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Background Platelet function tests such as thrombelastography platelet mapping and impedance aggregometry have demonstrated universal platelet dysfunction in trauma patients. In this study, we introduce the measurement of platelet contraction force as a test of platelet function. We hypothesize that force will correlate with established coagulation tests such as thrombelastography, demonstrate significant differences between healthy subjects and trauma patients, and identify critically ill trauma patients. Methods Blood samples were prospectively collected from level 1 trauma patients at initial presentation, assayed for force of and time to contraction and compared with thrombelastography. Blood from healthy subjects was assayed to establish a reference range. Results from trauma patients were compared with healthy controls and trauma patients that died. Results The study includes one hundred trauma patients with mean age 45 y, 74% were male, and median injury severity score of 14 ± 12. Patients that survived (n = 90) demonstrated significantly elevated platelet contraction force compared with healthy controls (n = 12) (6390 ± 2340 versus 4790 ± 470 μN, P = 0.043) and trauma patients that died (n = 10) (6390 ± 2340 versus 2860 ± 1830 μN, P = 0.0001). Elapsed time to start of platelet contraction was faster in trauma patients that survived compared with healthy controls (660 ± 467 versus 1130 ± 140 s, P = 0.0022) and those that died (660 ± 470 versus 1460 ± 1340 s, P Conclusions In contrast with all existing platelet function tests reported in the literature, which report platelet dysfunction in trauma patients, contractile force demonstrates hyperfunction in surviving trauma patients and dysfunction in nonsurvivors. Platelet contraction reflects platelet metabolic reserve and thus may be a potential biomarker for survival after trauma. Contractile force warrants further investigation to predict mortality in severely injured trauma patients.

The immune system plays critical roles in promoting tissue repair during recovery from neurotrauma but is also responsible for unchecked inflammation that causes neuronal cell death, systemic stress, and lethal immunodepression. Understanding the immune response to neurotrauma is an urgent priority, yet current models of traumatic brain injury (TBI) inadequately recapitulate the human immune response. Here, we report the first description of a humanized model of TBI and show that TBI places significant stress on the bone marrow. Hematopoietic cells of the marrow are regionally decimated, with evidence pointing to exacerbation of underlying graft-versus-host disease (GVHD) linked to presence of human T cells in the marrow. Despite complexities of the humanized mouse, marrow aplasia caused by TBI could be alleviated by cell therapy with human bone marrow mesenchymal stromal cells (MSCs). We conclude that MSCs could be used to ameliorate syndromes triggered by hypercytokinemia in settings of secondary inflammatory stimulus that upset marrow homeostasis such as TBI. More broadly, this study highlights the importance of understanding how underlying immune disorders including immunodepression, autoimmunity, and GVHD might be intensified by injury.

3D printing is an additive manufacturing process allowing the creation of solid objects directly from a digital file. We believe recent advances in additive manufacturing may be applicable to surgical instrument design. This study investigates the feasibility, design and fabrication process of usable 3D printed surgical instruments. The computer-aided design package SolidWorks (Dassault Systemes SolidWorks Corp., Waltham MA) was used to design a surgical set including hemostats, needle driver, scalpel handle, retractors and forceps. These designs were then printed on a selective laser sintering (SLS) Sinterstation HiQ (3D Systems, Rock Hill SC) using DuraForm EX plastic. The final printed products were evaluated by practicing general surgeons for ergonomic functionality and performance, this included simulated surgery and inguinal hernia repairs on human cadavers. Improvements were identified and addressed by adjusting design and build metrics. Repeated manufacturing processes and redesigns led to the creation of multiple functional and fully reproducible surgical sets utilizing the user feedback of surgeons. Iterative cycles including design, production and testing took an average of 3 days. Each surgical set was built using the SLS Sinterstation HiQ with an average build time of 6 h per set. Functional 3D printed surgical instruments are feasible. Advantages compared to traditional manufacturing methods include no increase in cost for increased complexity, accelerated design to production times and surgeon specific modifications.

We previously demonstrated that the intravenous delivery of multipotent adult progenitor cells (MAPCs) after traumatic brain injury (TBI) in rodents provides neuroprotection by preserving the blood-brain barrier and systemically attenuating inflammation in the acute time frame following cell treatment; however, the long-term behavioral and anti-inflammatory effects of MAPC administration after TBI have yet to be explored. We hypothesized that the intravenous injection of MAPCs after TBI attenuates the inflammatory response (as measured by microglial morphology) and improves performance at motor tasks and spatial learning (Morris water maze [MWM]). MAPCs were administered intravenously 2 and 24 hours after a cortical contusion injury (CCI). We tested four groups at 120 days after TBI: sham (uninjured), injured but not treated (CCI), and injured and treated with one of two concentrations of MAPCs, either 2 million cells per kilogram (CCI-2) or 10 million cells per kilogram (CCI-10). CCI-10 rats showed significant improvement in left hind limb deficit on the balance beam. On the fifth day of MWM trials, CCI-10 animals showed a significant decrease in both latency to platform and distance traveled compared with CCI. Probe trials revealed a significant decrease in proximity measure in CCI-10 compared with CCI, suggesting improved memory retrieval. Neuroinflammation was quantified by enumerating activated microglia in the ipsilateral hippocampus. We observed a significant decrease in the number of activated microglia in the dentate gyrus in CCI-10 compared with CCI. Our results demonstrate that intravenous MAPC treatment after TBI in a rodent model offers long-term improvements in spatial learning as well as attenuation of neuroinflammation.

BACKGROUND : Current abdominal compartment syndrome (ACS) models rely on intraperitoneal instillation of fluid, air, and other space-occupying substances. Although this allows for the study of the effects of increased abdominal pressure, it poorly mimics its pathogenesis. We have developed the first reported large animal model of ACS incorporating hemorrhagic shock/resuscitation. METHODS : Hemorrhagic shock was induced and maintained (1 hour) in 12 Yorkshire swine by bleeding to a mean arterial pressure (MAP) of 50 mm Hg. The collected blood plus two additional volumes of crystalloid was then reinfused. Mesenteric venous hypertension was induced by tightening a previously placed portal vein snare in a nonocclusive manner to mimic the effects of abdominal packing. Crystalloids were infused to maintain MAP. Hemodynamic measurements, abdominal pressure, peak inspiratory pressures, urine output, and blood chemistries were measured sequentially. Animals were studied for 36 hours after decompression. RESULTS : ACS (intra-abdominal pressure of > or =20 mm Hg with new organ dysfunction) developed in all animals. There were significant increases in peak inspiratory pressure, central venous pressure, and pulmonary artery pressure and decreases in MAP upon development of ACS. Urine output was significantly decreased before decompression. Mean blood lactate decreased and base excess increased significantly after decompression. CONCLUSIONS : We have created the first reported physiologic animal ACS model incorporating hemorrhagic shock/resuscitation and the effects of damage control surgery.

Traumatic brain injury (TBI) is a major cause of morbidity and mortality in the United States. Current clinical therapy is focused on optimization of the acute/subacute intracerebral milieu, minimizing continued cell death, and subsequent intense rehabilitation to ameliorate the prolonged physical, cognitive, and psychosocial deficits that result from TBI. Adult progenitor (stem) cell therapies have shown promise in pre-clinical studies and remain a focus of intense scientific investigation. One of the fundamental challenges to successful translation of the large body of pre-clinical work is the delivery of progenitor cells to the target location/organ. Classically used vehicles such as intravenous and intra arterial infusion have shown low engraftment rates and risk of distal emboli. Novel delivery methods such as nanofiber scaffold implantation could provide the structural and nutritive support required for progenitor cell proliferation, engraftment, and differentiation. The focus of this review is to explore the current state of the art as it relates to current and novel progenitor cell delivery methods.

In trauma patients, continuous arteriovenous (AV) rewarming can effectively reverse hypothermia even if associated with hypovolemia. In battlefield conditions, however, portable fluid warmers driven by battery power show limited capacities. We studied the efficacy and safety of a portable fluid warmer that utilizes controlled hydrocarbon combustion (nonflame) for heat generation during continuous AV rewarming in a large animal model of hypothermia and hemorrhagic shock. Six dogs (26.1 +/- 0.8 kg) were cooled to a core temperature of 30 degrees C (hypo 1). After rewarming to 37 degrees C, dogs were bled by 20% of their estimated blood volume and cooled again to 30 degrees C (hypo 2) followed by rewarming. We recorded temperature (blood, esophageal, rectal, and bladder), left ventricular performance, hemodynamic parameters including superior mesenteric artery (SMA) flow and blood flow through the fluid warmer. Especially, we measured the effect of the AV-shunt on cardiac output and regional blood flow (superior mesenteric artery). Rewarming after hypothermia took 45 +/- 6 minutes (hypothermia 1) and 55 +/- 6 minutes (hypothermia 2), respectively. The AV-shunt flow was correlated to the cardiac output and affected neither cardiac output nor regional blood flow at any time point during the experiment. Arteriovenous rewarming, using the tested portable fluid warmer, effectively reversed hypothermia without compromising hemodynamics or regional blood flow.

Background Patients with traumatic brain injury (TBI) often suffer from gastrointestinal dysfunction including intolerance to enteral feedings. However, it is unclear how TBI affects small intestinal contractile activity. The purpose of this study was to determine if TBI affects intestinal smooth muscle function. Methods Sprague–Dawley rats were subjected to controlled cortical impact injury (TBI). Sham animals underwent a similar surgery but no injury (SHAM). Animals were sacrificed 1, 3, and 7 days after TBI and intestinal smooth muscle tissue was collected for measurement of contractile activity and transit, NF-kB activity, and cytokine levels. Brains were collected after sacrifice to determine volume loss due to injury. Key Results Contractile activity decreased significantly in ileum, but not jejunum, in the TBI group 7 days after injury compared with SHAM. Brain volume loss increased significantly 7 days after injury compared with 3 days and correlated significantly with the contractile activity 1 day after injury. In the intestinal smooth muscle, NF-kB activity increased significantly in the TBI group 3 and 7 days after injury vs SHAM. Wet to dry weight ratio, indicating edema, also increased significantly in the TBI group. Interleukin-1α, -1β, and -17 increased significantly in the TBI group compared with SHAM. Conclusions & Inferences Traumatic brain injury causes a delayed but significant decrease in intestinal contractile activity in the ileum leading to delayed transit. The decreased intestinal contractile activity is attributed to secondary inflammatory injury as evidenced by increased NF-kB activity, increased edema, and increased inflammatory cytokines in the intestinal smooth muscle.

We demonstrate the design of thin flexible pressure sensors based on piezoelectric PVDF-TrFE (polyvinyledenedifluoride-tetrafluoroethylene) co-polymer film, which can be integrated onto a catheter, where the compact inner lumen space limit the dimensions of the pressure sensors. Previously, we demonstrated that the thin-film sensors of one micrometer thickness were shown to have better performance compared to the thicker film with no additional electrical poling or mechanical stretching due to higher crystallinity. The pressure sensors can be mass producible using standard lithography process, with excellent control of film uniformity and thickness down to one micrometer. The fabricated pressure sensors were easily mountable on external surface of commercial catheters. Elaborate experiments were performed to demonstrate the applicability of PVDF sensors towards catheter based biomedical application. The resonant frequency of the PVDF sensor was found to be 6.34 MHz. The PVDF sensors can operate over a broad pressure range of 0-300 mmHg. The average sensitivity of the PVDF sensor was found to be four times higher (99 μV/mmHg) than commercial pressure sensor while the PVDF sensor (0.26 s) had fivefold shorter response time than commercial pressure sensor (1.30 s), making the PVDF sensors highly suitable for real-time pressure measurements using catheters.

INTRODUCTION: Under normoxic conditions, cancer cells use aerobic glycolysis as opposed to glucose oxidation for energy production. This altered metabolic phenotype correlates with poor outcomes in neuroblastoma. Hypoxia-inducible factor-1 alpha (HIF-1a) and pyruvate dehydrogenase kinase 4 (PDK4) positively regulate aerobic glycolysis, while pyruvate dehydrogenase phosphatase 2 (PDP2) promotes glucose oxidation. We showed that gastrin-releasing peptide receptor (GRPR) signaling promotes aggressive phenotype in neuroblastoma. Here, we sought to determine whether GRPR regulates the glucose metabolic pathway and its effect on neuroblastoma tumorigenesis.

Background We sought to determine the effect of peritoneal fluid from a novel animal model of abdominal compartment syndrome (ACS) on the proinflammatory status of polymorphonuclear leukocytes (PMNs) and monocytes. We hypothesize that peritoneal fluid is a potential priming and/or activating agent for PMNs/monocytes. Methods ACS was induced in female Yorkshire swine, and peritoneal fluid was collected at the time of decompressive laparotomy. Naive PMNs/monocytes were primed and/or activated with peritoneal fluid, phosphatidylcholine (PAF) plus peritoneal fluid, peritoneal fluid plus n-formyl-met-leu-phe (fMLP), and peritoneal fluid plus phorbol 12-myristate 13-acetate (PMA). Activation was determined by surface marker expression of integrins (CD11b an CD18) and selectins (CD62L). Additionally, proinflammatory cytokines in peritoneal fluid were analyzed. Results Peritoneal fluid did not activate PMNs but increased CD11b expression on monocytes. When used as a primer for fMLP- or PMA-induced activation, peritoneal fluid significantly increased CD11b and CD18 expression on PMNs and monocytes. Peritoneal fluid collected at 6 and 12 h post decompressive laparotomy had similar effects. Interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were increased in peritoneal fluid. Conclusion Peritoneal fluid represents a primer for PMNs/monocytes and seems to act through receptor-dependent and receptor-independent pathways. Strategies to reduce the amount of peritoneal fluid may decrease the locoregional and systemic inflammatory response by reducing priming and activation of neutrophils/monocytes.

Cerebral edema is a common and potentially devastating sequel of traumatic brain injury. We developed and validated a system capable of tissue impedance analysis, which was found to correlate with cerebral edema.Constant sinusoidal current (50 microA), at frequencies from 500 to 5000 Hz, was applied across a bipolar electrode unit superficially placed in a rat brain after traumatic brain injury. Rats were randomized to three groups: severe controlled cortical injury (CCI), mild CCI, or sham injury. At 60 h post-CCI, cerebral voltage and phase angle were measured at each frequency at the site of injury, at the penumbral region, at the ipsilateral frontal region, and in the contralateral hemisphere. Impedance measurements were also obtained in vivo. The electrical properties of varied injuries and specified locations were compared using a repeated measures analysis of variance (RMANOVA), were correlated with regional tissue water percentage using regression analyses, and were combined to generate polar coordinates.The measured voltage was significantly different at the site of injury (P0.0001), in the penumbra (P=0.002), and in the contralateral hemisphere (P=0.005) when severe, mild, and sham CCI rats were compared. Severely injured rats had statistically different voltage measurements when the various sites were compared (P=0.002). The ex vivo measurements correlated with in vivo measurements. Further, the impedance measurements correlated with measured tissue water percentage at the site of injury (R2=0.69; P0.0001). The creation of a polar coordinate graph, incorporating voltage and phase angle measurements, enabled the identification of impedance areas unique to normal, mild edema, and severe edema measurements in the rat brain.Electrical measurements and tissue water percentages quantified regional and severity differences in rat brain edema after CCI. Impedance was inversely proportional to the tissue water percentage. Thus, impedance measurement can be used to quantify severity of cerebral edema in real time at specific sites.