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Ibdanelo Cortez,1,* Caitlyn M Gaffney,1,* Riddhi Vichare,2 Caitlin V Crelli,2 Lu Liu,2 Eric Lee,1 Jules Edralin,1 James M Nichols,1 Hoang Vu Pham,1 Syed Mehdi,1 Jelena M Janjic,2 Andrew J Shepherd1 1Laboratories of Neuroimmunology, Department of Symptom Research, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA; 2School of Pharmacy, Duquesne University, Pittsburgh, PA, 15282, USA*These authors contributed equally to this workCorrespondence: Jelena M Janjic, School of Pharmacy, Duquesne University, 600 Forbes Ave., Pittsburgh, PA, 15282, USA, Email janjicj@duq.edu Andrew J Shepherd, Laboratories of Neuroimmunology, Department of Symptom Research, the University of Texas MD Anderson Cancer Center, Unit 1055, 6565 MD Anderson Boulevard, Houston, TX, 77030, USA, Tel +1 713 745-7959, Fax +1 832 750-5153, Email ajshepherd@mdanderson.orgAbstract: Soft tissue injuries often involve muscle and peripheral nerves and are qualitatively distinct from single-tissue injuries. Prior research suggests that damaged innervation compromises wound healing. To test this in a traumatic injury context, we developed a novel mouse model of nerve and lower limb polytrauma, which features greater pain hypersensitivity and more sustained macrophage infiltration than either injury in isolation. We also show that macrophages are crucial mediators of pain hypersensitivity in this model by delivering macrophage-targeted nanoemulsions laden with the cyclooxygenase-2 (COX-2) inhibitor celecoxib. This treatment was more effective in males than females, and more effective when delivered 3 days post-injury than 7 days post-injury. The COX-2 inhibiting nanoemulsion drove widespread anti-inflammatory changes in cytokine expression in polytrauma-affected peripheral nerves. Our data shed new light on the modulation of inflammation by injured nerve input and demonstrate macrophage-targeted nanoimmunomodulation can produce rapid and sustained pain relief following complex injuries. Keywords: nerve injury, muscle contusion, inflammation, celecoxib, nanoemulsion, COX-2

The aim of this study was to investigate the presence of heavy metals/metalloids (Pb, Cd, Hg, Cu, Fe, Zn, As) in the muscle tissue of fish from the Danube River (two locations: Zemun and Grocka). For the purpose of heavy metal determination in fish muscle, 120 samples of six different fish species, Prussian carp, barbel, bream, carp, pike perch, and catfish were collected. For determining heavy metals, we used microwave oven digestion and atomic absorption spectrometer methods. The highest average content of Pb (0.084 ± 0.004 mg kg -1 ), Cd (0.082 ± 0.003 mg kg -1 ), Hg (0.466 ± 0.006 mg kg -1 ), and As (0.333 ± 0.007 mg kg -1 ) was found in the muscle of carp (an omnivorous fish) from Grocka, while the highest average level of Fe (13.60 ± 0.03 mg kg -1 ) was deposited in bream (also omnivorous) from Zemun. Also, the average Cu level (1.62 ± 0.13 mg kg -1 ) was the highest in catfish muscle (a carnivorous fish) from Grocka, while the highest Zn content (11.16 ± 0.17 mg kg -1 ) was determined in muscle of Prussian carp (an omnivorous fish) from Zemun. The highest content of heavy metals (Cu, Fe, and Zn, respectively) in muscle of the six different types of fish from both locations was symmetrically arranged by species (catfish, barbel, and Prussian carp, respectively). Concentrations of Pb, Hg, and As in the Danube River fish muscle were under the maximum residual levels prescribed by the European Union (EU) and the maximum allowed concentrations (MAC) for Serbia. On the other hand, in all fish muscle from both locations (Zemun and Grocka), higher concentrations of Cd than prescribed (MAC) were found, with the exception of bream and pike perch.