Introduction Cutaneous scars represent a common surgical complication, yet no effective drug therapy for scar treatment currently exists despite huge patient and physician demand. A connexin 43 (Cx43) carboxyl terminus (CT) mimetic peptide, alpha Connexin Carboxy-Terminus 1 (αCT1), has demonstrated efficacy in improving long-term scar appearance in pre-clinical and clinical trials. However, current understanding of the mechanism-of-action by which αCT1 improves long-term scar appearance with early intervention treatment is not well understood. Methods In vivo: Scar biopsies from 1) human, 2) Sprague-Dawley rat, and 3) IAF Hairless guinea pig trials of αCT1 were examined for collagen matrix structure at 4 weeks (all models), and 2 and 6 weeks (rat and guinea pig models only). Collagen matrix variables examined included local disorganization of the fibers, a variable that is higher in unwounded skin compared to scar tissue, and density of the fibers, which is higher in scar tissue but can also be used as an early temporal marker of the rate of healing. In vitro: Primary murine dermal fibroblasts were isolated from the whole dermis of 3-4 week old transgenic mice expressing collagen 1(α2) GFP-tpz. Cells were sorted for expression via FACS and plated on prealigned collagen substrate for 7 days under conditions favorable to generating extracellular matrix. Results: All in vivo scar biopsies demonstrated some level of altered collagen matrix structure with αCT1 treatment. Treated scars had higher local disorganization of the collagen fibers within the wound, and an increase in collagen matrix density compared to control at certain earlier timepoints that tended to decrease or disappear at later timepoints. The IAF Hairless guinea pig, a novel splinted wound healing model presented herein, was found to closely replicate the human dermal collagen profile and changes in collagen profile spurred by αCT1, significantly outperforming the traditional rat model. Primary dermal murine fibroblasts treated in vitro with αCT1 significantly increased synthesis of procollagen 1, the precursor of collagen 1 necessary for constructing the extracellular matrix, suggesting that at least part of the reason for higher collagen density at early in vivo timepoints is due to increased collagen synthesis by fibroblasts. Conclusion: αCT1 treatment in the early stages of wound healing prompts individual fibroblasts to increase their output of collagen and create a more disorganized early collagen matrix. These early changes potentially spur the long-term scar appearance improvements seen in clinical trials, and provide a basis for future work to discover the cellular pathways to alter in order to improve wound healing and cutaneous scarring outcomes. / Doctor of Philosophy / Skin wounds frequently result in scars that can range from barely visible to enormous eyesores. Almost everyone will experience at least one skin wound in their lifetime leading to a scar that they wish were less visible, feeding the multi-billion dollar market for anti-scarring agents. However, many of the products on store shelves that claim to reduce scar appearance have not proven those claims. Most of the therapies that do have some degree of scientific evidence to support their claims are difficult to use properly, such as silicone sheeting, and often result in only minor improvements to scar appearance. Alpha Connexin Carboxy-Terminus 1 (αCT1), marketed in clinical trials as Granexin® gel, is a protein-based therapy that works on the cellular level to fundamentally alter the skin's initial reaction to wounding and improving long-term scar appearance. This dissertation explores the link between cellular processes altered by αCT1 and long-term clinical improvements in scar appearance by studying both the extracellular matrix present in the scar in human and animal models and the creation of that extracellular matrix by dermal fibroblasts. In both human and animal models, topical application of αCT1 had no effect on skin surface appearance at early timepoints of 2-6 weeks, correlating with previous research that found scar appearance only improved at 3+ months post-injury. However, deep within the newly constructed tissue of the scar, these studies show the collagen organizational structure of αCT1-treated scars is more similar to unwounded skin and slightly more dense at early timepoints, suggesting αCT1 marginally improved the speed of healing. These findings in humans and animals were also verified in part in cell culture experiments that found dermal fibroblasts increased collagen output in response to αCT1 treatment. A novel wound healing model in the hairless guinea pig, superior at replicating human skin than established models like the rat, is also presented and shown to have effects strongly similar to the human with αCT1 treatment. These results provide a fundamental insight into the mode-of-action by which αCT1 may improve long term scar appearance and identifies early collagen structure as a target for future therapeutics to modify, as well as a new animal model in which to test them.

No / The global prevalence Type 2 diabetes mellitus (T2DM) is escalating at a rapid rate. Patients with T2DM suffer from a multitude of complications and one of these is impaired wound healing. This can lead to the development of non-healing sores or foot ulcers and ultimately to amputation. In healthy individuals, wound healing follows a controlled and overlapping sequence of events encompassing inflammation, proliferation, and remodelling. In T2DM, one or more of these steps becomes dysfunctional. Current models to study impaired wound healing in T2DM include in vitro scratch wound assays, skin equivalents, or animal models to examine molecular mechanisms underpinning wound healing and/or potential therapeutic options. However, these do not fully recapitulate the complex wound healing process in T2DM patients, and ex vivo human skin tests are problematic due to the ethics of taking punch biopsies from patients where it is known they will heal poorly. Here, a technique is described whereby expression profiles of the specific cells involved in the (dys)functional wound healing response in T2DM patients can be examined using surplus tissue discarded following amputation or elective cosmetic surgery. In this protocol samples of donated skin are collected, wounded, cultured ex vivo in the air liquid interface, fixed at different time points and sectioned. Specific cell types involved in wound healing (e.g., epidermal keratinocytes, dermal fibroblasts (papillary and reticular), the vasculature) are isolated using laser capture microdissection and differences in gene expression analyzed by sequencing or microarray, with genes of interest further validated by qPCR. This protocol can be used to identify inherent differences in gene expression between both poorly healing and intact skin, in patients with or without diabetes, using tissue ordinarily discarded following surgery. It will yield greater understanding of the molecular mechanisms contributing to T2DM chronic wounds and lower limb loss. / European Commission 7th Framework Programme for Research and Technical Development - Marie Curie Innovative Training Networks (ITN), Grant agreement no 607886. Aveda, Hair Innovation & Technology, USA

No / It is now recognised that psychosocial factors – anxiety and depression, social isolation, low economic status and pain, for example – are associated with delayed healing of wounds. However, little research has been undertaken to examine how these factors may not only be a consequence of delayed healing, but may also play an important role in delaying healing. It is suggested that an evaluation of a patient’s psychosocial status should therefore be included as part of a general wound assessment.

Yoga as a therapeutic modality for treating trauma is currently emerging as an important topic of research with several new studies being produced to analyze its effectiveness on varying populations of traumatized individuals. Research is beginning to demonstrate that individuals who suffer the effects of trauma have often experienced several negative events that accumulate over the course of one’s lifetime. It has been displayed that when treated early, the adverse effects of trauma may be much less debilitating. Recent studies indicate traumatic memories are often stored within the body and are difficult to recall through cognition alone. Therefore, somatic therapies such as yoga are proving to be an effective means of working through this unresolved trauma. Using a constructivist and postmodernist lens with a narrative methodology, this study explores the impact of yoga on children and youth who have experienced trauma as witnessed by yoga instructors teaching to these populations. Seven participants who reside in British Columbia, volunteered to share their stories and experiences through individual semi-structured interviews. The narratives highlight a potential pathway to healing trauma through several shared factors. These common threads indicate that yoga can provide children and youth a safe space to explore their bodies, develop a sense of community and belonging among peers, as well as engage in a mindfulness practice that incorporates several healing factors such as asana (the physical postures of yoga) and pranayama (connecting to one’s breath). Opening to vulnerability was another common thread indicated as a necessary component to healing that occurred for many children and youth throughout the practice of yoga. This study contributes to the growing research of yoga as a therapeutic modality for healing trauma in children and youth. / Graduate

The thesis showed preliminary evaluation of novel biodegradable and biocompatible agmatine-containing PAA crosslinkers. Hydrogels fabricated by this crosslinker can obtain controllable stiffness and excellent cell adhesion. The PAA contained thermo-sensitive hydrogel reported here is first employed as filler for depressed defects in rats. Results showed that such hydrogel can be injectable and biocompatible, might become a new material in plastic surgery in the clinic. The thesis also demonstrated a novel macro gels with self-healing capability and biocompatibility. The reversible photodimerization and photocleavage reactivity of coumarin has been successfully imparted to the polymer. / February 2015

The Emmanuel Movement is frequently cited by scholars of the history of religion and psychology in the United States. While the story of the movement has been told many times, scholars have missed key ideas about the movement that become clear when we compare the various historical approaches to the movement. I review the Emmanuel Movement’s ideas, taking note of its intellectual influences, its relationship to other liberal Protestant traditions, and its place in turn-of-the-century culture. By reviewing the ideas of the movement, I observe that the Emmanuel Movement brings into focus previously obscure intellectual figures in the history of the movement, foreshadows late-twentieth century cooperation between medicine and religion through mindfulness movements, and highlights a strand of liberal Protestantism that originates in a Jamesian psychology of the healing subconscious. This new look at the Emmanuel Movement thus provides new avenues of inquiry for students of religion and psychology. / text

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