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Tissue-Engineered Endothelial and Epithelial Implants Differentially and Synergistically Regulate Tissue Repair

a tissue engineering and epithelial technology, applied in the field of tissue engineering endothelial and epithelial implants differentially and synergistically regulate tissue repair, can solve the problems of tight association between functional imbalance and airway structure remodeling, limited current treatment options for airway disorders and other tubular structures, and often adverse effects, so as to reduce or inhibit abnormal or pathological tissue remodeling typified

Inactive Publication Date: 2013-03-14
MASSACHUSETTS INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a therapeutic composition that can reduce or prevent abnormal tissue remodeling in tubular structures such as airways. The composition includes cells and a biocompatible matrix that can reduce narrowing of the airway, epithelial damage, and other pathological conditions such as inflammation and fibrosis. The cells can also enhance the repair of damaged epithelial cells and reduce the growth of fibroblasts. The composition can be autogenic, allogenic, or xenogenic. Overall, the invention provides a promising therapy for treating injuries to tubular structures that can help improve breathing and alleviate symptoms associated with airway obstruction.

Problems solved by technology

In airway disorders—such as asthma and chronic obstructive pulmonary disease (COPD)—functional imbalance is tightly associated with remodeling of airway structure.
Current treatments for airway disorders and disorders of other tubular structures are limited and often have adverse consequences.

Method used

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  • Tissue-Engineered Endothelial and Epithelial Implants Differentially and Synergistically Regulate Tissue Repair
  • Tissue-Engineered Endothelial and Epithelial Implants Differentially and Synergistically Regulate Tissue Repair
  • Tissue-Engineered Endothelial and Epithelial Implants Differentially and Synergistically Regulate Tissue Repair

Examples

Experimental program
Comparison scheme
Effect test

example 1

Endothelial and Epithelial Cell Implants Differentially Regulate Airway Repair

[0094]In the present study, an in vivo airway injury model was employed to understand whether injury and repair of the airway is mediated by the first line sensor—the airway epithelium—or by the endothelial cells of the perfusing vasculature. Tissue engineered implants of the bronchial epithelium and endothelium promoted specific and synergistic repair of the airway through biochemical regulation of the airway microenvironment. While epithelial cells modulate local tissue composition and reaction, endothelial cells preserve the epithelium and perfusing microvasculature; together their relative impact was enhanced suggesting both cell types together increase airway repair. From these findings it may be inferred that in vascular injury, engineered endothelial cells implants recapitulate aspects of endothelial cells from both the epithelium and the perfusing microvasculature, while airways and other tubular o...

example 2

Fibroblast Growth Inhibited by Matrix-Embedded Cells

[0101]Fibroblasts are essential supporting cells of the airway and of the mesenchymal hyperplastic lesion. To determine the effect of matrix-embedded cells on fibroblast proliferation, normal human long fibroblasts (NHLF) were seeded at 5×104 cells / well and grown for 48 hours on 6-well transwell plates (Costar). Fresh medium (5 ml / well of BEGM:EGM-2, 1:1) was then added with or without 5 μM indomethacin (Sigma) and 24 mm inserts (0.4 μm membrane) with matrices (engrafted with endothelial cells, epithelial cells, or co-cultures of epithelial cells and endothelial cells) placed on top of the NHLF. After an additional 48 hours, NHLF were trypsinized and total cell number for each well was determined with a cell counter (Coulter Counter). Medium was collected and analysed using commercially available ELISA kits.

[0102]NHLF proliferation was maximally reduced when cocultured with matrices containing epithelial cells alone, modestly by em...

example 3

Tube Formation Inhibited by Matrix-Embedded Cells

[0104]The effect of matrix-embedded cells on angiogenesis in vitro was examined by tube formation of human umbilical vein epithelial cells (HUVEC) cultured with conditioned medium (CM). This process involved migration, invasion, and differentiation of HUVEC in the formation of the tubular network. A CAS™ HT tube formation kit (Trevigen) was used. Reduced growth factor basement membrane extract purified from Engelbreth-Holm-Swarm (EHS) tumor was pipetted into wells of a 48-well plate (100 μl / well) and incubated at 37° C. for 1 hours to allow the extract to solidify. HUVEC were plated at a density of 2×104 cells / well and incubated at 37° C. for 8 hours with either BEGM:EGM-2 (1:1) medium unconditioned (incubated at 37° C. without cells for 48 h) or conditioned for 48 hours from matrices engrafted with endothelial cells, epithelial cells, or epithelial cells / endothelial cells.

[0105]Eight hours after seeding, images of tube formation were...

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Abstract

Endothelial implants restore vascular homeostasis after injury without reconstituting vascular architecture. Endothelial cells line the vascular epithelium and underlying vasa vasorum precluding distinction between cellular controls. Unlike blood vessels, the airway epithelium is highly differentiated and distinct from endothelial cells that line the bronchial vasa allowing investigation of the differential control tissue engineered cells may provide in airways and blood vessels. Through airway injury and cell culture models, tissue engineered implants of the bronchial epithelium and endothelium were found to promote synergistic repair of the airway through biochemical regulation of the airway microenvironment. While epithelial cells modulate local tissue composition and reaction, endothelial cells preserve the epithelium; together their relative impact was enhanced suggesting both cell types act synergistically for airway repair.

Description

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0001]Work described herein was supported by Federal Grant No. R01, GM49039, awarded by the National Institutes of Health. The Government has certain rights to this invention.BACKGROUND[0002]Airways, intestines, ureters, fallopian tubes and other tubular structures possess a trilaminate form which offers structural integrity and flow modulation, as well as profound regulation of local inflammation, thrombosis and hemostasis, proliferation and remodeling. In these structures, a loose fibrous adventitia is replete with coursing arterioles, venules and neural forms, a middle muscularis layer provides control of luminal dimensions and tone, and a surface layer contains cells that biochemically regulate the wall response, and sense flow and luminal contents.[0003]In airway disorders—such as asthma and chronic obstructive pulmonary disease (COPD)—functional imbalance is tightly associated with remodeling of airway structure. R...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K35/12A61P17/02A61P1/00A61P15/00A61P11/00A61P9/00A61K35/42C12N5/071
CPCA61K35/12A61K35/36A61L27/3808C12N5/0688C12N2500/38C12N2501/11C12N2501/115C12N2501/25C12N2501/385C12N2501/39C12N2501/395C12N2501/81C12N2502/28C12N2533/00C12N2533/54A61K35/42A61P1/00A61P11/00A61P15/00A61P17/02A61P9/00
Inventor EDELMAN, ELAZER R.ZANI, BRETT G.
Owner MASSACHUSETTS INST OF TECH
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