An arteriovenous mock circulatory loop and accompanying bond graph model for in vitro study of peripheral intravascular bioartificial organs.

BACKGROUND: Silicon nanopore membrane-based implantable bioartificial organs are dependent on arteriovenous implantation of a mechanically robust and biocompatible hemofilter. The hemofilter acts as a low-resistance, high-flow network, with blood flow physiology similar to arteriovenous shunts commonly created for hemodialysis access. A mock circulatory loop (MCL) that mimics shunt physiology is an essential tool for refinement and durability testing of arteriovenous implantable bioartificial organs and silicon blood-interfacing membranes. We sought to develop a compact and cost-effective MCL to replicate flow conditions through an arteriovenous shunt and used data from the MCL and swine to inform a bond graph mathematical model of the physical setup. METHODS: Flow physiology through bioartificial organ prototypes was obtained in the MCL and during extracorporeal attachment to swine for biologic comparison. The MCL was tested for stability overtime by measuring pressurewave variability over a 48-h period. Data obtained in vitro and extracorporeally informed creation of a bond graph model of the MCL. RESULTS: The arteriovenous MCL was a cost-effective, portable system that reproduced flow rates and pressures consistent with a pulsatile arteriovenous shunt as measured in swine. MCL performance was stable over prolonged use, providing a cost-effective simulator for enhanced testing of peripherally implanted bioartificial organ prototypes. The corresponding bond graph model recapitulates MCL and animal physiology, offering a tool for further refinement of the MCL system.

Diseasome and comorbidities complexities of SARS-CoV-2 infection with common malignant diseases.

With the increasing number of immunoinflammatory complexities, cancer patients have a higher risk of serious disease outcomes and mortality with SARS-CoV-2 infection which is still not clear. In this study, we aimed to identify infectome, diseasome and comorbidities between COVID-19 and cancer via comprehensive bioinformatics analysis to identify the synergistic severity of the cancer patient for SARS-CoV-2 infection. We utilized transcriptomic datasets of SARS-CoV-2 and different cancers from Gene Expression Omnibus and Array Express Database to develop a bioinformatics pipeline and software tools to analyze a large set of transcriptomic data and identify the pathobiological relationships between the disease conditions. Our bioinformatics approach revealed commonly dysregulated genes (MARCO, VCAN, ACTB, LGALS1, HMOX1, TIMP1, OAS2, GAPDH, MSH3, FN1, NPC2, JUND, CHI3L1, GPNMB, SYTL2, CASP1, S100A8, MYO10, IGFBP3, APCDD1, COL6A3, FABP5, PRDX3, CLEC1B, DDIT4, CXCL10 and CXCL8), common gene ontology (GO), molecular pathways between SARS-CoV-2 infections and cancers. This work also shows the synergistic complexities of SARS-CoV-2 infections for cancer patients through the gene set enrichment and semantic similarity. These results highlighted the immune systems, cell activation and cytokine production GO pathways that were observed in SARS-CoV-2 infections as well as breast, lungs, colon, kidney and thyroid cancers. This work also revealed ribosome biogenesis, wnt signaling pathway, ribosome, chemokine and cytokine pathways that are commonly deregulated in cancers and COVID-19. Thus, our bioinformatics approach and tools revealed interconnections in terms of significant genes, GO, pathways between SARS-CoV-2 infections and malignant tumors.

Wearable and implantable artificial kidney devices for end-stage kidney disease treatment: Current status and review.

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.

Silicon membranes for extracorporeal life support: a comparison of design and fabrication methodologies.

Extracorporeal life support is an advanced therapy that circulates blood through an extracorporeal oxygenator, performing gas exchange outside the body. However, its use is limited by severe complications, including bleeding, clotting, and hemolysis. Semiconductor silicon-based membranes have emerged as an alternative to traditional hollow-fiber semipermeable membranes. These membranes offer excellent gas exchange efficiency and the potential to increase hemocompatibility by improving flow dynamics. In this work, we evaluate two next-generation silicon membrane designs, which are intended to be mechanically robust and efficient in gas exchange, while simultaneously reducing fabrication complexity. The "window" design features 10 µm pores on one side and large windows on the back side. The "cavern" design also uses 10 µm pores but contains a network of interconnected buried caverns to distribute the sweep gas from smaller inlet holes. Both designs were shown to be technically viable and able to be reproducibly fabricated. In addition, they both were mechanically robust and withstood 30 psi of transmembrane pressure without breakage or bubbling. At low sweep gas pressures, gas transfer efficiency was similar, with the partial pressure of oxygen in water increasing by 10.7 ± 2.3 mmHg (mean ± standard deviation) and 13.6 ± 1.9 mmHg for the window and cavern membranes, respectively. Gas transfer efficiency was also similar at higher pressures. At 10 psi, oxygen tension increased by 16.8 ± 5.7 mmHg (window) and 18.9 ± 1.3 mmHg (cavern). We conclude that silicon membranes featuring a 10 µm pore size can simplify the fabrication process and improve mechanical robustness while maintaining excellent efficiency.

Advances in extracorporeal membrane oxygenator design for artificial placenta technology.

Extreme prematurity, defined as a gestational age of fewer than 28 weeks, is a significant health problem worldwide. It carries a high burden of mortality and morbidity, in large part due to the immaturity of the lungs at this stage of development. The standard of care for these patients includes support with mechanical ventilation, which exacerbates lung pathology. Extracorporeal life support (ECLS), also called artificial placenta technology when applied to extremely preterm (EPT) infants, offers an intriguing solution. ECLS involves providing gas exchange via an extracorporeal device, thereby doing the work of the lungs and allowing them to develop without being subjected to injurious mechanical ventilation. While ECLS has been successfully used in respiratory failure in full-term neonates, children, and adults, it has not been applied effectively to the EPT patient population. In this review, we discuss the unique aspects of EPT infants and the challenges of applying ECLS to these patients. In addition, we review recent progress in artificial placenta technology development. We then offer analysis on design considerations for successful engineering of a membrane oxygenator for an artificial placenta circuit. Finally, we examine next-generation oxygenators that might advance the development of artificial placenta devices.

Ultrafiltration for management of fluid overload in patients with heart failure.

Heart failure is the number one cause of death in the United States and a significant burden to the healthcare system. One of the primary complications of heart failure is fluid overload, for which current treatments are limited. Medical therapy is first-line; however, rates of diuretic insensitivity are high, medications are not easily titrated, and they do not address the underlying physiologic derangement that leads to hypervolemia. Removal of isotonic fluid via hemofiltration and peritoneal dialysis is an understudied but promising therapy that enables decongestion without maladaptive stimulation of fluid retention pathways. Published studies report conflicting data on long-term outcomes of ultrafiltration but reach consensus on greater and more durable volume reduction with ultrafiltration than conventional medical therapy. These studies are noteworthy for their neglect to standardize both patient selection and fluid removal protocol, which likely contribute to outcome variation. Novel technology in preclinical testing includes implantable ultrafiltration, which has potential to treat volume overload while minimizing the adverse effects associated with conventional hemofiltration. We performed a literature review of English-language studies on hemo- and peritoneal filtration for management of fluid overload in congestive heart failure. Also included is a discussion of the pathophysiology of congestive heart failure and first-line management as well as emerging technologies for ultrafiltration.

Apical Shear Stress Enhanced Organic Cation Transport in Human OCT2/MATE1-Transfected Madin-Darby Canine Kidney Cells Involves Ciliary Sensing.

Active transport by renal proximal tubules plays a significant role in drug disposition. During drug development, estimates of renal excretion are essential to dose determination. Kidney bioreactors that reproduce physiologic cues in the kidney, such as flow-induced shear stress, may better predict in vivo drug behavior than do current in vitro models. In this study, we investigated the role of shear stress on active transport of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) by Madin-Darby canine kidney cells exogenously expressing the human organic cation transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Cells cultured in a parallel plate under continuous media perfusion formed a tight monolayer with a high barrier to inulin. In response to increasing levels of shear stress (0.2-2 dynes/cm2), cells showed a corresponding increase in transport of ASP+, reaching a maximal 4.2-fold increase at 2 dynes/cm2 compared with cells cultured under static conditions. This transport was inhibited with imipramine, indicating active transport was present under shear stress conditions. Cells exposed to shear stress of 2 dynes/cm2 also showed an increase in RNA expression of both transfected human and endogenous OCT2 (3.7- and 2.0-fold, respectively). Removal of cilia by ammonium sulfate eliminated the effects of shear on ASP+ transport at 0.5 dynes/cm2 with no effect on ASP+ transport under static conditions. These results indicate that shear stress affects active transport of organic cations in renal tubular epithelial cells in a cilia-dependent manner.

Compliance monitoring via a Bluetooth-enabled retainer: A prospective clinical pilot study.

OBJECTIVES: To conduct a prospective pilot trial to test the clinical efficacy and accuracy of a newly developed Bluetooth-enabled retainer, which was synchronized with an iOS mobile application, cloud database and provider webpage. SETTING AND SAMPLE POPULATION: Five orthodontic residents in a university setting. MATERIAL AND METHODS: At the delivery of the retainers (T0), each participant was given an Bluetooth-enabled retainer, logbook and iPod Touch installed with the mobile application. Participants were instructed to wear the retainer for 12 hours per day and record in the logbook each time the retainer was inserted or removed and trained to synchronize the device daily to the mobile application. After the 5-day study period (T1), statistical analysis was performed comparing the device-reported data to the logbook data using two calculation methods. RESULTS: From T0 - T1, the participants wore their retainers for a median of 11.55 hours per day and the median difference between the self-reported (logbook) data and the device data was 35 minutes or 5.1% over the 5-day study period. Using an adjusted method to calculate the device-reported wear time, the median error was 13 minutes or 1.9%. CONCLUSION: Subjects were able to successfully wear the retainer and upload the data to the mobile application and cloud database. Patient compliance and technical issues could be monitored daily via the provider webpage, and early intervention was possible with reminder messaging. The Bluetooth-enabled retainer showed a clinically acceptable level of accuracy and usability that validates it for future clinical testing.

A distributed solute model: an extended two-pore model with application to the glomerular sieving of Ficoll.

One of the many unresolved questions regarding the permeability of the glomerular filtration barrier is the reason behind the marked difference in permeability between albumin and polysaccharide probe molecules such as Ficoll and dextran of the same molecular size. Although the differences in permeability have been mainly attributed to charge effects, we have previously shown that this would require a highly charged filtration barrier, having a charge density that is ~10 times more than that on the albumin molecule. In this article, the classic two-pore model was extended by introducing size distributions on the solute molecules, making them conformationally flexible. Experimental sieving data for Ficoll from the rat glomerulus and from precision-made silicon nanopore membranes were analyzed using the model. For the rat glomerulus a small-pore radius of 36.2 Å and a geometric standard deviation (gSD) for the Ficoll size-distribution of 1.16 were obtained. For the nanopore membranes, a gSD of 1.24 and a small-pore radius of 43 Å were found. Interestingly, a variation of only ~16% in the size of the polysaccharide molecule is sufficient to explain the difference in permeability between albumin and Ficoll. Also, in line with previous data, the effects of applying a size distribution on the solute molecule are only evident when the molecular size is close to the pore size. Surely there is at least some variation in the pore radii, and, likely, the gSD obtained in the current study is an overestimation of the "true" variation in the size of the Ficoll molecule.

Innovations in Wearable and Implantable Artificial Kidneys.

More than 2 million people worldwide receive treatment for end-stage renal disease (ESRD). Current modalities of renal replacement therapy include in-center hemodialysis, peritoneal dialysis, home hemodialysis, and kidney transplantation. Patient survival has gradually increased during the past 2 decades and efforts continue to improve mortality and quality of life for patients with ESRD. Developments in sorbent technology, nanotechnology, and cell culture techniques provide promise for new innovations in ESRD management. New modalities currently in testing include wearable (WAKs) and implantable artificial kidneys (IAKs). The automated WAK (AWAK) and WAK are devices that have undergone small trials in humans. Additional study is needed before regulatory approval, coverage decisions, and widespread clinical implementation. The IAK is a biohybrid combining artificial filters and living cells currently in preclinical testing. These portable devices reduce the need for large quantities of water and continuous electrical supply. This could lower some barriers to home dialysis, making self-care renal replacement therapy more accessible and desirable. If widely successful, these devices could reduce the need to build and staff dialysis facilities, thus lowering health care costs associated with dialysis. The potential advantages and shortcomings of the AWAK, WAK, and IAK are described here.

Evaluation of silicon membranes for extracorporeal membrane oxygenation (ECMO).

While extracorporeal membrane oxygenation (ECMO) is a valuable therapy for patients with lung or heart failure, clinical use of ECMO remains limited due to hemocompatibility concerns with pro-coagulatory hollow fiber membrane geometries. Previously, we demonstrated the feasibility of silicon nanopore (SNM) and micropore (SµM) membranes for transport between two liquid-phase compartments in blood-contacting devices. Herein, we investigate various pore sizes of SNM and SµM membranes - alone or with a polydimethylsiloxane (PDMS) protective coating - for parameters that determine suitability for gas exchange. We characterized the bubble or rupture point of these membranes to determine sweep gas pressures at which gas emboli would form. The smallest pore size SNM and the SµM with PDMS coating could be pressurized in excess of 260 cmHg without rupture, which is comparable to hollow fiber sweep gas pressures. Oxygen flux for the SµM with and without PDMS was insignificantly different at 0.0306 ± 0.0028 and 0.0297 ± 0.0012 mL/min, respectively, while SNM flux was significantly lower at 0.0149 ± 0.0040 mL/min. However, the area-normalized mass transfer coefficient of the SNM was 338 ± 54 mL O2 m-2 min-1 cmHg-1 - an order of magnitude higher than that of the SµM with and without PDMS (57.3 ± 5.5 and 55.6 ± 2.2 mL O2 m-2 min-1 cmHg-1). Ultimately, we conclude that SµM-PDMS may make effective membranes for ECMO, since they are both mechanically robust and capable of high oxygen flux.

Silicon Micropore-Based Parallel Plate Membrane Oxygenator.

Extracorporeal membrane oxygenation (ECMO) is a life support system that circulates the blood through an oxygenating system to temporarily (days to months) support heart or lung function during cardiopulmonary failure until organ recovery or replacement. Currently, the need for high levels of systemic anticoagulation and the risk for bleeding are main drawbacks of ECMO that can be addressed with a redesigned ECMO system. Our lab has developed an approach using microelectromechanical systems (MEMS) fabrication techniques to create novel gas exchange membranes consisting of a rigid silicon micropore membrane (SµM) support structure bonded to a thin film of gas-permeable polydimethylsiloxane (PDMS). This study details the fabrication process to create silicon membranes with highly uniform micropores that have a high level of pattern fidelity. The oxygen transport across these membranes was tested in a simple water-based bench-top set-up as well in a porcine in vivo model. It was determined that the mass transfer coefficient for the system using SµM-PDMS membranes was 3.03 ± 0.42 mL O2 min-1 m-2 cm Hg-1 with pure water and 1.71 ± 1.03 mL O2 min-1 m-2 cm Hg-1 with blood. An analytic model to predict gas transport was developed using data from the bench-top experiments and validated with in vivo testing. This was a proof of concept study showing adequate oxygen transport across a parallel plate SµM-PDMS membrane when used as a membrane oxygenator. This work establishes the tools and the equipoise to develop future generations of silicon micropore membrane oxygenators.

Tabla: A Proof-of-Concept Auscultatory Percussion Device for Low-Cost Pneumonia Detection.

Pneumonia causes the deaths of over a million people worldwide each year, with most occurring in countries with limited access to expensive but effective diagnostic methods, e.g., chest X-rays. Physical examination, the other major established method of diagnosis, suffers from several drawbacks, most notably low accuracy and high interobserver error. We sought to address this diagnostic gap by developing a proof-of-concept non-invasive device to identify the accumulation of fluid in the lungs (consolidation) characteristic of pneumonia. This device, named Tabla after the percussive instrument of the same name, utilizes the technique of auscultatory percussion; a percussive input sound is sent through the chest and recorded with a digital stethoscope for analysis. Tabla analyzes differences in sound transmission through the chest at audible frequencies as a marker for lung consolidation. This paper presents preliminary data from five pneumonia patients and eight healthy subjects. We demonstrate 92.3% accuracy in distinguishing between healthy subjects and patients with pneumonia after data analysis with a K-nearest neighbors algorithm. This prototype device is low cost and simple to implement and may offer a rapid and inexpensive method for pneumonia diagnosis appropriate for general use and in areas with limited medical infrastructure.

Silicon nanoporous membranes as a rigorous platform for validation of biomolecular transport models.

Microelectromechanical systems (MEMS), a technology that resulted from significant innovation in semiconductor fabrication, have recently been applied to the development of silicon nanopore membranes (SNM). In contrast to membranes fabricated from polymeric materials, SNM exhibit slit-shaped pores, monodisperse pore size, constant surface porosity, zero pore overlap, and sub-micron thickness. This development in membrane fabrication is applied herein for the validation of the XDLVO (extended Derjaguin, Landau, Verwey, and Overbeek) theory of membrane transport within the context of hemofiltration. In this work, the XDLVO model has been derived for the unique slit pore structure of SNM. Beta-2-microglobulin (B2M), a clinically relevant "middle molecular weight" solute in kidney disease, is highlighted in this study as the solute of interest. In order to determine interaction parameters within the XDLVO model for B2M and SNM, goniometric measurements were conducted, yielding a Hamaker constant of 4.61× 10-21 J and an acid-base Gibbs free energy at contact of 41 mJ/m2. The XDLVO model was combined with existing models for membrane sieving, with predictions of the refined model in good agreement with experimental data. Furthermore, the results show a significant difference between the XDLVO model and the simpler steric predictions typically applied in membrane transport. The refined model can be used as a tool to tailor membrane chemistry and maximize sieving or rejection of different biomolecules.

Evolution of Gas Permeable Membranes for Extracorporeal Membrane Oxygenation.

Gas permeable membranes are a vital component of extracorporeal membrane oxygenation systems. Over more than half a century, membrane fabrication and packaging technology have progressed to enable safer and longer duration use of respiratory life support. Current research efforts seek to improve membrane efficiency and hemocompatibility, with the aim of producing smaller and more robust systems for ambulatory use. This review explores past and present innovations in oxygenator technology, suggesting possible applications of state-of-the-art membrane fabrication methods to address shortcomings of earlier concepts.

Progress and challenges in macroencapsulation approaches for type 1 diabetes (T1D) treatment: Cells, biomaterials, and devices.

Macroencapsulation technology has been an attractive topic in the field of treatment for Type 1 diabetes due to mechanical stability, versatility, and retrievability of the macro-capsule design. Macro-capsules can be categorized into extravascular and intravascular devices, in which solute transport relies either on diffusion or convection, respectively. Failure of macroencapsulation strategies can be due to limited regenerative capacity of the encased insulin-producing cells, sub-optimal performance of encapsulation biomaterials, insufficient immunoisolation, excessive blood thrombosis for vascular perfusion devices, and inadequate modes of mass transfer to support cell viability and function. However, significant technical advancements have been achieved in macroencapsulation technology, namely reducing diffusion distance for oxygen and nutrients, using pro-angiogenic factors to increase vascularization for islet engraftment, and optimizing membrane permeability and selectivity to prevent immune attacks from host's body. This review presents an overview of existing macroencapsulation devices and discusses the advances based on tissue-engineering approaches that will stimulate future research and development of macroencapsulation technology. Biotechnol. Bioeng. 2016;113: 1381-1402. © 2015 Wiley Periodicals, Inc.

The bioartificial kidney: current status and future promise.

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 engineering, which are based on the ability to expand stem or progenitor cells in tissue culture to perform differentiated tasks and to introduce these cells into the patient either via extracorporeal circuits or as implantable constructs. Cell therapy devices are currently being developed to replace the filtrative, metabolic, and endocrinologic functions of the kidney lost in both acute and chronic renal failure. This review summarizes the current state of development of a wearable or implantable bioartificial kidney. These devices have the promise to be combined to produce a wearable or implantable bioartificial kidney for full renal replacement therapy that may significantly diminish morbidity and mortality in patients with acute or chronic kidney disease.

Achieving more frequent and longer dialysis for the majority: wearable dialysis and implantable artificial kidney devices.

The long-term survival for many chronic kidney failure patients who remain treated by dialysis in economically advanced countries remains similar to that of those with solid-organ malignancy, despite a disproportionate amount of health-care expenditure. As such, the current paradigm of three times weekly in-center hemodialysis for 4 h or shorter sessions needs to change to improve patient outcomes. Although more frequent and longer dialysis sessions have been reported to improve cardiovascular risk surrogates and short-term outcomes, these options are only practically available to a very small fraction of the total dialysis population. As such, radically new approaches are required to improve patient outcomes and quality of life for the majority of dialysis patients. Currently, two different approaches are being developed, wearable devices based on current dialysis techniques and more futuristic implantable devices modeled on the natural nephron.

Response of bone marrow derived connective tissue progenitor cell morphology and proliferation on geometrically modulated microtextured substrates.

Varying geometry and layout of microposts on a cell culture substrate provides an effective technique for applying mechanical stimuli to living cells. In the current study, the optimal geometry and arrangement of microposts on the polydimethylsiloxane (PDMS) surfaces to enhance cell growth behavior were investigated. Human bone marrow derived connective tissue progenitor cells were cultured on PDMS substrates comprising unpatterned smooth surfaces and cylindrical post microtextures that were 10 µm in diameter, 4 heights (5, 10, 20 and 40 µm) and 3 pitches (10, 20, and 40 µm). With the same 10 µm diameter, post heights ranging from 5 to 40 µm resulted in a more than 535 fold range of rigidity from 0.011 nNµm⁻¹ (40 µm height) up to 5.888 nNµm⁻¹(5 µm height). Even though shorter microposts result in higher effective stiffness, decreasing post heights below the optimal value, 5 µm height micropost in this study decreased cell growth behavior. The maximum number of cells was observed on the post microtextures with 20 µm height and 10 µm inter-space, which exhibited a 675 % increase relative to the smooth surfaces. The cells on all heights of post microtextures with 10 µm and 20 µm inter-spaces exhibited highly contoured morphology. Elucidating the cellular response to various external geometry cues enables us to better predict and control cellular behavior. In addition, knowledge of cell response to surface stimuli could lead to the incorporation of specific size post microtextures into surfaces of implants to achieve surface-textured scaffold materials for tissue engineering applications.