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Therapeutic encapsulated mesenchymal stromal cells

a technology of mesenchymal stromal cells and therapeutic encapsulation, which is applied in the direction of skeletal/connective tissue cells, drug compositions, embryonic cells, etc., can solve the problems of msc tissue persistence, potential msc differentiation and/or msc migration away from the injury site, and is difficult to resolve, control and quantify. , to achieve the effect of reducing the inflammatory aspects of trauma-mediated tissue damage, promoting tissue repair,

Inactive Publication Date: 2017-04-13
RUTGERS THE STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

This patent describes a method of generating large amounts of neural cells from stem cells using a permeable microcapsule system. The method can be used for both clinical treatment and drug discovery. The microcapsules can also reduce inflammation and promote tissue repair by inducing a macrophage phenotype that promotes tissue remodeling and reducing the production of pro-inflammatory factors. Overall, this patent provides a scalable and promising approach for generating various neural cell types and has potential applications in the field of neurological disease research and treatment.

Problems solved by technology

Although studies have indicated that the microenvironment as well as the developmental status of MSCs can alter neural stem cell inductive signals (Croft, A. P. and Przyborski, S. A., Exp. Neurol., 216, 329-341 (2009)), MSC tissue persistence, potential MSC differentiation and / or MSC migration away from the injury site are very complex and present dynamic problems, which are difficult to resolve, control and quantify.
In particular, several drawbacks in current MSC implantation approaches limit safe and controlled clinical trial implementation.
These include, 1) directly transplanted MSCs exposed to the complex injury environment may be adversely affected early in the treatment process, 2) MSCs may migrate to undesired tissue locations, and 3) MSCs may differentiate into undesired end stage cells.
These issues severely limit the development of controlled feasibility studies and ultimately translatability of MSC treatments into clinical settings.
Moreover, although studies have established techniques to successfully differentiate stem cells into different mature cell lineages using growth factors or extracellular matrix protein supplementation in both two and three-dimensional configurations, their practicality is limited by lack of control and low yields of differentiated cells.

Method used

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  • Therapeutic encapsulated mesenchymal stromal cells
  • Therapeutic encapsulated mesenchymal stromal cells
  • Therapeutic encapsulated mesenchymal stromal cells

Examples

Experimental program
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Effect test

example 1

ES Cell Culture

[0133]All cell cultures were incubated in a humidified 37° C., 5% CO2 environment. The ES cell line D3 (ATCC, Manassas, Va.) was maintained in an undifferentiated state in T-75 gelatin-coated flasks (Biocoat, BD-Biosciences, Bedford, Mass.) in Knockout Dulbecco's modified Eagles medium (Gibco, Grand Island, N.Y.) containing 15% knockout serum (Gibco), 4 mM L-glutamine (Gibco), 100 U / ml penicillin (Gibco), 100 U / ml streptomycin (Gibco), 10 mg / ml gentamicin (Gibco), 1,000 U / ml ESGRO™ (Chemicon, Temecula, Calif.) and 0.1 mM 2-mercaptoethanol (Sigma-Aldrich, St. Louis, Mo.). Media was changed every two days until plates were confluent. ES cultures were split and passaged every 6 days. Following media aspiration, cells were washed with 10 mL of phosphate buffered solution (PBS) (Gibco), detached using 3 mL of trypsin EDTA (Gibco) for 3 minutes, and subsequently 12 mL of Knockout DMEM was added. Cells were then replated in gelatin-coated T-75 flasks at a density of 1 millio...

example 2

Alginate Encapsulation

[0134]Alginate solution was prepared by dissolving 2.2 g of alginic acid sodium salt (MW: 100,000-200,000 g / mol, G Content: 65%-70%, Sigma-Aldrich) in 100 mL of Ca2+ free DMEM (Gibco), using a heated magnetic stir plate at a temperature of 65° C. The solution was then filtered using a 45 μm syringe filter (Fisher Scientific, Pittsburg, Pa.). To create the cell-alginate mixture, 1 mL aliquot of cell suspension with a seeding density of 5×107 cells / mL was added to 9 mL of either 1.2%, 1.7%, 2.2% or 2.5% (w / v) alginate solution to yield a final cell seeding density of 5×106 cells / mL. This solution was transferred to a 10 mL syringe, and was connected to a syringe pump (KD Scientific, Mass.). Alginate beads were generated using an electrostatic bead generator (Nisco, Zurich, Switzerland) at a flow rate of 40 mL / h, and an applied voltage of 6.4 kV. The beads were extruded into a 200 mL bath of CaCl2 (100 mM), containing 145 mM NaCl, and 10 mM MOPS (all from Sigma-Al...

example 3

Assessment of Cell Proliferation and Neural Specific Protein Expressions

[0135]Under an optimized encapsulation condition (i.e. 2.2% w / v alginate and 5×106 cells / mL), experiments were designed to assess cell proliferation and the expression of an array of neural special markers during a 20-day differentiation period. Encapsulated cells were cultured in the presence or absence of RA, recovered on days 4, 8, 12, 16 and 20 post encapsulation by depolymerizating the alginate microcapsules, and cell number and viability were determined. As indicated in FIG. 1, encapsulated cell numbers in the presence or absence of retinoic acid were similar. The cell proliferation in both conditions exhibited biphasic kinetic properties, and the cultures ultimately reached a final density 2.5 times greater than the initial seeding density. Cell viability was greater than 95% in both conditions and throughout the culture period.

[0136]To assess the effect of RA on lineage commitment within the alginate mic...

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Abstract

This application discloses a micro-encapsulation system for immobilizing mesenchymal stromal cells (MSCs) while sustaining the molecular communication. Thus, the invention provides the use of encapsulated mesenchymal stromal cells in the cellular transplantation therapies. Moreover, the invention provides methods for delivery of encapsulated MSCs into the central nervous system and therapies derived therefrom, such as, the treatment of spinal cord injury (SCI) and other inflammatory conditions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 13 / 151,912 filed on Jun. 2, 2011, which claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. Nos. 61 / 350,760, filed on Jun. 2, 2010, and 61 / 354,998, filed on Jun. 15, 2010, which are both hereby incorporated by reference in their entirety for all purposes.FIELD OF THE INVENTION[0002]The present invention relates to alginate microencapsulation-mediated differentiation of stem cells and use of the stem cell differentiation method for the development of effective treatment of various diseases or disorders. The invention also relates to a micro-encapsulation system for immobilizing stem cells, methods for delivery of encapsulated stem cells into the central nervous system, and use of the encapsulated stem cells as cellular transplantation therapies.BACKGROUND OF THE INVENTION[0003]Unlike adult differentiated tissue cells, pluripotent stem cells, suc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/28A61K9/48A61K35/12
CPCA61K9/4816A61K35/28A61K2035/122A61K2035/128A61P25/00C12N5/0606C12N5/0618C12N5/0663C12N11/10C12N2501/58C12N2506/02C12N2533/74A61K35/545A61K47/36A61K2035/124C12N5/0622C12N2501/60
Inventor GRUMET, MARTINYARMUSH, MARTIN L.SCHLOSS, RENE S.BARMINKO, JEFFREY
Owner RUTGERS THE STATE UNIV
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