目的在於探討光動力療法對於傷口癒合的影響,利用經過適當劑量光動力療法刺激角質細胞 (以基底細胞癌細胞為實驗模式) 後生成分泌之細胞激素,在體外模式下評估給予不同濃度的細胞激素對於角質細胞移動表現情形,並將細胞激素製備成凝膠劑型,進一步治療藥物誘發糖尿病小鼠之表淺擦傷與全皮層傷口,評估細胞激素凝膠應用於傷口癒合影響。

  研究結果發現在光動力療法處理後之角質細胞產生介白素6表現含量會提高,當給予含有介白素6之細胞激素時能促使角質細胞由兩側向傷口中央移動,隨著介白素6濃度增加有加快移動趨勢。接著使用Pluronic F127聚合物分子製備細胞激素凝膠,進一步治療藥物誘發糖尿病小鼠之表淺擦傷與全皮層傷口。在表淺擦傷傷口方面,各實驗組間比較並未有明顯差異,顯示含有介白素6之細胞激素對於表淺擦傷傷口癒合沒有重要影響。在全皮層傷口方面,細胞激素凝膠組比較細胞激素溶液組 (P<0.0001)、凝膠對照組 (P<0.0001) 在傷口前期癒合有加快癒合趨勢,凝膠對照組相較溶液對照組 (P<0.05) 亦有幫助癒合效果,而傷口癒合天數則無差異改變。

  從本研究結果來看,適當劑量光動力療法可能經由介白素6加以調節傷口修復過程及加快表皮細胞移動,凝膠劑型也許可作為傷口細胞激素製劑治療考量。未來研究進行方向可探討光動力療法所誘發的其他細胞激素與介白素6間在傷口修復之協同或拮抗作用,了解細胞和胞外基質彼此交互影響,說明光動力療法對於傷口癒合機制功能,將光動力療法實際應用在臨床難癒合傷口治療方面。


英文摘要  Wound healing is a dynamic and interactive process involving cytokines, cells and extracellular matrix. Impaired wound healing often exists on poor physiology conditions such as diabetes, elderly, infection, malnutrition and so forth. Photodynamic therapy (PDT) requires a photosensitizer, light and molecular oxygen. After a photosensitizer is exposed to specific wavelength of light, highly cytotoxic reactive oxygen species (ROS) are generated to kill malignant tumor cells. Previous studies had shown that PDT could reduce microbial infection and improve wound healing. However, influence of PDT on wound healing has not been clear. It is known that PDT can stimulate cells to induce expression of Interleukin-6 (IL-6), a pro-inflammatory cytokine, resulting in increased inflammation and activation of immune function. IL-6 can also promote keratinocytes migration on the wound bed and enhance reepithelialization.

 In the present study, we investigated PDT effect on wound healing in vitro and in vivo, and IL-6 may play a critical role in the repair process. First, we applied adequate PDT level to stimulate cultured basal cell carcinoma (BCC) cells to secrete cytokines, and collected the supernatants containing IL-6. In vitro wound model, we tested the ability of the conditioned medium of cultured BCC cells by PDT treatment to promote BCC cells migration. Then we prepared the conditioned medium gel using Pluronic F127 copolymer for topical use. We also evaluated effect of the conditioned medium treatment on healing of superficial abrasive and full-thickness wound in streptozotocin (STZ)- induced diabetic mice.

 The results demonstrated that cultured BCC cells produced more IL-6 after adequate PDT stimulation. In vitro wounding assay, the conditioned medium significantly quickened BCC cells migration and the migration effect was a function of IL-6 level in the conditioned medium. In diabetic wound, the conditioned medium gel vs. the conditioned medium solution or the gel control significantly enhanced wound closure on the early healing of full-thickness wound (p < 0.0001 both), although the completed healing time of wound was no different from others. Significant effect was also observed with the gel control in contrast to the medium control (p < 0.05). However, the conditioned medium gel had no effect on superficial abrasive wound healing. It indicated that the conditioned medium was not critically helpful for superficial abrasive wound healing.

 In summary, the conditioned medium of cultured BCC cells by PDT treatment can enhance BCC cells migration and wound healing in diabetic mice. In this repair process, IL-6 may have played a critical role to induce inflammation and mediate cellular signaling transduction. In addition, the copolymer gel formed an adhesive film in situ at the wound site to prevent excess water evaporation and reduce bacterial infection as wound dressing. The hydrogel can also maintain a moist environment for cell migration and serve as a protein-release carrier. Further investigation and evaluation are needed to prove PDT effect on wound healing, and to clarify the role of other cytokines involved in cellular interaction with the extracellular matrix. Most importantly, PDT can be a practical therapy for impaired chronic wounds in clinicals.


論文目次 中文摘要 I
英文摘要 III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
縮寫表 XI
第壹章 文獻回顧 1
第一節 皮膚基本構造與生理功能 1
第二節 傷口癒合 4
第三節 介白素6 13
第四節 光化學動力療法 19
第五節 Pluronic® block copolymers 26
第貳章 研究目的 30
第參章 研究材料、儀器及方法 31
第一節 實驗材料 31
第二節 儀器裝置 35
第三節 研究方法 36
第肆章 研究設計 39
第一節 細胞激素生產 39
第二節 細胞激素凝膠製備 41
第三節 細胞激素凝膠體外釋放 42
第四節 體外(in vitro)傷口癒合模式 43
第五節 生體(in vivo)傷口癒合模式 45
第伍章 研究結果 49
第一節 細胞激素凝膠體外釋放情形 49
第二節 細胞激素溶液及凝膠對體外傷口癒合之表現 52
第三節 細胞激素溶液及凝膠對體內傷口癒合之表現 59
第陸章 討論 74
第一節 ALA濃度與刺激細胞激素生成之相關性 74
第二節 細胞激素濃度對體外傷口癒合之影響 78
第三節 細胞激素對表淺擦傷傷口與全皮層傷口之癒合差異 81
第四節 凝膠劑型應用在傷口癒合之效果 84
第五節 光動力療法治療傷口癒合之可行性 85
第柒章 結論 87
參考文獻 88
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