In the past decades, there has been a noticeable growth in the deployment of wireless sensor networks. These sensors/stimulators are typically powered by a battery which has limited life span. Power harvesting is one of the solutions to this problem. According to a medical-care experiment, the recovery process of an injured nerve has been boosted with the help of electrical stimulator. The latter is not only preferable to be portable but to be implantable as well in order to make medical treatment easier on the patient. This work has implemented two prototype versions of rectification circuitry used to harvest RF signal to power an electrical stimulator for peripheral nerve regeneration. The system consists an efficient rectifier, DC-limiter, biasing circuitry and modest regulator. In order to gain higher rectification efficiency, ON-OFF offset methodology is reviewed. Moreover, a mixed-signal design is proposed to construct a delay compensation mechanism. It is designed with 0.35 um AMS technology and it is assumed to read 13.56 MHz NFC signal from loop antennas. Schematic and layout levels are introduced with corresponding simulation findings. Moreover, tape-out is made for both architectures along with comparative results/discussions.

京都大学 / 新制・課程博士 / 博士(人間健康科学) / 甲第23426号 / 人健博第93号 / 新制||人健||6(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 山田 重人, 教授 林 悠, 教授 森本 尚樹 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

No description available.

Objetivo: Determinar o processo cicatricial e regenerativo da córnea em suas diferentes camadas diante do dano cirúrgico, através da Ceratectomia Fotorrefrativa (PRK) nos terços anteriores ou injúria do complexo Descemetendotélio no terço posterior. Métodos: Córneas de coelhos foram utilizadas a fim de identificar os nervos presentes, evidenciados através da técnica de imuno-histoquímica (IHQ) da acetilcolinesterase (AchE) e expressos numericamente após quantificação automatizada pelo software Image-Pro. Os seguintes grupos foram incluídos nessa análise: remoção do epitélio com e sem Mitomicina (MMC) 0.02%, -9.0D PRK com e sem MMC. O dano e a regeneração dos nervos foram avaliados através da análise dos grupos após 1 dia, 1, 2, 3 e 6 meses. A morfologia e a distribuição dos nervos foram realizadas através do estudo da tubulina Beta-III, um marcador de microtúbulos presentes em neurônios. Na córnea posterior, a fim de identificar a ocorrência de apoptose após a injúria mecânica do endotélio através de uma cânula romba, cortes desse tecido foram avaliados por meio de técnicas de IHQ através do método de fragmentação do DNA por dUTP e deoxinucleotidil terminal transferase (TUNEL) e microscopia de transmissão eletrônica (TEM) após 1 e 4 horas. A ocorrência de fibrose subsequente à lesão da córnea posterior foi avaliada nos grupos submetidos à Descemetorréxis ou à injúria mecânica do endotélio isolado após 1 mês. O estudo imunohistoquímico para actina de músculo liso (alfa-SMA) permitiu identificar a presença de miofibroblastos e a identificação morfológica da membrana de Descemet demonstrada através do Nidogênio-1 (Nid-1), tornando possível, portanto, a discriminação do papel das camadas posteriores no processo cicatricial da córnea. Olhos contralaterais foram incluídos como um grupo controle em todas as análises. Resultados: Na face anterior da córnea, uma menor área do complexo nervoso foi observada um dia após o PRK associado ao uso da MMC (p=0.0009) quandocomparado ao PRK sem o uso da medicação, que não se manteve após um mês (p=0.9). O PRK sem MMC demonstrou uma crescente capacidade regenerativa de seus nervos, que apresentaram valores comparáveis aos pré-operatórios após o terceiro mês. No entanto, tais fibras nervosas apresentaram uma morfologia aberrada mantida até a análise do mês seis. Na face posterior da córnea, apesar da presença de células TUNEL+ após 1 e 4 horas subsequentes ao dano mecânico do endotélio isolado, não houve a expressão de alfa-SMA no estroma posterior após um mês. A integridade estrutural da membrana de Descemet nesse grupo foi confirmada através do Nidogênio-1 (Nid-1), diferentemente do observado após o dano ao complexo Descemet-endotélio, em que houve ampla expressão de alfa-SMA identificando a presença de miofibroblastos e o consequente desenvolvimento de cicatrizes responsáveis pela perda de transparência na córnea. Conclusão: O uso do excimer laser na superfície anterior causou prejuízo à inervação da córnea. Todavia, a capacidade regenerativa das fibras nervosas foi demonstrada ao longo dos meses, apesar da persistência de uma anômala arquitetura e redistribuição dos nervos mesmo após o sexto mês. A MMC revelou uma discreta e precoce propriedade neurotóxica quando combinada ao uso do excimer laser, que não implica perda da segurança a médio/longo prazo do uso dessa droga na concentração e tempos utilizados nesse estudo. No terço posterior da córnea, a membrana de Descemet exibiu um importante papel modulador no processo de desenvolvimento de cicatrizes ou fibrose no estroma profundo. Uma vez lesada, torna constante o influxo de citocinas inflamatórias necessárias para a diferenciação e persistência do miofibroblasto. Tal processo mostrou-se análogo ao papel da membrana basal do epitélio como reguladora do processo de fibrose da córnea anterior / Purpose: To determine the wound-healing cascade and regeneration process of the cornea after surgical injury in its different layers, through Photorefractive Keratectomy (PRK) in the anterior thirds or Descemet-endothelium injury in the posterior third. Methods: Rabbit corneas were used to identify the nerves present in the central area of this tissue by the immunohistochemistry (IHQ) technique of acetylcholinesterase (AchE) and their numerical quantification by Image-Pro software. The following groups were included in this analysis: Removal of epithelium with and without Mitomycin (MMC) 0.02 %, -9.0D PRK with and without MMC. Damage and nerve regeneration were assessed by analyzing the groups after 1 day, 1, 2, 3 and 6 months. The morphology and distribution of nerves along the corneal layers was performed through tubulin beta-III study. At the posterior cornea, to distinguish the occurrence of apoptosis after the mechanical injury of the endothelium through a blunt cannula, sections of this tissue were evaluated by IHQ technique through DNA fragmentation by dUTP and deoxynucleotidyl terminal transferase (TUNEL) and electron transmission microscopy (TEM) after 1 and 4 hours. The occurrence of cornea fibrosis subsequent to posterior corneal injury was evaluated by the group undergoing Descemet membrane surgical removal or by the endothelium mechanical injury after 1 month. The immunohistochemical study for smooth muscle actin (alpha-SMA) allowed the identification of myofibroblasts and the structural integrity of Descemet demonstrated by Nidogen-1 (Nid-1). Thus, making it possible to discriminate the role of the posterior layers during the corneal wound-healing process. Contralateral eyes were included as a control group in all analyzes. Results: At the anterior surface of the cornea, a smaller area of the nervous complex was observed one day after PRK associated with the use of MMC (p = 0.0009) when compared to PRK without the association of the drug, which was not maintained after the first month (p = 0.9). The PRK without MMC demonstrated an increasing regenerative capacity of their nerves, which presented values comparable to preoperative measurements after the third month. However, morphological differences and an aberrant distribution of innervation were persistent. At the corneal posterior surface, despite the presence of TUNEL + cells after 1 and 4 hours subsequent to the mechanical damage of the isolated endothelium, there was no alpha-SMA expression in the posterior stroma after one month. The structural integrity of Descemet\'s membrane in this group was confirmed by Nidogen-1 (Nid-1). Differently from what was observed after damage to the Descemet membrane by it surgical removal, there was a large expression of alpha-SMA identifying the myofibroblasts and the consequent development of scars responsible for the loss of corneal transparency. Conclusion: The excimer laser use on the anterior surface caused destruction to the corneal innervation. However, the regenerative capacity of nerve fibers was demonstrated over the months, despite the persistence of anomalous architecture and redistribution of the corneal nerves that persisted even after six months. MMC exhibited a moderate and early neurotoxic effect when combined with the excimer laser treatment at the concentration and time used in this study At the inferior third of the cornea, Descemet\'s membrane exhibited an important role during the modulation process of scarring or fibrosis in the deep stroma. Once damaged, a constant influx of inflammatory cytokines into the stroma was guaranteed and a differentiation and persistence of the myofibroblast occur. This process has been shown to be analogous to the role of the corneal epithelial basement membrane as a regulator of the anterior cornea fibrosis process

As lesões que envolvem nervos periféricos, especialmente os traumatismos facias, são muito comuns e decorrentes principalmente de acidentes com veículos motorizados, lesões acidentais e quedas, que levam a fraturas do osso temporal ou lacerações da face e consequentemente lesões do nervo facial. A principal meta no estudo da regeneração nervosa é descobrir uma técnica adequada de reparo em lesões de nervos periféricos que traga como resultado a recuperação funcional das estruturas por eles inervadas. A sutura epineural é um método muito utilizado para recuperação de lesões nervosas, assim como o uso do adesivo de fibrina, que requer menor destreza do cirurgião. O adesivo derivado do veneno de serpente (CEVAP/UNESP, Botucatu-SP) é um selante biológico e biodegradável, pois não produz reações adversas, não contém sangue humano, apresenta uma boa capacidade adesiva, não transmite doenças infecciosas, e pode ser utilizado como coadjuvante em procedimentos de sutura convencional. Sendo assim, o objetivo deste trabalho foi comparar duas técnicas de recuperação de nervos periféricos lesionados: a sutura epineural término-terminal e o adesivo de fibrina derivado do veneno de serpente, e observar se o uso da laserterapia de baixa potência influencia esse processo de regeneração. Para isso, foram utilizados 42 ratos machos (Rattus norvegicus, Wistar), com 60 dias de vida, separados aleatoriamente em um Grupo Controle e quatro Grupos Experimentais, assim formados: Grupo Controle (GC, n=10), em que foi coletado o nervo facial íntegro aos 95 e 135 dias de vida; Grupo Experimental Sutura (GES, n=16) e Grupo Experimental Adesivo de Fibrina (GEF, n=16), onde no lado direito da face o ramo bucal do nervo facial foi seccionado e realizado a sutura epineural término-terminal e, no lado esquerdo da face, o ramo bucal do nervo facial foi seccionado e utilizado o adesivo de fibrina para coaptação das extremidades; Grupo Experimental Sutura e Laserterapia (GESL, n=16) e Grupo Experimental Adesivo de Fibrina e Laserterapia (GEFL, n=16), submetidos aos mesmos procedimentos de GES e GEF, adicionada a aplicação de Laser de Arseneto de Gálio Alumínio (GaAlAs) de pulso contínuo, comprimento de onda de 830 nm, 6J/cm2, por 24 segundos, três vezes por semana durante cinco semanas, em três pontos dos locais operados. Os animais dos Grupos Experimentais foram eutanasiados com 95 dias (cinco semanas pós-cirurgia) e 135 dias (dez semanas pós-cirurgia). As amostras coletadas foram submetidas à análise morfológica por microscopia óptica e eletrônica de transmissão, além de análise morfométrica da área e diâmetro da fibra, área e diâmetro do axônio, espessura e diâmetro da bainha de mielina. Observou-se brotamento axonal no coto distal do nervo facial em todos os Grupos Experimentais, com morfologia semelhante às fibras do Grupo Controle, e predomínio de fibras mielínicas sobre as amielínicas. Pode-se concluir que a reparação por meio da sutura epineural término-terminal apresentou melhores resultados em relação ao adesivo de fibrina e a laserterapia de baixa potência não influenciou o processo de regeneração. / The injuries involving peripheral nerves, especially facial traumatisms are very common and serious and longstanding facial paralysis lead to significant deterioration in the quality of the individuals life. The main goal in the study of nerve regeneration is finding a suitable repair technique for peripheral nerve injuries that bring results in the functional recovery of the structures innervated by them. Therefore, the aim of this study was to compare two techniques for recovery of injured peripheral nerves: the end-to-end epineural suture and fibrin adhesive derived from snake venom (CEVAP / UNESP, Botucatu-SP), and observeif the use of low-level laser therapy influences this regeneration process. For this purpose, 42 male rats (Rattus norvegicus, Wistar) were used , with 60 days of life, were randomly separated into a control group and four experimental groups, which were formed this way: Control Group (CG , n = 10), in which the intact facial nerve was collected at 95 and 135 days of life; Experimental Suture Group (ESG, n = 16 ) and Experimental Fibrin Adhesive Group (EFG, n = 16), where the right side of the face the buccal branch of the facial nerve was transectioned and the epineural end-to-end suture was performed and the left side of the face, the buccal branch of the facial nerve was transectioned and the fibrin glue was used for coaptation of the edges; Experimental Suture Laser Therapy Group (ESLG, n = 16) and Experimental Fibrin Adhesive Laser Therapy Group (EFLG, n = 16) underwent the same procedures of ESG and EFG , included the application of Laser Gallium- Aluminum-Arsenide (GaAlAs) by an 830 nm wavelength pulse continuous, 6 J/cm2, for 24 seconds, three times a week during five weeks at three points of the operated areas. The animals in the experimental groups were euthanized at 95 days (five weeks post-surgery) and 135 days (ten weeks post-surgery). The collected samples were subjected to morphological analysis by optical microscopy and transmission electronic microscopy, besides the morphometric analysis of the area and diameter of the fiber, area and diameter of the axon, thickness and diameter of the myelin sheath. It was observed axonal sprouting in the distal stump of the facial nerve in all experimental groups, with similar morphology to the fibers of the control group, and predominance of myelinated fibers to amyelinated. It can be concluded that the repair by epineural end-to-end suture showed better results in relation to fibrin adhesive and the low-level laser therapy did not influence the regeneration process

As lesões na face estão mais comuns na sociedade atual, envolvendo acidentes automobilísticos, quedas ou consequências iatrogênicas após procedimentos. Essas lesões podem afetar os nervos responsáveis pela musculatura facial repercutindo em alterações físicas, emocionais e psicossociais, por exemplo, no sistema estomatognático, na voz, na expressão e estética faciais, nos sentimentos e convívio social do indivíduo. Pesquisas atuais estão almejando melhores técnicas para o processo de reparo nervoso periférico e reabilitação funcional dessas lesões. As técnicas tradicionais como sutura epineural término-lateral e coaptação por meio de selante de fibrina são utilizadas com essa finalidade. O objetivo deste estudo foi avaliar a reparação do ramo bucal do nervo facial lesionado por meio da técnica términolateral de duas diferentes formas: sutura epineural e o novo selante heterólogo de fibrina, associadas ou não ao tratamento com laser de baixa potência. Foram utilizados trinta e dois ratos (Rattus norvegiccus, Wistar) com 80 dias de vida, distribuídos aleatoriamente em Grupo Controle (GC; n=8), e Grupos Experimentais (Grupo Experimental Sutura - GES e Grupo Experimental Fibrina GEF; n=12; Grupo Experimental Sutura Laser GESL e Grupo Experimental Fibrina Laser GEFL; n=12). Os animais do GC não receberam intervenção cirúrgica; no GES foi realizado, no lado direito da face, a secção do ramo bucal do nervo facial, onde o coto proximal foi suturado à tela subcutânea e o coto distal suturado de forma término-lateral ao ramo zigomático do nervo facial; no GEF, no lado esquerdo da face, foram realizados os mesmos procedimentos do GES, porém foi utilizada a coaptação com selante de fibrina do coto distal. Os grupos GESL e GEFL, além das técnicas descritas, receberam tratamento com aplicação de Laser Arseneto de Gálio Alumínio (GaAlAs), pulso contínuo, comprimento de onda de 830 nm, 6 J/cm2, por 24 segundos, três vezes por semana durante cinco semanas, em três pontos dos locais operados de ambos os lados. Foi realizada também a análise funcional do movimento das vibrissas de todos os grupos na 5ª e 10ª semanas pós-cirúrgica. Os animais foram eutanasiados 10 semanas após a cirurgia e as fibras nervosas foram analisadas morfologicamente, utilizando microscopia óptica e eletrônica, e morfometricamente por meio das medidas da área e diâmetro da fibra, área e diâmetro do axônio, espessura e diâmetro da bainha de mielina. Foi possível observar a regeneração no coto distal de fibras mielínicas e amielínicas. Nas variáveis mensuradas, ocorreu diferença significante na área da fibra nervosa entre os grupos GEF e GEFL. A recuperação funcional dos movimentos das vibrissas apresentou melhores resultados nos grupos com uso do selante de fibrina (GEF e GEFL), sendo que os grupos associados à laserterapia foram os que mais se aproximaram do GC. Portanto, concluiu-se que os dois métodos analisados para reparação nervosa periférica foram efetivos, permitindo o brotamento axonal no coto distal, e que a laserterapia proporcionou melhores resultados, tanto morfométricos quanto funcionais. / The injuries on the face are more common in today\'s society, involving motor vehicle accidents, falls or iatrogenic consequences after procedures. These injuries can affect the nerves responsible for facial muscles reflecting in physical, emotional and psychosocial changes, for example in the stomatognathic system, in voice, facial expression and aesthetics, feelings and social life of the individual. Current researches are aiming best techniques to the process of peripheral nerve repair and functional rehabilitation of these injuries. Traditional techniques such as end-to-side epineural suture coaptation by fibrin sealants are used for this purpose. The objective of this study was to evaluate the repair of buccal branch of the facial nerve injured by end-toside technique in two different ways: epineural suture and the new heterologous fibrin sealant, associated or not to treatment with low power laser. Thirty-two rats (Rattus norvegicus, Wistar) were used. They were 80 days old and were randomly divided into Control Group (CG, n=8) and Experimental Groups (Experimental Suture Group ESG and Experimental Fibrin Group - EFG; n=12; Experimental Suture Laser Group ESLG and Experimental Fibrin Laser Group - EFLG; n=12). The CG animals did not receive surgery; the ESG was performed on the right side of the face, the section of the buccal branch of the facial nerve, where the proximal stump was sutured to the subcutaneous tissue and the distal stump sutured end-to-side portion of the zygomatic branch of the facial nerve; EFG on the left side of the face, the same procedures were carried ESG, but was used coaptation with fibrin sealant of the distal stump. The groups ESLG and EFLG, and the techniques described, have been treated with the application of Laser Gallium Aluminum Arsenide (GaAlAs), continuous pulse, wave length 830 nm, 6J /cm2 for 24 seconds, three times per week for five weeks, at three points of the local operated from both sides. It also performed a functional analysis of the movement of the vibrissae of all groups in the 5th and 10th post-operativeweeks. The animals were euthanized 10 weeks after surgery and the fibers were morphologically analyzed, using light and electron microscopy, and morphometrically by means measures the area and diameter of the fiber, area and diameter of the axon, thickness and diameter of the myelin sheath. It was possible to observe regeneration in the distal stump of myelinated and unmyelinated fibers. The measured variables, there was a significant difference in the area of the nerve fiber between the EFG and EFLG groups. Functional recovery of the movements of the vibrissae the best results in the groups with fibrin sealant use (EFG and EFLG), and the groups associated with laser therapy were the most nearly CG. Therefore, it follows that the two methods discussed for peripheral nerve repair was effective, allowing for axonal sprouting in the distal stump, and that the laser treatment yielded better results, both morphometric and functional.

by Wai-Chi Kong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1997. / Includes bibliographical references (leaves 83-92). / Acknowledgements --- p.i / Abstract --- p.ii / Abbreviations Frequently Used --- p.v / Chapter Chapter1 --- General Introduction --- p.1 / Chapter Chapter2 --- Long term culture of whole-mount retinal explant --- p.16 / Chapter Chapter3 --- Responses of retinal ganglion cells after peripheral nerve transplantation in vivo and in vitro --- p.46 / Chapter Chapter4 --- Effect of optic nerve or peripheral nerve explants on cultured whole-mount retinal explants --- p.62 / Chapter Chapter5 --- General Discussion --- p.78 / References --- p.83 / Tables --- p.93

INTRODUÇÃO: O nervo facial (NF) desempenha um papel importante em diversas funções fisiológicas do organismo e controla a musculatura da mímica facial, responsável por transmitir sentimentos e emoções. O tratamento padrão-ouro para reconstrução do NF após trauma com secção é a anastomose término-terminal com cola de fibrina, que na maioria dos casos ainda produz resultados subótimos. Por isso, objetivou-se testar o efeito de uma nova técnica de reconstrução usando um protocolo de fusão axonal por polietilenoglicol (PEG), denominada sutura química, utilizando parâmetros eletrofisiológicos e histomorfométricos. MÉTODOS: Ratos Wistar foram divididos em 4 grupos. Após transecção do ramo mandibular do NF, o grupo controle foi submetido a anastomose dos cotos neurais com microssuturas. O grupo 2 foi tratado com microssuturas mais a sutura química. A sutura química consistiu de lavagem dos cotos neurais com solução de Krebs hipotônica contendo azul de metileno antes das microssuturas. Depois da sutura, seguiu-se a lavagem com solução de PEG e, por último, aplicação de solução de Krebs contendo cálcio. O grupo 3 recebeu microssuturas mais a solução com azul de metileno. E o grupo 4 foi tratado com microssuturas mais a solução de PEG. Os potenciais de ação musculares compostos (PAMCs) foram avaliados no pré-operatório e após 3 e 6 semanas das intervenções. A análise histomorfométrica foi realizada após 6 semanas. RESULTADOS: Os animais submetidos à sutura química apresentaram maior amplitude e menor duração dos PAMCs 3 e 6 semanas após a cirurgia em comparação com todos os demais grupos; na análise histológica, apresentaram maior contagem axonal e maior diâmetro axonal. CONCLUSÕES: A sutura química produziu recuperação mais intensa do NF após secção e sutura quando comparada à sutura isoladamente, pela avaliação eletrofisiológica e histomorfométrica, e pode ser útil em situações clinicas nas quais haja secção seguida de reparo neural imediato / BACKROUND: The gold standard treatment for traumatic transection of the FN continues to be end-to-end anastomosis using fibrin glue, which often yields unsatisfying results. OBJECTIVE: To test the outcome of a novel method of polyethylene glycol (PEG)-fusion on FN transection using electrophysiological and histophormometric parameters. METHODS: Wistar rats were divided into 4 groups. After FN transection, the control group was submitted to end-to-end anastomosis with microsutures. Group 2 was submitted to microsutures plus the PEG-fusion protocol. This protocol consisted in bathing nerve stumps with a calcium-free Krebs solution containing methylene blue (MB) before suturing. After suturing, the repaired nerve received a PEG solution followed by a calcium-containing Krebs solution. Group 3 received microsutures plus the MB solution and group 4 received microsutures plus the PEG solution. Compound muscle action potentials (CMAPs) were recorded before the intervention and 3 and 6 weeks afterwards. Histomorphometric analysis was done at 6 weeks time. RESULTS: The PEG-fusion protocol yielded larger CMAP amplitude, smaller CMAP duration at 3 and 6 weeks and a larger axon count and axon diameter. Between the other groups, no significant difference was seen. CONCLUSION: PEG-fusion produces better FN recovery after transection, when considering electrophysiological and histomorphometric analysis and may be of use in clinical scenarios of FN cut-severance followed by immediate repair

The control of cellular tyrosine phosphorylation levels is of great importance in many biological systems. Among the kinases and phosphatases that modulate these levels, the LAR-RPTPs have been suggested to act in several key aspects of neural development, and in a dysfunctional manner in various pathologies from diabetes to cancer. The aim of this thesis is to describe the physiological functions of one of the members of this subfamily of RPTPs, namely RPTPsigma. First, we showed that glucose homeostasis is altered in RPTPsigma null mice. They are hypoglycemic and more sensitive to exogenous insulin and we proposed that the insulin hypersensitivity observed in RPTPsigma-null mice is likely secondary to their neuroendocrine dysplasia and GH/IGF-1 deficiency. In addition to regulating nervous system development, RPTPsigma was previously shown to regulate axonal regeneration after injury. In the absence of RPTPsigma, axonal regeneration in the sciatic, facial and optical nerves was enhanced following nerve crush. However, myelin-associated growth inhibitory proteins and components of the glial scar such as CSPGs (chondroitin sulfate proteoglycans) have long been known to inhibit axonal regeneration in the CNS, making spinal cord injury irreversible. In collaboration with Dr Samuel David, we unveiled that RPTPsigma null mice are able to regenerate their corticospinal tract following spinal cord hemisections as opposed to their WT littermates. We then isolated primary neurons from both sets of animals and found that the absence of RPTPsigma promotes the ability of the neurons to adhere to certain inhibitory substrates. Finally, in order to better understand the physiological role of RPTPsigma, we used a yeast substrate-trapping approach, to screen a murine embryonic library for new substrates. This screen identified the RhoGAP p250GAP as a new substrate, suggesting a downstream role for RPTPsigma in RhoGTPase signaling. We also identified p130Cas and Fyn as new binding partners. All these proteins have clear functional links to neurite extension. The characterization of RPTPsigma and its signaling partners is essential for understanding its role in neurological development and may one day translate into treatments of neural diseases and injuries.

Severe extremity trauma often involves significant damage to multiple tissue types, including bones, skeletal muscles, peripheral nerves, and blood vessels. Such injuries present unique challenges for reconstruction, and improving structural and functional outcomes of intervention remains a pressing, unmet clinical need. While tissue engineering/regenerative medicine (TE/RM) therapeutics offer promising potential to overcome the status quo limitations of surgical reconstruction, very few products have transitioned to clinical practice. Improving treatment options will likely require advancing our understanding of the biological interactions occurring in the repair of damaged tissues. Bone tissue is known to be innervated and highly vascularized, and both tissue types are involved in normal bone physiology. However, the degree to which these tissue relationships influence the repair of large, multi-tissue defects remains unknown. Accordingly, the goal of this thesis was to investigate tissue regeneration in two novel composite injury models. First, we characterized interactions in a composite bone and nerve injury model where a segmental bone defect was combined with a peripheral nerve gap. Our results indicated that although tissue regeneration was not impaired, the composite injury group experienced a marked functional deficit in the operated limb compared to single-tissue injury. Second, we developed a model of composite bone and vascular extremity trauma by combining a critically-sized segmental bone defect with surgically-induced hind limb ischemia to evaluate the effects on BMP-2-mediated bone repair. Interestingly, our results demonstrated a stimulatory effect of the recovery response to ischemia on bone regeneration. Finally, we investigated early vascular growth and gene expression as potential mechanisms coupling the response to ischemia with bone defect repair. Although the response to ischemia promoted robust vascular growth in the thigh, it did not directly augment vascularization at the site of bone regeneration. In addition, the stimulatory effects of ischemia on bone regeneration could not be explained by gene expression alone based on the genes and time points investigated. Taken together, this thesis presents pioneering work on a new thrust of TE/RM research – tissue regeneration in models of composite injury. This work has provided new insights on the complexity of composite tissue repair, specifically in regard to the relationship between vascular tissue growth and bone healing. Going forward, successful leverage of models of composite tissue injuries will provide valuable test beds for screening new technologies, advance the understanding of tissue repair biology, and ultimately, may produce new therapeutic interventions for limb salvage and reconstruction that improve outcomes for extremity trauma patients.