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NIRT: Self-Assembled Nanohydrogels for Differential Cell Adhesion and Infection Control Matthew Libera, Woo Lee, Mercedes McKay, Svetlana Sukhishvili, Hongjun Wang Stevens Institute of Technology, Hoboken, New Jersey 07030 Project Overview Infection: A Major Mode of Orthopaedic Implant Failure Infection occurs in approximately 0.5 – 5% of all hip and knee replacements. It is a catastrophic problem, because bacteria that colonize an implant surface develop into biofilms where they are as much as 10,000 times more resistant to antibiotics than planktonic bacteria. The most effective therapy is to remove an infected implant, cure the infection, and then pursue a subsequent revision surgery. The consequences to patient well being and medical cost in this situation are compellingly significant. At its core, implant infection is a biomaterials problem. While surfaces have been developed which repel bacterial adhesion – e.g. PEGylated surfaces – these also repel the eukaryotic cells necessary for the development of a healthy implant-tissue interface. Instead, surfaces are needed that are differentially adhesive, i.e. that it promote eukaryotic (e.g. osteoblast) adhesion and proliferation while simultaneously repelling bacteria. This is a fundamental biomaterials problem that remains unsolved. BGS $.4, 5% Hips Bacterial biofilms form complex and hierarchically structured communities which are as much as 10kx more resistant to antibiotics than planktonic bacterial. 0.3 - 1% Knees 1 - 4% Fixation devices ~1 m Cell-Interactive nanohydrogels hierarchically structured on the surface of a macroscopically beaded surface of a modern orthopaedic implant. > 15% e.g. Intramedullary trauma rods ~2 mm Infection by Staphylococcal Biofilms This project explores a new mechanism to create differentially adhesive surfaces. The key idea rests in the fact that important staphylococcal bacterial cells are significantly smaller (~ 600-900 nm dia) Global Orthopaedic Markets (2005) than eukaryotic cells (~5-50 μm dia). Furthermore, the cell walls of these grampositive bacteria are less able to conform to a substrate than are eukaryotic cell walls. We hypothesize that heterostructures of nanosized hydrogels self assembled in 2D over micrometer length scales will allow focal contact formation and subsequent osteoblast adhesion but prevent bacterial adhesion. Biologics $1.0, 23% Infection Rates Differentially Adhesive Surfaces Repulsive to Bacteria but Attractive to Eukaryotic Cells attachment • S. aureus (40%) Polysaccharide secretion Maturation and biofilm growth Release of planktonic progeny ~350 m The biofilm cycle • S. epidermis (20%) adapted from Sauer, Genome Biology, 2003) osteoblast 5 m Hips $4.0, 9% S. aureus Spinal $4.0, 24% substrate Knees $5.0, 16% T rauma $3.0, 14% Extremities $0.4, 11% Sports Medicine $1.0, 9% Arthroscopy $1.0, 8% Bone Cement $0.3, 7% S. epi polycation primer layer 5 m Actin filaments (green) and vinculin containing focal adhesions (red) in fibroblasts S. epidermidis 9 hr culture on glass Ancillary $2.0, 10% self-assembled nanohydrogels repulsive adhesive Source: Merrill Lynch Courtesy of G. Grobe DePuy Orthopaedics Nanohydrogel Synthesis and Surface Self Assembly - - - - --- - -+ + -- -- -- -- -- -- --- + + + + Self-Assembled Nanohydrogels Reduce S. epidermidis Adhesion PEGDA/AA Multiplexed Microfluidic Methods to Assess Differential Cell Adhesion PL Primer Biological Framework of 3-D Microscale Environment + 0.04 Host Defense Mechanism 0.01 Self-Assembled Nanohydrogel Surface 0 in e GOAL: Develop, integrate and pilot two new educational modules that introduce forwardlooking ideas of nanotechnology to high school chemistry and biology curricula. ly s D A G PE D A/ Controlling nanoparticle adhesion via controlled surface chemistry S. epidermidis The Stevens Center for Innovation in Engineering and Science Education (CIESE), working with the Stevens NIRT Team, Stryker Orthopaedics and high-school teachers from New Jersey school districts, will: 0.02 G SEM Images of emulsionpolymerized PEG nanohydrogels on a silicon substrate Osteoblast 0.03 AA 200 nm Preconditioning Therapeutic Delivery 0.05 PE - Control of electrostatic interactions between nanohydrogels & substrate 0.06 Po ly - Selective functionalization of cell-adhesive ligands S. epi area fraction 10 m - Emulsion polymerization of PEGDA Outreach and Broader Impact A surface modified by< 6% coverage of poly(PEG-co acrylic acid) nanohydrogels reduces S. epi adhesion by a factor of more than 3 relative to a PL-treated surface. • Expose students to nanotechnology-based research • Demonstrate the societal relevance • Enhance/modernize biology & chemistry curricula • Create a real-world context for basic-science concepts Tool Functions • Microfluidic Multiplexing • Nontransparent Biomaterial • In-situ Imaging + Particle density #/m2 500 nm 5.0 + + + + 4.0 + 3.0 + 2.0 0.2 0.4 0.6 0.8 PAH thickness (nm) 1.0 At high pH, PAH polycationic films have higher charge, more conformational loops, and hence are thicker than those deposited at lower pH. Thicker films provide more adhesion sites for negatively charged Ag nanoparticles 200x30 m channel with 4 embedded microvalves Osteoblast Seeded in 800x200 m Channel 5 mm 800 m S. epidermidis Cultured in 100x100 mm Channel 100 m CIESE has nearly 20 years of K-12 curriculum and professional development expertise in STEM education, and has impacted over 20,000 educators worldwide