Compositions and methods of improved wound healing

Abstract

Compositions and methods are contemplated for treatment of a wound, and especially a sterile or TLR/NOD ligand-poor wound in which contemporaneous administration of a Ca 2+ -flux agonist (CFA) and a pattern recognition receptor (PRR) ligand improves wound healing.

What is claimed is: 
     
         1 . A method of improving healing of a sterile or toll-like receptor (TLR)/nucleotide-binding oligomerization domain receptor (NOD) ligand-poor wound, comprising:
 administering a Ca 2+ -flux agonist (CFA) at a concentration and a pattern recognition receptor (PRR) ligand to a patient under a protocol that ensures presence of at least a portion of the CFA and at least a portion of the PRR ligand at the wound;   wherein the concentration of CFA is below an amount providing the maximum response obtainable with the CFA in the absence of the PRR ligand;   wherein the portion of the CFA and the portion of the PRR ligand are present in the wound in an amount effective to improve healing of the wound;   wherein the PRR ligand is a TLR or a NOD ligand; and   wherein the CFA is a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor and/or a calcium ionophore.   
     
     
         2 . The method of  claim 1  wherein the PRR ligand is a DAMP ligand, an endogenous ligand, a high-mobility group box-1 protein, a heat shock protein, a component of extracellular matrix, or an oligosaccharide derived from hyaluronic acid or heparan sulfate. 
     
     
         3 . The method of  claim 2  wherein the PRR ligand is a DAMP ligand or an endogenous ligand. 
     
     
         4 . The method of  claim 1  wherein the PRR ligand is polyI:C. 
     
     
         5 . The method of  claim 1  wherein the PRR ligand is imiquimod. 
     
     
         6 . The method of  claim 1  wherein the CFA and PRR ligand are present in a single formulation that is formulated for topical administration. 
     
     
         7 . The method of  claim 1  wherein at least one of the CFA and PRR ligand are coupled to a surface of a medical item for wound treatment. 
     
     
         8 . The method of  claim 7  wherein the medical item for wound treatment is a suture, a staple, a clamp, an implant, or wound dressing. 
     
     
         9 . The method of  claim 1  wherein the wound is produced by a surgical procedure, or is a traumatic injury without an acute or persistent infection. 
     
     
         10 . The method of  claim 1  wherein the improved wound healing is characterized by at least one of reduced time to closure of a surface wound, reduced incidence of infection of the wound, and increased tissue remodeling within the wound. 
     
     
         11 . The method of  claim 1  wherein the protocol comprises directly and contemporaneously contacting the wound with the CFA and the PRR ligand. 
     
     
         12 . The method of  claim 11  wherein the step of contacting is topical administration to the wound and/or exposing the wound to a medical item for wound treatment to which the CFA and PRR are coupled. 
     
     
         13 . The method of  claim 1  wherein the CFA and the PRR ligand are present in synergistic quantities with respect to the improvement of the wound healing. 
     
     
         14 . A method of treating a sterile or TLR/NOD ligand-poor wound, comprising:
 administering to the wound a pattern recognition receptor (PRR) ligand to produce at the wound site a non-saturating stimulus for a TLR and/or NOD signaling pathway;
 administering to the wound a Ca 2+ -flux agonist (CFA) in an amount effective to amplify the stimulus; 
 wherein amplification of the stimulus is performed under a protocol that improves healing of the wound; 
 wherein the PRR ligand is a TLR or a NOD ligand; and 
 wherein the CFA is a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitor and/or a calcium ionophore. 
   
     
     
         15 . The method of  claim 14  wherein the PRR ligand is a DAMP ligand, an endogenous ligand, a high-mobility group box-1 protein, a heat shock protein, a component of extracellular matrix, or an oligosaccharide derived from hyaluronic acid or heparan sulfate. 
     
     
         16 . The method of  claim 15  wherein the PRR ligand is a DAMP ligand or an endogenous ligand. 
     
     
         17 . The method of  claim 14  wherein the PRR ligand is polyI:C. 
     
     
         18 . The method of  claim 14  wherein the PRR ligand is imiquimod. 
     
     
         19 . The method of  claim 14  wherein the CFA and PRR ligand are topically administered to the wound. 
     
     
         20 . The method of  claim 14  wherein the CFA and PRR ligand are coupled to a surface of a medical item for wound treatment, and wherein the steps of administering are performed by contacting the wound with the medical item.