Toward microfluidic continuous-flow and intelligent downstream processing of biopharmaceuticals.

Biopharmaceuticals have emerged as powerful therapeutic agents, revolutionizing the treatment landscape for various diseases, including cancer, infectious diseases, autoimmune and genetic disorders. These biotherapeutics pave the way for precision medicine with their unique and targeted capabilities. The production of high-quality biologics entails intricate manufacturing processes, including cell culture, fermentation, purification, and formulation, necessitating specialized facilities and expertise. These complex processes are subject to rigorous regulatory oversight to evaluate the safety, efficacy, and quality of biotherapeutics prior to clinical approval. Consequently, these drugs undergo extensive purification unit operations to achieve high purity by effectively removing impurities and contaminants. The field of personalized precision medicine necessitates the development of novel and highly efficient technologies. Microfluidic technology addresses unmet needs by enabling precise and compact separation, allowing rapid, integrated and continuous purification modules. Moreover, the integration of intelligent biomanufacturing systems with miniaturized devices presents an opportunity to significantly enhance the robustness of complex downstream processing of biopharmaceuticals, with the benefits of automation and advanced control. This allows seamless data exchange, real-time monitoring, and synchronization of purification steps, leading to improved process efficiency, data management, and decision-making. Integrating autonomous systems into biopharmaceutical purification ensures adherence to regulatory standards, such as good manufacturing practice (GMP), positioning the industry to effectively address emerging market demands for personalized precision nano-medicines. This perspective review will emphasize on the significance, challenges, and prospects associated with the adoption of continuous, integrated, and intelligent methodologies in small-scale downstream processing for various types of biologics. By utilizing microfluidic technology and intelligent systems, purification processes can be enhanced for increased efficiency, cost-effectiveness, and regulatory compliance, shaping the future of biopharmaceutical production and enabling the development of personalized and targeted therapies.

Ultrafast Flow Synthesis of o-Functionalized Benzenesulfonyl Fluorides and Subsequent SuFEx Connections via Lithiated Chemistry.

Herein we present a flow-based, rapid, and straightforward approach to synthesize diverse functionalized sulfonyl fluorides by harnessing an aryllithium intermediate. The aryllithium intermediate was fully utilized under optimized conditions (0.016 s, -18 °C) to afford various functionalized sulfonyl fluorides and also intramolecular SuFEx cyclization products in high yields (27-94%). Furthermore, the integrated synthesis incorporating subsequent SuFEx connections with even unstable organolithium nucleophiles facilitated one-flow molecular assembly in high yields (42-72%).

Preparation of Waste PP/Fly Ash/Waste Stone Powder Composites and Evaluation of Their Mechanical Properties.

The research was carried out to analyze the combined and mechanical properties of polypropylene (PP)/fly ash (FA)/waste stone powder (WSP) composite materials. PP, FA and WSP were mixed and prepared into PP100 (pure PP), PP90 (90 wt% PP + 5 wt% FA + 5 wt% WSP), PP80 (80 wt% PP + 10 wt% FA + 10 wt% WSP), PP70 (70 wt% PP + 15 wt% FA + 15 wt% WSP), PP60 (60 wt% PP + 20 wt% FA + 20 wt% WSP) and PP50 (50 wt% PP + 25 wt% FA + 25 wt% WSP) composite materials using an injection molding machine. The research results indicate that all PP/FA/WSP composite materials can be prepared through the injection molding process and there are no cracks or fractures found on the surface of the composite materials. The research results of thermogravimetric analysis are consistent with expectations, indicating that the preparation method of the composite materials in this study is reliable. Although the addition of FA and WSP powder cannot increase the tensile strength, it is very helpful to improve the bending strength and notched impact energy. Especially for notched impact energy, the addition of FA and WSP results in an increase in the notched impact energy of all PP/FA/WSP composite materials by 14.58-22.22%. This study provides a new direction for the reuse of various waste resources. Moreover, based on the excellent bending strength and notched impact energy, the PP/FA/WSP composite materials have great application potential in the composite plastic industry, artificial stone, floor tiles and other industries in the future.

Scalable Subsecond Synthesis of Drug Scaffolds via Aryllithium Intermediates by Numbered-up 3D-Printed Metal Microreactors.

Continuous-flow microreactors enable ultrafast chemistry; however, their small capacity restricts industrial-level productivity of pharmaceutical compounds. In this work, scale-up subsecond synthesis of drug scaffolds was achieved via a 16 numbered-up printed metal microreactor (16N-PMR) assembly to render high productivity up to 20 g for 10 min operation. Initially, ultrafast synthetic chemistry of unstable lithiated intermediates in the halogen-lithium exchange reactions of three aryl halides and subsequent reactions with diverse electrophiles were carried out using a single microreactor (SMR). Larger production of the ultrafast synthesis was achieved by devising a monolithic module of 4 numbered-up 3D-printed metal microreactor (4N-PMR) that was integrated by laminating four SMRs and four bifurcation flow distributors in a compact manner. Eventually, the 16N-PMR system for the scalable subsecond synthesis of three drug scaffolds was assembled by stacking four monolithic modules of 4N-PMRs.

A numbering-up metal microreactor for the high-throughput production of a commercial drug by copper catalysis.

Microreactors are emerging as an efficient, sustainable synthetic tool compared to conventional batch reactors. Here, we present a new numbering-up metal microreactor by integrating a flow distributor and a copper catalytic module for high productivity of a commercial synthetic drug. A flow distributor and an embedded baffle disc were manufactured by CNC machining and 3D printing of stainless steel (S/S), respectively, whereas a catalytic reaction module was composed of 25 copper coiled capillaries configured in parallel. Eventually, the numbering-up microreactor system assembled with functional modules showed uniform flow distribution and high mixing efficiency regardless of clogging, and achieved high-throughput synthesis of the drug "rufinamide", an anticonvulsant medicine, via a Cu(i)-catalyzed azide-alkyne cycloaddition reaction under optimized conditions.

Thermally Cross-Linkable Styrene-Based Host Materials for Solution-Processed Organic Light-Emitting Diodes.

Thermally cross-linkable host materials, DV-TPACZ, DV-TPADBCZ, and TV-TPBI, were designed and synthesized for solution-processed organic light-emitting diodes (OLEDs). The synthesized styrene-functionalized host materials were thermally cross-linked by curing at 150-200 °C without using a polymerization initiator. Excellent solvent resistance was observed for all cured host films. They exhibited low highest occupied molecular orbital energy levels of 5.4-5.7 eV, which indicated a low hole injection barrier from the hole transport layer to the emissive layer. A solution-processed red phosphorescent OLED with 5 wt% (MPHMQ)2Ir (tmd) dopant in the thermally cross-linkable DV-TPACZ host exhibited a current efficiency of 5.3 cd/A, power efficiency of 3.2 lm/W, and external quantum efficiency of 3.6%.

Determinants of Functional Outcomes Using Clinical Pathways for Rehabilitation After Hip Fracture Surgery.

BACKGROUND: This study evaluated functional outcomes using newly established clinical pathways after hip fracture surgery in older adults and analyzed the major determinants of successful functional outcomes in rehabilitation programs using standardized clinical pathways. METHODS: This was a retrospective cohort study performed in a tertiary rehabilitation facility. A total of 220 patients who had received unilateral hip fracture surgery were followed up from immediately after surgery to 6 months postoperatively. Clinical pathways for rehabilitation included early, individualized rehabilitation, education for activities of daily living, review of general medical conditions, and arrangement of discharge settings. One rehabilitation specialist consecutively checked ambulatory function using 3-level grading, and patients were classified into good recovery and poor recovery groups based on ambulatory function at 6 months postoperatively. Logistic regression analysis was performed using 7 representative variables (age, sex, bone mineral density, Mini-Mental Status Examination [MMSE], Berg Balance Scale [BBS], premorbid ambulatory function, and length of hospital stay). RESULTS: A total of 86.8% of patients could walk with or without assistance at 6 months after surgery and 75.5% of patients involved in the rehabilitation program were classified into the good recovery group in this study. the good recovery group showed higher mmse and bbs scores compared with the poor recovery group. the factors in the model most strongly correlated with recovery were mmse and bbs. CONCLUSION: This study showed that a well-designed rehabilitation program could improve ambulatory function in older patients after hip fracture surgery and that cognitive impairment and poor balance control may inhibit the recovery of ambulatory function.

Length of Hospital Stay After Stroke: A Korean Nationwide Study.

OBJECTIVE: To investigate the length of hospital stay (LOS) after stroke using the database of the Korean Health Insurance Review & Assessment Service. METHODS: We matched the data of patients admitted for ischemic stroke onset within 7 days in the Departments of Neurology of 12 hospitals to the data from the database of the Korean Health Insurance Review & Assessment Service. We recruited 3,839 patients who were hospitalized between January 2011 and December 2011, had a previous modified Rankin Scale of 0, and no acute hospital readmission after discharge. The patients were divided according to the initial National Institute of Health Stroke Scale score (mild, ≤5; moderate, >5 and ≤13; severe, >13); we compared the number of hospitals that admitted patients and LOS after stroke according to severity, age, and sex. RESULTS: The mean LOS was 115.6±219.0 days (median, 19.4 days) and the mean number of hospitals was 3.3±2.1 (median, 2.0). LOS was longer in patients with severe stroke (mild, 65.1±146.7 days; moderate, 223.1±286.0 days; and severe, 313.2±336.8 days). The number of admitting hospitals was greater for severe stroke (mild, 2.9±1.7; moderate, 4.3±2.6; and severe, 4.5±2.4). LOS was longer in women and shorter in patients less than 65 years of age. CONCLUSION: LOS after stroke differed according to the stroke severity, sex, and age. These results will be useful in determining the appropriate LOS after stroke in the Korean medical system.

Curcumin sensitizes human lung cancer cells to apoptosis and metastasis synergistically combined with carboplatin.

Although carboplatin is one of the standard chemotherapeutic agents for non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance. Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether curcumin can chemosensitize lung cancer cells to carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of curcumin and carboplatin alone and in combination. Combined treatment with curcumin and carboplatin inhibited tumor cell growth, migration, and invasion compared with either drug alone. Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone. mRNA and protein expression of caspase-3 and caspase-9 and proapoptotic genes was increased in cells treated with a combination of curcumin and carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of curcumin combined with carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism, curcumin has potential as a chemosensitizer for carboplatin in the treatment of patients with NSCLC.

A preliminary investigation of early smoking initiation and nicotine dependence in Korean adults.

BACKGROUND: Few studies have investigated the association between age at smoking initiation and Fagerström test for nicotine dependence (FTND) in adulthood. The goal of this study was to develop the Korean version of FTND (FTND-K) and to examine the relationship between age at smoking initiation and nicotine dependence. METHODS: This investigation used data from 268 current smokers who visited the Center for Cancer Prevention and Early Detection in the National Cancer Center, Korea. The internal consistency of the FTND-K was assessed by Cronbach's coefficient alpha. Pearson's correlation coefficients were used to assess the relationships between the FTND-K sum scores and urinary cotinine levels. One-way analysis of variance (ANOVA) and t-tests were used to assess differences in the FTND-K sum score between groups. Factor associated with nicotine dependence were identified through stepwise multiple logistic regression analysis. RESULTS: The standardized Cronbach's alpha of FTND-K was 0.72. A significant positive correlation was seen between the FTND-K sum score and urinary cotinine level (correlation coefficient = 0.49, P < 0.05). Age at smoking initiation had a significant association with the FTND-K sum score in univariate analysis. In multivariate analysis, nicotine dependence was higher in smokers that started smoking cigarettes at 19 years or earlier than in those that started at 25 years or later (OR = 11.25, 95% CIs, 1.46-97.10). CONCLUSIONS: The FTND-K is a valid assessment tool of nicotine dependence with acceptable levels of internal consistency and close correlation to urinary cotinine level. The finding that those who initiate smoking at an early age tend to be more nicotine dependent underscores and reinforces the public health significance of delaying smoking onset.