Mutant MCP-1 protein delivery from layer-by-layer coatings on orthopedic implants to modulate inflammatory response

Abstract

Total joint replacement (TJR) is a common and effective surgical procedure for hip or knee joint reconstruction. However, the production of wear particles is inevitable for all TJRs, which activates macrophages and initiates an inflammatory cascade often resulting in bone loss, prosthetic loosening and eventual TJR failure. Macrophage Chemoattractant Protein-1 (MCP-1) is one of the most potent cytokines responsible for macrophage cell recruitment, and previous studies suggest that mutant MCP-1 proteins such as 7ND may be used as a decoy drug to block the receptor and reduce inflammatory cell recruitment. Here we report the development of a biodegradable, layer-by-layer (LBL) coating platform that allows efficient loading and controlled release of 7ND proteins from the surface of orthopaedic implants using as few as 14 layers. Scanning electron microscopy and fluorescence imaging confirmed effective coating using the LBL procedure on titanium rods. 7ND protein loading concentration and release kinetics can be modulated by varying the polyelectrolytes of choice, the polymer chemistry, the pH of the polyelectrolyte solution, and the degradation rate of the LBL assembly. The released 7ND from LBL coating retained its bioactivity and effectively reduced macrophage migration towards MCP-1. Finally, the LBL coating remained intact following a femoral rod implantation procedure as determined by immunostaining of the 7ND coating. The LBL platform reported herein may be applied for in situ controlled release of 7ND protein from orthopaedic implants, to reduce wear particle-induced inflammatory responses in an effort to prolong the lifetime of implants.

Inflammation, fracture and bone repair

“…However, treatment of aseptic and septic loosening of orthopaedic and dental implants may benefit from considering the role of the immune system [166–168]. For example, blockade of pro-inflammatory mediators such as PGE2 [169], pro-inflammatory cytokines [170], or recruitment of monocyte/macrophage cells by interfering with CCL2/CCR2 axis [171, 172], or inactivation of the pro-inflammatory transcription factor NF-κB [173, 174] has been investigated. Another approach is centered on the modulation of macrophage phenotype from inactivated M0 or pro-inflammatory M1 macrophages toward the pro-remodeling M2 macrophages by using polarizing cytokines [175–177].…”

Engineered protein coatings to improve the osseointegration of dental and orthopaedic implants

“…[64] Briefly, Ti6Al4V rods were dip coated in a 5 wt.% ELP solution containing 0.15% wt.% ELP fluorescently labeled with rhodamine B isothiocyanate (Sigma). The intercondylar notch of cadaver mouse femurs was opened with successively larger needles ranging from 25-21 gauge to create a drill-hole reaching the medullary cavity.…”

Nanocoating for biomolecule delivery using layer-by-layer self-assembly

“…29 Surface coatings may be applied to control a biological response to the device ( e.g. peri-implant tissue formation 21 ), but may also represent the primary function of the device ( e.g. drug coating on transdermal needles 30 ).…”

“…Such an LbL platform can be applied for controlled release of the 7ND protein from orthopedic implants in situ to reduce wear particle-induced inflammatory responses, thereby prolonging the lifetime of implants and reducing the need for revision surgeries. 56 …”