50th Anniversary of Artificial Cells: Their Role in Biotechnology, Nanomedicine, Regenerative Medicine, Blood Substitutes, Bioencapsulation, Cell/Stem Cell Therapy and Nanorobotics

Figures & data

Figure 1 Original 1957 method of preparing artificial cells (for details see [[1], [5]]). Upper: drop method for preparing large artificial cells. Principle later extended for use in bioencapsulation of cells, stem cells, genetic engineered cells. Lower: emulsion phase separation method for preparing microscopic artificial cells (unlike above, “collodion” prepared by removing most of alcohol and replaced with ether). Principle extended to preparation of microscopic artificial cells and drug delivery systems and nano-dimension artificial cells (figure from [[5]] with copyright permission).

Table 1. Examples of areas of application (details in [[4], [5]]

Artificial organs: hemoperfusion

Drug delivery including biotechnological products

Blood substitutes

Enzyme and gene therapy

Cells therapy: cell/stem cells/genetic engineered cells

Agriculture & Industry

Nanomedicine

Regenerative medicine

Bioencapsulation

Nanoencapsulation

Microencapsulation

Liposomes

Nanocomputers and nanorobatics

Nanosensors

Basic research: cell and membrane

Others

Figure 2 Upper: Basic principle of early artificial cells. Middle: Different types of early artificial cells based on this basic principle. Lower: Present status of artificial cells with wide variations in contents, membrane material and dimensions From [[5]] with copyright permission.

Table 2. Artificial Cells (AC): Timeline of ideas first reported (references available from [[5]])

1957 Chang	First artificial cells prepared with a synthetic membrane to replace RBC membrane and containing hemoglobin and red blood cell enzymes (emulsion phase separation, extrusion method or spray coating)
1964 Chang (Science)	Artificial cells (AC) containing enzymes, hemoglobin and cells formed by interfacial coacervation or interfacial polymerization to form membranes of polymer, crosslinked protein, polymer conjugated with protein, also crosslinked protein microspheres
1964, 1965 Chang	Nanobiotechnology: crosslinked protein (polyHb) & conjugated Hb
1964, 1965 Chang 1966 Chang et al.	Extrusion drop method for AC to encapsulate intact cells for immunoisolation in cell therapy.
1965 Bangham et al.	Liquid crystal microspheres of multi-lamellar lipid (liposomes) as membrane model for basic research
1965, 1972a, 1973b Chang	AC for molecular sieve chromatography and separation
1965 Chang 1966 Chang et al.	AC with intracellular multi-compartments
1966 Chang	Silastic AC and microspheres containing protein.
1966 Chang	AC containing magnetic materials and biological materials.
1966, 1969a Chang	Ultrathin membrane AC containing adsorbents for hemoperfusion
1966 Clark & Gollan	Fluorocarbon as oxygen carrier
1967 Chang et al.	AC with polysaccharide complexed membrane for biocompatibility
1968 Chang & Poznansky (Nature)	Implanted enzyme AC for enzyme therapy in inborn error of metabolism (shown in congenital catalase-deficient acatalesemic mice)
1968 Bunn & Jandl	Intramolecularly crosslinked single Hb molecule
1968 Geyer et al.	Fluorocarbon effective in exchange transfusion in animal studies
1969d Chang 1972a Chang	AC with lipid-polymeric membrane or lipid-crosslinked protein membrane containing cyclic transport carrier. (AC contains proteins)
1970–1975 Chang et al.	First clinical use of artificial cells in patients (in hemoperfusion)
1971a Chang (Nature)	Implanted enzyme AC for lymphosarcoma suppression in mice
1971b Chang	Nanobiotechnology: glutaraldehyde crosslinked Hb into polyHb. Later, others used this method for blood substitutes in patients.
1972a Chang	First monograph on Artificial Cells
1972b Chang (Lancet)	AC hemoperfusion resulted in Grade IV hepatic coma patient recovering consciousness.
1973 Gregoriadis	First use of liposomes to entrap enzymes & drugs. Led to extensive development of liposomes as delivery systems
1975h Chang	Paper discussing one shot vaccine using AC
1976a Chang	Biodegradable polylactide microcapsules and microparticles containing proteins & hormones
1976 Tam, Blumenstein & Wong	Soluble dextran conjugated hemoglobin
1976 Bonhard et al.	Develop glutaraldehyde crosslinked polyHb as blood substitute
1977–1985 Chang with Campbell, Cousineau, Ilan, Grunwald, Wahl, Yu, etc.	Artificial cells containing multienzyme systems with cofactor recyclying for multistep enzyme reactions.
1978 Naito & Yokoyama	Developed perfluorodecalin as blood substitute towards clinical trials
1980 Lim & Sun (Science)	Alginate-polylysine-alginate AC encapsulated cells
1980 Rosenthal & Chang	AC membrane of lipid-protein-polymer containing Na^+K^+-ATPase
1980 Djordjevich & Miller	Lipid membrane AC encapsulated hemoglobin
1985 Mitsuno & Ohyanagi	Clinical trials of perfluorodecalin as red blood cell substitute
1986 Yuan & Chang	AC containing microsomes & cytosol
1986 Bourget & Chang	Oral enzyme AC for inborn error of metabolism (Phenyketonuria rat)
1986 Sipehia, Bannard & Chang	AC membrane that exclude small hydrophilic molecules but permeable to large lipophilic molecules
1986 Chang, Bourget & Lister	Novel finding of extensive enterorecirculation of amino acids leading to the use of oral enzyme AC therapy to selectively remove specific unwanted systemic amino acid.
1988 Tsuchida's group 2002 Tsuchida et al.	Development and in-vivo testing of synthetic heme complex either to liposome or to recombinant albumin as blood substitute.
1989a Chang, 1989 Palmour et al., Chang	Clinical use of oral enzyme artificial cells in a patient (patient with an inborn error of metabolism: Lesch-Nyhan disease)
1989 Moss et al.	Clinical trials with glutaraldehyde crosslinked PolyHb
1990 Hoffmann et al.	Recombinant human hemoglobin
1994 Yu & Chang	Biodegradable polymeric membrane nano-artificial red blood cells
1994 Soon-Shiong et al.	AC encapsulated islet transplantation in a type 1 diabetic patient. Insulin independence reported.
1996 Prakash & Chang (Nature Medicine)	Oral artificial cells containing genetically engineered cells lowers systemic urea in an uremic rats model
1996 Aebischer, Lysagth et al. (Nature Medicine)	Polymeric fiber encapsulation of genetically modified xenogeneic cells for intrathecal delivery of CNTF in amyotrophic lateral sclerosis patients
1998 D'Agnillo & Chang (Nature Biotechnology)	Nanobiotechnology of crosslinking of Hb, catalase and superoxide dismutase to form soluble nanodimension PolyHb-CAT-SOD
1998 Tsuchida	Lipid AC vesicle Hb : Develop and test in animal towards clinical use
1999 Philips et al.	PEG-lipid membrane AC containing Hb increases circulation time
2000 Liu & Chang	AC coencapsulating hepatocytes and adult stem cells
2001 Lörh et al. (Lancet)	Clinical trial of AC microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma in patients
2002 Gould et al.	The life-sustaining capacity of human polyhemoglobin in trauma surgery clinical trials
2002 Sprung et al.	The use of bovine polyhemoglobin in surgical patients: results of a multicenter, randomized, single-blinded trial
2003 Chang, Powanda, Yu	PEG-PLA membrane AC containing Hb & rbc enzymes
2004 Bloch et al., Aebischer	Phase I clinical study for Huntington's Disease, using encapsulated cells engineered to secrete Human Ciliary Neurotrophic Factor
2004 Yu & Chang (Melanoma Res J)	Nanobiotechnological approach of PolyHb-tyrosinase: delays the growth of melanoma in a rat model
2006 Liu & Chang (J Liver Transplantation)	AC encapsulated bone marrow stem cells regenerate liver resulting in recovery and survival of rats with 90% of liver surgically removed

Chang, T.M.S. (1957). Hemoglobin Corpuscles (report of a research project for Honours Physiology, Medical Library, McGill University); reprinted in 1988 as part of the 30th Anniversary in Artificial Red Blood Cells Research. J. Biomaterials, Artificial Cells & Artificial Organs 16: 1–9.

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Chang, T.M.S. (2007). Artificial Cells: Biotechnology, Nanomedicine, Regenerative Medicine, Blood Substitutes, Bioencapsulation and Cell/Stem Cell Therapy, Singapore: World Science Publisher.

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Chang, T.M.S. (2005). Therapeutic applications of polymeric artificial cells. Nature Review: Drug Discovery 4: 221–235.

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