Effect of Moisture Content on Ion Diffusion and Glass Transition Temperature in Wood Cell Walls.

Understanding and controlling the diffusion of ions and chemicals within the secondary plant cell walls are pivotal in various applications of biomasses. Recent studies have shown that inorganic ion diffusion through secondary cell walls is controlled by a moisture-induced glass transition in amorphous polysaccharides, including amorphous cellulose and hemicelluloses. Understanding the diffusion of ions in these structures has been the subject of numerous recent experiments; however, a deep understanding of the underlying mechanisms of interactions between ion atoms and water/hemicellulose molecules is still lacking. This study uses molecular dynamics simulations to elucidate the diffusion mechanisms of potassium and chloride ions in the cell walls under varying moisture content. The results reveal that a higher moisture content leads to the formation of solvent layers around the ions and reduces the charge interaction between the functional groups of wood polymers and ions. Hence, a higher moisture content results in an improved diffusion rate of ions within the domain. The simulation results also show that higher moisture content lowers the glass transition temperature, promoting diffusion of ions in the system. In contrast, increases in the ion concentration increase the glass transition temperature of the system and degrade the diffusion of ions in the system.

Finite Element-Based Personalized Simulation of Duodenal Hydrogel Spacer: Spacer Location Dependent Duodenal Sparing and a Decision Support System for Spacer-Enabled Pancreatic Cancer Radiation Therapy.

Purpose: Pancreatic cancer is the fourth leading cause of cancer-related death, with a very low 5-year overall survival rate (OS). Radiation therapy (RT) together with dose escalation significantly increases the OS at 2 and 3 years. However, dose escalation is very limited due to the proximity of the duodenum. Hydrogel spacers are an effective way to reduce duodenal toxicity, but the complexity of the anatomy and the procedure makes the success and effectiveness of the spacer procedure highly uncertain. To provide a preoperative simulation of hydrogel spacers, we presented a patient-specific spacer simulator algorithm and used it to create a decision support system (DSS) to provide a preoperative optimal spacer location to maximize the spacer benefits. Materials and Methods: Our study was divided into three phases. In the validation phase, we evaluated the patient-specific spacer simulator algorithm (FEMOSSA) for the duodenal spacer using the dice similarity coefficient (DSC), overlap volume histogram (OVH), and radial nearest neighbor distance (RNND). For the simulation phase, we simulated four virtual spacer scenarios based on the location of the spacer in para-duodenal space. Next, stereotactic body radiation therapy (SBRT) plans were designed and dosimetrically analyzed. Finally, in the prediction phase, using the result of the simulation phase, we created a Bayesian DSS to predict the optimal spacer location and biological effective dose (BED). Results: A realistic simulation of the spacer was achieved, reflected in a statistically significant increase in average target and duodenal DSC for the simulated spacer. Moreover, the small difference in average mean and 5th-percentile RNNDs (0.5 and 2.1 mm) and OVH thresholds (average of less than 0.75 mm) showed that the simulation attained similar separation as the real spacer. We found a spacer-location-independent decrease in duodenal V20Gy, a highly spacer-location-dependent change in V33Gy, and a strong correlation between L1cc and V33Gy. Finally, the Bayesian DSS predicted the change in BED with a root mean squared error of 3.6 Gys. Conclusions: A duodenal spacer simulator platform was developed and used to systematically study the dosimetric effect of spacer location. Further, L1cc is an informative anatomical feedback to guide the DSS to indicate the spacer efficacy, optimum location, and expected improvement.

A novel hardware duo of beam modulation and shielding to reduce scatter acquisition and dose in cone-beam breast CT.

PURPOSE: In cone-beam breast CT, scattered photons form a large portion of the acquired signal, adversely impacting image quality throughout the frequency response of the imaging system. Prior simulation studies provided proof of concept for utilization of a hardware solution to prevent scatter acquisition. Here, we report the design, implementation, and characterization of an auxiliary apparatus of fluence modulation and scatter shielding that does indeed lead to projections with a reduced level of scatter. METHODS: An apparatus was designed for permanent installation within an existing cone-beam CT system. The apparatus is composed of two primary assemblies: a "Fluence Modulator" (FM) and a "Scatter Shield" (SS). The design of the assemblies enables them to operate in synchrony during image acquisition, converting the sourced x-rays into a moving narrow beam. During a projection, this narrow beam sweeps the entire fan angle coverage of the imaging system. As the two assemblies are contingent on one another, their joint implementation is described in the singular as apparatus FM-SS. The FM and the SS assemblies are each comprised a metal housing, a sensory system, and a robotic system. A controller unit handles their relative movements. A series of comparative studies were conducted to evaluate the performance of a cone-beam CT system in two "modes" of operation: with and without FM-SS installed, and to compare the results of physical implementation with those previously simulated. The dynamic range requirements of the utilized detector in the cone-beam CT imaging system were first characterized, independent of the mode of operation. We then characterized and compared the spatial resolution of the imaging system with, and without, FM-SS. A physical breast phantom, representative of an average size breast, was developed and imaged. Actual differences in signal level obtained with, versus without, FM-SS were then compared to the expected level gains based on previously reported simulations. Following these initial assessments, the scatter acquisition in each projection in both modes of operation was investigated. Finally, as an initial study of the impact of FM-SS on radiation dose in an average size breast, a series of Monte Carlo simulations were coupled with physical measurements of air kerma, with and without FM-SS. RESULTS: With implementation of FM-SS, the detector's required dynamic range was reduced by a factor of 5.5. Substantial reduction in the acquisition of the scattered rays, by a factor of 5.1 was achieved. With the implementation of FM-SS, deposited dose was reduced by 27% in the studied breast. CONCLUSIONS: The disclosed implementation of FM-SS, within a cone-beam breast CT system, results in reduction of scatter-components in acquired projections, reduction of dose deposit to the breast, and relaxation of requirements for the detector's dynamic range. Controlling or correcting for patient motion occurring during image acquisition remains an open problem to be solved prior to practical clinical usage of FM-SS cone-beam breast CT.

Sensitivity of the stress field of the proximal femur predicted by CT-based FE analysis to modeling uncertainties.

Proximal femur anatomy and bone mineral density vary widely among individuals, precluding the use of one predefined finite element (FE) model to determine the stress field for all proximal femurs. This variability poses a challenge in current prosthetic hip design approach. Given the numerous options for generating computed tomography (CT)-based FE models, selecting the best methods for defining the mechanical behavior of the proximal femur is difficult. In this study, a combination of computational and experimental approaches was used to explore the susceptibility of the predicted stress field of the proximal femur to different combinations of density-elasticity relationships, element type, element size, and calibration error. Our results suggest that FE models with first-order voxelized elements generated by the Keyak and Falkinstein density-elasticity relationship or quadratic tetrahedral elements generated by the Morgan density-elasticity relationship lead to accurate estimations of the mechanical behavior of human femurs. Other combinations of element size, element type, and mathematical relationships produce less accurate results, especially in the cortical bone of the femoral neck and calcar region. The voxelized model was more susceptible to variation of element size and density-elasticity relationships than FE models with quadratic tetrahedral elements. Regardless of element type, the stress fields predicted by the Keyak and Falkinstein and the Morgan relationships were the most robust to calibration error when deriving material density from CT-generated Hounsfield data. These results provide insight into the implementation of a robust platform for designing patient-specific implants capable of maintaining or modifying the stress in bones.

FEMOSSA: Patient-specific finite element simulation of the prostate-rectum spacer placement, a predictive model for prostate cancer radiotherapy.

PURPOSE: Major advances in delivery systems in recent years have turned radiotherapy (RT) into a more effective way to manage prostate cancer. Still, adjacency of organs at risk (OARs) can severely limit RT benefits. Rectal spacer implant in recto-prostatic space provides sufficient separation between prostate and rectum, and therefore, the opportunity for potential dose escalation to the target and reduction of OAR dose. Pretreatment simulation of spacer placement can potentially provide decision support to reduce the risks and increase the efficacy of the spacer placement procedure. METHODS: A novel finite element method-oriented spacer simulation algorithm, FEMOSSA, was developed in this study. We used the finite element (FE) method to model and predict the deformation of rectum and prostate wall, stemming from hydrogel injection. Ten cases of prostate cancer, which undergone hydrogel placement before the RT treatment, were included in this study. We used the pre-injection organ contours to create the FE model and post-injection spacer location to estimate the distribution of the virtual spacer. Material properties and boundary conditions specific to each patient's anatomy were assigned. The FE analysis was then performed to determine the displacement vectors of regions of interest (ROIs), and the results were validated by comparing the virtually simulated contours with the real post-injection contours. To evaluate the different aspects of our method's performance, we used three different figures of merit: dice similarity coefficient (DSC), nearest neighbor distance (NND), and overlapped volume histogram (OVH). Finally, to demonstrate a potential dosimetric application of FEMOSSA, the predicted rectal dose after virtual spacer placement was compared against the predicted post-injection rectal dose. RESULTS: Our simulation showed a realistic deformation of ROIs. The post-simulation (virtual spacer) created the same separation between prostate and rectal wall, as post-injection spacer. The average DSCs for prostate and rectum were 0.87 and 0.74, respectively. Moreover, there was a statistically significant increase in rectal contour similarity coefficient (P < 0.01). Histogram of NNDs showed the same overall shape and a noticeable shift from lower to higher values for both post-simulation and post-injection, indicative of the increase in distance between prostate and rectum. There was less than 2.2- and 2.1-mm averaged difference between the mean and fifth percentile NNDs. The difference between the OVH distances and the corresponding predicted rectal dose was, on average, less than 1 mm and 1.5 Gy, respectively. CONCLUSIONS: FEMOSSA provides a realistic simulation of the hydrogel injection process that can facilitate spacer placement planning and reduce the associated uncertainties. Consequently, it increases the robustness and success rate of spacer placement procedure that in turn improves prostate cancer RT quality.

Conformational Transformation of pH-Responsive Hairy Cellulose NanoCrystalloids in Salt-Free Dilute Solutions.

Among biomaterials, pH-responsive nanoparticles have promising potential for overcoming nonspecific therapeutic delivery by taking advantage of the pH gradient between physiological and pathological states. This article discusses pH-dependent conformations of an organic nanoparticle that has a needle-shaped body from crystalline cellulose, sandwiched between two amorphous regions from chemically nanoengineered dicarboxylated cellulose (DCC). Computational study on a single free DCC chain elucidated that in a salt-free dilute solution, the chain undergoes a major transformation between pH ∼ 3 and ∼6.3. Through this transformation, the DCC chain nature varies from globular neutral polymer to coiled quasi-neutral polymer and finally to rodlike polyelectrolyte. Study on the particle nanostructure indicated that, at pH ∼ 3, the conformation of the amorphous regions is analogous to that of polymer brushes in poor solvents, whereas at pH ∼ 5, the conformation changes to that of quasi-neutral polymer brushes in good solvents. For pH > 6.3, the conformation transforms into that of star-like polyelectrolytes. The height of the amorphous region exhibits a regressive trend up to pH ∼ 6.3, followed by a progressive trend up to pH ∼ 10. Study on the hydrodynamic properties revealed a sharp decline in the diffusion rate as the pH varies from ∼3 to ∼5, followed by a plateau for higher pH. It was demonstrated that, at pH ∼ 3, the nanoparticle may form a coherent nanophase with a rodlike structure. These results may provide insight into designing pH-responsive nanocelluloses with a controlled expansion and diffusion coefficient.

Reverse pneumatic artificial muscles (rPAMs): Modeling, integration, and control.

Despite offering many advantages over traditional rigid actuators, soft pneumatic actuators suffer from a lack of comprehensive, computationally efficient models and precise embedded control schemes without bulky flow-control valves and extensive computer hardware. In this article, we consider an inexpensive and reliable soft linear actuator, called the reverse pneumatic artificial muscle (rPAM), which consists of silicone rubber that is radially constrained by symmetrical double-helix threading. We describe analytical and numerical static models of this actuator, and compare their performance against experimental results. To study the application of rPAMs to operate underlying kinematic linkage skeletons, we consider a single degree-of-freedom revolute joint that is driven antagonistically by two of these actuators. An analytical model is then derived, and its accuracy in predicting the static joint angle as a function of input pressures is presented. Using this analytical model, we perform dynamic characterization of this system. Finally, we propose a sliding-mode controller, and a sliding mode controller augmented by a feed-forward term to modulate miniature solenoid valves that control air flow to each actuator. Experiments show that both controllers function well, while the feed-forward term improves the performance of the controller following dynamic trajectories.

Concentration-Dependent, Membrane-Selective Activity of Human LL37 Peptides Modified with Collagen Binding Domain Sequences.

Antimicrobial peptides (AMPs) such as LL37 are promising alternatives to antibiotics to treat wound infections due to their broad activity, immunomodulatory functions, and low likelihood of antimicrobial resistance. To deliver LL37 to chronic wounds, we developed two chimeric LL37 peptides with C-terminal collagen binding domains (CBD) derived from collagenase ( cCBD-LL37) and fibronectin ( fCBD-LL37) as a strategy for noncovalent tethering of LL37 onto collagen-based, commercially available wound dressings. The addition of CBD sequences to LL37 resulted in differences in cytotoxicity against human fibroblasts and antimicrobial activity against common wound pathogens. In this study, we sought to determine the sequence-, structure-, and concentration-dependent properties underlying these differences in bioactivity. Molecular dynamics (MD) simulations allowed visualization of the structure of each peptide and calculation of residue-level helicity, revealing that residues within the CBD domains were not helical. Circular dichroism (CD) spectroscopy affirmed that the overall structures of LL37 and each CBD-LL37 peptide was primarily helical (greater than 67%) in a membrane-like solvent. Quartz crystal microbalance with dissipation (QCM-D) and imaging of fluorescent bilayers revealed unique, concentration-dependent interactions of each peptide with bilayers of different lipid compositions. Specifically, fCBD-LL37, which is less cytotoxic than LL37 and cCBD-LL37, demonstrated higher affinity toward anionic bilayers (model bacterial cell membranes) than zwitterionic bilayers (model mammalian cell membranes). In contrast, cCBD-LL37 and LL37 demonstrated similar affinities to both types of bilayers. This study demonstrates that the combination of MD, CD, and QCM-D may enable predictive modeling of the effects of primary sequence alterations on peptide secondary structure and membrane interactions. Understanding the structural and mechanistic properties of AMPs and their interactions with specific lipid bilayer compositions may enable the engineering of less cytotoxic AMPs with improved therapeutic indexes for human wound healing applications.

Thermal conductivity and rectification in asymmetric archaeal lipid membranes.

Nature employs lipids to construct nanostructured membranes that self-assemble in an aqueous environment to separate the cell interior from the exterior environment. Membrane composition changes among species and according to environmental conditions, which allows organisms to occupy a wide variety of different habitats. Lipid bilayers are phase-change materials that exhibit strong thermotropic and lyotropic phase behavior in an aqueous environment, which may also cause thermal rectification. Among different types of lipids, archaeal lipids are of great interest due to their ability to withstand extreme conditions. In this paper, nonequilibrium molecular dynamics simulations were employed to study the nanostructures and thermal properties of different archaeols and to investigate thermal rectification effects in asymmetric archaeal membranes. In particular, we are interested in understanding the role of bridged phytanyl chains and cyclopentane groups in controlling the phase transition temperature and heat flow across the membrane. Our results indicate that the bridged phytanyl chains decrease the molecular packing of lipids, whereas the existence of cyclopentane rings on the tail groups increases the molecular packing by enhancing the interactions between isoprenoid chains. We found that macrocyclic archaeols have the highest thermal conductivity, whereas macrocyclic archaeols with two cyclopentane rings have the lowest. The effect of the temperature on the variation of thermal conductivity was found to be progressive. Our results further indicate that small thermal rectification effects occur in asymmetric archaeol bilayer membranes at around 25 K temperature gradient. The calculated thermal rectification factor was around 0.09 which is in the range of rectification factor obtained experimentally for nanostructures such as carbon nanotubes (0.07). Such phenomena may be of biological significance and could also be optimized for use in various engineering applications.

Investigation of adhesive interactions in the specific targeting of Triptorelin-conjugated PEG-coated magnetite nanoparticles to breast cancer cells.

The understanding of adhesive interaction at the nanoscale between functionalized nanoparticles and biological cells is of great importance to develop effective theranostic nanocarriers for targeted cancer therapy. Here, we report a combination of experimental and computational approaches to evaluate the adhesion between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. The adhesion forces between Triptorelin-MNPs and normal/cancerous breast cells are obtained using atomic force microscopy. The corresponding work of adhesion is then estimated using Johnson-Kendall-Roberts model. Our results demonstrate that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to breast cancer cells than to normal breast cells. In addition, the work of adhesion between Triptorelin-MNPs and breast cancer cells is found to be three times more than that between unmodified MNPs and breast cancer cells. Hence, the experimental observation indicates that Triptorelin ligands facilitate the specific targeting of breast cancer cells. Furthermore, molecular dynamics simulations are performed to investigate the molecular origins of the adhesive interactions. The simulations reveal that the interactions between molecules (e.g. Triptorelin and PEG) and LHRH receptors are dominated by van der Waals energies, while the interactions of these molecules with cell membrane are dominated by electrostatic interactions. Moreover, both experimental and computational results reveal that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells that over-express LHRH receptors, while reduces the adhesion to normal breast cells. Our results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers. STATEMENT OF SIGNIFICANCE: Systematic investigation of adhesive interactions between functionalized nanoparticles and cancer cells is of great importance in developing effective theranostic nanocarriers for targeted cancer therapy. Herein, we use a combination of atomic force microscopy technique and molecular dynamics simulations approach to explore the adhesive interactions at the nanoscale between Triptorelin-conjugated polyethylene glycol (PEG)-coated magnetite nanoparticles and normal/cancerous breast cells. This study characterizes and quantifies the work of adhesion, as well as adhesion forces, at the nanocarrier/cell interfaces, unravels the molecular origins of adhesive interactions and highlights the effectiveness of PEG coatings and Triptorelin ligands in the specific targeting of breast cancer cells. Our findings expand the fundamental understanding of nanoparticle/cell adhesion and provide guidelines for the design of more rational nanocarriers.

Variation of thermal conductivity of DPPC lipid bilayer membranes around the phase transition temperature.

Given their amphiphilic nature and chemical structure, phospholipids exhibit a strong thermotropic and lyotropic phase behaviour in an aqueous environment. Around the phase transition temperature, phospholipids transform from a gel-like state to a fluid crystalline structure. In this transition, many key characteristics of the lipid bilayers such as structure and thermal properties alter. In this study, we employed atomistic simulation techniques to study the structure and underlying mechanisms of heat transfer in dipalmitoylphosphatidylcholine (DPPC) lipid bilayers around the fluid-gel phase transformation. To investigate this phenomenon, we performed non-equilibrium molecular dynamics simulations for a range of different temperature gradients. The results show that the thermal properties of the DPPC bilayer are highly dependent on the temperature gradient. Higher temperature gradients cause an increase in the thermal conductivity of the DPPC lipid bilayer. We also found that the thermal conductivity of DPPC is lowest at the transition temperature whereby one lipid leaflet is in the gel phase and the other is in the liquid crystalline phase. This is essentially related to a growth in thermal resistance between the two leaflets of lipid at the transition temperature. These results provide significant new insights into developing new thermal insulation for engineering applications.

Experimental and numerical measurements of adhesion energies between PHEMA and PGLYMA with hydroxyapatite crystal.

Synthetic orthopaedic materials consisting of a single bioinert polymeric material do not meet the complex biological and physical requirements of scaffold-guided bone tissue repair and regeneration. Of particular interest is the design of biocompatible hydrogel-hydroxyapatite composite bone substitutes with outstanding interfacial adhesion that would warranty the ability for the composite to withstand functional loadings without exhibiting brittle fractures during the dynamic guided tissue regeneration. For this purpose, the hydroxylated side chain of chemically cross-linked poly (2-hydroxyethyl methacrylate) (pHEMA) is substitute with a carboxylated side chain to make poly (glycerol methacrylate) (pGLYMA). Here, we carry out atomistic simulations and atomic force microscopy to predict and experimentally determine the interfacial adhesion energies of pHEMA and pGLYMA with the surface of single-crystalline hydroxyapatite (HA) whiskers. Both experimental and numerical results showed that pGLYMA has stronger adhesion forces with HA and may be used for preparing a high-affinity polymer-HA composite. The high adhesive interactions between pGLYMA and HA were found to be due to strong electrostatic energies.

Molecular Origin of Strength and Stiffness in Bamboo Fibrils.

Bamboo, a fast-growing grass, has a higher strength-to-weight ratio than steel and concrete. The unique properties of bamboo come from the natural composite structure of fibers that consists mainly of cellulose microfibrils in a matrix of intertwined hemicellulose and lignin called lignin-carbohydrate complex (LCC). Here, we have used atomistic simulations to study the mechanical properties of and adhesive interactions between the materials in bamboo fibers. With this aim, we have developed molecular models of lignin, hemicellulose and LCC structures to study the elastic moduli and the adhesion energies between these materials and cellulose microfibril faces. Good agreement was observed between the simulation results and experimental data. It was also shown that the hemicellulose model has stronger mechanical properties than lignin while lignin exhibits greater tendency to adhere to cellulose microfibrils. The study suggests that the abundance of hydrogen bonds in hemicellulose chains is responsible for improving the mechanical behavior of LCC. The strong van der Waals forces between lignin molecules and cellulose microfibril is responsible for higher adhesion energy between LCC and cellulose microfibrils. We also found out that the amorphous regions of cellulose microfibrils are the weakest interfaces in bamboo fibrils. Hence, they determine the fibril strength.

Fibronectin adsorption on functionalized electrospun polycaprolactone scaffolds: experimental and molecular dynamics studies.

Designing scaffolds to modulate protein adsorption is a key to building advanced scaffolds for tissue regeneration. Protein adsorption to tissue engineering scaffolds is critical in early cell attachment, survival, and eventual proliferation. The goal of this study is to examine the effect of functionalization on fibronectin adsorption to electrospun polycaprolactone (PCL) scaffolds through experimentation using fluorescently labeled fibronectin and to couple this experimental data with analysis of interaction energies obtained through molecular dynamics (MD) simulations to develop a better understanding of the adsorption process. This study is the first to analyze and compare experimental and MD simulation results of fibronectin adsorption on functionalized electrospun PCL scaffolds. Electrospun nanofiber PCL scaffolds were treated with either 1 N NaOH (hydrolyzed) or 46% hexamethylenediamine (HMD) (aminated) solution to be compared with untreated (control) scaffolds. We found that aminated PCL scaffolds experimentally adsorbed more fibronectin than control scaffolds, whereas hydrolyzed scaffolds showed decreased adsorption. MD simulations carried out with NVT ensemble at a temperature of 310 K indicated a higher work of adhesion for both functionalized scaffolds over control. Also, the simulations revealed different conformations of fibronectin on each scaffold type after adsorption, with the arginine-glycine-aspartic acid sequence appearing most accessible on the aminated scaffolds. This suggests that functionalization affects not only the quantity of protein that will adsorb on a scaffold but how it attaches as well, which could affect subsequent cell attachment.

Nano-scale adhesion in multilayered drug eluting stents.

Using stainless steel 316L for drug-eluting stents needs specific surface finishing due to corrosion phenomena that take place on the metal surface upon prolonged contact with human tissue. Poly (o-chloro-p-xylylene) (Parylene C) is one of the inert and biocompatible materials that are used for 316L coating with γ-methacryloxypropyltrimethoxysilane as an adhesion promoter. In this study, a combination of atomic force microscopy experiments and contact theories have been used to quantify the work of adhesion between parylene C/316L and silane added parylene C/316L. An atomistic simulation has been used, first, to investigate and compare the adhesion at the room temperature with the experiments and then, to investigate the effect of aqueous environment with higher temperature, inside the body, on the adhesion between layers in the structure of drug eluting stent. The simulation results of simplified model for 316L are in good agreement with the experimental results and suggest that the week affiliation between this polymer and 316L is mainly due to Van der Waals interactions. The effect of temperature on the adhesion is found to be regressive and as the water molecules permeate the polymer the adhesion decreases. They also imply that the effect of silane on the adhesion between parylene C and steel is modest.