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1.
Water Res ; 217: 118300, 2022 Jun 15.
Article in English | MEDLINE | ID: mdl-35397369

ABSTRACT

Fouling of microfiltration (MF)) membranes during water/wastewater treatment is predominantly caused by colloidal particles (size <1 µm) in the feed water. Until recently no online technology was available to directly measure the occurrence of colloidal particles in these waters. This study evaluated the viability of a novel online light scattering technology (Nanoparticle Tracking Analysis) to continuously monitor colloidal particles in the membrane feed water (a secondary-treated wastewater) for targeted removal by injecting coagulant at a dosage proportional to the measured concentration of colloidal particles. A diurnal variation was observed in the colloidal particle concentration in the feed water with the lowest concentration occurring at approximately 6 am and the highest concentration occurring after mid-day. The peak colloidal particle concentrations were 4 to 6 times higher than the lowest concentrations measured on the same day. Bench-scale studies were performed to develop a relationship between colloidal particle concentration and the optimum coagulant dosage required for their removal. Subsequently, a pilot-scale study was performed using two MF pilot units operated in parallel, one receiving targeted coagulant dosing and the other with no coagulant dosing, to demonstrate the effectiveness of targeted coagulant dosing in preventing membrane fouling. The pilot unit that received targeted coagulant dose experienced only 4 to 20% of the transmembrane pressure increase of the increase experienced by the pilot unit that received no coagulant. Evaluation of fouling resistance indicated that targeted coagulation improved flux by predominantly lowering the irreversible fouling. The filtrate water quality measured by colloidal particle concentration, chemical oxygen demand (COD), and turbidity were very similar for the two pilot units. This suggests that although the efficiency of particle and organic materials removal does not change with coagulant addition, the particles filtered by the membrane in the control unit contributed to membrane irreversible fouling, while in the coagulant-treated unit, the coagulated colloidal particles were removed away from the membrane into the backwash stream during the frequent backwash/air scour procedures.


Subject(s)
Drinking Water , Water Purification , Membranes, Artificial , Ultrafiltration/methods , Wastewater , Water Purification/methods , Water Quality
2.
J Mol Med (Berl) ; 99(5): 663-671, 2021 05.
Article in English | MEDLINE | ID: mdl-33398468

ABSTRACT

Mesenchymal stem cells (MSCs) are promising candidates for the development of cell-based drug delivery systems for autoimmune inflammatory diseases, such as multiple sclerosis (MS). Here, we investigated the effect of Ro-31-8425, an ATP-competitive kinase inhibitor, on the therapeutic properties of MSCs. Upon a simple pretreatment procedure, MSCs spontaneously took up and then gradually released significant amounts of Ro-31-8425. Ro-31-8425 (free or released by MSCs) suppressed the proliferation of CD4+ T cells in vitro following polyclonal and antigen-specific stimulation. Systemic administration of Ro-31-8425-loaded MSCs ameliorated the clinical course of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, displaying a stronger suppressive effect on EAE than control MSCs or free Ro-31-8425. Ro-31-8425-MSC administration resulted in sustained levels of Ro-31-8425 in the serum of EAE mice, modulating immune cell trafficking and the autoimmune response during EAE. Collectively, these results identify MSC-based drug delivery as a potential therapeutic strategy for the treatment of autoimmune diseases. KEY MESSAGES: MSCs can spontaneously take up the ATP-competitive kinase inhibitor Ro-31-8425. Ro-31-8425-loaded MSCs gradually release Ro-31-8425 and exhibit sustained suppression of T cells. Ro-31-8425-loaded MSCs have more sustained serum levels of Ro-31-8425 than free Ro-31-8425. Ro-31-8425-loaded MSCs are more effective than MSCs and free Ro-31-8425 for EAE therapy.


Subject(s)
Drug Delivery Systems/methods , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Enzyme Inhibitors/administration & dosage , Indoles/administration & dosage , Maleimides/administration & dosage , Mesenchymal Stem Cells/drug effects , Multiple Sclerosis/drug therapy , Transplantation, Heterologous/methods , Animals , Cell Proliferation/drug effects , Drug Liberation , Encephalomyelitis, Autoimmune, Experimental/blood , Encephalomyelitis, Autoimmune, Experimental/immunology , Enzyme Inhibitors/blood , Female , Humans , Immunity/drug effects , Indoles/blood , Maleimides/blood , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Multiple Sclerosis/blood , Multiple Sclerosis/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Tissue Distribution , Treatment Outcome
3.
Cell Mol Bioeng ; 10(5): 501-513, 2017 Oct.
Article in English | MEDLINE | ID: mdl-31719873

ABSTRACT

INTRODUCTION: Notch signaling is amongst the key intrinsic mechanisms regulating satellite cell fate, promoting the transition of activated satellite cells to highly proliferative myogenic progenitor cells and preventing their premature differentiation. Although much is known about the biochemical milieu that drives myogenic progression, less is known about the spatial cues providing spatiotemporal control of skeletal muscle repair in the context of Notch signaling. METHODS: Using a murine injury model, we quantified in vivo biophysical changes that occur within the skeletal muscle during regeneration. Employing tunable poly(ethylene glycol)-based hydrogel substrates, we modeled the measured changes in bulk stiffness in the context of Notch ligand signaling, which are present in the regenerative milieu at the time of injury. RESULTS: Following injury, there is a transient increase in the bulk stiffness of the tibialis anterior muscle that may be explained in part by changes in extracellular matrix deposition. When presented to primary myoblasts, Jagged-1, Jagged-2, and Dll1 in a tethered format elicited greater degrees of Notch activity compared to their soluble form. Only tethered Jagged-1 effects were tuned by substrate stiffness, with the greatest Notch activation observed on stiff hydrogels matching the stiffness of regenerating muscle. When exposed to tethered Jagged-1 on stiff hydrogels, fewer primary myoblasts expressed myogenin, and pharmacological inhibitor studies suggest this effect is Notch and RhoA dependent. CONCLUSION: Our study proposes that tethered Jagged-1 presented in the context of transient tissue stiffening serves to tune Notch activity in myogenic progenitors during skeletal muscle repair and delay differentiation.

4.
Biomaterials ; 91: 140-150, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27019026

ABSTRACT

Despite considerable advances in prostate cancer research, there is a major need for a systemic delivery platform that efficiently targets anti-cancer drugs to sites of disseminated prostate cancer while minimizing host toxicity. In this proof-of-principle study, human mesenchymal stem cells (MSCs) were loaded with poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) that encapsulate the macromolecule G114, a thapsigargin-based prostate specific antigen (PSA)-activated prodrug. G114-particles (∼950 nm in size) were internalized by MSCs, followed by the release of G114 as an intact prodrug from loaded cells. Moreover, G114 released from G114 MP-loaded MSCs selectively induced death of the PSA-secreting PCa cell line, LNCaP. Finally, G114 MP-loaded MSCs inhibited tumor growth when used in proof-of-concept co-inoculation studies with CWR22 PCa xenografts, suggesting that cell-based delivery of G114 did not compromise the potency of this pro-drug in-vitro or in-vivo. This study demonstrates a potentially promising approach to assemble a cell-based drug delivery platform, which inhibits cancer growth in-vivo without the need of genetic engineering. We envision that upon achieving efficient homing of systemically infused MSCs to cancer sites, this MSC-based platform may be developed into an effective, systemic 'Trojan Horse' therapy for targeted delivery of therapeutic agents to sites of metastatic PCa.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Delivery Systems/methods , Mesenchymal Stem Cell Transplantation , Prodrugs/administration & dosage , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cells, Cultured , Humans , Lactic Acid/chemistry , Male , Mesenchymal Stem Cells/cytology , Mice, Nude , Polyglycolic Acid/chemistry , Polylactic Acid-Polyglycolic Acid Copolymer , Prodrugs/therapeutic use , Prostate/drug effects , Prostate/metabolism , Prostate/pathology , Prostate-Specific Antigen/metabolism , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology
5.
Cell Stem Cell ; 18(1): 25-38, 2016 Jan 07.
Article in English | MEDLINE | ID: mdl-26748754

ABSTRACT

Organoid systems leverage the self-organizing properties of stem cells to create diverse multi-cellular tissue proxies. Most organoid models only represent single or partial components of a tissue, and it is often difficult to control the cell type, organization, and cell-cell/cell-matrix interactions within these systems. Herein, we discuss basic approaches to generate stem cell-based organoids, their advantages and limitations, and how bioengineering strategies can be used to steer the cell composition and their 3D organization within organoids to further enhance their utility in research and therapies.


Subject(s)
Cell Culture Techniques , Organoids/cytology , Stem Cells/cytology , Animals , Brain/metabolism , Cell Communication , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Intestinal Mucosa/metabolism , Microfluidics , Organogenesis , Regeneration , Tissue Engineering/methods
6.
Cell Rep ; 10(8): 1261-1268, 2015 Mar 03.
Article in English | MEDLINE | ID: mdl-25732817

ABSTRACT

Poor homing of systemically infused cells to disease sites may limit the success of exogenous cell-based therapy. In this study, we screened 9,000 signal-transduction modulators to identify hits that increase mesenchymal stromal cell (MSC) surface expression of homing ligands that bind to intercellular adhesion molecule 1 (ICAM-1), such as CD11a. Pretreatment of MSCs with Ro-31-8425, an identified hit from this screen, increased MSC firm adhesion to an ICAM-1-coated substrate in vitro and enabled targeted delivery of systemically administered MSCs to inflamed sites in vivo in a CD11a- (and other ICAM-1-binding domains)-dependent manner. This resulted in a heightened anti-inflammatory response. This represents a new strategy for engineering cell homing to enhance therapeutic efficacy and validates CD11a and ICAM-1 as potential targets. Altogether, this multi-step screening process may significantly improve clinical outcomes of cell-based therapies.


Subject(s)
Mesenchymal Stem Cells/cytology , Small Molecule Libraries/chemistry , Animals , CD11a Antigen/genetics , CD11a Antigen/metabolism , Cell Adhesion/drug effects , Cell Line , Cell Movement , High-Throughput Screening Assays , Humans , Indoles/chemistry , Indoles/pharmacology , Inflammation/chemically induced , Inflammation/pathology , Inflammation/therapy , Intercellular Adhesion Molecule-1/chemistry , Intercellular Adhesion Molecule-1/metabolism , Lipopolysaccharides/toxicity , Maleimides/chemistry , Maleimides/pharmacology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Mice , Mice, Inbred C57BL , Microscopy, Confocal , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Up-Regulation
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