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Renal Assist Device (RAD), containing human renal tubule cells (RTC) is part of the two circuit system: a standard hemofilter and a bioreactor (RAD). The ultrafiltrate produced by the hemofilter enters the RAD lumen (A) upon which the RTC have been grown, and then discarded (B); The blood from the hemofilter enters the extracapillary space of the hollow fiber cartridge (C); in the RAD, the blood is separated from the RTC by the semipermeable hollow fiber membrane and returned to the patient (D).
Source publication
In this article, we examine the advanced clinical development of bioartificial organs and describe the challenges to implementing such systems into patient care. The case for bioartificial organs is evident: they are meant to reduce patient morbidity and mortality caused by the persistent shortage of organs available for allotransplantation. The wi...
Contexts in source publication
Context 1
... FDA has allowed only one bioartificial kidney to be evaluated in human clinical trials. The renal assist device (RAD), developed by Humes [27,28], RenaMed Biologics, Inc. (Lincoln, RI, USA), was an extracorporeal treatment system utilizing a standard hemofiltration cartridge containing approximately 10 9 renal tubule cells (RTC) grown along the inner surface of the fibers. The RAD was seeded with the RTC derived from human kidneys not suitable for transplantation, mainly due to anatomical defects, and cells were expanded in a culture medium [11,29]. The hollow fibers provide support for the cellular system, allow for the transport of essential cell products and nutrients, and prevent the cells from entering the circulatory system. The RAD Circuit consisted of two perfusion loops. The first one was the Continuous Veno-Venous Hemofiltration (CVVH) loop, which is a conventional CVVH system. The second was the RAD loop, which contained the RAD cartridge ( Figure 2). During the RAD treatment, blood from the patient was perfused through a conventional hemofilter, which separates the blood into an ultrafiltrate component and a blood cellular ...
Context 2
... [32] summarized over 30 different cell-based liver support devices that have been reported since 1987. More than 14 systems have been evaluated in clinical trials for their capacity to provide liver functions [6,10,33]. Although primary human hepatocytes would seem to be the cells of choice in a bioartificial liver, the availability of these cells is limited. As an alternative, immortalized cell lines of the C3A human hepatoblastoma line have been used in a bioartificial liver device. Primary Figure 2. Renal Assist Device (RAD), containing human renal tubule cells (RTC) is part of the two circuit system: a standard hemofilter and a bioreactor (RAD). The ultrafiltrate produced by the hemofilter enters the RAD lumen (A) upon which the RTC have been grown, and then discarded (B); The blood from the hemofilter enters the extracapillary space of the hollow fiber cartridge (C); in the RAD, the blood is separated from the RTC by the semipermeable hollow fiber membrane and returned to the patient ...
Citations
... Therefore, porcine hepatocytes are employed as the main cells in existing BAL systems, including HepatAssist, BLSS, MELS, and AMC-BAL, which have already entered clinical trials. HepatAssist, composed of a hollow fiber bioreactor with cryopreserved porcine hepatocytes, was the first BAL system tested in a large-scale Phase II/III clinical trial [17]. However, the phenotype of porcine hepatocytes tends to be unstable. ...
Acute liver failure (ALF) is a rapidly progressive disease with high morbidity and mortality rates. Liver transplantation and artificial liver support systems, such as artificial livers (ALs) and bioartificial livers (BALs), are the two major therapies for ALF. Compared to ALs, BALs are composed of functional hepatocytes that provide essential liver functions, including detoxification, metabolite synthesis, and biotransformation. Furthermore, BALs can potentially provide effective support as a form of bridging therapy to liver transplantation or spontaneous recovery for patients with ALF. In this review, we systematically discussed the currently available state-of-the-art designs and manufacturing processes for BAL support systems. Specifically, we classified the cell sources and bioreactors that are applied in BALs, highlighted the advanced technologies of hepatocyte culturing and bioreactor fabrication, and discussed the current challenges and future trends in developing next generation BALs for large scale clinical applications.
... Survival of pig-to-nonhuman primate heterotopic heart, kidney, and islet xenotransplantation over 900 days, over 400 days, and over 600 days respectively has been reported [7]. Bioartificial organs that contain pig cells or tissues have gained considerable clinical experience and the risks have been reduced [8]. For the time being, the indications of xenografting seem unclear but should be kept aside for exceptional cases. ...
The gap between organ demand and supply is an universal problem in organ and tissue transplantation therapy. The gap is growing in spite of efforts spent in medical, educational, social areas and mass media support. This reality has created the need for completely new therapeutic alternatives for the management of end-stage organ disease. The present research should continue in future aiming to discover systems and devices capable of totally replacing the traditional transplantation. On the other hand, a different progress in underway in transplantation. The indication for solid organ transplantation is to save life and promote quality of life. The new developing transplantations of composite tissue, uterus and face are performed with completely different indications. Facial defects caused by various insults cause serious functional and esthetic disorders, psychological and social problems. Facial transplant surgery is accomplished to overcome such problems. Uterus transplantation is emerging as an alternative to female infertility. Transplantation of composite tissue includes different organs. The main purpose of composite tissue transplantation is to restore reduced or completely lost functions and to increase the quality of life. Nerve regeneration must occur as a consequence of transplant to regain sensory and motor functions. It appears that the future of transplantation involves developments in two main streams; invention of completely new tools for solid organ transplantation and advances in the transplantation of different organs including uterus, face and composite tissue.
... To supplement the actual scheme of pancreatic ECM composition and organization in order to identify parameters liable to improve islets isolation and transplantation, we have combined three complementary techniques to unravel some specificity on the organization, composition, and three-dimensional structure of the pancreatic ECM in mice and pigs. Mouse is a wide spread animal model on diabetes and pancreatic functions, and pig is more and more considered for pancreatic xenograft, a foreseen solution for organ donors shortage [19,20]. By the mean of commercially available antibodies against EHS-laminin, laminin-a4, laminin-b2, collagen type IV and collagen type V, we have analysed by immunohistochemistry their localization within the exocrine and endocrine pancreas of both mouse and pig. ...
The epidemic expansion of diabetes is a major concern of public health. A promising treatment is the transplantation of islets of Langerhans isolated from the whole pancreas but the yields of islets isolation and the rates of successful engraftments still have to be improved to make this therapy effective. The extracellular matrix (ECM) of the pancreatic tissue is partially lost during the isolation process and a comprehensive knowledge of the pancreatic ECM composition and organization could identify targets to improve islets isolation and transplantation or highlight new therapeutics for pancreatic diseases. The organization, composition and three-dimensional architecture of the pancreatic ECM were analysed in mouse and pig by three different techniques. Laminin α-4 and β-2 chains are localized by immunohistochemistry in the exocrine tissue and inside islets of mouse pancreas but not around islets that are surrounded by an ECM made of collagen type IV and type V. Collagen type I, III, and VI were identified by proteomics as specific constituents of the pig pancreatic ECM along with the low-abundance isoforms α3(IV) α4(IV) α5(IV) and α1(V) α2(V) α3(V) of collagen type IV and type V respectively. The three-dimensional ECM architecture is analysed on decellularized mouse pancreas by scanning electron microscopy and is organized in honeycomb structures made of thin ECM fibers assembled in thicker bundles. The combination of immunohistochemistry, proteomics and scanning electron microscopy gives complementary perspective on the pancreatic ECM composition and organization. It represents a valuable toolbox for deeper investigations of ECMs and proposes clues in tissue engineering of the pancreas.
Acute liver failure (ALF) has a mortality rate of more than 40%. Currently, orthotopic liver transplantation is the sole clinical treatment for ALF, but its wide usage is severely limited due to donor shortage and immunological rejection. An emerging and promising technology for ALF treatment is liver tissue engineering (LTE), wherein porous scaffolds serve as a crucial component. Nanofiber scaffolds, which mimic the inherent structures of fibrous extracellular matrix well, provide an ideal environment for cell growth and tissue regeneration. Recently, several functional nanofiber scaffolds for LTE have been developed, which show impressive results in regulating cell function and repairing liver injury when combined with appropriate seeding cells and/or growth factors. This review firstly introduces the etiologies and treatment indicators of ALF. Subsequently, typical fabrication technologies of nanofiber scaffolds and their related applications for function regulation of liver-related cells and treatment of ALF are comprehensively summarized. Particular emphasis is placed on the strategies involving an appropriate combination of suitable seeding cells and growth factors. Finally, the current challenges and the future research and development prospects of nanofiber scaffold-based LTE are discussed. This review will serve as a valuable reference for designing and modifying novel nanofiber scaffolds, further promoting their potential application in LTE and other biomedical fields.
Background
Cytotherapy products can be described as “living drugs”. Cytotherapy is the swiftest growing fields in the treatment of cancer, heart diseases, aging population and neuromuscular ailments. Biomimetic approaches are processes developed by humans such as devices, substances, or systems that mimic nature or natural processes.
Objective and Method
It aims at developing a base for personalized medicine with allogeneic, autologous and xenogenic therapies where cells are modified for target selection. Such drug delivery methods appear to be complex and challenging. Literature for approximately past two decades was collected and reviewed for the present article.
Results and Conclusion
The opportunities and challenges in cytotherapy have been classified, discussed and demystified. Various process inputs, materials and process conditions required in bioprocessing and preservation have been discussed at length. The review also focuses on the regulatory requirements in India, Europe and U.S.
Background:
Survival and longevity of xenotransplants depend on immune function and ability to integrate energy metabolism between cells from different species. However, mechanisms for interspecies cross talk in energy metabolism are not well understood. White adipose tissue stores energy and is capable of mobilization and dissipation of energy as heat (thermogenesis) by adipocytes expressing uncoupling protein 1 (Ucp1). Both pathways are under the control of vitamin A metabolizing enzymes. Deficient retinoic acid production in aldehyde dehydrogenase 1 A1 (Aldh1a1) knockout adipocytes (KO) inhibits adipogenesis and increases thermogenesis. Here we test the role Aldh1a1 in regulation of lipid metabolism in xenocultures.
Methods:
Murine wide-type (WT) and KO pre-adipocytes were encapsulated into a poly-L-lysine polymer that allows exchange of humoral factors <32kD via nanopores. Encapsulated murine adipocytes were co-incubated with primary differentiated canine adipocytes. Then, expression of adipogenic and thermogenic genes in differentiated canine adipocytes was detected by real-time polymerase chain reaction (PCR). The regulatory factors in WT and KO cells were identified by comparison of secretome using proteomics and in transcriptome by gene microarray.
Results:
Co-culture of encapsulated mouse KO vs WT adipocytes increased expression of peroxisome proliferator-activated receptor gamma (Pparg), but reduced expression of its target genes fatty acid binding protein 4 (Fabp4), and adipose triglyceride lipase (Atgl) in canine adipocytes, suggesting inhibition of PPARγ activation. Co-culture with KO adipocytes also induced expression of Ucp1 in canine adipocytes compared to expression in WT adipocytes. Cumulatively, murine KO compared to WT adipocytes decreased lipid accumulation in canine adipocytes. Comparative proteomics revealed significantly higher levels of vitamin A carriers, retinol binding protein 4 (RBP4), and lipokalin 2 (LCN2) in KO vs WT adipocytes.
Conclusions:
Our data demonstrate the functional exchange of regulatory factors between adipocytes from different species for regulation of energy balance. RBP4 and LCN2 appear to be involved in the transport of retinoids for regulation of lipid accumulation and thermogenesis in xenocultures. While the rarity of thermogenic adipocytes in humans and dogs precludes their use for autologous transplantation, our study demonstrates that xenotransplantation of engineered cells could be a potential solution for the reduction in obesity in dogs and a strategy for translation to patients.
