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Solid organ transplant has emerged over the last half century as an important treatment for solid organ failure. Management has matured dramatically over the past two decades with improvements in acute rejection, but long-term graft survival has improved very little and current treatment is limited by the side-effects and toxicities of immunosuppressive medications. Nanoparticle delivery of therapeutics, improving transport characteristics and decreasing systemic and local toxicity has emerged as a dynamic treatment modality, but little work has been done using nanoparticles in transplantation. Our research examined the use of CD4-targeted nanoparticles encapsulated with mycophenolic acid (MPA), a commonly used immunosuppressant in organ transplantation. This work is the first to examine antigen-specific targeting of nanoparticles in any transplant model. MPA-loaded particles show a slow and continuous release profile and biodistribution suggested retention in the spleen. Targeting of nanoparticles to CD4 T cells was suggested using ex vivo and in vitro flow cytometry. In the fully allogeneic MHCII mismatch BALB/C to C57BL/6 mice we found improved graft survival in the non-targeted MPA group and even greater graft survival in the CD4-targeted group. Targeted and non-targeted particle groups showed equal delay in rejection in the less immunogenic single MHC mismatch B6.H-2bm12 to C57BL/6 model that we showed to be CD4 dependent. In both models, graft survival times were increased over free drug and controls with roughly one thousand fold lower dose of drug in the nanoparticles as compared with free MPA. Consistent with these findings were decreased proliferation with targeted and non-targeted MPA-nanoparticles using in vitro and ex vivo mixed lymphocyte reactions. We postulated that the similar rejection times in targeted and non-targeted groups was due to dendritic cell (DC) involvement and we found active uptake of nanoparticles in DCs, a decrease in inflammatory cytokine production and a decrease in treated DCs ability to stimulate T cells via mixed lymphocyte reactions. Furthermore we found a possible mechanism in the DC interaction with T cells through the upregulation of the inhibiting co-stimulatory molecules B7-DC and B7-H1 on DCs treated with MPA-nanoparticles. We also found possible upregulation of CD4+CD25+ Foxp3 expressing Tregs which may serve to increase graft acceptance. These results explore the involvement of dendritic cells in the process of nanoparticle-induced graft acceptance and suggest the feasibility of using nanoparticle drug vectors in clinical transplant.

The location of the immunologic response to an allograft is not known with certainty. However, organized collections of T cells, B cells and antigen presenting cells have been found in peripheral tissue, in close proximity to organs undergoing rejection. It is hypothesized that this tertiary lymphoid tissue may be a location in which activation of lymphocytes can occur, leading to rejection of an allograft. We report here that in a splenectomized aly/aly mouse, which is devoid of secondary lymphoid organs and will normally fail to reject an allograft, the presence of tertiary lymphoid organs is associated with graft rejection. We additionally find that tertiary lymphoid organs can act as lymph nodes, and can support effector and memory allograft rejection responses. It is demonstrated that ectopic lymphoid tissue in aly/aly mice will support the multiplication and transformation of transferred naïve CD4 and CD8 T cells into cells that display phenotypic markers characteristic of effector and memory lymphocytes. These results demonstrate that ectopic lymphoid tissue is associated with the loss of immunologic ignorance and is sufficient to enable graft rejection. This suggests that allograft rejection may take place within ectopic lymphoid tissue, and suggests that techniques to interfere with the development of this tissue might offer a therapeutic approach to preserving organ allografts.

Purpose: To compare the costs and length of disability for conservative treatment versus skin grafting of distal finger and thumb tip amputations. Methods: Thirty-five zone I finger or thumb tip amputations in thirty-five workers in the Southeastern United States were included in this study. Twenty-four were treated with conservative treatment (bandaging to protect the wound). Eleven were treated with skin grafting. The total cost of medical care, total cost including wage replacement, and the length of disability were compared between the two groups. Impairment at the end of treatment was considered. Results: Even when the cost of wage replacement was taken into account, the total cost for skin graft treatment for these injuries is significantly higher. The length of disability was not statistically different between the two treatment groups. There was not a significant difference in impairment reported at the end of treatment. Conclusion: This study did not demonstrate any economic or medical advantage for treating zone I finger or thumb tip amputations with skin grafts. The size of the defect in the skin graft group was significantly larger, though, and the results obtained in this comparison may not allow us to draw valid conclusions about the comparison of these two treatments.

This thesis presents a foundation for developing a business case for companies interested in the reconstructive and cosmetic procedure markets. The focus is on reviewing adipose tissue engineering research and proposing technology opportunities that could be applied to challenging soft tissue reconstruction cases and adjacently applied to cosmetic applications. To establish the foundation for this type of program, this thesis includes an evaluation of the reconstructive and cosmetic procedure markets, current practices in these markets and their constraints, as well as a literature review of research in adipose tissue engineering and its potential clinical applications. Additionally it captures the competitive landscape of major players in the reconstructive market as well as up-and-coming players in the adipose tissue engineering field. Technology development opportunities with associated customer and business value are discussed with a recommendation for the development of a detailed business case to evaluate specific product development opportunities in these markets. / text

The purpose of this study was to investigate the presence of arterial insufficiency in patients undergoing CABG surgery and whether arterial insufficiency is a risk factor for postoperative wound infections in the harvesting leg. Patients who had CABG surgery were enrolled consecutively. A total of 144 patients participated in the study. During their hospital stay demographic data was recorded, as well as pre-, intra-, and postoperative tests and risk factors. The patients answered a questionnaire regarding postoperative wound infections 30 days after surgery patients answered a questionnaire regarding infections. The known and potential risk factors that were recorded were BMI, HB, tobacco usage, diagnosed diabetes, hyperglycemia, duration of surgery, the lowest temperature during surgery and clinical or subclinical arterial insufficiency. The result showed that 34% had postoperative wound infections in the harvesting leg and 26 patients had an ABI (Ankel Brachial Index) indicating arterial insufficiency. There was no significant relationship between ABI and postoperative wound infections in the lower extremity in the total study group (p = 0.36) nor among men (p = 0.92). There was a significant correlation between ABI and postoperative wound infections in the lower extremity (p = 0.02) among women. The conclusion is that arterial insufficiency is more prevalent in women. The relationship between postoperative infections of the lower limbs and arterial insufficiency was significant for the participating women, but not in the total group nor among the men.

Objectives: The purpose of this study was to evaluate whether the effects of hyperbaric oxygen (HBO) therapy could alter the critical size defect (CSD) diameter and to evaluate the effect of HBO on the repair of CSD in the presence and absence of a non-vascularized autogenous bone graft (ABG). Study Design: Twenty rabbits were divided in two groups of ten animals each. CSD were created in the parietal bones bilaterally. Defects were critical-sized, 15 mm on one side and supracritical-sized, 18 mm on the contralateral side. Group 1 received a 90-min HBO treatment sessions at 2.4 absolute atmospheric pressure (ATA) for 90 minutes per day for 20 days. Group 2 served as a normobaric roomair control (NBO). Additional ten animals were divided into 2 groups of 5 animals each. Bilateral CSD were created. ABG were allocated to one side of each calvarium. Group 1 received HBO treatments. Group 2 served as NBO. After sacrifice, data were collected including qualitative assessment, radiographic analysis, Micro CT bone analysis and histomorphometric analysis. ANOVA and paired sample t test were used for statistical analysis. Results: Both radiographic analysis and histomorphometric analysis demonstrated more new bone in the HBO CSD (p<.001). Micro CT analysis indicated a higher bone mineral content (BMC) in ABG CSD (p<.05). Histologically, complete bridging of the defect was observed in ABG defects. Histomorphometric analysis showed that HBO treatment increased new bone and marrow and reduced fibrous tissue in the defects (p<.01 for all). Conclusion: Bone regeneration was significantly greater in the HBO animals regardless of the defect size. HBO may have changed the accepted diameter of CSD to more than 18 mm. HBO enhances bony healing in non-grafted CSD.

The aim of this research work was to improve the compatibility of polymer blends made from poly(lactic acid) and natural rubber (PLA/NR blends) by using modified natural rubber as a compatibilizer. Natural rubber was chemically modified into two categories: natural rubber grafted poly(vinyl acetate) copolymer (NR-g-PVAc) and block copolymers (PLA-NR diblock copolymer and PLA-NR-PLA triblock copolymer). PLA/NR blends were prepared by melting blending in a twin screw extruder and compression molded to obtain a 2-mm thick sheet. The blends contained 10-20 wt% of NR and modified NR, and the impact strength and tensile properties were investigated. The compatibilization effect was determined by DMTA, DSC and SEM. NR-g-PVAc was synthesized by emulsion polymerization to obtain different PVAc graft contents (1%, 5% and 12%). Characterization by DMTA showed an enhancement in miscibility of the PLA/NR-g-PVAc blends. NR-g-PVAc could be used as a toughening agent of PLA and as a compatibilizer of the PLA/NR blend. The block copolymers were synthesized following two routes: (1) hydroxyl telechelic natural rubber (HTNR) and lactide and (2) HTNR and PLA prepolymer. In the former route, lactide was in situ polymerized via a ring opening polymerization to be a PLA block segment during block copolymerization. In the latter route PLA prepolymer was synthesized by a condensation polymerization of L-lactic acid prior to block copolymerization. Both block copolymers acted as good compatibilizers for the PLA/NR blend by increasing the impact strength and decreasing the NR particle size. Triblock copolymers provided higher impact strength than diblock copolymers, and they were a less effective compatibilizer than NR-g-PVAc. In contrast to NR and NR-g-PVAc, the block copolymer was not a good toughening agent for PLA.

A degradable/polar/hydrophobic/ionic (D-PHI) polyurethane with properties intended to promote tissue regeneration in a small diameter peripheral artery vascular graft was evaluated for cell biocompatibility and growth. Films were cast in polypropylene 96 well plates for monocyte/endothelial cell (EC) co-culture in vitro studies and porous scaffold discs were implanted in an in vivo subcutaneous mouse model. After 7 days in culture the co-culture demonstrated cell adhesion and growth, low esterase activity (a measure of degradative potential and cell activation), no detectable release of pro-inflammatory cytokine (tumour necrosis factor -α) but measurable anti-inflammatory interleukin (IL)-10. The EC and the co-culture expressed the EC biomarker CD31, whereas the monocyte monoculture did not. Cytokine array analysis of the in vivo characterization of D-PH supported an anti-inflammatory phenotype of cells at the site of the implant. Levels of IL-6 significantly decreased over time while IL-10 was significantly higher at 6 weeks post implant. TNF-α levels did not change significantly from 24 hours onwards, however the trend was towards lesser amounts following the initial time point. Histological analysis of the explanted scaffolds showed excellent tissue ingrowth and vascularization. A live/dead stain showed that the cells infiltrating the scaffolds were viable. Both the in vitro and in vivo results of this thesis indicate that D-PHI is a good candidate material for tissue engineering a peripheral artery vascular graft.

Objectives: The purpose of this study was to evaluate whether the effects of hyperbaric oxygen (HBO) therapy could alter the critical size defect (CSD) diameter and to evaluate the effect of HBO on the repair of CSD in the presence and absence of a non-vascularized autogenous bone graft (ABG). Study Design: Twenty rabbits were divided in two groups of ten animals each. CSD were created in the parietal bones bilaterally. Defects were critical-sized, 15 mm on one side and supracritical-sized, 18 mm on the contralateral side. Group 1 received a 90-min HBO treatment sessions at 2.4 absolute atmospheric pressure (ATA) for 90 minutes per day for 20 days. Group 2 served as a normobaric roomair control (NBO). Additional ten animals were divided into 2 groups of 5 animals each. Bilateral CSD were created. ABG were allocated to one side of each calvarium. Group 1 received HBO treatments. Group 2 served as NBO. After sacrifice, data were collected including qualitative assessment, radiographic analysis, Micro CT bone analysis and histomorphometric analysis. ANOVA and paired sample t test were used for statistical analysis. Results: Both radiographic analysis and histomorphometric analysis demonstrated more new bone in the HBO CSD (p<.001). Micro CT analysis indicated a higher bone mineral content (BMC) in ABG CSD (p<.05). Histologically, complete bridging of the defect was observed in ABG defects. Histomorphometric analysis showed that HBO treatment increased new bone and marrow and reduced fibrous tissue in the defects (p<.01 for all). Conclusion: Bone regeneration was significantly greater in the HBO animals regardless of the defect size. HBO may have changed the accepted diameter of CSD to more than 18 mm. HBO enhances bony healing in non-grafted CSD.