The separation membranes in artificial organs

Separation membranes play a crucial role in the functioning of artificial organs, such as hemodialysis machines, membrane oxygenators, and artificial liver models. The current COVID-19 pandemic has highlighted the importance of these technologies in the medical community. However, membrane technology in artificial organs faces significant challenges, such as the clearance of low-middle-molecule and protein-bound toxins and limited blood compatibility. In this review, we will discuss the separation mechanisms, separation performance, and biocompatibility of different types of separation membranes used in artificial organs. We will also highlight the opportunities and challenges for next-generation membrane technology in this field, including the need for improved clearance of toxins and increased blood compatibility, as well as the potential for microfluidic devices.

LONG-TERM SUPER HIGH-FLUX HEMODIALYSIS (OR EXPANDED HEMODIALYSIS;HDx) DOES NOT ALTER NUTRITION STATUS WITH THE SIGNIFICANTLY REDUCED MIDDLE-MOLECULE AND PROTEIN-BOUND UREMIC TOXINS IN HEMODIALYSIS PATIENTS

Introduction: Super high-flux hemodialysis (SHF-HD) provides comparable effectiveness in terms of middle-molecule and protein-bound uremic toxin removal to online hemodiafiltration in prevalent end-stage kidney disease (ESKD). However, dialysate albumin loss is raised awareness of the long-term using SHF-HD. The study aims to monitor the long-term use of SHF-HD in nutritional status change and the sustained effect of uremic toxin removal. Method(s): The present study was prospectively conducted on the 15 prevalent ESKD patients from a run-in period of standard high-flux hemodialysis (HF-HD) with ELISIO-H21 dialyzer for 4 weeks to thereafter 15 months follow-up with SHF-HD. The patients provided high-efficiency (high blood flow and dialysate flow rate) SHF-HD using PES17D alpha dialyzers for the first three months. After the amendment protocol, SHF-HD was run with the same type of dialyzer;ELISIO-17Hx (Nipro Corporation, Osaka, Japan) due to the COVID-19 pandemic. Nutritional parameters, BCM;body composition monitor (FMC, Bad Homburg, Germany), and uremic toxins were measured at baseline and every three months during SHF-HD. Result(s): Fourteen of 15 patients could complete the study. One patient was early terminated due to undergoing kidney transplantation. After 15 months of SHF-HD treatment compared to HF-HD at baseline, there was not a statistically significant change in clinical and laboratory parameters on nutritional status. The mean serum albumin levels were 4.09 (1.36) versus 4.01 (0.3) g/dL, respectively (p=0.52), and the mean difference (SE) of normalized protein catabolic rate (nPCR) was -0.04 (0.08), 95% confidence interval [CI] -0.19, 0.11. On the other hand, lean tissue mass (LTM) was significantly decreased, and fat mass was significantly increased (mean difference (SE) of -3.66 (1.07) gram, 95% CI -5.76, -1.55, and 1.79 (0.80), 95% CI 0.21, 3.36). SHF-HD sustainably and significantly removed medium to large middle-molecule uremic toxins including pre-dialysis beta-2 microglobulin, kappa-free light chain, and lambda-free light chain. In addition, protein-bound uremic toxin;indoxyl sulfate was significantly reduced during long-term follow-up using SHF-HD. SHF-HD with PES17D alpha dialyzer resulted in more dialysate albumin leaks than a newer type of SHF-HD with ELISIO-Hx17. Conclusion(s): Long-term use of SHF-HD in ESKD patients was associated with nutritional safety and effectiveness in middle-molecule and protein-bound uremic toxin removal. Although serum albumin and BMI were not changed. LTM was significantly reduced with lower levels of nPCR than in other studies but trended to increase over time. The LTM absolute levels are not below the 10 percentiles of the healthy reference range. Increasing protein intake to reach the current recommendation and physical activity was advised with long-term use of SHF-HD to avoid further reduce LTM. [Formula presented] [Formula presented] [Formula presented] No conflict of interestCopyright © 2023

Evolutions of extracorporeal membrane oxygenator (ECMO): perspectives for advanced hollow fiber membrane.

Hollow fiber membrane is incorporated into an extracorporeal membrane oxygenator (ECMO), and the function of the membrane determines the ECMO's functions, such as gas transfer rate, biocompatibility, and durability. In Japan, the membrane oxygenator to assist circulation and ventilation is approved for ECMO support. However, in all cases, the maximum use period has been only 6 h, and so-called 'off-label use' is common for ECMO support of severely ill COVID-19 patients. Under these circumstances, the HLS SET Advanced (Getinge Group Japan K.K.) was approved in 2020 for the first time in Japan as a membrane oxygenator with a two-week period of use. Following this membrane oxygenator, it is necessary to establish a domestic ECMO system that is approved for long-term use and suitable for supporting patients. Looking back on the evolution of ECMO so far, Japanese researchers and manufacturers have also contributed to the developments of ECMO globally. Currently, excellent membrane oxygenators and systems have been marketed by Japanese manufacturers and some of them are globally acclaimed, but in fact, most of the ECMO membranes are not made in Japan. Fortunately, Japan has led the world in the fields of membrane separation technology and hollow fiber membrane production. In the wake of this pandemic, from the perspective of medical and economic security, the practical use of purely domestic hollow fiber membranes and membrane oxygenators for long-term ECMO is imperative in anticipation of the next pandemic.

Why Molnupiravir Fails in Hospitalized Patients.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has radically altered daily life. Effective antiviral therapies to combat COVID-19, especially severe disease, remain scarce. Molnupiravir is an antiviral that has shown clinical efficacy against mild-to-moderate COVID-19 but failed to provide benefit to hospitalized patients with severe disease. Here, we explained the mechanism behind the failure of molnupiravir in hospitalized patients and identified alternative dosing strategies that would improve therapeutic outcomes in all patients with COVID-19. We showed that delaying therapy initiation markedly decreased the antiviral effect of molnupiravir, and these results were directly related to intracellular drug triphosphate pools and intracellular viral burden at the start of therapy. The adverse influence of therapeutic delay could be overcome by increasing drug exposure, which increased intracellular molnupiravir triphosphate concentrations that inhibited viral replication. These findings illustrated that molnupiravir must be administered as early as possible following COVID-19 symptom onset to maximize therapeutic efficacy. Higher doses may be effective in patients hospitalized with severe disease, but the safety of high-dose molnupiravir regimens is unknown. Our findings could be extended to design effective regimens with nucleoside analogs for other RNA viruses, especially those with pandemic potential. IMPORTANCE In this study, we showed that early intervention with molnupiravir resulted in a greater antiviral effect, and we explained the mechanism behind this phenomenon. Our results predicted and explained the failure of molnupiravir in hospitalized patients and highlighted the utility of preclinical pharmacodynamic studies to design optimal antiviral regimens for the treatment of viral diseases. This contrasts with the procedure that was implemented early in the pandemic in which clinical studies were conducted in the absence of preclinical experimentation. These findings are significant and demonstrated the importance of experimental approaches in antiviral development for treatments against COVID-19 as well as other viral diseases.

Minimal recovery of drug from extracorporeal treatment in a case of phenytoin toxicity associated with coma and hypothermia

Background: The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup provides a weak conditional recommendation in support of hemodialysis (HD) for select patients with severe phenytoin poisoning. Despite this recommendation, the HD clearance of phenytoin is poorly studied. We present a patient who developed phenytoin toxicity that was treated with hemodialysis and report on the efficacy of phenytoin removal during HD. Case report: An 87-year-old man with epilepsy who was maintained on a stable dose of 300mg phenytoin extended-release daily was admitted to the hospital for treatment of Coronavirus Disease 2019 and congestive heart failure. On hospital day 14, the patient had a gradual onset of depressed mental status with hypothermia (nadir 35 degrees Celsius). At this time, he had a rising total blood phenytoin concentration (peak 49.3 mcg/mL [therapeutic 10-20mcg/mL] with an albumin of 3.8 g/dL [normal 3.4-5.4 g/dL]). The patient's other medications included furosemide, aspirin, atorvastatin, digoxin, doxycycline, metoprolol tartrate, and warfarin;he was also receiving albumin and crystalloid for hypovolemia (albumin nadir on hospital day 14: 2.5 g/dL). Free phenytoin concentrations were not available. Alternate etiologies of hypothermia (endocrine, infectious) were excluded. The Poison Control Center was consulted and recommended HD because of the concern for prolonged coma, as per EXTRIP guidelines. The patient received three sessions of HD over a period of 6 days at 2.5-3 h per session using an F160 Optiflux membrane filter (Fresenius Medical Care, Waltham, MA, USA), with a blood flow rate of 350mL/min and a dialysate flow rate of 700mL/min. After the first session of HD (2.5 h) on hospital day 21, his hypothermia resolved and his phenytoin concentration fell from 39.2mcg/mL to 34.2 mcg/mL with only mild improvement in his mental status. After 6 days (hospital day 27), his phenytoin concentration decreased to 19.5 mcg/mL and his mental status normalized. Effluent from the first HD session had phenytoin concentrations below the limit of detection (0.50mcg/mL). Thus, no greater than 52mg of phenytoin was removed during a 2.5-h session of hemodialysis. Discussion(s): The reason for the sudden increase in blood phenytoin concentrations in this patient is unclear in the absence of drug-drug interactions or dosing changes to the phenytoin. Although uncommonly reported, patients with phenytoin toxicity can experience hypothermia. In this case, the patient's hypothermia resolved during HD, although it is unclear if this was related to changes in phenytoin concentration or (more likely) direct extracorporeal warming via the HD machine. If the patient's phenytoin clearance from the first session were extrapolated to subsequent sessions an estimated maximum of 166.4mg of phenytoin would be removed in 8 total hours of HD, which is far less than previously reported phenytoin clearances on the order of grams. This difference may be related to the use of high cutoff dialysis membranes in prior studies, which are not routinely used. Conclusion(s): Although HD rapidly resolved this patient's hypothermia, a minimal amount of phenytoin was recovered in the patient's dialysate. Prior studies suggesting consequential clearance and efficacy of phenytoin removal by extracorporeal treatment may not apply to routine HD methods. Further studies on the utility of extracorporeal treatment for phenytoin toxicity are needed.

IN VITRO TO IN VIVO: COMBATING MULTIDRUG-RESISTANT ENTEROBACTERIACAE IN THE AGE OF COVID-19

SESSION TITLE: COVID-19 Co-Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: The COVID-19 pandemic has highlighted the emergence of multidrug-resistant bacterial pathogens. Here we present a case of the successful treatment of a COVID-19 superinfection with Citrobacter freundii, which produced both a Klebsiella pneumoniae carbapenemase (KPC) as well as a New Delhi Metallo-Beta-Lactamase (NDM-1). CASE PRESENTATION: A 53-year-old male without significant past medical history was admitted to the intensive care unit for acute hypoxemic respiratory failure due to COVID-19 pneumonia. His hospital course was complicated by progressive hypoxia requiring intubation and mechanical ventilation. Due to persistent fevers and increased respiratory secretions, he was placed on empiric antibiotic therapy including vancomycin, cefepime, and briefly meropenem. Blood cultures were periodically drawn and ultimately demonstrated no growth. However, a respiratory culture via bronchoalveolar lavage was positive for multidrug-resistant Citrobacter freundii. Susceptibilities showed high level of resistance to meropenem, Imipenem, Ceftazidime-Avibactam as well as Aztreonam. Molecular testing confirmed the presence of both KPC and NDM-1 β-lactamases. The patient was treated with a combination of Aztreonam 2g plus Ceftazidime-Avibactam 2.5g IV every eight hours via simultaneous infusion for fourteen days, resulting in clinical improvement and discharge to a rehabilitation facility. DISCUSSION: The emergence of carbapenem-resistant enterobacteria has been identified as a major clinical problem. The high rates and high mortality of carbapenem-resistant enterobacteria complicating the course of COVID patients during the pandemic highlighted the importance of this issue. Among the Enterobacteriaceae, β-lactam resistance is primarily caused by enzymatic degradation by β-lactamases. Two carbapenemase subclasses are especially problematic: KPC and NDM-1. Horizontal gene transfer and clonal expansion have enabled KPC and NDM-1 to spread worldwide. However, coexistence of these two resistant mechanisms within the same pathogen has rarely been reported. Recently, high stability, non-inferior fitness, and transferability among patients of KPC-2-NDM-1-CRKPs have been documented, raising further concerns about the risk for further spread and increasing rates [1]. Therapeutic options are limited. We used a combination of Ceftazidime/Avibactam plus Aztreonam for treatment, based on limited in vitro studies demonstrating a synergistic effect and superior clearance rather than either antibiotic alone or administered in sequence [2,3]. CONCLUSIONS: Superinfections with carbapenem-resistant enterobacteria have increased in the context of the COVID-19 pandemic and are likely to become more prevalent in our hospitals. Prompt recognition and appropriate therapeutic selection are paramount for treating these highly resistant organisms. Reference #1: Gao H, Liu Y, Wang R, Wang Q, Jin L, Wang H. The transferability and evolution of NDM-1 and KPC-2 co-producing Klebsiella pneumoniae from clinical settings. EBioMedicine. 2020 Jan;51:102599. doi: 10.1016/j.ebiom.2019.102599. Epub 2020 Jan 3. PMID: 31911273;PMCID: PMC6948161. Reference #2: Marshall S, Hujer AM, Rojas LJ, Papp-Wallace KM, Humphries RM, Spellberg B, Hujer KM, Marshall EK, Rudin SD, Perez F, Wilson BM, Wasserman RB, Chikowski L, Paterson DL, Vila AJ, van Duin D, Kreiswirth BN, Chambers HF, Fowler VG Jr, Jacobs MR, Pulse ME, Weiss WJ, Bonomo RA. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae? Antimicrob Agents Chemother. 2017 Mar 24;61(4):e02243-16. doi: 10.1128/AAC.02243-16. PMID: 28167541;PMCID: PMC5365724. Reference #3: Lodise TP, Smith NM, O'Donnell N, et al. Determining the optimal dosing of a novel combination regimen of ceftazidime/avibactam with aztreonam against NDM-1-producing Enterobacteriaceae using a hollow-fibre infection model. J Antimicrob Chemother 202 ;75(9): 2622-32 DISCLOSURES: No relevant relationships by wisam daoud No relevant relationships by Christopher Walker No relevant relationships by Amanda Westbrook No relevant relationships by Nicola Zetola

Polypropylene Hollow Fiber Membrane by Dissolution-Inducing Pore Methods.

Plasma leakage limits the development of polypropylene membranes as oxygenated membranes. Here, a new method named the dissolution-induced pore method was adapted to prepare polypropylene hollow fiber membranes: after polypropylene and polyvinyl chloride were melt-blended and extruded, the polyvinyl chloride was removed by N, N-dimethylacetamide to obtain a porous polypropylene membrane material. The variation of membranes has been explored in detail with respect to the influence of different parameters on the flux and mechanical properties of membranes and the feasibility of the polyvinyl chloride recovery. The resulting polypropylene hollow fiber membrane shows that plasma penetration was zero within 6 h of test, gas flux can reach 189,000 L/(m2·h·0.1 MPa), and its strength at break reaches 65 MPa and the elongation at break is 890%; polyvinyl chloride recovery achieves more than 99%. This research has developed a promising and low-cost extracorporeal membrane oxygenation material, which provides benefits for patients with less capacity for medical expenditure.

Evaluation of a downstream process for the recovery and concentration of a Cell-Culture-Derived rVSV-Spike COVID-19 vaccine candidate.

rVSV-Spike (rVSV-S) is a recombinant viral vaccine candidate under development to control the COVID-19 pandemic and is currently in phase II clinical trials. rVSV-S induces neutralizing antibodies and protects against SARS-CoV-2 infection in animal models. Bringing rVSV-S to clinical trials required the development of a scalable downstream process for the production of rVSV-S that can meet regulatory guidelines. The objective of this study was the development of the first downstream unit operations for cell-culture-derived rVSV-S, namely, the removal of nucleic acid contamination, the clarification and concentration of viral harvested supernatant, and buffer exchange. Retaining the infectivity of the rVSV-S during the downstream process was challenged by the shear sensitivity of the enveloped rVSV-S and its membrane protruding spike protein. Through a series of screening experiments, we evaluated and established the required endonuclease treatment conditions, filter train composition, and hollow fiber-tangential flow filtration parameters to remove large particles, reduce the load of impurities, and concentrate and exchange the buffer while retaining rVSV-S infectivity. The combined effect of the first unit operations on viral recovery and the removal of critical impurities was examined during scale-up experiments. Overall, approximately 40% of viral recovery was obtained and the regulatory requirements of less than 10 ng host cell DNA per dose were met. However, while 86-97% of the host cell proteins were removed, the regulatory acceptable HCP levels were not achieved, requiring subsequent purification and polishing steps. The results we obtained during the scale-up experiments were similar to those obtained during the screening experiments, indicating the scalability of the process. The findings of this study set the foundation for the development of a complete downstream manufacturing process, requiring subsequent purification and polishing unit operations for clinical preparations of rVSV-S.

Modification strategies to improve the membrane hemocompatibility in extracorporeal membrane oxygenator (ECMO).

ABSTRACT: Since extracorporeal membrane oxygenator (ECMO) has been utilized to save countless lives by providing continuous extracorporeal breathing and circulation to patients with severe cardiopulmonary failure. In particular, it has played an important role during the COVID-19 epidemic. One of the important composites of ECMO is membrane oxygenator, and the core composite of the membrane oxygenator is hollow fiber membrane, which is not only a place for blood oxygenation, but also is a barrier between the blood and gas side. However, the formation of blood clots in the oxygenator is a key problem in the using process. According to the study of the mechanism of thrombosis generation, it was found that improving the hemocompatibility is an efficient approach to reduce thrombus formation by modifying the surface of materials. In this review, the corresponding modification methods (surface property regulation, anticoagulant grafting, and bio-interface design) of hollow fiber membranes in ECMO are classified and discussed, and then, the research status and development prospects are summarized.

Transforming waste polypropylene face masks into S-doped porous carbon as the cathode electrode for supercapacitors.

The spread of COVID-19 has led to an explosive increase in the number of waste polypropylene face masks worldwide, landfill and incineration of which will cause serious pollution and resource waste. This study aims to develop a new method for the safe and high-added value reuse of materials for polypropylene face masks based on carbonization of porous polymer. The waste masks were first sulfonated in an autoclave, then used as carbon source and turned into a dense hollow fiber porous structure after a one-step heat treatment. This porous structure has a high specific capacitance, namely 328.9 F g-1 at a current density of 1 A g-1. Besides, the assembled solid-state capacitor possesses a good energy density of 10.4 W h kg-1 at a power density of 600 W kg-1, and excellent cycling stability with a capacitance retention rate of 81.1% after 3000 cycles. These findings indicate that the novel carbonization technology in this study can not only be used to obtain high-performance supercapacitor electrode materials but also provide a new idea for the recycling and utilization of wastes such as medical devices.

Development of a large volume concentration method for recovery of coronavirus from wastewater.

Levels of severe acute respiratory coronavirus type 2 (SARS CoV 2) RNA in wastewater could act as an effective means to monitor coronavirus disease 2019 (COVID-19) within communities. However, current methods used to detect SARS CoV 2 RNA in wastewater are limited in their ability to process sufficient volumes of source material, inhibiting our ability to assess viral load. Typically, viruses are concentrated from large liquid volumes using two stage concentration, primary and secondary. Here, we evaluated a dead-end hollow fiber ultrafilter (D-HFUF) for primary concentration, followed by the CP Select™ for secondary concentration from 2 L volumes of primary treated wastewater. Various amendments to each concentration procedure were investigated to optimally recover seeded OC43 (betacoronavirus) from wastewater. During primary concentration, the D-HFUF recovered 69 ± 18% (n = 29) of spiked OC43 from 2 L of wastewater. For secondary concentration, the CP Select™ system using the Wastewater Application settings was capable of processing 100 mL volumes of primary filter eluates in <25 min. A hand-driven syringe elution proved to be significantly superior (p = 0.0299) to the CP Select™ elution for recovering OC43 from filter eluates, 48 ± 2% compared to 31 ± 3%, respectively. For the complete method (primary and secondary concentration combined), the D-HFUF and CP select/syringe elution achieved overall 22 ± 4% recovery of spiked OC43 through (n = 8) replicate filters. Given the lack of available standardized methodology confounded by the inherent limitations of relying on viral RNA for wastewater surveillance of SARS CoV 2, it is important to acknowledge these challenges when interpreting this data to estimate community infection rates. However, the development of methods that can substantially increase sample volumes will likely allow for reporting of quantifiable viral data for wastewater surveillance, equipping public health officials with information necessary to better estimate community infection rates.

Stable dechlorination of Trichloroacetic Acid (TCAA) to acetic acid catalyzed by palladium nanoparticles deposited on H2-transfer membranes.

Trichloroacetic acid (TCAA) is a common disinfection byproduct (DBP) produced during chlorine disinfection. With the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic, the use of chlorine disinfection has increased, raising the already substantial risks of DBP exposure. While a number of methods are able to remove TCAA, their application for continuous treatment is limited due to their complexity and expensive or hazardous inputs. We investigated a novel system that employs palladium (Pd0) nanoparticles (PdNPs) for catalytic reductive dechlorination of TCAA. H2 was delivered directly to PdNPs in situ coated on the surface of bubble-free hollow-fiber gas-transfer membranes. The H2-based membrane Pd film reactor (H2-MPfR) achieved a high catalyst-specific TCAA reduction rate, 32 L/g-Pd/min, a value similar to the rate of using homogeneously suspended PdNP, but orders of magnitude higher than with other immobilized PdNP systems. In batch tests, over 99% removal of 1 mM TCAA was achieved in 180 min with strong product selectivity (≥ 93%) to acetic acid. During 50 days of continuous operation, over 99% of 1 mg/L influent TCAA was removed, again with acetic acid as the major product (≥ 94%). We identified the reaction pathways and their kinetics for TCAA reductive dechlorination with PdNPs using direct delivery of H2. Sustained continuous TCAA removal, high selectivity to acetic acid, and minimal loss of PdNPs support that the H2-MPfR is a promising catalytic reactor to remove chlorinated DBPs in practice.

Newly Developed Pediatric Membrane Oxygenator that Suppresses Excessive Pressure Drop in Cardiopulmonary Bypass and Extracorporeal Membrane Oxygenation (ECMO).

This article developes a pediatric membrane oxygenator that is compact, high performance, and highly safe. This novel experimental approach, which imaging the inside of a membrane oxygenator during fluid perfusion using high-power X-ray CT, identifies air and blood retention in the local part of a membrane oxygenator. The cause of excessive pressure drop in a membrane oxygenator, which has been the most serious dysfunction in cardiovascular surgery and extracorporeal membrane oxygenation (ECMO), is the local retention of blood and air inside the oxygenator. Our designed blood flow channel for a membrane oxygenator has a circular channel and minimizes the boundary between laminated parts. The pressure drop in the blood flow channel is reduced, and the maximum gas transfer rates are increased by using this pediatric membrane oxygenator, as compared with the conventional oxygenator. Furthermore, it would be possible to reduce the incidents, which have occurred clinically, due to excessive pressure drop in the blood flow channel of the membrane oxygenator. The membrane oxygenator is said to be the "last stronghold" for patients with COVID-19 receiving ECMO treatment. Accordingly, the specification of our prototype is promising for low weight and pediatric patients.