REVIEWSNATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | MARCH 2005 | 221The concept of using ‘artificial cells’— ultra-thin poly-mer membrane microcapsules — to encapsulate mate-rials such as transplanted cells, enzymes and absorbentswas first put forward 40 years ago1–3 (TIMELINE). Encap-sulation was proposed as a means to protect theenclosed materials from the external environment,thereby helping to prevent rejection by the immunesystem1–3.Since then, significant advances have madethe translation of this concept to clinical use — forexample, in the treatment of type 1 diabetes usingencapsulated islets4— increasingly practicable5,6.However, there are a number of key challenges thatneed to be addressed before products based on theseapproaches can enter clinical development6,which willbe discussed in this article.The first routine clinical application of artificialcells — in this case, those encapsulating adsorbentssuch as activated charcoal — has been in removingtoxins and drugs from the blood7–10.Numerous otherapplications of polymeric artificial cells have emerged,because many types of biologically active materials,such as enzymes, can be micro-encapsulated individ-ually or in combination1–3,11–20 (FIG. 1), as well as wholecells (FIG. 2).Biologically active materials inside the artificialcells are prevented from coming into direct con-tact with external entities such as leukocytes, anti-bodies or tryptic enzymes (FIG. 1).However, smallermolecules, such as hormones, peptides and smallproteins, can equilibrate rapidly across the mem-brane of artificial cells. The ultra-thin membrane(0.02 µm) and membrane equivalent pore radius of14 Å, together with the large total surface area of theartificial cells (10 ml of 20-µm-diameter artificialcells have a total surface area of about 20,000 cm2—equivalent to that of a haemodialysis machine),allows for extremely fast equilibration of moleculessmaller than large proteins.The permeability, composition and configurationof the membrane can be varied using different types ofmaterials, which allows for extensive variations in theproperties and functions of artificial cells. The artificialcells can also range in size from macro-dimensionsof up to 2-mm diameter, through micron- and nano-dimensions down to molecular dimensions (BOX 1).Now that drug discovery based on biotechnologyand molecular biology has come of age, the potentialtherapeutic applications of polymeric artificial cellsare just beginning to be realized and demonstrated.The discussion that follows focuses on polymeric arti-ficial cells, including the principles, the development,present status, future perspectives and challenges.This review does not discuss the use of polymericartificial cells in drug delivery systems, as excellentreviews of this field have already been published inthis journal21–23.THERAPEUTIC APPLICATIONS OFPOLYMERIC ARTIFICIAL CELLSThomas Ming Swi ChangAbstract | Polymeric artificial cells have the potential to be used for a wide variety oftherapeutic applications, such as the encapsulation of transplanted islet cells to treat diabeticpatients. Recent advances in biotechnology, molecular biology, nanotechnology and polymerchemistry are now opening up further exciting possibilities in this field. However, it is alsorecognized that there are several key obstacles to overcome in bringing such approaches intoroutine clinical use. This review describes the historical development and principles behindpolymeric artificial cells, the present state of the art in their therapeutic application, and thepromises and challenges for the future.Artificial Cells and OrgansResearch Center,Departments of Physiology,Medicine and BiomedicalEngineering,Faculty of Medicine,McGill University,3655, Drummond Street,Montreal, Quebec,Canada H3G 1H6.e-mail:[email protected]:10.1038/nrd1659222 | MARCH 2005 | VOLUME 4 www.nature.com/reviews/drugdiscREVIEWSArtificial cells for cell encapsulationMany attempts have been made to prevent the rejectionof transplanted cells by the immune system by usingdialysers, ultrafiltrators, membrane sacs, membranedisks and polymeric devices. However, in these configu-rations, one of the major problems is low cell viability,owing to limitations of mass transfer for oxygen andnutrients. Polymeric artificial cellswith microscopicdimensions (less than 2 mm in diameter) provide a highsurface-to-volume ratio, which allows for good masstransfer of oxygen and nutrients, while also acting toprotect the cells from immunorejection1–3,14.There has been an increasing realization of the poten-tial of cell encapsulation with polymeric artificial cells inrecent years6,34 (FIG. 2) — as highlighted, for example, by a2003 consensus paper from several leading groups pub-lished in Nature Medicine6.Indeed, cell-based products,including cells with synthetic biomaterials, are now rec-ognized as a new category of therapeutic products by theUS Pharmacopeia and National Formulation35.Encapsulation of islets. As mentioned above, the idea ofusing polymeric cells to encapsulate transplanted cells(in particular islet cells) (FIG. 2), and to thereby protectthem from immune rejection, was first proposed in the1960s1–3.The method is based on a drop technique, inwhich a haemoglobin solution containing cells is addeddrop-wise to a silicone liquid containing diacid. Thehydrophobic diacid only crosslinks haemoglobin atthe interface of the two solutions, to form a membraneby interfacial polymerization1; the encapsulated cells inthe resulting artificial cells thereby remain intact2,3,14.Although the idea of encapsulation of islets for thetreatment of diabetes was proposed in the 1960s1–3,14,itwas not until 1980 that this idea was successfullyArtificial cells containing bioadsorbentAs mentioned above, the microscopic dimensions ofartificial cells result in a large surface-to-volume ratio.This, together with the ultra-thin membranes, makesartificial cells that contain bioadsorbents much moreeffective in removing toxins and drugs from the blood ofpatients when compared with standard haemodialysis7–10.Themost common and earliest such approach is theuse of microscopic polymeric artificial cells thatencapsulated activated charcoal7–9,15,which solved themajor problems relating to the release of embolizingparticles and subsequent damage to blood cells whenbioadsorbents were used without the artificial cellmembranes. Since the early 1980s, this approach hasbeen used
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