Design Of A Modular Endothelialized Platform For Vascularized Bone Regeneration

The gold standard for bone regeneration requires harvesting a piece of healthy bone from the patient through a painful procedure, but this piece of autologous bone graft contains the bone and endothelial cells required to rapidly regenerate bone in a defect. We have developed a modular bone regeneration platform, composed of mesenchymal stem cells (MSCs) and hydroxyapatite (HAP) microgranules encapsulated in microcapsules, to replace autologous graft harvesting. The microcapsules are composed of a polyelectrolyte membrane formed by the ionic-complex reaction between chondroitin 4-sulfate (C4S) and chitosan. The specific aims of this thesis were to 1) examine the ability of C4S/HAP/chitosan microcapsules to support osteogenesis of encapsulated MSCs, 2) characterize how microcapsule mineralization influences mechanical properties of fused microcapsule constructs, and 3) analyze how endothelial progenitors (EPs) attached to the microcapsule exterior influence the vascularization of fused constructs in vivo. The microcapsules supported the osteogenesis of encapsulated MSCs, and an in vitro analysis showed enhanced alkaline phosphatase (ALP), osteocalcin and osteopontin expression. Furthermore, biochemical assays and Scanning Electron Microscopy (SEM) confirmed that osteoinduced MSCs deposited a calcium and collagen rich mineralized extracellular matrix (ECM) in the microcapsule interior after 4 weeks osteoinduction in vitro. Hydrated, compressive mechanical testing demonstrated that fused constructs composed of mineralized microcapsules exhibited significant resistance to compression, up to a yield strength of 10.4 + 4.4 MPa. Analysis of the yield strength and elastic moduli demonstrated that the compressive mechanical properties depend primarily on active mineralization of the microcapsules by differentiating MSCs, and to a lesser extent on HAP microgranules. Micro computed tomography (MicroCT) and SEM analysis of fused constructs showed that the organization and architecture of the mineral within the microcapsules determined the overall mechanical properties of fused constructs. EPs or MSCs were cultured on the microcapsule exterior, and fused constructs were fabricated with these microcapsules, so that the EPs/MSCs were localized to the intercapsule pore space. Fused constructs containing EPs or MSCs in the pore space were evaluated for their vascularization and tissue regeneration in a rat subcutaneous model. Doppler Ultrasound (US) analysis of blood flow through implanted constructs revealed that microcapsules with EPs or MSCs in the construct pore space had enhanced vascularization 4 weeks post-surgery, compared to fused constructs with only encapsulated osteoprogenitors and acellular constructs. Results indicate that the C4S/HAP/Chitosan microcapsules can function as the basis of a bone regeneration platform, and that culture of either EPs or undifferentiated MSCs can enhance the vascularization of fused microcapsule constructs in vivo. Our studies warrant further development and optimization of the C4S/HAP/Chitosan microcapsules as a replacement for painful autologous bone graft harvesting

CASE STUDY: Rockwell Collins and IBEW Locals 1362 and 1634

The post-September 11th economy has confronted Rockwell Collins in Cedar Rapids, Iowa with hard choices. Faced with the need to cut costs, including laying off significant portions of the work force, the company and its unions still maintain a commitment to knowledge retention and knowledge building. This case study chronicles the efforts of this leading producer of advanced communication and aviation electronics for the commercial market and the defense industry to balance the costs of maintaining productive effectiveness while responding to market pressures. The company is faced with increased technical requirements and depressed demand for its products, which include: in-flight entertainment systems, aircraft communication systems, global positioning systems (GPS), flight deck displays (including collision alert systems and virtual landing aids), communications systems, and automatic flight controls. Survival depends on walking a strategic knife edge to sustain the bottom line and still maintain the innovation and flexibility needed to build products to market demand

CASE STUDY: International Association of Machinists and Boeing Joint Quality Through Training Programs

The International Association of Machinists (IAM) and Boeing Company Quality Through Training Program (QTTP) is playing a vital role within the Boeing Company to cope with a complicated situation: reducing the workforce, implementing lean manufacturing, and the upcoming training of a new workforce as thousands of workers prepare for retirement in the coming years. QTTP Joint Training Programs were not created with these specific uses in mind, but because the programs are already established, they provide a foundation on which to build these new roles. Internal union and management groups are now relying on the credibility and connections of the QTTP leadership to facilitate organizational problem-solving. This case study describes how the joint program has responded to new organizational needs heightened by sudden changes in the aerospace industry. The events of September 11, 2001 were devastating for the aerospace industry. One year after the tragic events, (you say below that airlines postponed or cancelled orders) business air travel had declined approximately 30% while air travel overall was off approximately 11%. The airline industry was projected to lose more than $5 billion in 2002, on top of losing$7.7 billion in 2001. United Airlines filed for bankruptcy, while most other airlines continue to post stunning losses. In response to the drop in air travel demand, the airlines reduced the number of flights – requiring less aircraft. As a result, airlines postponed or cancelled orders for new planes. Boeing’s commercial business was hit hard and the company has announced the layoff of 30,000 workers. Despite this rather bleak picture, the QTTP leaders and representatives continue to skillfully promote joint, innovative activities that are mutually beneficial to those they represent. The activities described in this case are examples of the initiatives that QTTP is promoting. Of note is the consideration and respect that form the basis upon which decisions are made within the group

A Comparison of Lower Extremity Joint Power in the Squat and Deadlift

The squat (SQ) and deadlift (DL) are commonly utilized to improve sport performance. An important variable in sport performance is joint power, as greater joint power has been associated with adaptations that improve performance such as higher vertical jump height. Therefore, picking exercises that result in greater joint power production can be beneficial in improving sport performance. PURPOSE: The purpose of this study was to compare joint power at the hip, knee, and ankle between the SQ and the DL. We hypothesized that the DL will have greater hip joint power, while the SQ will have greater joint power production at the knee and ankle. METHODS: 28 healthy participants (17 male, 11 female, 23.7±4.0 yrs., 1.76±0.09 m, 78.10±10.91kg) who had trained the SQ and DL at least once per week for the last three months were recruited for data collection. 2 visits were required from each participant with the first visit involving one- repetition-maximum (1RM) testing. During the second visit, participants underwent 3-D biomechanical analyses for the SQ and DL at 85% 1RM for each exercise in a randomized order, with a five-minute rest period. The 2nd of the three repetitions was used for analysis. A 2 (exercise) by 3 (joint) repeated measures analysis of variance (ANOVA) was used to compare peak joint powers at the hip, knee, and ankle. Post hoc comparisons were assessed using a Bonferroni adjustment (0.05/3 = 0.0167). RESULTS The 2 (exercise) by 3 (joint) repeated measures ANOVA for joint powers was significant (F1,27=3.08, p=0.05). Knee joint power was greater in the SQ compared to the DL (1.09±0.88 vs 0.53±0.44 W/kg-1, p=0.002), as well as ankle joint power (0.32±0.33 vs 0.13±0.11 W/kg-1, p=0.009). No differences were found in hip joint power (p=0.052). CONCLUSION: Because the SQ resulted in greater joint power at the knee and ankle, the SQ could be more beneficial than the DL if the goal is to improve sport performance, particularly sports that involve vertical jumping. However, there are other factors other than joint power that need be assessed before drawing final conclusions

The Association Between Ankle Dorisflexion and Force-related Sport Performance Variables

The back squat (BS) is commonly implemented in strength training programs to improve athletic performance. In order to perform the BS successfully, individuals must have adequate ankle dorsiflexion as it allows the knee to travel forward and lower the center of mass. However, it is currently unknown whether ankle dorsiflexion during the squat is associated with important sport performance variables, such as BS 1-rep max (1RM), peak ground reaction force (GRF) or rate of force development (RFD). PURPOSE: The purpose of this study was to determine the relationship between peak ankle dorsiflexion angle (DFA) and BS 1RM, peak GRF, and RFD during the BS exercise. We hypothesized there would be a positive correlation between DFA and BS 1RM, peak GRF, and RFD. METHODS: 28 healthy participants (17 male, 11 female, 23.7±4.0 yrs., 1.76±0.09 m, 78.10±10.91kg) who had trained the BS at least once per week for the last three months were recruited for data collection. 2 visits were required from each participant with the first visit involving one-repetition-maximum (1RM) testing During the second visit, participants underwent 3-D biomechanical analyses for the BS at 85% 1RM. The 2nd of the three repetitions was used for analysis. A Pearson’s correlation was run to determine the relationship between peak ankle DFA and BS 1RM, peak GRF, and RFD. RESULTS: No correlations were found between DFA and BS 1RM (p=0.699), peak GRF (p=0.56), or RFD (p=0.982). CONCLUSION: Our results contradict our hypothesis as peak DFA is not associated with how much an individual can squat, greater GRF production, or RFD. This suggests that although some amount of ankle dorsiflexion is required to successfully perform a squat, the peak DFA is not a determinant of squat strength or force-related variables. Future studies may aim to examine the influence of hip or knee kinematics on force-related variables rather than ankle kinematics

Metabolomic profiling of macrophages determines the discrete metabolomic signature and metabolomic interactome triggered by polarising immune stimuli

Priming and activating immune stimuli have profound effects on macrophages, however, studies generally evaluate stimuli in isolation rather than in combination. In this study we have investigated the effects of pro-inflammatory and anti-inflammatory stimuli either alone or in combination on macrophage metabolism. These stimuli include host factors such as IFNγ and ovalbumin-immunoglobulin immune complexes, or pathogen factors such as LPS. Untargeted LC-MS based metabolomics provided an in-depth profile of the macrophage metabolome, and revealed specific changes in metabolite abundance upon either individual stimuli or combined stimuli. Here, by factoring in an interaction term in the linear model, we define the metabolome interactome. This approach allowed us to determine whether stimuli interact in a synergistic or antagonistic manner. In conclusion this study demonstrates a robust approach to interrogate immune-metabolism, especially systems that model host-pathogen interactions

Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds

RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood