A Framework for Concussion Management Strategies in Law Enforcement Officers.

Athletic trainers are increasingly utilized in non-traditional settings, such as in law enforcement, where they can contribute to healthcare management, including concussion management of law enforcement officers (LEOs). Despite the prevalence of concussions among LEOs, there is a notable gap in concussion management guidelines for this population. LEOs may lack the education and resources necessary for concussion recognition and proper management. Drawing on advancements in concussion management in athletes and military personnel, here we present a comprehensive framework for concussion management in LEOs encompassing concussion education, a graduated return to duty (RTD) protocol, and considerations for implementation and documentation specific to law enforcement. We also present several barriers and facilitators to implementation. Due to job requirements, it is critical for law enforcement organizations and their medical providers to adopt a concussion management strategy. Without proper concussion management, LEOs may risk subsequent injury and/or suffer from prolonged recovery and adverse long-term outcomes.

Characterizing Head Acceleration Events in Law Enforcement Cadets During Subject Control Technique Training.

Law enforcement cadets (LECs) complete weeks of subject control technique training. Similar sport-related combat training has been shown to expose participants to head acceleration events (HAEs) that have potential to result in short- and long-term impairments. The purpose of this study was to describe the number and magnitude of HAEs in LECs throughout their training. 37 LECs (7 females; age = 30.6 ± 8.8 years; BMI = 30.0 ± 6.0) were recruited from a law enforcement organization. Participants wore instrumented mouthguards, which recorded all HAEs exceeding a resultant 5 g threshold for training sessions with the potential for HAEs. Participants completed three defensive tactics (DT) training sessions, a DT skill assessment (DTA), and three boxing sessions. Outcome measures included the number of HAEs, peak linear acceleration (PLA), and peak rotational velocity (PRV). There were 2758 true-positive HAEs recorded across the duration of the study. Boxing sessions accounted for 63.7% of all true-positive HAEs, while DT accounted for 31.4% and DTA accounted for 4.9%. Boxing sessions resulted in a higher number of HAEs per session (F2,28 = 48.588, p < 0.001, ηp2 = 0.776), and higher median PLA (F2,28 = 8.609, p = 0.001, ηp2 = 0.381) and median PRV (F2,28 = 11.297, p < 0.001, ηp2 = 0.447) than DT and DTA. The LECs experience a high number of HAEs, particularly during boxing sessions. Although this training is necessary for job duties, HAE monitoring may lead to modifications in training structure to improve participant safety and enhance recovery.

Human Adipose- and Amnion-Derived Mesenchymal Stromal Cells Similarly Mitigate Osteoarthritis Progression in the Dunkin Hartley Guinea Pig.

BACKGROUND: Clinical trials are currently underway to investigate the efficacy of intra-articular administration of mesenchymal stromal cells (MSCs) to mitigate osteoarthritis (OA) progression in the knee. Although multiple MSC sources exist, studies have yet to determine whether differences in therapeutic efficacy exist between them. PURPOSE: To compare the ability of intra-articularly injected adipose-derived MSCs (AD-MSCs) and amnion-derived MSCs (AM-MSCs) to mitigate the progression of knee OA in a small animal model of spontaneous OA, as well as to compare the therapeutic potential of MSCs in hyaluronic acid (HA) and in HA only with saline (OA) controls. STUDY DESIGN: Controlled laboratory study. METHODS: Injections of AD-MSCs or AM-MSCs suspended in HA or HA only were performed in the rear stifle joints of 3-month-old Dunkin Hartley guinea pigs (DHGPs). Repeat injections occurred at 2 and 4 months after the initial injection in each animal. Contralateral limbs received saline injections and served as untreated controls. Subsequently, joints were analyzed for osteoarthritic changes of the cartilage and subchondral bone via histologic and biochemical analyses. To evaluate MSC retention time in the joint space, DHGPs received a single intra-articular injection of fluorescently labeled AD-MSCs or AM-MSCs, and the fluorescence intensity was longitudinally tracked via an in vivo imaging system. RESULTS: No statistically significant differences in outcomes were found when comparing the ability of AD-MSCs and AM-MSCs to mitigate OA. However, the injection of AD-MSCs, AM-MSCs, and HA-only treatments more effectively mitigated cartilage damage compared with that of saline controls by demonstrating higher amounts of cartilage glycosaminoglycan content and improved histological proteoglycan scoring while reducing the percentage of osteophytes present. CONCLUSION: Intra-articular injection of AD-MSCs, AM-MSCs, or HA only was able to similarly mitigate the progression of cartilage damage and reduce the percentage of osteophytes compared with that of saline controls in the DHGP. However, this study was unable to establish the superiority of AD-MSCs versus AM-MSCs as a treatment to mitigate spontaneous OA. CLINICAL RELEVANCE: MSCs demonstrate the ability to mitigate the progression of knee OA and thus may be used in a prophylactic approach to delay the need for end-stage treatment strategies.

Ibrutinib as a potential therapeutic for cocaine use disorder.

Cocaine use presents a worldwide public health problem with high socioeconomic cost. No current pharmacologic treatments are available for cocaine use disorder (CUD) or cocaine toxicity. To explore pharmaceutical treatments for tthis disorder and its sequelae we analyzed gene expression data from post-mortem brain tissue of individuals with CUD who died from cocaine-related causes with matched cocaine-free controls (n = 71, Mage = 39.9, 100% male, 49% with CUD, 3 samples/brain regions). To match molecular signatures from brain pathology with potential therapeutics, we leveraged the L1000 database honing in on neuronal mRNA profiles of 825 repurposable compounds (e.g., FDA approved). We identified 16 compounds that were negatively associated with CUD gene expression patterns across all brain regions (padj < 0.05), all of which outperformed current targets undergoing clinical trials for CUD (all padj > 0.05). An additional 43 compounds were positively associated with CUD expression. We performed an in silico follow-up potential therapeutics using independent transcriptome-wide in vitro (neuronal cocaine exposure; n = 18) and in vivo (mouse cocaine self-administration; n = 12-15) datasets to prioritize candidates for experimental validation. Among these medications, ibrutinib was consistently linked with the molecular profiles of both neuronal cocaine exposure and mouse cocaine self-administration. We assessed the therapeutic efficacy of ibrutinib using the Drosophila melanogaster model. Ibrutinib reduced cocaine-induced startle response and cocaine-induced seizures (n = 61-142 per group; sex: 51% female), despite increasing cocaine consumption. Our results suggest that ibrutinib could be used for the treatment of cocaine use disorder.

A High Throughput Microplate Feeder Assay for Quantification of Consumption in Drosophila.

Quantifying food intake in Drosophila is used to study the genetic and physiological underpinnings of consumption-associated traits, their environmental factors, and the toxicological and pharmacological effects of numerous substances. Few methods currently implemented are amenable to high throughput measurement. The Microplate Feeder Assay (MFA) was developed for quantifying the consumption of liquid food for individual flies using absorbance. In this assay, flies consume liquid food medium from select wells of a 1536-well microplate. By incorporating a dilute tracer dye into the liquid food medium and loading a known volume into each well, absorbance measurements of the well acquired before and after consumption reflect the resulting change in volume (i.e., volume consumed). To enable high throughput analysis with this method, a 3D-printed coupler was designed that allows flies to be sorted individually into 96-well microplates. This device precisely orients 96- and 1536-well microplates to give each fly access to up to 4 wells for consumption, thus enabling food preference quantification in addition to regular consumption. Furthermore, the device has barrier strips that toggle between open and closed positions to allow for controlled containment and release of a column of samples at a time. This method enables high throughput measurements of consumption of aqueous solutions by many flies simultaneously. It also has the potential to be adapted to other insects and to screen consumption of nutrients, toxins, or pharmaceuticals.

Characterization of chondroitinase-induced lumbar intervertebral disc degeneration in a sheep model intended for assessing biomaterials.

Intervertebral disc (IVD) degeneration (IVDD) leads to structural and functional changes. Biomaterials for restoring IVD function and promoting regeneration are currently being investigated; however, such approaches require validation using animal models that recapitulate clinical, biochemical, and biomechanical hallmarks of the human pathology. Herein, we comprehensively characterized a sheep model of chondroitinase-ABC (ChABC) induced IVDD. Briefly, ChABC (1 U) was injected into the L1/2 , L2/3 , and L3/4 IVDs. Degeneration was assessed via longitudinal magnetic resonance (MR) and radiographic imaging. Additionally, kinematic, biochemical, and histological analyses were performed on explanted functional spinal units (FSUs). At 17-weeks, ChABC treated IVDs demonstrated significant reductions in MR index (p = 0.030) and disc height (p = 0.009) compared with pre-operative values. Additionally, ChABC treated IVDs exhibited significantly increased creep displacement (p = 0.004) and axial range of motion (p = 0.007) concomitant with significant decreases in tensile (p = 0.034) and torsional (p = 0.021) stiffnesses and long-term viscoelastic properties (p = 0.016). ChABC treated IVDs also exhibited a significant decrease in NP glycosaminoglycan: hydroxyproline ratio (p = 0.002) and changes in microarchitecture, particularly in the NP and endplates, compared with uninjured IVDs. Taken together, this study demonstrated that intradiscal injection of ChABC induces significant degeneration in sheep lumbar IVDs and the potential for using this model in evaluating biomaterials for IVD repair, regeneration, or fusion.

Ethanol-mediated compaction and cross-linking enhance mechanical properties and degradation resistance while maintaining cytocompatibility of a nucleus pulposus scaffold.

Intervertebral disc degeneration is a complex, cell-mediated process originating in the nucleus pulposus (NP) and is associated with extracellular matrix catabolism leading to disc height loss and impaired spine kinematics. Previously, we developed an acellular bovine NP (ABNP) for NP replacement that emulated human NP matrix composition and supported cell seeding; however, its mechanical properties were lower than those reported for human NP. To address this, we investigated ethanol-mediated compaction and cross-linking to enhance the ABNP's dynamic mechanical properties and degradation resistance while maintaining its cytocompatibility. First, volumetric and mechanical effects of compaction only were confirmed by evaluating scaffolds after various immersion times in buffered 28% ethanol. It was found that compaction reached equilibrium at ~30% compaction after 45 min, and dynamic mechanical properties significantly increased 2-6× after 120 min of submersion. This was incorporated into a cross-linking treatment, through which scaffolds were subjected to 120 min precompaction in buffered 28% ethanol prior to carbodiimide cross-linking. Their dynamic mechanical properties were evaluated before and after accelerated degradation by ADAMTS-5 or MMP-13. Cytocompatibility was determined by seeding stem cells onto scaffolds and evaluating viability through metabolic activity and fluorescent staining. Compacted and cross-linked scaffolds showed significant increases in DMA properties without detrimentally altering their cytocompatibility, and these mechanical gains were maintained following enzymatic exposure. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B:2488-2499, 2019.

Tailoring the subchondral bone phase of a multi-layered osteochondral construct to support bone healing and a cartilage analog.

Focal chondral and osteochondral defects create significant pain and disability for working-aged adults. Current osteochondral repair grafts are limited in availability and often fail due to insufficient osseous support and integration. Thus, a need exists for an off-the-shelf osteochondral construct with the propensity to overcome these shortcomings. Herein, a scalable process was used to develop a multi-layered osteochondral graft with a subchondral bone (ScB) phase tailored to support bone healing and integration. Multiple ScB formulations and fabrication techniques were screened via degradation, bioactivity, and unconfined compression testing. An optimized ScB construct was selected and its cytotoxicity assessed. Additionally, a cartilage analog was secured to the optimized ScB construct via a calcified cartilage layer, and the resulting osteochondral construct was characterized via interfacial shear and dynamic mechanical testing. The optimized ScB construct did not significantly alter local pH during degradation, exhibited measurable bioactivity in vitro, and had significantly greater compressive mechanical strength compared to other constructs. The attachment strength of the cartilage analog was significantly greater by an increase in compressive dynamic mechanical properties. Furthermore, this ScB construct was found to be cytocompatible with human bone marrow-derived mesenchymal stromal cells. Taken together, this optimized ScB material forms the robust foundation of a novel, off-the-shelf osteochondral construct to be used in defect repair. STATEMENT OF SIGNIFICANCE: The quality of life for millions of individuals worldwide is detrimentally affected by focal chondral or osteochondral defects. Current off-the-shelf biomaterial constructs often fail to repair these defects due to insufficient osseous support and integration. Herein, we used a scalable process to fabricate and optimize a novel boney construct. This optimized boney construct demonstrated biochemical, physical, and mechanical properties tailored to promote bone healing. Furthermore, a novel cartilage analog was successfully attached to the boney construct, forming a multi-layered osteochondral construct.

Decellularization and characterization of a whole intervertebral disk xenograft scaffold.

Intervertebral disk (IVD) degeneration is a multifactor process that results in the physical destruction of the nucleus pulposus (NP) and annulus fibrosus (AF). This compromises IVD function and causes significant disability and economic burden. Strategies to replace the entire composite structure of the IVD are limited and most approaches do not recapitulate the heterogenous biochemical composition, microarchitecture or mechanical properties of the native tissue. Our central hypothesis was that donor IVDs which resemble the size and biochemistry of human lumbar IVDs could be successfully decellularized while retaining the tissue's structure and function with the long-term goal of creating a composite scaffold for tissue engineering the human IVD. Accordingly, we optimized a procedure to decellularize bovine tail IVDs using a combination of detergents, ultrasonication, freeze-thaw cycles, and nucleases. The resultant decellularized whole IVD xenografts retained distinct AF and NP regions which contained no visible intact cell nuclei and minimal residual bovine deoxyribose nucleic acid (DNA; 65.98 ± 4.07 and 47.12 ± 13.22 ng/mg, respectively). Moreover, the NP region of decellularized IVDs contained 313.40 ± 50.67 µg/mg glycosaminoglycan. The presence of collagen type II was confirmed via immunohistochemistry. Additionally, histological analysis of the AF region of decellularized IVDs demonstrated retention of the native angle-ply collagen microarchitecture. Unconfined compression testing demonstrated no significant differences in swelling pressure and toe-region modulus between fresh and decellularized IVDs. However, linear region moduli, peak stress and equilibrium moduli were all significantly reduced. Together, this research demonstrates a successful initial step in developing a biomimetic acellular whole IVD xenograft scaffold for use in IVD tissue engineering. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2412-2423, 2018.

Angle-ply biomaterial scaffold for annulus fibrosus repair replicates native tissue mechanical properties, restores spinal kinematics, and supports cell viability.

Annulus fibrosus (AF) damage commonly occurs due to intervertebral disc (IVD) degeneration/herniation. The dynamic mechanical role of the AF is essential for proper IVD function and thus it is imperative that biomaterials developed to repair the AF withstand the mechanical rigors of the native tissue. Furthermore, these biomaterials must resist accelerated degradation within the proteolytic environment of degenerate IVDs while supporting integration with host tissue. We have previously reported a novel approach for developing collagen-based, multi-laminate AF repair patches (AFRPs) that mimic the angle-ply architecture and basic tensile properties of the human AF. Herein, we further evaluate AFRPs for their: tensile fatigue and impact burst strength, IVD attachment strength, and contribution to functional spinal unit (FSU) kinematics following IVD repair. Additionally, AFRP resistance to collagenase degradation and cytocompatibility were assessed following chemical crosslinking. In summary, AFRPs demonstrated enhanced durability at high applied stress amplitudes compared to human AF and withstood radially-directed biaxial stresses commonly borne by the native tissue prior to failure/detachment from IVDs. Moreover, FSUs repaired with AFRPs and nucleus pulposus (NP) surrogates had their axial kinematic parameters restored to intact levels. Finally, carbodiimide crosslinked AFRPs resisted accelerated collagenase digestion without detrimentally effecting AFRP tensile properties or cytocompatibility. Taken together, AFRPs demonstrate the mechanical robustness and enzymatic stability required for implantation into the damaged/degenerate IVD while supporting AF cell infiltration and viability. STATEMENT OF SIGNIFICANCE: The quality of life for millions of individuals globally is detrimentally impacted by IVD degeneration and herniation. These pathologies often result in the structural demise of IVD tissue, particularly the annulus fibrosus (AF). Biomaterials developed for AF repair have yet to demonstrate the mechanical strength and durability required for utilization in the spine. Herein, we demonstrate the development of an angle-ply AF repair patch (AFRP) that can resist the application of physiologically relevant stresses without failure and which contributes to the restoration of functional spinal unit axial kinematics following repair. Furthermore, we show that this biomaterial can resist accelerated degradation in a simulated degenerate environment and supports AF cell viability.

Effect of organic acids on calcium phosphate nucleation and osteogenic differentiation of human mesenchymal stem cells on peptide functionalized nanofibers.

Carboxylate-rich organic acids play an important role in controlling the growth of apatite crystals and the extent of mineralization in the natural bone. The objective of this work was to investigate the effect of organic acids on calcium phosphate (CaP) nucleation on nanofiber microsheets functionalized with a glutamic acid peptide and osteogenic differentiation of human mesenchymal stem cells (hMSCs) seeded on the CaP-nucleated microsheets. High molecular weight poly(dl-lactide) (DL-PLA) was mixed with low molecular weight L-PLA conjugated with Glu-Glu-Gly-Gly-Cys peptide, and the mixture was electrospun to generate aligned nanofiber microsheets. The nanofiber microsheets were incubated in a modified simulated body fluid (mSBF) supplemented with different organic acids for nucleation and growth of CaP crystals on the nanofibers. Organic acids included citric acid (CA), hydroxycitric acid (HCA), tartaric acid (TART), malic acid (MA), ascorbic acid (AsA), and salicylic acid (SalA). HCA microsheets had the highest CaP content at 240 ± 10% followed by TART and CA with 225 ± 8% and 225 ± 10%, respectively. The Ca/P ratio and percent crystallinity of the nucleated CaP in TART microsheets was closest to that of stoichiometric hydroxyapatite. The extent of CaP nucleation and growth on the nanofiber microsheets depended on the acidic strength and number of hydrogen-bonding hydroxyl groups of the organic acids. Compressive modulus and degradation of the CaP nucleated microsheets were related to percent crystallinity and CaP content. Osteogenic differentiation of hMSCs seeded on the microsheets and cultured in osteogenic medium increased only for those microsheets nucleated with CaP by incubation in CA or AsA-supplemented mSBF. Further, only CA microsheets stimulated bone nodule formation by the seeded hMSCs.

Digital fluoroscopic video assessment of glenohumeral migration: Static vs. Dynamic conditions.

The purpose was to compare glenohumeral (GH) migration, during dynamic shoulder elevation and statically held positions using digital fluoroscopic videos (DFV). Thirty male volunteers (25+/-4 years) without right shoulder pathology were analyzed using DFV (30Hz) during arm elevation in the scapular plane. DFV were obtained at the arm at side position, 45 degrees , 90 degrees , and 135 degrees for static and dynamic conditions. GH migration was measured as the distance from the center of the humeral head migrated superiorly or inferiorly relative to the center of the glenoid fossa. Inter-rater reliability was considered good; ICC (2,3) ranged from 0.83 to 0.92. A main effect was revealed for contraction type (p=0.031), in which post-hoc t-tests revealed that humeral head was significantly more superior on the glenoid fossa during dynamic contraction. A main effect was also revealed for arm angle (p<0.001), in which post-hoc t-tests revealed significantly more superior humeral head positioning at 45 degrees , 90 degrees , and 135 degrees when compared to arm at side (p<0.001), as well as at 90 degrees compared to 45 degrees (p=0.024). There was no interaction effect between angle and contraction type (p=0.400). Research utilizing static imaging may underestimate the amount of superior GH migration that occurs dynamically.