Intraosseous Delivery of Bone Morphogenic Protein-2 Using a Self-Assembling Peptide Hydrogel.
Osteonecrosis of the femoral head (ONFH) is a debilitating hip disorder, which often produces a permanent femoral head deformity and osteoarthritis. The local delivery of biological agents capable of stimulating bone healing offer potential new treatment options for patients with ONFH. Previous studies from our laboratory have shown that a local intraosseous infusion of bone morphogenic protein-2 (BMP-2) was effective in stimulating new bone formation in a piglet model of ischemic ONFH. However, infusion of BMP-2 solution was associated with unwanted dissemination of BMP-2 out of the femoral head and produced heterotopic ossification in the hip capsule. Injectable hydrogels offer a potential method to control the dissemination of biological molecules in vivo. In the present study, we evaluated the potential of a peptide-based, self-assembling hydrogel called RADA16 to transition from a solution to a gel following infusion into the femoral head, thereby preventing backflow, as well as its potential use as a delivery vehicle for BMP-2. Cadaver pig femoral heads were used to study the backflow and the distribution of RADA16 following an intraosseous infusion. Microcomputed tomography analysis following the infusion of RADA16 mixed with a radiocontrast agent revealed a significant decrease in the amount of back flow of radiocontrast agent down the needle track compared to the soluble infusion of radiocontrast without RADA16. Furthermore, RADA16 mixed with radiocontrast agent showed good distribution within the femoral head. In addition, in vitro experiments revealed that higher concentrations of RADA16 decreased the rate of BMP-2 dissemination out of the hydrogel. The BMP-2 that was released from RADA16 maintains its biological activity, inducing the phosphorylation of SMAD1/5/8 in pig primary bone marrow stromal cells. Lastly, pig primary bone marrow stromal cells showed significantly increased in vitro proliferation on RADA16 hydrogels over 1 week compared to tissue culture plastic, suggesting that it is a suitable matrix for supporting cellular proliferation. In conclusion, RADA16 showed potential for use as a drug delivery vehicle to control the delivery of BMP-2 within the femoral head. This novel therapy may be able to provide benefits to patients suffering from debilitating conditions such as osteonecrosis of the femoral head.
Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children , Dallas, Texas 75219, United States.
Matthew C
MC
Phipps
Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children , Dallas, Texas 75219, United States.|Department of Bioengineering, University of Texas at Arlington , Arlington, Texas 76019, United States.
Felipe
F
Monte
3-D Matrix, Inc., Waltham, Massachusetts 02451, United States.
Manav
M
Mehta
Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children , Dallas, Texas 75219, United States.|Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center , Dallas, Texas 75390, United States.
Harry K W
HK
Kim
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D005270:Femur Head / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage / Q000737:chemistry*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry; D010766:Phosphorylation / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013552:Swine; D055114:X-Ray Microtomography
D055396:Bone Morphogenetic Protein 2; D010455:Peptides; C546681:RADA16-I; D051785:Smad Proteins; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate