Browsing by Author "McKinley, Todd O."

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    A Two-Stage Approach Integrating Provisional Biomaterial-Mediated Stabilization Followed by a Definitive Treatment for Managing Volumetric Muscle Loss Injuries
    (MDPI, 2024-06-06) Clark, Andrew R.; Kulwatno, Jonathan; Kanovka, Sergey S.; Klarmann, George J.; Hernandez, Claudia E.; Natoli, Roman M.; McKinley, Todd O.; Potter, Benjamin K.; Dearth, Christopher L.; Goldman, Stephen M.; Orthopaedic Surgery, School of Medicine
    Treatment of volumetric muscle loss (VML) faces challenges due to its unique pathobiology and lower priority in severe musculoskeletal injury management. Consequently, a need exists for multi-stage VML treatment strategies to accommodate delayed interventions owing to comorbidity management or prolonged casualty care in combat settings. To this end, polyvinyl alcohol (PVA) was used at concentrations of 5%, 7.5%, and 10% to generate provisional muscle void fillers (MVFs) of varying stiffness values (1.125 kPa, 3.700 kPa, and 7.699 kPa) to stabilize VML injuries as part of a two-stage approach. These were implanted into a rat model for a duration of 4 weeks, then explanted and either left untreated (control) or treated through minced muscle grafting (MMG). Additional benchmarks included acute MMG and unrepaired groups. At the MVF explant, the 7.5% PVA group exhibited superior neuromuscular function compared to the 5% and 10% PVA groups, the least fibrosis, and the largest median myofiber size among all groups at the 12-week endpoint. Despite the 7.5% PVA’s superiority amongst the two-stage treatment groups, neuromuscular function was neither improved nor impaired relative to acute treatment benchmarks. This suggests that the future success of a two-stage VML treatment strategy will necessitate a more effective definitive intervention.
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    Blood Purification by Non-Selective Hemoadsorption Prevents Death after Traumatic Brain Injury and Hemorrhagic Shock in Rats
    (Wolters Kluwer, 2018-09) McKinley, Todd O.; Lei, Zhigang; Kalbas, Yannik; White, Fletcher A.; Shi, Zhongshang; Wu, Fan; Xu, Zao C.; Rodgers, Richard B.; Anesthesia, School of Medicine
    Background Patients who sustain traumatic brain injury (TBI) and concomitant hemorrhagic shock (HS) are at high risk of high-magnitude inflammation which can lead to poor outcomes and death. Blood purification by hemoadsorption (HA) offers an alternative intervention to reduce inflammation after injury. We tested the hypothesis that HA would reduce mortality in a rat model of TBI and HS. Methods Male Sprague Dawley rats were subjected to a combined injury of a controlled cortical impact (CCI) to their brain and pressure-controlled hemorrhagic shock (HS). Animals were subsequently instrumented with an extracorporeal blood circuit that passed through a cartridge for sham or experimental treatment. In experimental animals, the treatment cartridge was filled with proprietary beads (Cytosorbents; Monmouth Junction, NJ) that removed circulating molecules between 5 KDa and 60 KDa. Sham rats had equivalent circulation but no blood purification. Serial blood samples were analyzed with multiplex technology to quantify changes in a trauma-relevant panel of immunologic mediators. The primary outcome was survival to 96hr post-injury. Results HA improved survival from 47% in sham treated rats to 86% in HA treated rats. There were no treatment-related changes in histologic appearance. HA affected biomarker concentrations both during the treatment and over the ensuing four days after injury. Distinct changes in biomarker concentrations were also measured in survivor and non-survivor rats from the entire cohort of rats indicating biomarker patterns associated with survival and death after injury. Conclusions Blood purification by non-selective HA is an effective intervention to prevent death in a combined TBI/HS rat model. HA changed circulating concentrations of multiple inmmunologically active mediators during the treatment time frame and after treatment. HA has been safely implemented in human patients with sepsis and may be a treatment option after injury.
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    Bone Morphogenetic Protein-2 Rapidly Heals Two Distinct Critical Sized Segmental Diaphyseal Bone Defects in a Porcine Model
    (Oxford University Press, 2023) McKinley, Todd O.; Childress, Paul; Jewell, Emily; Griffin, Kaitlyn S.; Wininger, Austin E.; Tucker, Aamir; Gremah, Adam; Savaglio, Michael K.; Warden, Stuart J.; Fuchs, Robyn K.; Natoli, Roman M.; Shively, Karl D.; Anglen, Jeffrey O.; Chu, Tien-Min Gabriel; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Introduction: Segmental bone defects (SBDs) are devastating injuries sustained by warfighters and are difficult to heal. Preclinical models that accurately simulate human conditions are necessary to investigate therapies to treat SBDs. We have developed two novel porcine SBD models that take advantage of similarities in bone healing and immunologic response to injury between pigs and humans. The purpose of this study was to investigate the efficacy of Bone Morphogenetic Protein-2 (BMP-2) to heal a critical sized defect (CSD) in two novel porcine SBD models. Materials and methods: Two CSDs were performed in Yucatan Minipigs including a 25.0-mm SBD treated with intramedullary nailing (IMN) and a 40.0-mm SBD treated with dual plating (ORIF). In control animals, the defect was filled with a custom spacer and a bovine collagen sponge impregnated with saline (IMN25 Cont, n = 8; ORIF40 Cont, n = 4). In experimental animals, the SBD was filled with a custom spacer and a bovine collage sponge impregnated with human recombinant BMP-2 (IMN25 BMP, n = 8; ORIF40 BMP, n = 4). Healing was quantified using monthly modified Radiographic Union Score for Tibia Fractures (mRUST) scores, postmortem CT scanning, and torsion testing. Results: BMP-2 restored bone healing in all eight IMN25 BMP specimens and three of four ORIF40 BMP specimens. None of the IMN25 Cont or ORIF40 Cont specimens healed. mRUST scores at the time of sacrifice increased from 9.2 (±2.4) in IMN25 Cont to 15.1 (±1.0) in IMN25 BMP specimens (P < .0001). mRUST scores increased from 8.2 (±1.1) in ORIF40 Cont to 14.3 (±1.0) in ORIF40 BMP specimens (P < .01). CT scans confirmed all BMP-2 specimens had healed and none of the control specimens had healed in both IMN and ORIF groups. BMP-2 restored 114% and 93% of intact torsional stiffness in IMN25 BMP and ORIF40 BMP specimens. Conclusions: We have developed two porcine CSD models, including fixation with IMN and with dual-plate fixation. Porcine models are particularly relevant for SBD research as the porcine immunologic response to injury closely mimics the human response. BMP-2 restored healing in both CSD models, and the effects were evident within the first month after injury. These findings support the use of both porcine CSD models to investigate new therapies to heal SBDs.
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    CAMKK2 is Upregulated in Primary Human Osteoarthritis and its Inhibition Protects Against Chondrocyte Apoptosis
    (Elsevier, 2023) Dilley, Julian E.; Seetharam, Abhijit; Ding, Xinchun; Bello, Margaret A.; Shutter, Jennifer; Burr, David B.; Natoli, Roman M.; McKinley, Todd O.; Sankar, Uma; Anatomy, Cell Biology and Physiology, School of Medicine
    Objective: To investigate the role of calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) in human osteoarthritis. Materials and methods: Paired osteochondral plugs and articular chondrocytes were isolated from the relatively healthier (intact) and damaged portions of human femoral heads collected from patients undergoing total hip arthroplasty for primary osteoarthritis (OA). Cartilage from femoral plugs were either flash frozen for gene expression analysis or histology and immunohistochemistry. Chondrocyte apoptosis in the presence or absence of CAMKK2 inhibition was measured using flow cytometry. CAMKK2 overexpression and knockdown in articular chondrocytes were achieved via Lentivirus- and siRNA-mediated approaches respectively, and their effect on pro-apoptotic and cartilage catabolic mechanisms was assessed by immunoblotting. Results: CAMKK2 mRNA and protein levels were elevated in articular chondrocytes from human OA cartilage compared to paired healthier intact samples. This increase was associated with elevated catabolic marker matrix metalloproteinase 13 (MMP-13), and diminished anabolic markers aggrecan (ACAN) and type II collagen (COL2A1) levels. OA chondrocytes displayed enhanced apoptosis, which was suppressed following pharmacological inhibition of CAMKK2. Levels of MMP13, pSTAT3, and the pro-apoptotic marker BAX became elevated when CAMKK2, but not its kinase-defective mutant was overexpressed, whereas knockdown of the kinase decreased the levels of these proteins. Conclusions: CAMKK2 is upregulated in human OA cartilage and is associated with elevated levels of pro-apoptotic and catabolic proteins. Inhibition or knockdown of CAMKK2 led to decreased chondrocyte apoptosis and catabolic protein levels, whereas its overexpression elevated them. CAMKK2 may be a therapeutic target to prevent or mitigate human OA.
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    A Comprehensive Review of Mouse Diaphyseal Femur Fracture Models
    (Elsevier, 2020-07) Gunderson, Zachary J.; Campbell, Zachery R.; McKinley, Todd O.; Natoli, Roman M.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    Complications related to treatment of long bone fractures still stand as a major challenge for orthopaedic surgeons. Elucidation of the mechanisms of bone healing and development, and the subsequent alteration of these mechanisms to improve outcomes, typically requires animal models as an intermediary between in vitro and human clinical studies. Murine models are some of the most commonly used in translational research, and mouse fracture models are particularly diverse, offering a wide variety of customization with distinct benefits and limitations depending on the study. This review critically examines three common femur fracture models in the mouse, namely cortical hole, 3-point fracture (Einhorn), and segmental bone defect. We lay out the general procedure for execution of each model, evaluate the practical implications and important advantages/disadvantages of each and describe recent innovations. Furthermore, we explore the applications that each model is best adapted for in the context of the current state of murine orthopaedic research.
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    Computational evidence for an early, amplified systemic inflammation program in polytrauma patients with severe extremity injuries
    (PLOS, 2019-06-04) Almahmoud, Khalid; Abboud, Andrew; Namas, Rami A.; Zamora, Ruben; Sperry, Jason; Peitzman, Andrew B.; Truitt, Michael S.; Gaski, Greg E.; McKinley, Todd O.; Billiar, Timothy R.; Vodovotz, Yoram; Orthopaedic Surgery, School of Medicine
    Extremity and soft tissue injuries contribute significantly to inflammation and adverse in-hospital outcomes for trauma survivors; accordingly, we examined the complex association between clinical outcomes inflammatory responses in this setting using in silico tools. Two stringently propensity-matched, moderately/severely injured (Injury Severity Score > 16) patient sub-cohorts of ~30 patients each were derived retrospectively from a cohort of 472 blunt trauma survivors and segregated based on their degree of extremity injury severity (above or below 3 on the Abbreviated Injury Scale). Serial blood samples were analyzed for 31 plasma inflammatory mediators. In addition to standard statistical analyses, Dynamic Network Analysis (DyNA) and Principal Component Analysis (PCA) were used to model systemic inflammation following trauma. Patients in the severe extremity injury sub-cohort experienced longer intensive care unit length of stay (LOS), total LOS, and days on a mechanical ventilator, with higher Marshall Multiple Organ Dysfunction (MOD) Scores over the first 7 days post-injury as compared to the mild/moderate extremity injury sub-cohort. The higher severity cohort had statistically significant elevated lactate, base deficit, and creatine phosphokinase on first blood draw, along with significant changes in multiple circulating inflammatory mediators. DyNA pointed to a sustained role for type 17 immunity in both sub-cohorts, along with IFN-γ in the severe extremity injury group. DyNA network complexity increased over 7 days post-injury in the severe injury group, while generally decreasing over this same time period in the mild/moderate injury group. PCA suggested a more robust activation of multiple pathways in the severe extremity injury group as compared to the mild/moderate injury group. These studies thus point to the possibility of self-sustaining inflammation following severe extremity injury vs. resolving inflammation following less severe extremity injury.
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    Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials
    (BioMed Central, 2020-09-30) Sprague, Sheila; Scott, Taryn; Dodds, Shannon; Pogorzelski, David; McKay, Paula; Harris, Anthony D.; Wood, Amber; Thabane, Lehana; Bhandari, Mohit; Mehta, Samir; Gaski, Greg; Boulton, Christina; Marcano-Fernández, Francesc; Guerra-Farfán, Ernesto; Hebden, Joan; O’Hara, Lyndsay M.; Slobogean, Gerard P.; Slobogean, Gerard P.; Sprague, Sheila; Wells, Jeffrey; Bhandari, Mohit; D’Alleyrand, Jean-Claude; Harris, Anthony D.; Mullins, Daniel C.; Thabane, Lehana; Wood, Amber; Della Rocca, Gregory J.; Hebden, Joan; Jeray, Kyle J.; Marchand, Lucas; O’Hara, Lyndsay M.; Zura, Robert; Gardner, Michael J.; Blasman, Jenna; Davies, Jonah; Liang, Stephen; Taljaard, Monica; Devereaux, P. J.; Guyatt, Gordon H.; Heels-Ansdell, Diane; Marvel, Debra; Palmer, Jana; Friedrich, Jeff; O’Hara, Nathan N.; Grissom, Frances; Gitajn, I. Leah; Morshed, Saam; O’Toole, Robert V.; Petrisor, Bradley A.; Camara, Megan; Mossuto, Franca; Joshi, Manjari G.; Fowler, Justin; Rivera, Jessica; Talbot, Max; Dodds, Shannon; Garibaldi, Alisha; Li, Silvia; Nguyen, Uyen; Pogorzelski, David; Rojas, Alejandra; Scott, Taryn; Del Fabbro, Gina; Szasz, Olivia Paige; McKay, Paula; Howe, Andrea; Rudnicki, Joshua; Demyanovich, Haley; Little, Kelly; Mullins, C. Daniel; Medeiros, Michelle; Kettering, Eric; Hale, Diamond; Eglseder, Andrew; Johnson, Aaron; Langhammer, Christopher; Lebrun, Christopher; Manson, Theodore; Nascone, Jason; Paryavi, Ebrahim; Pensy, Raymond; Pollak, Andrew; Sciadini, Marcus; Degani, Yasmin; Demyanovich, Haley K.; Joseph, Katherine; Petrisor, Brad A.; Johal, Herman; Ristevski, Bill; Williams, Dale; Denkers, Matthew; Rajaratnam, Krishan; Al-Asiri, Jamal; Leonard, Jordan; Marcano-Fernández, Francesc A.; Gallant, Jodi; Persico, Federico; Gjorgjievski, Marko; George, Annie; Natoli, Roman M.; Gaski, Greg E.; McKinley, Todd O.; Virkus, Walter W.; Sorkin, Anthony T.; Szatkowski, Jan P.; Baele, Joseph R.; Mullis, Brian H.; Hill, Lauren C.; Hudgins, Andrea; Osborn, Patrick; Pierrie, Sarah; Martinez, Eric; Kimmel, Joseph; Adams, John D.; Beckish, Michael L.; Bray, Christopher C.; Brown, Timothy R.; Cross, Andrew W.; Dew, Timothy; Faucher, Gregory K.; Gurich, Richard W.; Lazarus, David E.; Millon, S. John; Palmer, M. Jason; Porter, Scott E.; Schaller, Thomas M.; Sridhar, Michael S.; Sanders, John L.; Rudisill, L. Edwin; Garitty, Michael J.; Poole, Andrew S.; Sims, Michael L.; Walker, Clark M.; Carlisle, Robert M.; Hofer, Erin Adams; Huggins, Brandon S.; Hunter, Michael D.; Marshall, William A.; Ray, Shea Bielby; Smith, Cory D.; Altman, Kyle M.; Bedard, Julia C.; Loeffler, Markus F.; Pichiotino, Erin R.; Cole, Austin A.; Maltz, Ethan J.; Parker, Wesley; Ramsey, T. Bennett; Burnikel, Alex; Colello, Michael; Stewart, Russell; Wise, Jeremy; Moody, M. Christian; Tanner, Stephanie L.; Snider, Rebecca G.; Townsend, Christine E.; Pham, Kayla H.; Martin, Abigail; Robertson, Emily; Miclau, Theodore; Kandemir, Utku; Marmor, Meir; Matityahu, Amir; McClellan, R. Trigg; Meinberg, Eric; Shearer, David; Toogood, Paul; Ding, Anthony; Donohue, Erin; Belaye, Tigist; Berhaneselase, Eleni; Paul, Alexandra; Garg, Kartik; Gary, Joshua L.; Warner, Stephen J.; Munz, John W.; Choo, Andrew M.; Achor, Timothy S.; Routt, Milton L. “ Chip”; Rao, Mayank; Pechero, Guillermo; Miller, Adam; Hagen, Jennifer E.; Patrick, Matthew; Vlasak, Richard; Krupko, Thomas; Sadasivan, Kalia; Koenig, Chris; Bailey, Daniel; Wentworth, Daniel; Van, Chi; Schwartz, Justin; Dehghan, Niloofar; Jones, Clifford B.; Watson, J. Tracy; McKee, Michael; Karim, Ammar; Talerico, Michael; Sietsema, Debra L.; Williams, Alyse; Dykes, Tayler; Obremskey, William T.; Jahangir, Amir Alex; Sethi, Manish; Boyce, Robert; Stinner, Daniel J.; Mitchell, Phillip; Trochez, Karen; Rodriguez, Andres; Gajari, Vamshi; Rodriguez, Elsa; Pritchett, Charles; Boulton, Christina; Lowe, Jason; Wild, Jason; Ruth, John T.; Taylor, Michel; Seach, Andrea; Saeed, Sabina; Culbert, Hunter; Cruz, Alejandro; Knapp, Thomas; Hurkett, Colin; Lowney, Maya; Prayson, Michael; Venkatarayappa, Indresh; Horne, Brandon; Jerele, Jennifer; Clark, Linda; Marcano-Fernández, Francesc; Jornet-Gibert, Montsant; Martínez-Carreres, Laia; Martí-Garín, David; Serrano-Sanz, Jorge; Sánchez-Fernández, Joel; Sanz-Molero, Matsuyama; Carballo, Alejandro; Pelfort, Xavier; Acerboni-Flores, Francesc; Alavedra-Massana, Anna; Anglada-Torres, Neus; Berenguer, Alexandre; Cámara-Cabrera, Jaume; Caparros-García, Ariadna; Fillat-Gomà, Ferran; Fuentes-López, Ruben; Garcia-Rodriguez, Ramona; Gimeno-Calavia, Nuria; Graells-Alonso, Guillem; Martínez-Álvarez, Marta; Martínez-Grau, Patricia; Pellejero-García, Raúl; Ràfols-Perramon, Ona; Peñalver, Juan Manuel; Domènech, Mònica Salomó; Soler-Cano, Albert; Velasco-Barrera, Aldo; Yela-Verdú, Christian; Bueno-Ruiz, Mercedes; Sánchez-Palomino, Estrella; Guerra-Farfán, Ernesto; García, Yaiza; Romeo, Nicholas M.; Vallier, Heather A.; Breslin, Mary A.; Fraifogl, Joanne; Wilson, Eleanor S.; Wadenpfuhl, Leanne K.; Halliday, Paul G.; Viskontas, Darius G.; Apostle, Kelly L.; Boyer, Dory S.; Moola, Farhad O.; Perey, Bertrand H.; Stone, Trevor B.; Lemke, H. Michael; Zomar, Mauri; Spicer, Ella; Fan, Chen “Brenda”; Payne, Kyrsten; Phelps, Kevin; Bosse, Michael; Karunakar, Madhav; Kempton, Laurence; Sims, Stephen; Hsu, Joseph; Seymour, Rachel; Churchill, Christine; Bartel, Claire; Mayberry, Robert Miles; Brownrigg, Maggie; Girardi, Cara; Mayfield, Ada; Hymes, Robert A.; Schwartzbach, Cary C.; Schulman, Jeff E.; Malekzadeh, A. Stephen; Holzman, Michael A.; Ramsey, Lolita; on behalf of the PREP-IT Investigators; Orthopaedic Surgery, School of Medicine
    An amendment to this paper has been published and can be accessed via the original article.
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    Costs and Radiographic Outcomes of Rotational Ankle Fractures Treated by Orthopaedic Surgeons With or Without Trauma Fellowship Training
    (Wolters Kluwer, 2018-06) Virkus, Walter W.; Wetzel, Robert J.; McKinley, Todd O.; Sorkin, Anthony T.; Cheesman, Jeffrey S.; Hill, Lauren C.; Kempton, Laurence B.; Orthopaedic Surgery, School of Medicine
    Introduction: We evaluated the radiographic outcomes and surgical costs of surgically treated rotational ankle fractures in our health system between providers who had completed a trauma fellowship and those who had not. Methods: We grouped patients into those treated by trauma-trained orthopaedic surgeons (TTOS) and non–trauma-trained orthopaedic surgeons (NTTOS). We graded the quality of fracture reductions and calculated implant-related costs of treatment. Results: A total of 208 fractures met the inclusion criteria, with 119 in the TTOS group and 89 in the NTTOS group. Five patients lost reduction during the follow-up period. The adequacy of fracture reduction at final follow-up did not differ (P = 0.29). The median surgical cost was $2,940 for the NTTOS group and $1,233 for the TTOS group (P < 0.001). Discussion: We found no notable differences in radiographic outcomes between the TTOS and NTTOS groups. Cost analysis demonstrated markedly higher implant-related costs for the NTTOS group, with the median surgical cost being more than twice that for the TTOS group. Level of Evidence: Level III
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    Deep Surgical Site Infection after Fracture Has a Profound Effect on Functional Outcomes
    (Wolters Kluwer, 2024-01-09) Gitajn, Ida Leah; Werth, Paul M.; Carlini, Anthony R.; Bosse, Michael J.; Gary, Joshua L.; Firoozabadi, Reza; Obremskey, William; McKinley, Todd O.; Castillo, Renan C.; O’Toole, Robert V.; Orthopaedic Surgery, School of Medicine
    Background: Fracture-related infection is one of the most challenging complications in orthopaedic trauma surgery. However, the effect of infection on functional and pain-related outcomes has not been well established. The aims of this study were to evaluate functional recovery for patients with fracture and a deep surgical site infection compared with patients with fracture without infection and to evaluate whether pain severity, social support, and preinjury mental health have a moderating effect on the magnitude and direction of the relationship between deep surgical site infection and functional recovery. Methods: This is a secondary retrospective cohort study using prospectively collected data from the VANCO trial (Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection) and the OXYGEN (Supplemental Perioperative Oxygen to Reduce Surgical Site Infection After High Energy Fracture Surgery) trial. In this study, 2,116 patients with tibial plateau, pilon, or calcaneal fractures at high risk for infection were included. Patients were divided into cohorts of patients who experienced a deep surgical site infection and those who did not. The primary outcome measure was the functional outcome using the Veterans RAND 12-Item Health Survey (VR-12). Results: After controlling for covariates, deep surgical site infection was independently associated with functional outcome, with a 3.3-point reduction in the VR-12 Physical Component Score, and pain severity was independently associated with functional outcome, with a 2.5-point reduction in the VR-12 Physical Component Score. Furthermore, the Brief Pain Inventory pain severity demonstrated an important moderating effect on the relationship between infection and functional outcome. In patients with lower pain scores, infection had a large negative impact on functional outcome, whereas, in patients with higher pain scores, infection had no significant impact on functional outcome. Furthermore, the functional outcome in the entire cohort remains at only 61% of baseline. Conclusions: This study documents the negative impact of postoperative infection on functional recovery after injury, as well as the novel finding of pain severity as an important moderating factor. This study emphasizes not only the importance of developing effective interventions designed to reduce postoperative infection, but also the role that factors that moderate pain severity plays in limiting recovery of physical function.
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    Development of a step-down method for altering male C57BL/6 mouse housing density and hierarchical structure: Preparations for spaceflight studies
    (Elsevier, 2018-05) Scofield, David C.; Rytlewski, Jeffrey D.; Childress, Paul; Shah, Kishan; Tucker, Aamir; Khan, Faisal; Peveler, Jessica; Li, Ding; McKinley, Todd O.; Chu, Tien-Min G.; Hickman, Debra L.; Kacena, Melissa A.; Orthopaedic Surgery, School of Medicine
    This study was initiated as a component of a larger undertaking designed to study bone healing in microgravity aboard the International Space Station (ISS). Spaceflight experimentation introduces multiple challenges not seen in ground studies, especially with regard to physical space, limited resources, and inability to easily reproduce results. Together, these can lead to diminished statistical power and increased risk of failure. It is because of the limited space, and need for improved statistical power by increasing sample size over historical numbers, NASA studies involving mice require housing mice at densities higher than recommended in the Guide for the Care and Use of Laboratory Animals (National Research Council, 2011). All previous NASA missions in which mice were co-housed, involved female mice; however, in our spaceflight studies examining bone healing, male mice are required for optimal experimentation. Additionally, the logistics associated with spaceflight hardware and our study design necessitated variation of density and cohort make up during the experiment. This required the development of a new method to successfully co-house male mice while varying mouse density and hierarchical structure. For this experiment, male mice in an experimental housing schematic of variable density (Spaceflight Correlate) analogous to previously established NASA spaceflight studies was compared to a standard ground based housing schematic (Normal Density Controls) throughout the experimental timeline. We hypothesized that mice in the Spaceflight Correlate group would show no significant difference in activity, aggression, or stress when compared to Normal Density Controls. Activity and aggression were assessed using a novel activity scoring system (based on prior literature, validated in-house) and stress was assessed via body weights, organ weights, and veterinary assessment. No significant differences were detected between the Spaceflight Correlate group and the Normal Density Controls in activity, aggression, body weight, or organ weight, which was confirmed by veterinary assessments. Completion of this study allowed for clearance by NASA of our bone healing experiments aboard the ISS, and our experiment was successfully launched February 19, 2017 on SpaceX CRS-10.