Controlled Release of Small Molecules from Elastomers for Reducing

Aug 3, 2016 - The elevated infection rise associated with indwelling devices can compromise the performance of percutaneous devices and increase the r...
0 downloads 0 Views 2MB Size
Download PDF
Article pubs.acs.org/journal/abseba

Controlled Release of Small Molecules from Elastomers for Reducing Epidermal Downgrowth in Percutaneous Devices Pitirat Pholpabu,† Saigopalakrishna S. Yerneni,† Congcong Zhu,§ Phil G. Campbell,*,‡ and Christopher J. Bettinger*,†,§ †

Department of Biomedical Engineering, ‡Institute for Complex Engineered Systems, and §Department of Materials Science and Engineering, Carnegie Mellon University, 5000 Forbes Avenue, Pittsburgh, Pennsylvania 15213, United States S Supporting Information *

ABSTRACT: The elevated infection rise associated with indwelling devices can compromise the performance of percutaneous devices and increase the risk of complications. High infection rates are associated with both the high bacterial load on the skin and epidermal downgrowth at the interface of the indwelling material. Here, we propose a drug-eluting material that promotes local dermal regeneration to reduce epidermal downgrowth. Mesoporous elastomeric matrices composed of naturally occurring monomers were prepared by a combination of photo- and thermal-crosslinking. Elastomeric devices loaded with conjugated linoleic acids (CLA), a class of small molecules that promote local antiinflammatory responses, can deliver these compounds for 7 d (DCLA‑elastomer = 3.94 × 10−9 cm2/s, 95% CI [3.12 × 10−9, 4.61 × 10−9]). In a mouse model, CLA-eluting elastomeric matrices increase the M2 population (5.0 × 103 ± 1.4 × 103 cells/cm2), compared to blank devices (3.8 × 103 ± 2.2 × 103 cells/cm2), and also reduce skin contraction (98.9 ± 6.4%), compared to blank devices (70.9 ± 9.3%) at 7 d. Dermal downgrowth is also attenuated at 14 d (60.4 ± 32.4 μm) compared to blank devices (171.7 ± 93.8 μm). CLA-eluting elastomers are therefore a viable strategy to reduce epidermal downgrowth in percutaneous devices. KEYWORDS: biodegradable elastomer, percutaneous device, controlled release, macrophage, regenerative integration

■

INTRODUCTION

delivery of macrophage modulating small molecules to reduce epidermal downgrowth in percutaneous devices.

■

Indwelling catheters are important in healthcare because they provide transcorporal egress.1,2 However, these medical devices are a major source of nosocomial bloodstream infection that gives rise to notable morbidity and mortality.3,4 Percutaneous devices induce dermal migration downward along the skindevice interface and create recessed tissue circumferentially arranged about the device.5 Dermal downgrowth and high bacterial loads increase the risk of bloodstream infection.6 Previous strategies to reduce the skin-device mismatch primarily focus on microporous catheters to promote dermal integration.7,8 Modulating local macrophage populations may offer another strategy for reducing epidermal downgrowth. Macrophages serve as a key component to regulate inflammation, regeneration, and remodeling. Attenuating proinflammatory (M1) macrophages and increasing regenerative (M2) macrophages may accelerate the healing processes and reduce epidermal downgrowth.9,10 Local delivery of linoleic acid (LA) and its isomer, conjugated linoleic acid (CLA), is a viable approach for biasing macrophage populations. LA and CLA are small molecule agonists that polarize macrophages toward M2 phenotypes.11−13 Furthermore, LA and CLA have molecular weights of 280 g/mol and hydrodynamic radii between 2.8 and 3.1 Å,14,15 thereby permitting delivery from mesoporous elastomeric matrices. Here, we design the design and characterization of drug-eluting elastomers for local © XXXX American Chemical Society

MATERIALS AND METHODS

Device Fabrication and Characterization of Drug-Eluting Matrices. PGS-CinA films were prepared as previously described.16 Briefly, PGS-CinA films were prepared from PGS-CinA precursors with a degree of substitution (DS) of 26% using photodimerization with UV light (λmax = 315 nm; intensity = 115 mW/cm2; polymerization time = 3 h; Intelli Ray Shuttered UV Flood Light, Integrated Dispensing Solutions, Agoura Hills, CA). Solid PGS-CinA cylinders were fabricated by creating “jelly rolls” from coupons (W × L × t = 1.5 cm × 1.5 cm × 100 μm) followed by additional curing at 120 °C for 12 h in vacuum (70% released), yet the M2 macrophage density is increased, and downgrowth is decreased at 7 d compared to other treatments. These data suggest that there is temporal coordination between CLA release kinetics, M2 macrophage density, and dermal downgrowth. Furthermore, the local M2 macrophage density is correlated with reduced

Figure 3. (a) Plot of effective diffusion coefficient (Def f) and (b) mesh size (ξ) versus swelling ratio (Q). Continuous lines indicate predicted values of Def f and ξ as a function of a hypothetical Q (eq 5). Experimentally determined values of Qdim and Qef f generate two corresponding values for Def f and ξ. The value of Qdim produces a value of Def f that is consistent with analytical models derived from Fick’s second law (eq 3 and eq 4).

determined values for Def f are in close agreement with swelling ratios extracted from dimensional measurements Qdim. Experimental values for Def f and Qdim extracted from eq 5 also generate a value for mesh size ξPGS‑CinA that is internally consistent with that calculated using the Canal and Peppas model (eq 1) (Figure 3b). These data suggest that CLA diffusion through PGS-CinA networks is governed by the mesoscale structure of the crosslinks. Histological Analysis of Mouse Skin Inserted with Elastomeric Matrices. Drug-eluting PGS-CinA matrices bias local macrophage populations to an M2 phenotype (CD163+) depending on the small molecule that is delivered (Figure 4). M2 macrophage densities at t = 3, 7, 10, and 14 d exhibit significant statistical interaction between the treatments (LPS, CLA, or LPS+CLA) and time (two-way ANOVA, F = 4.627, p < 0.001). Both blank and CLA-eluting PGS-CinA matrices produce comparable trends in M2 macrophage density at 3 d. These observations are attributed to the fact that the effect of CLA may be dwarfed by the pro-inflammatory signals at the implantation site during early stages of wound healing.54−56 D

DOI: 10.1021/acsbiomaterials.6b00192 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Article

ACS Biomaterials Science & Engineering

Figure 6. Measurement of skin bridge length. (a, i). Schematic showing two cylindrical PGS-CinA matrices that are implanted percutaneously through the back skin of murine animal subjects. An arrow indicates skin bridge length that measures the length between two insertion sites. (a, ii) Representative skin bridges of each treatment at 0 and 7 d. (b) Normalized percentage of skin bridge length. An asterisk indicates significant difference using Kruskal−Wallis (* p < 0.05).

Figure 5. Dermal downgrowth at the insertion site. (a) Schematic of sectioned mouse skin layers with the percutaneous device at the bottom. (b) Representative H&E histology image of mouse skin at the tube insertion site at 7 d post-surgery. (c) Quantified dermal downgrowth (two-way ANOVA, *** p < 0.001, n = 4). Boxes and whiskers show SEMs with medians and 90th−10th percentiles, respectively. Diamonds represent the mean.

■

CONCLUSIONS

■

ASSOCIATED CONTENT

Here, we designed cylindrical percutaneous matrices to provide a controlled release of small molecules that alter macrophage expressions. Our results show that PGS-CinA exhibits suitable properties of biomaterials for percutaneous devices: (1) a Young’s modulus in the elastomeric regime that matches that of the native epidermis; (2) a crosslinked polymeric network with a mesh size that controls the release of small molecules; and (3) an attenuated fibrous capsule response. PGS-CinA matrices achieve controlled release CLA for 7 d, which increases the local density of macrophages with M2 phenotypes in vivo. CLA-mediated macrophage polarization is concomitant with reduced dermal downgrowth and skin contraction. Taken together, CLA-eluting PGS-CinA elastomers represent a viable coating strategy to reduce epidermal downgrowth in percutaneous devices.

downgrowth. CLA-eluting elastomeric matrices are therefore suitable as coatings for catheters that need regular weekly replacement. The 7-day time period exceeds minimum intravenous catheter replacement time (72−96 h) that the US Centers for Disease Control and Prevention (CDC) currently recommends.59 This approach can therefore extend the use of catheters in a prospective clinical setting. The fibrous capsule thickness surrounding percutaneous elastomeric implants was measured (two-way ANOVA, F = 0.0872, p < 0.001) (Figure S4). Fibrous capsule thickness surrounding CLAeluting matrices and the blank matrices at 14 d were measured to be 88.99 ± 28.31 μm and 60.49 ± 7.54 μm, respectively. The fibrous capsule is well within the nominal 200−250 μm threshold that is suggested for implanted biomaterials.60 Contraction of Mouse Skin over Inserted Elastomeric Matrices. Skin over the percutaneous implants or a skin bridge (Figure 6a) was contracted over time after a surgery. Prior work suggests that contraction correlates with dermal migration around a percutaneous device in a mouse model and should be assessed for long-term implants.7 However, in this study, dermal contraction occurs within 1 week for all matrices (Figure 6). These findings suggest that skin bridge length and dermal downgrowth are decoupled. CLA-eluting matrices best preserve the bridge length (98.9 ± 6.4%) at 7 d, compared to other matrices (Kruskal−Wallis, p < 0.05). As mentioned earlier, the density of M2 macrophages around CLA-eluting PGS-CinA implants is also the highest compared to all other conditions at 7 d. We cautiously speculate that CLA-eluting matrices increase the local density of M2 macrophages, which ultimately contribute to reduced dermal contraction.

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsbiomaterials.6b00192. Mechanical and physical characterization of PGS-CinA elastomer, quantifying dermal downgrowth, gross examination of implanted mouse, in vitro assessment of inflammatory response to small molecules, inhibition of NF-κB activation by IL-10, CLA, and LA, fibrous capsule thickness, elastic modulus of PGS-CinA films as a function of the degree of substitution and cross-linking process, loading concentration, and release kinetics (PDF) E

DOI: 10.1021/acsbiomaterials.6b00192 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Article

ACS Biomaterials Science & Engineering

■

(14) Iwahashi, M.; Kasahara, Y.; Minami, H.; Matsuzawa, H.; Suzuki, M.; Ozaki, Y. Molecular Behaviors of n-Fatty Acids in Liquid State. J. Oleo Sci. 2002, 51 (3), 157−164. (15) Iwahashi, M.; Yamaguchi, Y.; Ogura, Y.; Suzuki, M. Dynamical Structures of Normal Alkanes, Alcohols, and Fatty Acids in the Liquid State as Determined by Viscosity, Self-Diffusion Coefficient, Infrared Spectra, and 13C NMR Spin-Lattice Relaxation Time Measurements. Bull. Chem. Soc. Jpn. 1990, 63 (8), 2154−2158. (16) Zhu, C.; Kustra, S. R.; Bettinger, C. J. Photocrosslinkable biodegradable elastomers based on cinnamate-functionalized polyesters. Acta Biomater. 2013, 9 (7), 7362−7370. (17) Badylak, S. F.; Valentin, J. E.; Ravindra, A. K.; McCabe, G. P.; Stewart-Akers, A. M. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng., Part A 2008, 14 (11), 1835− 1842. (18) Zhang, L.; Cao, Z.; Bai, T.; Carr, L.; Ella-Menye, J.-R.; Irvin, C.; Ratner, B. D.; Jiang, S. Zwitterionic hydrogels implanted in mice resist the foreign-body reaction. Nat. Biotechnol. 2013, 31 (6), 553−556. (19) Sussman, E. M.; Halpin, M. C.; Muster, J.; Moon, R. T.; Ratner, B. D. Porous Implants Modulate Healing and Induce Shifts in Local Macrophage Polarization in the Foreign Body Reaction. Ann. Biomed. Eng. 2014, 42 (7), 1508−1516. (20) Bettinger, C. J.; Bruggeman, J. P.; Borenstein, J. T.; Langer, R. S. Amino alcohol-based degradable poly(ester amide) elastomers. Biomaterials 2008, 29 (15), 2315−2325. (21) Hu, W.; Xie, J.; Chau, H. W.; Si, B. C. Evaluation of parameter uncertainties in nonlinear regression using Microsoft Excel Spreadsheet. Environ. Syst. Res. 2015, 4 (1), 1−12. (22) Chehroudi, B.; Brunette, D. M. Subcutaneous microfabricated surfaces inhibit epithelial recession and promote long-term survival of percutaneous implants. Biomaterials 2002, 23 (1), 229−237. (23) Fleckman, P.; Olerud, J. E. Models for the histologic study of the skin interface with percutaneous biomaterials. Biomed. Mater. 2008, 3 (3), 34006. (24) Nam, K.; Matsushima, R.; Kimura, T.; Fujisato, T.; Kishida, A. In Vivo Characterization of a Decellularized Dermis-Polymer Complex for Use in Percutaneous Devices. Artif. Organs 2014, 38 (12), 1060− 1065. (25) Seidi, A.; Ramalingam, M.; Elloumi-Hannachi, I.; Ostrovidov, S.; Khademhosseini, A. Gradient biomaterials for soft-to-hard interface tissue engineering. Acta Biomater. 2011, 7 (4), 1441−1451. (26) Viswanathan, P.; Guvendiren, M.; Chua, W.; Telerman, S. B.; Liakath-Ali, K.; Burdick, J. A.; Watt, F. M. Mimicking the topography of the epidermal−dermal interface with elastomer substrates. Integr. Biol. 2016, 8 (1), 21−29. (27) Yoda, R. Elastomers for biomedical applications. J. Biomater. Sci., Polym. Ed. 1998, 9 (6), 561−626. (28) Li, Y.; Thouas, G. A.; Chen, Q.-Z. Biodegradable soft elastomers: synthesis/properties of materials and fabrication of scaffolds. RSC Adv. 2012, 2 (22), 8229−8242. (29) Webb, A. R.; Yang, J.; Ameer, G. A. Biodegradable polyester elastomers in tissue engineering. Expert Opin. Biol. Ther. 2004, 4 (6), 801−812. (30) Casey, M. E.; Jedlicka, S. S. Neuronal Outgrowth and Differentiation on Poly(glycerol sebacate). In Symposium KK − Biomaterials for Tissue Regeneration; MRS Online Proceedings Library Archive; Materials Research Society, 2012; Vol. 1417, p mrsf11-1417kk06-16 (9 pages). DOI: 10.1557/opl.2012.744 (31) Liang, X.; Boppart, S. A. Biomechanical Properties of In Vivo Human Skin From Dynamic Optical Coherence Elastography. IEEE Trans. Biomed. Eng. 2010, 57 (4), 953−959. (32) Hendriks, F. M.; Brokken, D.; Van Eemeren, J. T. W. M.; Oomens, C. W. J.; Baaijens, F. P. T.; Horsten, J. B. a. M. A numericalexperimental method to characterize the non-linear mechanical behaviour of human skin. Skin Res. Technol. 2003, 9 (3), 274−283. (33) Cervera, M.; Dolz, M.; Herraez, J. V.; Belda, R. Evaluation of the elastic behaviour of central venous PVC, polyurethane and silicone catheters. Phys. Med. Biol. 1989, 34 (2), 177−183.

AUTHOR INFORMATION

Corresponding Authors

*(P.G.C.) E-mail: [email protected]. *(C.J.B.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the following people for their help: Dr. Newell Washburn for use of the Leica DM IL LED microscope, and Lauren Ernst, and Dr. Marcel Bruchez (Director) of MBIC/ CMU for use of the MBIC facilities at Carnegie Mellon University. We also acknowledge funding provided by the National Institutes of Health (NIBIB R21RB015165).

■

REFERENCES

(1) van Baal, M. C.; van Santvoort, H. C.; Bollen, T. L.; Bakker, O. J.; Besselink, M. G.; Gooszen, H. G. Systematic review of percutaneous catheter drainage as primary treatment for necrotizing pancreatitis. Br. J. Surg. 2011, 98 (1), 18−27. (2) Pittiruti, M.; Hamilton, H.; Biffi, R.; MacFie, J.; Pertkiewicz, M. ESPEN. ESPEN Guidelines on Parenteral Nutrition: central venous catheters (access, care, diagnosis and therapy of complications). Clin. Nutr. 2009, 28 (4), 365−377. (3) Wenzel, R. P.; Edmond, M. B. The impact of hospital-acquired bloodstream infections. Emerging Infect. Dis. 2001, 7 (2), 174−177. (4) Edgeworth, J. D.; Treacher, D. F.; Eykyn, S. J. A 25-year study of nosocomial bacteremia in an adult intensive care unit. Crit. Care Med. 1999, 27 (8), 1421−1428. (5) von Recum, A. F. Applications and failure modes of percutaneous devices: A review. J. Biomed. Mater. Res. 1984, 18 (4), 323−336. (6) Maki, D. G.; Kluger, D. M.; Crnich, C. J. The Risk of Bloodstream Infection in Adults With Different Intravascular Devices: A Systematic Review of 200 Published Prospective Studies. Mayo Clin. Proc. 2006, 81 (9), 1159−1171. (7) Fleckman, P.; Usui, M.; Zhao, G.; Underwood, R.; Maginness, M.; Marshall, A.; Glaister, C.; Ratner, B.; Olerud, J. Cutaneous and inflammatory response to long-term percutaneous implants of spheretemplated porous/solid poly(HEMA) and silicone in mice. J. Biomed. Mater. Res., Part A 2012, 100A (5), 1256−1268. (8) Walboomers, X. F.; Jansen, J. A. Effect of microtextured surfaces on the performance of percutaneous devices. J. Biomed. Mater. Res., Part A 2005, 74A (3), 381−387. (9) Brown, B. N.; Londono, R.; Tottey, S.; Zhang, L.; Kukla, K. A.; Wolf, M. T.; Daly, K. A.; Reing, J. E.; Badylak, S. F. Macrophage Phenotype as a Predictor of Constructive Remodeling following the Implantation of Biologically Derived Surgical Mesh Materials. Acta Biomater. 2012, 8 (3), 978−987. (10) Brown, B. N.; Ratner, B. D.; Goodman, S. B.; Amar, S.; Badylak, S. F. Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine. Biomaterials 2012, 33 (15), 3792−3802. (11) Yu, Y.; Correll, P. H.; Vanden Heuvel, J. P. Conjugated linoleic acid decreases production of pro-inflammatory products in macrophages: evidence for a PPARγ-dependent mechanism. Biochim. Biophys. Acta, Mol. Cell Biol. Lipids 2002, 1581 (3), 89−99. (12) Rodrigues, H. G.; Vinolo, M. A. R.; Magdalon, J.; Vitzel, K.; Nachbar, R. T.; Pessoa, A. F. M.; dos Santos, M. F.; Hatanaka, E.; Calder, P. C.; Curi, R. Oral Administration of Oleic or Linoleic Acid Accelerates the Inflammatory Phase of Wound Healing. J. Invest. Dermatol. 2012, 132 (1), 208−215. (13) McCarthy, C.; Duffy, M. M.; Mooney, D.; James, W. G.; Griffin, M. D.; Fitzgerald, D. J.; Belton, O. IL-10 mediates the immunoregulatory response in conjugated linoleic acid-induced regression of atherosclerosis. FASEB J. 2013, 27 (2), 499−510. F

DOI: 10.1021/acsbiomaterials.6b00192 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX

Article

ACS Biomaterials Science & Engineering (34) Sun, Z.-J.; Chen, C.; Sun, M.-Z.; Ai, C.-H.; Lu, X.-L.; Zheng, Y.F.; Yang, B.-F.; Dong, D.-L. The application of poly (glycerol− sebacate) as biodegradable drug carrier. Biomaterials 2009, 30 (28), 5209−5214. (35) Liu, Q.; Jiang, L.; Shi, R.; Zhang, L. Synthesis, preparation, in vitro degradation, and application of novel degradable bioelastomers A review. Prog. Polym. Sci. 2012, 37 (5), 715−765. (36) Canal, T.; Peppas, N. A. Correlation between mesh size and equilibrium degree of swelling of polymeric networks. J. Biomed. Mater. Res. 1989, 23 (10), 1183−1193. (37) Fetters, L. J.; Lohse, D. J.; Colby, R. H. Chain Dimensions and Entanglement Spacings. In Physical Properties of Polymers Handbook; Mark, J. E., Ed.; Springer: New York, 2007; pp 447−454. (38) Wang, Y.; Ameer, G. A.; Sheppard, B. J.; Langer, R. A tough biodegradable elastomer. Nat. Biotechnol. 2002, 20 (6), 602−606. (39) Deng, B.; Wehling-Henricks, M.; Villalta, S. A.; Wang, Y.; Tidball, J. G. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J. Immunol. 2012, 189 (7), 3669−3680. (40) Makita, N.; Hizukuri, Y.; Yamashiro, K.; Murakawa, M.; Hayashi, Y. IL-10 enhances the phenotype of M2 macrophages induced by IL-4 and confers the ability to increase eosinophil migration. Int. Immunol. 2015, 27 (3), 131−141. (41) Baker, P. R. S.; Lin, Y.; Schopfer, F. J.; Woodcock, S. R.; Groeger, A. L.; Batthyany, C.; Sweeney, S.; Long, M. H.; Iles, K. E.; Baker, L. M. S.; et al. Fatty Acid Transduction of Nitric Oxide Signaling Multiple Nitrated Unsaturated Fatty Acid Derivatives Exist in Human Blood and Urine and Serve As Endogenous Peroxisome Proliferator-Activated Receptor Ligands. J. Biol. Chem. 2005, 280 (51), 42464−42475. (42) Bouhlel, M. A.; Derudas, B.; Rigamonti, E.; Dièvart, R.; Brozek, J.; Haulon, S.; Zawadzki, C.; Jude, B.; Torpier, G.; Marx, N.; et al. PPARγ Activation Primes Human Monocytes into Alternative M2Macrophages with Anti-inflammatory Properties. Cell Metab. 2007, 6 (2), 137−143. (43) Sica, A.; Mantovani, A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 2012, 122 (3), 787−795. (44) Schopfer, F. J.; Lin, Y.; Baker, P. R. S.; Cui, T.; Garcia-Barrio, M.; Zhang, J.; Chen, K.; Chen, Y. E.; Freeman, B. A. Nitrolinoleic acid: An endogenous peroxisome proliferator-activated receptor γ ligand. Proc. Natl. Acad. Sci. U. S. A. 2005, 102 (7), 2340−2345. (45) Mantovani, A.; Sica, A.; Sozzani, S.; Allavena, P.; Vecchi, A.; Locati, M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004, 25 (12), 677−686. (46) Keepers, T. R.; Gross, L. K.; Obrig, T. G. Monocyte Chemoattractant Protein 1, Macrophage Inflammatory Protein 1α, and RANTES Recruit Macrophages to the Kidney in a Mouse Model of Hemolytic-Uremic Syndrome. Infect. Immun. 2007, 75 (3), 1229− 1236. (47) Aurell, C. A.; Wistrom, A. O. Critical Aggregation Concentrations of Gram-Negative Bacterial Lipopolysaccharides (LPS). Biochem. Biophys. Res. Commun. 1998, 253 (1), 119−123. (48) Siepmann, J.; Siegel, R. A.; Siepmann, F. Diffusion Controlled Drug Delivery Systems. In Fundamentals and Applications of Controlled Release Drug Delivery; Siepmann, J., Siegel, R. A., Rathbone, M. J., Eds.; Advances in Delivery Science and Technology; Springer: New York, 2012; pp 127−152. (49) Korsmeyer, R. W.; Gurny, R.; Doelker, E.; Buri, P.; Peppas, N. A. Mechanisms of solute release from porous hydrophilic polymers. Int. J. Pharm. 1983, 15 (1), 25−35. (50) Handbook of Pharmaceutical Controlled Release Technology, 1st ed.; CRC Press: Boca Raton, FL, 2000; pp 13−14. (51) Lustig, S. R.; Peppas, N. A. Solute diffusion in swollen membranes. IX. Scaling laws for solute diffusion in gels. J. Appl. Polym. Sci. 1988, 36 (4), 735−747. (52) Zhang, X.-Z.; Wu, D.-Q.; Chu, C.-C. Synthesis, characterization and controlled drug release of thermosensitive IPN−PNIPAAm hydrogels. Biomaterials 2004, 25 (17), 3793−3805.

(53) Stringer, J. L.; Peppas, N. A. Diffusion of small molecular weight drugs in radiation-crosslinked poly(ethylene oxide) hydrogels. J. Controlled Release 1996, 42 (2), 195−202. (54) Novak, M. L.; Weinheimer-Haus, E. M.; Koh, T. J. Macrophage Activation and Skeletal Muscle Healing Following Traumatic Injury. J. Pathol. 2014, 232 (3), 344−355. (55) Khanna, S.; Biswas, S.; Shang, Y.; Collard, E.; Azad, A.; Kauh, C.; Bhasker, V.; Gordillo, G. M.; Sen, C. K.; Roy, S. Macrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice. PLoS One 2010, 5 (3), e9539. (56) Brown, B. N.; Sicari, B. M.; Badylak, S. F. Rethinking Regenerative Medicine: A Macrophage-Centered Approach. Front. Immunol. 2014, 5. DOI: 10.3389/fimmu.2014.00510. (57) Jetten, N.; Roumans, N.; Gijbels, M. J.; Romano, A.; Post, M. J.; de Winther, M. P. J.; van der Hulst, R. R. W. J.; Xanthoulea, S. Wound Administration of M2-Polarized Macrophages Does Not Improve Murine Cutaneous Healing Responses. PLoS One 2014, 9 (7), e102994. (58) Pini, M.; Touch, S.; Poirier, H.; Dalmas, E.; Niot, I.; Rouault, C.; Druart, C.; Delzenne, N.; Clément, K.; André, S.; et al. Adipose tissue adaptive response to trans-10,cis-12-conjugated linoleic acid engages alternatively activated M2 macrophages. FASEB J. 2016, 30 (1), 241− 251. (59) O’Grady, N. P.; Alexander, M.; Burns, L. A.; Dellinger, E. P.; Garland, J.; Heard, S. O.; Lipsett, P. A.; Masur, H.; Mermel, L. A.; Pearson, M. L.; et al. Guidelines for the prevention of intravascular catheter-related infections. Am. J. Infect. Control 2011, 39 (4), S1−S34. (60) Imai, Y.; Masuhara, E. Long-term in vivo studies of poly(2hydroxyethyl methacrylate). J. Biomed. Mater. Res. 1982, 16 (5), 609− 617.

G

DOI: 10.1021/acsbiomaterials.6b00192 ACS Biomater. Sci. Eng. XXXX, XXX, XXX−XXX