Time-dependent Release Research Articles

Influence of Loading History on Delamination in Multilayered Beam with Creep

The present paper deals with an analytical study of the time-dependent delamination in a multilayered inhomogeneous cantilever beam with considering of the loading history. The multilayered beam exhibits creep behaviour that is treated by using a non-linear stress-strain-time relationship. The material properties are continuously distributed along the thickness and length of the layers. The external loading is applied in steps in order to describe the loading history. The analysis reveals that during each step of the loading, the strain energy release rate increases with time. The influences of crack length and location on the time-dependent strain energy release rate are also investigated.

Influence of Creep on Longitudinal Fracture of Inhomogeneous Rod Loaded in Torsion and Bending

The present paper analyzes the influence of creep on longitudinal fracture in continuously inhomogeneous rod of circular cross-section loaded in torsion and bending. The rod exhibits continuous material inhomogeneity in both radial and longitudinal directions. The creep is described by using non-linear time-dependent relations between the principle stresses and strains. A time-dependent solution to the strain energy release rate is derived by analyzing the complementary strain energy. The time-dependent strain energy release rate is found also by considering the energy balance for verification. The solutions are applied to perform a parametric study of the strain energy release rate under creep.

An Efficient Clicked Degradable Template Model Responsive to Encapsulation and Release of Fluorescent Dye

We invoked one-step synthesis for degradable organogel material via metal-free thiol-alkene click chemistry. The thermally clicked hydrothiolation formed ester-based xerogel. The xerogel showed switch in swellability with switch of solvent polarity. Though the material showed no response in swellability to solvents of low-polarity index but swelled in organic polar and chlorinated solvents. Encapsulation and release of 8-hydroxyquinoline were studied. The analyzed xerogel showed thermal stability analyzed using thermogravimetric analysis. The degradability at 6N HCl is unique, which was well monitored via time-dependent release of encapsulated 8-hydroxyquinoline. Cryo TEM analysis revealed such nanogel can prove to be a vital model to carry encapsulated low molecular weight (LMW) drug and efficient release at [Formula: see text] via self-degradation.

Protein adsorption/desorption dynamics on Ca-enriched titanium surfaces: biological implications

Calcium ions are used in the development of biomaterials for the promotion of coagulation, bone regeneration, and implant osseointegration. Upon implantation, the time-dependent release of calcium ions from titanium implant surfaces modifies the physicochemical characteristics at the implant–tissue interface and thus, the biological responses. The aim of this study is to examine how the dynamics of protein adsorption on these surfaces change over time. Titanium discs with and without Ca were incubated with human serum for 2 min, 180 min, and 960 min. The layer of proteins attached to the surface was characterised using nLC-MS/MS. The adsorption kinetics was different between materials, revealing an increased adsorption of proteins associated with coagulation and immune responses prior to Ca release. Implant–blood contact experiments confirmed the strong coagulatory effect for Ca surfaces. We employed primary human alveolar osteoblasts and THP-1 monocytes to study the osteogenic and inflammatory responses. In agreement with the proteomic results, Ca-enriched surfaces showed a significant initial inflammation that disappeared once the calcium was released. The distinct protein adsorption/desorption dynamics found in this work demonstrated to be useful to explain the differential biological responses between the titanium and Ca-ion modified implant surfaces.Graphic abstract

Formation of Microcages from a Collagen Mimetic Peptide via Metal-Ligand Interactions.

Here, the hierarchical assembly of a collagen mimetic peptide (CMP) displaying four bipyridine moieties is described. The CMP was capable of forming triple helices followed by self-assembly into disks and domes. Treatment of these disks and domes with metal ions such as Fe(II), Cu(II), Zn(II), Co(II), and Ru(III) triggered the formation of microcages, and micron-sized cup-like structures. Mechanistic studies suggest that the formation of the microcages proceeds from the disks and domes in a metal-dependent fashion. Fluorescently-labeled dextrans were encapsulated within the cages and displayed a time-dependent release using thermal conditions.

3D printed multicompartmental capsules for a progressive drug release

The temporal delivery of chemical compounds to target organs and tissues is a key-topic for pharmacological and therapeutic applications. Dealing with ad hoc systems that can be properly designed to deliver drugs when are really needed is regarded as a valuable approach to improve the effectiveness of a clinical protocol. For this aim, 3D printing can be a suitable means to fabricate structured reservoirs to allow a prolonged release of the loaded pharmacological agent.This study reports the fabrication and characterization of multicompartmental capsules made of polyvinyl alcohol (PVA) processed by fused deposition modelling (FDM) to be considered for a time dependent release therapeutic approach. Thermal assessment of the printed devices was carried out to evaluate a possible influence of FDM high temperatures on the polymer, while dimensional consistency was evaluated through optical microscopy. Regarding the expected application, different designs were investigated in order to validate the proof-of-concept by in vitro assessing the release of curcumin, as a drug model. Three capsule models were tested, including single, double and triple reservoirs, which provided different dissolution periods, ranging from about 180 to 390 min.The collected results supported the potential to easily tailor 3D printed devices, specifically modified for drug delivery purposes.

Fermentation of Multi-Targeted Products: A statistical Approach Discussed the Production of Cell Wall Hydrolytic Enzymes from Streptomyces rochei for Pathogenic Fungi biocontrol

The production of synergistically multi-acting cell wall hydrolyzing enzymes such as chitinase, glucanase, protease and whole cell-wall lytic enzymes “WCL” was highly observed in the culture filtrate of a strain molecularly characterized as Streptomyces rochei MZ227230. Enzymes productivity was monitored in different media and superiority of the modified lytic enzymes production medium (M4) was clearly noticed. Then the simultaneous optimization production of these enzymes through application of statistical modelling was conducted. Box-Behnken design (BBD) using the key components of M4 (C. albicans cell walls, baker yeast, chitin and peptone) followed by independent analysis for productivity of each enzyme helped to conduct four significant models describing four media that were specifically optimized to produce the utmost yields of chitinase (14.97), glucanase (27.89), protease (137.59) and WCL (65.28 U/ml). Pearson’s correlation analysis indicated the impossibility to potentiate the tested enzymes to the utmost yields simultaneously. However, the coproduction medium potentiated more than 80% of the maximal yields for all enzymes. Furthermore, the crude filtrate showed potent fungicidal effect against Fusarium graminearum, Mucor racemosus, Fusarium solani, and Candida albicans which should be attributed to its hydrolytic activity as indicated by the dose and time-dependent release of DNA, RNA and protein constituents of C. albicans

Rapid Release of Interleukin-1β from Human Platelets Is Independent of NLRP3 and Caspase.

Platelets are critical in mediating both rapid responses to injury and the development and progression of coronary disease. Several studies have shown that, after prolonged exposure to agonists, they produce and release inflammatory mediators including interleukin-1β (IL-1β), via the classical pathway (NLRP3 inflammasome and caspase-1 cleavage to release active IL-1β) as described for leukocytes. This study aimed to determine whether there is rapid release of IL-1β in response to soluble platelet agonists and whether such rapid release is NLRP3- and caspase-1-dependent. Using flow cytometry to detect platelet activation (and release of α and dense granule contents) and the combination of Western blotting, enzyme-linked-immunosorbent assay, and immunogold labeling transmission electron and immunofluorescence microscopy, we identified that resting human platelets contain mature IL-1β. Platelets release IL-1β within minutes in response to adenosine diphosphate (ADP), collagen, and thrombin receptor agonists, but not in response to conventional NLRP3 inflammasome agonists-lipopolysaccharide and adenosine triphosphate. The rapid release of IL-1β in response to ADP and thrombin receptor agonists was independent of caspases (including caspase-1) and NLRP3. Immature and mature IL-1β were identified as low-abundance proteins on transmission electron microscopy of human platelets, and were localized to the platelet cytosol, open canalicular system, and the periphery of α granules. Unlike monocytes and neutrophils, human platelets are capable of rapid agonist- and time-dependent release of IL-1β by a mechanism which is independent of caspase-1 and NLRP3.

1193-P: Investigating the Role of Intestinal L-Cell Secretagogin in Circadian GLP-1 Secretion in a Mouse Model of Type 2 Diabetes

The intestinal L-cell hormone Glucagon-like Peptide-1 (GLP-1) increases glucose-dependent insulin secretion and is thus used in the treatment of T2D. GLP-1 secretion from the L-cell exhibits a circadian pattern in rodents and varies by time-of-day in humans. We have shown that KD of the SNARE-regulatory protein, secretagogin (SCGN) prevents time-dependent GLP-1 release. SCGN KD in ß-cells also decreases insulin secretion and SCGN levels are reduced in T2D islets. We thus hypothesized that SCGN is decreased in the L-cell in T2D, causing alterations in the physiological pattern of GLP-1 secretion. High-fat diet, low-dose streptozotocin (HFD-STZ) mice, a model of T2D, exhibited increased fasting glucose (5.5 vs. 15.6 mmol/L; p<0.001) and decreased ß-cell area (by 75%, p<0.001). Unexpectedly, oral glucose tolerance tests conducted in 4-hour intervals through the 24-hr day showed that HFD-STZ mice exhibit a 10x increase in GLP-1 responses (400 vs. 4000 pg/ml*60 min, p<0.001) and exhibit an anti-phasic rhythm to controls. Basal GLP-1 levels remained unchanged between HFD-STZ and controls. Unexpectedly, insulin responses were not reduced in HFD-STZ mice, suggesting that increased GLP-1 levels could act as a compensatory mechanism. HFD-STZ mice also exhibited hyperglucagonemia compared to control, with increased glucagon secretion across timepoints following glucose administration (–243 vs. 800 pg/ml*60 min, p<0.001). RT-qPCR of intestinal mucosa showed an anti-phasic Scgn rhythm in the HFD-STZ model, with a 1.5-fold increase in average expression across timepoints (p<0.05), which could explain the drastically increased GLP-1 secretion. These data show that GLP-1 secretion is both increased and arrhythmic in a murine model of T2D, and that this occurs in association with an unanticipated increase in Scgn expression. Further investigation into the role of SGCN in the L-cell may serve as an avenue for therapeutics aimed at increasing endogenous GLP-1 release. Disclosure A. Biancolin: None. P. L. Brubaker: None. Funding Canadian Institutes of Health Research (PJT-15308)

Tracking the nuclear movement of the carbonyl sulfide cation after strong-field ionization by time-resolved Coulomb-explosion imaging

We studied the ultrafast nuclear dynamics during the dissociation of ${\mathrm{OCS}}^{+}$ molecules using a strong IR-laser pump and probe technique in combination with the coincidence measurement. The nuclear movement is tracked by analyzing the time-dependent kinetic energy release (KER) spectra. The involved dissociation states and pathways are assigned with the help of the semiclassical Landau-Zener surface hopping calculations. The real-time bond-breaking dynamics of the ${3}^{2}\phantom{\rule{0.16em}{0ex}}A{}^{\ensuremath{'}}$ coupling to other states are observed for the two-body dissociation channel and the three-body dissociation channel but with high KER. The three-body dissociation channel with low KER is assigned to the direct breaking process from the ${3}^{2}\phantom{\rule{0.16em}{0ex}}A{}^{\ensuremath{''}}$ state. The overall agreements between the experimental and theoretical results demonstrate that the time-resolved Coulomb-explosion imaging is a valuable way to monitor the bond breaking and structural evolution of complex molecules.

Lumit&[trade] Immunoassays for Simple and Rapid Determination of Cytokine Release from Cell Culture Models

Abstract Rapid (< 70 min), add-and-read assays for cytokine determination were developed with Lumit™ immunoassay technology. Separate antibodies labeled with complementary SmBiT or LgBiT subunits bind to their shared cytokine target, resulting in proximity-driven reconstitution of NanoBiT luciferase and luminescence signal. Lumit immunoassays for human IL-1β, IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α exhibit LLODs < 10 pg/ml and linearity > 3 logs of analyte in 96-well format. Maximal S/B ratios are greater than 1000, and an assay signal T1/2 of 2 h accommodates batch plate processing. 384-well, assay performance (Z′ > 0.7) on treated human peripheral blood mononuclear cells (hPBMC) indicates the assay format is amenable to screening applications. Assay reagents were added directly to cell wells for multiple culture models. For hPBMC, LPS, R848, or a combination of PMA and ionomycin (CSC) produced dose-and time-dependent release of cytokines with a wide range of responses, all measurable without sample dilution. In a mix of purified CD8+ T cells and target Raji B cells treated with the bispecific T-cell engager Blincyto®, IL-2, IFN-γ, and TNF-α release was observed with an EC50 of ~0.2 ng/ml and max S/B ratios of 82-, 168-, and 31-fold, respectively. For Th2 cells, significant release of IL-4 was observed in response to CSC treatment. An alternative to the no-transfer assay method, split-sample analysis, can be performed to easily determine the levels of multiple cytokines released in the same cell well. The implementation of this novel detection chemistry will enable simple and rapid assay of cytokine release from cells for both low-and high-throughput applications, including quantitative assessments of T cell activation and differentiation.

A promising dual-drug targeted delivery system in cancer therapy: nanocomplexes of folate–apoferritin-conjugated cationic solid lipid nanoparticles

Various nano-sized protein and lipid complexes are being investigated as drug delivery systems. The encapsulation of more than one drug in a single nanocomplex carrier could enhance the therapeutic potency and afford synergistic therapeutic effects. In this study, we developed a novel protein-lipid nanocomplex as a controlled drug delivery system for two important cancer drugs, doxorubicin (DOX) and mitoxantrone (MTO). Apoferritin (AFr) functionalized with folic acid (FA) was used to encapsulate DOX to create the targeted protein nanocomplexes (TPNs). The second drug, MTO, was loaded into the cationic solid lipid nanoparticles (cSLN) to form the liposomal drug nanocomplex particles (MTO-cSLNs). Two complexes were then assembled by tight coupling through ionic interactions to obtain the final drug delivery system, the dual-targeted protein-lipid nanocomplexes (DTPLNs). UV-Vis and fluorescence spectroscopy were used for structural characterization of TPNs and DTPLNs. Transmission electron microscopy (TEM) was used for comprehensive analysis of the final DTPLNs. We confirmed that the DTPLNs display desired time-dependent and pH-dependent drug release behaviors. We also demonstrated the improved anti-cancer efficacy of DOX and MTO in their encapsulated DTPLNs as compared to their free forms. Our results provide promising prospects for the application of the DTPLNs as efficient drug delivery systems.

Kinetic Release Studies of Antibiotic Patches for Local Transdermal Delivery.

This study investigates the usage of electrohydrodynamic (EHD)-3D printing for the fabrication of bacterial cellulose (BC)/polycaprolactone (PCL) patches loaded with different antibiotics (amoxicillin (AMX), ampicillin (AMP), and kanamycin (KAN)) for transdermal delivery. The composite patches demonstrated facilitated drug loading and encapsulation efficiency of drugs along with extended drug release profiles. Release curves were also subjected to model fitting, and it was found that drug release was optimally adapted to the Higuchi square root model for each drug. They performed a time-dependent and diffusion-controlled release from the patches and followed Fick’s diffusion law by the Korsmeyer–Peppas energy law equation. Moreover, produced patches demonstrated excellent antimicrobial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) strains, so they could be helpful in the treatment of chronic infectious lesions during wound closures. As different tests have confirmed, various types of antibiotics could be loaded and successfully released regardless of their types from produced BC/PCL patches. This study could breathe life into the production of antibiotic patches for local transdermal applications in wound dressing studies and improve the quality of life of patients.

Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice.

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.

Polyethylene Glycol Coated Magnetic Nanoparticles: Hybrid Nanofluid Formulation, Properties and Drug Delivery Prospects.

Magnetic nanoparticles (MNPs) are widely used materials for biomedical applications owing to their intriguing chemical, biological and magnetic properties. The evolution of MNP based biomedical applications (such as hyperthermia treatment and drug delivery) could be advanced using magnetic nanofluids (MNFs) designed with a biocompatible surface coating strategy. This study presents the first report on the drug loading/release capability of MNF formulated with methoxy polyethylene glycol (referred to as PEG) coated MNP in aqueous (phosphate buffer) fluid. We have selected MNPs (NiFe2O4, CoFe2O4 and Fe3O4) coated with PEG for MNF formulation and evaluated the loading/release efficacy of doxorubicin (DOX), an anticancer drug. We have presented in detail the drug loading capacity and the time-dependent cumulative drug release of DOX from PEG-coated MNPs based MNFs. Specifically, we have selected three different MNPs (NiFe2O4, CoFe2O4 and Fe3O4) coated with PEG for the MNFs and compared their variance in the loading/release efficacy of DOX, through experimental results fitting into mathematical models. DOX loading takes the order in the MNFs as CoFe2O4 > NiFe2O4 > Fe3O4. Various drug release models were suggested and evaluated for the individual MNP based NFs. While the non-Fickian diffusion (anomalous) model fits for DOX release from PEG coated CoFe2O4, PEG coated NiFe2O4 NF follows zero-order kinetics with a slow drug release rate of 1.33% of DOX per minute. On the other hand, PEG coated NiFe2O4 follows zero-order DOX release. Besides, several thermophysical properties and magnetic susceptibility of the MNFs of different concentrations have been studied by dispersing the MNPs (NiFe2O4, CoFe2O4 and Fe3O4) in the base fluid at 300 K under ultrasonication. This report on the DOX loading/release capability of MNF will set a new paradigm in view that MNF can resolve problems related to the self-heating of drug carriers during mild laser treatment with its thermal conducting properties.

The Release Kinetics of Eosinophil Peroxidase and Mitochondrial DNA Is Different in Association with Eosinophil Extracellular Trap Formation.

Eosinophils are a subset of granulocytes characterized by a high abundance of specific granules in their cytoplasm. To act as effector cells, eosinophils degranulate and form eosinophil extracellular traps (EETs), which contain double-stranded DNA (dsDNA) co-localized with granule proteins. The exact molecular mechanism of EET formation remains unknown. Although the term “EET release” has been used in scientific reports, it is unclear whether EETs are pre-formed in eosinophils and subsequently released. Moreover, although eosinophil degranulation has been extensively studied, a precise time-course of granule protein release has not been reported until now. In this study, we investigated the time-dependent release of eosinophil peroxidase (EPX) and mitochondrial DNA (mtDNA) following activation of both human and mouse eosinophils. Unexpectedly, maximal degranulation was already observed within 1 min with no further change upon complement factor 5 (C5a) stimulation of interleukin-5 (IL-5) or granulocyte/macrophage colony-stimulating factor (GM-CSF)-primed eosinophils. In contrast, bulk mtDNA release in the same eosinophil populations occurred much slower and reached maximal levels between 30 and 60 min. Although no single-cell analyses have been performed, these data suggest that the molecular pathways leading to degranulation and mtDNA release are at least partially different. Moreover, based on these data, it is likely that the association between the mtDNA scaffold and granule proteins in the process of EET formation occurs in the extracellular space.

Tragacanth gum-based multifunctional hydrogels and green synthesis of their silver nanocomposites for drug delivery and inactivation of multidrug resistant bacteria

This study investigated natural polymer-based stimuli-responsive hydrogels (TGIAVE) and their silver nanocomposites (TGIAVE-Ag). The hydrogels were composed of tragacanth gum, N-isopropyl acrylamide, and 2-(vinlyoxy) ethanol and were prepared via simple redox polymerization using N,N′-methylene-bis-acrylamide as a crosslinker and potassium persulfate as an initiator. The TGIAVE-Ag were synthesized via a green method involving an aqueous extract of Terminalia bellirica seeds. Structural, thermal, crystallinity, morphology, and size characteristics of the TGIAVE and TGIAVE-Ag were investigated by FTIR, UV–Vis, XRD, DSC, SEM, EDS, DLS, and TEM. To understand the physicochemical interaction and diffusion characteristics of TGIAVEs, network parameters such as zero-order, first-order, Hixson-Crowell, Higuchi, and Korsmeyer-Peppas values were calculated by assessing swelling data. TGIAVE hydrogels at pH 1.2 and 7.4 and temperatures of 25 and 37 °C may be used for time-dependent controlled release of 5-fluorouracil, an anticancer drug, TGIAVE-Ag may be applied for the inactivation of multidrug resistant (MDR) bacteria.

Enhanced Analytic Approach for Describing pH Triggered Fast Drug Release Systems.

pH sensitive dendrimers attached to nanocarriers, as one of the drug release systems, have become quite popular due to their ease of manufacture in experimental conditions and the ability to generate fast drug release in the targeted area. This kind of fast release behavior cannot be represented properly in most of the existing kinetic mathematical models. Besides, these models have either no pH dependence or pH dependence added separately. Therefore, they remained one dimensional. The aim of this study was to establish the proper analytic equation to describe the fast release of drugs from pH sensitive nanocarrier systems, and to combine it with the pH dependent equation for to establish a two-dimensional model for whole system. We used four common kinetic models for the comparison and we fitted them to the release data. As a result, only Higuchi and Korsmeyer-Peppas models show acceptable suitable results. None of these models have pH dependence. To get a better description for pH triggered fast release, we observed the behavior of the slope angle of the release curve. Then we proposed a new analytic equation by using relation between the slope angle and time. By adding a pH dependent equation, we assumed the drug release is "on" or "off" above/below specific pH value and we modified a step function to get a desired behavior. Our new analytic model shows good fitting, not only one-dimensional time dependent release, but also two-dimensional pH dependent release, that provides a useful analytic model to represent release profiles of pH sensitive fast drug release systems.

Longitudinal vertical crack analysis in beam with relaxation stresses

PurposeThis paper is concerned with analysis of the time-dependent strain energy release rate for a longitudinal crack in a beam subjected to linear relaxation. A viscoelastic model with an arbitrary number of parallel units is used for treating the relaxation. Each unit has one dashpot and two springs. A stress-strain-time relationship is derived for the case when the coefficient of viscosity in each unit of the viscoelastic model changes continuously with time. The beam exhibits continuous material inhomogeneity along the thickness. Thus, the moduli of elasticity and the coefficients of viscosity vary continuously in the thickness direction. The aim of the present paper is to obtain time-dependent solutions to the strain energy release rate that take into account the relaxation when the coefficient of viscosity changes with time.Design/methodology/approachTime-dependent solutions to the strain energy release rate are derived by considering the time-dependent strain energy and also by using the compliance method. The two solutions produce identical results.FindingsThe variation of the strain energy release rate with time due to the relaxation is analysed. The influence of material inhomogeneity and the crack location along the beam width on the strain energy release rate are evaluated. The effects of change of the coefficients of viscosity with time and the number of units in the viscoelastic model on the strain energy release rate are assessed by applying the solutions derived.Originality/valueThe time-dependent strain energy release rate for a longitudinal vertical crack in a beam under relaxation is analysed for the case when the coefficients of viscosity change with time.

Viscoelastic inhomogeneous beams under step loading: a longitudinal fracture analysis

The present paper describes a longitudinal fracture analysis of an inhomogeneous vscoelastic cantilever beam under step loading. The beam exhibits continuous material inhomogeneity along its thickness, width and length. The creep behaviour is treated by using a linear viscoelastic model. The beam is loaded by a bending moment applied in steps at the free end of the lower crack arm. The time-dependent longitudinal fracture behaviour is studied in terms of the strain energy release rare. For this purpose, a methodology for deriving the time-dependent strain energy release rate with taking into account the creep behaviour under step loading is developed by using the compliance of the beam. A time-dependent solution to the strain energy release rate under step loading is derived also by considering the strain energy cumulated in the beam structure for verification. The change of the strain energy release rate with the time due to creep under step loading is investigated by applying the methodology developed. The effects of the location and length of the crack and the continuous material inhomogeneity on the time-dependent strain energy release rate are analyzed.