Quality by Design in continuous bioprocessing: Investigating the impact of critical process parameters of multi-column chromatography during steady-state and transient phases.

Given the complexities of continuous bioprocessing, it is critical to thoroughly investigate the process parameters unique to multi-column chromatography (MCC) and their potential impacts. However, existing studies have focused on either loading densities or residence time at steady states only, and their combined impact on critical quality attributes (CQAs) especially during transient phases were less known. In this study, we investigated the impact of critical process parameters during both steady-state and transient phases (start-up, close-down, and intermediate perturbation) through full factorial design.

Biomass specific perfusion rate as a control lever for the continuous manufacturing of biosimilar monoclonal antibodies from CHO cell cultures.

Continuous manufacturing enables high volumetric productivities of biologics such as monoclonal antibodies. However, it is challenging to maintain both high viable cell densities and productivities at the same time for long culture durations. One of the key controls in a perfusion process is the perfusion rate which determines the nutrient availability and potentially controls the cell metabolism.

Nanocomplexes of Biodegradable Anticancer Macromolecules: Prolonged Plasma Half-Life, Reduced Toxicity, and Increased Tumor Targeting.

Anticancer drug resistance is a large contributing factor to the global mortality rate of cancer patients. Anticancer macromolecules such as polymers have been recently reported to overcome this issue. Anticancer macromolecules have unselective toxicity because they are highly positively charged.

Drug-free neutrally charged polypeptide nanoparticles as anticancer agents.

Cationic synthetic anticancer polymers and peptides have attracted increasing attention for advancing cancer treatment without causing drug resistance development. To circumvent in vivo instability and toxicity caused by cationic charges of the anticancer polymers/peptides, we report, for the first time, a nanoparticulate delivery system self-assembled from a negatively charged pH-sensitive polypeptide poly(ethylene glycol)-b-poly(ʟ-lysine)-graft-cyclohexene-1,2-dicarboxylic anhydride and a cationic anticancer polypeptide guanidinium-functionalized poly(ʟ-lysine) (PLL-Gua) via electrostatic interaction. The formation of nanoparticles (Gua-NPs) neutralized the positive charges of PLL-Gua.

Potent Antiviral and Antimicrobial Polymers as Safe and Effective Disinfectants for the Prevention of Infections.

Disinfection using effective antimicrobials is essential in preventing the spread of infectious diseases. This COVID-19 pandemic has brought the need for effective disinfectants to greater attention due to the fast transmission of SARS-CoV-2. Current active ingredients in disinfectants are small molecules that microorganisms can develop resistance against after repeated long-term use and may penetrate the skin, causing harmful side-effects.

Combination of guanidinium and quaternary ammonium polymers with distinctive antimicrobial mechanisms achieving a synergistic antimicrobial effect.

The increasing emergence and spread of antimicrobial resistance are urgent and important global challenges today. The clinical pipeline is lacking in innovative drugs that avoid the development of drug resistance. Macromolecular antimicrobials kill bacteria and fungi through physical disruptions to the cell membrane, which is difficult for microbes to overcome.

Surface tethering of stromal cell-derived factor-1α carriers to stem cells enhances cell homing to ischemic muscle.

Mesenchymal stem cells are promising medicine for treating diseases and tissue defects because of their innate ability to secrete therapeutic factors. Intravenous delivery of stem cells, although favored for its minimal invasiveness, is often plagued by low cellular engraftment in the target tissue. To this end, this study hypothesizes that in situ activation of cellular expression of CXC chemokine 4 (CXCR4) would significantly improve cellular migration to injured tissue.

Surface Tethering of Inflammation-Modulatory Nanostimulators to Stem Cells for Ischemic Muscle Repair.

Stem cell transplantation has been a promising treatment for peripheral arterial diseases in the past decade. Stem cells act as living bioreactors of paracrine factors that orchestrate tissue regeneration. Prestimulated adipose-derived stem cells (ADSCs) have been proposed as potential candidates but have been met with challenges in activating their secretory activities for clinical use.

Degradable antimicrobial polycarbonates with unexpected activity and selectivity for treating multidrug-resistant Klebsiella pneumoniae lung infection in mice.

Multidrug resistant (MDR) Klebsiella pneumoniae is a major cause of healthcare-associated infections around the world, with attendant high rates of morbidity and mortality. Progressive reduction in potency of antibiotics capable of treating MDR K. pneumoniae infections - including lung infection - as a consequence of escalating drug resistance provides the motivation to develop drug candidates targeting MDR K.

Pericyte transplantation improves skeletal muscle recovery following hindlimb immobilization.

Conditions of extended bed rest and limb immobilization can initiate rapid and significant loss of skeletal muscle mass and function. Physical rehabilitation is standard practice following a period of disuse, yet mobility may be severely compromised, and recovery is commonly delayed or incomplete in special populations. Thus, a novel approach toward recovery of muscle mass is highly desired.

Stimulus-Responsive Anti-Oxidizing Drug Crystals and their Ecological Implication.

Various antioxidants are being used to neutralize the harmful effects of reactive oxygen species (ROS) overproduced in diseased tissues and contaminated environments. Polymer-directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through molecular dissolution. However, most recrystallized antioxidants undertake continuous dissolution independent of the ROS level, thus causing side-effects.

Surface tethering of stem cells with HO-responsive anti-oxidizing colloidal particles for protection against oxidation-induced death.

Mesenchymal stem cells are the new generation of medicine for treating numerous vascular diseases and tissue defects because of their ability to secrete therapeutic factors. Poor cellular survival in an oxidative diseased tissue, however, hinders the therapeutic efficacy. To this end, we hypothesized that tethering the surface of stem cells with colloidal particles capable of discharging antioxidant cargos in response to elevated levels of hydrogen peroxide (HO) would maintain survival and therapeutic activity of the stem cells.

Pore Diameter of Mesoporous Silica Modulates Oxidation of HO-Sensing Chromophore in a Porous Matrix.

Hydrogen peroxide (HO) is an attractive chemical because of its bleaching properties in paper and pulp industry and as a disinfectant in the food, water, and medical industries. However, it is important to monitor the residual HO level after its usage and prevent any unintended health problems or chemical reactions. Most HO sensors often utilize fluorophores or electrical circuitry that requires an additional irradiation or a digital display.

Diatom Microbubbler for Active Biofilm Removal in Confined Spaces.

Bacterial biofilms form on and within many living tissues, medical devices, and engineered materials, threatening human health and sustainability. Removing biofilms remains a grand challenge despite tremendous efforts made so far, particularly when they are formed in confined spaces. One primary cause is the limited transport of antibacterial agents into extracellular polymeric substances (EPS) of the biofilm.

Disease-directed design of biodegradable polymers: Reactive oxygen species and pH-responsive micellar nanoparticles for anticancer drug delivery.

Herein, we report reactive oxygen species (ROS)- and pH-responsive biodegradable polyethylene glycol (PEG)-block-polycarbonate by installing thioether groups onto the polycarbonate and its self-assembled core/shell structured micelles for anticancer drug delivery. Oxidation of thioethers to sulfoxide and subsequently sulfone induces an increase in hydrophilicity, resulting in more hydrophilic micellar core. This phase-change caused the micelles to swell and enhance cargo release.

Engineering Polymersomes for Diagnostics and Therapy.

Engineered polymer vesicles, termed as polymersomes, confer a flexibility to control their structure, properties, and functionality. Self-assembly of amphiphilic copolymers leads to vesicles consisting of a hydrophobic bilayer membrane and hydrophilic core, each of which is loaded with a wide array of small and large molecules of interests. As such, polymersomes are increasingly being studied as carriers of imaging probes and therapeutic drugs.

Active Antioxidizing Particles for On-Demand Pressure-Driven Molecular Release.

Overproduced reactive oxygen species (ROS) are closely related to various health problems including inflammation, infection, and cancer. Abnormally high ROS levels can cause serious oxidative damage to biomolecules, cells, and tissues. A series of nano- or microsized particles has been developed to reduce the oxidative stress level by delivering antioxidant drugs.

Enzyme-Induced Matrix Softening Regulates Hepatocarcinoma Cancer Cell Phenotypes.

The progression of cancer is often accompanied by changes in the mechanical properties of an extracellular matrix. However, limited efforts have been made to reproduce these biological events in vitro. To this end, this study demonstrates that matrix remodeling caused by matrix metalloproteinase (MMP)-1 regulates phenotypic activities and modulates radiosensitivity of cancer cells exclusively in a 3D matrix.

Chemical and mechanical modulation of polymeric micelle assembly.

Recently, polymeric micelles self-assembled from amphiphilic polymers have been studied for various industrial and biomedical applications. This nanoparticle self-assembly typically occurs in a solvent-exchange process. In this process, the quality of the resulting particles is uncontrollably mediated by polymeric solubility and mixing conditions.

Ultrafast Killing and Self-Gelling Antimicrobial Imidazolium Oligomers.

Infectious diseases and the increasing threat of worldwide pandemics have underscored the importance of antibiotics and hygiene. Intensive efforts have been devoted to developing new antibiotics to meet the rapidly growing demand. In particular, advancing the knowledge of the structure-property-activity relationship is critical to expedite the design and development of novel antimicrobial with the needed potential and efficacy.

Combined modality doxorubicin-based chemotherapy and chitosan-mediated p53 gene therapy using double-walled microspheres for treatment of human hepatocellular carcinoma.

The therapeutic efficiency of combined chemotherapy and gene therapy on human hepatocellular carcinoma HepG2 cells was investigated using double-walled microspheres that consisted of a poly(D,L-lactic-co-glycolic acid) (PLGA) core surrounded by a poly(L-lactic acid) (PLLA) shell layer and fabricated via the precision particle fabrication (PPF) technique. Here, double-walled microspheres were used to deliver doxorubicin (Dox) and/or chitosan-DNA nanoparticles containing the gene encoding the p53 tumor suppressor protein (chi-p53), loaded in the core and shell phases, respectively. Preliminary studies on chi-DNA nanoparticles were performed to optimize gene transfer to HepG2 cells.