Scaled-up Microfluidic Lung Assist Device for Artificial Placenta Application with High Gas Exchange Capacity.

Premature neonates with underdeveloped lungs experience respiratory issues and need respiratory support, such as mechanical ventilation or extracorporeal membrane oxygenation (ECMO). The "artificial placenta" (AP) is a noninvasive approach that supports their lungs and reduces respiratory distress, using a pumpless oxygenator connected to the systemic circulation, and can address some of the morbidity issues associated with ECMO. Over the past decade, microfluidic blood oxygenators have garnered significant interest for their ability to mimic physiological conditions and incorporate innovative biomimetic designs. Achieving sufficient gas transfer at a low enough pressure drop for a pumpless operation without requiring a large volume of blood to prime such an oxygenator has been the main challenge with microfluidic lung assist devices (LAD). In this study, we improved the gas exchange capacity of our microfluidic-based artificial placenta-type LAD while reducing its priming volume by using a modified fabrication process that can accommodate large-area thin film microfluidic blood oxygenator (MBO) fabrication with a very high gas exchange surface. Additionally, we demonstrate the effectiveness of a LAD assembled by using these scaled-up MBOs. The LAD based on our artificial placenta concept effectively increases oxygen saturation levels by 30% at a flow rate of 40 mL/min and a pressure drop of 23 mmHg in room air, which is sufficient to support partial oxygenation for 1 kg preterm neonates in respiratory distress. When the gas ambient environment was changed to pure oxygen at atmospheric pressure, the LAD would be able to support premature neonates weighing up to 2 kg. Furthermore, our experiments reveal that the LAD can handle high blood flow rates of up to 150 mL/min and increase oxygen saturation levels by ∼20%, which is equal to an oxygen transfer of 7.48 mL/min in an enriched oxygen environment and among the highest for microfluidic AP type devices. Such performance makes this LAD suitable for providing essential support to 1-2 kg neonates in respiratory distress.

Numerical Simulation of Mass Transfer in Hollow Fiber Membrane Module for Membrane-Based Artificial Organs.

The mass transfer behavior in a hollow fiber membrane module of membrane-based artificial organs (such as artificial liver or artificial kidney) were studied by numerical simulation. A new computational fluid dynamics (CFD) method coupled with K-K equation and the tortuous capillary pore diffusion model (TCPDM) was proposed for the simulations. The urea clearance rate predicted by the use of the numerical model agrees well with the experimental data, which verifies the validity of our numerical model. The distributions of concentration, pressure, and velocity in the hollow fiber membrane module were obtained to analyze the mass transfer behaviors of bilirubin and bovine serum albumin (BSA), and the effects of tube-side flow rate, shell-side flow rate, and fiber tube length on the bilirubin or BSA clearance rate were studied. The results show that the solute transport mainly occurred in the near inlet regions in the hollow fiber membrane module. Increasing the tube-side flow rate and the fiber tube length can effectively enhance the solute clearance rate, while the shell-side flow rate has less influence on the BSA clearance. The clearance of macromolecule BSA is dominated by convective solute transport, while the clearance of small molecule bilirubin is significantly affected by both convective and diffusive solute transport.

Numerical simulation and experimental testing for static failure prediction in additively manufactured below-knee prosthetic sockets.

The socket of a transtibial prosthesis is a structural part customized to a patient's amputated residual lower limb. The free-form geometry of the socket can be suitable for additive manufacturing (AM) to save time and cost. However, the mechanical fracture of additively manufactured lower limb prostheses is not yet fully understood. A novel experimental method and numerical approach by finite element method (FEM) to test the strength and fracture behavior of a lower limb prosthetic socket of acrylonitrile butadiene styrene (ABS), reverse-engineered using computer-aided design (CAD) from the actual amputee's residual limb and manufactured using fused filament fabrication (FFF) are proposed in the present work. The mechanical behavior, von Mises stress distribution, and the damage status of layered AM sockets of different thicknesses were simulated by FEM using Hashin's transversely isotropic mechanical damage model, initially developed for composite materials. The experimental work showed that the fracture failure initiated at the corner of the lobe in the 4 mm thickness socket at a failure load of 918.5 N. The FEM results predicted this failure load to be 896.6 N, with only a 2.45% error as compared to the experiment. The failure loads predicted by FEM in the sockets with thicknesses of 3, 5, and 6 mm were 618.1, 1008.6, and 1105.2 N, respectively. The present work provides a dependable method for testing a below-knee prosthetic socket against static failure and arriving at a factor-of-safety (FoS) based socket thickness selection for any amputee.

Analysis of the Suitability of an Effective Viscosity to Represent Interactions Between Red Blood Cells in Shear Flow.

Many methods to computationally predict red blood cell damage have been introduced, and among these are Lagrangian methods that track the cells along their pathlines. Such methods typically do not explicitly include cell-cell interactions. Due to the high volume fraction of red blood cells (RBCs) in blood, these interactions could impact cell mechanics and thus the amount of damage caused by the flow. To investigate this question, cell-resolved simulations of red blood cells in shear flow were performed for multiple interacting cells, as well as for single cells in unbounded flow at an effective viscosity. Simulations run without adjusting the bulk viscosity produced larger errors unilaterally and were not considered further for comparison. We show that a periodic box containing at least 8 cells and a spherical harmonic of degree larger than 10 are necessary to produce converged higher-order statistics. The maximum difference between the single-cell and multiple-cell cases in terms of peak strain was 3.7%. To achieve this, one must use the whole blood viscosity and average over multiple cell orientations when adopting a single-cell simulation approach. The differences between the models in terms of average strain were slightly larger (maximum difference of 6.9%). However, given the accuracy of the single-cell approach in predicting the maximum strain, which is useful in hemolysis prediction, and its computational cost that is orders of magnitude less than the multiple-cell approach, one may use it as an affordable cell-resolved approach for hemolysis prediction.

Management of ectopic intestinal variceal bleeding following pancreatic transplant: Two cases.

Ectopic variceal bleeding is a potentially under recognized source of gastrointestinal (GI) hemorrhage. While vascular complications following pancreatic transplant are relatively common, the development of symptomatic ectopic venous varices has rarely been reported. We report two patients with a remote history of simultaneous kidney pancreas transplant (SPK) presenting two decades after transplant with an occult GI bleed. In both cases, a lengthy diagnostic course was required. The varices were treated with coil embolization via transhepatic approach. Our findings add to the limited literature on this topic and aid in the recognition, diagnosis, and management of this unusual presentation.

Renal Embolization-Induced Uremic Swine Model for Assessment of Next-Generation Implantable Hemodialyzers.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled externally for connection to a dialysate recirculation pump. SNMHD clearance was determined by intermittent sampling of recirculating dialysate. Creatinine and urea clearance through the SNMHD were 76-105 mL/min/m2 and 140-165 mL/min/m2, respectively, without albumin leakage. Normalized creatinine and urea clearance measured in the SNMHD may translate to a fully implantable clinical-scale device. This pilot study establishes a path toward therapeutic testing of the clinical-scale SNMHD and other implantable RRT devices.

New Solutions for Old Problems: How Reproductive Tissue Engineering Has Been Revolutionizing Reproductive Medicine.

Acquired disorders and congenital defects of the male and female reproductive systems can have profound impacts on patients, causing sexual and endocrine dysfunction and infertility, as well as psychosocial consequences that affect their self-esteem, identity, sexuality, and relationships. Reproductive tissue engineering (REPROTEN) is a promising approach to restore fertility and improve the quality of life of patients with reproductive disorders by developing, replacing, or regenerating cells, tissues, and organs from the reproductive and urinary systems. In this review, we explore the latest advancements in REPROTEN techniques and their applications for addressing degenerative conditions in male and female reproductive organs. We discuss current research and clinical outcomes and highlight the potential of 3D constructs utilizing biomaterials such as scaffolds, cells, and biologically active molecules. Our review offers a comprehensive guide for researchers and clinicians, providing insights into how to reestablish reproductive tissue structure and function using innovative surgical approaches and biomaterials. We highlight the benefits of REPROTEN for patients, including preservation of fertility and hormonal production, reconstruction of uterine and cervical structures, and restoration of sexual and urinary functions. Despite significant progress, REPROTEN still faces ethical and technical challenges that need to be addressed. Our review underscores the importance of continued research in this field to advance the development of effective and safe REPROTEN approaches for patients with reproductive disorders.

Human lung simulants subjected to underwater explosions - An experimental investigation.

An experimental investigation was performed on human lung simulants to evaluate their response to an underwater explosive blast. The artificial lungs were instrumented with sensors to record changes in the internal pressure and strains for a specimen with and without a surrounding ribcage. The lungs were to-scale models representative of a 50th-percentile male. The experiments were performed using 65.5 mg of explosive charge placed 0.5 m from the lungs in an 8,200-liter water tank. The tank was instrumented with blast transducers and high-speed cameras to measure the pressure from the explosive charge and record the lung deformation history through high-speed images and digital image correlation. Results showed a significantly delayed response to the underwater blast due to the lungs' inertia. In addition, the lung response was indifferent to its orientation relative to the shock direction. The lungs initially contracted after the underwater shock and then expanded, showing a 50% change in relative volume, from minimum to maximum volume, over a 7 ms duration. Results and observations qualitatively relate to the types of injuries observed during preexisting case studies.

Intrinsically Disordered Synthetic Polymers in Biomedical Applications.

In biology and medicine, intrinsically disordered synthetic polymers bio-mimicking intrinsically disordered proteins, which lack stable three-dimensional structures, possess high structural/conformational flexibility. They are prone to self-organization and can be extremely useful in various biomedical applications. Among such applications, intrinsically disordered synthetic polymers can have potential usage in drug delivery, organ transplantation, artificial organ design, and immune compatibility. The designing of new syntheses and characterization mechanisms is currently required to provide the lacking intrinsically disordered synthetic polymers for biomedical applications bio-mimicked using intrinsically disordered proteins. Here, we present our strategies for designing intrinsically disordered synthetic polymers for biomedical applications based on bio-mimicking intrinsically disordered proteins.

Red Blood Cell Sublethal Damage: Hemocompatibility Is not the Absence of Hemolysis.

Blood is a complex fluid owing to its two-phase suspension of formed cellular elements within a protein-rich plasma. Vital to its role in distributing nutrients throughout the circulatory system, the mechanical properties of blood - and particularly red blood cells (RBC)-primarily determine bulk flow characteristics and microcirculatory flux. Various factors impair the physical properties of RBC, including cellular senescence, many diseases, and exposure to mechanical forces. Indeed, the latter is increasingly relevant following the advent of modern life support, such as mechanical circulatory support (MCS), which induce unique interactions between blood and artificial environments that leave blood cells with the signature of aging, albeit accelerated, and crucially underlie various serious complications, including death. Accumulating evidence indicates that these complications appear to be associated with mechanical shear forces present within MCS that are not extreme enough to overtly rupture cells, yet may still induce "sublethal" injury and "fatigue" to vital blood constituents. Impaired RBC physical properties following elevated shear exposure-a hallmark of sublethal injury to blood-are notable and may explain, at least in part, systemic complications and premature mortality associated with MCS. Design of optimal next-generation MCS devices thus requires consideration of biocompatibility and blood-device interactions to minimize potential blood complications and promote clinical success. Presented herein is a contemporary understanding of "blood damage," with emphasis on shear exposures that alter microrheological function but do not overtly destroy cells (ie, sublethal damage). Identification of key cellular factors perturbed by supraphysiological shear exposure are examined, offering potential pathways to enhance design of MCS and blood-contacting medical devices.

A review on background, process and application of electrospun nanofibers for tissue regeneration.

Electrospinning is a versatile method which is used to synthesize nano/micro sized fibers under the influence of an electric field. Electrospun nanoscaffolds are one of the widely accepted platforms for cultivating soft and hard tissues as they create a perfect micro-environment for cell adhesion, proliferation and differentiation. Nanoscaffolds are widely used in the field of tissue engineering due to their versatility in aiding the growth of different types of cells and tissues for varied applications. The composition, molecular weight and structure of polymer used to fabricate nanoscaffold plays an important role in determining the size and strength of the nanofibers prepared. This review gives information about the background, process and different types of polymers used in electrospinning. Recent advances in culturing liver cells, osteoblasts, skin cells, neural cells and coronary artery smooth muscle cells on nanoscaffolds are also elucidated.

Polymeric Membranes for Biomedical Applications.

Polymeric membranes are selective materials used in a wide range of applications that require separation processes, from water filtration and purification to industrial separations. Because of these materials' remarkable properties, namely, selectivity, membranes are also used in a wide range of biomedical applications that require separations. Considering the fact that most organs (apart from the heart and brain) have separation processes associated with the physiological function (kidneys, lungs, intestines, stomach, etc.), technological solutions have been developed to replace the function of these organs with the help of polymer membranes. This review presents the main biomedical applications of polymer membranes, such as hemodialysis (for chronic kidney disease), membrane-based artificial oxygenators (for artificial lung), artificial liver, artificial pancreas, and membranes for osseointegration and drug delivery systems based on membranes.

Current status and future directions in the development and optimization of thoracic and abdominal artificial organs.

INTRODUCTION: Artificial organs are engineered devices with the capacity to be implanted or integrated into a living body to replace a failing organ, or to duplicate or augment one or multiple functions of the diseased organ. AREAS COVERED: We evaluate the present landscape and future possibilities of artificial organ engineering by exploring the spectrum of four distinguishable device features: mobility, compatibility, functionality, and material composition. These mechanical and functional differences provide the framework through which we examine the current status and future possibilities of the abdominal and thoracic artificial organs. EXPERT OPINION: Transforming the artificial organs landscape in ways that expand the scope of existing device capabilities and improve the clinical utility of artificial organs will require making improvements upon existing technologies and multidisciplinary cooperation to create and discover new capacities.

Early-Phase Clinical Trials of Bio-Artificial Organ Technology: A Systematic Review of Ethical Issues.

Regenerative medicine has emerged as a novel alternative solution to organ failure which circumvents the issue of organ shortage. In preclinical research settings bio-artificial organs are being developed. It is anticipated that eventually it will be possible to launch first-in-human transplantation trials to test safety and efficacy in human recipients. In early-phase transplantation trials, however, research participants could be exposed to serious risks, such as toxicity, infections and tumorigenesis. So far, there is no ethical guidance for the safe and responsible design and conduct of early-phase clinical trials of bio-artificial organs. Therefore, research ethics review committees will need to look to related adjacent fields of research, including for example cell-based therapy, for guidance. In this systematic review, we examined the literature on early-phase clinical trials in these adjacent fields and undertook a thematic analysis of relevant ethical points to consider for early-phase clinical trials of transplantable bio-artificial organs. Six themes were identified: cell source, risk-benefit assessment, patient selection, trial design, informed consent, and oversight and accountability. Further empirical research is needed to provide insight in patient perspectives, as this may serve as valuable input in determining the conditions for ethically responsible and acceptable early clinical development of bio-artificial organs.

Spleen extracellular matrix provides a supportive microenvironment for ß-cell function.

Objectives: Type 1 diabetes mellitus is a common autoimmune and multifactorial disorder. Researchers have been interested in making a favorable islet-like tissue model for the treatment of diabetes. The main objective of this study was to determine the effects of the spleen extracellular matrix (S-ECM) on the function of the MIN6 cell line (a ß-cell model). Materials and Methods: In this experimental research, Wistar rat spleens were decellularized by sodium dodecyl sulfate (SDS) and Triton X-100. S-ECM was characterized by histological assessments, scanning electron microscopy, determination of residua DNA, and examination of the mechanical tensile property. Then, MIN6 cells were seeded on S-ECM scaffold. Glucose-stimulated insulin secretion and mRNA expression of insulin-related genes were examined to confirm the function of the cells. Results: The main components of S-ECM such as collagen and glycosaminoglycan remained after decellularization. Furthermore, very low residual DNA and appropriate mechanical behavior of S-ECM provided an ideal extracellular microenvironment for the MIN6 cells. GSIS results showed that the seeded cells in S-ECM secreted more insulin than the traditional two-dimensional (2D) culture. The expression of specific insulin-related genes such as PDX-1, insulin, Maf-A, and Glut-2 in the recellularized scaffold was more significant than in the 2D traditional cultured cells. Also, MTT assay results showed that S-ECM were no cytotoxic effects on the MIN6 cells. Conclusion: These results collectively have evidenced that S-ECM is a suitable scaffold for stabilizing artificial pancreatic islands.

Initial clinical validation of a hybrid in silico-in vitro cardiorespiratory simulator for comprehensive testing of mechanical circulatory support systems.

Simulators are expected to assume a prominent role in the process of design-development and testing of cardiovascular medical devices. For this purpose, simulators should capture the complexity of human cardiorespiratory physiology in a realistic way. High fidelity simulations of pathophysiology do not only allow to test the medical device itself, but also to advance practically relevant monitoring and control features while the device acts under realistic conditions. We propose a physiologically controlled cardiorespiratory simulator developed in a mixed in silico-in vitro simulation environment. As inherent to this approach, most of the physiological model complexity is implemented in silico while the in vitro system acts as an interface to connect a medical device. As case scenarios, severe heart failure was modeled, at rest and at exercise and as medical device a left ventricular assist device (LVAD) was connected to the simulator. As initial validation, the simulator output was compared against clinical data from chronic heart failure patients supported by an LVAD, that underwent different levels of exercise tests with concomitant increase in LVAD speed. Simulations were conducted reproducing the same protocol as applied in patients, in terms of exercise intensity and related LVAD speed titration. Results show that the simulator allows to capture the principal parameters of the main adaptative cardiovascular and respiratory processes within the human body occurring from rest to exercise. The simulated functional interaction with the LVAD is comparable to the one clinically observed concerning ventricular unloading, cardiac output, and pump flow. Overall, the proposed simulation system offers a high fidelity in silico-in vitro representation of the human cardiorespiratory pathophysiology. It can be used as a test bench to comprehensively analyze the performance of physically connected medical devices simulating clinically realistic, critical scenarios, thus aiding in the future the development of physiologically responding, patient-adjustable medical devices. Further validation studies will be conducted to assess the performance of the simulator in other pathophysiological conditions.

Translating Organoids into Artificial Kidneys.

Purpose of Review: Kidney disease affects more than 13% of the world population, and current treatment options are limited to dialysis and organ transplantation. The generation of kidney organoids from human-induced pluripotent stem (hiPS) cells could be harnessed to engineer artificial organs and help overcome the challenges associated with the limited supply of transplantable kidneys. The purpose of this article is to review the progress in kidney organoid generation and transplantation and highlight some existing challenges in the field. We also examined possible improvements that could help realize the potential of organoids as artificial organs or alternatives for kidney transplantation therapy. Recent Findings: Organoids are useful for understanding the mechanisms of kidney development, and they provide robust platforms for drug screening, disease modeling, and generation of tissues for organ replacement therapies. Efforts to design organoids rely on the ability of cells to self-assemble and pattern themselves into recognizable tissues. While existing protocols for generating organoids result in multicellular structures reminiscent of the developing kidney, many do not yet fully recapitulate the complex cellular composition, structure, and functions of the intact kidney. Recent advances toward achieving these goals include identifying cell culture conditions that produce organoids with improved vasculature and cell maturation and functional states. Still, additional improvements are needed to enhance tissue patterning, specialization, and function, and avoid tumorigenicity after transplantation. Summary: This report focuses on kidney organoid studies, advancements and limitations, and future directions for improvements towards transplantation.

Biomimetic materials based on zwitterionic polymers toward human-friendly medical devices.

This review summarizes recent research on the design of polymer material systems based on biomimetic concepts and reports on the medical devices that implement these systems. Biomolecules such as proteins, nucleic acids, and phospholipids, present in living organisms, play important roles in biological activities. These molecules are characterized by heterogenic nature with hydrophilicity and hydrophobicity, and a balance of positive and negative charges, which provide unique reaction fields, interfaces, and functionality. Incorporating these molecules into artificial systems is expected to advance material science considerably. This approach to material design is exceptionally practical for medical devices that are in contact with living organisms. Here, it is focused on zwitterionic polymers with intramolecularly balanced charges and introduce examples of their applications in medical devices. Their unique properties make these polymers potential surface modification materials to enhance the performance and safety of conventional medical devices. This review discusses these devices; moreover, new surface technologies have been summarized for developing human-friendly medical devices using zwitterionic polymers in the cardiovascular, cerebrovascular, orthopedic, and ophthalmology fields.