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Achievements and challenges in bioartificial kidney development.

Tasnim F, Deng R, Hu M, Liour S, Li Y, Ni M, Ying JY, Zink D - Fibrogenesis Tissue Repair (2010)

Bottom Line: The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions.Currently, primary human renal proximal tubule cells are most relevant for clinical applications.However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore. dzink@ibn.a-star.edu.sg.

ABSTRACT
Bioartificial kidneys (BAKs) combine a conventional hemofilter in series with a bioreactor unit containing renal epithelial cells. The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions. Currently, primary human renal proximal tubule cells are most relevant for clinical applications. However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges. BAKs have been applied in Phase I/II and Phase II clinical trials for the treatment of critically ill patients with acute renal failure. Significant effects on cytokine concentrations and long-term survival were observed. A subsequent Phase IIb clinical trial was discontinued after an interim analysis, and these results showed that further intense research on BAK-based therapies for acute renal failure was required. Development of BAK-based therapies for the treatment of patients suffering from end-stage renal disease is even more challenging, and related problems and research approaches are discussed herein, along with the development of mobile, portable, wearable and implantable devices.

No MeSH data available.


Related in: MedlinePlus

Madin-Darby canine kidney (MDCK) cells form a polarized epithelium on the inner surface of polyethersulfone/polyvinylpyrrolidone (PES/PVP) hollow fiber membranes. (a) Confluent monolayer of MDCK cells on the inner surface of a PES/PVP hollow fiber membrane. Cracks in the monolayer (indicated by arrowheads) are artifacts resulting from sample preparation (scale bar = 100 μm). (b) Luminal surface of the MDCK cell layer on the inner surface of a PES/PVP hollow fiber membrane (scale bar = 1 μm). The cell surface is densely covered with microvilli. The inset in the lower left corner shows an enlargement of the microvilli-covered surface (scale bar = 1 μm). All images were obtained by scanning electron microscopy.
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Figure 1: Madin-Darby canine kidney (MDCK) cells form a polarized epithelium on the inner surface of polyethersulfone/polyvinylpyrrolidone (PES/PVP) hollow fiber membranes. (a) Confluent monolayer of MDCK cells on the inner surface of a PES/PVP hollow fiber membrane. Cracks in the monolayer (indicated by arrowheads) are artifacts resulting from sample preparation (scale bar = 100 μm). (b) Luminal surface of the MDCK cell layer on the inner surface of a PES/PVP hollow fiber membrane (scale bar = 1 μm). The cell surface is densely covered with microvilli. The inset in the lower left corner shows an enlargement of the microvilli-covered surface (scale bar = 1 μm). All images were obtained by scanning electron microscopy.

Mentions: It is mandatory that the renal cells form a confluent differentiated epithelium sealed by tight junctions on the porous membranes of the device. If this does not occur, the cellular functions would be absent or compromised. Under such conditions, the entire BAK would only perform the functions of a normal hemofiltration device, with the undesired diffusion of ultrafiltrate components back into the blood in the bioreactor unit. The problem with using animal cells for BAK research is that animal cell lines and probably also primary animal cells would show different requirements for growth and differentiation from the primary human cells. This is obvious, for instance, with regard to the formation of differentiated epithelia on different membrane materials. Figure 1 shows hollow fiber membranes consisting of polyethersulfone/polyvinylpyrrolidone (PES/PVP), within which MDCK cells form a polarized epithelium with a well-developed brush border. No such results could be obtained with HPTCs, which would not grow and survive on PES/PVP, regardless of whether it was coated with an extracellular matrix (ECM) or not (M. Ni, J. C. M. Teo, M. S. bin Ibrahim, K. Zhang, F. Tasnim, P.-Y. Chow, D. Zink and J. Y. Ying, unpublished results). It was also found that HPTCs would not grow well on polysulfone (PSF) membranes or membranes consisting of PSF blended with a phospholipid polymer; membranes coated with a fibronectin ECM did not improve the situation [68]. In contrast, MDCK and LLC-PK1 cells formed confluent monolayers on these materials, regardless of whether an ECM coating was present [68]. Furthermore, we found that HPTCs would not grow and survive on polysulfone/polyvinylpyrrolidone (PSF/PVP) membranes, and in this case, cell performance could not be sufficiently improved by a single coating of a suitable ECM consisting of collagen IV (M. Ni, J. C. M. Teo, M. S. bin Ibrahim, K. Zhang, F. Tasnim, P.-Y. Chow, D. Zink and J. Y. Ying, unpublished results).


Achievements and challenges in bioartificial kidney development.

Tasnim F, Deng R, Hu M, Liour S, Li Y, Ni M, Ying JY, Zink D - Fibrogenesis Tissue Repair (2010)

Madin-Darby canine kidney (MDCK) cells form a polarized epithelium on the inner surface of polyethersulfone/polyvinylpyrrolidone (PES/PVP) hollow fiber membranes. (a) Confluent monolayer of MDCK cells on the inner surface of a PES/PVP hollow fiber membrane. Cracks in the monolayer (indicated by arrowheads) are artifacts resulting from sample preparation (scale bar = 100 μm). (b) Luminal surface of the MDCK cell layer on the inner surface of a PES/PVP hollow fiber membrane (scale bar = 1 μm). The cell surface is densely covered with microvilli. The inset in the lower left corner shows an enlargement of the microvilli-covered surface (scale bar = 1 μm). All images were obtained by scanning electron microscopy.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC2925816&req=5

Figure 1: Madin-Darby canine kidney (MDCK) cells form a polarized epithelium on the inner surface of polyethersulfone/polyvinylpyrrolidone (PES/PVP) hollow fiber membranes. (a) Confluent monolayer of MDCK cells on the inner surface of a PES/PVP hollow fiber membrane. Cracks in the monolayer (indicated by arrowheads) are artifacts resulting from sample preparation (scale bar = 100 μm). (b) Luminal surface of the MDCK cell layer on the inner surface of a PES/PVP hollow fiber membrane (scale bar = 1 μm). The cell surface is densely covered with microvilli. The inset in the lower left corner shows an enlargement of the microvilli-covered surface (scale bar = 1 μm). All images were obtained by scanning electron microscopy.
Mentions: It is mandatory that the renal cells form a confluent differentiated epithelium sealed by tight junctions on the porous membranes of the device. If this does not occur, the cellular functions would be absent or compromised. Under such conditions, the entire BAK would only perform the functions of a normal hemofiltration device, with the undesired diffusion of ultrafiltrate components back into the blood in the bioreactor unit. The problem with using animal cells for BAK research is that animal cell lines and probably also primary animal cells would show different requirements for growth and differentiation from the primary human cells. This is obvious, for instance, with regard to the formation of differentiated epithelia on different membrane materials. Figure 1 shows hollow fiber membranes consisting of polyethersulfone/polyvinylpyrrolidone (PES/PVP), within which MDCK cells form a polarized epithelium with a well-developed brush border. No such results could be obtained with HPTCs, which would not grow and survive on PES/PVP, regardless of whether it was coated with an extracellular matrix (ECM) or not (M. Ni, J. C. M. Teo, M. S. bin Ibrahim, K. Zhang, F. Tasnim, P.-Y. Chow, D. Zink and J. Y. Ying, unpublished results). It was also found that HPTCs would not grow well on polysulfone (PSF) membranes or membranes consisting of PSF blended with a phospholipid polymer; membranes coated with a fibronectin ECM did not improve the situation [68]. In contrast, MDCK and LLC-PK1 cells formed confluent monolayers on these materials, regardless of whether an ECM coating was present [68]. Furthermore, we found that HPTCs would not grow and survive on polysulfone/polyvinylpyrrolidone (PSF/PVP) membranes, and in this case, cell performance could not be sufficiently improved by a single coating of a suitable ECM consisting of collagen IV (M. Ni, J. C. M. Teo, M. S. bin Ibrahim, K. Zhang, F. Tasnim, P.-Y. Chow, D. Zink and J. Y. Ying, unpublished results).

Bottom Line: The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions.Currently, primary human renal proximal tubule cells are most relevant for clinical applications.However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore. dzink@ibn.a-star.edu.sg.

ABSTRACT
Bioartificial kidneys (BAKs) combine a conventional hemofilter in series with a bioreactor unit containing renal epithelial cells. The epithelial cells derived from the renal tubule should provide transport, metabolic, endocrinologic and immunomodulatory functions. Currently, primary human renal proximal tubule cells are most relevant for clinical applications. However, the use of human primary cells is associated with many obstacles, and the development of alternatives and an unlimited cell source is one of the most urgent challenges. BAKs have been applied in Phase I/II and Phase II clinical trials for the treatment of critically ill patients with acute renal failure. Significant effects on cytokine concentrations and long-term survival were observed. A subsequent Phase IIb clinical trial was discontinued after an interim analysis, and these results showed that further intense research on BAK-based therapies for acute renal failure was required. Development of BAK-based therapies for the treatment of patients suffering from end-stage renal disease is even more challenging, and related problems and research approaches are discussed herein, along with the development of mobile, portable, wearable and implantable devices.

No MeSH data available.


Related in: MedlinePlus