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      Hydrogel-Based Cell Therapies for Kidney Regeneration: Current Trends in 
Biofabrication and In Vivo Repair

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          Abstract

          Facing the problems of limited renal regeneration capacity and the persistent shortage of do-nor kidneys, dialysis remains the only treatment option for many end-stage renal disease patients. Un-fortunately, dialysis is only a medium-term solution because large and protein-bound uremic solutes are not efficiently cleared from the body and lead to disease progression over time. Current strategies for improved renal replacement therapies (RRTs) range from whole organ engineering to biofabrication of renal assist devices and biological injectables for in vivo regeneration. Notably, all approaches coincide with the incorporation of cellular components and biomimetic micro-environments. Concerning the latter, hydrogels form promising materials as scaffolds and cell carrier systems due to the demonstrated biocompatibility of most natural hydrogels, tunable biochemical and mechanical properties, and various application possibilities. In this review, the potential of hydrogel-based cell therapies for kidney regen-eration is discussed. First, we provide an overview of current trends in the development of RRTs and in vivo regeneration options, before examining the possible roles of hydrogels within these fields. We dis-cuss major application-specific hydrogel design criteria and, subsequently, assess the potential of emer-gent biofabrication technologies, such as micromolding, microfluidics and electrodeposition for the development of new RRTs and injectable stem cell therapies.

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          Most cited references136

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          RGD and other recognition sequences for integrins.

          Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.
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            Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis.

            The human kidney contains up to 2 million epithelial nephrons responsible for blood filtration. Regenerating the kidney requires the induction of the more than 20 distinct cell types required for excretion and the regulation of pH, and electrolyte and fluid balance. We have previously described the simultaneous induction of progenitors for both collecting duct and nephrons via the directed differentiation of human pluripotent stem cells. Paradoxically, although both are of intermediate mesoderm in origin, collecting duct and nephrons have distinct temporospatial origins. Here we identify the developmental mechanism regulating the preferential induction of collecting duct versus kidney mesenchyme progenitors. Using this knowledge, we have generated kidney organoids that contain nephrons associated with a collecting duct network surrounded by renal interstitium and endothelial cells. Within these organoids, individual nephrons segment into distal and proximal tubules, early loops of Henle, and glomeruli containing podocytes elaborating foot processes and undergoing vascularization. When transcription profiles of kidney organoids were compared to human fetal tissues, they showed highest congruence with first trimester human kidney. Furthermore, the proximal tubules endocytose dextran and differentially apoptose in response to cisplatin, a nephrotoxicant. Such kidney organoids represent powerful models of the human organ for future applications, including nephrotoxicity screening, disease modelling and as a source of cells for therapy.
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              Designing cell-compatible hydrogels for biomedical applications.

              Hydrogels are polymeric materials distinguished by high water content and diverse physical properties. They can be engineered to resemble the extracellular environment of the body's tissues in ways that enable their use in medical implants, biosensors, and drug-delivery devices. Cell-compatible hydrogels are designed by using a strategy of coordinated control over physical properties and bioactivity to influence specific interactions with cellular systems, including spatial and temporal patterns of biochemical and biomechanical cues known to modulate cell behavior. Important new discoveries in stem cell research, cancer biology, and cellular morphogenesis have been realized with model hydrogel systems premised on these designs. Basic and clinical applications for hydrogels in cell therapy, tissue engineering, and biomedical research continue to drive design improvements using performance-based materials engineering paradigms.
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                Author and article information

                Journal
                Curr Pharm Des
                Curr. Pharm. Des
                CPD
                Current Pharmaceutical Design
                Bentham Science Publishers
                1381-6128
                1873-4286
                July 2017
                July 2017
                : 23
                : 26
                : 3845-3857
                Affiliations
                Division of Pharmacology and Division of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences , Utrecht, , The Netherlands
                Author notes
                [# ]Address correspondence to these authors at the Utrecht University Div. Pharmacology Department of Pharmaceutical Sciences Universiteitsweg 99, 3584 CG Utrecht The Netherlands; Tel: +31-30-253-3529; Fax: +31-30-253-7900; E-mail: r.masereeuw@ 123456uu.nl
                [*]

                = contributed equally.

                Article
                CPD-23-3845
                10.2174/1381612823666170710155726
                6302346
                28699526
                439c845e-e0b9-412f-b909-2fcbce416d1b
                © 2017 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 24 April 2017
                : 19 June 2017
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                proximal tubules,uremic toxin secretion,renal assist devices,injectable formulations,hydrogels,stem cells

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