從微藻萃取之類胡蘿蔔素被認為是可行的天然抗氧化劑，類胡蘿蔔素中的葉黃素 是人體眼球黃斑區之重要成分，有助於降低年齡相關性黃斑部病變(AMD)的風險。本 論文即針對以微藻生產葉黃素進行研究。本論文的第一部份，乃針對原始型 Chlorella sorokiniana MB-1 藻株及其突變株 Chlorella sorokiniana MB-1-M12 之葉黃素生產能力 進行測試。結果發現，在使用 6.0 g/L 的醋酸鈉為有機碳源進行混營培養時，原始型 藻株 MB-1 有較佳的葉黃素含量和產率，分別為 5.86 mg/g 和 2.39 mg/L/d;在相同條 件下，突變型藻株 MB-1-M12 的葉黃素生產性能優於原始型藻株，其葉黃素含量和產 率分別為 7.52 mg/g 和 3.63 mg/L/d。突變藻株 MB-1-M12 在戶外培養時，其葉黃素含 量 (6.85 mg/g)與室內培養的效果相似，但相對於可控制於全天候光照條件下的室內 培養相比，其產率 (1.35 mg/L/d)則相對降低。但大致而言，突變藻株 MB-1-M12 於戶 外培養的葉黃素生產能力相當不錯，具有進行葉黃素商業生產的潛力。
本研究的第二部分，乃藉由各項優化操作策略，提升突變藻株 MB-1-M12 於混營 培養時之葉黃素生產效率。結果顯示，採用 75%培養基置換率的半連續式培養，葉黃 素產率及葉黃素濃度分別為 6.24 mg/L/d 及 50.6 mg/L，明顯高於以批次方式和饋料批 次方式培養之效果。在模擬戶外培養條件下 (即為 35°C/25°C、12 小時/12 小時、光/ 暗循環)，可獲得最高的葉黃素產率及葉黃素濃度，分別為 3.34 mg/L/d 和 30.8 mg/L。 最後，使用 60 升管柱型光生物反應器於戶外培養突變型藻株 MB-1-M12，培養基置 換率為 75%時，可得 4.46 mg/L/d 的葉黃素產率及 27.4 mg/L 的葉黃素濃度，此結果 顯示此突變藻株於戶外培養生產葉黃素的可行性。
在本研究第三部分，乃應用此突變微藻藻株來處理台南某養蝦場的養蝦廢水。突 變型藻株 MB-1-M12 先在鹽度為 0.5%的 BG-11 培養基中生長，獲得生物量濃度及產 率分別為 4.35 g/L 及 1.56 g/L/d。當 80%的 BG-11 營養源添加到 1 升的 75%的養蝦廢 水時，葉黃素含量和產率分別提升到 5.19 mg/g 和 5.55 mg/L/d。隨後進行一種定期交 換淡水及養蝦廢水的新型操作策略，結合先前所使用的半連續培養的操作策略，可獲 得最佳的生物量及葉黃素生產，平均生物量濃度、生物量產率、葉黃素含量和葉黃素 產率分別為 3.5 g/L、1.3 g/L/d、3.89 mg/g 和 5.0 mg/L/d。
在本研究的第四部分中，評估了原始型藻株 MB-1 及其突變型藻株 MB-1-M12 的 生長、生物量產量和三種不同培養模式(光自營、混營及異營)下的葉黃素累積。突變型藻株 MB-1-M12 於異營條件下能有效生長，但葉黃素含量較低，顯示葉黃素累積需 要藉由光誘導之必要性。本研究亦針對原始型藻株 MB-1 和突變型藻株 MB-1-M12 在 自營生長條件下進行代謝分析，結果顯示，與原始型藻株 MB-1 相比，突變型藻株中 的碳同化及代謝物朝向類胡蘿蔔素生成路徑的累積增加，代表突變型藻株較原始型藻 株有利於葉黃素之代謝生產。最後，本研究採用創新之兩階段替換培養策略(自營/異 營及混營/異營培養)以提高突變型藻株 MB-1-M12 之葉黃素產量。結果顯示，使用最 佳兩階段操作的異營轉混營(TSHM)策略時，可獲得最高葉黃素含量 (6.17mg/g)和葉 黃素濃度 (33.64 mg/L)。
最後，本研究第五部分中，首先藉由光照和曝氣條件的結果，證明葉黃素的生成 受到光照及 CO2 曝氣的影響。隨後以最佳培養條件的 TSHM 系統進行實驗，獲得了 近 10 g/L 的生物量濃度和 7.42 mg/g 的葉黃素含量。透過 TSHM 系統結合饋料批次/ 半連續操作策略，葉黃素含量可提高至 6.5 mg/g 以上，而葉黃素濃度達到約 80 mg/L。 在 5 升醱酵槽中放大培養，獲得了極高的葉黃素含量 (8.71 mg/g)和濃度 (181.11 mg/L)，由此可知，突變型藻株 MB-1-M12 用 TSHM 系統生產葉黃素具有高度的可行 性。
以微藻進行葉黃素生產，除了葉黃素本身以游離形式存在之優勢外，更具有生長 速度快、高葉黃素含量及產率、減少土地及用水使用率、可使用海水培養、培養不受 季節變化限制及全年皆可收成等優勢，因此有極高的潛力能夠做為葉黃素商業化生產 之原料來源。本研究建立的兩階段葉黃素生產策略，可結合混營及異營培養之優勢， 達到雙贏的局面，顯示出此系統具有未來商業化應用之潛力。

Microalgae-derived carotenoids are increasingly being considered as feasible green alternatives for synthetic antioxidants. Lutein is a xanthophyll carotenoid found in the macular region of the human eye, which helps in reducing the risk of age-related macular degeneration (AMD). Humans are devoid of the carotenoid biosynthetic pathway, and dietary uptake of lutein is crucial in maintaining ocular health and visual acuity in older adults. Green leafy vegetables, eggs and nuts are potential lutein-rich foods, and lutein supplements are commonly used. Commercial lutein extraction utilizes the bright yellow petals of the marigold flower – Tagetus sp.. Recently, microalgae are recognized as an alternative sustainable source for beneficial health supplements such as lutein. Lutein is an essential carotenoid in green algae, participating in light-harvesting and protection of the photosynthetic apparatus against high light-induced oxidative damage. This study explores the applications of microalgal biomass as a potential source of lutein for human health supplementation.
In this context, lutein-rich microalgal strains were selected by bioprospecting, random mutagenesis and screening. Chlorella sorokiniana MB-1 was chosen as the ideal lutein-rich microalgal strain for further studies. C. sorokiniana MB-1 was then subjected to random chemical mutagenesis to arrive at high lutein yielding strains. Lutein production from the wild-type Chlorella sorokiniana MB-1 and the mutants generated by random mutagenesis were tested for their lutein productivity. The wild-type C. sorokiniana MB-1 obtained the highest lutein productivity and lutein content of 5.86 mg/g and 2.39 mg/L/day, respectively, when 6.0 g/L sodium acetate was used as the organic carbon source in mixotrophic cultivation. Under the same conditions, mutant strain MB-1-M12 had better lutein production performance than that of the wild-type strain, exhibiting a lutein content and productivity of 7.52 mg/g and 3.63 mg/L/day, respectively. Outdoor cultivation of mutant strain MB-1-M12 obtained a slightly lower lutein content of 6.85 mg/g and markedly lower productivity of 1.35 mg/L/day when compared to the indoor culture operated under well-controlled conditions with continuous illumination. The satisfactory lutein production performance from the outdoor culture of MB-1-M12 strain demonstrates the potential in commercial production of lutein using the mutant strain.
In the second part of the study, the lutein-enriched mutant, Chlorella sorokiniana MB- 1-M12 was grown mixotrophically for lutein production. The lutein production efficiency of the strain was enhanced by optimizing the operating strategies. The results show that the application of semi-continuous cultivation with a medium replacement ratio of 75% resulted in a higher lutein productivity and lutein concentration of 6.24 mg/L/d and 50.6 mg/L, respectively, which were markedly higher than those obtained from batch and fed-batch cultivation. Cultivation under simulated outdoor cultivation conditions (i.e., the temperature of 35°C/25°C for a 12 h/12 h light/dark cycle) could achieve the highest lutein productivity and lutein concentration of 3.34 mg/L/d and 30.8 mg/L, respectively. Lutein production by outdoor cultivation of MB-1-M12 strain with a 60-L tubular photobioreactor was performed using semi-continuous operation. With a medium replacement ratio of 75%, improved lutein productivity (4.46 mg/L/d) and concentration (27.4 mg/L) were obtained, indicating the feasibility of producing lutein under outdoor cultivation of the microalgal strain.
In the third part of the study, microalgal cultivation was applied as a feasible strategy for treating shrimp culture wastewater (SCW) from a shrimp farm in southern Tainan. Chlorella sorokiniana MB-1-M12 was first grown on a BG-11 medium with 0.5% salinity (mimicking the wastewater salinity), obtaining a biomass concentration and productivity of 4.35 g/L and 1.56 g/L/d, respectively. When 80% of BG-11 nutrients were added to 75% strength SCW, lutein content and productivity increased to 5.19 mg/g and 5.55 mg/L/d, respectively. A novel operation strategy involving a periodic exchange of freshwater and SCW was designed for semi-continuous cultivation of MB-1-M12 strain for optimal biomass and lutein production. The average biomass concentration, productivity, lutein content, and productivity were 3.5 g/L, 1.3 g/L/d, 3.89 mg/g, and 5.0 mg/L/d, respectively. Although microalgae have been considered as an alternative natural source of lutein, this work is among the earliest reports describing lutein production from microalgae cultivated with wastewater in a circular economy concept.
In the fourth part of the study, the lutein high-yielding strain (Chlorella sorokiniana MB-1) and its mutant derivative (Chlorella sorokiniana MB-1-M12) were evaluated for their growth, biomass production, and lutein accumulation in three different cultivation modes - photoautotrophy, mixotrophy, and heterotrophy. M12 could grow effectively under heterotrophic conditions, but the lutein content was lower, indicating the necessity of photo-induction for lutein accumulation. Metabolic analysis of MB-1 and M12 in autotrophic growth in the presence of carbon dioxide indicated that carbon assimilation and channeling of the fixed metabolites towards carotenoid accumulation was elevated in M12 compared to MB-1. Novel two-stage alternative cultivation strategies (Autotrophic/Heterotrophic and Mixotrophic/Heterotrophic cultures) were applied for enhancing lutein production in M12. Maximum lutein quantity (6.17 mg/g) and concentration (33.64 mg/L) were obtained with the TSHM (two-stage heterotrophic/mixotrophic) strategy that was determined as the best two-stage operational strategy.
In the fifth part of the study, M12 was grown under autotrophic, mixotrophic, and heterotrophic conditions for lutein production. The lutein production efficiency of the strain was enhanced via optimal cultivation conditions and a novel operation strategy. It was demonstrated that lutein production in M12 was affected by illumination (150 μmol/m2/s) and CO2 supply (2% v/v CO2). The TSHM system obtained nearly 10 g/L biomass concentration and high lutein content of 7.42 mg/g with the optimal light intensity and CO2 supply. Integration of fed-batch/semi-batch operation in the TSHM system enhanced the lutein content to >6.5 mg/g, and a lutein concentration of 80 mg/L. Scale-up in a 5-L fermenter improved the lutein content (8.71 mg/g) and concentration (181.11 mg/L), indicating the feasibility and potential of the TSHM strategy for lutein production by M12.
Microalgal lutein production has numerous advantages over their synthetic or plant-derived counterparts including the higher growth rate and lutein productivity in microalgae, the existence of lutein in the free form, non-interference with agricultural resources, and year around availability of the lutein-rich biomass for processing. The two-stage strategy for lutein production established in this study complement the shortcomings of both the mixotrophic and heterotrophic cultivation and resulted in the highest lutein productivity and yield. This system has potential applications for commercial lutein production and the realization of microalgae as a sustainable alternative for commercial lutein extraction.

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