1
Introduction to artificial cells: concept, history, design, current status and future
S. Prakash; J.R. Bhathena; H. Chen McGill University, Canada
1.1 Introduction: concept and history
The emergence of cellular life is one of the major transitions in evolution. The existence of a cell boundary allows metabolism and genetic information to be part of a well-defined component. Theoretical models and experimental data support the idea that simple protocells should be obtainable from simple systems of coupled reactions dealing with these three topics. The building of an artificial cell would be a fundamental breakthrough in our understanding of life, its origins and evolution, not to mention a wide array of potential medical and technological applications.
Artificial cells – ultrathin polymeric or biological membranes of cellular dimensions – were first prepared in the laboratory of T.M.S. Chang at McGill University in Canada in the 1960s.1 Artificial cell microencapsulation is used to encapsulate biologically active materials in specialized ultrathin semipermeable polymer membranes.1,2 The polymer membrane protects encapsulated materials from harsh external environments while at the same time allowing for the metabolism of selected solutes capable of passing into and out of the microcapsule. In this manner, the enclosed material (live bacteria, DNA, proteins, drugs, etc.) can be retained inside and separated from the external milieu, making microencapsulation particularly useful for biomedical and clinical applications.3–5 Since the 1980s, microencapsulation research has made great strides in developing approaches for the controlled release of therapeutic agents, targeted delivery of drugs, bacterial cells, mammalian cells, DNA and other nucleic acids, proteins, etc. (Table 1.1) to the host. An encapsulation membrane serves as an immunobarrier, allows the bi-directional exchange of small molecules including nutrients, wastes, selected substrates and products, and prevents the passage of large substances such as cells, immunocytes and antibodies (Fig. 1.1).57,58
Table 1.1
Concept and relevance of artificial cells
| Year | Innovation | Reference |
| 1957 | First polymeric artificial cells developed. | 6 |
| 1964 | The first scientific publication describing the principle of artificial cells, including methods of preparation, in vitro and in vivo studies and potential areas of biotechnological and medical applications. Polymeric artificial cells containing enzymes and haemoglobin developed. Intermolecularly crosslinked protein produced and conjugation of haemoglobin to polymer achieved. | 1 |
| 1965–1966 | Extrusion drop technique for encapsulating intact cells for immuno-isolation developed. Multi-compartment artificial cells developed. | 7–9 |
| 1966 | Silastic artificial cells and microspheres containing protein produced. Artificial cells containing magnetic materials with other materials produced. The first report on the use of biodegradable membrane microcapsules and microparticles as delivery systems for drugs and biotechnology products. This forms the basis of many of the present approaches using biodegradable microcapsules, microparticles, nanocapsules, nanoparticles and others. | 10, 11 |
| 1966–1969 | Artificial cells with ultra-thin membranes, and which contain adsorbents for use in hemoperfusion developed. | 11–13 |
| 1968 | Implanted enzyme containing artificial cells used for enzyme therapy in acatalesmic mice. The first scientific report of the implantation of polymeric artificial cells containing an enzyme for replacement of the deficient gene in a mouse model of an inborn error of metabolism. | 14 |
| 1970–1975 | First clinical use of artificial cells in patients (for hemoperfusion). | 11, 15, 16 |
| 1971 | Implanted enzyme-containing artificial cells used for lymphosarcoma suppression. Glutaraldehyde-crosslinked haemoglobin used to form soluble polyhemoglobin. | 17, 18 |
| 1972 | Crosslinked protein–lipid membrane artificial cells with transport carrier produced. | 8, 19 |
| 1976 | Biodegradable polylactide microcapsules and microparticles containing proteins and hormones produced. | 20 |
| 1977–1978 | Artificial cells containing multi-enzyme systems with cofactor recycling developed. | 20–22 |
| 1980 | Alginate–polylysine–alginate encapsulated islets implanted into diabetic rats. Artificial cell membrane with Na+K+-ATPase produced. The first report on the laboratory demonstration of encapsulation of islets and the ability of this to maintain a normal blood glucose level when implanted. | 5, 19 |
| 1986 | Artificial cell membrane that excludes small hydrophilic molecules but which is permeable to large lipophilic molecules produced. Novel finding of extensive enterorecirculation of amino acids, which could allow oral therapy with artificial cells containing enzymes to selectively remove specific unwanted systemic amino acids. | 23–29 |
| 1989 | First clinical use of artificial cells containing enzymes in a patient with Lesch–Nyhan disease | 30, 31 |
| 1994 | Biodegradable polymeric nano-artificial red blood cells developed. First clinical report of the use of encapsulated islets in a diabetic patient. | 32–35 |
| 1996 | Hollow polymeric fiber for encapsulation of genetically engineered cells developed. Encapsulated bacteria lower high plasma urea levels to normal in uremic rats with induced kidney failure. | 36, 37 |
| 1999 | Artificial cell microcapsules containing genetically engineered Escherichia coli DH5 cells to lower plasma potassium, phosphate, magnesium, sodium, chloride, uric acid, cholesterol, and creatinine developed. Microcapsules as bio-organs for somatic gene therapy. | 4, 38–41 |
| 2000–2003 | Artificial cells co-encapsulating hepatocytes and adult stem cells developed. | 42–44 |
| 2001 | Monitoring of the mechanical stability of various types of microcapsules, predicting the performance of microcapsules in vivo, and quality control of microcapsules during scale-up productions developed. | 45 |
| 2002 | Treatment of hemophilia B in mice with non-autologous somatic gene therapeutics. Novel approach to tumor suppression with microencapsulated recombinant cells. | 46, 47 |
| 2003 | Antiangiogenic cancer therapy with microencapsulated cells. | 48 |
| 2004 | First report of microencapsulated genetically engineered lactobacilli for lowering cholesterol. Combined immunotherapy and antiangiogenic therapy of cancer with microencapsulated cells. | 49, 50 |
| 2005 | First studies of artificial cell microcapsules as an alternative to liver cell transplants for the treatment of liver failure. Novel targeted drug delivery using polymeric microcapsule for treatment of Crohn’s and inflammatory bowel disease (IBD). New effective characterization of microcapsules using genipin. Encapsulation of recombinant cells with a novel magnetized alginate for magnetic resonance imaging. | 38, 39, 51–56 |
1.1 The basic concept of artificial cells.
It is also possible to prepare artificial cells in the molecular, nano- or even macro-dimensions. Cell encapsulation promises immuno-isolation, which has initiated a flurry of research into bioartificial organs and tissue engineering, while the prospect of encapsulation increasing long-term in vivo cell survivability has opened new avenues for both targeted and recurrent therapeutic drug delivery systems. Recent advances in molecular biology, cell biology, biotechnology, nanotechnology and other areas have resulted in rapid developments in this area for basic research and for gene therapy, enzyme therapy, cell therapy, blood substitutes, liver support systems and other areas. Significant advances have made the translation of this concept to clinical use – for example, in the treatment of type 1 diabetes using encapsulated islets – increasingly practicable. The potential therapeutic applications of encapsulated cells are enormous,7,59–67 preferentially include replacement organ functions, correction of hormone/enzyme deficiencies, treatment of cancers, central nervous system (CNS) diseases and other disorders (Table 1.2).
