Sarah L. Kieweg

Squeezing Flows of Vaginal Gel Formulations Relevant to Microbicide Drug Delivery

Efficacy of topical microbicidal drug delivery formulations against HIV depends in part on their ability to coat, distribute, and be retained on epithelium. Once applied to the vagina, a formulation is distributed by physical forces including: gravity, surface tension, shearing, and normal forces from surrounding tissues, i.e., squeezing forces. The present study focused on vaginal microbicide distribution due to squeezing forces. Mathematical simulations of squeezing flows were compared with squeezing experiments, using model vaginal gel formulations. Our objectives were: (1) to determine if mathematical simulations can accurately describe squeezing flows of vaginal gel formulations; (2) to find the best model and optimized parameter sets to describe these gels; and (3) to examine vaginal coating due to squeezing using the best models and summary parameters for each gel. Squeezing flow experiments revealed large differences in spreadability between formulations, suggesting different coating distributions in vivo. We determined the best squeezing flow models and summary parameters for six test gels of two compositions, cellulose and polyacrylic acid (PAA). We found that for some gels it was preferable to deduce model input parameters directly from squeezing flow experiments. For the cellulose gels, slip conditions in squeezing flow experiments needed to be evaluated. For PAA gels, we found that in the absence of squeezing experiments, rotational viscometry measurements (to determine Herschel-Bulkley parameters) led to reasonably accurate predictions of squeezing flows. Results indicated that yield stresses may be a strong determinant of squeezing flow mechanics. This study serves as a template for further investigations of other gels and determination of which sources of rheological data best characterize potential microbicidal formulations. These mathematical simulations can serve as useful tools for exploring drug delivery parameters, and optimizing formulations, prior to costly clinical trials.

Effect of photoinitiator system and water content on dynamic mechanical properties of a light‐cured bisGMA/HEMA dental resin

The selection of an appropriate photoinitiator system is critical for efficient polymerization of dental resins with satisfactory mechanical and physical properties. The purpose of this study was to evaluate the influence of adding an iodonium salt to two-component photoinitiator systems. Four photoinitiator systems were included in a model bisGMA/HEMA resin and used to prepare samples at different water contents; the dynamic mechanical properties and the final degree of conversion of the samples were then characterized. Addition of the iodonium salt to the two-component photoinitiator systems increased the final degree of conversion, glass transition temperature, rubbery modulus, and crosslink density. The photoinitiator system containing ethyl-4-(dimethylamino) benzoate as a coinitiator and the iodonium salt exhibited the highest rubbery modulus. The enhanced properties in the presence of the iodonium salt can be attributed to the production of an active phenyl radical with regeneration of the original camphorquinone, which may increase the compatibility between monomers and initiators, especially in the presence of water. The results support the hypothesis that a photoinitiator system containing an iodonium salt can increase both mechanical properties and final conversion of model resin polymerized in the presence of water.

Viscoelastic and fatigue properties of model methacrylate-based dentin adhesives

The objective of the current study is to characterize the viscoelastic and fatigue properties of model methacrylate-based dentin adhesives under dry and wet conditions. Static, creep, and fatigue tests were performed on cylindrical samples in a 3-point bending clamp. Static results showed that the apparent elastic modulus of the model adhesive varied from 2.56 to 3.53 GPa in the dry condition, and from 1.04 to 1.62 GPa in the wet condition, depending upon the rate of loading. Significant differences were also found for the creep behavior of the model adhesive under dry and wet conditions. A linear viscoelastic model was developed by fitting the adhesive creep behavior. The developed model with 5 Kelvin Voigt elements predicted the apparent elastic moduli measured in the static tests. The model was then utilized to interpret the fatigue test results. It was found that the failure under cyclic loading can be due to creep or fatigue, which has implications for the failure criterion that are applied for these types of tests. Finally, it was found that the adhesive samples tested under dry conditions were more durable than those tested under wet conditions.

Fatigue life prediction of dentin-adhesive interface using micromechanical stress analysis

OBJECTIVES The objective of this work was to develop a methodology for the prediction of fatigue life of the dentin-adhesive (d-a) interface. METHODS At the micro-scale, the d-a interface is composed of dissimilar material components. Under global loading, these components experience different local stress amplitudes. The overall fatigue life of the d-a interface is, therefore, determined by the material component that has the shortest fatigue life under local stresses. Multiple 3d finite element (FE) models were developed to determine the stress distribution within the d-a interface by considering variations in micro-scale geometry, material composition and boundary conditions. The results from these models were analyzed to obtain the local stress concentrations within each d-a interface component. By combining the local stress concentrations and experimentally determined stress versus number of cycle to failure (S-N) curves for the different material components, the overall fatigue life of the d-a interface was predicted. RESULTS The fatigue life was found to be a function of the applied loading amplitude, boundary conditions, microstructure and the mechanical properties of the material components of the d-a interface. In addition, it was found that the overall fatigue life of the d-a interface is not determined by the weakest material component. In many cases, the overall fatigue life was determined by the adhesive although exposed collagen was the weakest material component. Comparison of the predicted results with experimental data from the literature showed both qualitative and quantitative agreement. SIGNIFICANCE The methodology developed for fatigue life prediction can provide insight into the mechanisms that control degradation of the bond formed at the d-a interface.

Tensile Strength of a Surgeon's or a Square Knot

OBJECTIVE To test the integrity of surgeons knots and flat square knots using 4 different suture materials. STUDY DESIGN Chromic catgut, polyglactin 910, silk, and polydioxanone sutures were tied in the 2 types of knot configurations. For all sutures, a 0-gauge United States Pharmacopeia suture was used. Knots were tied by a single investigator (J.B.). The suture was soaked in 0.9% sodium chloride for 60 s and subsequently transferred to a tensiometer where the tails were cut to 3-mm length. We compared the knots, measuring knot strength with a tensiometer until the sutures broke or untied. RESULTS A total of 119 throws were tied. We found no difference in mean tension at failure between a surgeons knot (79.7 N) and a flat square knot (82.9 N). Using a chi(2) test, we did not find a statistically significant difference in the likelihood of knots coming untied between surgeons knots (29%) and flat square knots (38%). CONCLUSIONS Under laboratory conditions, surgeons knots and flat square knots did not differ in tension at failure or in likelihood of untying.

Synthesis and evaluation of novel dental monomer with branched aromatic carboxylic acid group.

A new glycerol-based dimethacrylate monomer with an aromatic carboxylic acid, 2-((1,3-bis(methacryloyloxy)propan-2-yloxy)carbonyl)benzoic acid (BMPB), was synthesized, characterized, and proposed as a possible dental co-monomer for dentin adhesives. Dentin adhesives containing 2-hydroxyethyl methacrylate (HEMA) and 2,2-bis[4-(2-hydroxy-3-methacryloxypropoxy) phenyl]propane (BisGMA) in addition to BMPB were formulated with water at 0, 5, 10, and 15 wt % to simulate wet, oral conditions, and photo-polymerized. Adhesives were characterized with regard to viscosity, real-time photopolymerization behavior, dynamic mechanical analysis, and microscale 3D internal morphologies and compared with HEMA/BisGMA controls. When formulated under wet conditions, the experimental adhesives showed lower viscosities (0.04-0.07 Pa s) as compared to the control (0.09-0.12 Pa s). The experimental adhesives showed higher glass transition temperature (146-157°C), degree of conversion (78-89%), and rubbery moduli (33-36 MPa), and improved water miscibility (no voids) as compared to the controls (123-135°C, 67-71%, 15-26 MPa, and voids, respectively). The enhanced properties of these adhesives suggest that BMPB with simple, straightforward synthesis is a promising photocurable co-monomer for dental restorative materials.

Chondroinduction from Naturally Derived Cartilage Matrix: A Comparison Between Devitalized and Decellularized Cartilage Encapsulated in Hydrogel Pastes.

Hydrogel precursors are liquid solutions that are prone to leaking after surgical placement. This problem was overcome by incorporating either decellularized cartilage (DCC) or devitalized cartilage (DVC) microparticles into traditional photocrosslinkable hydrogel precursors in an effort to achieve a paste-like hydrogel precursor. DCC and DVC were selected specifically for their potential to induce chondrogenesis of stem cells, given that materials that are chondroinductive on their own without growth factors are a revolutionary goal in orthopedic medicine. We hypothesized that DVC, lacking the additional chemical processing steps in DCC to remove cell content, would lead to a more chondroinductive hydrogel with rat bone marrow-derived mesenchymal stem cells. Hydrogels composed of methacrylated hyaluronic acid (MeHA) and either DCC or DVC microparticles were tested with and without exposure to transforming growth factor (TGF)-β3 over a 6 week culture period, where swelling, mechanical analysis, and gene expression were observed. For collagen II, Sox-9, and aggrecan expression, MeHA precursors containing DVC consistently outperformed the DCC-containing groups, even when the DCC groups were exposed to TGF-β3. DVC consistently outperformed all TGF-β3-exposed groups in aggrecan and collagen II gene expression as well. In addition, when the same concentrations of MeHA with DCC or DVC microparticles were evaluated for yield stress, the yield stress with the DVC microparticles was 2.7 times greater. Furthermore, the only MeHA-containing group that exhibited shape retention was the group containing DVC microparticles. DVC appeared to be superior to DCC in both chondroinductivity and rheological performance of hydrogel precursors, and therefore DVC microparticles may hold translational potential for cartilage regeneration.

Enabling Surgical Placement of Hydrogels Through Achieving Paste-Like Rheological Behavior in Hydrogel Precursor Solutions

Hydrogels are a promising class of materials for tissue regeneration, but they lack the ability to be molded into a defect site by a surgeon because hydrogel precursors are liquid solutions that are prone to leaking during placement. Therefore, although the main focus of hydrogel technology and developments are on hydrogels in their crosslinked form, our primary focus is on improving the fluid behavior of hydrogel precursor solutions. In this work, we introduce a method to achieve paste-like hydrogel precursor solutions by combining hyaluronic acid nanoparticles with traditional crosslinked hyaluronic acid hydrogels. Prior to crosslinking, the samples underwent rheological testing to assess yield stress and recovery using linear hyaluronic acid as a control. The experimental groups containing nanoparticles were the only solutions that exhibited a yield stress, demonstrating that the nanoparticulate rather than the linear form of hyaluronic acid was necessary to achieve paste-like behavior. The gels were also photocrosslinked and further characterized as solids, where it was demonstrated that the inclusion of nanoparticles did not adversely affect the compressive modulus and that encapsulated bone marrow-derived mesenchymal stem cells remained viable. Overall, this nanoparticle-based approach provides a platform hydrogel system that exhibits a yield stress prior to crosslinking, and can then be crosslinked into a hydrogel that is capable of encapsulating cells that remain viable. This behavior may hold significant impact for hydrogel applications where a paste-like behavior is desired in the hydrogel precursor solution.

Mapping Glycosaminoglycan–Hydroxyapatite Colloidal Gels as Potential Tissue Defect Fillers

Malleable biomaterials such as Herschel–Bulkley (H–B) fluids possess shear responsive rheological properties and are capable of self-assembly and viscoelastic recovery following mechanical disruption (e.g., surgical placement via injection or spreading). This study demonstrated that the addition of moderate molecular weight glycosaminoglycans (GAGs) such as chondroitin sulfate (CS) (Mw = 15–30 kDa) and hyaluronic acid (HA) (Mw = 20–41 kDa) can be used to modify several rheological properties including consistency index (K), flow-behavior index (n), and yield stress (τy) of submicrometer hydroxyapatite (HAP) (Davg ≤ 200 nm) colloidal gels. GAG–HAP colloidal mixtures exhibited substantial polymer–particle synergism, likely due to “bridging” flocculation, which led to a synergistic increase in consistency index (KGAG-HAP ≥ KGAG + KHAP) without compromising shear-thinning behavior (n < 1) of the gel. In addition, GAG–HAP colloids containing high concentrations of HAP (60–80% w/v) exhibited substantial yield stress (τy ≥ 100 Pa) and viscoelastic recovery properties (G′recovery ≥ 64%). While rheological differences were observed between CS–HAP and HA–HAP colloidal gels, both CS and HA represent feasible options for future studies involving bone defect filling. Overall, this study identified mixture regions where rheological properties in CS–HAP and HA–HAP colloidal gels aligned with desired properties to facilitate surgical placement in non-load-bearing tissue-filling applications such as calvarial defects.

Mathematical model of microbicidal flow dynamics and optimization of rheological properties for intra-vaginal drug delivery: Role of tissue mechanics and fluid rheology

Topically applied microbicide gels can provide a self-administered and effective strategy to prevent sexually transmitted infections (STIs). We have investigated the interplay between vaginal tissue elasticity and the yield-stress of non-Newtonian fluids during microbicide deployment. We have developed a mathematical model of tissue deformation driven spreading of microbicidal gels based on thin film lubrication approximation and demonstrated the effect of tissue elasticity and fluid yield-stress on the spreading dynamics. Our results show that both elasticity of tissue and yield-stress rheology of gel are strong determinants of the coating behavior. An optimization framework has been demonstrated which leverages the flow dynamics of yield-stress fluid during deployment to maximize retention while reaching target coating length for a given tissue elasticity.