Characterisation of Drug Delivery Efficacy Using Microstructure-Assisted Application of a Range of APIs.

Polymer-based solid microstructures (MSts) have the potential to significantly increase the quantity and range of drugs that can be administered across the skin. MSt arrays are used to demonstrate their capacity to bypass the skin barrier and enhance permeability by creating microchannels through the stratum corneum, in a minimally invasive manner. This study is designed to demonstrate the ability of MSts to exceed the current boundaries for transdermal delivery of compounds with different molecular weights, partition coefficients, acid dissociation constants, melting points, and water solubilities. In vitro permeation of a range of selected molecules, including acetyl salicylic acid (aspirin), galantamine, selegiline hydrochloride (Sel-HCl), insulin, caffeine, hydrocortisone (HC), hydrocortisone 21-hemisuccinate sodium salt (HC-HS) and bovine serum albumin (BSA) has been studied across excised porcine skin with and without poke and patch application of MSts. Permeation of the molecules was monitored using Franz diffusion cells over 24 h. MSts significantly increased the permeation of all selected molecules up to 40 times, compared to topical applications of the molecules without MSts. The greatest increase in permeation was observed for caffeine with 70 ± 8% permeation and the lowest enhancement was observed for HC with a 2.4 ± 1.3% increase in permeation. The highest obtained flux was BSA (8133 ± 1365 µg/cm2/h) and the lowest flux observed for HC (11 ± 4 µg/cm2/h). BSA and HC also showed the highest (16,275 ± 3078 µg) and the lowest (73 ± 47 µg) permeation amount after 24 h respectively. MSt-treated skin exhibits greatly increased permeation. The molecule parameters (size, acid dissociation constant, partition coefficient and solubility)-traditional hurdles associated with passive diffusion through intact skin-are overcome using MSt skin treatment.

Fracture resistance of endodontically treated teeth without ferrule using a novel H-shaped short post.

OBJECTIVE: To evaluate the fracture resistance and failure types of modified H-designed intradental short retention preparation for computer-aided design/computer-assisted manufacture (CAD/CAM) restorations, in cases where no ferrule is possible. METHOD AND MATERIALS: A combined finite element analysis and in vitro testing was employed. Forty extracted single-rooted premolars were selected and prepared for the following four groups (n = 10 per group): Group A, H-post preparation restored with glass-ceramic crowns; group B, H-post preparation restored with lithium disilicate crowns; group C, endocrowns (negative control group); and group D, 2-mm ferrule preparation and restoration with fiber posts (positive control). After cementation, specimens were loaded to fracture (1 mm/min) in a universal testing machine. The data were analyzed using Kolmogorov-Smirnov, Shapiro-Wilk test, one-way ANOVA, followed by post-hoc Scheffé test and chisquare test. RESULTS: The H-post group restored with lithium disilicate crowns (group B) presented higher fracture resistance compared to the H-post group with glass-ceramic crowns (group A) and the endocrowns (group C). Among the failure analysis, only specimens of group C were all repairable after fracture load test, while the specimens of remaining groups A, B, and D accounted for 90%, 70%, and 50% repairable fracture modes, respectively. CONCLUSION: The modification of the short intracoronal restoration anchorage profile may be a valid concept to improve the retention and fracture resistance, given that the materials are adjusted for this purpose in terms of mechanical resistance and internal adaptation. Numerical evaluations and future in vitro studies may help to select the best designs and materials.

FEA evaluation of the resistance form of a premolar crown.

PURPOSE: The purpose of this study was to evaluate the influence of buccal and lingual wall convergence angles on the ability of the preparation to resist rotational displacement. MATERIALS AND METHODS: An intact premolar digitized by micro-CT yielded a 3D reproduction of a human tooth. Simulated crown preparations with known buccolingual axial wall convergence angles (4°, 8°, 12°, 16°, 20°, 24°, 28° 32°), sloped-shoulder marginal area, and occlusal reduction were created and restored with a ceramic crown. The tooth restoration was loaded with a 200 N force at 45° to the incline of the buccal cusp. The responses of the restored tooth with luting agents were analyzed using the 3D finite element method. RESULTS: This study demonstrated that a convergence angle of the preparation above 12° produced a decrease of the resistance of the crown to rotational effects. The study also showed that the use of luting agents that provide bonding between the restoration and dentine improved the rotational resistance of the crown on preparations with large convergence angles. CONCLUSIONS: Use of buccolingual convergence angles greater than 12° reduced the resistance form of the preparation. Luting agents capable of delivering strong bonding between the crown and the preparation improved the resistance in highly tapered preparations.

Induction of osteopenia during experimental tooth movement in the rat: alveolar bone remodelling and the mechanostat theory.

Increases in bone strains above a certain threshold have a positive effect on bone mass, whereas reductions in strain magnitude lead to bone loss and osteopenia; the term 'mechanostat' has been introduced to describe this tissue-level negative feedback mechanism. The mechanobiology of bone and particularly alveolar bone is poorly understood, and whether the mechanostat theory has any relevance to explaining the osseous changes that occur during orthodontic tooth movement remains unclear. To investigate the relationship further, an expansile force of 0.2 N was applied to the maxillary molars of 36, 6-week-old Wistar rats by helical coil springs. The animals were sacrificed at 1, 2, 4, and 8 days and the tissue response analyzed by histological, biochemical, and finite element (FE) methods. Differences between groups were determined by Student's t-test (two-tailed). The appliance produced an increase in the intermolar width averaging 0.5 mm after 8 days. Tetracycline uptake in the control rats suggested a rapid turnover of bone in both the interradicular domain and the bone-periodontal ligament interface. In the experimental group, however, incorporation of tetracycline into the interradicular domain was reduced and conventional histology revealed evidence of bone loss and osteopenia, in both the experimental and a group of sham-treated positive controls (with inactive, annealed springs). Serum alkaline phosphatase declined significantly in both experimental and sham-treated groups over the 8-day time course, indicating decreased bone formation. Serum acid phosphatase also declined, suggesting a concomitant decrease in bone resorption. Three-dimensional FE analysis of the stresses generated in the bone following occlusal (2 N) and orthodontic loading showed that the orthodontic force created a constant loading condition shielding some areas of bone from mechanical stress. Areas of low mechanical stimulation were coincident with sites of bone loss observed histologically, while bone mass was preserved in areas with higher levels of loading. These findings suggest that (1) the osteopenia resulted from stress shielding of the interradicular bone by the appliance, and a consequent reduction in occlusal loading below the critical threshold required for maintaining normal osseous architecture and (2) the mechanostat model can be employed to explain, at least in part, the response of the bone to orthodontic loading.

Mechanical responses to orthodontic loading: a 3-dimensional finite element multi-tooth model.

INTRODUCTION: The initial mechanical response to orthodontic loading comprises biologic reactions that remain unclear, despite their clinical significance. We used a 3-dimensional finite element analysis to investigate the stress-strain responses of teeth to orthodontic loading. METHODS: The model was derived from computed tomography data, with adequate boundary conditions and tissue characterization, with orthodontic hardware to provide a more accurate reflection of events during orthodontic therapy. This study also incorporated the adjacent dentition. Two cases were analyzed: a single-tooth system with a mandibular canine, and a multi-tooth system consisting of the mandibular incisor, the canine, and the first premolar, subjected to orthodontic tipping forces. RESULTS AND CONCLUSIONS: The systems experienced elevated distortion strain energies in the alveolar crest, whereas the tensile and compressive stresses coincided with the apical sites clinically associated with root resorption. Stress levels were considerably greater in the multi-tooth system than in the single-tooth system. The results for the single-tooth model agree with those previously reported. The numeric studies show how orthodontic tooth movement develops different stress fields and how root resorption might occur as a result of hydrostatic compressive stress-induced tissue necrosis.

Measuring intraoral pressure: adaptation of a dental appliance allows measurement during function.

This article introduces a new way of recording intraoral pressures from a range of locations within the oral cavity. To measure pressure flow dynamics during swallowing, we fitted eight miniature pressure transducers capable of measuring absolute pressures to a chrome-cobalt palatal appliance with a labial bow. Unlike previous devices, our design provides a rigid, custom-fitted platform for the simultaneous recording of pressures at eight locations within the oral cavity during function. We placed an anterior pair of gauges to measure lingual and labial contact against the left central incisor tooth, and two pairs of gauges to measure pressure contributions of the lateral tongue margin and cheeks on the canine and first molar teeth. Finally, lingual pressure on the midline of the palate was measured by two gauges, one at the position of the premolars and one on the posterior boundary of the hard palate. We then recorded intraoral pressures in five adult volunteers seated in an upright position and asked to swallow 10 ml of water. Labial pressures on the canine rose rapidly from a resting level of 10 kPa to 33 kPa, while pressure profiles from the labial aspects of the incisor and first molar teeth followed a negative pattern, peaking at -12 kPa for the incisor and -15 kPa for the molar sensor. Pressure profiles recorded from the palatal aspects of the first molar and the canine appeared to be similar, but the former fell to -13 kPa before rising to 9 kPa, and the canine pressure rapidly increased to 22 kPa before returning to its resting level of 4 kPa. The pressure profile of the palatal aspect of the central incisor was strikingly different; at the start of the swallow, pressure dropped precipitously to -20 kPa, before slowly rising to 10 kPa. It then followed the general pattern of the other two sensors, before peaking again at 10 kPa and then returning to a resting level of 4 kPa. We also showed that there were significant negative pressures in the mouth during function, and that pressure profiles varied markedly between individuals.

Analysis of experimental cranial skin wounding from screwdriver trauma.

As part of a more extensive investigation of skin wounding mechanisms, we studied wounds created by five common screwdrivers (straight, star, square or Robertson, Posidriv and Phillips) on the shaven foreheads of 12 freshly slaughtered pigs. We fixed the different screwdriver heads to a 5-kg metal cylinder which was directed vertically onto each pig head by a droptube of 700 mm length. We examined skin lesions by photography and also by scanning electron microscopy (SEM). Our evaluation of differences in wound shape and size was based on geometric morphometric methods. Our results show that there are obvious morphological differences between the straight head and the other types. The straight-headed screwdriver penetrates the skin by a mode II crack which results in a compressed skin plug with bundles of collagen fibres forming skin tabs within the actual wound. The sharper-tipped screwdrivers wedge open the skin (mode I), with a clearly defined edge with no skin plugs. Geometric morphometric analysis indicates that shapes of skin wounds created by the five screwdriver types could be classified into three different groups. The straight head results in the most differentiated wound profile, with the Robertson or square and some specimens of star, and also the Posidriv and Phillips giving similar wound outlines. SEM evaluation of wounds created by a new and worn straight-head screwdrivers shows that the outline of the worn screwdriver head is reflected in the shape of the wound it created.

Experimental simulation of non-ballistic wounding by sharp and blunt punches.

Despite a long history of gross and microscopic descriptions of blunt and sharp force injury to the dermal tissues, few have addressed the mechanisms underlying such trauma. The need to develop an understanding of how non-ballistic injury occurs calls for an ability to biomechanically model the process. We recently introduced a basic skin and subcutaneous model, which we used to investigate wounding from a spherical object. Here we employ the same model to examine wounding caused by a sharp wedge shaped object and a blunt rectangular object. Macroscopic examination and SEM views of the surface and cross sections of blunt and sharp force tears show that while in the former there is a clean cut through the skin into the underlying sponge, in the latter there is a tissue plug confined to the skin that is smaller than the impacting rectangle. Fracture initiation in the subdermal tissue occurs at the angles of the impacting object. In sharp force trauma, there is localized breaching of the skin layer coupled with the wedging action of the impacting object. Because the subdermal tissue, in this case the underlying hydrated foam, is attached to the base of the skin, it will contribute to further tearing of the foam beneath the line of contact.

The biomechanical modelling of non-ballistic skin wounding: blunt-force injury.

Knowledge of the biomechanical dynamics of blunt force trauma is indispensable for forensic reconstruction of a wounding event. In this study, we describe and interpret wound features on a synthetic skin model under defined laboratory conditions. To simulate skin and the sub-dermal tissues we used open-celled polyurethane sponge (foam), covered by a silicone layer. A drop tube device with three tube lengths (300, 400, and 500 mm), each secured to a weighted steel scaffold and into which a round, 5-kg Federal dumbbell of length 180 mm and diameter 8 cm was placed delivered blows of known impact. To calculate energy and velocity at impact the experimental set-up was replicated using rigid-body dynamics and motion simulation software. We soaked each foam square in 500 mL water, until fully saturated, immediately before placing it beneath the drop tube. We then recorded and classified both external and internal lacerations. The association between external wounding rates and the explanatory variables sponge type, sponge thickness, and height were investigated using Poisson regression. Tears (lacerations) of the silicone skin layer resembled linear lacerations seen in the clinical literature and resulted from only 48.6% of impacts. Poisson regression showed there was no significant difference between the rate of external wounding for different sponge types (P = 0.294) or different drop heights (P = 0.276). Most impacts produced "internal wounds" or subsurface cavitation (96%). There were four internal "wound" types; Y-shape (53%), linear (25%), stellate (16%), and double crescent (6%). The two-way interaction height by sponge type was statistically significant in the analysis of variance model (P = 0.035). The other two-way interactions; height by thickness and sponge type by thickness, were also bordering on statistical significance (P = 0.061 and P = 0.071, respectively). The observation that external wounds were present for less than half of impacts only, but that nearly all impacts resulted in internal wounds, might explain the observed haematoma formation and contusions so often associated with blunt-force injuries. Our study also confirms the key role of hydrodynamic pressure changes in the actual tearing of subcutaneous tissue. At the moment and site of impact, transferred kinetic energy creates a region of high pressure on the fluid inside the tissue. As a result of the incompressibility of the fluid, this will be displaced away from the impact at a rate that depends on the velocity (or kinetic energy) of impact and the permeability and stiffness of the polymeric foam and skin layer.

Tongue contractions during speech may have led to the development of the bony geometry of the chin following the evolution of human language: a mechanobiological hypothesis for the development of the human chin.

One of the most fundamental yet unanswered questions of human evolution is that of the development of the chin. Whereas it is known that the chin, or mentum osseum, is an unique anatomical feature of modern humans that emerged during the Middle and Late Pleistocene, its origin and biomechanical significance are the subjects of intense controversy. Theories range from the suggestion that the chin evolved as a result of progressive reduction of the dental arch, which left it as a protrusion, to the hypothesis that it provided resistance to mandibular bending during mastication. Until now however, no accepted functional explanation of the human chin has emerged. Here, we develop the hypothesis that the actions of the tongue and non-masticatory orofacial muscles may have played a significant role on the development of the human chin. We report numerical simulations of the forces and resultant stresses developed in hypothetical chinned and non-chinned mandibles. Using empirical data and estimates of the forces generated by the human tongue during speech, our hypothesis suggests that the chin might in fact have developed as a result of the actions of the tongue and perioral muscles, rather than as a buttress to withstand masticatory induced stress. This provides a new perspective on the generation of the chin and importantly, suggests that its appearance may be causally related to the development of the human language.