The effect of fibre cell remodelling on the power and optical quality of the lens.

Vertebrate eye lenses are uniquely adapted to form a refractive index gradient (GRIN) for improved acuity, and to grow slowly in size despite constant cell proliferation. The mechanisms behind these adaptations remain poorly understood. We hypothesize that cell compaction contributes to both.

A Chemomechanical Model for Regulation of Contractility in the Embryonic Brain Tube.

Morphogenesis is regulated by genetic, biochemical, and biomechanical factors, but the feedback controlling the interactions between these factors remains poorly understood. A previous study has found that compressing the brain tube of the early chick embryo induces changes in contractility and nuclear shape in the neuroepithelial wall. Assuming this response involves mechanical feedback, we use experiments and computational modeling to investigate a hypothetical mechanism behind the observed behavior.

Molecular and mechanical signals determine morphogenesis of the cerebral hemispheres in the chicken embryo.

During embryonic development, the telecephalon undergoes extensive growth and cleaves into right and left cerebral hemispheres. Although molecular signals have been implicated in this process and linked to congenital abnormalities, few studies have examined the role of mechanical forces. In this study, we quantified morphology, cell proliferation and tissue growth in the forebrain of chicken embryos during Hamburger-Hamilton stages 17-21.

Reduced embryonic blood flow impacts extracellular matrix deposition in the maturing aorta.

Background: Perturbations to embryonic hemodynamics are known to adversely affect cardiovascular development. Vitelline vein ligation (VVL) is a model of reduced placental blood flow used to induce cardiac defects in early chick embryo development. The effect of these hemodynamic interventions on maturing elastic arteries is largely unknown.

Dynamic patterns of cortical expansion during folding of the preterm human brain.

During the third trimester of human brain development, the cerebral cortex undergoes dramatic surface expansion and folding. Physical models suggest that relatively rapid growth of the cortical gray matter helps drive this folding, and structural data suggest that growth may vary in both space (by region on the cortical surface) and time. In this study, we propose a unique method to estimate local growth from sequential cortical reconstructions.

How mechanical forces shape the developing eye.

In the vertebrate embryo, the eyes develop from optic vesicles that grow laterally outward from the brain tube and contact the overlying surface ectoderm. Within the region of contact, each optic vesicle and the surface ectoderm thicken to form placodes, which then invaginate to create the optic cup and lens pit, respectively. Eventually, the optic cup becomes the retina, while the lens pit closes to form the lens vesicle.

Apoptosis generates mechanical forces that close the lens vesicle in the chick embryo.

During the initial stages of eye development, optic vesicles grow laterally outward from both sides of the forebrain and come into contact with the surrounding surface ectoderm (SE). Within the region of contact, these layers then thicken locally to create placodes and invaginate to form the optic cup (primitive retina) and lens vesicle (LV), respectively. This paper examines the biophysical mechanisms involved in LV formation, which consists of three phases: (1) lens placode formation; (2) invagination to create the lens pit (LP); and (3) closure to form a complete ellipsoidally shaped LV.

Real-world utilization of once-daily extended-release abuse deterrent formulation of hydrocodone: a comparison with the pre-approval randomized clinical trials.

Background And Objective: Hydrocodone bitartrate extended release (Hysingla ER, HYD) was previously studied in a 12-week randomized, double-blind, placebo-controlled trial and a 52-week open-label safety study. Both of these preapproval studies allowed dose titration to efficacy. The purpose of the present analysis was to compare dosing and utilization patterns in these previous clinical trials with real-world data (RWD) usage in a retrospective claim analysis performed 12-14 months post approval in the US.

Safety and effectiveness of once-daily Hysingla extended-release tablets in patients with baseline depression or anxiety.

Aim: Long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone bitartrate (HYD) for the treatment of moderate to severe noncancer and nonneuropathic pain among patients with and without concurrent depression/anxiety at baseline.

Materials & Methods: Post hoc analysis.

Results: HYD demonstrated a safety profile consistent with μ-opioid agonists: Serious adverse events in 12% patients with depression/anxiety including four deaths; 6% without depression/anxiety including one death.

A new hypothesis for foregut and heart tube formation based on differential growth and actomyosin contraction.

For decades, it was commonly thought that the bilateral heart fields in the early embryo fold directly towards the midline, where they meet and fuse to create the primitive heart tube. Recent studies have challenged this view, however, suggesting that the heart fields fold diagonally. As early foregut and heart tube morphogenesis are intimately related, this finding also raises questions concerning the traditional view of foregut formation.

Hysingla® ER, a once-daily, single-entity hydrocodone with abuse-deterrent properties in treating chronic nonmalignant and nonneuropathic pain in patients with osteoarthritis.

Objectives: Osteoarthritis (OA)-related chronic pain is associated with physical and psychosocial impairment as well as poorer quality of life. There is limited literature on long-term opioid therapy in OA patients. This post hoc analysis of OA patients assessed the long-term safety and effectiveness of a once-daily, single-entity, extended-release formulation of hydrocodone (HYD) with abuse-deterrent properties for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which other treatment options are inadequate.

Contraction and stress-dependent growth shape the forebrain of the early chicken embryo.

During early vertebrate development, local constrictions, or sulci, form to divide the forebrain into the diencephalon, telencephalon, and optic vesicles. These partitions are maintained and exaggerated as the brain tube inflates, grows, and bends. Combining quantitative experiments on chick embryos with computational modeling, we investigated the biophysical mechanisms that drive these changes in brain shape.

Tissue growth constrained by extracellular matrix drives invagination during optic cup morphogenesis.

In the early embryo, the eyes form initially as relatively spherical optic vesicles (OVs) that protrude from both sides of the brain tube. Each OV grows until it contacts and adheres to the overlying surface ectoderm (SE) via an extracellular matrix (ECM) that is secreted by the SE and OV. The OV and SE then thicken and bend inward (invaginate) to create the optic cup (OC) and lens vesicle, respectively.

How the embryonic chick brain twists.

During early development, the tubular embryonic chick brain undergoes a combination of progressive ventral bending and rightward torsion, one of the earliest organ-level left-right asymmetry events in development. Existing evidence suggests that bending is caused by differential growth, but the mechanism for the predominantly rightward torsion of the embryonic brain tube remains poorly understood. Here, we show through a combination of experiments, a physical model of the embryonic morphology and mechanics analysis that the vitelline membrane (VM) exerts an external load on the brain that drives torsion.

Long-term safety and effectiveness of once-daily, single-entity, extended-release hydrocodone over 76 weeks of an open-label study in patients with chronic noncancer and nonneuropathic pain.

Objective: To evaluate long-term use of Hysingla(®) ER (HYD), a single-entity, extended-release, once-daily hydrocodone bitartrate tablet with abuse-deterrent properties in patients with moderate-to-severe chronic noncancer and nonneuropathic pain.

Methods: This open-label study consisted of a dose-titration period (up to 45 days), a 52-week maintenance period and a 24-week extension period. Opioid-naïve or opioid-experienced patients with controlled or uncontrolled chronic pain conditions were treated with HYD 20-120 mg daily.

12-Month safety and effectiveness of once-daily hydrocodone tablets formulated with abuse-deterrent properties in patients with moderate to severe chronic pain.

Objective: To characterize the long-term safety and effectiveness of Hysingla™ ER, single-entity, once-daily, extended-release hydrocodone bitartrate tablets formulated with abuse-deterrent properties (HYD), offering a new treatment option for appropriate patients with chronic pain.

Design: An open-label study with a dose-titration period (up to 45 days) and a maintenance period (12 months).

Patients, Participants: A total of 922 patients with chronic nonmalignant and non-neuropathic moderate to severe pain received open-label HYD tablets 20-120 mg; 728 of these achieved a stabilized dose of HYD at the end of dose-titration and entered the maintenance period.

Why is cytoskeletal contraction required for cardiac fusion before but not after looping begins?

Cytoskeletal contraction is crucial to numerous morphogenetic processes, but its role in early heart development is poorly understood. Studies in chick embryos have shown that inhibiting myosin-II-based contraction prior to Hamburger-Hamilton (HH) stage 10 (33 h incubation) impedes fusion of the mesodermal heart fields that create the primitive heart tube (HT), as well as the ensuing process of cardiac looping. If contraction is inhibited at or after looping begins at HH10, however, fusion and looping proceed relatively normally.

Mechanical effects of the surface ectoderm on optic vesicle morphogenesis in the chick embryo.

Precise shaping of the eye is crucial for proper vision. Here, we use experiments on chick embryos along with computational models to examine the mechanical factors involved in the formation of the optic vesicles (OVs), which grow outward from the forebrain of the early embryo. First, mechanical dissections were used to remove the surface ectoderm (SE), a membrane that contacts the outer surfaces of the OVs.

Probing regional mechanical properties of embryonic tissue using microindentation and optical coherence tomography.

Physical forces regulate morphogenetic movements and the mechanical properties of embryonic tissues during development. Such quantities are closely interrelated, as increases in material stiffness can limit force-induced deformations and vice versa. Here we present a minimally invasive method to quantify spatiotemporal changes in mechanical properties during morphogenesis.

Simple and accurate methods for quantifying deformation, disruption, and development in biological tissues.

When mechanical factors underlie growth, development, disease or healing, they often function through local regions of tissue where deformation is highly concentrated. Current optical techniques to estimate deformation can lack precision and accuracy in such regions due to challenges in distinguishing a region of concentrated deformation from an error in displacement tracking. Here, we present a simple and general technique for improving the accuracy and precision of strain estimation and an associated technique for distinguishing a concentrated deformation from a tracking error.

Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry.

The morphogenetic process of cardiac looping transforms the straight heart tube into a curved tube that resembles the shape of the future four-chambered heart. Although great progress has been made in identifying the molecular and genetic factors involved in looping, the physical mechanisms that drive this process have remained poorly understood. Recent work, however, has shed new light on this complicated problem.

Morphomechanics: transforming tubes into organs.

After decades focusing on the molecular and genetic aspects of organogenesis, researchers are showing renewed interest in the physical mechanisms that create organs. This review deals with the mechanical processes involved in constructing the heart and brain, concentrating primarily on cardiac looping, shaping of the primitive brain tube, and folding of the cerebral cortex. Recent studies suggest that differential growth drives large-scale shape changes in all three problems, causing the heart and brain tubes to bend and the cerebral cortex to buckle.

Bending of the looping heart: differential growth revisited.

In the early embryo, the primitive heart tube (HT) undergoes the morphogenetic process of c-looping as it bends and twists into a c-shaped tube. Despite intensive study for nearly a century, the physical forces that drive looping remain poorly understood. This is especially true for the bending component, which is the focus of this paper.

Computational and experimental study of the mechanics of embryonic wound healing.

Wounds in the embryo show a remarkable ability to heal quickly without leaving a scar. Previous studies have found that an actomyosin ring (purse string) forms around the wound perimeter and contracts to close the wound over the course of several dozens of minutes. Here, we report experiments that reveal an even faster mechanism which remarkably closes wounds by more than 50% within the first 30s.