title: Early detection and treatment of wear particle-induced inflammation and bone loss in a mouse calvarial osteolysis model using HPMA copolymer conjugates.
abstract: Wear particle-induced inflammation is considered to be the major cause of aseptic implant loosening and clinical failure after total joint replacement. Due to the frequent absence of symptoms, early detection and intervention prior to implant failure presents a significant challenge. To address this issue, a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based optical imaging contrast agent (P-IRDye) was developed and used for the detection of wear particle-induced inflammation employing a murine calvaria osteolysis model. The particle-induced osteolysis of calvaria was evaluated by H&E, tartrate-resistant acid phosphatase (TRAP) staining and μ-CT after necropsy. One-day post particle implantation, P-IRDye was administrated to the mice via tail vein injection. Live imaging of the animals 6 days after implantation revealed the preferential distribution and sustained retention of the macromolecular contrast agent at the site of particle implantation. Immunohistochemical staining and FACS analyses of the calvaria-associated soft tissue revealed extensive uptake of the HPMA copolymer by F4/80, Ly-6G (Gr1) and CD11c positive cells, which accounts for the retention of the macromolecular probes at the inflammatory sites. To test the potential of the system for therapeutic intervention, an acid-labile HPMA copolymer-dexamethasone conjugate (P-Dex) was prepared and shown to prevent the particle-induced inflammation and bone damage in the calvaria osteolysis model.
authors: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198-6025, USA.
authors: Ke
authors: K
authors: Ren
authors: P Edward
authors: PE
authors: Purdue
authors: Lyndsey
authors: L
authors: Burton
authors: Ling-dong
authors: LD
authors: Quan
authors: Edward V
authors: EV
authors: Fehringer
authors: Geoffrey M
authors: GM
authors: Thiele
authors: Steven R
authors: SR
authors: Goldring
authors: Dong
authors: D
authors: Wang
mesh_terms: D000178:Acrylamides; D000818:Animals; D001862:Bone Resorption / Q000175:diagnosis*; D016025:Bone Transplantation / Q000009:adverse effects*; D003287:Contrast Media; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000175:diagnosis* / Q000473:pathology; D008297:Male; D051379:Mice; D010014:Osteolysis / Q000175:diagnosis* / Q000473:pathology; D012886:Skull / Q000000981:diagnostic imaging / Q000473:pathology*; D055114:X-Ray Microtomography
chemical_list: D000178:Acrylamides; D003287:Contrast Media; C032976:N-(2-hydroxypropyl)methacrylamide