Cell encapsulation

Cell microencapsulation technology involves immobilization of the cells within a polymeric semi-permeable membrane that permits the bidirectional diffusion of molecules such as the influx of oxygen, nutrients, growth factors etc. essential for cell metabolism and the outward diffusion of waste products and therapeutic proteins. At the same time, the semi-permeable nature of the membrane prevents immune cells and antibodies from destroying the encapsulated cells regarding them as foreign invaders.

The main motive of cell encapsulation technology is to overcome the existing problem of graft rejection in tissue engineering applications and thus reduce the need for long-term use of immunosuppressive drugs after an organ transplant to control side effects.

Schematic illustrating cell microencapsulation.
Schematic illustrating cell microencapsulation.

History

In 1933 Vincenzo Bisceglie made the first attempt to encapsulate cells in polymer membranes. He demonstrated that tumor cells in a polymer structure transplanted into pig abdominal cavity remained viable for a long period without being rejected by the immune system.[1]

Thirty years later in 1964, the idea of encapsulating cells within ultra thin polymer membrane microcapsules so as to provide immunoprotection to the cells was then proposed by Thomas Chang who introduced the term "artificial cells" to define this concept of bioencapsulation.[2] He suggested that these artificial cells produced by a drop method not only protected the encapsulated cells from immunorejection but also provided a high surface-to-volume relationship enabling good mass transfer of oxygen and nutrients.[2] Twenty years later, this approach was successfully put into practice in small animal models when alginate-polylysine-alginate (APA) microcapsules immobilizing xenograft islet cells were developed.[3] The study demonstrated that when these microencapsulated islets were implanted into diabetic rats, the cells remained viable and controlled glucose levels for several weeks. Human trials utilising encapsulated cells were performed in 1998.[4][5][6] Encapsulated cells expressing a cytochrome P450 enzyme to locally activate an anti-tumour prodrug were used in a trial for advanced, non-resectable pancreatic cancer. Approximately a doubling of survival time compared to historic controls was demonstrated.

Cell microencapsulation as a tool for tissue engineering and regenerative medicine

Questions could arise as to why the technique of encapsulation of cells is even required when therapeutic products could just be injected at the site. An important reason for this is that the encapsulated cells would provide a source of sustained continuous release of therapeutic products for longer durations at the site of implantation. Another advantage of cell microencapsulation technology is that it allows the loading of non-human and genetically modified cells into the polymer matrix when the availability of donor cells is limited.[7] Microencapsulation is a valuable technique for local, regional and oral delivery of therapeutic products as it can be implanted into numerous tissue types and organs. For prolonged drug delivery to the treatment site, implantation of these drug loaded artificial cells would be more cost effective in comparison to direct drug delivery. Moreover, the prospect of implanting artificial cells with similar chemical composition in several patients irrespective of their leukocyte antigen could again allow reduction in costs.[7]

Key parameters of cell microencapsulation technology

The potential of using cell microencapsulation in successful clinical applications can be realized only if several requirements encountered during the development process are optimized such as the use of an appropriate biocompatible polymer to form the mechanically and chemically stable semi-permeable matrix, production of uniformly sized microcapsules, use of an appropriate immune-compatible polycations cross-linked to the encapsulation polymer to stabilized the capsules, selection of a suitable cell type depending on the situation.

Biomaterials

The use of the best biomaterial depending on the application is crucial in the development of drug delivery systems and tissue engineering. The polymer alginate is very commonly used due to its early discovery, easy availability and low cost but other materials such as cellulose sulphate, collagen, chitosan, gelatin and agarose have also been employed.

Alginate

Several groups have extensively studied several natural and synthetic polymers with the goal of developing the most suitable biomaterial for cell microencapsulation.[8][9] Extensive work has been done using alginates which are regarded as the most suitable biomaterials for cell microencapsulation due to their abundance, excellent biocompatibility and biodegradability properties. Alginate is a natural polymer which can be extracted from seaweed and bacteria[10] with numerous compositions based on the isolation source.[10]

Alginate is not free from all criticism. Some researchers believe that alginates with high-M content could produce an inflammatory response[11][12] and an abnormal cell growth[13] while some have demonstrated that alginate with high-G content lead to an even higher cell overgrowth[14][15] and inflammatory reaction in vivo as compared to intermediate-G alginates.[16][17] Even ultrapure alginates may contain endotoxins, and polyphenols which could compromise the biocompatibility of the resultant cell microcapsules.[15][18][19] It has been shown that even though purification processes successfully lower endotoxin and polyphenol content in the processed alginate, it is difficult to lower the protein content[18] and the purification processes could in turn modify the properties of the biomaterial.[19] Thus it is essential that an effective purification process is designed so as to remove all the contaminants from alginate before it can be successfully used in clinical applications.

Modification and functionalization of alginate

Researchers have also been able to develop alginate microcapsules with an altered form of alginate with enhanced biocompatibility and higher resistance to osmotic swelling.[20][21] Another approach to increasing the biocompatibility of the membrane biomaterial is through surface modification of the capsules using peptide and protein molecules which in turn controls the proliferation and rate of differentiation of the encapsulated cells. One group that has been working extensively on coupling the amino acid sequence Arg-Gly-Asp (RGD) to alginate hydrogels demonstrated that the cell behavior can be controlled by the RGD density coupled on the alginate gels. Alginate microparticles loaded with myoblast cells and functionalized with RGD allowed control over the growth and differentiation of the loaded cells.[22][23] Another vital factor that controls the use of cell microcapsules in clinical applications is the development of a suitable immune-compatible polycation to coat the otherwise highly porous alginate beads and thus impart stability and immune protection to the system.[24] Poly-L-lysine is the most commonly used polycation but its low biocompatibility restricts the successful clinical use of these PLL formulated microcapsules which attract inflammatory cells thus inducing necrosis of the loaded cells.[25] Studies have also shown that alginate-PLL-alginate (APA) microcapsules demonstrate low mechanical stability and short term durability. Thus several research groups have been looking for alternatives to PLL and have demonstrated promising results with poly-L-ornithine[26] and poly(methylene-co-guanidine) hydrochloride[27] by fabricating durable microcapsules with high and controlled mechanical strength for cell encapsulation.

Several groups have also investigated the use of chitosan which is a naturally derived polycation as a potential replacement for PLL to fabricate alginate-chitosan (AC) microcapsules for cell delivery applications.[28][29] However, studies have also shown that the stability of this AC membrane is again limited[30][31] and one group demonstrated that modification of this alginate-chitosan microcapsules with genipin, a naturally occurring iridoid glucosid from gardenia fruits, to form genipin cross-linked alginate-chitosan (GCAC) microcapsules could augment stability of the cell loaded microcapsules.[30]

Microphotographs of the alginate-chitosan (AC) microcapsules.
Microphotographs of the alginate-chitosan (AC) microcapsules.

Collagen

Collagen, a major protein component of the ECM, provides support to tissues like skin, cartilage, bones, blood vessels and ligaments and is thus considered a model scaffold or matrix for tissue engineering due to its properties of biocompatibility, biodegradability and ability to promote cell binding.[32] This ability allows chitosan to control distribution of cells inside the polymeric system. Thus, Type-I collagen obtained from animal tissues is now successfully being used commercially as tissue engineered biomaterial for multiple applications.[33] Collagen has also been used in nerve repair[34] and bladder engineering.[27] Immunogenicity has limited the applications of collagen. Gelatin has been considered as an alternative for that reason.[35]

Gelatin

Gelatin is prepared from the denaturation of collagen and many desirable properties such as biodegradability, biocompatibility, non-immunogenity in physiological environments, and easy processability make this polymer a good choice for tissue engineering applications.[36] It is used in engineering tissues for the skin, bone and cartilage and is used commercially for skin replacements.[37]

Chitosan

Chitosan is a polysaccharide composed of randomly distributed β-(1-4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It is derived from the N-deacetylation of chitin and has been used for several applications such as drug delivery,[38] space-filling implants[39] and in wound dressings.[40] However, one drawback of this polymer is its weak mechanical properties and is thus often combined with other polymers such collagen to form a polymer with stronger mechanical properties for cell encapsulation applications.[41]

Agarose

Agarose is a polysaccharide derived from seaweed used for nanoencapsulation of cells and the cell/agarose suspension[42] can be modified to form microbeads by reducing the temperature during preparation.[43] However, one drawback with the microbeads so obtained is the possibility of cellular protrusion through the polymeric matrix wall after formation of the capsules.

Cellulose Sulphate

Cellulose sulphate is derived from cotton and, once processed appropriately, can be used as a biocompatible base in which to suspend cells. When the poly-anionic cellulose sulphate solution is immersed in a second, poly-cationic solution (e.g. pDADMAC), a semi-permeable membrane is formed around the suspended cells as a result of gelation between the two poly-ions. Both mammalian cell lines and bacterial cells remain viable and continue to replicate within the capsule membrane in order to fill-out the capsule. As such, in contrast to some other encapsulation materials, the capsules can be used to grow cells and act as such like a mini-bioreactor. The biocompatible nature of the material has been demonstrated by observation during studies using the cell-filled capsules themselves for implantation as well as isolated capsule material.[44] Capsules formed from cellulose sulphate have been successfully used, showing safety and efficacy, in clinical and pre-clinical trials in both humans and animals, primarily as anti-cancer treatments, but also exploring possible uses for gene therapy or antibody therapies.[4][45][46][47][48] Using cellulose sulphate it has been possible to manufacture encapsulated cells as a pharmaceutical product at large scale and fulfilling Good Manufacturing Process (cGMP) standards. This was achieved by the company Austrianova in 2007.[49]

Biocompatibility

The use of an ideal high quality biomaterial with the inherent properties of biocompatibility is the most crucial factor that governs the long term efficiency of this technology. An ideal biomaterial for cell encapsulation should be one that is totally biocompatible, does not trigger an immune response in the host and does not interfere with cell homeostasis so as to ensure high cell viability.[50] However, one major limitation has been the inability to reproduce the different biomaterials and the requirements to obtain a better understanding of the chemistry and biofunctionality of the biomaterials and the microencapsulation system.[42] Several studies demonstrate that surface modification of these cell containing microparticles allows control over the growth and cellular differentiation.[42][51] of the encapsulated cells.[52]

One study proposed the use of zeta potential which measures the electric charge of the microcapsule as a means to predict the interfacial reaction between microcapsule and the surrounding tissue and in turn the biocompatibility of the delivery system.[53]

Microcapsule permeability

A fundamental criterion that must be established while developing any device with a semi-permeable membrane is to adjust the permeability of the device in terms of entry and exit of molecules.[54][55] It is essential that the cell microcapsule is designed with uniform thickness and should have a control over both the rate of molecules entering the capsule necessary for cell viability and the rate of therapeutic products and waste material exiting the capsule membrane. Immunoprotection of the loaded cell is the key issue that must be kept in mind while working on the permeability of the encapsulation membrane as not only immune cells but also antibodies and cytokines should be prevented entry into the microcapsule which in fact depends on the pore size of the biomembrane.[55]

It has been shown that since different cell types have different metabolic requirements, thus depending on the cell type encapsulated in the membrane the permeability of the membrane has to be optimized.[56] Several groups have been dedicated towards the study of membrane permeability of cell microcapsules[51][52] and although the role of permeability of certain essential elements like oxygen has been demonstrated,[57] the permeability requirements of each cell type are yet to be determined.

Mechanical strength and durability

It is essential that the microcapsules have adequate membrane strength (mechanical stability) to endure physical and osmotic stress such as during the exchange of nutrients and waste products. The microcapsules should be strong enough and should not rupture on implantation as this could lead to an immune rejection of the encapsulated cells.[55] For instance, in the case of xenotransplantation, a tighter more stable membrane would be required in comparison to allotransplantation. Also, while investigating the potential of using APA microcapsules loaded with bile salt hydrolase (BSH) overproducing active Lactobacillus plantarum 80 cells, in a simulated gastro intestinal tract model for oral delivery applications, the mechanical integrity and shape of the microcapsules was evaluated. It was shown that APA microcapsules could potentially be used in the oral delivery of live bacterial cells.[58] However, further research proved that the GCAC microcapsules possess a higher mechanical stability as compared to APA microcapsules for oral delivery applications.[59] Martoni et al. were experimenting with bacteria-filled capsules that would be taken by mouth to reduce serum cholesterol. The capsules were pumped through a series of vessels simulating the human GI tract to determine how well the capsules would survive in the body. Extensive research into the mechanical properties of the biomaterial to be used for cell microencapsulation is necessary to determine the durability of the microcapsules during production and especially for in vivo applications where a sustained release of the therapeutic product over long durations is required.

Illustration the of APA microcapsule integrity and morphological changes during simulated GI transit. (a) Pre-stomach transit. (b) Post-stomach transit (60 minutes). (c) Post-stomach (60 minutes) and intestinal (10-hour) transit. Microcapsule size: (a) 608 ± 36 μm (b) 544 ± 40 μm (c) 725 ± 55 μm.
Illustration the of APA microcapsule integrity and morphological changes during simulated GI transit. (a) Pre-stomach transit. (b) Post-stomach transit (60 minutes). (c) Post-stomach (60 minutes) and intestinal (10-hour) transit. Microcapsule size: (a) 608 ± 36 μm (b) 544 ± 40 μm (c) 725 ± 55 μm. From Martoni et al. (2007).

Microcapsule size

The diameter of the microcapsules is an important factor that influences both the immune response towards the cell microcapsules as well as the mass transport across the capsule membrane. Studies show that the cellular response to smaller capsules is much lesser as compared to larger capsules[60] and in general the diameter of the cell loaded microcapsules should be between 350-450 µm so as to enable effective diffusion across the semi-permeable membrane.[61][62]

Cell choice

The cell type chosen for this technique depends on the desired application of the cell microcapsules. The cells put into the capsules can be from the patient (autologous cells), from another donor (allogeneic cells) or from other species (xenogeneic cells).[63] The use of autologous cells in microencapsulation therapy is limited by the availability of these cells and even though xenogeneic cells are easily accessible, danger of possible transmission of viruses, especially porcine endogenous retrovirus to the patient restricts their clinical application,[64] and after much debate several groups have concluded that studies should involve the use of allogeneic instead of xenogeneic cells.[65] Depending on the application, the cells can be genetically altered to express any required protein.[66] However, enough research has to be carried out to validate the safety and stability of the expressed gene before these types of cells can be used.

This technology has not received approval for clinical trial because of the high immunogenicity of cells loaded in the capsules. They secrete cytokines and produce a severe inflammatory reaction at the implantation site around the capsules, in turn leading to a decrease in viability of the encapsulated cells.[15][67] One promising approach being studied is the administration of anti-inflammatory drugs to reduce the immune response produced due to administration of the cell loaded microcapsules.[68][69] Another approach which is now the focus of extensive research is the use of stem cells such as mesenchymal stem cells for long term cell microencapsulation and cell therapy applications in hopes of reducing the immune response in the patient after implantation.[70] Another issue which compromises long term viability of the microencapsulated cells is the use of fast proliferating cell lines which eventually fill up the entire system and lead to decrease in the diffusion efficiency across the semi-permeable membrane of the capsule.[66] A solution to this could be in the use of cell types such as myoblasts which do not proliferate after the microencapsulation procedure.

Non-Therapeutic Applications

Probiotics are increasingly being used in numerous dairy products such as ice cream, milk powders, yoghurts, frozen dairy desserts and cheese due to their important health benefits. But, low viability of probiotic bacteria in the food still remains a major hurdle. The pH, dissolved oxygen content, titratable acidity, storage temperature, species and strains of associative fermented dairy product organisms and concentration of lactic and acetic acids are some of the factors that greatly affect the probiotic viability in the product.[71][72][73] As set by Food and Agriculture Organization (FAO) of the United Nations and the World Health Organization (WHO), the standard in order to be considered a health food with probitic addition, the product should contain per gram at least 106-107 cfu of viable probiotic bacteria.[74] It is necessary that the bacterial cells remain stable and healthy in the manufactured product, are sufficiently viable while moving through the upper digestive tract and are able to provide positive effects upon reaching the intestine of the host.[75]

Cell microencapsulation technology has successfully been applied in the food industry for the encapsulation of live probiotic bacteria cells to increase viability of the bacteria during processing of dairy products and for targeted delivery to the gastrointestinal tract.[76]

Apart from dairy products, microencapsulated probiotics have also been used in non-dairy products, such as TheresweetTM which is a sweetener. It can be used as a convenient vehicle for delivery of encapsulated Lactobacillus to the intestine although it is not itself a dairy product.

Therapeutic Applications

Diabetes

The potential of using bioartificial pancreas, for treatment of diabetes mellitus, based on encapsulating islet cells within a semi permeable membrane is extensively being studied by scientists. These devices could eliminate the need for of immunosuppressive drugs in addition to finally solving the problem of shortage of organ donors. The use of microencapsulation would protect the islet cells from immune rejection as well as allow the use of animal cells or genetically modified insulin-producing cells.[77] It is hoped that development of these islet encapsulated microcapsules could prevent the need for the insulin injections needed several times a day by type 1 diabetic patients.[63] The Edmonton protocol involves implantation of human islets extracted from cadaveric donors and has shown improvements towards the treatment of type 1 diabetics who are prone to hypoglycemic unawareness.[78] However, the two major hurdles faced in this technique are the limited availability of donor organs and with the need for immunosuppresents to prevent an immune response in the patient’s body.

Several studies have been dedicated towards the development of bioartificial pancreas involving the immobilization of islets of Langerhans inside polymeric capsules. The first attempt towards this aim was demonstrated in 1980 by Lim et al. where xenograft islet cells were encapsulated inside alginate polylysine microcapsules and showed significant in vivo results for several weeks.[3] It is envisaged that the implantation of these encapsulated cells would help to overcome the use of immunosuppressive drugs and also allow the use of xenograft cells thus obviating the problem of donor shortage.

The polymers used for islet microencapsulation are alginate,[79] chitosan,[80] polyethylene glycol (PEG),[81] agarose,[82] sodium cellulose sulfate and water insoluble polyacrylates with alginate and PEG being commonly used polymers. With successful in vitro studies being performed using this technique, significant work in clinical trials using microencapsulated human islets is being carried out. In 2003, the use of alginate/PLO microcapsules containing islet cells for pilot phase-1 clinical trials was permitted to be carried out at the University of Perugia by the Italian Ministry of Health.[54] In another study, the potential of clinical application of PEGylation and low doses of the immunosuppressant cyclosporine A were evaluated. The trial which began in 2005 by Novocell, now forms the phase I/II of clinical trials involving implantation of islet allografts into the subcutaneous site.[83] However, there have been controversial studies involving human clinical trials where Living Cell technologies Ltd demonstrated the survival of functional xenogeneic cells transplanted without immunosuppressive medication for 9.5 years.[84] However, the trial received harsh criticism from the International Xenotransplantation Association as being risky and premature.[85] However, even though clinical trials are under way, several major issues such as biocompatibility and immunoprotection need to be overcome.[86]

Potential alternatives to encapsulating isolated islets (of either allo- or xenogeneic origin) are also being explored. Using sodium cellulose sulphate technology from Austrianova Singapore an islet cell line was encapsulated and it was demonstrated that the cells remain viable and release insulin in response to glucose.[87] In pre-clinical studies, implanted, encapsulated cells were able to restore blood glucose levels in diabetic rats over a period of 6 months.[88]

Cancer

The use of cell encapsulated microcapsules towards the treatment of several forms of cancer has shown great potential. One approach undertaken by researchers is through the implantation of microcapsules containing genetically modified cytokine secreting cells. An example of this was demonstrated by Cirone et al. when genetically modified IL-2 cytokine secreting non-autologous mouse myoblasts implanted into mice showed a delay in the tumor growth with an increased rate of survival of the animals.[89] However, the efficiency of this treatment was brief due to an immune response towards the implanted microcapsules. Another approach to cancer suppression is through the use of angiogenesis inhibitors to prevent the release of growth factors which lead to the spread of tumors. The effect of implanting microcapsules loaded with xenogenic cells genetically modified to secrete endostatin, an antiangiogenic drug which causes apoptosis in tumor cells, has been extensively studied.[90][91] However, this method of local delivery of microcapsules was not feasible in the treatment of patients with many tumors or in metastasis cases and has led to recent studies involving systemic implantation of the capsules.[92][93]

In 1998, a murine model of pancreatic cancer was used to study the effect of implanting genetically modified cytochrome P450 expressing feline epithelial cells encapsulated in cellulose sulfate polymers for the treatment of solid tumors.[94] The approach demonstrated for the first time the application of enzyme expressing cells to activate chemotherapeutic agents. On the basis of these results, an encapsulated cell therapy product, NovaCaps, was tested in a phaseI/II clinical trial for the treatment of pancreatic cancer in patients[95][96] and has recently been designated by the European medicines agency (EMEA) as an orphan drug in Europe. A further phase I/II clinical trial using the same product confirmed the results of the first trial, demonstrating an approximate doubling of survival time in patients with stage IV pancreatic cancer.[97] In all of these trials using cellulose sulphate, in addition to the clear anti-tumour effects, the capsules were well tolerated and there were no adverse reactions seen such as immune response to the capsules, demonstrating the biocompatible nature of the cellulose sulphate capsules. In one patient the capsules were in place for almost 2 years with no side effects.

These studies show the promising potential application of cell microcapsules towards the treatment of cancers.[42] However, solutions to issues such as immune response leading to inflammation of the surrounding tissue at the site of capsule implantation have to be researched in detail before more clinical trials are possible.

Heart Diseases

Numerous studies have been dedicated towards the development of effective methods to enable cardiac tissue regeneration in patients after ischemic heart disease. An emerging approach to answer the problems related to ischemic tissue repair is though the use of stem cell-based therapy.[98] However, the actual mechanism due to which this stem cell-based therapy has generative effects on cardiac function is still under investigation. Even though numerous methods have been studied for cell administration, the efficiency of the number of cells retained in the beating heart after implantation is still very low. A promising approach to overcome this problem is through the use of cell microencapsulation therapy which has shown to enable a higher cell retention as compared to the injection of free stem cells into the heart.[99]

Another strategy to improve the impact of cell based encapsulation technique towards cardiac regenerative applications is through the use of genetically modified stem cells capable of secreting angiogenic factors such as vascular endothelial growth factor (VEGF) which stimulate neovascularization and restore perfusion in the damaged ischemic heart.[100][101] An example of this is shown in the study by Zang et al. where genetically modified xenogeneic CHO cells expressing VEGF were encapsulated in alginate-polylysine-alginate microcapsules and implanted into rat myocardium.[102][102] It was observed that the encapsulation protected the cells from an immunorespone for three weeks and also led to an improvement in the cardiac tissue post-infarction due to increased angiogenesis.

Monoclonal Antibody Therapy

The use of monoclonal antibodies for therapy is now widespread for treatment of cancers and inflammatory diseases. Using cellulose sulphate technology, scientists have successfully encapsulated antibody producing hybridoma cells and demonstrated subsequent release of the therapeutic antibody from the capsules.[45][46] The capsules containing the hybridoma cells were used in pre-clinical studies to deliver neutralising antibodies to the mouse retrovirus FrCasE, successfully preventing disease.

Other conditions

Many other medical conditions have been targeted with encapsulation therapies, especially those involving a deficiency in some biologically derived protein. One of the most successful approaches is an external device that acts similarly to a dialysis machine, only with a reservoir of pig hepatocytes surrounding the semipermeable portion of the blood-infused tubing.[103] This apparatus can remove toxins from the blood of patients suffering severe liver failure. Other applications that are still in development include cells that produce Ciliary-derived neurotrophic factor for the treatment of ALS and Huntington's Disease, Glial-derived neurotrophic factor for Parkinson's Disease, Erythropoietin for Anemia, and HGH for Dwarfism.[104] In addition, monogeneic diseases such as haemophilia, Gaucher’s disease and some Mucopolysaccharide disorders could also potentially be targeted by encapsulated cells expressing the protein that is otherwise lacking in the patient.

References

  1. ↑ Bisceglie V (1993). "Uber die antineoplastische Immunität; heterologe Einpflanzung von Tumoren in Hühner-embryonen". Zeitschrift für Krebsforschung 40: 122–140. doi:10.1007/bf01636399.
  2. ↑ 2.0 2.1 CHANG TM (October 1964). "SEMIPERMEABLE MICROCAPSULES". Science 146 (3643): 524–5. doi:10.1126/science.146.3643.524. PMID 14190240.
  3. ↑ 3.0 3.1 Lim F, Sun AM (November 1980). "Microencapsulated islets as bioartificial endocrine pancreas". Science 210 (4472): 908–10. doi:10.1126/science.6776628. PMID 6776628.
  4. ↑ 4.0 4.1 Löhr, M; Bago, ZT; Bergmeister, H; Ceijna, M; Freund, M; Gelbmann, W; Günzburg, WH; Jesnowski, R; Hain, J; Hauenstein, K; Henninger, W; Hoffmeyer, A; Karle, P; Kröger, JC; Kundt, G; Liebe, S; Losert, U; Müller, P; Probst, A; Püschel, K; Renner, M; Renz, R; Saller, R; Salmons, B; Walter, I (April 1999). "Cell therapy using microencapsulated 293 cells transfected with a gene construct expressing CYP2B1, an ifosfamide converting enzyme, instilled intra-arterially in patients with advanced-stage pancreatic carcinoma: a phase I/II study.". Journal of molecular medicine (Berlin, Germany) 77 (4): 393–8. doi:10.1007/s001090050366. PMID 10353444.
  5. ↑ Löhr, M; Hoffmeyer, A; Kröger, J; Freund, M; Hain, J; Holle, A; Karle, P; Knöfel, WT; Liebe, S; Müller, P; Nizze, H; Renner, M; Saller, RM; Wagner, T; Hauenstein, K; Günzburg, WH; Salmons, B (May 19, 2001). "Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma.". Lancet 357 (9268): 1591–2. doi:10.1016/S0140-6736(00)04749-8. PMID 11377651.
  6. ↑ Lohr, M; Kroger, J-C., Hoffmeyer, A., Freund, M., Hain, J., Holle, A., Knofel, W. T., Liebe, S., Nizze, H., Renner, M., Saller, R., Karle, P., Muller, P., Wagner, T., Hauenstein, K., Salmons, B. and Gunzberg, W. H. (2003). "Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic carcinoma in a phase I/II trial". Cancer Therapy 1: 121–31.
  7. ↑ 7.0 7.1 Murua A, Portero A, Orive G, Hernández RM, de Castro M, Pedraz JL (December 2008). "Cell microencapsulation technology: towards clinical application". J Control Release 132 (2): 76–83. doi:10.1016/j.jconrel.2008.08.010. PMID 18789985.
  8. ↑ Sakai S, Kawabata K, Ono T, Ijima H, Kawakami K (August 2005). "Development of mammalian cell-enclosing subsieve-size agarose capsules (<100 microm) for cell therapy". Biomaterials 26 (23): 4786–92. doi:10.1016/j.biomaterials.2004.11.043. PMID 15763258.
  9. ↑ Cellesi F, Weber W, Fussenegger M, Hubbell JA, Tirelli N (December 2004). "Towards a fully synthetic substitute of alginate: optimization of a thermal gelation/chemical cross-linking scheme ("tandem" gelation) for the production of beads and liquid-core capsules". Biotechnol. Bioeng. 88 (6): 740–9. doi:10.1002/bit.20264. PMID 15532084.
  10. ↑ 10.0 10.1 Govan JR, Fyfe JA, Jarman TR (July 1981). "Isolation of alginate-producing mutants of Pseudomonas fluorescens, Pseudomonas putida and Pseudomonas mendocina". J. Gen. Microbiol. 125 (1): 217–20. doi:10.1099/00221287-125-1-217. PMID 6801192.
  11. ↑ Otterlei M, Ostgaard K, Skjåk-Braek G, Smidsrød O, Soon-Shiong P, Espevik T (August 1991). "Induction of cytokine production from human monocytes stimulated with alginate". J. Immunother. 10 (4): 286–91. doi:10.1097/00002371-199108000-00007. PMID 1931864.
  12. ↑ Espevik T, Otterlei M, Skjåk-Braek G, Ryan L, Wright SD, Sundan A (January 1993). "The involvement of CD14 in stimulation of cytokine production by uronic acid polymers". Eur. J. Immunol. 23 (1): 255–61. doi:10.1002/eji.1830230140. PMID 7678226.
  13. ↑ Soon-Shiong P, Otterlie M, Skjak-Braek G et al. (February 1991). "An immunologic basis for the fibrotic reaction to implanted microcapsules". Transplant. Proc. 23 (1 Pt 1): 758–9. PMID 1990681.
  14. ↑ Clayton HA, London NJ, Colloby PS, Bell PR, James RF (1991). "The effect of capsule composition on the biocompatibility of alginate-poly-l-lysine capsules". J Microencapsul 8 (2): 221–33. doi:10.3109/02652049109071490. PMID 1765902.
  15. ↑ 15.0 15.1 15.2 Orive G, Tam SK, Pedraz JL, Hallé JP (July 2006). "Biocompatibility of alginate-poly-l-lysine microcapsules for cell therapy". Biomaterials 27 (20): 3691–700. doi:10.1016/j.biomaterials.2006.02.048. PMID 16574222.
  16. ↑ De Vos P, De Haan B, Van Schilfgaarde R (February 1997). "Effect of the alginate composition on the biocompatibility of alginate-polylysine microcapsules". Biomaterials 18 (3): 273–8. doi:10.1016/S0142-9612(96)00135-4. PMID 9031730.
  17. ↑ De Vos, Paul; R. van Schifgaarde (September 1999). "Biocompatibility issues". In Kühtreiber, Willem M.; Lanza, Robert P.; Chick, William L. Cell Encapsulation Technology and Therapeutics. Birkhäuser Boston. ISBN 978-0-8176-4010-1.
  18. ↑ 18.0 18.1 Dusseault J, Tam SK, Ménard M et al. (February 2006). "Evaluation of alginate purification methods: effect on polyphenol, endotoxin, and protein contamination". J Biomed Mater Res A 76 (2): 243–51. doi:10.1002/jbm.a.30541. PMID 16265647.
  19. ↑ 19.0 19.1 Tam SK, Dusseault J, Polizu S, Ménard M, Hallé JP, Yahia L (March 2006). "Impact of residual contamination on the biofunctional properties of purified alginates used for cell encapsulation". Biomaterials 27 (8): 1296–305. doi:10.1016/j.biomaterials.2005.08.027. PMID 16154192.
  20. ↑ King A, Strand B, Rokstad AM et al. (March 2003). "Improvement of the biocompatibility of alginate/poly-l-lysine/alginate microcapsules by the use of epimerized alginate as a coating". J Biomed Mater Res A 64 (3): 533–9. doi:10.1002/jbm.a.10276. PMID 12579568.
  21. ↑ Strand BL, Mørch YA, Syvertsen KR, Espevik T, Skjåk-Braek G (March 2003). "Microcapsules made by enzymatically tailored alginate". J Biomed Mater Res A 64 (3): 540–50. doi:10.1002/jbm.a.10337. PMID 12579569.
  22. ↑ Rowley JA, Mooney DJ (2002). "Alginate type and RGD density control myoblast phenotype". Journal of Biomedical Materials Research 60 (2): 217–223. doi:10.1002/jbm.1287.
  23. ↑ Boontheekul T, Kong HJ Hsiong SX, Huang YC et al. (2008). "Quantifying the relation between bond number and myoblast proliferation". Faraday Discuss 139: 57–30. doi:10.1039/B719928G.
  24. ↑ Orive G, Hernández RM, Gascón AR et al. (January 2003). "Cell encapsulation: promise and progress". Nat. Med. 9 (1): 104–7. doi:10.1038/nm0103-104. PMID 12514721.
  25. ↑ Strand BL, Ryan TL, In't Veld P et al. (2001). "Poly-l-lysine induces fibrosis on alginate microcapsules via the induction of cytokines". Cell Transplant 10 (3): 263–75. PMID 11437072.
  26. ↑ Calafiore R, Basta G, Luca G et al. (June 1999). "Transplantation of pancreatic islets contained in minimal volume microcapsules in diabetic high mammalians". Annals of the New York Academy of Sciences 875: 219–32. doi:10.1111/j.1749-6632.1999.tb08506.x. PMID 10415570.
  27. ↑ 27.0 27.1 Wang T, Lacík I, Brissová M et al. (April 1997). "An encapsulation system for the immunoisolation of pancreatic islets". Nat. Biotechnol. 15 (4): 358–62. doi:10.1038/nbt0497-358. PMID 9094138.
  28. ↑ Haque T, Chen H, Ouyang W et al. (March 2005). "In vitro study of alginate-chitosan microcapsules: an alternative to liver cell transplants for the treatment of liver failure". Biotechnol. Lett. 27 (5): 317–22. doi:10.1007/s10529-005-0687-3. PMID 15834792.
  29. ↑ Green DW, Leveque I, Walsh D et al. (April 2005). "Biomineralized polysaccharide capsules for encapsulation, organization, and delivery of human cell types and growth factors". Advanced Functional Materials 15 (6): 917–923. doi:10.1002/adfm.200400322.
  30. ↑ 30.0 30.1 Chen H, Ouyang W, Jones M et al. (2007). "Preparation and characterization of novel polymeric microcapsules for live cell encapsulation and therapy". Cell Biochem. Biophys. 47 (1): 159–68. doi:10.1385/cbb:47:1:159. PMID 17406068.
  31. ↑ Krasaekoopt W, Bhandari B, Deeth H (August 2004). "The influence of coating materials on some properties of alginate beads and survivability of microencapsulated probiotic bacteria". International Dairy Journal 14 (8): 737–743. doi:10.1016/j.idairyj.2004.01.004.
  32. ↑ Chevallay B, Herbage D (March 2000). "collagen-based biomaterials as 3D scaffold for cell cultures: applications for tissue engineering and gene therapy". Med Biol Eng Comput 38 (2): 211–8. doi:10.1007/bf02344779. PMID 10829416.
  33. ↑ Malafaya PB, Silva GA, Reis RL (May 2007). "Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications". Adv. Drug Deliv. Rev. 59 (4-5): 207–33. doi:10.1016/j.addr.2007.03.012. PMID 17482309.
  34. ↑ Liu S, Peulve P, Jin O et al. (August 1997). "Axonal regrowth through collagen tubes bridging the spinal cord to nerve roots". J. Neurosci. Res. 49 (4): 425–32. doi:10.1002/(SICI)1097-4547(19970815)49:4<425::AID-JNR4>3.0.CO;2-A. PMID 9285519.
  35. ↑ Chung HJ, Park TG (May 2007). "Surface engineered and drug releasing pre-fabricated scaffolds for tissue engineering". Adv. Drug Deliv. Rev. 59 (4-5): 249–62. doi:10.1016/j.addr.2007.03.015. PMID 17482310.
  36. ↑ Young S, Wong M, Tabata Y, Mikos AG (December 2005). "Gelatin as a delivery vehicle for the controlled release of bioactive molecules". J Control Release 109 (1-3): 256–74. doi:10.1016/j.jconrel.2005.09.023. PMID 16266768.
  37. ↑ Pieper JS, Hafmans T, van Wachem PB et al. (November 2002). "Loading of collagen-heparan sulfate matrices with bFGF promotes angiogenesis and tissue generation in rats". J. Biomed. Mater. Res. 62 (2): 185–94. doi:10.1002/jbm.10267. PMID 12209938.
  38. ↑ Aiedeh K, Gianasi E, Orienti I, Zecchi V (1997). "chitosan microcapsules as controlled release systems for insulin". J Microencapsul 14 (5): 567–76. doi:10.3109/02652049709006810. PMID 9292433.
  39. ↑ Muzzarelli R, Baldassarre V, Conti F et al. (May 1988). "Biological activity of chitosan: ultrastructural study". Biomaterials 9 (3): 247–52. doi:10.1016/0142-9612(88)90092-0. PMID 3408796.
  40. ↑ Altiok D, Altiok E, Tihminlioglu F (July 2010). "Physical, antibacterial and antioxidant properties of chitosan films incorporated with thyme oil for potential wound healing applications". J Mater Sci Mater Med 21 (7): 2227–36. doi:10.1007/s10856-010-4065-x. PMID 20372985.
  41. ↑ Tan W, Krishnaraj R, Desai TA (April 2001). "Evaluation of nanostructured composite collagen--chitosan matrices for tissue engineering". Tissue Eng. 7 (2): 203–10. doi:10.1089/107632701300062831. PMID 11304455.
  42. ↑ 42.0 42.1 42.2 42.3 Venkat Chokkalingam, Jurjen Tel, Florian Wimmers, Xin Liu, Sergey Semenov, Julian Thiele, Carl G. Figdor, Wilhelm T.S. Huck, Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics, Lab on a Chip, 13, 4740-4744, 2013, DOI: 10.1039/C3LC50945A, http://pubs.rsc.org/en/content/articlelanding/2013/lc/c3lc50945a#!divAbstract
  43. ↑ Hartgerink JD, Beniash E, Stupp SI (November 2001). "Self-assembly and mineralization of peptide-amphiphile nanofibers". Science 294 (5547): 1684–8. doi:10.1126/science.1063187. PMID 11721046.
  44. ↑ Dautzenberg, H; Schuldt, U; Grasnick, G; Karle, P; Müller, P; Löhr, M; Pelegrin, M; Piechaczyk, M; Rombs, KV; Günzburg, WH; Salmons, B; Saller, RM (Jun 18, 1999). "Development of cellulose sulfate-based polyelectrolyte complex microcapsules for medical applications.". Annals of the New York Academy of Sciences 875: 46–63. doi:10.1111/j.1749-6632.1999.tb08493.x. PMID 10415557.
  45. ↑ 45.0 45.1 Pelegrin, M; Marin, M; Noël, D; Del Rio, M; Saller, R; Stange, J; Mitzner, S; Günzburg, WH; Piechaczyk, M (June 1998). "Systemic long-term delivery of antibodies in immunocompetent animals using cellulose sulphate capsules containing antibody-producing cells.". Gene therapy 5 (6): 828–34. doi:10.1038/sj.gt.3300632. PMID 9747463.
  46. ↑ 46.0 46.1 Pelegrin, M; Marin, M; Oates, A; Noël, D; Saller, R; Salmons, B; Piechaczyk, M (Jul 1, 2000). "Immunotherapy of a viral disease by in vivo production of therapeutic monoclonal antibodies.". Human gene therapy 11 (10): 1407–15. doi:10.1089/10430340050057486. PMID 10910138.
  47. ↑ Armeanu, S; Haessler, I; Saller, R; Engelmann, MG; Heinemann, F; Krausz, E; Stange, J; Mitzner, S; Salmons, B; Günzburg, WH; Nikol, S (Jul–Aug 2001). "In vivo perivascular implantation of encapsulated packaging cells for prolonged retroviral gene transfer.". Journal of microencapsulation 18 (4): 491–506. doi:10.1080/02652040010018047. PMID 11428678.
  48. ↑ Winiarczyk, S; Gradski, Z; Kosztolich, B; Gabler, C; König, G; Renner, M; Saller, RM; Prosl, H; Salmons, B; Günzburg, WH; Hain, J (September 2002). "A clinical protocol for treatment of canine mammary tumors using encapsulated, cytochrome P450 synthesizing cells activating cyclophosphamide: a phase I/II study.". Journal of molecular medicine (Berlin, Germany) 80 (9): 610–4. doi:10.1007/s00109-002-0356-0. PMID 12226743.
  49. ↑ Salmons, B; Hauser, O., Gunzburg, W. H. and Tabotta, W. (2007). "GMP production of an encapsulated cell therapy product: issues and considerations". BioProcessing Journal 6 (2): 37–44.
  50. ↑ Rabanel, Michel; Nicolas Bertrand, Shilpa Sant, Salma Louati, , Patrice Hildgen (June 2006). "Polysaccharide Hydrogels for the Preparation of Immunoisolated Cell Delivery Systems". ACS Symposium Series, Vol. 934. American Chemical Society. pp. 305–309. ISBN 978-0-8412-3960-9.
  51. ↑ 51.0 51.1 Benoit DS, Schwartz MP, Durney AR, Anseth KS (October 2008). "Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells". Nat Mater 7 (10): 816–23. doi:10.1038/nmat2269. PMC 2929915. PMID 18724374.
  52. ↑ 52.0 52.1 Orive G, De Castro M, Kong HJ et al. (May 2009). "Bioactive cell-hydrogel microcapsules for cell-based drug delivery". J Control Release 135 (3): 203–10. doi:10.1016/j.jconrel.2009.01.005. PMID 19344677.
  53. ↑ de Vos P, de Haan BJ, Kamps JA, Faas MM, Kitano T (March 2007). "Zeta-potentials of alginate-PLL capsules: a predictive measure for biocompatibility?". J Biomed Mater Res A 80 (4): 813–9. doi:10.1002/jbm.a.30979. PMID 17058213.
  54. ↑ 54.0 54.1 Orive G, Hernández RM, Rodríguez Gascón A et al. (February 2004). "History, challenges and perspectives of cell microencapsulation". Trends Biotechnol. 22 (2): 87–92. doi:10.1016/j.tibtech.2003.11.004. PMID 14757043.
  55. ↑ 55.0 55.1 55.2 Rabanel JM, Banquy X, Zouaoui H, Mokhtar M, Hildgen P (2009). "Progress technology in microencapsulation methods for cell therapy". Biotechnol. Prog. 25 (4): 946–63. doi:10.1002/btpr.226. PMID 19551901.
  56. ↑ Uludag H, De Vos P, Tresco PA (August 2000). "Technology of mammalian cell encapsulation". Adv. Drug Deliv. Rev. 42 (1-2): 29–64. doi:10.1016/S0169-409X(00)00053-3. PMID 10942814.
  57. ↑ Yuet PK, Harris TJ, Goosen MF (1995). "Mathematical modelling of immobilized animal cell growth". Artif Cells Blood Substit Immobil Biotechnol 23 (1): 109–33. doi:10.3109/10731199509117672. PMID 7719442.
  58. ↑ Martoni C, Bhathena J, Jones ML, Urbanska AM, Chen H, Prakash S (2007). "Investigation of microencapsulated BSH active Lactobacillus in the simulated human GI tract". J. Biomed. Biotechnol. 2007 (7): 13684. doi:10.1155/2007/13684. PMC 2217584. PMID 18273409.
  59. ↑ Chen H, Ouyang W, Martoni C et al. (2010). "Investigation of genipin Cross-Linked Microcapsule for oral Delivery of Live bacterial Cells and Other Biotherapeutics: Preparation and In Vitro Analysis in Simulated Human Gastrointestinal Model". International Journal of Polymer Science 2010: 1–10. doi:10.1155/2010/985137. 985137.
  60. ↑ Sakai S, Mu C, Kawabata K, Hashimoto I, Kawakami K (August 2006). "Biocompatibility of subsieve-size capsules versus conventional-size microcapsules". J Biomed Mater Res A 78 (2): 394–8. doi:10.1002/jbm.a.30676. PMID 16680700.
  61. ↑ Sugiura S, Oda T, Izumida Y et al. (June 2005). "Size control of calcium alginate beads containing living cells using micro-nozzle array". Biomaterials 26 (16): 3327–31. doi:10.1016/j.biomaterials.2004.08.029. PMID 15603828.
  62. ↑ Renken A, Hunkeler D, (1998). "Microencapsulation: a review of polymers and technologies with a focus on bioartificial organs". Polimery 43: 530–539.
  63. ↑ 63.0 63.1 Orive G, Gascón AR, Hernández RM, Igartua M, Luis Pedraz J (May 2003). "Cell microencapsulation technology for biomedical purposes: novel insights and challenges". Trends Pharmacol. Sci. 24 (5): 207–10. doi:10.1016/S0165-6147(03)00073-7. PMID 12767713.
  64. ↑ Günzburg WH, Salmons B (May 2000). "Xenotransplantation: is the risk of viral infection as great as we thought?". Mol Med Today 6 (5): 199–208. doi:10.1016/s1357-4310(00)01708-1. PMID 10782067.
  65. ↑ Hunkeler D (November 2001). "Allo transplants xeno: as bioartificial organs move to the clinic. Introduction". Annals of the New York Academy of Sciences 944: 1–6. doi:10.1111/j.1749-6632.2001.tb03818.x. PMID 11797662.
  66. ↑ 66.0 66.1 Bowie KM, Chang PL (August 1998). "Development of engineered cells for implantation in gene therapy". Adv. Drug Deliv. Rev. 33 (1-2): 31–43. doi:10.1016/S0169-409X(98)00018-0. PMID 10837651.
  67. ↑ de Groot M, Schuurs TA, van Schilfgaarde R (September 2004). "Causes of limited survival of microencapsulated pancreatic islet grafts". J. Surg. Res. 121 (1): 141–50. doi:10.1016/j.jss.2004.02.018. PMID 15313388.
  68. ↑ Figliuzzi M, Plati T, Cornolti R et al. (March 2006). "Biocompatibility and function of microencapsulated pancreatic islets". Acta Biomater 2 (2): 221–7. doi:10.1016/j.actbio.2005.12.002. PMID 16701881.
  69. ↑ Bünger CM, Tiefenbach B, Jahnke A et al. (May 2005). "Deletion of the tissue response against alginate-pll capsules by temporary release of co-encapsulated steroids". Biomaterials 26 (15): 2353–60. doi:10.1016/j.biomaterials.2004.07.017. PMID 15585238.
  70. ↑ Goren A, Dahan N, Goren E, Baruch L, Machluf M (January 2010). "Encapsulated human mesenchymal stem cells: a unique hypoimmunogenic platform for long-term cellular therapy". FASEB J. 24 (1): 22–31. doi:10.1096/fj.09-131888. PMID 19726759.
  71. ↑ Dave RI, Shah NP (January 1997). "Viability of yoghurt and probiotic bacteria in yoghurts made from commercial starter cultures". International Dairy Journal 7 (1): 31–41. doi:10.1016/S0958-6946(96)00046-5.
  72. ↑ Kailasapathy K, Supriadi D (1996). "Effect of whey protein concentrate on the survival of lactobacillus acidophilus in lactose hydrolysed yoghurt during refrigerated storage". Milchwissenschaft 51: 565–569.
  73. ↑ Lankaputhra WED, Shah NP, Britz ML (1996). "Survival of Bifidobacteria during refrigerated storage in the presence of acid and hydrogen peroxide". Milchwissenschaft 51: 65–70.
  74. ↑ "Health and nutritional properties of probiotics in food including powder milk with live lactic acid bacteria". FAO/WHO Experts’ Report (FAQ/WHO). 2001.
  75. ↑ Gilliland SE (October 1989). "Acidophilus milk products: a review of potential benefits to consumers". J. Dairy Sci. 72 (10): 2483–94. doi:10.3168/jds.S0022-0302(89)79389-9. PMID 2513349.
  76. ↑ Anal A, Singh H (May 2007). "Recent advances in microencapsulation of probiotics for industrial applications and targeted delivery". Trends in Food Science & Technology 18 (5): 240–251. doi:10.1016/j.tifs.2007.01.004.
  77. ↑ Kizilel S, Garfinkel M, Opara E (December 2005). "The bioartificial pancreas: progress and challenges". Diabetes Technol. Ther. 7 (6): 968–85. doi:10.1089/dia.2005.7.968. PMID 16386103.
  78. ↑ Shapiro AM, Lakey JR, Ryan EA et al. (July 2000). "Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen". N. Engl. J. Med. 343 (4): 230–8. doi:10.1056/NEJM200007273430401. PMID 10911004.
  79. ↑ Calafiore R (April 2003). "Alginate microcapsules for pancreatic islet cell graft immunoprotection: struggle and progress towards the final cure for type 1 diabetes mellitus". Expert Opin Biol Ther 3 (2): 201–5. doi:10.1517/14712598.3.2.201. PMID 12662135.
  80. ↑ Hardikar AA, Risbud MV, Bhonde RR (June 2000). "Improved post-cryopreservation recovery following encapsulation of islets in chitosan-alginate microcapsules". Transplant. Proc. 32 (4): 824–5. doi:10.1016/s0041-1345(00)00995-7. PMID 10856598.
  81. ↑ Cruise GM, Hegre OD, Lamberti FV et al. (1999). "In vitro and in vivo performance of porcine islets encapsulated in interfacially photopolymerized polyethylene glycol diacrylate membranes". Cell Transplant 8 (3): 293–306. PMID 10442742.
  82. ↑ Kobayashi T, Aomatsu Y, Kanehiro H, Hisanaga M, Nakajima Y (February 2003). "Protection of NOD islet isograft from autoimmune destruction by agarose microencapsulation". Transplant. Proc. 35 (1): 484–5. doi:10.1016/S0041-1345(02)03829-0. PMID 12591496.
  83. ↑ "Clinical trial information". Retrieved 21 November 2010.
  84. ↑ Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, Buchanan C (March 2007). "Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation". Xenotransplantation 14 (2): 157–61. doi:10.1111/j.1399-3089.2007.00384.x. PMID 17381690.
  85. ↑ Grose S (April 2007). "Critics slam Russian trial to test pig pancreas for diabetics". Nat. Med. 13 (4): 390–1. doi:10.1038/nm0407-390b. PMID 17415358.
  86. ↑ de Vos P, Hamel AF, Tatarkiewicz K (February 2002). "Considerations for successful transplantation of encapsulated pancreatic islets". Diabetologia 45 (2): 159–73. doi:10.1007/s00125-001-0729-x. PMID 11935147.
  87. ↑ Stadlbauer, V; Stiegler, PB; Schaffellner, S; Hauser, O; Halwachs, G; Iberer, F; Tscheliessnigg, KH; Lackner, C (July 2006). "Morphological and functional characterization of a pancreatic beta-cell line microencapsulated in sodium cellulose sulfate/poly(diallyldimethylammonium chloride).". Xenotransplantation 13 (4): 337–44. doi:10.1111/j.1399-3089.2006.00315.x. PMID 16768727.
  88. ↑ Steigler, P; Stadlbauer, V., Hackl, F., Iberer, F., Lackner, C., Hauser, O., Schaffellner, S., Strunk, D. and Tscheliessnigg, K. (2009). "Xenotransplantation of NaCS microencapsulated porcine islet cells in diabetic rats". Organ Biology 16 (1): 104.
  89. ↑ Cirone P, Bourgeois JM, Austin RC, Chang PL (July 2002). "A novel approach to tumor suppression with microencapsulated recombinant cells". Hum. Gene Ther. 13 (10): 1157–66. doi:10.1089/104303402320138943. PMID 12133269.
  90. ↑ Joki T, Machluf M, Atala A et al. (January 2001). "Continuous release of endostatin from microencapsulated engineered cells for tumor therapy". Nat. Biotechnol. 19 (1): 35–9. doi:10.1038/83481. PMID 11135549.
  91. ↑ Read TA, Sorensen DR, Mahesparan R et al. (January 2001). "Local endostatin treatment of gliomas administered by microencapsulated producer cells". Nat. Biotechnol. 19 (1): 29–34. doi:10.1038/83471. PMID 11135548.
  92. ↑ Teng H, Zhang Y, Wang W, Ma X, Fei J (April 2007). "Inhibition of tumor growth in mice by endostatin derived from abdominal transplanted encapsulated cells". Acta Biochim. Biophys. Sin. (Shanghai) 39 (4): 278–84. doi:10.1111/j.1745-7270.2007.00273.x. PMID 17417683.
  93. ↑ Cirone P, Bourgeois JM, Chang PL (July 2003). "Antiangiogenic cancer therapy with microencapsulated cells". Hum. Gene Ther. 14 (11): 1065–77. doi:10.1089/104303403322124783. PMID 12885346.
  94. ↑ Karle P, Müller P, Renz R et al. (1998). "Intratumoral injection of encapsulated cells producing an oxazaphosphorine activating cytochrome P450 for targeted chemotherapy". Adv. Exp. Med. Biol. 451: 97–106. doi:10.1007/978-1-4615-5357-1_16. PMID 10026857.
  95. ↑ Löhr M, Hoffmeyer A, Kröger J et al. (May 2001). "Microencapsulated cell-mediated treatment of inoperable pancreatic carcinoma". Lancet 357 (9268): 1591–2. doi:10.1016/S0140-6736(00)04749-8. PMID 11377651.
  96. ↑ Lohr M, Kroger JC, Hoffmeyer A et al. (2003). "Safety, feasibility and clinical benefit of localized chemotherapy using microencapsulated cells for inoperable pancreatic carcinoma in a phase I/II trial". Ccancer Ther 1: 121–131.
  97. ↑ Lam, P; Khan, G; Stripecke, R; Hui, KM; Kasahara, N; Peng, KW; Guinn, BA (March 2013). "The innovative evolution of cancer gene and cellular therapies.". Cancer gene therapy 20 (3): 141–9. doi:10.1038/cgt.2012.93. PMID 23370333.
  98. ↑ Collins SD, Baffour R, Waksman R (2007). "Cell therapy in myocardial infarction". Cardiovasc Revasc Med 8 (1): 43–51. doi:10.1016/j.carrev.2006.11.005. PMID 17293268.
  99. ↑ Paul A, Ge Y, Prakash S, Shum-Tim D (September 2009). "Microencapsulated stem cells for tissue repairing: implications in cell-based myocardial therapy". Regen Med 4 (5): 733–45. doi:10.2217/rme.09.43. PMID 19761398.
  100. ↑ Madeddu P (May 2005). "Therapeutic angiogenesis and vasculogenesis for tissue regeneration". Exp. Physiol. 90 (3): 315–26. doi:10.1113/exphysiol.2004.028571. PMID 15778410.
  101. ↑ Jacobs J (December 2007). "Combating cardiovascular disease with angiogenic therapy". Drug Discov. Today 12 (23-24): 1040–5. doi:10.1016/j.drudis.2007.08.018. PMID 18061883.
  102. ↑ 102.0 102.1 Zhang H, Zhu SJ, Wang W, Wei YJ, Hu SS (January 2008). "Transplantation of microencapsulated genetically modified xenogeneic cells augments angiogenesis and improves heart function". Gene Ther. 15 (1): 40–8. doi:10.1038/sj.gt.3303049. PMID 17943144.
  103. ↑ Bonavita, AG; Quaresma K; Cotta-de-Almeida V; Pinto MA; Saraiva RM (May–June 2010). "Hepatocyte xenotransplantation for treating liver disease". Xenotrasplantation 17 (3): 181–187. doi:10.1111/j.1399-3089.2010.00588.x. PMID 20636538.
  104. ↑ Lysaght, Micheal J.; Patrick Aebischer (April 1999). "Encapsulated Cells as Therapy". Scientific American: 76–82.