Engineering at the Extracellular Level
The extracellular matrix (ECM) provides a spectrum of biophysical and biochemical clues that influence cell and tissue response. Biophysical and biochemical clues come from the molecular composition of the ECM and come in the form of chemical, morphological, and mechanical cues. Our laboratory has focused largely on the glycosaminoglycan (GAG), or long chain sugar biopolymers, and the role they instructive play in the ECM. The GAGs themselves can be chemically modified and used to form hydrogels for tissue engineering. The modified GAGs can also be used to engineer mimetics of the proteoglycans found within the ECM. Synthesis and evaluation of proteoglycan mimetics composes a large portion of the more recent effort in the Panitch laboratory. These molecules can be designed to mimic many of the properties of native proteoglycans, and we have used them in vascular, dermal, and cartilage applications. Our published work has shown that these mimics can inhibit dermal scarring, improve vessel healing after balloon angioplasty and suppress osteoarthritis following traumatic joint injury. Ongoing efforts include partnering to translate these therapeutics into the market place in addition to developing new ECM therapeutics.
Engineering at the Intracellular Level
Inflammation plays a critical role in tissue healing. Thus, fine-tuning the inflammatory process to promote normal tissue repair, while preventing scar formation is an on going effort in many labs throughout the world. Our laboratory has focused on the design of cell-penetrating peptide therapeutics that help regulate the inflammatory response by controlling key pathways in both inflammation and fibrosis. Our main effort has been focused on optimization and delivery of peptide inhibitors of the kinase Mitogen-Activated Protein Kinase-Activated Protein Kinase II, or MK2. Past efforts involving optimization of the peptide showed that both the cell-penetrating peptide and the kinase inhibitor sequencecontribute to the specificity and activity of the peptide. With key collaborators we have shown that the peptide is effective at inhibiting surgical adhesions, intimal hyperplasia following vein-graft bypass, and the progression ofidiopathic pulmonary fibrosis. Current efforts include developing methodologies to study key cellular delivery mechanisms, developing nanoparticle delivery technologies to improve efficacy, and expanding into the bioinformatics area, through collaborations with the Rundell and Kinzer-Ursem laboratories to elucidate how the MK2 signaling pathway interfaces with the AKT and TGF-β1 pathways to regulate tissue healing.