In-vivo Behavior Research Articles

Decomposition and Changes in InVivo Post-HA Filler Injection: A Review.

Hyaluronic acid (HA) fillers are widely used in aesthetic medicine, but their invivo behavior and long-term effects are not fully understood. To review the decomposition and changes occurring in the body following HA filler injections, focusing on crosslinking agents, degradation processes, and tissue responses. This review analyzed oxidative and enzymatic degradation processes of HA fillers, evaluated the impact of 1,4-Butanediol Diglycidyl Ether (BDDE) crosslinking, and examined histological changes post-injection. Uncrosslinked HA degrades rapidly due to endogenous hyaluronidase, while crosslinked HA undergoes slower degradation via free radicals and hyaluronidase. Complete cross-linking (C-MoD) showed better durability compared to partially cross-linked BDDE (P-MoD). The concept of modification efficiency (MoE) was proposed to optimize filler safety and viscoelastic properties. Histological analysis revealed collagen capsule formation and autologous tissue replacement, affecting long-term outcomes. The degree of chemical modification (MoD) influences filler durability and safety, with concerns raised about potential delayed immune reactions from accumulated pendent BDDE. Clinicians should consider injection site, tissue conditions, and filler properties for safe and effective HA filler use. Emphasizing thorough BDDE removal and optimal crosslinking can enhance treatment safety and efficacy. The balance between achieving desired viscoelastic properties and minimizing potential risks is crucial. Future studies should include diverse ethnic groups to validate findings and further explore long-term tissue responses to HA fillers.

Unveiling Invisible Extracellular Vesicles: Cutting-Edge Technologies for Their in Vivo Visualization.

Extracellular vesicles (EVs), nanosized lipid bilayer vesicles released by nearly all types of cells, play pivotal roles as intercellular signaling mediators with diverse biological activities. Their adaptability has attracted interest in exploring their role as disease biomarker theranostics. However, the invivo biodistribution and pharmacokinetic profiles of EVs, particularly following administration into living subjects, remain unclear. Thus, invivo imaging is vital to enhance our understanding of the homing and retention patterns, blood and tissue half-life, and excretion pathways of exogenous EVs, thereby advancing real-time monitoring within biological systems and their therapeutic applications. This review examines state-of-the-art methods including EV labeling with various agents, including optical imaging, magnetic resonance imaging, and nuclear imaging. The strengths and weaknesses of each technique are comprehensively explored, emphasizing their clinical translation. Despite the potential of EVs as cancer theranostics, achieving a thorough understanding of their invivo behavior is challenging. This review highlights the urgency of addressing current questions in the biology and therapeutic applications of EVs. It underscores the need for continued research to unravel the complexities surrounding EVs and their potential clinical implications. By identifying these challenges, this review contributes to ongoing efforts to optimize EV imaging techniques for clinical use. Ultimately, bridging the gap between research advancements and clinical applications will facilitate the integration of EV-based theranostics, marking a crucial step toward harnessing the full potential of EVs in medical practice.

Nanomaterials in Wound Healing: Mechanisms, Applications, and Future Prospects

Background: Poor wound healing poses a significant global health challenge, leading to increased mortality rates and considerable healthcare expenses. Nanotechnology has emerged as a promising approach to address the complexities associated with wound healing, offering potential solutions to enhance the wound microenvironment and promote efficient tissue repair. Aim: This review aims to comprehensively summarize recent advancements in the application of nanomaterials for wound healing, with a focus on their mechanisms of action. The review also explores the prospects and challenges of using nanomaterials in wound dressings, specifically in the context of antimicrobial, anti-inflammatory, and angiogenic effects. Results: The integration of nanomaterials in wound healing has demonstrated significant progress in addressing key challenges, such as providing a suitable environment for cell migration, controlling microbial infections, and managing inflammation. Nanomaterials have been found to stimulate cellular and molecular processes, promoting hemostasis, immune regulation, and tissue proliferation, thereby accelerating wound closure and tissue regeneration. Conclusion: Nanotechnology-based wound healing has shown great promise in revolutionizing wound care. Nanomaterials offer unique physicochemical and biological properties that can be harnessed to develop advanced wound dressings capable of sustained therapeutic agent delivery and targeted bacterial detection and treatment. Despite these promising advancements, challenges such as reproducibility, stability, toxicity, and histocompatibility must be addressed to ensure successful translation from laboratory research to clinical applications. Further research is required to better understand the in-vivo behaviour of nanomaterial-based wound dressings and to explore innovative approaches, such as intelligent wound dressings that detect and treat infections synergistically, to enhance wound healing outcomes. Overall, nanomaterials hold tremendous potential for future wound healing strategies, paving the way for improved patient outcomes and reduced healthcare burdens.

In Vivo Behavior of Hydrolyzable Tannins after Oral Administration of the Trapa bispinosa Extract to Rats.

The pericarp extract of Trapa bispinosa (TBPE), which is rich in hydrolyzable tannins, has been reported to inhibit α-glucosidase and glycation reactions. We investigated the in vivo behavior of hydrolyzable tannins and related metabolites after administration of TBPE to rats. Using high pressure liquid chromatography-electrospray ionization-tandem mass spectroscopy (HPLC-ESI-MS/MS), 12 ellagitannin metabolites, such as urolithins and 6 gallotannin metabolites, produced in the collected plasma and urine were quantified. Urolithins and gallic acid metabolites reached their maximum blood concentration after 24 and 1 h of administration, respectively. Conversely, the excretion of urolithins in urine required up to 72 h and followed a sigmoidal curve, whereas gallic acid metabolites were rapidly excreted earlier after administration. The results suggest that the metabolites gallotannin and ellagitannin are responsible for the antiglycation effect of TBPE, which proceeds via different mechanisms and times. Our findings provide basic data demonstrating the functionality of hydrolyzable tannins as well as Trapa ingredients.

Nanostructured Lipid Carriers Mediated Drug Delivery to Posterior Segment of Eye and their In-vivo Successes.

The disease of the posterior segment of the eye is a major concern worldwide, and it affects more than 300 million people and leads to serious visual deterioration. The current treatment available is invasive and leads to serious eye complications. These shortcomings and patient discomfort lead to poor patient compliance. In the last decade, Nanostructured lipid carriers (NLC) have established a remarkable milestone in the delivery of drug substances to the posterior segment of the eye. Additionally, NLC can reduce the clearance due to adhesive properties which are imparted due to nano-metric size. This attribute might reduce the adverse effects associated with intravitreal therapy and thus enhance therapeutic efficacy, eventually raising patient adherence to therapy. The current review provides an inclusive account of NLC as a carrier to target diseases of the posterior segment of the eye. The review focuses on the various barrier encountered in the delivery of drugs to the posterior segment of the eye and the detail about the physicochemical property of drug substances that are considered to be suitable candidates for encapsulation to lipid carriers. Therefore, a plethora of literature has been included in this review. The review is an attempt to describe methods adopted for assessing the in-vivo behavior that strengthens the potential of NLC to treat the disease of the posterior segment of the eye. These NLC-based systems have proven to be a promising alternative in place of invasive intravitreal injections with improved patient compliance.

Combined Experiments with in Vivo Fiber Photometry and Behavior Tests Can Facilitate the Measurement of Neuronal Activity in the Primary Somatosensory Cortex and Hyperalgesia in an Inflammatory Pain Mice Model.

The pain matrix, which includes several brain regions that respond to pain sensation, contribute to the development of chronic pain. Thus, it is essential to understand the mechanism of causing chronic pain in the pain matrix such as anterior cingulate (ACC), or primary somatosensory (S1) cortex. Recently, combined experiment with the behavior tests and in vivo calcium imaging using fiber photometry revealed the interaction between the neuronal function in deep brain regions of the pain matrix including ACC and the phenotype of chronic pain. However, it remains unclear whether this combined experiment can identify the interaction between neuronal activity in S1, which receive pain sensation, and pain behaviors such as hyperalgesia or allodynia. In this study, to examine whether the interaction between change of neuronal activity in S1 and hyperalgesia in hind paw before and after causing inflammatory pain was detected from same animal, the combined experiment of in vivo fiber photometry system and von Frey hairs test was applied. This combined experiment detected that amplitude of calcium responses in S1 neurons increased and the mechanical threshold of hind paw decreased from same animals which have an inflammatory pain. Moreover, we found that the values between amplitude of calcium responses and mechanical thresholds were shifted to negative correlation after causing inflammatory pain. Thus, the combined experiment with fiber photometry and the behavior tests has a possibility that can simultaneously consider the interaction between neuronal activity in pain matrix and pain induced behaviors and the effects of analgesics or pain treatments.

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery (Adv. Therap. 2/2024)

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery (Adv. Therap. 2/2024)

A remodeled ivermectin polycaprolactone-based nanoparticles for inhalation as a promising treatment of pulmonary inflammatory diseases

In recent years, ivermectin (IVM), an antiparasitic drug of low water solubility and poor oral bioavailability, has shown a profound effect on inflammatory mediators involved in diseases, such as acute lung injury, lung fibrosis, and COVID-19. In order to maximize drug bioavailability, polymeric nanoparticles can be delivered through nebulizers for pulmonary administration. The aim of this study was to prepare IVM-loaded polycaprolactone (PCL) nanoparticles (NPs) by solvent evaporation method. Box-Benkhen design (BBD) was used to optimize entrapment efficiency (Y1), percent drug release after 6 h (Y2), particle size (Y3), and zeta potential (Y4). A study was conducted examining the effects of three independent variables: PCL-IVM ratio (A), polyvinyl alcohol (PVA) concentration (B), and sonication time (C). The optimized formula was also compared to the oral IVM dispersion for lung deposition, in-vivo behavior, and pharmacokinetic parameters. The optimized IVM-PCL-NPs formulation was spherical in shape with entrapment efficiency (% EE) of 93.99 ± 0.96 %, about 62.71 ± 0.53 % released after 6 h, particle size of 100.07 ± 0.73 nm and zeta potential of -3.30 ± 0.23 mV. Comparing the optimized formulation to IVM-dispersion, the optimized formulation demonstrated greater bioavailability with greater area under the curve AUC0–t of 710.91 ± 15.22 μg .ml−1.h for lung and 637.97 ± 15.43 μg .ml−1.h for plasma. Based on the results, the optimized NPs accumulated better in lung tissues, exhibiting a twofold longer residence time (MRT 4.78 ± 0.55 h) than the IVM-dispersion (MRT 2.64 ± 0.64 h). The optimized nanoparticle formulation also achieved higher cmax (194.90 ± 5.01 μg/ml), and lower kel (0.21 ± 0.04 h−1) in lungs. Additionally, the level of inflammatory mediators was markedly reduced. To conclude, inhalable IVM-PCL-NPs formulation was suitable for the pulmonary delivery and may be one of the most promising approaches to increase IVM bioavailability for the successful treatment of a variety of lung diseases.

Adult and pediatric physiologically-based biopharmaceutics modeling to explain lamotrigine immediate release absorption process.

Physiologically-based biopharmaceutics modeling (PBBM) has potential to accelerate the development of new drug and formulations. An important application of PBBM is for special populations such as pediatrics that have pharmacokinetics dependent on the maturation process. Lamotrigine (LTG) is a Biopharmaceutics Classification System (BCS) II drug and is widely prescribed. Therefore, the goal of this study was to assess the biopharmaceutics risk of the low-soluble drug LTG when the ontogeny on gastrointestinal tract (GIT) physiological parameters are considered. An oral physiologically-based pharmacokinetic model and a PBBM were developed and verified using GastroPlus™ software for both adults and children (2-12 years old, 12-52 kg). The biopharmaceutics properties and GIT physiological parameters were evaluated by sensitivity analysis. High doses were simulated assuming a worst case scenario, that is, the dose of 200 mg for adults and 5 mg/kg (up to the maximum of 200 mg) for 2-year-old children. Although several authors have suggested that ontogeny may have an effect on gastrointestinal fluid volume, our study found no evidence of interference between fluid and dose volumes with invivo dissolution of LTG. The most impactful parameter was found to be the gastric transit time. Therefore, the hypothesis is developed to examine whether LTG exhibits characteristics of a BCS II classification invitro while showing BCS I-like behavior invivo. This hypothesis could act as a base for conducting novel studies on model-informed precision dosing, tailored to specific populations and clinical conditions. In addition, it could be instrumental in assessing the influence of various release profiles on invivo performance for both adult and pediatric populations.

In Vivo Behavior of Systemically Administered Encapsulin Protein Nanocages and Implications for their use in Targeted Drug Delivery

AbstractEncapsulins, self‐assembling protein nanocages derived from prokaryotes, are promising nanoparticle‐based drug delivery systems (NDDS). However, the in vivo behavior and fate of encapsulins are poorly understood. In this study, the interactions between the model encapsulin from Thermotoga maritima (TmEnc) and key biological barriers encountered by NDDS are probed. Here, a purified TmEnc formulation that exhibits colloidal stability, storability, and blood compatibility is intravenously injected into BALB/c mice. TmEnc has an excellent nanosafety profile, with no abnormal weight loss or gross pathology observed, and only temporary alterations in toxicity biomarkers are detected. Notably, TmEnc demonstrates immunogenic properties, inducing the generation of nanocage‐specific IgM and IgG antibodies, but without any prolonged pro‐inflammatory effects. An absence of antibody cross‐reactivity also suggests immune‐orthogonality among encapsulin systems. Moreover, TmEnc forms a serum‐derived protein corona on its surface which changes dynamically and appears to play a role in immune recognition. TmEnc's biodistribution profile further reveals its sequestration from the blood circulation by the liver and then biodegrades within Kupffer cells, thus indicating clearance via the mononuclear phagocyte system. Collectively, these findings provide critical insights into how encapsulins behave in vivo, thereby informing their future design, modification, and application in targeted drug delivery.

A new capacity of gut microbiota: Fermentation of engineered inorganic carbon nanomaterials into endogenous organic metabolites

Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the invivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.

In Vivo Behavior of Ultrasmall Spherical Nucleic Acids.

The biological properties of spherical nucleic acids (SNAs) are largely independent of nanoparticle core identity but significantly affected by oligonucleotide surface density. Additionally, the payload-to-carrier (i.e., DNA-to-nanoparticle) mass ratio of SNAs is inversely proportional to core size. While SNAs with many core types and sizes have been developed, all in vivo analyses of SNA behavior have been limited to cores >10nm in diameter. However, "ultrasmall" nanoparticle constructs (<10nm diameter) can exhibit increased payload-to-carrier ratios, reduced liver accumulation, renal clearance, and enhanced tumor infiltration. Therefore,wehypothesized that SNAs with ultrasmall cores exhibit SNA-like properties, but with in vivo behavior akin to traditional ultrasmall nanoparticles. To investigate,wecompared the behavior of SNAs with 1.4-nm Au102 nanocluster cores (AuNC-SNAs) and SNAs with 10-nm gold nanoparticle cores (AuNP-SNAs). Significantly, AuNC-SNAs possess SNA-like properties (e.g., high cellular uptake, low cytotoxicity) but show distinct in vivo behavior. When intravenously injected in mice, AuNC-SNAs display prolonged blood circulation, lower liver accumulation, and higher tumor accumulation than AuNP-SNAs. Thus, SNA-like properties persist at the sub-10-nm length scale and oligonucleotide arrangement and surface density are responsible for the biological properties of SNAs. This work has implications for the design of new nanocarriers for therapeutic applications.

On the need of a scale-dependent material characterization to describe the mechanical behavior of 3D printed Ti6Al4V custom prostheses using finite element models

Additive manufacturing is widely used in the orthopaedic industry for the high freedom and flexibility in the design and production of personalized custom implants made of Ti6Al4V. Within this context, finite element modeling of 3D printed prostheses is a robust tool both to guide the design phase and to support clinical evaluations, possibly virtually describing the in-vivo behavior of the implant. Given realistic scenarios, a suitable description of the overall implant's mechanical behavior is unavoidable. Considering typical custom prostheses' designs (i.e. acetabular and hemipelvis implants), complex designs involving solid and/or trabeculated parts, and material distribution at different scales hinder a high-fidelity modeling of the prostheses.Moreover, uncertainties in the production and in the material characterization of small parts approaching the accuracy limit of the additive manufacturing technology still exist.While recent works suggest that the mechanical properties of thin 3D-printed parts may be peculiarly affected by specific processing parameters (i.e. powder grain size, printing orientation, samples’ thickness) as compared to conventional Ti6Al4V alloy, the current numerical models make gross simplifications in describing the complex material behavior of each part at different scales.The present study focuses on two patient-specific acetabular and hemipelvis prostheses, with the aim of experimentally characterizing and numerically describing the dependency of the mechanical behavior of 3D printed parts on their peculiar scale, therefore, overcoming one major limitation of current numerical models. Coupling experimental activities with finite element analyses, the authors initially characterized 3D printed Ti6Al4V dog-bone samples at different scales, representative of the main material components of the investigated prostheses. Afterwards, the authors implemented the characterized material behaviors into finite element models to compare the implications of adopting scale-dependent vs. conventional scaleindependent approaches in predicting the experimental mechanical behavior of the prostheses in terms of their overall stiffness and the local strain distribution. The material characterization results highlighted the need for a scale-dependent reduction of the elastic modulus for thin samples compared to the conventional Ti6Al4V, which is fundamental to properly describe the overall stiffness and local strain distribution on the prostheses.The presented works demonstrate how an appropriate material characterization and a scale-dependent material description is needed to develop reliable FE models of 3D printed implants characterized by a complex material distribution at different scales.

Lipid Nanobiotechnology: An Alternative Strategy to Targeted Drug and Vaccine Delivery System and Its Biomedical Applications as Nanomedicine

Nanobiotechnology has very compelling role in vaccine development. Delivery system orientates toward less immunogenic minimal compositions and formulations that boost antigen effectiveness. Latest advancements in LNPs formulations as targeted vaccine delivery systems, like anticancer and nucleic acid therapeutics. Nanomedicine expel challenges and promote growth opportunities inareas, like biomedical imaging, nutraceuticals, biomedicine, gene technology, and basic sciences. The fundamental understanding regarding the in-vivo behavior of nanoparticles explored, which can perform as either a delivery system to enhance antigen processing and/or as an immunostimulant adjuvant to activate or enhance immunity. The utilization of nanoparticles in vaccine development allows targeted delivery, improved antigen stability and immunogenicity.

The non-intuitive, in-vivo behavior of aponeuroses in a unipennate muscle

Experimental observations and theoretical models suggest that the loading of muscular aponeuroses is complex, causing strain patterns that are not reconcilable with the frequently assumed mechanical “in series” arrangement of aponeuroses with muscles and tendons. The purpose of this work was to measure the in-vivo longitudinal strains of the distal and proximal aponeuroses and force of the unipennate Medial Gastrocnemius (MG) muscle during locomotor activities. Sonomicrometry crystals and a force buckle transducer were implanted to measure aponeurosis strains and MG forces in the left hindlimb of four healthy female sheep while walking at different speeds and inclination angles on a motorized treadmill. The resulting aponeurosis strains versus the corresponding muscle forces resulted in a complex interaction that is not reconcilable with a mechanical “in series” arrangement of aponeuroses with either the free tendon or muscle, as has frequently been assumed when trying to determine the storage and release of mechanical energy in muscles or the stiffness and elastic modulus of in-vivo aponeurosis tissues. We conclude that the interaction of muscle tissue with aponeuroses in the sheep MG allows for elongation of the aponeuroses at low forces in the passive muscle, while elongation in the active muscle is greatly reduced possibly due to the complex shear forces and pressures produced when the muscle is activated. It is likely that the observed aponeurosis mechanics are similar in other unipennate skeletal muscles, but the current study was limited to a single muscle and therefore does not allow for such extrapolation at this time.

PRD-2 mediates clock-regulated perinuclear localization of clock gene RNAs within the circadian cycle of Neurospora

The transcription-translation negative feedback loops underlying animal and fungal circadian clocks are remarkably similar in their molecular regulatory architecture and, although much is understood about their central mechanism, little is known about the spatiotemporal dynamics of the gene products involved. A common feature of these circadian oscillators is a significant temporal delay between rhythmic accumulation of clock messenger RNAs (mRNAs) encoding negative arm proteins, for example, frq in Neurospora and Per1-3 in mammals, and the appearance of the clock protein complexes assembled from the proteins they encode. Here, we report use of single-molecule RNA fluorescence in situ hybridization (smFISH) to show that the fraction of nuclei actively transcribing the clock gene frq changes in a circadian manner, and that these mRNAs cycle in abundance with fewer than five transcripts per nucleus at any time. Spatial point patterning statistics reveal that frq is spatially clustered near nuclei in a time of day-dependent manner and that clustering requires an RNA-binding protein, PRD-2 (PERIOD-2), recently shown also to bind to mRNA encoding another core clock component, casein kinase 1. An intrinsically disordered protein, PRD-2 displays behavior invivo and invitro consistent with participation in biomolecular condensates. These data are consistent with a role for phase-separating RNA-binding proteins in spatiotemporally organizing clock mRNAs to facilitate local translation and assembly of clock protein complexes.

Assessment of the inherent chondrogenic potential of human articular cartilage-derived chondroprogenitors in pellet culture using a novel whole pellet processing approach

PurposeCartilage-derived chondroprogenitors have been reported to possess the biological potential for cartilage repair. However, its inherent chondrogenic potential in pellet culture needs evaluation. In-vitro cartilage regeneration models based on pellet cultures have been employed to evaluate the chondrogenic potential of stem cells. Evaluation of the degree of differentiation routinely involves paraffin embedding, sectioning, and immunohistochemical staining of the pellet. However, since chondrogenic differentiation is commonly non-uniform, processing random sections could lead to inaccurate conclusions. The study aimed at assessing the inherent lineage bias of chondroprogenitors with and without chondrogenic induction, using a novel whole pellet processing technique. MethodsHuman chondroprogenitors (n=3) were evaluated for MSC markers and processed in pellet cultures either with stromal medium (uninduced) or chondrogenic differentiation medium (induced) for 28 days. The whole pellets and the conventional paraffin-embedded sectioned pellets were subjected to Collagen type II immunostaining and assessed using confocal laser microscopy. The staining intensities of the whole pellet were compared to the paraffin sections and revalidated using qRT-PCR for COL2A1 expression. ResultsUninduced and induced pellets displayed Collagen type II in all the layers with comparable fluorescence intensities. COL2A1 expression in both pellets was comparable to confocal results. The study demonstrated that uninduced chondroprogenitors in pellet culture possess promising inherent chondrogenic potential. Confocal imaging of whole pellets displayed different degrees of chondrogenic differentiation in the entire pellet, thus its probable in-vivo behavior. ConclusionThe novel approach presented in this study could serve as an efficient in-vitro alternative for understanding translational application for cartilage repair.

Female self-incompatibility type in heterostylous Primula is determined by the brassinosteroid-inactivating cytochrome P450 CYP734A50

Most flowering plants are hermaphrodites, with flowers having both male and female reproductive organs. One widespread adaptation to limit self-fertilization is self-incompatibility (SI), where self-pollen fails to fertilize ovules.1,2 In homomorphic SI, many morphologically indistinguishable mating types are found, although in heteromorphic SI, the two or three mating types are associated with different floral morphologies.3-6 In heterostylous Primula, a hemizygous supergene determines a short-styled S-morph and a long-styled L-morph, corresponding to two different mating types, and full seed set only results from intermorph crosses.7-9 Style length is controlled by the brassinosteroid (BR)-inactivating cytochrome P450 CYP734A50,10 yet it remains unclear what defines the male and female incompatibility types. Here, we show that CYP734A50 also determines the female incompatibility type. Inactivating CYP734A50 converts short S-morph styles into long styles with the same incompatibility behavior as L-morph styles, and this effect can be mimicked by exogenous BR treatment. Invitro responses of S- and L-morph pollen grains and pollen tubes to increasing BR levels could only partly explain their different invivo behavior, suggesting both direct and indirect effects of the different BR levels in S- versus L-morph stigmas and styles in controlling pollen performance. This BR-mediated SI provides a novel mechanism for preventing self-fertilization. The joint control of morphology and SI by CYP734A50 has important implications for the evolutionary buildup of the heterostylous syndrome and provides a straightforward explanation for why essentially all of the derived self-compatible homostylous Primula species are long homostyles.11.

Design of particle size distribution for custom dissolution profiles by solving the inverse problem

Dissolution testing is widely used to measure the rate of drug release and predict its in-vivo behavior. The release rate can be controlled by adjusting the particle size distribution (PSD). However, experimental investigation of various particle sizes requires many time-consuming experiments. To reduce the need for them, we propose an optimization framework to solve the inverse problem, i.e., design a PSD that results in a prescribed dissolution profile. The framework's computational core predicts a dissolution profile using a population balance model coupled with a mass balance equation, while the optimization algorithm obtains the inverse solution. The model was validated using mono- and multimodal particle populations of a reference compound (KCl). The validation resulted in a good agreement between the simulated and experimental data. This suggests that the usage of the framework can provide a fast determination of the required PSD, reducing the number of experiments needed.

Analysis of expansion within a pressure inflated section of an urethral stricture model

Abstract The Urethra is a long tubular structure in the genitourinary tract and serves important functions. Researchers have experimented with some approaches to model the urethra and to analyse its biomechanical properties. However, experiments to model the in-vivo behaviour of urethra with strictures is not thoroughly explored. To analyse the in-vivo urethral properties and specifically for supporting treatment of strictures, a new inflatable sensor-actuator system is being developed. The capabilities of this sensor shall be evaluated in simulations which require appropriate modelling of the human male urethra with strictures. This forms a part of the identification procedure for a variety of urethra conditions and geometries, which in turn forms a basis for inverse modelling. As an initial simplified approach, an axisymmetric Finite Element model was generated that resembled the urethra incorporating a stricture region. An ideal actuator with sensor elements exerting a pressure on inner wall of this urethra was simulated. Three circumference measurement zones within the sensor height (top surface, centre and bottom surface) were implemented. The resulting pressure-extension (circumferential) responses were determined at these measurement zones. The sensor was placed at different lengths within this urethral tube and inflated and the pressure-extension responses were noted. It was found that depending on the position of the sensor-actuator, the extension of tissue can vary. The possible factors for this variation were the finite length of the actuator as well as the influence of tissue properties around the measurement zones. This is important information for the interpretation of sensor data to be gained by the current development. It was possible to generate datasets based on an ideal sensor model, that proved helpful in the evaluation of biomechanical tissue properties in healthy and stricture conditions. This indicates simulations are a versatile and prospective way to test new sensors prior to real experiments.