Medical micromotors have the potential to lead to a paradigm shift in future biomedicine, as they may perform active drug delivery, microsurgery, tissue engineering, or assisted fertilization in a minimally invasive manner. However, the translation to clinical treatment is challenging, as many applications of single or few micromotors require real-time tracking and control at high spatiotemporal resolution in deep tissue. Although optical techniques are a popular choice for this task, absorption and strong light scattering lead to a pronounced decrease of the signal-to-noise ratio with increasing penetration depth. Here, a highly reflective micromotor is introduced which reflects more than tenfold the light intensity of simple gold particles and can be precisely navigated by external magnetic fields. A customized optical IR imaging setup and an image correlation technique are implemented to track single micromotors in real-time and label-free underneath phantom and ex vivo mouse skull tissues. As a potential application, the micromotors speed is recorded when moving through different viscous fluids to determine the viscosity of diverse physiological fluids toward remote cardiovascular disease diagnosis. Moreover, the micromotors are loaded with a model drug to demonstrate their cargotransport capability. The proposed reflective micromotor is suitable as theranostic tool for sub-skin or organ-on-a-chip applications.

In dieser Arbeit wurde ein Arbeitsablauf entwickelt, um ein möglichst realistisches, biomechanisches Modell eines menschlichen Schädelknochens anhand eines Patienten-CT Datensatzes zu erstellen. Mit diesem Modell konnten Experimente aus der Literatur realistisch nachgestellt und anschließend der Mechanismus einer Orbitawandfraktur genauer untersucht werden. Es konnte gezeigt werden, dass das entwickelte Schädelmodell als Alternative für experimentelle biomechanische Untersuchungen verwendet werden kann. Somit sind eine Vielzahl parametrischer biomechanischer Studien möglich, ohne dabei auf Humanpräparate angewiesen zu sein.

Stem cells are crucial players during development, homeostasis and tissue regeneration and their interactions with the surrounding microenvironment are key to regulate stem cell fate. The skull's stem cell niches reside in the fibrous joints that connect flat bones of the skull. In the embryo, bone and sutures develop in concert to form a complex, multi-facted structure that requires interaction with multiple differentiating cell types to maintain balance between growth and differentiation. Disruption of this balance drives changes in size and shape of skull bones and can severely impact quality of life. Cranial sutures, often seen as simple extracellular matrix-rich structures bridging the rigid plates of the skull, are major actors in craniofacial morphogenesis of as they harmonize bone growth with expansion of the developing brain and participate in providing osteoblasts during repair. The complexity of the extracellular environment and the important role for sutures in skeletal development makes these niches a compelling structure to investigate how interactions with the surrounding microenvironment can modulate stem cells fate. The key role of sutures in development is highlighted by the numerous severe dysmorphisms arising from failure to maintain suture patency. The ability of the suture to respond to brain growth or trauma and the dysmophisms presented by patients with defective sutures is mediated by both biochemical and mechanical cues but the cell biology of these niches remains elusive, especially during their development. In particular, few studies have shed light on the underlying cellular behaviors behind microenvironmental regulation of cranial suture stem cell fate and what role mechanical inputs play in the establishment of this niche. In my thesis, I addressed gaps in our understanding of suture biology by characterizing the suture stem cell niche microenvironment and exploring how cell-ECM interactions serve as regulators of suture stem cell fate. Making use of various microscopy and analytical techniques I first characterized the composition of the microenvironment in a developing suture niche, such as organization of ECM, cytoskeleton and nuclear morphologies. My work builds on an incomplete transcriptional understanding of suture cell development, such that specific genetic markers are rarely useful for identifying distinct suture cell populations during its morphogenesis. By applying shape description tools to parse suture cells and test whether shape correlates to cell identity, we concluded that suture nuclei are distinct and less spherical than those of other cranial tissues. Using 'global' markers such as nuclear stains, I have also identified physical distinctions between suture nuclei and neighboring tissues, indicating that cell shape is an integral part of midline suture identity and can be used to explore coordination of fate choice and morphogenesis in this enigmatic structure. In addition, I present evidence that supports that maturation of extracellular matrix begins during early stages of suture development. In particular, embryonic midline sutures express high levels of fibrillary collagen, which contributes to the formation of a complex extracellular environment that provides the suture with physical properties distinct from those of developing bones. My work shows the presence of cell-ECM and cell-cell adhesions in the developing midline sutures, as well as a complex actin cytoskeleton that is, in part, mediated by physical stresses resultant from underlying brain expansion. Secondly, I aimed to address how perturbations in ECM composition can affect cell specification. To investigate the importance of ECM maturation in regulating suture cell fate I inhibited the function of lysyl oxidase, a collagen crosslinker, during embryonic development. Disruption of collagen crosslinking altered expression of collagen and ECM receptor encoding genes. In addition, this inhibition induced changes in the shape and size of collagen fibers in the embryonic midline suture and decreased tissue bulk stiffness relative to WT. These abnormal properties of the ECM impact tissue delineation in the cranial mesenchyme through nuclear shape analyses. This might be explained by observed changes in the composition of the nuclear envelop of suture cells as we find altered lamin concentration and localization upon lysyl oxidase inhibition. The work developed during myPhD steps away from the traditional genetic approaches used to study the embryonic suture and provides the first in-depth analysis of the physical properties of the developing midline suture at stages preceding known establishment of the niche. The various methods and analyses applied reveal a complex organization of embryonic suture ECM and its tight relationship with shape and fate in this tissue. This work serves as a foundation for future studies that can explore the mechanisms through which ECM regulates fate and development of the suture niche, and potentially skeletal development more generally.

Indiana University-Purdue University Indianapolis (IUPUI) / Down syndrome (DS) is caused by trisomy of human chromosome 21 (Hsa21) and occurs in ~1 of every 700 live births. Individuals with DS present craniofacial abnormalities, specifically an undersized, dysmorphic mandible which may lead to difficulty with eating, breathing, and speech. Using the Ts65Dn DS mouse model, which mirrors these phenotypes and contains three copies of ~50% Hsa21 homologues, our lab has traced the mandibular deficit to a neural crest cell (NCC) deficiency in the first pharyngeal arch (PA1 or mandibular precursor) at embryonic day 9.5 (E9.5). At E9.5, the PA1 is reduced in size and contains fewer cells due to fewer NCC populating the PA1 from the neural tube (NT) as well as reduced cellular proliferation in the PA1. We hypothesize that both the deficits in NCC migration and proliferation may cause the reduction in size of the PA1. To identify potential genetic mechanisms responsible for trisomic PA1 deficits, we generated RNA-sequence (RNA-seq) data from euploid and trisomic E9.25 NT and E9.5 PA1 (time points occurring before and after observed deficits) using a next-generation sequencing platform. Analysis of RNA-seq data revealed differential trisomic expression of 53 genes from E9.25 NT and 364 genes from E9.5 PA1, five of which are present in three copies in Ts65Dn. We also further analyzed the data to find that fewer alternative splicing events occur in trisomic tissues compared to euploid tissues and in PA1 tissue compared to NT tissue. In a subsequent study, to test gene-specific treatments to rescue PA1 deficits, we targeted Dyrk1A, an overexpressed DS candidate gene implicated in many DS phenotypes and predicted to cause the NCC and PA1 deficiencies. We hypothesize that treatment of pregnant Ts65Dn mothers with Epigallocatechin gallate (EGCG), a known Dyrk1A inhibitor, will correct NCC deficits and rescue the undersized PA1 in trisomic E9.5 embryos. To test our hypothesis, we treated pregnant Ts65Dn mothers with EGCG from either gestational day 7 (G7) to G8 or G0 to G9.5. Our study found an increase in PA1 volume and NCC number in trisomic E9.5 embryos after treatment on G7 and G8, but observed no significant improvements in NCC deficits following G0-G9.5 treatment. We also observed a developmental delay of embryos from trisomic mothers treated with EGCG from G0-G9.5. Together, these data show that timing and sufficient dosage of EGCG treatment is most effective during the developmental window the few days before NCC deficits arise, during G7 and G8, and may be ineffective or harmful when administered at earlier developmental time points. Together, the findings of both studies offer a better understanding of potential mechanisms altered by trisomy as well as preclinical evidence for EGCG as a potential prenatal therapy for craniofacial disorders linked to DS.

No description available.

With regards to Swedish succession rights, and the distribution of the inheritance as such, there is an underlying conflict of a fundamental nature betweenthe deceased´s former interest in how the estate should be distributed on theone hand, and the interest of the primary heirs in the preservation of theinheritance on the other. The deceased´s interest can be derived from the rightto private ownership, while the interest of the primary heirs rests upon thestatutory minimum portion of the inheritance (laglott) which they are entitled to by law. The statutory minimum portion of the inheritance is half of the sharethat is due by law (arvslott) to the primary heirs if there is no will, i.e. if theintestate succession (legala arvsordningen) is followed. Furthermore, this conflictof interest can provoke an individual to plan their estate with the intention ofminimizing the inheritance of one or more of their primary heirs. This pertainsespecially to children who are not the offspring of the surviving spouse,considering that they are entitled to receive their statutory minimum portion ofthe inheritance immediately upon the deceased’s – their parent's – death. Thedispositions at hand for someone who wants to plan their estate (dödsrättshandlingar) according to Swedish law are of two particular types. Wills (testamenten)and beneficiary designations (förmånstagarförordnanden). Gifts made in contemplation of the donor’s impending death (gåvor för dödsfalls skull), ties into thiscategory as well. Namely, gifts of this nature are in this respect equated to wills.Another rationale for sorting these three different dispositions together can befound in their common purpose, i.e. to benefit someone else with all or someof the estate. In the most abstract terms, these three categories could be called,gratuitous legal dispositions made ad mortis causa, (benefika dispositioner fördödsfalls skull). In light of this the thesis explores and examines whether a primaryheir´s legal protection – especially if the statutory minimum portion of theinheritance – has an equal efficiency in relation to this broad category –constituted of the three aforementioned subsets – accessible to someone whowants to plan their estate. The result of the thesis is primarily that such adifference in fact does exist and secondarily that this inconsistency to some extent is unjustifiable considering (1) the similar nature and purpose of these dispositions, and (2) the presence and function of the legal institute of forcedheirship in Swedish law.

Significance Cerebrospinal fluid (CSF) rhinorrhea (leakage of brain fluid from the nose) can be difficult to identify and currently requires invasive procedures, such as intrathecal fluorescein, which requires a lumbar drain placement. Fluorescein is also known to have rare but significant side effects including seizures and death. As the number of endonasal skull base cases increases, the number of CSF leaks has also increased for which an alternative diagnostic method would be highly advantageous to patients. Aim We aim to develop an instrument to identify CSF leaks based on water absorption in the shortwave infrared (SWIR) without the need of intrathecal contrast agents. This device needed to be adapted to the anatomy of the human nasal cavity while maintaining low weight and ergonomic characteristics of current surgical instruments. Approach Absorption spectra of CSF and artificial CSF were obtained to characterize the absorption peaks that could be targeted with SWIR light. Different illumination systems were tested and refined prior to adapting them into a portable endoscope for testing in 3D-printed models and cadavers for feasibility. Results We identified CSF to have an identical absorption profile as water. In our testing, a narrowband laser source at 1480 nm proved superior to using a broad 1450 nm LED. Using a SWIR enabling endoscope set up, we tested the ability to detect artificial CSF in a cadaver model. Conclusions An endoscopic system based on SWIR narrowband imaging can provide an alternative in the future to invasive methods of CSF leak detection.

Thesis (MSc)--University of Stellenbosch, 1982. / ENGLISH ABSTRACT:This study deals with the development of the ethmoidal region of Ascaphus truei Stejneger with special interest to the development of the nasal sacs, the diverticulum medium and the Jacobson's organ. This is to gather more information regarding the phylogeny of the structures. The opinions concerning the phylogenetical migration of the Jacobson's organ, are corroborated by the development of the organ in Ascaphus. The possible origin of the diverticulum medium from the nasal end of the nasolacrimal duct also is commented on. / No Afrikaans abstract available

Facial Artery Musculomucosal Flap in Skull Base Reconstruction Xie L. MD, Lavigne F. MD, Rahal A. MD, Moubayed SP MD, Ayad T. MD Introduction: Failure in skull base defects reconstruction can have serious consequences such as meningitis and pneumocephalus. The nasoseptal flap is usually the first choice but alternatives are necessary when this flap is not available. The facial artery musculomucosal (FAMM) flap has proven to be successful in head and neck reconstruction but it has never been reported in skull base reconstruction. Objective: To show that the FAMM flap can reach some key areas of the skull base and be considered as a new alternative in skull base defects reconstruction. Methods: We conducted a cadaveric study with harvest of modified FAMM flaps, endoscopic skull base dissection and maxillectomies in 13 specimens. Measures were taken for each harvested FAMM flap. Results: The approximate mean area for reconstruction from the combination of the distal FAMM and the extension flaps is 15.90 cm2. The flaps successfully covered the simulated defects of the frontal sinus, the ethmoid areas, the planum sphenoidale, and the sella turcica. Conclusion: The FAMM flap can be considered as a new alternative in the reconstruction of skull base defects. Modifications add extra length to the traditional FAMM flap and can contribute to a tighter seal of the defect as opposed to the FAMM flap alone. / Le lambeau musculomuqueux de la joue dans la reconstruction de la base du crâne Xie L. MD, Lavigne F. MD, Rahal A. MD, Moubayed SP MD, Ayad T. MD Introduction: Un échec dans la reconstruction de la base du crâne peut avoir des conséquences graves telles que la méningite ou la pneumocéphalie. Le premier choix de la reconstruction est le lambeau nasoseptal. Lorsque ce dernier n’est pas disponible, d’autres alternatives sont nécessaires. Le lambeau musculomuqueux de la joue (FAMM) a une place établie dans la reconstruction des déficits de la tête et du cou, mais il n’a pas jamais été décrit dans la reconstruction de la base du crâne. Objectif: Démontrer que le lambeau de FAMM peut atteindre des zones clés de la base du crâne et être considéré comme une nouvelle option de reconstruction de cette région. Méthode: Nous avons entrepris une étude cadavérique avec prélèvement de lambeaux de FAMM modifiés et une dissection endoscopique de la base du crâne sur 13 spécimens. Des mesures ont été prises pour chaque lambeau prélevé. Résultats: L’aire de reconstruction moyenne du lambeau de FAMM et des extensions est de 15.90 cm2. Les lambeaux couvrent totalement les déficits simulés du sinus frontal, des ethmoïdes, le toit du sphénoïde et la selle turcique. Conclusion: Le lambeau de FAMM peut être considéré comme une nouvelle alternative dans la reconstruction des déficits de la base du crâne. Les modifications apportent une longueur additionnelle et contribuent à une couverture plus étanche du déficit que le lambeau de FAMM seul.

L’ibéromaurusien (23 000 - 9500 Cal BC) et le Capsien (9600 - 5000 Cal BC) sont deux cultures de la fin du paléolithique supérieur et de l’épipaléolithique d’Afrique du nord ; elles ont été définies sur la base de la typologie de leur assemblage d’industrie lithique. L’Ibéromaurusien est caractérisé par une industrie lamellaire microlithique et la Capsien par une industrie microlithique riche en segments minuscules, en microburins et microlamelles. La discontinuité biologique prêtée à ces deux groupes, sur la base d’arguments anthropologiques discutables, a fortement influencé le débat sur leur mode de remplacement. Ainsi une origine Moyen-Orientale a été proposée à la culture capsienne. Nous avons souhaité vérifier cette théorie à partir de l’étude du traitement funéraire dans ces deux groupes. En appliquant les méthodes de l’anthropologie funéraire moderne, nous proposons une révision critique de l’ensemble du corpus aujourd’hui disponible. Il comprend une soixantaine de sépultures Ibéromaurusiennes, renfermant 126 individus découverts dans 10 sites, 48 sépultures Capsiennes contenant 55 individus, issues de 13 sites, et enfin 38 sépultures du site de Columnata, livrant 89 individus. Nous avons scrupuleusement analysé les contextes de découvertes de ces individus dans les publications et les carnets de fouilles. Nous avons révisé les dénombrements, la détermination du sexe et l’estimation de l’âge au décès. Nous avons également exploré la surface de l’os à la recherche de stigmates permettant de valider ce que l’analyse taphonomique des sépultures laissait présager. Nous avons d’abord caractérisé le système funéraire de chacun de ces deux groupes, puis nous avons comparé les composants de ces deux systèmes afin de rechercher une éventuelle transmission ou rupture de coutume entre les deux sociétés. Les normes funéraires telles que nous les avons établies, confirment la spécificité de chacun de ces deux groupes. Les gestes funéraires sont différents et l’absence de transmission directe entre ces deux groupes de chasseurs cueilleurs est d’abord envisagée. Toutefois, l’interprétation ostéo-archéologique des sépultures révèle la présence d’une coutume funéraire minoritaire (conditionnelle), longue dans sa durée d’exécution, et complexe par la technique qu’elle requiert, quasi identique dans les deux groupes. Ce traitement passe par une étape de découpe du cadavre (décollation, désarticulation, décarnisation et éviscération), la tête après dépouillement est décorée parfois surmodelée. Enfin, le corps ainsi partitionné est inhumé en blocs anatomiques disloqués. Ce traitement, par les degrés d’apprentissage qu’il nécessite et la complexité de sa conception, suggère un lien direct entre les deux traditions. Cet héritage culturel Ibéromaurusien chez les Capsiens nous conduit à privilégier l’hypothèse d’une relation ancêtre-descendant et une origine locale de la culture Capsienne. / The iberomaurusien (23,000 - 9500 cal BC) and the Capsian (9600-5000 cal BC) are two cultures dating from the end of the upper Palaeolithic and Epipalaeolithic in North Africa. They have been established on the basis of the characterisitics of their lithic industries. The Iberomaurusien is characterized by a lamellar microblade industry and Capsian by a microblade industry rich in tiny segments and microburins microbladelets. Biological discontinuity of these two groups has been assumed on the basis of questionable anthropological arguments which have strongly influenced debate on their origins. Thus a Middle-Eastern origin has been proposed for the Capsian. We wanted to test this theory using a study of the mortuary practices in these two groups. By applying the perspective of modern mortuary anthropology, we offer a critical review of the entire available corpus. This includes 60 Iberomaurian graves, containing 126 individuals discovered in 10 sites, 48 Capsian graves containing 55 individuals from 13 sites, and 38 burials from the Columnata site providing 89 individuals. We carefully analyzed the contexts of discovery of these individuals as described in publications and field notes. We have revised the counts, the sex-determination and estimation of the age at death. We also explored the surface of the bones looking for stigmata to validate what a taphonomic analysis of the graves might reveal. We first characterized the burial system of each of these two groups, and then the components of these two systems were compared to find a possible transmission or break in burial custom between the two societies. The funeral practices as we have established them, confirm the specificity of these two groups. Funeral rituals are different and the absence of direct transfer between these two groups of hunter-gatherers is first considered. However, the osteo-archaeological interpretation of the graves revealed the presence of a (conditional) minority funeral custom, which lasted a long time, and required a complex technique, that was almost identical in the two groups. This treatment goes through a stage of dismembering the cadaver (beheading, disarticulation, butchering and evisceration), and the skull after flaying is sometimes plastered. Finally, thus partitioned, the body is buried assembled in dislocated anatomical blocks. This treatment, by the levels of knowledge that it requires, and the complexity of its design, suggests a direct link between the two traditions. This endurance of Iberomaurusian cultural heritage in the Capsian leads us to confirm the hypothesis of an ancestor-descendant relationship and a local origin of the Capsian culture.