Drug Release and Pharmacokinetic Evaluation of Novel Implantable Mometasone Furoate Matrices in Rabbit Maxillary Sinuses.

BACKGROUND: Intranasal corticosteroid sprays (INCSs) used to treat chronic rhinosinusitis are suboptimal due to limited penetration into the middle meatus, rapid clearance, and poor patient compliance. A bioresorbable drug matrix, developed with the XTreoTM drug delivery platform, may overcome the limitations of INCS by providing continuous dosing over several months. OBJECTIVE: To evaluate the in vitro drug release and in vivo pharmacokinetics of novel mometasone furoate (MF) matrices in a rabbit dorsal maxillary osteotomy model. METHODS: XTreoTM matrices were formulated to consistently elute MF for up to 6 months. Matrices were surgically placed bilaterally into the maxillary sinuses of New Zealand White (NZW) rabbits. Tissue and plasma MF concentrations were measured to assess the in vivo drug delivery. The in vivo and in vitro drug release kinetics of the matrices were quantified and compared to those of rabbits receiving daily Nasonex® MF nasal sprays. RESULTS: XTreoTM matrices self-expanded upon deployment to conform to the irregular geometry of the maxillary sinus cavities in the NZW rabbits. Sustained release of MF was demonstrated in vitro and in vivo for 2 MF matrices of distinct release durations and an in vitro-in vivo correlation was established. Therapeutic levels of MF in local tissues were measured throughout the intended dosing durations. In contrast to the variable peaks and troughs of daily nasal sprays, sustained dosing via a single administration of MF matrices was confirmed by quantifiable plasma MF concentrations over the intended dosing duration. CONCLUSION: The XTreoTM MF matrices provided targeted and efficient dosing to local sinus tissues that was superior to INCS. Sustained drug release was confirmed both in vitro and in vivo. The novel XTreoTM technology may provide precisely tuned, long-lasting drug delivery to sinus tissues with a single treatment.

Design and Synthesis of Waterborne Polyurethanes.

Waterborne polyurethanes (WBPUs) have attracted increasing attention in a wide range of industrial applications because of their versatile properties as well as ecofriendly nature. Although extensive research has been carried out on WBPU synthesis, the roles of some of the key synthesis components remain unclear. In this study, through systematically controlling and fine tuning the precursor compositions and reaction conditions, over 300 WBPUs are synthesized. This research enables the roles of several key components that govern WBPU physicochemical properties and ultimately the potential WBPU applications to be identified. Using hair styling as an example, it is demonstrated that only the WBPUs with an optimal range of properties (e.g., Young's modulus >150 MPa, elongation at break: 15-300%, moisture uptake <10%) can achieve strong styling performance. To further improve the natural-feel sensory benefits in the final styling products, a number of fatty acids with different carbon chain lengths or unsaturation levels are incorporated into WBPUs. Among the ten fatty acids studied, linoleic acid is identified as the most preferred additive. Both in vitro and in vivo testing demonstrate that WBPUs with optimal properties are promising materials for developing strong, long-lasting styling products with natural feel.

Shape memory activation can affect cell seeding of shape memory polymer scaffolds designed for tissue engineering and regenerative medicine.

The ability of a three-dimensional scaffold to support cell seeding prior to implantation is a critical criterion for many scaffold-based tissue engineering and regenerative medicine strategies. Shape memory polymer functionality may present important new opportunities and challenges in cell seeding, but the extent to which shape memory activation can positively or negatively affect cell seeding has yet to be reported. The goal of this study was to determine whether shape memory activation can affect cell seeding. The hypothesis was that shape memory activation of porous scaffolds during cell seeding can affect both the number of cells seeded in a scaffold and the distribution (in terms of average infiltration distance) of cells following seeding. Here, we used a porous shape memory foam scaffold programmed to expand when triggered to study cell number and average cell infiltration distance following shape memory activation. We found that shape memory activation can affect both the number of cells and the average cell infiltration distance. The effect was found to be a function of rate of shape change and scaffold pore interconnectivity. Magnitude of shape change had no effect. Only reductions in cell number and infiltration distance (relative to control and benchmark) were observed. The findings suggest that strategies for tissue engineering and regenerative medicine that involve shape memory activation in the presence of a cell-containing medium in vitro or in vivo should consider how recovery rate and scaffold pore interconnectivity may ultimately impact cell seeding.

Osteogenic Capacity of Human Adipose-Derived Stem Cells is Preserved Following Triggering of Shape Memory Scaffolds.

Recent advances in shape memory polymers have enabled the study of programmable, shape-changing, cytocompatible tissue engineering scaffolds. For treatment of bone defects, scaffolds with shape memory functionality have been studied for their potential for minimally invasive delivery, conformal fitting to defect margins, and defect stabilization. However, the extent to which the osteogenic differentiation capacity of stem cells resident in shape memory scaffolds is preserved following programmed shape change has not yet been determined. As a result, the feasibility of shape memory polymer scaffolds being employed in stem cell-based treatment strategies remains unclear. To test the hypothesis that stem cell osteogenic differentiation can be preserved during and following triggering of programmed architectural changes in shape memory polymer scaffolds, human adipose-derived stem cells were seeded in shape memory polymer foam scaffolds or in shape memory polymer fibrous scaffolds programmed to expand or contract, respectively, when warmed to body temperature. Osteogenic differentiation in shape-changing and control scaffolds was compared using mineral deposition, protein production, and gene expression assays. For both shape-changing and control scaffolds, qualitatively and quantitatively comparable amounts of mineral deposition were observed; comparable levels of alkaline phosphatase activity were measured; and no significant differences in the expression of genetic markers of osteogenesis were detected. These findings support the feasibility of employing shape memory in scaffolds for stem cell-based therapies for bone repair.

Self-deploying shape memory polymer scaffolds for grafting and stabilizing complex bone defects: A mouse femoral segmental defect study.

Treatment of complex bone defects places a significant burden on the US health care system. Current strategies for treatment include grafting and stabilization using internal metal plates/screws, intramedullary rods, or external fixators. Here, we introduce the use of shape memory polymer (SMP) materials for grafting and adjunct stabilization of segmental defects. Self-deploying SMP grafts and SMP sleeves capable of expanding and contracting, respectively, under intraoperative conditions were developed and evaluated in a mouse segmental defect model in vivo. Integration between grafts/sleeves and native bone was assessed using x-ray radiography, microcomputed tomography, and torsional mechanical testing. We found that SMP grafts were able to integrate with the native bone after 12 weeks, maintain defect stability, and provide torsional mechanical properties comparable to an allograft alone treatment; however no gross de novo bone formation was observed. SMP sleeves did not inhibit bony bridging at the margins, and limbs treated with a sleeve/allograft combination had torsional mechanical properties comparable to limbs treated with an allograft alone. In vitro torsional and bending tests suggest sleeves may provide additional torsional stability to defects. Incorporation of shape memory into synthetic bone graft substitutes and adjunct stabilization devices is anticipated to enhance functionality of synthetic materials employed in both applications.

Shape-memory-actuated change in scaffold fiber alignment directs stem cell morphology.

Tissue engineering scaffolds have traditionally been static physical structures poorly suited to mimicking the complex dynamic behavior of in vivo microenvironments. Here we present a thermoresponsive scaffold that can be programmed to change macroscopic shape and microscopic architecture during cell culture. The scaffold, which was prepared by electrospinning a shape memory polymer (SMP), was used to test the hypothesis that a shape-memory-actuated change in scaffold fiber alignment could be used to control the behavior of attached and viable cells. To test this hypothesis, we stretched an SMP scaffold of randomly oriented fibers and fixed the scaffold in a temporary but stable elongated shape in which fibers were aligned by the strain. Following seeding and culture of human adipose-derived stem cells on the strain-aligned scaffold, the scaffold was triggered to transition back to its initial shape and random fiber orientation via shape memory actuation using a cytocompatible temperature increase. We found that cells preferentially aligned along the fiber direction of the strain-aligned scaffold before shape memory actuation. After shape memory actuation, cells remained attached and viable but lost preferential alignment. These results demonstrate that shape-memory-actuated changes in scaffold fiber alignment can be achieved with attached and viable cells and can control cell morphological behavior. The incorporation of shape memory into cytocompatible scaffolds is anticipated to facilitate the development, delivery and functionality of tissue engineering scaffolds and the in vitro and in vivo study and application of mechanobiology.