||Study of Conditioned Medium from Photodynamic Therapy on Wound Healing
||Institute of Clinical Pharmacy
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。
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.
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
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