||The efficacy of non-thermal micro-plasma versus negative pressure for promoting surgical excision wound healing in mice : a comparative study
||Department of Materials Science and Engineering
在本活體內(In vivo)研究中，選用手術切除小鼠皮膚之傷口作為模擬急性傷口的模式。而傷口處理為將傷口暴露於實驗室開發的非熱型微電漿(Non-thermal micro-plasma)下，其為一種新興的物理性傷口處理法，本研究將非熱型微電漿與現今臨床常見的負壓處理，於傷口癒合效用上做比較。經實驗處理後，皆將傷口覆蓋上3M的透氣敷料。本實驗採用直徑6 mm的手術切除傷口並黏貼矽膠環於傷口處，並依其處理分成四組: (1) OD組(Occlusive Dressing, 敷料貼附組)、(2) OD-gf組(Occlusive Dressing + gas flow, 敷料配合氣吹組)、(3) OD+MPT5組(Occlusive Dressing + Micro-Plasma treatment 5 times, 敷料配合電漿處理組)及(4) OD+NP組(Occlusive Dressing + Negative Pressure, 敷料配合負壓處理組)，其中OD組為OD+NP組的對照組，而OD-gf組為OD+MPT5組的對照組。非熱微電漿系統以射頻電源供應器作為激發源，工作距離固定為4 mm。主要激發氣體為氬氣與氮氣，流量分別為5 slm與25 sccm。在此工作距離下，調控電漿激發功率與氮氣及氬氣混合比例進行電漿物種與溫度診斷。因此以激發功率為13 W，且氮氣混合比例為0.5%時，電漿具有溫度低於37oC和NO物種有較高之相對強度等特點，來作為實驗處理的參數。以此電漿處理參數，每天對傷口暴露30秒，並連續暴露五天。而負壓處理的參數為對傷口抽取 -90 mmHg之負壓，且每隔兩天做一次處理，並處理三次。
在活體外(Ex vivo)的實驗中，暴露由傷口組織萃取的蛋白質液體於微電漿噴流下，觀察到ROS與RNS的值會隨著微電漿暴露時間的增加而上升。在活體內(In vivo)的實驗結果中，顯示OD+MPT5組與OD+NP組有相近的傷口縮合效率、血流強度和膠原纖維分佈。在非侵入性的光學訊號與侵入性的組織切片中，於第六天的觀察結果顯示，新生上皮與肉芽組織在 OD+MPT5組與OD+NP組較OD組與OD-gf組早形成。根據以上結果推測，非熱微電漿處理能透過暴露傷口床於活性電漿物種下，進而刺激再上皮的形成，而負壓處理是透過連續擠壓與抽取傷口床，進而刺激肉芽組織的形成。故非熱微電漿處理及負壓處理於促進正常C57BL/6小鼠之手術切除傷口上皆有相近的癒合功效。
In this in vivo study, surgical excise in mice skin was employed as the indication for imitating an acute wound. The subsequent wound management was taken by negative pressure, in comparison with a novel physical method - non-thermal micro-plasma technique. A certificated dressing was subsequently covered for both techniques. In the experiment, a 6-mm-diameter surgical excision wound in mice was created. Four study-groups on both sides of mice were examined, namely, (1) occlusive dressing (OD) after gas flow (OD-gf) and OD after micro-plasma treatment with five times (OD+MPT5) for one; (2) OD-only and OD after negative pressure treatment (OD+NP) for the other. The excitation state for micro-plasma was: the generation power of 13 W, the plasma composition of Ar with 0.5% N2 (by mass flow control), the working distance of 4 mm, and the treatment time of 30 sec per wound area to treat daily for 5 days. The applied negative pressure treatment was -90 mmHg. During micro-plasma treatment on the wound area, an average temperature of 37oC and high NO content were maintained. In the ex vivo experiment on the wound tissue lysates, ROS and RNS levels might increase with micro-plasma exposure time. The in vivo study result demonstrates that OD+MPT5 and OD+NP exhibit analogous wound closure efficacy, intensity of blood flow, and detection of total collagen fibers. By comparing their optical signals and histological examinations, the formation of new epithelium in OD+MPT5 or OD+NP on 6 days wound (dw) was earlier than the control groups (OD-only or OD-gf) and the formation of granulation tissue. It is hypothesized that OD+MPT5 is competent to stimulate the formation of re-epithelialization through the coverage of reactive plasma species, while OD+NP is advantageous to stimulate the formation of granulation tissue through the continuation of extrusion and fluid removal. Both techniques are proved to have a comparable efficacy to promote surgical excision wound healing in normal C57BL/6 mice.
Extended Abstract II
第一章 緒論 1
1.1 前言 1
1.2 研究動機 2
1.3 文獻回顧 5
1.3.1 微電漿形式 5
1.3.2 非熱微電漿在動物模式上傷口癒合的可適用性 7
1.3.3 以非熱微電漿產生一氧化氮分子對傷口癒合之影響 12
1.3.4 非熱微電漿系統應用於手術傷口癒合之可適用性 14
1.4 研究目的 21
第二章 理論基礎 22
2.1 皮膚組織 22
2.1.1 表皮組織 22
2.1.2 真皮組織 22
2.1.3 皮下組織 22
2.2 傷口癒合 23
2.3 手術傷口 24
2.4 負壓傷口治療法 25
2.4.1 負壓傷口治療法簡介 25
2.4.2 負壓傷口治療法效應 27
2.5 電漿 34
2.5.1 電漿簡介 34
2.5.2 大氣電漿 35
2.5.3 微電漿 36
2.5.4 電漿中的物種與效應 40
第三章 材料與方法 44
3.1 實驗設計與流程 44
3.2 實驗材料與製備 46
3.2.1 實驗動物 46
3.2.2 傷口環(splinting ring)製作 46
3.2.3 傷口模型製作 47
3.2.4 非熱微電漿系統 48
3.2.5 負壓傷口治療(Negative pressure wound therapy)系統 51
3.3 分析儀器 53
3.3.1 光學放射光譜儀 53
3.3.2 螢光式光纖溫度計 55
3.3.3 雷射都卜勒血流分佈造影 55
3.3.4 光學同調斷層掃描 57
3.3.5 電漿活性物種動能分析 58
3.3.6 組織病理學分析 63
第四章 非熱微電漿系統診斷 67
4.1 非熱微電漿系統溫度量測 67
4.2 非熱微電漿系統之特性光譜解析 - 光學放射光譜儀 69
4.2.1 電漿全區光譜掃描分析 69
4.2.2 電漿中特定物種之光譜掃描與半定量分析 70
4.3 活性電漿物種(Reactive Plasma Species, RPS)動力學探討 74
4.3.1 活性電漿物種 - ROS 74
4.3.2 活性電漿物種 - RNS 76
第五章 非熱微電漿系統在傷口癒合速率、光學訊號與組織學的評估 80
5.1 傷口縮合效率 - 傷口面積評估法 81
5.2 非侵入性之光學訊號評估 85
5.2.1 血流分布評估 85
5.2.2 光學同調斷層掃描 89
5.3 傷口在組織學的評估 93
5.3.1 組織化學染色 - H&E stain 93
5.3.2 組織化學染色 - Masson's trichrome stain 95
5.4 非熱微電漿對促進手術傷口癒合之可能並比較負壓傷口處理法之療效 97
 M. McGuckin, R. Goldman, L. Bolton, and R. Salcido, "The clinical relevance of microbiology in acute and chronic wounds," Advances in Skin & Wound Care, vol. 16, pp. 12-23, 2003.
 S. V. Pollack, "The wound healing process," Clinics in Dermatology, vol. 2, pp. 8-16, 1984.
 A. J. Singer and A. B. Dagum, "Current Management of Acute cutaneous wounds," The New England Journal of Medicine, vol. 359, pp. 1037-1046, 2008.
 C. Harvey, "Wound Healing," Orthopaedic Nursing, vol. 24, pp. 143-157, 2005.
 P. Martin, "Wound Healing--Aiming for Perfect Skin Regeneration," Science, vol. 276, pp. 75-81, 1997.
 G. C. Gurtner, S. Werner, Y. Barrandon, and M. T. Longaker, "Wound repair and regeneration," Nature, vol. 453, pp. 314-321, 2008.
 C. Whelan, J. Stewart, and B. Schwartz, "Mechanics of Wound Healing and Importance of Vacuum Assisted Closure® in Urology," The Journal of Urology, vol. 173, pp. 1463-1470, 2005.
 L. M. Morton and T. J. Phillips, "Wound healing update," Seminars in cutaneous medicine and surgery, vol. 31, pp. 33-37, 2012.
 H. Brem and M. Tomic-Canic, "Cellular and molecular basis of wound healing in diabetes," The Journal of Clinical Investigation, vol. 117, pp. 1219-1222, 2007.
 C. Plafki, P. Peters, M. Almeling, W. Welslau, and R. Busch, "Complications and side effects of hyperbaric Oxygen therapy," Aviation, Space, and Environmental Medicine, vol. 71, pp. 119-124, 2000.
 M. P. Clare, T. C. Fitzgibbons, S. T. McMullen, R. C. Stice, D. F. Hayes, and L. Henkel, "Experience with the Vacuum Assisted Closure Negative Pressure Technique in the Treatment of Non-healing Diabetic and Dysvascular Wounds," Foot & Ankle International, vol. 23, pp. 896-901, 2002.
 H. Birke-Sorensen, M. Malmsjo, P. Rome, D. Hudson, E. Krug, L. Berg, et al., "Evidence-based recommendations for negative pressure wound therapy: treatment variables (pressure levels, wound filler and contact layer)--steps towards an international consensus," Journal of Plastic, Reconstructive & Aesthetic Surgery, vol. 64, pp. S1-S16, Sep 2011.
 N. K. Kanakaris, C. Thanasas, N. Keramaris, G. Kontakis, M. S. Granick, and P. V. Giannoudis, "The efficacy of negative pressure wound therapy in the management of lower extremity trauma: review of clinical evidence," Injury, vol. 38, pp. S9-S18, 2007.
 C. M. Moues, F. Heule, and S. E. Hovius, "A review of topical negative pressure therapy in wound healing: sufficient evidence?," The American Journal of Surgery, vol. 201, pp. 544-556, 2011.
 H. Sano and S. Ichioka, "Involvement of nitric oxide in the wound bed microcirculatory change during negative pressure wound therapy," International Wound Journal, pp. 1-5, 2013.
 S. S. Scherer, G. Pietramaggiori, J. C. Mathews, and D. P. Orgill, "Short periodic applications of the vacuum-assisted closure device cause an extended tissue response in the diabetic mouse model," Plastic and Reconstructive Surgery, vol. 124, pp. 1458-1465, 2009.
 S. S. Scherer, G. Pietramaggiori, J. C. Mathews, M. J. Prsa, S. Huang, and D. P. Orgill, "The mechanism of action of the vacuum-assisted closure device," Plastic and Reconstructive Surgery, vol. 122, pp. 786-797, 2008.
 S. Vig, C. Dowsett, L. Berg, C. Caravaggi, P. Rome, H. Birke-Sorensen, et al., "Evidence-based recommendations for the use of negative pressure wound therapy in chronic wounds: steps towards an international consensus," Journal of Tissue Viability, vol. 20, pp. S1-S18, 2011.
 W. K. Huang, C. C. Weng, J. D. Liao, Y. C. Wang, and S. F. Chuang, "Capillary-tube-based micro-plasma system for disinfecting dental biofilm," International Journal of Radiation Biology, vol. 89, pp. 364-370, 2013.
 G. Fridman, G. Friedman, A. Gutsol, A. B. Shekhter, V. N. Vasilets, and A. Fridman, "Applied Plasma Medicine," Plasma Processes and Polymers, vol. 5, pp. 503-533, 2008.
 M. Moreau, N. Orange, and M. G. Feuilloley, "Non-thermal plasma technologies: new tools for bio-decontamination," Biotechnology Advances, vol. 26, pp. 610-617, 2008.
 J. A. Pérez-Martínez, R. Peña-Eguiluz, R. López-Callejas, A. Mercado-Cabrera, R. A. Valencia, S. R. Barocio, et al., "An RF microplasma facility development for medical applications," Surface and Coatings Technology, vol. 201, pp. 5684-5687, 2007.
 K. D. Weltmann, R. Brandenburg, T. von Woedtke, J. Ehlbeck, R. Foest, M. Stieber, et al., "Antimicrobial treatment of heat sensitive products by miniaturized atmospheric pressure plasma jets (APPJs)," Journal of Physics D: Applied Physics, vol. 41, p. 194008, 2008.
 I. Langmuir, "Oscillations in Ionized Gases," Proceedings of the National Academy of Sciences, vol. 14, pp. 627-637, 1928.
 A. Schutze, J. Y. Jeong, S. E. Babayan, J. Park, G. S. Selwyn, and R. F. Hicks, "The Atmospheric-Pressure Plasma Jet: A Review and Comparison to Other Plasma Sources," IEEE Transactions on Plasma Science, vol. 26, pp. 1685-1694, 1998.
 C. Tendero, C. Tixier, P. Tristant, J. Desmaison, and P. Leprince, "Atmospheric pressure plasmas: A review," Spectrochimica Acta Part B: Atomic Spectroscopy, vol. 61, pp. 2-30, 2006.
 S. P. Kuo, C.-Y. Chen, C.-S. Lin, and S.-H. Chiang, "Applications of Air Plasma for Wound Bleeding Control and Healing," IEEE Transactions on plasma science, vol. 40, pp. 1117-1723, 2012.
 E. Garcia-Alcantara, R. Lopez-Callejas, P. R. Morales-Ramirez, R. Pena-Eguiluz, R. Fajardo-Munoz, A. Mercado-Cabrera, et al., "Accelerated mice skin acute wound healing in vivo by combined treatment of argon and helium plasma needle," Archives of Medical Research, vol. 44, pp. 169-177, 2013.
 A. B. Shekhter, V. A. Serezhenkov, T. G. Rudenko, A. V. Pekshev, and A. F. Vanin, "Beneficial effect of gaseous nitric oxide on the healing of skin wounds," Nitric Oxide, vol. 12, pp. 210-219, 2005.
 王奕程, "非熱微電漿對促進傷口癒合之效用探討," 碩士論文,台南：成功大學材料科學及工程研究所, 2013.
 Nasruddin, Y. Nakajima, K. Mukai, H. S. E. Rahayu, M. Nur, T. Ishijima, et al., "Cold plasma on full-thickness cutaneous wound accelerates healing through promoting inflammation, re-epithelialization and wound contraction," Clinical Plasma Medicine, 2014.
 M. Teschke, J. Kedzierski, E. G. Finantu-Dinu, D. Korzec, and J. Engemann, "High-speed photographs of a dielectric barrier atmospheric pressure plasma jet," IEEE TRANSACTIONS ON PLASMA SCIENCE, vol. 33, pp. 310-311, 2005.
 H.-R. Metelmann, T. T. Vu, H. T. Do, T. N. B. Le, T. H. A. Hoang, T. T. T. Phi, et al., "Scar formation of laser skin lesions after cold atmospheric pressure plasma (CAP) treatment: A clinical long term observation," Clinical Plasma Medicine, vol. 1, pp. 30-35, 2013.
 W. Funk, F. Podmelle, C. Guiol, and H. R. Metelmann, "Aesthetic satisfaction scoring - introducing an aesthetic numeric analogue scale (ANA-scale)," Journal of Cranio-Maxillo-Facial Surgery, vol. 40, pp. 439-442, 2012.
 G. Lloyd, G. Friedman, S. Jafri, G. Schultz, A. Fridman, and K. Harding, "Gas Plasma: Medical Uses and Developments in Wound Care," Plasma Processes and Polymers, vol. 7, pp. 194-211, 2010.
 V. Falanga, "Wound healing and its impairment in the diabetic foot," The Lancet, vol. 366, pp. 1736-1743, 2005.
 H. Galkowska, U. Wojewodzka, and W. L. Olszewski, "Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers," Wound Repair and Regeneration, vol. 14, pp. 558-565, 2006.
 I. Goren, E. Müller, J. Pfeilschifter, and S. Frank, "Severely Impaired Insulin Signaling in Chronic Wounds of Diabetic ob/ob Mice," The American Journal of Pathology, vol. 168, pp. 765-777, 2006.
 R. D. Galiano, O. M. Tepper, C. R. Pelo, K. A. Bhatt, M. Callaghan, N. Bastidas, et al., "Topical Vascular Endothelial Growth Factor Accelerates Diabetic Wound Healing through Increased Angiogenesis and by Mobilizing and Recruiting Bone Marrow-Derived Cells," The American Journal of Pathology, vol. 164, pp. 1935-1947, 2004.
 K. Maruyama, J. Asai, M. Ii, T. Thorne, D. W. Losordo, and P. A. D'Amore, "Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing," The American Journal of Pathology, vol. 170, pp. 1178-1191, 2007.
 D. G. Armstrong and L. A. Lavery, "Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial," The Lancet, vol. 366, pp. 1704-1710, 2005.
 S. Ichioka, H. Watanabe, N. Sekiya, M. Shibata, and T. Nakatsuka, "A technique to visualize wound bed microcirculation and the acute effect of negative pressure," Wound Repair and Regeneration, vol. 16, pp. 460-465, 2008.
 A. Sch¨utze, J. Y. Jeong, S. E. Babayan, J. Park, G. S. Selwyn, and a. R. F. Hicks, "The atmospheric-pressure plasma jet: a review and comparison to other plasma sources," IEEE Transactios on plasma science, vol. 26, pp. 1685-1694, 1998.
 K. H. Becker, K. H. Schoenbach, and J. G. Eden, "Microplasmas and applications," Journal of Physics D: Applied Physics, vol. 39, pp. R55-R70, 2006.
 K. H. Becker, N. M. Masoud, K. E. Martus, and K. H. Schoenbach, "Electron-driven processes in high-pressure plasmas," The European Physical Journal D, vol. 35, pp. 279-297, 2005.
 A. L. Garner, "Cathode spot motion in an oblique magnetic field," Applied Physics Letters, vol. 92, p. 011505, 2008.
 Y.-H. Lee, C.-H. Yi, M.-J. Chung, and G.-Y. Yeom, "Characteristics of He/O2 atmospheric pressure glow discharge and its dry etching properties of organic materials," Surface and Coatings Technology, vol. 146-147, pp. 474-479, 2001.
 J. W. Fluhr, S. Sassning, O. Lademann, M. E. Darvin, S. Schanzer, A. Kramer, et al., "In vivo skin treatment with tissue-tolerable plasma influences skin physiology and antioxidant profile in human stratum corneum," Exp Dermatol, vol. 21, pp. 130-134, 2012.
 J. Heinlin, G. Isbary, W. Stolz, G. Morfill, M. Landthaler, T. Shimizu, et al., "Plasma applications in medicine with a special focus on dermatology," Journal of the European Academy of Dermatology and Venereology, vol. 25, pp. 1-11, 2011.
 J. Heinlin, G. Morfill, M. Landthaler, W. Stolz, G. Isbary, J. L. Zimmermann, et al., "Plasma medicine: possible applications in dermatology," Journal der Deutschen Dermatologischen Gesellschaft vol. 8, pp. 968-976, 2010.
 T. von Woedtke, S. Reuter, K. Masur, and K. D. Weltmann, "Plasmas for medicine," Physics Reports, vol. 530, pp. 291-320, 2013.
 J. M. Wong and T. R. Billiar, "Regulation and Function of Inducible Nitric Oxide Synthase during Sepsis and Acute Inflammation," in Advances in Pharmacology. vol. 34, I. Louis and M. Ferid, Eds., ed: Academic Press, 1995, pp. 155-170.
 林天送, "一氧化氮醫學," 科學發展, vol. 461, pp. 72-75, 2011.
 H. Kleinert, A. Pautz, K. Linker, and P. M. Schwarz, "Regulation of the expression of inducible nitric oxide synthase," European Journal of Pharmacology, vol. 500, pp. 255-266, 2004.
 M. B. Witte and A. Barbul, "Role of nitric oxide in wound repair," The American Journal of Surgery, vol. 183, pp. 406-412, 2002.
 M. Rizk, M. B. Witte, and A. Barbul, "Nitric oxide and wound healing," World Journal of Surgery, vol. 28, pp. 301-306, 2004.
 J. L. Garcia, A. Asadinezhad, J. Pachernik, M. Lehocky, I. Junkar, P. Humpolicek, et al., "Cell proliferation of HaCaT keratinocytes on collagen films modified by argon plasma treatment," Molecules, vol. 15, pp. 2845-2856, 2010.
 M. Hoentsch, T. von Woedtke, K.-D. Weltmann, and J. Barbara Nebe, "Time-dependent effects of low-temperature atmospheric-pressure argon plasma on epithelial cell attachment, viability and tight junction formationin vitro," Journal of Physics D: Applied Physics, vol. 45, p. 025206, 2012.
 A. Villalobo, "Nitric oxide and cell proliferation," FEBS Journal, vol. 273, pp. 2329-2344, 2006.
 A. Schwentker, Y. Vodovotz, R. Weller, and T. R. Billiar, "Nitric oxide and wound repair: role of cytokines?," Nitric Oxide, vol. 7, pp. 1-10, 2002.
 B. B. Childress and J. K. Stechmiller, "Role of Nitric Oxide in Wound Healing," Biological Research For Nursing, vol. 4, pp. 5-15, 2002.
 J. Liebmann, J. Scherer, N. Bibinov, P. Rajasekaran, R. Kovacs, R. Gesche, et al., "Biological effects of nitric oxide generated by an atmospheric pressure gas-plasma on human skin cells," Nitric Oxide, vol. 24, pp. 8-16, 2011.
 郭. a. 張天長, "外傷傷口癒合與慢性傷口," 家庭醫學與基層醫療, vol. 27, pp. 414-421, 2012.
 S. Kalghatgi, G. Friedman, A. Fridman, and A. M. Clyne, "Endothelial cell proliferation is enhanced by low dose non-thermal plasma through fibroblast growth factor-2 release," Annals of Biomedical Engineering, vol. 38, pp. 748-757, 2010.
 R. Huo, Q. Ma, J. J. Wu, K. Chin-Nuke, Y. Jing, J. Chen, et al., "Noninvasive electromagnetic fields on keratinocyte growth and migration," Journal of Surgical Research, vol. 162, pp. 299-307, 2010.
 M. J. Callaghan, E. I. Chang, N. Seiser, S. Aarabi, S. Ghali, E. R. Kinnucan, et al., "Pulsed electromagnetic fields accelerate normal and diabetic wound healing by increasing endogenous FGF-2 release," Plastic and Reconstructive Surgery, vol. 121, pp. 130-141, 2008.
 X. Wang, J. Ge, E. E. Tredget, and Y. Wu, "The mouse excisional wound splinting model, including applications for stem cell transplantation," Nature Protocols, vol. 8, pp. 302-309, 2013.
 C. I. Wright, C. I. Kroner, and R. Draijer, "Non-invasive methods and stimuli for evaluating the skin's microcirculation," Journal of Pharmacological and Toxicological Methods, vol. 54, pp. 1-25, 2006.
 E. R. La Hei, A. J. Holland, and H. C. Martin, "Laser Doppler imaging of paediatric burns: burn wound outcome can be predicted independent of clinical examination," Burns, vol. 32, pp. 550-553, 2006.
 P. G. McGuire and T. R. Howdieshell, "The importance of engraftment in flap revascularization: confirmation by laser speckle perfusion imaging," Journal of Surgical Research, vol. 164, pp. 201-212, 2010.
 K. Sahu, Y. Verma, M. Sharma, K. D. Rao, and P. K. Gupta, "Non-invasive assessment of healing of bacteria infected and uninfected wounds using optical coherence tomography," Skin Research and Technology, vol. 16, pp. 428-437, 2010.
 M. J. Cobb, Y. Chen, R. A. Underwood, M. L. Usui, J. Olerud, and X. Li, "Noninvasive assessment of cutaneous wound healing using ultrahigh-resolution optical coherence tomography," Journal of Biomedical Optics vol. 11, p. 064002, 2006.
 T. Gambichler, G. Moussa, M. Sand, D. Sand, P. Altmeyer, and K. Hoffmann, "Applications of optical coherence tomography in dermatology," Journal of Dermatological Science, vol. 40, pp. 85-94, 2005.
 K. H. Kim, M. C. Pierce, G. Maguluri, B. H. Park, S. J. Yoon, M. Lydon, et al., "In vivo imaging of human burn injuries with polarization-sensitive optical coherence tomography," Journal of Biomedical Optics, vol. 17, p. 066012, 2012.
 M. Boone, G. B. Jemec, and V. Del Marmol, "High-definition optical coherence tomography enables visualization of individual cells in healthy skin: comparison to reflectance confocal microscopy," Experimental Dermatology, vol. 21, pp. 740-744, 2012.
 K. G. Phillips, Y. Wang, D. Levitz, N. Choudhury, E. Swanzey, J. Lagowski, et al., "Dermal reflectivity determined by optical coherence tomography is an indicator of epidermal hyperplasia and dermal edema within inflamed skin," Journal of Biomedical Optics, vol. 16, p. 040503, 2011.
 J. F. de Boer, S. M. Srinivas, B. H. Park, T. H. Pham, Z. Chen, T. E. Milner, et al., "Polarization Effects in Optical Coherence Tomography of Various Biological Tissues," The IEEE Journal of Selected Topics in Quantum Electronics vol. 5, pp. 1200-1204, 1999.
 M. Kuck, H. Strese, S. A. Alawi, M. C. Meinke, J. W. Fluhr, G. J. Burbach, et al., "Evaluation of optical coherence tomography as a non-invasive diagnostic tool in cutaneous wound healing," Skin Research and Technology, vol. 20, pp. 1-7, 2014.
 A. A. Alfadda and R. M. Sallam, "Reactive oxygen species in health and disease," Journal of Biomedicine and Biotechnology, vol. 2012, pp. 1-14, 2012.
 P. Newsholme, E. Rebelato, F. Abdulkader, M. Krause, A. Carpinelli, and R. Curi, "Reactive oxygen and nitrogen species generation, antioxidant defenses, and beta-cell function: a critical role for amino acids," Journal of Endocrinology, vol. 214, pp. 11-20, 2012.
 M. D. Maria B. Witte and M. D. Adrian Barbul, "Role of nitric oxide in wound repair," The American Journal of Surgery, vol. 183, pp. 406-412, 2002.
 E. Garcia-Alcantara, R. Lopez-Callejas, P. R. Morales-Ramirez, R. Pena-Eguiluz, R. Fajardo-Munoz, A. Mercado-Cabrera, et al., "In Vivo Accelerated Acute Wound Healing in Mouse Skin Using Combined Treatment of Argon and Helium Plasma Needle," Archives of Medical Research, vol. 44, pp. 169-177, 2013.
 N. A. Mauskar, S. Sood, T. E. Travis, S. E. Matt, M. J. Mino, M. S. Burnett, et al., "Donor site healing dynamics: molecular, histological, and noninvasive imaging assessment in a porcine model," Journal of Burn Care & Research, vol. 34, pp. 549-562, 2013.
 S. Werner and R. Grose, "Regulation of Wound Healing by Growth Factors and Cytokines," Physiological reviews, vol. 83, pp. 835-870, 2003.
 K. Safferling, T. Sutterlin, K. Westphal, C. Ernst, K. Breuhahn, M. James, et al., "Wound healing revised: a novel reepithelialization mechanism revealed by in vitro and in silico models," The Journal of Cell Biology, vol. 203, pp. 691-709, 2013.
 王德華, "光動力療法," 科學發展, vol. 403, pp. 28-33, 2006.
 P. Babilas, S. Schreml, M. Landthaler, and R. M. Szeimies, "Photodynamic therapy in dermatology: state-of-the-art," Photodermatol Photoimmunol Photomed, vol. 26, pp. 118–132, 2010.