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人工细胞 (查看源代码)

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===History===

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历史

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In the 1960s [[Thomas Chang]] developed microcapsules which he would later call "artificial cells", as they were cell-sized compartments made from artificial materials.<ref>{{cite journal | vauthors = Chang TM | title = SEMIPERMEABLE MICROCAPSULES | journal = Science | volume = 146 | issue = 3643 | pages = 524–525 | date = October 1964 | pmid = 14190240 | doi = 10.1126/science.146.3643.524 | s2cid = 40740134 | bibcode = 1964Sci...146..524C }}</ref> These cells consisted of ultrathin membranes of nylon, collodion or crosslinked protein whose [[semipermeable]] properties allowed [[diffusion]] of small molecules in and out of the cell. These cells were micron-sized and contained [[Cell (biology)|cells]], [[enzymes]], [[hemoglobin]], magnetic materials, [[adsorption|adsorbents]] and [[proteins]].<ref name="Chang 2007" />

In the 1960s Thomas Chang developed microcapsules which he would later call "artificial cells", as they were cell-sized compartments made from artificial materials. These cells consisted of ultrathin membranes of nylon, collodion or crosslinked protein whose semipermeable properties allowed diffusion of small molecules in and out of the cell. These cells were micron-sized and contained cells, enzymes, hemoglobin, magnetic materials, adsorbents and proteins.

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~~= = 历史 = =~~ 20世纪60年代，托马斯 · 张研制出了微囊，后来他称之为“人造细胞”，因为它们是由人造材料制成的细胞大小的隔间。这些细胞由尼龙、火棉胶或交联蛋白质的超薄膜组成，其半透性特性使得小分子可以扩散进出细胞。这些细胞是微米大小，含有细胞，酶，血红蛋白，磁性材料，吸附剂和蛋白质。

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20世纪60年代，托马斯 · 张研制出了微胶囊，由于它们是由人造材料制成的细胞大小的隔室，后来他称之为“人工细胞”。这些细胞由尼龙、火棉胶或交联蛋白质的超薄膜组成，其半透性使得小分子可以扩散进出细胞。这些细胞是微米大小，含有细胞，酶，血红蛋白，磁性材料，吸附剂和蛋白质。

Later artificial cells have ranged from hundred-micrometer to nanometer dimensions and can carry microorganisms, [[vaccines]], [[genes]], drugs, [[hormones]] and [[peptides]].<ref name="Chang 2007" /> The first clinical use of artificial cells was in [[hemoperfusion]] by the encapsulation of [[activated charcoal]].<ref name="Chang 1996">{{cite journal | vauthors = Chang TM | title=Editorial: past, present and future perspectives on the 40th anniversary of hemoglobin based red blood cell substitutes | journal=Artificial Cells Blood Substit Immobil Biotechnol | year=1996 | volume=24 | pages=ixxxvi }}</ref>

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Later artificial cells have ranged from hundred-micrometer to nanometer dimensions and can carry microorganisms, vaccines, genes, drugs, hormones and peptides. The first clinical use of artificial cells was in hemoperfusion by the encapsulation of activated charcoal.

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后来人造细胞的尺寸从百微米到纳米不等，可以携带微生物、疫苗、基因、药物、激素和多肽。人工细胞的第一次临床应用是以药用活性炭为包囊进行血液灌流。

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后来人工细胞的尺寸从百微米到纳米不等，可以携带微生物、疫苗、基因、药物、激素和多肽。人工细胞的第一次临床应用是以药用活性炭为包囊进行血液灌流。

In the 1970s, researchers were able to introduce enzymes, proteins and hormones to biodegradable microcapsules, later leading to clinical use in diseases such as [[Lesch–Nyhan syndrome]].<ref>{{cite journal | vauthors = Palmour RM, Goodyer P, Reade T, Chang TM | title = Microencapsulated xanthine oxidase as experimental therapy in Lesch-Nyhan disease | journal = Lancet | volume = 2 | issue = 8664 | pages = 687–688 | date = September 1989 | pmid = 2570944 | doi = 10.1016/s0140-6736(89)90939-2 | s2cid = 39716068 }}</ref> Although Chang's initial research focused on artificial [[red blood cells]], only in the mid-1990s were biodegradable artificial red blood cells developed.<ref>{{cite book | vauthors = Chang TM | title=Blood substitutes | year=1997 | publisher=Karger | location=Basel | isbn=978-3-8055-6584-4 }}</ref> Artificial cells in biological cell encapsulation were first used in the clinic in 1994 for treatment in a diabetic patient<ref>{{cite journal | vauthors = Soon-Shiong P, Heintz RE, Merideth N, Yao QX, Yao Z, Zheng T, Murphy M, Moloney MK, Schmehl M, Harris M | display-authors = 6 | title = Insulin independence in a type 1 diabetic patient after encapsulated islet transplantation | journal = Lancet | volume = 343 | issue = 8903 | pages = 950–951 | date = April 1994 | pmid = 7909011 | doi = 10.1016/S0140-6736(94)90067-1 | s2cid = 940319 }}</ref> and since then other types of cells such as [[hepatocytes]], adult [[stem cells]] and genetically engineered cells have been encapsulated and are under study for use in tissue regeneration.<ref>{{cite journal | vauthors = Liu ZC, Chang TM | title = Coencapsulation of hepatocytes and bone marrow stem cells: in vitro conversion of ammonia and in vivo lowering of bilirubin in hyperbilirubemia Gunn rats | journal = The International Journal of Artificial Organs | volume = 26 | issue = 6 | pages = 491–497 | date = June 2003 | pmid = 12894754 | doi = 10.1177/039139880302600607 | s2cid = 12447199 }}</ref><ref>{{cite journal | vauthors = Aebischer P, Schluep M, Déglon N, Joseph JM, Hirt L, Heyd B, Goddard M, Hammang JP, Zurn AD, Kato AC, Regli F, Baetge EE | display-authors = 6 | title = Intrathecal delivery of CNTF using encapsulated genetically modified xenogeneic cells in amyotrophic lateral sclerosis patients | journal = Nature Medicine | volume = 2 | issue = 6 | pages = 696–699 | date = June 1996 | pmid = 8640564 | doi = 10.1038/nm0696-696 | s2cid = 8049662 }}</ref>

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In the 1970s, researchers were able to introduce enzymes, proteins and hormones to biodegradable microcapsules, later leading to clinical use in diseases such as Lesch–Nyhan syndrome. Although Chang's initial research focused on artificial red blood cells, only in the mid-1990s were biodegradable artificial red blood cells developed. Artificial cells in biological cell encapsulation were first used in the clinic in 1994 for treatment in a diabetic patient and since then other types of cells such as hepatocytes, adult stem cells and genetically engineered cells have been encapsulated and are under study for use in tissue regeneration.

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在20世纪70年代，研究人员能够将酶、蛋白质和激素引入到可生物降解的微胶囊中，后来这种微胶囊在诸如莱希－尼亨氏症候群之类的疾病中得到临床应用。尽管 Chang 最初的研究集中在人造红细胞上，但直到20世纪90年代中期，才出现了可生物降解的人造红细胞。1994年，生物细胞封装的人工细胞首次在临床上用于治疗糖尿病患者，此后，其他类型的细胞，如肝细胞、成体干细胞和基因工程细胞已被封装，并正在研究用于组织再生。

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在20世纪70年代，研究人员能够将酶、蛋白质和激素引入到可生物降解的微胶囊中，后来这种微胶囊在诸如莱希－尼亨氏症候群之类的疾病中得到临床应用。尽管张最初的研究集中在人工红细胞上，但直到20世纪90年代中期，才出现了可生物降解的人工红细胞。1994年，生物细胞封装的人工细胞首次在临床上用于治疗糖尿病患者，此后，其他类型的细胞，如肝细胞、成体干细胞和基因工程细胞已被封装，并正在研究用于组织再生。

===Materials===

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= = = 材料 = =

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[[File:Artificial cell membranes.png|thumb|450px|Representative types of artificial cell membranes.|链接=Special:FilePath/Artificial_cell_membranes.png]]

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[[File:Artificial cell membranes.png|thumb|450px|Representative types of artificial cell membranes.典型的人工细胞膜。|链接=Special:FilePath/Artificial_cell_membranes.png]]

thumb|450px|alt=Different types of artificial cell membranes. |Representative types of artificial cell membranes.

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~~不同类型的人造细胞膜。~~| ~~有代表性的人造细胞膜。~~

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不同类型的人工细胞膜。| 典型的人工细胞膜。

Membranes for artificial cells can be made of simple [[polymers]], crosslinked proteins, [[lipid membranes]] or polymer-lipid complexes. Further, membranes can be engineered to present surface [[proteins]] such as [[albumin]], [[antigens]], [[Na+/K+-ATPase|Na/K-ATPase]] carriers, or pores such as [[ion channels]]. Commonly used materials for the production of membranes include hydrogel polymers such as [[alginic acid|alginate]], [[cellulose]] and [[thermoplastic]] polymers such as hydroxyethyl methacrylate-methyl methacrylate (HEMA- MMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), as well as variations of the above-mentioned.<ref name=Prakash/> The material used determines the permeability of the cell membrane, which for polymer depends on the [[Molecular Weight Cut Off|molecular weight cut off]] (MWCO).<ref name=Prakash/> The MWCO is the maximum molecular weight of a molecule that may freely pass through the pores and is important in determining adequate [[diffusion]] of nutrients, waste and other critical molecules. Hydrophilic polymers have the potential to be [[Biocompatibility|biocompatible]] and can be fabricated into a variety of forms which include polymer [[micelles]], [[sol-gel]] mixtures, physical blends and crosslinked particles and nanoparticles.<ref name=Prakash/> Of special interest are stimuli-responsive polymers that respond to [[pH]] or temperature changes for the use in targeted delivery. These polymers may be administered in the liquid form through a macroscopic injection and solidify or gel ''in situ'' because of the difference in pH or temperature. [[Nanoparticle]] and [[liposome]] preparations are also routinely used for material encapsulation and delivery. A major advantage of liposomes is their ability to [[Lipid bilayer fusion|fuse]] to cell and [[organelle]] membranes.

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Membranes for artificial cells can be made of simple polymers, crosslinked proteins, lipid membranes or polymer-lipid complexes. Further, membranes can be engineered to present surface proteins such as albumin, antigens, Na/K-ATPase carriers, or pores such as ion channels. Commonly used materials for the production of membranes include hydrogel polymers such as alginate, cellulose and thermoplastic polymers such as hydroxyethyl methacrylate-methyl methacrylate (HEMA- MMA), polyacrylonitrile-polyvinyl chloride (PAN-PVC), as well as variations of the above-mentioned. The material used determines the permeability of the cell membrane, which for polymer depends on the molecular weight cut off (MWCO). The MWCO is the maximum molecular weight of a molecule that may freely pass through the pores and is important in determining adequate diffusion of nutrients, waste and other critical molecules. Hydrophilic polymers have the potential to be biocompatible and can be fabricated into a variety of forms which include polymer micelles, sol-gel mixtures, physical blends and crosslinked particles and nanoparticles. Of special interest are stimuli-responsive polymers that respond to pH or temperature changes for the use in targeted delivery. These polymers may be administered in the liquid form through a macroscopic injection and solidify or gel in situ because of the difference in pH or temperature. Nanoparticle and liposome preparations are also routinely used for material encapsulation and delivery. A major advantage of liposomes is their ability to fuse to cell and organelle membranes.

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~~用于人造细胞的膜可以由简单的聚合物、交联蛋白质、脂质膜或聚合物~~-脂质复合物制成。此外，膜可以被设计成表面蛋白如白蛋白、抗原、 Na/k-~~atp~~ 酶载体或孔隙如离子通道。常用的水凝胶聚合物如海藻酸钠、纤维素和热塑性聚合物如甲基丙烯酸羟乙酯-甲基丙烯酸甲酯(HEMA-MMA)、聚丙烯腈-聚氯乙烯(PAN-PVC) ~~，以及上述各种聚合物的变化。所用的材料决定了细胞膜的渗透性，对于聚合物来说，这取决于分子量截止~~(MWCO)。MWCO 是可以自由通过孔隙的分子的最大分子量，对于确定营养物质、废物和其他临界分子的充分扩散很重要。亲水性聚合物具有生物相容性的潜力，可以制成多种形式，包括聚合物胶束、溶胶-~~凝胶混合物、物理共混物以及交联粒子和纳米粒子。特别感兴趣的是刺激反应性聚合物，这种聚合物对 pH 值或温度变化作出反应，用于靶向传递。由于~~ pH 值和温度的不同，这些聚合物可以通过宏观注射和凝固或原位凝胶以液体形式给药。纳米颗粒和脂质体制剂也常用于材料的包封和递送。脂质体的一个主要优点是它们能够与细胞膜和细胞器膜融合。

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用于人工细胞的膜可以由简单的聚合物、交联蛋白质、脂质膜或聚合物-脂质复合物制成。此外，膜可以被设计成表面蛋白如白蛋白、抗原、 Na/K-ATP 酶载体或孔隙如离子通道。常用的水凝胶聚合物如海藻酸钠、纤维素和热塑性聚合物如甲基丙烯酸羟乙酯-甲基丙烯酸甲酯(HEMA-MMA)、聚丙烯腈-聚氯乙烯(PAN-PVC) ，以及上述各种聚合物的变异。所用的材料决定了细胞膜的渗透性，对于聚合物来说，这取决于截留分子量(MWCO)。MWCO 是可以自由通过孔隙的分子的最大分子量，对于确定营养物质、废物和其他临界分子的充分扩散很重要。亲水性聚合物具有生物相容性的潜力，可以制成多种形式，包括聚合物胶束、溶胶-凝胶混合物、物理共混物以及交联粒子和纳米粒子。特别令人感兴趣的是对pH值或温度变化有反应的刺激性聚合物，用于靶向传递。由于 pH 值和温度的不同，这些聚合物可以通过宏观注射和凝固或原位凝胶以液体形式给药。纳米颗粒和脂质体制剂也常用于材料的包封和递送。脂质体的一个主要优点是它们能够与细胞膜和细胞器膜融合。

===Preparation===

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制备

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Many variations for artificial cell preparation and encapsulation have been developed. Typically, vesicles such as a [[Nanoparticle#Synthesis|nanoparticle]], [[Polymersome#Preparation|polymersome]] or [[Liposome#Manufacturing|liposome]] are synthesized. An emulsion is typically made through the use of high pressure equipment such as a high pressure [[homogenizer]] or a [[Microfluidizer]]. Two [[micro-encapsulation]] methods for nitrocellulose are also described below.

Many variations for artificial cell preparation and encapsulation have been developed. Typically, vesicles such as a nanoparticle, polymersome or liposome are synthesized. An emulsion is typically made through the use of high pressure equipment such as a high pressure homogenizer or a Microfluidizer. Two micro-encapsulation methods for nitrocellulose are also described below.

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人工细胞的制备和包封已经发展出许多不同的方法。通常，囊泡，如纳米颗粒，聚合物或脂质体被合成。乳剂通常是通过使用高压设备，如高压均质器或微射流器制成的。硝化纤维素的两种微囊化方法也在下面描述。

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人工细胞的制备和包封已经发展出许多不同的方法。通常，如纳米粒子、聚合物或脂质体等小泡被合成。乳化液通常是通过高压设备，如高压匀浆器或微射流机来制造的。下面将介绍硝化纤维素的两种微胶囊化方法.

====High-pressure homogenization====

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高压均质化

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In a high-pressure homogenizer, two liquids in oil/liquid suspension are forced through a small orifice under very high pressure. This process divides the products and allows the creation of extremely fine particles, as small as 1 nm.

In a high-pressure homogenizer, two liquids in oil/liquid suspension are forced through a small orifice under very high pressure. This process divides the products and allows the creation of extremely fine particles, as small as 1 nm.

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= = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = = =.这个过程分割的产品，并允许创造极其微小的颗粒，只有1纳米。

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在高压匀浆器中，油/液悬浮液中的两种液体在很高的压力下通过一个小孔。这一过程划分了产品，并允许产生极细的颗粒，小到1nm。

====Microfluidization====

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微射流处理

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This technique uses a patented Microfluidizer to obtain a greater amount of homogenous suspensions that can create smaller particles than homogenizers. A homogenizer is first used to create a coarse suspension which is then pumped into the microfluidizer under high pressure. The flow is then split into two streams which will react at very high velocities in an interaction chamber until desired particle size is obtained.<ref>{{cite journal | vauthors = Vivier A, Vuillemard JC, Ackermann HW, Poncelet D | title = Large-scale blood substitute production using a microfluidizer | journal = Biomaterials, Artificial Cells, and Immobilization Biotechnology | volume = 20 | issue = 2-4 | pages = 377–397 | year = 1992 | pmid = 1391454 | doi = 10.3109/10731199209119658 }}</ref> This technique allows for large scale production of phospholipid liposomes and subsequent material nanoencapsulations.

This technique uses a patented Microfluidizer to obtain a greater amount of homogenous suspensions that can create smaller particles than homogenizers. A homogenizer is first used to create a coarse suspension which is then pumped into the microfluidizer under high pressure. The flow is then split into two streams which will react at very high velocities in an interaction chamber until desired particle size is obtained. This technique allows for large scale production of phospholipid liposomes and subsequent material nanoencapsulations.

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= = = = = 微射流技术使用专利的微射流器获得更多的均质悬浮液，可以产生比均质器更小的颗粒。均质器首先被用来制造粗颗粒悬浮液，然后在高压下被泵入微流体器。然后将流体分成两股流体，这两股流体将在相互作用室中以非常高的速度反应，直到得到所需的粒子尺寸。这种技术允许大规模生产磷脂脂质体和后续材料纳米包埋。

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微射流技术使用专利的微射流机获得更多的均质悬浮液，可以产生比匀浆器更小的颗粒。匀浆器首先被用来制造粗颗粒悬浮液，然后在高压下被泵入微射流机。然后将流体分成两股流体，这两股流体将在相互作用室中以非常高的速度反应，直到得到所需的粒子尺寸。这种技术允许大规模生产磷脂脂质体和后续材料纳米包埋。

====Drop method====

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点滴法

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In this method, a cell solution is incorporated dropwise into a [[collodion]] solution of cellulose nitrate. As the drop travels through the collodion, it is coated with a membrane thanks to the interfacial polymerization properties of the collodion. The cell later settles into paraffin where the membrane sets and is finally suspended a saline solution. The drop method is used for the creation of large artificial cells which encapsulate biological cells, stem cells and genetically engineered stem cells.

In this method, a cell solution is incorporated dropwise into a collodion solution of cellulose nitrate. As the drop travels through the collodion, it is coated with a membrane thanks to the interfacial polymerization properties of the collodion. The cell later settles into paraffin where the membrane sets and is finally suspended a saline solution. The drop method is used for the creation of large artificial cells which encapsulate biological cells, stem cells and genetically engineered stem cells.

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在这种方法中，细胞溶液滴入硝酸纤维素的火棉胶溶液中。当液滴通过火棉胶时，由于火棉胶的界面聚合特性，它被涂上了一层膜。细胞随后沉积在石蜡中，细胞膜凝固，最后悬浮在盐溶液中。液滴法用于制造大型人造细胞，包裹生物细胞、干细胞和基因工程干细胞。

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在这种方法中，细胞溶液滴入硝酸纤维素的火棉胶溶液中。当液滴通过火棉胶时，由于火棉胶的界面聚合特性，它被涂上了一层膜。细胞随后沉积在石蜡中，细胞膜凝固，最后悬浮在盐溶液中。点滴法用于制造大型人工细胞，包裹生物细胞、干细胞和基因工程干细胞。

====Emulsion method====

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乳化法

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The [[emulsion]] method differs in that the material to be encapsulated is usually smaller and is placed in the bottom of a reaction chamber where the collodion is added on top and centrifuged, or otherwise disturbed in order to create an emulsion. The encapsulated material is then dispersed and suspended in saline solution.

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====Drug release and delivery====

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药物的释放和运送

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Artificial cells used for [[drug delivery]] differ from other artificial cells since their contents are intended to diffuse out of the membrane, or be engulfed and digested by a host target cell. Often used are submicron, lipid membrane artificial cells that may be referred to as nanocapsules, nanoparticles, polymersomes, or other variations of the term.

Artificial cells used for drug delivery differ from other artificial cells since their contents are intended to diffuse out of the membrane, or be engulfed and digested by a host target cell. Often used are submicron, lipid membrane artificial cells that may be referred to as nanocapsules, nanoparticles, polymersomes, or other variations of the term.

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= = = = 药物的释放和运送 = = = = = = 用于药物运送的人造细胞与其他人造细胞不同，因为其内容物的目的是扩散出细胞膜，或者被宿主的靶细胞吞噬和消化。通常使用的是亚微米，脂膜人工细胞，可称为纳米胶囊，纳米粒子，聚合体，或其他任期的变种。

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用于药物运送的人工细胞与其他人工细胞不同，是由于其内容物要扩散出细胞膜，或者被宿主靶细胞吞噬和消化。通常使用的是亚微米，脂质膜人工细胞，可称为纳米胶囊，纳米粒子，聚合体，或其他变体。

====Enzyme therapy====

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酶疗法

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[[Enzyme]] therapy is being actively studied for [[inborn error of metabolism|genetic metabolic diseases]] where an enzyme is over-expressed, under-expressed, defective, or not at all there. In the case of under-expression or expression of a defective [[enzyme]], an active form of the enzyme is introduced in the body to compensate for the deficit. On the other hand, an enzymatic over-expression may be counteracted by introduction of a competing non-functional enzyme; that is, an enzyme which [[Metabolism|metabolizes]] the substrate into non-active products. When placed within an artificial cell, enzymes can carry out their function for a much longer period compared to free enzymes<ref name= 'Chang 2007' /> and can be further optimized by polymer conjugation.<ref>Park et al. 1981</ref>

Enzyme therapy is being actively studied for genetic metabolic diseases where an enzyme is over-expressed, under-expressed, defective, or not at all there. In the case of under-expression or expression of a defective enzyme, an active form of the enzyme is introduced in the body to compensate for the deficit. On the other hand, an enzymatic over-expression may be counteracted by introduction of a competing non-functional enzyme; that is, an enzyme which metabolizes the substrate into non-active products. When placed within an artificial cell, enzymes can carry out their function for a much longer period compared to free enzymes and can be further optimized by polymer conjugation.Park et al. 1981

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目前正在积极研究酶疗法，用于治疗遗传代谢性疾病，其中一种酶过度表达、表达不足、有缺陷或根本不存在。在有缺陷的酶表达不足或表达不足的情况下，在体内引入一种活性形式的酶，以补偿缺陷。另一方面，酶的过度表达可以通过引入竞争性的非功能性酶来抵消，也就是说，一种酶将底物代谢为非活性产物。当置于人工细胞中时，酶可以比游离酶更长时间地发挥作用，并且可以通过聚合物接合进一步优化。帕克等。1981

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目前正在积极研究酶疗法，用于治疗有某种酶过度表达、表达不足、有缺陷或根本不存在等表现的遗传代谢性疾病。在有缺陷的酶的表达不足或表达不足的情况下，活性形式的该种酶将被引入人体以弥补缺陷。另一方面，酶的过度表达可以通过引入竞争性的非功能性酶来抵消，也就是说，一种将底物代谢为非活性产物的酶。当置于人工细胞中时，酶可以比游离酶更长时间地发挥作用，并且可以通过聚合物接合进一步优化。帕克等。1981

The first enzyme studied under artificial cell encapsulation was [[asparaginase]] for the treatment of [[lymphosarcoma]] in mice. This treatment delayed the onset and growth of the [[tumor]].<ref>{{cite journal | vauthors = Chang TM | title = The in vivo effects of semipermeable microcapsules containing L-asparaginase on 6C3HED lymphosarcoma | journal = Nature | volume = 229 | issue = 5280 | pages = 117–118 | date = January 1971 | pmid = 4923094 | doi = 10.1038/229117a0 | s2cid = 4261902 | bibcode = 1971Natur.229..117C }}</ref> These initial findings led to further research in the use of artificial cells for enzyme delivery in [[tyrosine]] dependent [[melanomas]].<ref>{{cite journal | vauthors = Yu B, Chang TM | title = Effects of long-term oral administration of polymeric microcapsules containing tyrosinase on maintaining decreased systemic tyrosine levels in rats | journal = Journal of Pharmaceutical Sciences | volume = 93 | issue = 4 | pages = 831–837 | date = April 2004 | pmid = 14999721 | doi = 10.1002/jps.10593 }}</ref> These tumors have a higher dependency on [[tyrosine]] than normal cells for growth, and research has shown that lowering systemic levels of tyrosine in mice can inhibit growth of melanomas.<ref>{{cite journal | vauthors = Meadows GG, Pierson HF, Abdallah RM, Desai PR | title = Dietary influence of tyrosine and phenylalanine on the response of B16 melanoma to carbidopa-levodopa methyl ester chemotherapy | journal = Cancer Research | volume = 42 | issue = 8 | pages = 3056–3063 | date = August 1982 | pmid = 7093952 }}</ref> The use of artificial cells in the delivery of [[tyrosinase]]; and enzyme that digests tyrosine, allows for better enzyme stability and is shown effective in the removal of tyrosine without the severe side-effects associated with tyrosine depravation in the diet.<ref>{{cite journal | vauthors = Chang TM | title = Artificial cell bioencapsulation in macro, micro, nano, and molecular dimensions: keynote lecture | journal = Artificial Cells, Blood Substitutes, and Immobilization Biotechnology | volume = 32 | issue = 1 | pages = 1–23 | date = February 2004 | pmid = 15027798 | doi = 10.1081/bio-120028665 | s2cid = 37799530 }}</ref>

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Artificial cell enzyme therapy is also of interest for the activation of prodrugs such as ifosfamide in certain cancers. Artificial cells encapsulating the cytochrome p450 enzyme which converts this prodrug into the active drug can be tailored to accumulate in the pancreatic carcinoma or implanting the artificial cells close to the tumor site. Here, the local concentration of the activated ifosfamide will be much higher than in the rest of the body thus preventing systemic toxicity. The treatment was successful in animals and showed a doubling in median survivals amongst patients with advanced-stage pancreatic cancer in phase I/II clinical trials, and a tripling in one-year survival rate.

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~~人工细胞酶疗法对于激活诸如异环磷酰胺之类的前药在某些癌症中也很有意义。将细胞色素~~ p450酶包裹在人工细胞中，将其转化为活性药物，可以特制地在胰腺癌中积累，或将人工细胞移植到肿瘤部位附近。在这里，被激活的异环磷酰胺的局部浓度将远远高于身体其他部位，从而防止全身中毒。这种治疗在动物身上取得了成功，在 i/II ~~期临床试验中，晚期胰腺癌患者的中位生存率增加了一倍，一年生存率增加了两倍。~~

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在某些癌症中，人工细胞酶疗法对于激活诸如异环磷酰胺之类的前药也很有意义。将细胞色素 p450酶包裹在人工细胞中，将其转化为活性药物，可以特制地在胰腺癌中积累，或将人工细胞移植到肿瘤部位附近。在这里，被激活的异环磷酰胺的局部浓度将远远高于身体其他部位，从而防止全身中毒。这种治疗在动物身上取得了成功，在 I/II 期临床试验中，晚期胰腺癌患者的生存率中位数增加了一倍，一年生存率增加了两倍。

====Gene therapy====

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基因疗法

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In treatment of genetic diseases, [[gene therapy]] aims to insert, alter or remove [[genes]] within an afflicted individual's cells. The technology relies heavily on viral [[vector (molecular biology)|vectors]] which raises concerns about insertional [[mutagenesis]] and systemic [[immune response]] that have led to human deaths<ref>{{cite journal | vauthors = Carmen IH | title = A death in the laboratory: the politics of the Gelsinger aftermath | journal = Molecular Therapy | volume = 3 | issue = 4 | pages = 425–428 | date = April 2001 | pmid = 11319902 | doi = 10.1006/mthe.2001.0305 }}</ref><ref>{{cite journal | vauthors = Raper SE, Chirmule N, Lee FS, Wivel NA, Bagg A, Gao GP, Wilson JM, Batshaw ML | display-authors = 6 | title = Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer | journal = Molecular Genetics and Metabolism | volume = 80 | issue = 1-2 | pages = 148–158 | date = 1 September 2003 | pmid = 14567964 | doi = 10.1016/j.ymgme.2003.08.016 }}</ref> and development of [[leukemia]]<ref>{{cite journal | vauthors = Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A | display-authors = 6 | title = Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease | journal = Science | volume = 288 | issue = 5466 | pages = 669–672 | date = April 2000 | pmid = 10784449 | doi = 10.1126/science.288.5466.669 | bibcode = 2000Sci...288..669C }}</ref><ref>{{cite journal | vauthors = Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, Lim A, Osborne CS, Pawliuk R, Morillon E, Sorensen R, Forster A, Fraser P, Cohen JI, de Saint Basile G, Alexander I, Wintergerst U, Frebourg T, Aurias A, Stoppa-Lyonnet D, Romana S, Radford-Weiss I, Gross F, Valensi F, Delabesse E, Macintyre E, Sigaux F, Soulier J, Leiva LE, Wissler M, Prinz C, Rabbitts TH, Le Deist F, Fischer A, Cavazzana-Calvo M | display-authors = 6 | title = LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1 | journal = Science | volume = 302 | issue = 5644 | pages = 415–419 | date = October 2003 | pmid = 14564000 | doi = 10.1126/science.1088547 | s2cid = 9100335 | bibcode = 2003Sci...302..415H }}</ref> in clinical trials. Circumventing the need for vectors by using naked or plasmid DNA as its own delivery system also encounters problems such as low [[Transduction (genetics)|transduction]] efficiency and poor tissue targeting when given systemically.<ref name=Prakash/>

In treatment of genetic diseases, gene therapy aims to insert, alter or remove genes within an afflicted individual's cells. The technology relies heavily on viral vectors which raises concerns about insertional mutagenesis and systemic immune response that have led to human deaths and development of leukemia in clinical trials. Circumventing the need for vectors by using naked or plasmid DNA as its own delivery system also encounters problems such as low transduction efficiency and poor tissue targeting when given systemically.

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在基因疾病的治疗中，基因疗法旨在插入、改变或移除受影响个体细胞内的基因。该技术严重依赖于病毒载体，这引起了对插入突变和系统免疫反应的关注，这些在临床试验中导致了人类死亡和白血病的发展。系统给药时，以裸质粒或质粒 DNA 作为自身的传递系统来规避载体的需要，也会遇到传递效率低、组织靶向性差等问题。

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在基因疾病的治疗中，基因疗法旨在插入、改变或移除受影响个体细胞内的基因。该技术严重依赖于病毒载体，这引起了对插入突变和系统免疫反应的关注，它们在临床试验中导致了人类死亡和白血病的发展。利用裸DNA或质粒DNA作为载体载体本身的传递系统，避免了载体的需要，同时也遇到了系统传递效率低、组织靶向性差等问题。

Artificial cells have been proposed as a non-viral vector by which genetically modified non-autologous cells are encapsulated and implanted to deliver recombinant proteins ''in vivo''.<ref>{{cite journal | vauthors = Chang PL, Van Raamsdonk JM, Hortelano G, Barsoum SC, MacDonald NC, Stockley TL | title = The in vivo delivery of heterologous proteins by microencapsulated recombinant cells | journal = Trends in Biotechnology | volume = 17 | issue = 2 | pages = 78–83 | date = February 1999 | pmid = 10087608 | doi = 10.1016/S0167-7799(98)01250-5 }}</ref> This type of [[immunoisolate|immuno-isolation]] has been proven efficient in mice through delivery of artificial cells containing mouse [[growth hormone]] which rescued a growth-retardation in mutant mice.<ref>{{cite journal | vauthors = al-Hendy A, Hortelano G, Tannenbaum GS, Chang PL | title = Correction of the growth defect in dwarf mice with nonautologous microencapsulated myoblasts--an alternate approach to somatic gene therapy | journal = Human Gene Therapy | volume = 6 | issue = 2 | pages = 165–175 | date = February 1995 | pmid = 7734517 | doi = 10.1089/hum.1995.6.2-165 }}</ref> A few strategies have advanced to human clinical trials for the treatment of [[pancreatic cancer]], lateral sclerosis and pain control.<ref name= 'Prakash'/>

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Artificial cells have been proposed as a non-viral vector by which genetically modified non-autologous cells are encapsulated and implanted to deliver recombinant proteins in vivo. This type of immuno-isolation has been proven efficient in mice through delivery of artificial cells containing mouse growth hormone which rescued a growth-retardation in mutant mice. A few strategies have advanced to human clinical trials for the treatment of pancreatic cancer, lateral sclerosis and pain control.

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人工细胞作为一种非病毒载体已被提出，通过基因修饰的非自体细胞被包裹和植入，在体内传递重组蛋白。这种类型的免疫隔离已被证明是有效的小鼠通过人工细胞含有小鼠生长激素，挽救生长阻滞的突变小鼠。一些治疗胰腺癌、脊髓侧索硬化症和疼痛控制的策略已经进入人体临床试验。

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人工细胞被认为是一种非病毒载体，将转基因非自体细胞包裹起来并植入体内以表达重组蛋白。通过传递含有小鼠生长激素的人工细胞，挽救了突变小鼠的生长迟缓，这种免疫分离已经被证明是有效的。一些治疗胰腺癌、脊髓侧索硬化症和疼痛控制的方案已经进入人体临床试验阶段。

====Hemoperfusion====

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血液灌流

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The first clinical use of artificial cells was in [[hemoperfusion]] by the encapsulation of [[activated charcoal]].<ref name="Chang 1996"/> Activated charcoal has the capability of adsorbing many large molecules and has for a long time been known for its ability to remove toxic substances from the blood in accidental poisoning or overdose. However, [[perfusion]] through direct charcoal administration is toxic as it leads to [[embolism]]s and damage of blood cells followed by removal by platelets.<ref>{{cite journal | vauthors = Dunea G, Kolff WJ | title = CLINICAL EXPERIENCE WITH THE YATZIDIS CHARCOAL ARTIFICIAL KIDNEY | journal = Transactions - American Society for Artificial Internal Organs | volume = 11 | pages = 178–182 | year = 1965 | pmid = 14329080 | doi = 10.1097/00002480-196504000-00035 }}</ref> Artificial cells allow toxins to diffuse into the cell while keeping the dangerous cargo within their ultrathin membrane.<ref name= 'Chang 1996' />

The first clinical use of artificial cells was in hemoperfusion by the encapsulation of activated charcoal. Activated charcoal has the capability of adsorbing many large molecules and has for a long time been known for its ability to remove toxic substances from the blood in accidental poisoning or overdose. However, perfusion through direct charcoal administration is toxic as it leads to embolisms and damage of blood cells followed by removal by platelets. Artificial cells allow toxins to diffuse into the cell while keeping the dangerous cargo within their ultrathin membrane.

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人工细胞的第一次临床应用是通过药用活性炭的包囊进行血液灌流。药用活性炭具有吸附许多大分子的能力，长期以来因其在意外中毒或过量服用中能够去除血液中的有毒物质而闻名。然而，通过直接使用木炭进行灌注是有毒的，因为它会导致血栓和血细胞损伤，随后血小板会被清除。人造细胞允许毒素扩散进入细胞，同时保持危险的货物在他们的超薄膜。

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临床上第一次使用人工细胞的方法是用活性炭包裹血液灌流。药用活性炭具有吸附许多大分子的能力，长期以来因其在意外中毒或过量服用中能够去除血液中的有毒物质而闻名。然而，通过直接使用木炭进行灌注是有毒的，因为它会导致血栓和血细胞损伤，随后被血小板清除。人工细胞允许毒素扩散到细胞中，同时将危险物质保存在超薄的膜内。

Artificial cell [[hemoperfusion]] has been proposed as a less costly and more efficient detoxifying option than [[hemodialysis]],<ref name="Chang 2007"/> in which blood filtering takes place only through size separation by a physical membrane. In hemoperfusion, thousands of adsorbent artificial cells are retained inside a small container through the use of two screens on either end through which patient blood [[perfusion|perfuses]]. As the blood circulates, [[toxins]] or drugs diffuse into the cells and are retained by the absorbing material. The membranes of artificial cells are much thinner those used in dialysis and their small size means that they have a high membrane [[surface area]]. This means that a portion of cell can have a theoretical mass transfer that is a hundredfold higher than that of a whole artificial kidney machine.<ref name='Chang 2007' /> The device has been established as a routine clinical method for patients treated for accidental or suicidal poisoning but has also been introduced as therapy in [[liver failure]] and [[renal failure|kidney failure]] by carrying out part of the function of these organs.<ref name= 'Chang 2007' />

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Artificial cell hemoperfusion has also been proposed for use in immunoadsorption through which antibodies can be removed from the body by attaching an immunoadsorbing material such as albumin on the surface of the artificial cells. This principle has been used to remove blood group antibodies from plasma for bone marrow transplantation and for the treatment of hypercholesterolemia through monoclonal antibodies to remove low-density lipoproteins. Hemoperfusion is especially useful in countries with a weak hemodialysis manufacturing industry as the devices tend to be cheaper there and used in kidney failure patients.

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与血液透析相比，人工细胞血液灌流被认为是一种成本更低、效率更高的解毒方法。在血液灌流中，成千上万的吸附性人造细胞通过使用病人血液灌流的两个屏幕被保留在一个小容器中。随着血液循环，毒素或药物扩散进入细胞，并被吸收材料所保留。人工细胞的细胞膜比透析用细胞的细胞膜要薄得多，细胞膜的小体积意味着细胞膜的表面积很大。这意味着一部分细胞理论上的质量传递比整个人工肾脏机器的质量传递高百倍。该装置已被确立为意外或自杀性中毒治疗患者的常规临床方法，但也被引入治疗肝功能衰竭和肾功能衰竭，实现这些器官的部分功能。人工细胞血液灌流也被提议用于免疫吸附，通过在人工细胞表面粘附免疫吸附材料，如白蛋白，可将抗体从体内除去。这一原理已被应用于从骨髓移植患者血浆中去除血型抗体，以及通过单克隆抗体去除低密度脂蛋白治疗高胆固醇血症。血液灌流在血液透析制造业薄弱的国家尤其有用，因为那里的血液透析设备往往更便宜，而且用于肾衰竭患者。

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与血液透析相比，人工细胞血液灌流被认为是一种成本更低、效率更高的解毒方法。在血液灌流中，成千上万的吸附性人工细胞通过在病人血液灌流的两端使用两个筛子被保存在一个小容器内。随着血液循环，毒素或药物扩散进入细胞，并被吸收材料所保留。人工细胞的细胞膜比透析用细胞的细胞膜要薄得多，细胞膜的小体积意味着细胞膜的表面积很大。这意味着一部分细胞理论上的质量传递比整个人工肾脏机器的质量传递高百倍。该装置已被确立为治疗意外或自杀性中毒患者的常规临床方法，但也被引入治疗肝功能衰竭和肾功能衰竭，以实现这些器官的部分功能。人工细胞血液灌流也被提议用于免疫吸附，通过在人工细胞表面粘附免疫吸附材料，如白蛋白，可将抗体从体内除去。这一原理已被应用于从骨髓移植患者血浆中去除血型抗体，以及通过单克隆抗体去除低密度脂蛋白治疗高胆固醇血症。血液灌流在血液透析制造业薄弱的国家尤其有用，因为那里的血液透析设备往往更便宜，而且用于肾衰竭患者。

====Encapsulated cells====

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= = = = 封装细胞 = = = =

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[[File:Cell capsule schematic.png|thumb|300px|Schematic representation of encapsulated cells within artificial membrane.|链接=Special:FilePath/Cell_capsule_schematic.png]]

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[[File:Cell capsule schematic.png|thumb|300px|Schematic representation of encapsulated cells within artificial membrane.细胞封装在人工膜内的示意图。|链接=Special:FilePath/Cell_capsule_schematic.png]]

thumb|300px|alt=Schematic of cells encapsulated within an artificial membrane.|Schematic representation of encapsulated cells within artificial membrane.

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~~细胞封装在人造膜内的示意图。~~

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细胞封装在人工膜内的示意图。

The most common method of preparation of artificial cells is through [[cell encapsulation]]. Encapsulated cells are typically achieved through the generation of controlled-size droplets from a liquid cell [[Suspension (chemistry)|suspension]] which are then rapidly solidified or gelated to provide added stability. The stabilization may be achieved through a change in temperature or via material crosslinking.<ref name=Prakash/> The microenvironment that a cell sees changes upon encapsulation. It typically goes from being on a [[monolayer]] to a suspension in a polymer scaffold within a polymeric membrane. A drawback of the technique is that encapsulating a cell decreases its viability and ability to proliferate and differentiate.<ref>{{cite book | veditors = Wolff JA | vauthors = Chang PL | date = 1994 | chapter = Calcium phosphate-mediated DNA transfection | pages = 157–179 | title = Gene Therapeutics | location = Boston | publisher = Birkhauser | isbn = 978-1-4684-6822-9 | doi = 10.1007/978-1-4684-6822-9_9 }}</ref> Further, after some time within the microcapsule, cells form clusters that inhibit the exchange of oxygen and metabolic waste,<ref>{{cite journal | vauthors = Ponce S, Orive G, Gascón AR, Hernández RM, Pedraz JL | title = Microcapsules prepared with different biomaterials to immobilize GDNF secreting 3T3 fibroblasts | journal = International Journal of Pharmaceutics | volume = 293 | issue = 1-2 | pages = 1–10 | date = April 2005 | pmid = 15778039 | doi = 10.1016/j.ijpharm.2004.10.028 }}</ref> leading to [[apoptosis]] and [[necrosis]] thus limiting the efficacy of the cells and activating the host's [[immune system]].

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