REVIEWS THERAPEUTIC APPLICATIONS OF POLYMERIC ARTIFICIAL CELLS Thomas Ming Swi Chang Abstract Polymeric artificial cells have the potential to be used for a wide variety of therapeutic applications such as the encapsulation of transplanted islet cells to treat diabetic patients Recent advances in biotechnology molecular biology nanotechnology and polymer chemistry are now opening up further exciting possibilities in this field However it is also recognized that there are several key obstacles to overcome in bringing such approaches into routine clinical use This review describes the historical development and principles behind polymeric artificial cells the present state of the art in their therapeutic application and the promises and challenges for the future Artificial Cells and Organs Research Center Departments of Physiology Medicine and Biomedical Engineering Faculty of Medicine McGill University 3655 Drummond Street Montreal Quebec Canada H3G 1H6 e mail artcell med mcgill ca doi 10 1038 nrd1659 The concept of using artificial cells ultra thin polymer membrane microcapsules to encapsulate materials such as transplanted cells enzymes and absorbents was first put forward 40 years ago1 3 TIMELINE Encapsulation was proposed as a means to protect the enclosed materials from the external environment thereby helping to prevent rejection by the immune system1 3 Since then significant advances have made the translation of this concept to clinical use for example in the treatment of type 1 diabetes using encapsulated islets4 increasingly practicable5 6 However there are a number of key challenges that need to be addressed before products based on these approaches can enter clinical development6 which will be discussed in this article The first routine clinical application of artificial cells in this case those encapsulating adsorbents such as activated charcoal has been in removing toxins and drugs from the blood7 10 Numerous other applications of polymeric artificial cells have emerged because many types of biologically active materials such as enzymes can be micro encapsulated individually or in combination1 3 11 20 FIG 1 as well as whole cells FIG 2 Biologically active materials inside the artificial cells are prevented from coming into direct contact with external entities such as leukocytes antibodies or tryptic enzymes FIG 1 However smaller NATURE REVIEWS DRUG DISCOVERY molecules such as hormones peptides and small proteins can equilibrate rapidly across the membrane of artificial cells The ultra thin membrane 0 02 m and membrane equivalent pore radius of 14 together with the large total surface area of the artificial cells 10 ml of 20 m diameter artificial cells have a total surface area of about 20 000 cm2 equivalent to that of a haemodialysis machine allows for extremely fast equilibration of molecules smaller than large proteins The permeability composition and configuration of the membrane can be varied using different types of materials which allows for extensive variations in the properties and functions of artificial cells The artificial cells can also range in size from macro dimensions of up to 2 mm diameter through micron and nanodimensions down to molecular dimensions BOX 1 Now that drug discovery based on biotechnology and molecular biology has come of age the potential therapeutic applications of polymeric artificial cells are just beginning to be realized and demonstrated The discussion that follows focuses on polymeric artificial cells including the principles the development present status future perspectives and challenges This review does not discuss the use of polymeric artificial cells in drug delivery systems as excellent reviews of this field have already been published in this journal21 23 VOLUME 4 MARCH 2005 2 2 1 REVIEWS Timeline Concepts and applications of polymeric artificial cells Extrusion drop technique for encapsulating intact cells for immuno isolation developed2 3 14 First polymeric artificial cells containing proteins developed11 1957 1964 Multicompartment artificial cells developed 2 3 14 1965 1966 Polymeric artificial cells containing enzymes and haemoglobin developed 1 Intermolecularly crosslinked protein for example polyhaemoglobin produced and conjugation of haemoglobin to polymer achieved1 222 Artificial cells with ultra thin membranes and which contain adsorbents for use in haemoperfusion developed7 8 15 1966 1966 1969 Silastic artificial cells and microspheres containing protein produced15 First clinical use of artificial cells in patients for haemoperfusion 8 9 31 1968 1970 1975 Implanted enzymecontaining artificial cells used for enzyme therapy in acatalesmic mice12 Artificial cells containing magnetic materials with other materials produced16 Crosslinked protein lipid membrane artificial cells with transport carrier produced14 134 1971 1972 Implanted enzyme containing artificial cells used for lymphosarcoma suppression13 Artificial cells containing multi enzyme systems with cofactor recycling developed136 138 1976 1977 1978 Biodegradable polylactide microcapsules and microparticles containing proteins and hormones produced16 Glutaraldehyde crosslinked haemoglobin used to form soluble polyhaemoglobin17 Artificial cells containing bioadsorbent Artificial cells for cell encapsulation As mentioned above the microscopic dimensions of artificial cells result in a large surface to volume ratio This together with the ultra thin membranes makes artificial cells that contain bioadsorbents much more effective in removing toxins and drugs from the blood of patients when compared with standard haemodialysis7 10 The most common and earliest such approach is the use of microscopic polymeric artificial cells that encapsulated activated charcoal7 9 15 which solved the major problems relating to the release of embolizing particles and subsequent damage to blood cells when bioadsorbents were used without the artificial cell membranes Since the early 1980s this approach has been used routinely worldwide for the treatment of acute poisoning in adults and children especially in suicidal overdose9 10 24 30 This is particularly useful in situations in which haemodialysis units are not easily accessible or available This approach has also been shown to effectively remove toxic uraemia products resulting in the relief of uraemic symptoms in uraemic patients8 10 14 although components for the removal of other uraemic metabolites need to be developed In
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