Temporal progression of the host response to implanted poly(ethylene glycol)-based hydrogels.

Poly(ethylene glycol) (PEG) hydrogels hold great promise as in vivo cell carriers for tissue engineering. To ensure appropriate performance of these materials when implanted, the host response must be well understood. The objectives for this study were to characterize the temporal evolution of the foreign body reaction (FBR) to acellular PEG-based hydrogels prepared from PEG diacrylate precursors when implanted subcutaneously in immunocompentent c57bl/6 mice by (immuno)histochemical analysis and gene expression. Compared with a normal FBR elicited by silicone (SIL), PEG hydrogels without or with a cell adhesion ligand RGD elicited a strong early inflammatory response evidenced by a thick band of macrophages as early as day 2, persisting through two weeks, and by increased interleukin-1β expression. PEG-only hydrogels showed a slower, but more sustained progression of inflammation over PEG-RGD. Temporal changes in gene expression were observed in response to PEG-based materials and in general exhibited, elevated expression of inflammatory and wound healing genes in the tissues surrounding the implants, while the expression patterns were more stable in response to SIL. While a stabilized FBR was achieved with SIL and to a lesser degree with PEG-RGD, the PEG-only hydrogels had not yet stabilized after 4 weeks. In summary, PEG-only hydrogels elicit a strong early inflammatory reaction, which persists throughout the course of the implantation even as a collagenous capsule begins to form. However, the incorporation of RGD tethers partially attenuates this response within 2 weeks leading to an improved FBR to PEG-based hydrogels.

[1]  Ronald V Maier,et al.  Effects of adsorbed proteins and surface chemistry on foreign body giant cell formation, tumor necrosis factor alpha release and procoagulant activity of monocytes. , 2004, Journal of biomedical materials research. Part A.

[2]  U. Tantry,et al.  Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. , 2000, Surgery.

[3]  L. Huber,et al.  Identification and dynamics of proteins adhering to the surface of medical silicones in vivo and in vitro. , 2007, Journal of proteome research.

[4]  J. Anderson,et al.  Cytokine and growth factor production by monocytes/macrophages on protein preadsorbed polymers. , 1992, Journal of biomedical materials research.

[5]  M. Harmsen,et al.  Cellular and molecular dynamics in the foreign body reaction. , 2006, Tissue engineering.

[6]  D. Schmidt,et al.  Monocyte activation in response to polyethylene glycol hydrogels grafted with RGD and PHSRN separated by interpositional spacers of various lengths. , 2007, Journal of biomedical materials research. Part A.

[7]  David M. Mosser,et al.  Exploring the full spectrum of macrophage activation , 2010, Nature Reviews Immunology.

[8]  U. Tantry,et al.  The role of iNOS in wound healing. , 2001, Surgery.

[9]  Matthew C. Phipps,et al.  The effect of RGD peptides on osseointegration of hydroxyapatite biomaterials. , 2008, Biomaterials.

[10]  J M Anderson,et al.  Foreign-body giant cells and polyurethane biostability: in vivo correlation of cell adhesion and surface cracking. , 1991, Journal of biomedical materials research.

[11]  W. Ahn,et al.  Evaluations of Poly(vinyl alcohol) Hydrogels Cross-linked under γ-Ray Irradiation , 2005 .

[12]  W C de Bruijn,et al.  Late degradation tissue response to poly(L-lactide) bone plates and screws. , 1995, Biomaterials.

[13]  J. Hubbell,et al.  In Vitro and in Vivo Performance of Porcine Islets Encapsulated in Interfacially Photopolymerized Poly(Ethylene Glycol) Diacrylate Membranes , 1999, Cell transplantation.

[14]  R. Abboud,et al.  Stability of housekeeping genes in alveolar macrophages from COPD patients , 2006, European Respiratory Journal.

[15]  James M. Anderson,et al.  Quantitative in vivo cytokine analysis at synthetic biomaterial implant sites. , 2008, Journal of biomedical materials research. Part A.

[16]  S. Santavirta,et al.  ASEPTIC LOOSENING OF TOTAL HIP REPLACEMENT: MACROPHAGE EXPRESSION OF INDUCIBLE NITRIC OXIDE SYNTHASE AND CYCLO-OXYGENASE-2, TOGETHER WITH PEROXYNITRITE FORMATION, AS A POSSIBLE MECHANISM FOR EARLY PROSTHESIS FAILURE , 1997 .

[17]  J. Anderson,et al.  Alkylsilane-modified surfaces: inhibition of human macrophage adhesion and foreign body giant cell formation. , 1999, Journal of biomedical materials research.

[18]  M. Dadsetan,et al.  In vivo biocompatibility and biodegradation of poly(ethylene carbonate). , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[19]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[20]  J M Anderson,et al.  Effects of surface-coupled polyethylene oxide on human macrophage adhesion and foreign body giant cell formation in vitro. , 1999, Journal of biomedical materials research.

[21]  R. Gamelli,et al.  Vascular endothelial growth factor mediates angiogenic activity during the proliferative phase of wound healing. , 1998, The American journal of pathology.

[22]  Peter Thomsen,et al.  The inflammatory cell influx and cytokines changes during transition from acute inflammation to fibrous repair around implanted materials , 2006, Journal of biomaterials science. Polymer edition.

[23]  Takehisa Matsuda,et al.  In vivo leukocyte cytokine mRNA responses to biomaterials are dependent on surface chemistry. , 2003, Journal of biomedical materials research. Part A.

[24]  Jacqueline A. Jones,et al.  Characterization of topographical effects on macrophage behavior in a foreign body response model. , 2010, Biomaterials.

[25]  D. Grainger,et al.  Localized immunosuppressive environment in the foreign body response to implanted biomaterials. , 2009, The American journal of pathology.

[26]  Robert Langer,et al.  Controlled‐release of IGF‐I and TGF‐β1 in a photopolymerizing hydrogel for cartilage tissue engineering , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[27]  J L West,et al.  Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. , 2001, Biomaterials.

[28]  Jacqueline A. Jones,et al.  Phenotypic dichotomies in the foreign body reaction. , 2007, Biomaterials.

[29]  W. Reichert,et al.  Cytokine profiling using monocytes/macrophages cultured on common biomaterials with a range of surface chemistries. , 2009, Journal of biomedical materials research. Part A.

[30]  M. Mahoney,et al.  Development of porous PEG hydrogels that enable efficient, uniform cell-seeding and permit early neural process extension. , 2009, Acta biomaterialia.

[31]  Milica Radisic,et al.  Microfabricated poly(ethylene glycol) templates enable rapid screening of triculture conditions for cardiac tissue engineering. , 2009, Journal of biomedical materials research. Part A.

[32]  M. Pfaffl,et al.  A new mathematical model for relative quantification in real-time RT-PCR. , 2001, Nucleic acids research.

[33]  S. Bryant,et al.  The role of hydrogel structure and dynamic loading on chondrocyte gene expression and matrix formation. , 2008, Journal of biomechanics.

[34]  Joseph D. Andrade,et al.  Protein—surface interactions in the presence of polyethylene oxide: II. Effect of protein size , 1991 .

[35]  P. Manson,et al.  The effect of incorporating RGD adhesive peptide in polyethylene glycol diacrylate hydrogel on osteogenesis of bone marrow stromal cells. , 2005, Biomaterials.

[36]  Anderson,et al.  Host response to tissue engineered devices. , 1998, Advanced drug delivery reviews.

[37]  D. Beezhold,et al.  Stimulation of rat macrophage interleukin 1 secretion by plasma fibronectin. , 1987, Immunological investigations.

[38]  Stephanie J Bryant,et al.  Characterization of the in vitro macrophage response and in vivo host response to poly(ethylene glycol)-based hydrogels. , 2009, Journal of biomedical materials research. Part A.

[39]  Joseph D. Andrade,et al.  Protein—surface interactions in the presence of polyethylene oxide , 1991 .

[40]  M. Mahoney,et al.  Entrapped collagen type 1 promotes differentiation of embryonic pancreatic precursor cells into glucose-responsive beta-cells when cultured in three-dimensional PEG hydrogels. , 2009, Tissue engineering. Part A.

[41]  R. A. Smith.  Monocytes and Macrophages , 1998 .

[42]  James M. Anderson,et al.  Foreign body reaction to biomaterials. , 2008, Seminars in immunology.

[43]  Buddy D Ratner,et al.  Plasma-deposited tetraglyme surfaces greatly reduce total blood protein adsorption, contact activation, platelet adhesion, platelet procoagulant activity, and in vitro thrombus deposition. , 2007, Journal of biomedical materials research. Part A.

[44]  I. Charles,et al.  Nitric oxide synthase is expressed in human macrophages during foreign body inflammation. , 1997, The American journal of pathology.