Interfacial solvation-structure regulation for stable Li metal anode by a desolvation coating technique.

Rechargeable lithium (Li) metal batteries face challenges in achieving stable cycling due to the instability of the solid electrolyte interphase (SEI). The Li-ion solvation structure and its desolvation process are crucial for the formation of a stable SEI on Li metal anodes and improving Li plating/stripping kinetics. This research introduces an interfacial desolvation coating technique to actively modulate the Li-ion solvation structure at the Li metal interface and regulate the participation of the electrolyte solvent in SEI formation. Through experimental investigations conducted using a carbonate electrolyte with limited compatibility to Li metal, the optimized desolvation coating layer, composed of 12-crown-4 ether-modified silica materials, selectively displaces strongly coordinating solvents while simultaneously enriching weakly coordinating fluorinated solvents at the Li metal/electrolyte interface. This selective desolvation and enrichment effect reduce solvent participation to SEI and thus facilitate the formation of a LiF-dominant SEI with greatly reduced organic species on the Li metal surface, as conclusively verified through various characterization techniques including XPS, quantitative NMR, operando NMR, cryo-TEM, EELS, and EDS. The interfacial desolvation coating technique enables excellent rate cycling stability (i.e., 1C) of the Li metal anode and prolonged cycling life of the Li||LiCoO2 pouch cell in the conventional carbonate electrolyte (E/C 2.6 g/Ah), with 80% capacity retention after 333 cycles.

2D Ionic Liquid-Like State of Charged Rare-Earth Clusters on a Metal Surface.

Rare-earth complexes are vital for separation chemistry and useful in many advanced applications including emission and energy upconversion. Here, 2D rare-earth clusters having net charges are formed on a metal surface, enabling investigations of their structural and electronic properties on a one-cluster-at-a-time basis using scanning tunneling microscopy. While these ionic complexes are highly mobile on the surface at ≈100 K, their mobility is greatly reduced at 5 K and reveals stable and self-limiting clusters. In each cluster, a pair of charged rare-earth complexes formed by electrostatic and dispersive interactions act as a basic unit, and the clusters are chiral. Unlike other non-ionic molecular clusters formed on the surfaces, these rare-earth clusters show mechanical stability. Moreover, their high mobility on the surface suggests that they are in a 2D liquid-like state.

A solid-state Li-air battery: computational studies of interfaces and relevance to discharge mechanism.

There is much interest in developing new energy storage systems to replace currently available ones that mainly work based on Li-ion intercalations. One attractive area is the Li-air battery for which most of the research has involved liquid electrolytes. There have been few studies on the use of a solid electrolyte in a Li-air battery. Recently, we reported the successful use of a solid-state electrolyte in a Li-air battery resulting in a Li2O product and potentially much higher energy density than in a Li-air battery based on either a Li2O2 or LiO2 product (Science, 2023, 379, 499). In this paper we discuss how the discharge mechanism involved in this solid-state Li-air battery differs from that of a Li-air battery with a liquid electrolyte. The solid-state mechanism is further explored with density functional studies of various interfaces involving the discharge product. We discuss the relevance of the results to the discharge mechanism in the solid-state Li-air battery.

Revealing the Anion-Solvent Interaction for Ultralow Temperature Lithium Metal Batteries.

Anion solvation in electrolytes can largely change the electrochemical performance of the electrolytes, yet has been rarely investigated. Herein, three anions of bis(trifluoromethanesulfonyl)imide (TFSI), bis(fluorosulfonyl)imide (FSI), and derived asymmetric (fluorosulfonyl)(trifluoro-methanesulfonyl)imide (FTFSI) are systematically examined in a weakly Li+ cation solvating solvent of bis(3-fluoropropyl)ether (BFPE). In-situ liquid secondary ion mass spectrometry demonstrates that FTFSI- and FSI- anions are associated with BFPE solvent, while weak TFSI- /BFPE cluster signals are detected. Molecular modeling further reveals that the anion-solvent interaction is accompanied by the formation of H-bonding-like interactions. Anion solvation enhances the Li+ cation transfer number and reduces the organic component in solid electrolyte interphase, which enhances the Li plating/stripping Coulombic efficiency at a low temperature of -30 °C from 42.4% in TFSI-based electrolytes to 98.7% in 1.5 m LiFTFSI and 97.9% in LiFSI-BFPE electrolytes. The anion-solvent interactions, especially asymmetric anion solvation also accelerate the Li+ desolvation kinetics. The 1.5 m LiFTFSI-BFPE electrolyte with strong anion-solvent interaction enables LiNi0.8 Mn0.1 Co0.1 O2 (NMC811)||Li (20 µm) full cell with stable cyclability even under -40 °C, retaining over 92% of initial capacity (115 mAh g-1 , after 100 cycles). The anion-solvent interactions insights allow to rational design the electrolyte for lithium metal batteries and beyond to achieve high performance.

The immunology of PF4 polyanion interactions.

PURPOSE OF REVIEW: Platelet factor 4 (PF4, CXCL4), the most abundant α-granule platelet-specific chemokine, forms tetramers with an equatorial ring of high positive charge that bind to a wide range of polyanions, after which it changes conformation to expose antigenic epitopes. Antibodies directed against PF4 not only help to clear infection but can also lead to the development of thrombotic disorders such as heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombocytopenia and thrombosis (VITT). This review will outline the different mechanisms through which PF4 engagement with polyanions combats infection but also contributes to the pathogenesis of inflammatory and thrombotic disease states. RECENT FINDINGS: Recent work has shown that PF4 binding to microbial polyanions may improve outcomes in infection by enhancing leukocyte-bacterial binding, tethering pathogens to neutrophil extracellular traps (NETs), decreasing the thrombotic potential of NET DNA, and modulating viral infectivity. However, PF4 binding to nucleic acids may enhance their recognition by innate immune receptors, leading to autoinflammation. Lastly, while HIT is induced by platelet activating antibodies that bind to PF4/polyanion complexes, VITT, which occurs in a small subset of patients treated with COVID-19 adenovirus vector vaccines, is characterized by prothrombotic antibodies that bind to PF4 alone. SUMMARY: Investigating the complex interplay of PF4 and polyanions may provide insights relevant to the treatment of infectious disease while also improving our understanding of the pathogenesis of thrombotic disorders driven by anti-PF4/polyanion and anti-PF4 antibodies.

Light- and Chemical-Doping-Induced Magnetic Behavior of Eu Molecular Systems.

Variable temperature electron paramagnetic resonance (VT-EPR) was used to investigate the role of the environment and oxidation states of several coordinated Eu compounds. We find that while Eu(III) chelating complexes are diamagnetic, simple chemical reduction results in the formation of paramagnetic species. In agreement with the distorted D3h symmetry of Eu molecular complexes investigated in this study, the EPR spectrum of reduced complexes showed axially symmetric signals (g⊥ = 2.001 and g∥ = 1.994) that were successfully simulated with two Eu isotopes with nuclear spin 5/2 (151Eu and 153Eu with 48% and 52% natural abundance, respectively) and nuclear g-factors 151Eu/153Eu = 2.27. Illumination of water-soluble complex Eu(dipic)3 at 4 K led to the ligand-to-metal charge transfer (LMCT) that resulted in the formation of Eu(II) in a rhombic environment (gx = 2.006, gy = 1.995, gz = 1.988). The existence of LMCT affects the luminescence of Eu(dipic)3, and pre-reduction of the complex to Eu(II)(dipic)3 reversibly reduces red luminescence with the appearance of a weak CT blue luminescence. Furthermore, encapsulation of a large portion of the dipic ligand with Cucurbit[7]uril, a pumpkin-shaped macrocycle, inhibited ligand-to-metal charge transfer, preventing the formation of Eu(II) upon illumination.

Advanced cell-based products generated via automated and manual manufacturing platforms under the quality by design principle: Are they equivalent or different?

Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that can be isolated from bone marrow, adipose tissue, the umbilical cord, dental pulp, etc. These cells have unique properties that give them excellent therapeutic potential, including immunoregulation, immunomodulation, and tissue regeneration functions. MSC-based products are considered advanced therapy medicinal products (ATMPs) under European regulations (1394/2007); thus, they must be manufactured under good manufacturing practices and via effective manufacturing methods. The former can be achieved via a proper laboratory design and compliance with manufacturing protocols, whereas the latter requires an approach that ensures that the quality of the products is consistent regardless of the manufacturing procedure. To meet these daunting requirements, this study proposes an exchangeable approach that combines optimized and equivalent manufacturing processes under the Quality by Design (QbD) principle, allowing investigators to convert from small laboratory-scale to large-scale manufacturing of MSC-based products for clinical applications without altering the quality and quantity of the cell-based products.

Characterization of just one atom using synchrotron X-rays.

Since the discovery of X-rays by Roentgen in 1895, its use has been ubiquitous, from medical and environmental applications to materials sciences1-5. X-ray characterization requires a large number of atoms and reducing the material quantity is a long-standing goal. Here we show that X-rays can be used to characterize the elemental and chemical state of just one atom. Using a specialized tip as a detector, X-ray-excited currents generated from an iron and a terbium atom coordinated to organic ligands are detected. The fingerprints of a single atom, the L2,3 and M4,5 absorption edge signals for iron and terbium, respectively, are clearly observed in the X-ray absorption spectra. The chemical states of these atoms are characterized by means of near-edge X-ray absorption signals, in which X-ray-excited resonance tunnelling (X-ERT) is dominant for the iron atom. The X-ray signal can be sensed only when the tip is located directly above the atom in extreme proximity, which confirms atomically localized detection in the tunnelling regime. Our work connects synchrotron X-rays with a quantum tunnelling process and opens future X-rays experiments for simultaneous characterizations of elemental and chemical properties of materials at the ultimate single-atom limit.

Microkinetic insights into the role of catalyst and water activity on the nucleation, growth, and dissolution during COF-5 synthesis.

The chemical pathway for synthesizing covalent organic frameworks (COFs) involves a complex medley of reaction sequences over a rippling energy landscape that cannot be adequately described using existing theories. Even with the development of state-of-the-art experimental and computational tools, identifying primary mechanisms of nucleation and growth of COFs remains elusive. Other than empirically, little is known about how the catalyst composition and water activity affect the kinetics of the reaction pathway. Here, for the first time, we employ time-resolved in situ Fourier transform infrared spectroscopy (FT-IR) coupled with a six-parameter microkinetic model consisting of ∼10 million reactions and over 20 000 species. The integrated approach elucidates previously unrecognized roles of catalyst pKa on COF yield and water on growth rate and size distribution. COF crystalline yield increases with decreasing pKa of the catalysts, whereas the effect of water is to reduce the growth rate of COF and broaden the size distribution. The microkinetic model reproduces the experimental data and quantitatively predicts the role of synthesis conditions such as temperature, catalyst, and precursor concentration on the nucleation and growth rates. Furthermore, the model also validates the second-order reaction mechanism of COF-5 and predicts the activation barriers for classical and non-classical growth of COF-5 crystals. The microkinetic model developed here is generalizable to different COFs and other multicomponent systems.

Energetic preference and topological constraint effects on the formation of DNA twisted toroidal bundles.

DNA toroids are compact torus-shaped bundles formed by one or multiple DNA molecules being condensed from the solution due to various condensing agents. It has been shown that the DNA toroidal bundles are twisted. However, the global conformations of DNA inside these bundles are still not well understood. In this study, we investigate this issue by solving different models for the toroidal bundles and performing replica-exchange molecular dynamics (REMD) simulations for self-attractive stiff polymers of various chain lengths. We find that a moderate degree of twisting is energetically favorable for toroidal bundles, yielding optimal configurations of lower energies than for other bundles corresponding to spool-like and constant radius of curvature arrangements. The REMD simulations show that the ground states of the stiff polymers are twisted toroidal bundles with the average twist degrees close to those predicted by the theoretical model. Constant-temperature simulations show that twisted toroidal bundles can be formed through successive processes of nucleation, growth, quick tightening, and slow tightening of the toroid, with the two last processes facilitating the polymer threading through the toroid's hole. A relatively long chain of 512 beads has an increased dynamical difficulty to access the twisted bundle states due to the polymer's topological constraint. Interestingly, we also observed significantly twisted toroidal bundles with a sharp U-shaped region in the polymer conformation. It is suggested that this U-shaped region makes the formation of twisted bundles easier by effectively reducing the polymer length. This effect can be equivalent to having multiple chains in the toroid.

A room temperature rechargeable Li2O-based lithium-air battery enabled by a solid electrolyte.

A lithium-air battery based on lithium oxide (Li2O) formation can theoretically deliver an energy density that is comparable to that of gasoline. Lithium oxide formation involves a four-electron reaction that is more difficult to achieve than the one- and two-electron reaction processes that result in lithium superoxide (LiO2) and lithium peroxide (Li2O2), respectively. By using a composite polymer electrolyte based on Li10GeP2S12 nanoparticles embedded in a modified polyethylene oxide polymer matrix, we found that Li2O is the main product in a room temperature solid-state lithium-air battery. The battery is rechargeable for 1000 cycles with a low polarization gap and can operate at high rates. The four-electron reaction is enabled by a mixed ion-electron-conducting discharge product and its interface with air.

Neutrophil extracellular trap stabilization by platelet factor 4 reduces thrombogenicity and endothelial cell injury.

Neutrophil extracellular traps (NETs) are abundant in sepsis, and proposed NET-directed therapies in sepsis prevent their formation or accelerate degradation. Yet NETs are important for microbial entrapment, as NET digestion liberates pathogens and NET degradation products (NDPs) that deleteriously promote thrombosis and endothelial cell injury. We proposed an alternative strategy of NET-stabilization with the chemokine, platelet factor 4 (PF4, CXCL4), which we have shown enhances NET-mediated microbial entrapment. We now show that NET compaction by PF4 reduces their thrombogenicity. In vitro, we quantified plasma thrombin and fibrin generation by intact or degraded NETs and cell-free (cf) DNA fragments, and found that digested NETs and short DNA fragments were more thrombogenic than intact NETs and high molecular weight genomic DNA, respectively. PF4 reduced the thrombogenicity of digested NETs and DNA by interfering, in part, with contact pathway activation. In endothelial cell culture studies, short DNA fragments promoted von Willebrand factor release and tissue factor expression via a toll-like receptor 9-dependent mechanism. PF4 blocked these effects. Cxcl4-/- mice infused with cfDNA exhibited higher plasma thrombin anti-thrombin (TAT) levels compared to wild-type controls. Following challenge with bacterial lipopolysaccharide, Cxcl4-/- mice had similar elevations in plasma TAT and cfDNA, effects prevented by PF4 infusion. Thus, NET-stabilization by PF4 prevents the release of short fragments of cfDNA, limiting the activation of the contact coagulation pathway and reducing endothelial injury. These results support our hypothesis that NET-stabilization reduces pathologic sequelae in sepsis, an observation of potential clinical benefit.

A KMnO4-Generated Colloidal Electrolyte for Redox Mediation and Anode Protection in a Li-Air Battery.

The rechargeable lithium-oxygen (Li-O2) battery has the highest theoretical specific energy density of any rechargeable batteries and could transform energy storage systems if a practical device could be attained. However, among numerous challenges, which are all interconnected, are polarization due to sluggish kinetics, low cycle life, small capacity, and slow rates. In this study, we report on use of KMnO4 to generate a colloidal electrolyte made up of MnO2 nanoparticles. The resulting electrolyte provides a redox mediator for reducing the charge potential and lithium anode protection to increase cycle life. This electrolyte in combination with a stable binary transition metal dichalcogenide alloy, Nb0.5Ta0.5S2, as the cathode enables the operation of a Li-O2 battery at a current density of 1 mA·cm-2 and specific capacity ranging from 1000 to 10 000 mA·h·g-1 (corresponding to 0.1-1 mA·h·cm-2) in a dry air environment with a cycle life of up to 150. This colloidal electrolyte provides a robust approach for advancing Li-air batteries.

Atomically precise control of rotational dynamics in charged rare-earth complexes on a metal surface.

Complexes containing rare-earth ions attract great attention for their technological applications ranging from spintronic devices to quantum information science. While charged rare-earth coordination complexes are ubiquitous in solution, they are challenging to form on materials surfaces that would allow investigations for potential solid-state applications. Here we report formation and atomically precise manipulation of rare-earth complexes on a gold surface. Although they are composed of multiple units held together by electrostatic interactions, the entire complex rotates as a single unit when electrical energy is supplied from a scanning tunneling microscope tip. Despite the hexagonal symmetry of the gold surface, a counterion at the side of the complex guides precise three-fold rotations and 100% control of their rotational directions is achieved using a negative electric field from the scanning probe tip. This work demonstrates that counterions can be used to control dynamics of rare-earth complexes on materials surfaces for quantum and nanomechanical applications.

Left ventricular size and function in patients with systemic lupus erythematosus associate with lupus anticoagulant: An echocardiographic follow-up study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with increased risk of cardiac dysfunction. The pathophysiological mechanisms are poorly understood, and prognostic markers are warranted. PURPOSE: We aimed to identify SLE-characteristics associated with measures of cardiac size and function during a five-year follow-up. METHODS: We included 108 patients with SLE: 90% females, mean age 46 ± 13 years, median disease duration 14 (range 7-21) years. We performed blood sampling for potential biomarkers as well as a standard echocardiography at baseline and at a 5-year follow-up. To investigate associations with baseline and prospective 5-year changes in echocardiographic parameters, we performed multivariate regression analyses of SLE-related baseline variables (clinical disease activity, lupus nephritis, chronic kidney disease, anti-cardiolipin and/or anti-beta-2 glycoprotein I antibodies, and lupus anticoagulant (LAC)) and adjusted for traditional risk factors. RESULTS: During follow-up, diastolic function regressed in two out of five echocardiographic measures (E/A ratio 1.4 ± 0.5 vs. 1.3 ± 0.5, p = 0.002; tricuspid regurgitation peak velocity 2.0 ± 0.6 vs. 2.2 ± 0.4 mmHg, p < 0.001). Left ventricular (LV) end-diastolic volume index increased (43.7 ± 13.9 vs. 52.5 ± 15.7 mL/m2, p < 0.001). Left and right ventricular systolic function remained stationary. LAC was associated with inferior diastolic function: lower E/A ratio (p = 0.04) and higher E/e' ratio at baseline (p = 0.04) and increased left ventricular atrial volume index during follow-up (p = 0.01). LAC was further associated with LV dilatation during follow-up (p = 0.01). CONCLUSION: Presence of LAC was associated with measures of diastolic function as well as progressive LV dilatation during the 5-year follow-up. Thus, LAC might be a predictor of cardiac dysfunction in SLE patients. LAC is known to have implications for the microvascular circulation, but the clinical significance of the present findings is yet to be elucidated.

Stem cell-based therapy for human diseases.

Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.

Irreversible alteration of extracellular vesicle and cell-free messenger RNA profiles in human plasma associated with blood processing and storage.

The discovery and utility of clinically relevant circulating biomarkers depend on standardized methods that minimize preanalytical errors. Despite growing interest in studying extracellular vesicles (EVs) and cell-free messenger RNA (cf-mRNA) as potential biomarkers, how blood processing and freeze/thaw impacts the profiles of these analytes in plasma was not thoroughly understood. We utilized flow cytometric analysis to examine the effect of differential centrifugation and a freeze/thaw cycle on EV profiles. Utilizing flow cytometry postacquisition analysis software (FCMpass) to calibrate light scattering and fluorescence, we revealed how differential centrifugation and post-freeze/thaw processing removes and retains EV subpopulations. Additionally, cf-mRNA levels measured by RT-qPCR profiles from a panel of housekeeping, platelet, and tissue-specific genes were preferentially affected by differential centrifugation and post-freeze/thaw processing. Critically, freezing plasma containing residual platelets yielded irreversible ex vivo generation of EV subpopulations and cf-mRNA transcripts, which were not removable by additional processing after freeze/thaw. Our findings suggest the importance of minimizing confounding variation attributed to plasma processing and platelet contamination.

Synthesis of Fluorine-Doped Lithium Argyrodite Solid Electrolytes for Solid-State Lithium Metal Batteries.

Solid-state lithium metal batteries (SSLMBs) that utilize novel solid electrolytes (SEs) have garnered much attention because of their potential to yield safe and high-energy-density batteries. Sulfide-based argyrodite-class SEs are an attractive option because of their impressive ionic conductivity. Recent studies have shown that LiF at the interface between Li and SE enhances electrochemical stability. However, the synthesis of F-doped argyrodites has remained challenging because of the high temperatures used in the state-of-the-art solid-state synthesis methods. In this work, for the first time, we report F-doped Li5+yPS5Fy argyrodites with a tunable doping content and dual dopants (F-/Cl- and F-/Br-) that were synthesized through a solvent-based approach. Among all compositions, Li6PS5F0.5Cl0.5 exhibits the highest Li-ion conductivity of 3.5 × 10-4 S cm-1 at room temperature (RT). Furthermore, Li symmetric cells using Li6PS5F0.5Cl0.5 show the best cycling performance among the tested cells. X-ray photoelectron spectroscopy and ab initio molecular dynamics simulations revealed that the enhanced interfacial stability of Li6PS5F0.5Cl0.5 SE against Li metal can be attributed to the formation of a stable solid electrolyte interphase (SEI)-containing conductive species (Li3P), alongside LiCl and LiF. These findings open new opportunities to develop high-performance SSLMBs using a novel class of F-doped argyrodite electrolytes.

Nanostructured Conductive Metal Organic Frameworks for Sustainable Low Charge Overpotentials in Li-Air Batteries.

Lithium-oxygen batteries are among the most attractive alternatives for future electrified transportation. However, their practical application is hindered by many obstacles. Due to the insulating nature of Li2 O2 product and the slow kinetics of reactions, attaining sustainable low charge overpotentials at high rates becomes a challenge resulting in the battery's early failure and low round trip efficiency. Herein, outstanding characteristics are discovered of a conductive metal organic framework (c-MOF) that promotes the growth of nanocrystalline Li2 O2 with amorphous regions. This provides a platform for the continuous growth of Li2 O2 units away from framework, enabling a fast discharge at high current rates. Moreover, the Li2 O2 structure works in synergy with the redox mediator (RM). The conductivity of the amorphous regions of the Li2 O2 allows the RM to act directly on the Li2 O2 surface instead of catalyst edges and then transport through the electrolyte to the Li2 O2 surface. This direct charge transfer enables a small charge potential of <3.7 V under high current densities (1-2 A g-1 ) sustained for a long cycle life (100-300 cycles) for large capacities (1000-2000 mAh g-1 ). These results open a new direction for utilizing c-MOFs towards advanced energy storage systems.

Clinical Study of Mesenchymal Stem/Stromal Cell Therapy for the Treatment of Frailty: A Proposed Experimental Design for Therapeutic and Mechanistic Investigation.

Frailty, a specific condition of increased vulnerability and reduced general health associated with aging in older people, is an emerging problem worldwide with major implications for clinical practice and public health. Recent preclinical and clinical studies have supported the safety of mesenchymal stem/stromal cells (MSCs) in the treatment of frailty. Comprehensive study is needed to assess the interrelationship between the condition of frailty and the effects of MSC-based therapy. This randomized controlled phase I/II trial aims to investigate the safety and potential therapeutic efficacy of the allogeneic administration of umbilical cord-derived MSCs (UC-MSCs) in combination with the standard treatment for frailty in Vietnam. Moreover, this study describes the rationales, study designs, methodologies, and analytical strategies currently employed in stem cell research and clinical studies. The primary outcome measures will include the incidences of prespecified administration-associated adverse events and serious adverse events. The potential efficacy will be evaluated based on improvements in frailty conditions (including those determined through a physical examination, patient-reported outcomes, quality of life, immune markers of frailty, metabolism analysis, and cytokine markers from patient plasma). This clinical trial and stem cell analysis associated with patient sampling at different time points aim to identify and characterize the potential effects of UC-MSCs on improving frailty based on the stem cell quality, cytokine/growth factor secretion profiles of UC-MSCs, cellular senescence, and metabolic analysis of patient CD3+ cells providing fundamental knowledge for designing and implementing research strategies in future studies. Clinical Trials Registration Number: NCT04919135.