Rapidly polymerizing injectable click hydrogel therapy to delay bone growth in a murine re-synostosis model.

Abstract

Craniosynostosis is the premature fusion of cranial sutures, which can result in progressive cranial deformations, increased intracranial pressure, and restricted brain growth. Most cases of craniosynostosis require surgical reconstruction of the cranial vault with the goal of increasing the intracranial volume and correcting the craniofacial deformities. However, patients often experience rapid post-operative bone regrowth, known as re-synostosis, which necessitates additional surgical intervention. Bone morphogenetic protein (BMP) inhibitors have tremendous potential to treat re-synostosis, but the realization of a clinically viable inhibitor-based therapeutic requires the development of a delivery vehicle that can localize the release to the site of administration. Here, we present an in situ rapidly crosslinking injectable hydrogel that has the properties necessary to encapsulate co-administered proteins and demonstrate that the delivery of rmGremlin1 via our hydrogel system delays bone regrowth in a weanling mouse model of re-synostosis. Our hydrogel is composed of two mutually reactive poly(ethylene glycol) macromolecules, which when mixed crosslink via a bio-orthogonal Cu free click reaction. Hydrogels containing Gremlin caused a dose dependent inhibition of bone regrowth. In addition to craniofacial applications, our injectable click hydrogel has the potential to provide customizable protein, small molecule, and cell delivery to any site accessible via needle or catheter.

• Authors: Christopher D Hermann, David S Wilson, Kelsey A Lawrence, Xinghai Ning, Rene Olivares-Navarrete, Joseph K Williams, Robert E Guldberg, Niren Murthy, Zvi Schwartz, Barbara D Boyan
• Journal: Biomaterials (Biomaterials) Vol. 35 Issue 36 Pg. 9698-708 (Dec 2014) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 25176067 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Drug Carriers
• Grem1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Hydrogel, Polyethylene Glycol Dimethacrylate
• Polyethylene Glycols
• Copper

Topics

• Animals
• Bone Development (drug effects)
• Click Chemistry
• Copper (chemistry)
• Craniosynostoses (drug therapy, pathology)
• Drug Carriers (chemistry)
• Hydrogel, Polyethylene Glycol Dimethacrylate (chemistry)
• Injections
• Intercellular Signaling Peptides and Proteins (administration & dosage, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Polyethylene Glycols (chemistry)
• Polymerization