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Concept illustration of an implantable bioartificial kidney (BAK). The device consists of a silicon hemofilter for toxin filtration and a bioreactor of renal epithelial cells for metabolic and endocrine functions. Courtesy of Shuvo Roy
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The rapid understanding of the cellular and molecular bases of organ function and disease processes will be translated in the next decade into new therapeutic approaches to a wide range of clinical disorders, including acute and chronic renal failure. Central to these new therapies are the developing technologies of cell therapy and tissue engineer...
Citations
... The platform can accommodate membranes, bioactive compounds, and therapeutic cells that enhance dialysis performance. From these benefits, progress and understanding in cell therapy and tissue engineering, bioartificial kidneys (BAK) have been developed aiming to replace renal functions of the original native cells with minimal invasion 64 . ...
... BAK is developed to be an implantable device or an operational unit for an extracorporeal circuit outside of the body. Wearable bioartificial kidney (WEBAK) utilizes the sorbent-based technology and bioartificial renal epithelial cell system (BRECS) to accomplish the therapeutic functions 64 . BRECS is designed to be a miniaturized cryo-preservable bioreactor with porous niobium-coated carbon disks to accommodate dense cell growth and adhesion 65 . ...
Extracorporeal blood therapeutic devices (ETDs) are medical devices capable of performing treatments outside of the body through an extracorporeal circuit. These devices are widely used in both clinical/hospital settings and at-home care. A prototypical example is the treatment of nephrological diseases through hemodialysis and continuous renal replacement therapy using a hemodialyzer or an artificial kidney. The various applications of ETDs share common limitations such as coagulation, hemolysis, air embolism, and sensitivity reactions, all of which arise from the interactions of human physiology with the treatment mechanisms. Researchers are implementing microscale-based technology to achieve the next-generation ETD that can address persistent problems and improve therapeutic performance.
This review article focuses on the evolution of the structure and development of
conventional ETDs towards the miniaturization of the device. We begin with a narrow
but common definition of ETDs as well as their current form and uses for renal replacement followed by a review of the importance and progression of microscale-based ETD
development together with future directions towards achieving fully functional microscale-based ETDs that reflects contemporary technological and engineering advancements.
... In a series of publications by Mihajlovic et al., a line of ciPTEC proximal tubular cells reversibly immortalized using temperature-induced SV40 and hTERT [103] was evaluated for possible use in a bioartificial kidney (while dialysis machines only compensate for the filtration function of the kidney, the bioartificial kidney has the potential to compensate for the homeostatic, regulatory, metabolic, and endocrine functions of the kidneys [104]). This is a device with a hemodialysis function (external or implantable), some design variations of which assume that the cells of the construct will be fenced off from the internal environment of the body by a membrane, so the issue of oncogenicity and immunogenicity of the future construct is much less acute here. ...
In modern science, immortalized cells are not only a convenient tool in fundamental research, but they are also increasingly used in practical medicine. This happens due to their advantages compared to the primary cells, such as the possibility to produce larger amounts of cells and to use them for longer periods of time, the convenience of genetic modification, the absence of donor-to-donor variability when comparing the results of different experiments, etc. On the other hand, immortalization comes with drawbacks: possibilities of malignant transformation and/or major phenotype change due to genetic modification itself or upon long-term cultivation appear. At first glance, such issues are huge hurdles in the way of immortalized cells translation into medicine. However, there are certain ways to overcome such barriers that we describe in this review. We determined four major areas of usage of immortalized cells for practical medicinal purposes, and each has its own means to negate the drawbacks associated with immortalization. Moreover, here we describe specific fields of application of immortalized cells in which these problems are of much lesser concern, for example, in some cases where the possibility of malignant growth is not there at all. In general, we can conclude that immortalized cells have their niches in certain areas of practical medicine where they can successfully compete with other therapeutic approaches, and more preclinical and clinical trials with them should be expected.
... A key component of such device is a "living membrane" that consists of a PTEC monolayer on a porous membrane that allows the transport of molecules from one side to the other. Previous BAK research has focused on determining its feasibility, safety, effectiveness, and design optimization [15][16][17]. While these characteristics are important for clinical translation, there is still a lack of information regarding the cytocompatibility of the DF, a solution that will be in direct contact with the BAK-containing cells. ...
Patients with end-stage kidney disease (ESKD) suffer from high levels of protein-bound uremic toxins (PBUTs) that contribute to various comorbidities. Conventional dialysis methods are ineffective in removing these PBUTs. A potential solution could be offered by a bioartificial kidney (BAK) composed of porous membranes covered by proximal tubule epithelial cells (PTECs) that actively secrete PBUTs. However, BAK development is currently being hampered by a lack of knowledge regarding the cytocompatibility of the dialysis fluid (DF) that comes in contact with the PTECs. Here, we conducted a comprehensive functional assessment of the DF on human conditionally immortalized PTECs (ciPTECs) cultured as monolayers in well plates, on Transwell® inserts, or on hollow fiber membranes (HFMs) that form functional units of a BAK. We evaluated cell viability markers, monolayer integrity, and PBUT clearance. Our results show that exposure to DF did not affect ciPTECs’ viability, membrane integrity, or function. Seven anionic PBUTs were efficiently cleared from the perfusion fluid containing a PBUTs cocktail or uremic plasma, an effect which was enhanced in the presence of albumin. Overall, our findings support that the DF is cytocompatible and does not compromise ciPTECs function, paving the way for further advancements in BAK development and its potential clinical application.
... The initial focus in kidney tissue engineering was to develop an extracorporeal bioartificial device that would consist of a conventional synthetic hemofilter with a RAD. As of 2013, proof of concept for a wearable BAK was achieved by combining existing PD technology with a bioartificial renal epithelial system [10]. The renal epithelial system is needed because tubular functionality of the kidneys cannot be replaced with inanimate devices as can filtration functionality. ...
... A bioartificial tubule was constructed with renal tubule progenitor cells seeded onto semipermeable hollow-fiber membranes that have been layered with an extracellular matrix (ECM) to enhance the attachment and growth of epithelial cells. These membranes provided both a scaffold for the cells to grow on and immunoprotection, similar to what has been documented for bioartificial pancreas implantation in a xenogenic host [10,11]. The next step in the process was to improve the wearable bioartificial technology to be implantable and more fully mimic a donor kidney. ...
... MEMS is an industrial toolkit that applies mature manufacturing techniques from the semiconductor industry to miniature electromechanical devices, such as pumps, valves, and sensors. This technology can be used to produce silicon membranes containing 'slit-shaped' pores that are necessary for producing an implantable BAK [10]. Another engineering challenge for the implantable BAK is to design it such that the membrane maximizes water permeability while minimizing leakage of albumin and other important macromolecules. ...
The current standard of care for patients with end-stage renal disease (ERSD) is a kidney transplant or dialysis when a donor organ is not available. The growing gap between patients who require a kidney transplant and the availability of donor organs as well as the negative effects of long-term dialysis, such as infection, limited mobility, and risk of cancer development, drive the impetus to develop alternative renal replacement technology. The goal of this review is to assess the potential of two of the most recent innovations in kidney transplant technology-the implantable bioartificial kidney (BAK) and kidney regeneration technology-in addressing the aforementioned problems related to kidney replacement for patients with ERSD. Both innovations are fully implantable, autologous, personalized with patient cells, and can replace all aspects of kidney function. Not only do these new innovations have the potential to improve the possibility of transplantation for more patients, they also have potential to improve the outcome of transplantation or dialysis-related renal cancer diagnosis. A major limitation of the current technology is that both implantable BAK and kidney regeneration technology are still in preclinical stages, and thus their potential effects cannot be comprehensively generalized to human patients.
... Although the treatment led to a statistically significant improved survival in the group treated for 72 h with the BAK compared to a non-treated control group, phase IIb trials were not completed due to difficulties with the manufacturing of the device and problems with the study design. 84 The group of Saito et al. also used hollow fiber modules, but with ethylene vinyl alcohol copolymer (EVAL) membranes that were claimed to be superior to polysulfone, yet also required a coating with ECM molecules called "attachin" to improve the growth and functionality of kidney epithelial cells. This could demonstrate the functionality of the device in their studies. ...
Background:
Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low.
Observation:
Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world.
Conclusions:
Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.
... There is great demand for new therapies, as current treatment methods, such as dialysis, do not provide all essential functionalities of a kidney and are not long-term solutions 1 . For example, toxins are insufficiently removed and the sodium and fluid homeostasis are distorted by intermittent treatment, while the metabolic and endocrine functions are completely neglected 2,3 . Dialysis can replace many functions of the kidney but is associated with high morbidity, mortality, reduced quality of life, and high costs. ...
The kidney is among the most complex organs in terms of the variety of cell types. The cellular complexity of human kidneys is not fully unraveled and this challenge is further complicated by the existence of multiple progenitor pools and differentiation pathways. Researchers disagree on the variety of renal cell types due to a lack of research providing a comprehensive picture and the challenge to translate findings between species. To find an answer to the number of human renal cell types, we discuss research that used single-cell RNA sequencing on developing and adult human kidney tissue and compares these findings to the literature of the pre-single-cell RNA sequencing era. We find that these publications show major steps towards the discovery of novel cell types and intermediate cell stages as well as complex molecular signatures and lineage pathways throughout development. The variety of cell types remains variable in the single-cell literature, which is due to the limitations of the technique. Nevertheless, our analysis approaches an accumulated number of 41 identified cell populations of renal lineage and 32 of non-renal lineage in the adult kidney, and there is certainly much more to discover. There is still a need for a consensus on a variety of definitions and standards in single-cell RNA sequencing research, such as the definition of what is a cell type. Nevertheless, this early-stage research already proves to be of significant impact for both clinical and regenerative medicine, and shows potential to enhance the generation of sophisticated in vitro kidney tissue.
... Another way to improve the removal of free and protein-bound uremic toxins is by enhancing classic hemodialysis (referred to herein as 'dialysis' for simplicity, though the authors recognize other forms of dialysis exist) by culturing a living cell layer on top of the hollow fiber membranes [10][11][12][13][14][15]. This cell layer then contributes to the active removal of protein-bound toxins through dedicated transporters (e.g., organic anion transporter 1 (OAT1)) on their basolateral and apical surface. ...
Kidney dialysis is the most widespread treatment method for end-stage renal disease, a debilitating health condition common in industrialized societies. While ubiquitous, kidney dialysis suffers from an inability to remove larger toxins, resulting in a gradual buildup of these toxins in dialysis patients, ultimately leading to further health complications. To improve dialysis, hollow fibers incorporating a cell-monolayer with cultured kidney cells have been proposed; however, the design of such a fiber is nontrivial. In particular, the effects of fluid wall-shear stress have an important influence on the ability of the cell layer to transport toxins. In the present work, we introduce a model for cell-transport aided dialysis, incorporating the effects of the shear stress. We analyze the model mathematically and establish its well-posedness. We then present a series of numerical results, which suggest that a hollow-fiber design with a wavy profile may increase the efficiency of the dialysis treatment. We investigate numerically the shape of the wavy channel to maximize the toxin clearance. These results demonstrate the potential for the use of computational models in the study and advancement of renal therapies.
... 65 The graphene NATMs with superior permeance might be a promising candidate for portable hemodialysis, which requires the dialysis membrane to have better permeance and selectivity to remove kidney toxins, thus achieving efficient water utilization or miniaturization. 66 3.5. Further Discussions. ...
... Hearing loss [53] Closed-loop Cardiac assist Pacemaker Arrhythmia, heart attack, etc. [54][55][56] Cardioverter defibrillator(ICD) Ventricular assist device Kidney assist Implantable bioartificial kidney Kidney failure [57,58] Adv Funct Mater. Author manuscript; available in PMC 2021 October 28. ...
Implantable and ingestible biomedical electronic devices can be useful tools for detecting physiological and pathophysiological signals, and providing treatments that cannot be done externally. However, one major challenge in the development of these devices is the limited lifetime of their power sources. The state‐of‐the‐art of powering technologies for implantable and ingestible electronics is reviewed here. The structure and power requirements of implantable and ingestible biomedical electronics are described to guide the development of powering technologies. These powering technologies include novel batteries that can be used as both power sources and for energy storage, devices that can harvest energy from the human body, and devices that can receive and operate with energy transferred from exogenous sources. Furthermore, potential sources of mechanical, chemical, and electromagnetic energy present around common target locations of implantable and ingestible electronics are thoroughly analyzed; energy harvesting and transfer methods befitting each energy source are also discussed. Developing power sources that are safe, compact, and have high volumetric energy densities is essential for realizing long‐term in‐body biomedical electronics and for enabling a new era of personalized healthcare.
... Renal substitution therapy with hemodialysis (HD) or peritoneal dialysis (PD) has been the only successful long-term organ substitution therapy. The lack of wide-spread availability of suitable transplantable organs has made kidney transplantation a difficult solution in most cases of chronic renal failure.Bioengineering of an implantable bioartificial kidney couldbe advantageous to patients by increasing life time, activity and overall quality of life, with lower risk of infection and in being much more economical (Humes, et al., 2014) Artificial kidneys can be of better value in treatment of poisoning as well. ...
