title: 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.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology Atlanta, GA, USA; Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Hermann
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Wilson
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: Kelsey A
authors.initials: KA
authors.lastname: Lawrence
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: Xinghai
authors.initials: X
authors.lastname: Ning
authors.affiliation: Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Olivares-Navarrete
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Williams
authors.affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology Atlanta, GA, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Guldberg
authors.affiliation: Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA. Electronic address: nmurthy@berkeley.edu.
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.affiliation: Department of Bioengineering, University of California at Berkeley, Berkeley, CA, USA.
authors.forename: Zvi
authors.initials: Z
authors.lastname: Schwartz
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology Atlanta, GA, USA; Department of Biomedical Engineering, School of Engineering, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: bboyan@vcu.edu.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Boyan
mesh_terms: D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D057930:Click Chemistry; D003300:Copper / Q000737:chemistry; D003398:Craniosynostoses / Q000188:drug therapy* / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry*; D007267:Injections; D036341:Intercellular Signaling Peptides and Proteins / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000737:chemistry*; D058105:Polymerization; D016207:Cytokines
chemical_list: D003300:Copper; D004337:Drug Carriers; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D036341:Intercellular Signaling Peptides and Proteins; D011092:Polyethylene Glycols; C113178:Grem1 protein, mouse; D016207:Cytokines
keywords: BMP (bone morphogenetic protein); Bone ingrowth; Craniosynostosis; Hydrogel; Re-synostosis