An enzymatically crosslinked collagen type II/hyaluronic acid hybrid hydrogel: A biomimetic cell delivery system for cartilage tissue engineering.

This study presents new injectable hydrogels based on hyaluronic acid and collagen type II that mimic the polysaccharide-protein structure of natural cartilage. After collagen isolation from chicken sternal cartilage, tyramine-grafted hyaluronic acid and collagen type II (HA-Tyr and COL-II-Tyr) were synthesized. Hybrid hydrogels were prepared with different ratios of HA-Tyr/COL-II-Tyr using horseradish peroxidase and noncytotoxic concentrations of hydrogen peroxide to encapsulate human bone marrow-derived mesenchymal stromal cells (hBM-MSCs). The findings showed that a higher HA-Tyr content resulted in a higher storage modulus and a lower hydrogel shrinkage, resulting in hydrogel swelling. Incorporating COL-II-Tyr into HA-Tyr hydrogels induced a more favorable microenvironment for hBM-MSCs chondrogenic differentiation. Compared to HA-Tyr alone, the hybrid HA-Tyr/COL-II-Tyr hydrogel promoted enhanced chondrocyte adhesion, spreading, proliferation, and upregulation of cartilage-related gene expression. These results highlight the promising potential of injectable HA-Tyr/COL-II-Tyr hybrid hydrogels to deliver cells for cartilage regeneration.

The development of a dental light curable PRFe-loaded hydrogel as a potential scaffold for pulp-dentine complex regeneration: An in vitro study.

AIM: The study aimed to develop a bicomponent bioactive hydrogel formed in situ and enriched with an extract of platelet-rich fibrin (PRFe) and to assess its potential for use in pulp-dentine complex tissue engineering via cell homing. METHODOLOGY: A bicomponent hydrogel based on photo-activated naturally derived polymers, methacrylated chitosan (ChitMA) and methacrylated collagen (ColMA), plus PRFe was fabricated. The optimized formulation of PRFe-loaded bicomponent hydrogel was determined by analysing the mechanical strength, swelling ratio and cell viability simultaneously. The physical, mechanical, rheological and morphological properties of the optimal hydrogel with and without PRFe were determined. Additionally, MTT, phalloidin/DAPI and live/dead assays were carried out to compare the viability, cytoskeletal morphology and migration ability of stem cells from the apical papilla (SCAP) within the developed hydrogels with and without PRFe, respectively. To further investigate the effect of PRFe on the differentiation of encapsulated SCAP, alizarin red S staining, RT-PCR analysis and immunohistochemical detection were performed. Statistical significance was established at p < .05. RESULTS: The optimized formulation of PRFe-loaded bicomponent hydrogel can be rapidly photocrosslinked using available dental light curing units. Compared to bicomponent hydrogels without PRFe, the PRFe-loaded hydrogel exhibited greater viscoelasticity and higher cytocompatibility to SCAP. Moreover, it promoted cell proliferation and migration in vitro. It also supported the odontogenic differentiation of SCAP as evidenced by its promotion of biomineralization and upregulating the gene expression for ALP, COL I, DSPP and DMP1 as well as facilitated angiogenesis by enhancing VEGFA gene expression. CONCLUSIONS: The new PRFe-loaded ChitMA/ColMA hydrogel developed within this study fulfils the criteria of injectability, cytocompatibility, chemoattractivity and bioactivity to promote odontogenic differentiation, which are fundamental requirements for scaffolds used in pulp-dentine complex regeneration via cell-homing approaches.

Advances in scaffolds used for pulp-dentine complex tissue engineering: A narrative review.

BACKGROUND: Pulp-dentine complex regeneration via tissue engineering is a developing treatment modality that aims to replace necrotic pulps with newly formed healthy tissue inside the root canal. Designing and fabricating an appropriate scaffold is a crucial step in such a treatment. OBJECTIVES: The present study aimed to review recent advances in the design and fabrication of scaffolds for de novo regeneration of pulp-dentine complexes via tissue engineering approaches. METHODS: A literature search was conducted using PubMed, Europe PMC, Scopus and Google Scholar databases. To highlight bioengineering techniques for de novo regeneration of pulp-dentine complexes, both in vitro and in vivo studies were included, and clinical studies were excluded. RESULTS: In the present review, four main classes of scaffolds used to engineer pulp-dentine complexes, including bioceramic-based scaffolds, synthetic polymer-based scaffolds, natural polymer-based scaffolds and composite scaffolds, are covered. Additionally, recent advances in the design, fabrication and application of such scaffolds are analysed along with their advantages and limitations. Finally, the importance of vascular network establishment in the success of pulp-dentine complex regeneration and strategies used to create scaffolds to address this challenge are discussed. DISCUSSION: In the tissue engineering platform, scaffolds provide structural support for cells to adhere and proliferate and also regulate cell differentiation and metabolism. Up to now, considerable progress has been achieved in the field of pulp-dentine complex tissue engineering, and a spectrum of scaffolds ranging from bioceramic-based to naturally derived scaffolds has been fabricated. However, in designing a suitable scaffold for engineering pulp-dentine complexes, a variety of characteristic parameters related to biological, structural, physical and chemical features should be considered. CONCLUSION: The variety of biomaterials and fabrication techniques provides a great opportunity to address some of the requirements for scaffolds in regenerative endodontics. However, more studies are required to develop an ideal scaffold for use in a clinical setting.

Design of an effective piezoelectric microcantilever biosensor for rapid detection of COVID-19.

Acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also called COVID-19, is one of the most contagious viruses resulting in a progressive pandemic. Since specific antiviral treatments have not been developed yet and its fatal rate is almost high, early and fast detection is critical for controlling the outbreak. In this study, a piezoelectric microcantilever biosensor has been designed for detecting COVID-19 samples directly without requiring preparation steps. The biosensor acts as a transducer and is coated with the related antibody. When the SARS-CoV-2 antigens adsorbed on the microcantilever top surface through their spike proteins, a surface stress due to the mass change would be prompted leading to the measurable tip deflection and floating voltage. To obtain a biosensor with optimum parameters, different shapes and piezoelectric materials have been assessed and it was concluded that a Poly (vinylidene fluoride) (PVDF) biosensor in a shape of a holed punched form triangle, represented the best result. Therefore, the highly sensitive microcantilever biosensor can detect COVID-19 in clinical samples with various viral loads, rapidly. Also, it is selective enough to differentiate SARS-CoV-2 from other viruses with similar symptoms.

Electrochemical prostate-specific antigen biosensors based on electroconductive nanomaterials and polymers.

Prostate cancer (PCa), the second most malignant neoplasm in men, is also the fifth leading cause of cancer-related deaths in men globally. Unfortunately, this malignancy remains largely asymptomatic until late-stage emergence when treatment is limited due to the lack of effective metastatic PCa therapeutics. Due to these limitations, early PCa detection through prostate-specific antigen (PSA) screening has become increasingly important, resulting in a more than 50% decrease in mortality. Conventional assays for PSA detection, such as enzyme-linked immunosorbent assay (ELISA), are labor intensive, relatively expensive, operator-dependent and do not provide adequate sensitivity. Electrochemical biosensors overcome these limitations because they are rapid, cost-effective, simple to use and ultrasensitive. This article reviews electrochemical PSA biosensors using electroconductive nanomaterials such as carbon-, metal-, metal oxide- and peptide-based nanostructures, as well as polymers to significantly improve conductivity and enhance sensitivity. Challenges associated with the development of these devices are discussed thus providing additional insight into their analytic strength as well as their potential use in early PCa detection.

Serological assays and host antibody detection in coronavirus-related disease diagnosis.

Coronaviruses (CoV) are a family of viral pathogens that infect both birds and mammals, including humans. Seven human coronaviruses (HCoV) have been recognized so far. HCoV-229E, -OC43, -NL63, and -HKU1 account for one-third of common colds with mild symptoms. The other three members are severe acute respiratory syndrome (SARS)-CoV, Middle East respiratory syndrome (MERS)-CoV, and SARS-CoV-2. These viruses are responsible for SARS, MERS, and CoV disease 2019 (COVID-19), respectively. A variety of diagnostic techniques, including chest X-rays, computer tomography (CT) scans, analysis of viral nucleic acids, proteins, or whole virions, and host antibody detection using serological assays have been developed for the detection of these viruses. In this review, we discuss conventional serological tests, such as enzyme-linked immunosorbent assay (ELISA), western blot (WB), immunofluorescence assay (IFA), lateral flow immunoassay (LFIA), and chemiluminescence immunoassay (CLIA), as well as biosensor-based assays that have been developed for diagnosing HCoV-associated diseases since 2003, with an in-depth focus on COVID-19.

Laboratory detection methods for the human coronaviruses.

Coronaviruses are a group of envelop viruses which lead to diseases in birds and mammals as well as human. Seven coronaviruses have been discovered in humans that can cause mild to lethal respiratory tract infections. HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1 are the low-risk members of this family and the reason for some common colds. Besides, SARS-CoV, MERS-CoV, and newly identified SARS-CoV-2, which is also known as 2019-nCoV, are the more dangerous viruses. Due to the rapid spread of this novel coronavirus and its related disease, COVID-19, a reliable, simple, fast, and low-cost detection method is necessary for patient diagnosis and tracking worldwide. Human coronaviruses detection methods were classified and presented in this article. The laboratory detection techniques include RT-PCR, RT-LAMP, electrochemical and optical biosensors for RNA detection, and whole virus or viral proteins detection assays.

A hybrid scaffold of gelatin glycosaminoglycan matrix and fibrin as a carrier of human corneal fibroblast cells.

A hybrid scaffold of gelatin-glycosaminoglycan matrix and fibrin (FGG) has been synthesized to improve the mechanical properties, degradation time and cell response of fibrin-like scaffolds. The FGG scaffold was fabricated by optimizing some properties of fibrin-only gel and gelatin-glycosaminoglycan (GG) scaffolds. Mechanical analysis of optimized fibrin-only gel showed the Young module and tensile strength of up to 72 and 121 KPa, respectively. Significantly, the nine-fold increase in the Young modulus and a seven-fold increase in tensile strength was observed when fibrin reinforced with GG scaffold. Additionally, the results demonstrated that the degradation time of fibrin was enhanced successfully up to 7 days which was much longer time compared to fibrin-only gel with 38 h of degradation time. More than 45% of FGG initial mass was preserved on day 7 in the presence of aprotinin. Human corneal fibroblast cells (HCFCs) were seeded on the FGG, fibrin-only gel and GG scaffolds for 5 days. The FGG scaffold showed excellent cell viability over 5 days, and the proliferation of HCFCs also increased significantly in comparison with fibrin-only gel and GG scaffolds. The FGG scaffold illustrates the great potential to use in which appropriate stability and mechanical properties are essential to tissue functionality.

Bioengineering Approaches for Corneal Regenerative Medicine.

BACKGROUND: Since the cornea is responsible for transmitting and focusing light into the eye, injury or pathology affecting any layer of the cornea can cause a detrimental effect on visual acuity. Aging is also a reason for corneal degeneration. Depending on the level of the injury, conservative therapies and donor tissue transplantation are the most common treatments for corneal diseases. Not only is there a lack of donor tissue and risk of infection/rejection, but the inherent ability of corneal cells and layers to regenerate has led to research in regenerative approaches and treatments. METHODS: In this review, we first discussed the anatomy of the cornea and the required properties for reconstructing layers of the cornea. Regenerative approaches are divided into two main categories; using direct cell/growth factor delivery or using scaffold-based cell delivery. It is expected delivered cells migrate and integrate into the host tissue and restore its structure and function to restore vision. Growth factor delivery also has shown promising results for corneal surface regeneration. Scaffold-based approaches are categorized based on the type of scaffold, since it has a significant impact on the efficiency of regeneration, into the hydrogel and non-hydrogel based scaffolds. Various types of cells, biomaterials, and techniques are well covered. RESULTS: The most important characteristics to be considered for biomaterials in corneal regeneration are suitable mechanical properties, biocompatibility, biodegradability, and transparency. Moreover, a curved shape structure and spatial arrangement of the fibrils have been shown to mimic the corneal extracellular matrix for cells and enhance cell differentiation. CONCLUSION: Tissue engineering and regenerative medicine approaches showed to have promising outcomes for corneal regeneration. However, besides proper mechanical and optical properties, other factors such as appropriate sterilization method, storage, shelf life and etc. should be taken into account in order to develop an engineered cornea for clinical trials.

Construction of 3D fibrous PCL scaffolds by coaxial electrospinning for protein delivery.

In this study, a three-dimensional tablet-like porous scaffold, comprising core-shell fibers to host proteins inside the core, was developed. The fabrication method involved the novel combination of coaxial and wet electrospinning in a single setting. Poly (ε-caprolactone) was chosen as the based polymer and bovine serum albumin was used as a model protein. These 3D tablet-like scaffolds exhibited adequate porosity and suitable pore size for cell culture and cell infiltration, in addition to appropriate mechanical properties for cartilage tissue engineering. The effects of different parameters on the behavior of the system have been studied and the 3D scaffold based on the core-shell fiber was compared with that based on the matrix fiber. The core-shell structure showed superior performance in comparison to the matrix structure by sustaining protein release kinetics at least for 12 days in PBS. The results from in vitro cell cytotoxicity study revealed that the presented scaffold was biocompatible and non-toxic. Coaxial electrospinning was shown to be a versatile technique in achieving the delivery of biochemical signals in a controlled manner for the regeneration of cartilage. These 3D tablet-like PCL scaffolds incorporated with protein solutions are engineered systems that closely mimic the characteristics of cartilage tissue.

Stereolithography 3D Bioprinting Method for Fabrication of Human Corneal Stroma Equivalent.

3D bioprinting technology is a promising approach for corneal stromal tissue regeneration. In this study, gelatin methacrylate (GelMA) mixed with corneal stromal cells was used as a bioink. The visible light-based stereolithography (SLA) 3D bioprinting method was utilized to print the anatomically similar dome-shaped structure of the human corneal stroma. Two different concentrations of GelMA macromer (7.5 and 12.5%) were tested for corneal stroma bioprinting. Due to high macromer concentrations, 12.5% GelMA was stiffer than 7.5% GelMA, which made it easier to handle. In terms of water content and optical transmittance of the bioprinted scaffolds, we observed that scaffold with 12.5% GelMA concentration was closer to the native corneal stroma tissue. Subsequently, cell proliferation, gene and protein expression of human corneal stromal cells encapsulated in the bioprinted scaffolds were investigated. Cytocompatibility in 12.5% GelMA scaffolds was observed to be 81.86 and 156.11% at day 1 and 7, respectively, which were significantly higher than those in 7.5% GelMA scaffolds. Elongated corneal stromal cells were observed in 12.5% GelMA samples after 7 days, indicating the cell attachment, growth, and integration within the scaffold. The gene expression of collagen type I, lumican and keratan sulfate increased over time for the cells cultured in 12.5% GelMA scaffolds as compared to those cultured on the plastic tissue culture plate. The expression of collagen type I and lumican were also visualized using immunohistochemistry after 28 days. These findings imply that the SLA 3D bioprinting method with GelMA hydrogel bioinks is a promising approach for corneal stroma tissue biofabrication.

Developing hyaluronic acid microgels for sustained delivery of platelet lysate for tissue engineering applications.

Platelet lysate (PL), a blood product that contains high concentrations of growth factors (GFs), can be considered as a cost-effective source of multiple GFs. In this study, hyaluronic acid (HA) based microgels were developed for delivery of PL proteins. Spherical microgel were prepared using a water in oil emulsion method. First, hyaluronic acid was grafted with tyramine groups, after which prepared microdroplets were crosslinked via an enzymatic reaction in the presence of hydrogen peroxide and horseradish peroxidase. Because of electrostatic interactions, these microgels are promising carriers for positively charged proteins entrapment like most of the GFs. When microgels are incubated in PL solution, protein loading takes place which is mainly governed by nonspecific adsorption of plasma proteins. Although this hampered loading efficiency, loading could be increased by repeated washing and incubation steps. The loaded microgels presented a sustained release of PL growth factors for a period of two weeks. When PL enriched microgels were embedded in a HA bulk hydrogel, cell proliferation was higher compared to constructs without microgels. These findings suggest that the developed microgels are a potential candidate for sustained delivery of PL growth factors and present a solution to the issue of their short half-lives in vivo.

3D simulation of solutes concentration in urinary concentration mechanism in rat renal medulla.

In this work, a mathematical model was developed to simulate the urinary concentration mechanism. A 3-D geometry was derived based on the detail physiological pictures of rat kidney. The approximate region of each tubule was obtained from the volume distribution of structures based on Walter Pfaller's monograph and Layton's region-based model. Mass and momentum balances were applied to solve for the change in solutes concentration and osmolality. The osmolality of short and long descending nephrons at the end of the outer medulla was obtained to be 530 mOsmol/kgH2O and 802 mOsmol/kgH2O, respectively, which were in acceptable agreement with experimental data. The fluid osmolality of the short and long ascending nephrons was also compatible with experimental data. The osmolality of CD fluid at the end of the inner medulla was determined to be 1198 mOsmol/kgH2O which was close the experimental data (1216 ±â€¯118). Finally, the impact of the position of each tubule on the fluid osmolality and solutes concentration were obvious in the results; for example, short descending limb a1, which is the closest tubule to the collecting duct, had the highest urea concentration in all tubules. This reflects the important effect of the 3D modeling on the precise analysis of urinary concentration mechanism.

An injectable platelet lysate-hyaluronic acid hydrogel supports cellular activities and induces chondrogenesis of encapsulated mesenchymal stem cells.

Developing scaffolds that can provide cells and biological cues simultaneously in the defect site is of interest in tissue engineering field. In this study, platelet lysate (PL) as an autologous and inexpensive source of growth factors was incorporated into a cell-laden injectable hyaluronic acid-tyramine (HA-TA) hydrogel. Subsequently, the effect of platelet lysate on cell attachment, viability and differentiation of human mesenchymal stem cell (hMSCs) toward chondrocytes was investigated. HA-TA conjugates having a degree of substitution of 20 TA moieties per 100 disaccharide units were prepared and crosslinked in the presence of horseradish peroxidase and low concentrations of hydrogen peroxide. The storage moduli of the gels ranged from 500 to 2000 Pa and increased with increasing polymer concentration. In contrast to a retained round shape of the cells when using pure HA-TA hydrogel, the hMSCs attached and spread out in PL enriched matrix. The enrichment of hMSCs laden HA-TA hydrogels with PL induced a cartilage like extra cellular matrix deposition in vitro. The hMSCs increasingly deposited collagen type II and proteoglycans over time. The deposition of the new extracellular matrix (ECM) is simultaneous with gel degradation and resulted ultimately in the formation of a tough dense matrix. These findings demonstrate the potential of injectable HA-TA-PL hydrogel as a cell delivery system for cartilage regeneration. STATEMENT OF SIGNIFICANCE: Cartilage tissue has limited ability to self-repair because of its avascular nature. To have an efficient cartilage tissue regeneration, we combined platelet lysate (PL), as an autologous and inexpensive source of growth factors, with an injectable hyaluronic acid tyramine (HA-TA) hydrogel scaffold. Platelet lysate had a vital role in supporting human mesenchymal stem cells (hMSCs) activities, like cell attachment, viability and proliferation in the 3D hydrogel structure. Also, the hMSCs encapsulated HA-TA induced hyaline cartilage generation when placed in chondrogenic differentiation medium. This study introduces a new system for cartilage tissue engineering, which can be injected in a minimally invasive manner and is rich with patient's own growth factors and biological cues.

Facilitation of transscleral drug delivery by drug loaded magnetic polymeric particles.

A unique method was used to facilitate ocular drug delivery from periocular route by drug loaded magnetic sensitive particles. Injection of particles in periocular space along the eye axis followed by application of magnetic field in front of the eye would trigger the magnetic polymeric particles to move along the direction of magnetic force and reside against the outer surface of the sclera. This technique prevents removal of drug in the periocular space, observed in conventional transscleral drug delivery systems and hence higher amount of drug can enter the eye in a longer period of time. The experiments were performed by fresh human sclera and an experimental setup. Experimental setup was designed by side by side diffusion cell and hydrodynamic and thermal simulation of the posterior segment of the eye were applied. Magnetic polymeric particles were synthesized by alginate as a model polymer, iron oxide nanoparticles as a magnetic agent and diclofenac sodium as a model drug and characterized by SEM, TEM, DLS and FT-IR techniques. According to the SEM images, the size range of particles is around 60 to 800nm. The results revealed that the cumulative drug transfer from magnetic sensitive particles across the sclera improves by 70% in the presence of magnetic field. The results of this research show promising method of drug delivery to use magnetic properties to facilitate drug delivery to the back of the eye.

Agitation increases expansion of cord blood hematopoietic cells and promotes their differentiation into myeloid lineage.

Mechanical stress caused by agitation is one of the factors that can affect hematopoietic stem cell expansion in suspension bioreactors. Therefore, we have investigated the effects of agitation on umbilical cord blood hematopoietic stem cell (UCB-HSC) growth and differentiation. A comparison was made between various agitation rates (20, 40 and 60 rpm) in spinner-flask and cells cultured in glass petri dish as a static culture. Moreover, the fluid dynamic at various agitation rates of spinner-flask was analyzed to determine shear stress. The spinner-flask contained a rotational moving mixer with glass ball and was kept in tissue culture incubator. To reduce consumption of cytokines, UCB-serum was used which widely decreased the costs. Our results determined that, agitation rate at 40 rpm promoted UCB-HSCs expansion and their colony forming potential. Myeloid progenitors were the main type of cells at 40 rpm agitation rate. The results of glucose consumption and lactic acid production were in complete agreement with colony assay and expansion data and indicated the superiority of culture in spinner-flask when agitated at 40 rpm over to other agitation speeds and also static culture. Cell viability and colony count was affected by changing the agitation speed. We assume that changes in cell growth resulted from the effect of shear stress directly on cell viability, and indirectly on signaling pathways that influence the cells to differentiate.

Computational modeling of drug distribution in the posterior segment of the eye: effects of device variables and positions.

A computational model was developed to simulate drug distribution in the posterior segment of the eye after intravitreal injection and ocular implantation. The effects of important factors in intravitreal injection such as injection time, needle gauge and needle angle on the ocular drug distribution were studied. Also, the influences of the position and the type of implant on the concentration profile in the posterior segment were investigated. Computational Fluid Dynamics (CFD) calculations were conducted to describe the 3D convective-diffusive transport. The geometrical model was constructed based on the human eye dimensions. To simulate intravitreal injection, unlike previous studies which considered the initial shape of the injected drug solution as a sphere or cylinder, the more accurate shape was obtained by level-set method in COMSOL. The results showed that in intravitreal injection the drug concentration profile and its maximum value depended on the injection time, needle gauge and penetration angle of the needle. Considering the actual shape of the injected solution was found necessary to obtain the real concentration profile. In implant insertion, the vitreous cavity received more drugs after intraocular implantation, but this method was more invasive compared to the periocular delivery. Locating the implant in posterior or anterior regions had a significant effect on local drug concentrations. Also, the shape of implant influenced on concentration profile inside the eye. The presented model is useful for optimizing the administration variables to ensure optimum therapeutic benefits. Predicting and quantifying different factors help to reduce the possibility of tissue toxicity and to improve the treatment efficiency.

Molecularly imprinted polydopamine nano-layer on the pore surface of porous particles for protein capture in HPLC column.

Bio-inspired Human Serum Albumin (HSA) imprinted polydopamine nano-layer was produced through oxidative polymerization of dopamine on the pore surface of HSA modified porous silica particles. The coating thickness was controlled by the reaction time and thereby varied within 0-12 nm. The samples were characterized by elemental analysis, FT-IR, DSC, SEM, TEM, TGA, physisorption and thermoporometry. The characterization confirmed the success of evolution and deposition of polydopamine layer on the silica pore surface. Batch rebinding experiment showed that the molecularly imprinted polymer (MIP) with 8.7 nm coating thickness, in comparison with the thinner and thicker coatings, displays the highest uptake of the target protein. The chromatographic evaluation of the materials packed in HPLC columns showed that the HSA imprinted polydopamine offers good mechanical stability and retains practically all the target protein from an HSA solution or human plasma. Affinity of the imprinting column was examined by using Bovine Serum Albumin (BSA) and Immunoglobulin G (IgG) as competitive proteins. The results showed that the template, HSA, was the most adsorbed protein by the imprinted polydopamine layer.

Design of pH-responsive nanoparticles of terpolymer of poly(methacrylic acid), polysorbate 80 and starch for delivery of doxorubicin.

This work focused on the design of new pH-responsive nanoparticles for controlled delivery of anticancer drug doxorubicin (Dox). Nanoparticles of poly(methacrylic acid)-polysorbate 80-grafted starch (PMAA-PS 80-g-St) were synthesized by using a one-pot method that enabled simultaneous grafting of PMAA and PS 80 onto starch and nanoparticle formation in an aqueous medium. The particles were characterized by FTIR, (1)H NMR, TEM, DLS, and potentiometric titration. Dox loading and in vitro release from the nanoparticles were investigated. The FTIR and (1)H NMR confirmed the chemical composition of the graft terpolymer. The nanoparticles were relatively spherical with narrow size distribution and porous morphology. They exhibited pH-dependent swelling in a physiological pH range. The particle size and magnitude of phase transition were dependent on polymer composition and formulation parameters such as concentrations of surfactant and cross-linking agent and total monomer concentration. The nanoparticles with optimized compositions showed high loading capacity for Dox and sustained Dox release. The results suggest that the new pH-responsive terpolymer nanoparticles are useful in controlled drug delivery.

Retina-choroid-sclera permeability for ophthalmic drugs in the vitreous to blood direction: quantitative assessment.

PURPOSE: To determine the outward permeability of retina-choroid-sclera (RCS) layer for different ophthalmic drugs and to develop correlations between drug physicochemical properties and RCS permeability. METHODS: A finite volume model was developed to simulate pharmacokinetics in the eye following drug administration by intravitreal injection. The RCS permeability was determined for 32 compounds by best fitting the drug concentration-time profile obtained by simulation with previously reported experimental data. Multiple linear regression was then used to develop correlations between best fit RCS permeability and drugs physicochemical properties. RESULTS: The RCS drug permeabilities had values that ranged over 3 × 10(-6) m/s. Regression analysis for hydrophilic compounds showed that more than 92% of the variation in permeability values can be explained by correlative models of drug properties that include logarithm of the octanol-water partition coefficient (LogP), protein binding (PB), number of hydrogen bond acceptors (HBA), hydrogen bond donors (HBD), polar surface area (PSA) and dissociation constant (pKa) as independent variables. Regression analysis for lipophilic compounds showed that no significant correlation can be found between just physicochemical properties and RCS permeability. CONCLUSION: Using the RCS permeability obtained from this study for different drugs, one can predict pharmacokinetics of intravitreal drug delivery systems such as solid implants or colloidal systems. Furthermore, the developed correlations between RCS permeability and physicochemical properties of drugs are useful in early drug development by predicting RCS permeability and drug concentration in the vitreous without experimental data.