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

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.

1 . A therapeutic composition comprising:
 a biocompatible matrix and a mixture of bronchial epithelial cells and non-epithelial cells or functional analogs of any one of the foregoing cell types in an amount sufficient to treat an injury.   
     
     
         2 . (canceled) 
     
     
         3 . The therapeutic composition of  claim 1  wherein the non-epithelial cells are endothelial cells. 
     
     
         4 . The therapeutic composition of  claim 1  wherein the bronchial epithelial cells comprise a mixture of bronchial epithelial cells and non-bronchial epithelial cells. 
     
     
         5 . The therapeutic composition of  claim 1  wherein the injury is an injury to a multilaminate tubular structure. 
     
     
         6 . The therapeutic composition of  claim 5  wherein the injury is an injury to an airway. 
     
     
         7 . The therapeutic composition of  claim 6  wherein the injury of the airway is a tracheal injury or a bronchial injury. 
     
     
         8 . (canceled) 
     
     
         9 . The therapeutic composition  claim 5  wherein the injury is as a result of disease, trauma or medical procedure. 
     
     
         10 . The therapeutic composition of  claim 1  wherein the composition reduces an area of the injury. 
     
     
         11 . The therapeutic composition of  claim 1  wherein the composition reduces one or more of hypervascularity, angiogenesis, neovascularization, fibrosis, collagen deposition, inflammatory cell infiltration or necrosis. 
     
     
         12 . The therapeutic composition of  claim 6  wherein the composition reduces the extent of luminal narrowing or obstruction of the airway. 
     
     
         13 . The therapeutic composition of  claim 1  wherein the composition enhances repair of injured epithelial cells or tissue. 
     
     
         14 . The therapeutic composition of  claim 1  wherein the composition reduces mesenchymal hyperplasia at or nearby the site of injury. 
     
     
         15 . The therapeutic composition of  claim 1  wherein the composition reduces hypervascularity at or nearby the site of injury. 
     
     
         16 . The therapeutic composition of  claim 1  wherein the cells secrete an effective amount of prostaglandin E2. 
     
     
         17 . The therapeutic composition of  claim 1  wherein the cells reduce proliferation of lung fibroblasts. 
     
     
         18 . The therapeutic composition of  claim 1  wherein the cells are autogenic, allogenic, or xenogenic. 
     
     
         19 . The therapeutic composition of  claim 1  wherein the biocompatible matrix is biodegradable. 
     
     
         20 . The therapeutic composition of  claim 1  wherein the biocompatible matrix is a flexible planar material or a flowable composition. 
     
     
         21 . (canceled) 
     
     
         22 . The therapeutic composition of  claim 20  wherein the flowable composition comprises particles, beads, gels, foams, suspensions or microcapsules or combinations of any one of the foregoing. 
     
     
         23 - 24 . (canceled) 
     
     
         25 . A method for treating a subject, comprising the step of:
 providing to the subject a therapeutic composition comprising a biocompatible matrix and a mixture of bronchial epithelial cells and non-epithelial cells or functional analogs of any one of the foregoing cell types in an amount sufficient to treat an injury; wherein the composition is localized at, adjacent to or in the vicinity of the injury; and further wherein the providing step is accomplished via an open-field surgical procedure or a minimally-invasive surgical procedure.   
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 25  wherein the non-epithelial cells are endothelial cells. 
     
     
         28 . The method of  claim 25  wherein the bronchial epithelial cells comprise a mixture of bronchial epithelial cells and non-bronchial epithelial cells. 
     
     
         29 . The method of  claim 25  wherein the injury is an injury to a tubular structure. 
     
     
         30 . The method of  claim 29  wherein the injury is an injury to an airway. 
     
     
         31 . The method of  claim 30  wherein the injury of the airway is a tracheal injury or a bronchial injury. 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 25  wherein the injury is as a result of disease, trauma or medical procedure. 
     
     
         34 - 41 . (canceled) 
     
     
         42 . The method of  claim 25  wherein the cells are autogenic, allogenic, or xenogenic. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 25  wherein the biocompatible matrix is a flexible planar material or a flowable composition. 
     
     
         45 . (canceled) 
     
     
         46 . The method of  claim 44  wherein the flowable composition is particles, beads, gels, foams, suspensions or microcapsules or combinations thereof. 
     
     
         47 - 48 . (canceled) 
     
     
         49 . The method of  claim 25 , wherein the injury is an airway injury and wherein the therapeutic composition reduces stridor resulting from the airway injury. 
     
     
         50 - 51 . (canceled) 
     
     
         52 . A method of effecting localized repair of a vascular injury, said method comprising the step of:
 providing a composition comprising a mixture of bronchial epithelial cells and non-epithelial cells or functional analogs of any one of the foregoing cell types wherein the composition, when administered to a non-luminal surface of an injured vascular structure, promotes vascular functionality within the vasa vasorum in the vicinity of the injury while simultaneously promoting endothelial functionality within the luminal endothelium in the vicinity of the injury.   
     
     
         53 . A method of effecting localized repair of injury to a multilaminate tubular structure, said method comprising the step of:
 providing a composition comprising a mixture of bronchial epithelial cells and non-epithelial cells or functional analogs of any one of the foregoing cell types wherein the composition, when administered to a non-luminal surface of an injured tubular structure, promotes vascular functionality in the vicinity of the injury while simultaneously promoting epithelial functionality within the luminal epithelium in the vicinity of the injury.   
     
     
         54 . The method of  claim 53  wherein the composition promotes vascular functionality within the vasa vasorum in the vicinity of the injury.