Biocompatible Polymers and Processing Techniques in Drug Delivery and Tissue Engineering

In situ forming hydrogels of new amino hyaluronic acid/benzoyl-cysteine derivatives as potential scaffolds for cartilage regeneration

A new chemical strategy is described to link ethylenediamino (EDA) groups to primary hydroxyl groups of hyaluronic acid (HA) and the obtained derivatives have been characterized by 1H-NMR and 13C-NMR analyses. Such HA–EDA derivatives have been exploited to control the functionalization degree in benzoyl-cysteine (BC) groups, chosen as moieties able to allow both self-assembling in aqueous media and an oxidative crosslinking. In particular, the kinetics of oxidation of thiol groups in HA–EDA–BC derivatives has been studied in Dulbecco's Phosphate Buffer Solution (DPBS) pH 7.4 by colorimetric assays and rheological measurements. Mechanical properties of chemical hydrogels obtained after oxida…

Nanofibrillar scaffold resists to bile and urine action: experiences in pigs

Biomaterial-based-scaffolds’ functions are to replace anatomical and functional features loss of an injured tissue. They can replace native tissue after their reabsorption. Material and methods. In our experimental procedures we utilized the PHEA-PLA+PCL scaffold in 2 female pigs to assess its resistance to bile and urine. Results. Both pigs survived to surgical procedures. After a month fibres appeared unchanged in term of form and dimension at electronic microscopy. Cells and ECM factors were founded inside the scaffold in a microscopical evaluation. Conclusion. Planar and tubular scaffolds were colonized by cells and extracellular matrix elements. The study conducted on pig suggested tha…

Interpenetrating composite biomaterials of hyaluronic acid derivatives and silk fibroin

pH-sensitive hydrogel based on a novel photocross-linkable copolymer.

A pH sensitive hydrogel has been prepared by a UV irradiation technique. Starting polymer was the PHM (poly hydroxyethylaspartamide methacrylated) obtained from polyaspartamide (PHEA) partially derivatized with methacrylic anhydride (MA). This new copolymer has been further derivatized with succinic anhydride (SA) to obtain PHM-SA that has been cross-linked by UV irradiation to form a pH sensitive hydrogel. The network, recovered after washing as a powder, has been been characterized by FT-IR spectrophotometry and particle size distribution analysis. Moreover, to have information about water affinity of the prepared sample, swelling measurements have been carried out in aqueous media mimick…

Biocompatible hydrogels based on hyaluronic acid cross-linked with a polyaspartamide derivative as delivery systems for epithelial limbal cells.

The aim of this work was to evaluate the potential use of hydrogels based on hyaluronic acid (HA) chemically cross-linked with α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) as substitutes for the amniotic membrane able to release limbal cells for corneal regeneration. Hydrogels, shaped as films, with three different molar ratios (X) between PHEA-EDA and HA (X = 0.5, 1.0 and 1.5) have been investigated. First, it has been evaluated their swelling ability, hydrolytic resistance in simulated physiological fluid and cell compatibility by using human dermal fibroblasts chosen as a model cell line. Then adhesion studies in comparison with collagen gel, have been pe…

POLYSACCHARIDE-POLYAMINOACID HYDROGEL FILMS FOR POTENTIAL CORNEAL CELL RELEASE

COMPOSITE NANOPARTICLES FOR I.V. DRUG ADMINISTRATION

In-situ forming gel-like depot of a polyaspartamide-polylactide copolymer for once a week administration of Sulpiride

Abstract Objectives An in-situ forming gel-like depot, prepared by using an appropriate polyaspartamide-polylactide graft copolymer, has been employed to release in a sustained way sulpiride. Methods α,β-poly(N-2-hydroxyethyl)-D,L-aspartamide-g-polylactic acid (PHEA-g-PLA) has been used as a polymer component. Its physicochemical properties make possible to dissolve it in N-methyl-2-pyrrolidone, with the obtainment of a solution able to form a gel-like depot once injected into a physiological medium. Cell compatibility of PHEA-g-PLA depot has been investigated, using murine dermal fibroblasts as cell model. 3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazo…

Composite nanoparticles based on hyaluronic acid chemically cross-linked with alpha,beta-polyaspartylhydrazide.

In this paper, new composite nanoparticles based on hyaluronic acid (HA) chemically cross-linked with alpha,beta polyaspartylhydrazide (PAHy) were prepared by the use of a reversed-phase microemulsion technique. HA-PAHy nanoparticles were characterized by FT-IR spectroscopy, confirming the occurrence of the chemical cross-linking, dimensional analysis, and transmission electron micrography, showing a sub-micrometer size and spherical shape. Zeta potential measurements demonstrated the presence of HA on the nanoparticle surface. A remarkable affinity of the obtained nanoparticles toward aqueous media that simulate some biological fluids was found. Stability studies showed the absence of chem…

A new hyaluronic acid pH sensitive derivative obtained by ATRP for potential oral administration of proteins

Atom transfer radical polymerization (ATRP) has been successfully employed to obtain a new derivative of hyaluronic acid (HA) able to change its solubility as a function of external pH and then to be potentially useful for intestinal release of bioactive molecules, included enzymes and proteins. In particular, a macroinitiator has been prepared by linking 2-bromo-2-methypropionic acid (BMP) to the amino groups of ethylenediamino derivative of tetrabutyl ammonium salt of HA (HA-TBA-EDA). This macroinititor, named HA-TBA-EDA-BMP has been used for the ATRP of sodium methacrylate (MANa) using a complex of Cu(I) and 2,2'-bipyridyl (Byp) as a catalyst. The resulting copolymer, named HA-EDA-BMP-MA…

Bioactive Scaffolds Based on Amine-Functionalized Gellan Gum for the Osteogenic Differentiation of Gingival Mesenchymal Stem Cells

With the aim to produce a cellularized construct for the guided bone regeneration of dento-alveolar defects, here we produce a porous scaffold using an amine derivative of gellan gum to host gingival mesenchymal stem cells (GMSCs) and allow their osteochondral differentiation. Three derivatives were produced by using the same synthetic procedure, and the viscoelastic properties of their aqueous dispersions were investigated and compared to those of the native polysaccharide to choose the derivative with suitable properties for the scaffold production. Freeze-drying was used to obtain a porous sponge that can be rehydrated with the cells’ suspension to produce an implantable cell containing …

Effect of alkyl derivatization of gellan gum during the fabrication of electrospun membranes

Electrospun nanofibers based on polysaccharides represent a consolidated approach in Tissue Engineering and Regenerative Medicine (TERM) and nanomedicine as a drug delivery system (DDS). In this work, two chemical derivatives of a low molecular weight gellan gum (96.7 kDa) with aliphatic pendant tails were processed by electrospinning technique into non-woven nanofibrous mats. In order to generate spinnable blends, it was necessary to associate poly vinyl alcohol (PVA). The relationships between the physicochemical properties and the processability via electrospinning technique of gellan gum alkyl derivatives (GG-C8 and GG-C12 having a degree of alkyl chain derivatization of 17 mol % and 1…

Hybrid Gold/Silica/Quantum-Dots supramolecular-nanostructures encapsulated in polymeric micelles as potential theranostic tool for targeted cancer therapy

Abstract Efficient theranostic tools are today more and more frequently represented by the nano-sized systems. In this paper, polymeric micelles were produced and exploited to encapsulate both an antitumor drug (Doxorubicin) and gold core–shell quantum dots nanoparticles (Au-SiO2/QDs). α,β-poly(N-hydroxyethyl)- dl -aspartamide (PHEA) was functionalized with lipoic acid (LA), polyethylenglycol (PEG), and folic acid (FA) pendant moieties to obtain a synthetic derivative (PHEA-LA-PEG-FA) able to self assemble in aqueous medium giving rise to the formation of polymeric micelles exposing on their surface both targeting groups (FA) and hydrophilic chains (PEG). The drug carrying ability of PHEA-L…

HYDROGELS OF HYALURONIC ACID AND alpha, beta-POLYASPARTYLHYDRAZIDE AND THEIR BIOMEDICAL AND PHARMACEUTICAL USES

Compositions and products based on the chemical crosslinking of hyaluronic acid with a polyfunctional polymer having a protein-like structure, bearing hydrazido pendent groups along the polymeric chain. The polymer is preferably, alpha-beta-polyaspartylhydrazide, a biocompatible macromolecule. The materials obtained after crosslinking, specifically hydrogels, undergo a reduced chemical and enzymatic degradation, unlike the starting hyaluronic acid, and they can be used to prepare systems for applications in the biomedical and pharmaceutical field.

Novel Biocompatible Cationic Copolymers Based on Polyaspartylhydrazide Being Potent as Gene Vector on Tumor Cells

Introduction. The reaction between !,"-poly(aspartylhydrazide) (PAHy), a water soluble synthetic polymer and 3-(carboxypropyl)trimethyl-ammonium chloride (CPTACl) produced copolymers bearing permanent positive charges (PAHy–CPTA) with molecular weight of 10 kDa and PAHy–CPTA copolymers differing in positive charge amount (18–58%) were chosen for biological investigations. Materials and methods. Biophysical properties of DNA/PAHy–CPTA polyplexes were evaluated in terms of DNA condensation, zeta potential and size distribution. Cytotoxicity studies on Neuro2A murine neuroblastoma cells evidenced absence of toxicity of these copolymers up to 300 2g/ml unlike linear polyethylenimine (LPEI) that…

TABLET DI ACIDO IALURONICO FUNZIONALIZZATO CON CATENE IDROFOBICHE PER IL RILASCIO LOCOREGIONALE DI PACLITAXEL

NEW HYALURONAN-BASED HYDROGEL AS RESOBABLE ANTIBACTERIAL COATING FOR PREVENTION OF IMPLANT-RELATED INFECTION IN ORTHOPAEDICS

In situ crosslinkable hyaluronan hydrogels for tissue engineering

We describe the development of an injectable, cell-containing hydrogel that supports cell proliferation and growth to permit in vivo engineering of new tissues. Two thiolated hyaluronan (HA) derivatives were coupled to four alpha,beta-unsaturated ester and amide derivatives of poly(ethylene glycol) (PEG) 3400. The relative chemical reactivity with cysteine decreased in the order PEG-diacrylate (PEGDA)>>PEG-dimethacrylate>PEG-diacrylamide>PEG-dimethacrylamide. The 3-thiopropanoyl hydrazide derivative (HA-DTPH) was more reactive than the 4-thiobutanoyl hydrazide, HA-DTBH. The crosslinking of HA-DTPH with PEGDA in a molar ratio of 2:1 occurred in approximately 9 min, suitable for an in situ cr…

Uptake of silica covered Quantum Dots into living cells: Long term vitality and morphology study on hyaluronic acid biomaterials

Quantum Dots (QDs) are promising very bright and stable fluorescent probes for optical studies in the biological field but water solubility and possible metal bio-contamination need to be addressed. In this work, a simple silica-QD hybrid system is prepared and the uptake in bovine chondrocytes living cells without any functionalization of the external protective silica shield is demonstrated. Moreover, long term treated cells vitality (up to 14 days) and the transfer of silica-QDs to the next cell generations are here reported. Confocal fluorescence microscopy was also used to determine the morphology of the so labelled cells and the relative silica-QDs distribution. Finally, we employ sil…

Scaffolds of Hyaluronan crosslinked with alpha,beta-polyaspartylhydrazide for uses in tissue engineering field

Innovative polymer - and lipid - based nanotechnologies for drug and nucleic acid delivery

NANODEVICES FOR THE TARGETED DRUG AND GENE DELIVERY

Ciprofloxacin releasing gellan gum/polydopamine based hydrogels with near infrared activated photothermal properties.

Abstract In this work, with the aim to obtain a wound dressing hydrogel, an amine derivative of gellan gum was crosslinked in the presence of 4arm-polyethylenglycole-vinylsulfone. Through this easy and reproducible chemical procedure, a hydrogel with advanced elastic properties and hydrolytic resistance under physiological conditions was obtained. The incorporation of different quantities of polydopamine in the gelling solutions allows to obtain different hydrogels with marked photothermal properties when irradiated with a laser in the near infrared at 810 nm. The organic nanoparticles, reacting with the amino groups of the polysaccharide derivative, contribute to increase the storage modul…

Hyaluronic Acid-g-Copolymers: Synthesis, Properties, and Applications

The aim of this chapter is to review hyaluronic acid (HA) graft copolymers focusing in the description of chemical strategies employed for their synthesis, characterization procedures, and applications in biomedical and pharmaceutical field. Usually biocompatible synthetic polymers and peptides with therapeutic activity are grafted to HA to modify in appropriate way the physicochemical properties of the starting polysaccharide for a specific purpose and at the same time to exploit its biological role, biocompatibility, and targeting ability toward cells with receptors for HA. The use of such HA graft copolymers in the production of nanocarriers or hydrogels for modified drug release and sca…

New injectable depot systems based on alpha,beta-poly(N-2-hydroxyethyl)-D,L-aspartammide copolymers

NANOPARTICLES OBTAINED FROM HYALURONIC ACID AND POLYASPARTYLHYDRAZIDE

Polybutylene Succinate Processing and Evaluation as a Micro Fibrous Graft for Tissue Engineering Applications

A microfibrous tubular scaffold has been designed and fabricated by electrospinning using poly (1,4-butylene succinate) as biocompatible and biodegradable material. The scaffold morphology was optimized as a small diameter and micro-porous conduit, able to foster cell integration, adhesion, and growth while avoiding cell infiltration through the graft’s wall. Scaffold morphology and mechanical properties were explored and compared to those of native conduits. Scaffolds were then seeded with adult normal human dermal fibroblasts to evaluate cytocompatibility in vitro. Haemolytic effect was evaluated upon incubation with diluted whole blood. The scaffold showed no delamination, and mech…

Biomaterials for Biotechnological and Pharmaceutical application

An asymmetric electrospun membrane for the controlled release of ciprofloxacin and FGF-2: Evaluation of antimicrobial and chemoattractant properties.

Here, an asymmetric double-layer membrane has been designed and fabricated by electrospinning as a tool for a potential wound healing application. A hydrophobic layer has been produced by using a polyurethane-polycaprolactone (PU-PCL) copolymer and loaded with the antibacterial ciprofloxacin whereas an ion responsive hydrophilic layer has been produced by using an octyl derivative of gellan gum (GG-C8) and polyvinyl alcohol (PVA) and loaded with the growth factor FGF-2. This study investigated how the properties of this asymmetric membrane loaded with actives, were influenced by the ionotropic crosslinking of the hydrophilic layer. In particular, the treatment in DPBS and the crosslinking i…

Antibacterial hydrogel and use thereof in orthopedics.

HYALURONIC ACID DERIVATIVE MICELLES AS OCULAR PLATFORMS TO DRUG RELEASE AND CORNEAL PERMEATION

In traditional ocular formulations, only small amount of the administered drug penetrates the cornea to reach the intraocular tissue. One approach to improve the drug ocular bioavailability was to develop colloidal drug delivery systems. Polymeric micelles seem to be very promising for their capacity to dissolve a variety of hydrophobic drugs by enhancing their water solubility and so their bioavailability. They are able to increase ocular drug permeability due to interact with the complex corneal structure. Considering the advantages to use mucoadhesive polymer to increase drug residence time on the ocular surface, the aim of this work was to prepare hyaluronic acid-based micelles as a pla…

CONTROLLED RELEASE OF IgG BY NOVEL UV INDUCED POLYSACCHARIDE/POLY(AMINO ACID)HYDROGELS

The development of new protein and peptide drugs needs new delivery systems able to entrap such drugs in safe conditions without affecting their structure and biological activity. In this context, the present work reports a new approach to load IgG, used as a model of therapeutic proteins such as anti-TNF-alpha monoclonal antibodies, into a polymeric system able to release the entrapped IgG in a controlled manner. In particular, new polysaccharide/poly(amino acid) UV induced hydrogels are proposed as colon delivery systems for human IgG. The poly(amino acid), alpha,beta-poly[N-(2-hydroxyethyl)-D,L-aspartamide], has been functionalized with methacrylic anhydride, while the polysaccharide, in…

HYALURONIC ACID-graft-ELASTIN BASED SCAFFOLDS FOR POTENTIAL TISSUE ENGINEERING APPLICATIONS

IDROGELI DI ACIDO IALURONICO E alfa,beta-POLIASPARTILIDRAZIDE E LORO APPLICAZIONI IN CAMPO BIOMEDICO E FARMACEUTICO

Hyaluronic acid based microparticles for applications in regenerative medicine

Blend scaffolds with polyaspartamide/polyester structure fabricated via TIPS and their RGDC functionalization to promote osteoblast adhesion and proliferation

Target of this work was to prepare a RGDC functionalized hybrid biomaterial via TIPS technique to achieve a more efficient control of osteoblast adhesion and diffusion on the three-dimensional (3D) scaffolds. Starting from a crystalline poly(l-lactic acid) (PLLA) and an amorphous alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-d,l-aspartamide-graft-polylactic acid (PHEA-EDA-g-PLA) copolymer, blend scaffolds were characterized by an appropriate porosity and pore interconnection. The PHEA-EDA-PLA interpenetration with PLLA improved hydrolytic susceptibility of hybrid scaffolds. The presence of free amino groups on scaffolds allowed to tether the cyclic RGD peptide (RGDC) via Michael…

Hyaluronic acid based hydrogels for antibiotics and enzymes release: from academic research to industry

Conclusion: HA-g-PDLLA hydrogel is suitable to coat a prosthesis remaining adherent to it and distributing itself in the bone cavity. The hydrogel has been proven effective in a rabbit model of highly contaminated implant. In vivo studies have demonstrated how the intraoperative coating of implants with DAC is safe and feasible. HA-EDA-MA hydrogel is able to protect PEP from alteration during storage and it seems a good candidate for a potential once-daily oral formulation in the treatment of celiac disease.

NEW GENERATION OF BIOCOMPATIBLE GRAFT COPOLYMERS FOR THE PRODUCTION OF NANODEVICES

Perfluorocarbon functionalized hyaluronic acid derivatives as oxygenating systems for cell culture

A set of new hyaluronic acid (HA) derivatives was obtained by binding fluorinated oxadiazole (OXA) moieties to an amino derivative of the polysaccharide (HA-EDA). The obtained HA-EDA-OXA biomaterials are potentially able to improve oxygenation into a scaffold for tissue engineering purposes. The oxygen solubility in aqueous dispersions of the obtained derivatives showed that polymers were able to improve oxygen uptake and maintenance in the medium. The HA-EDA-OXA was employed to form a hydrogel in situ by reaction with a vinyl sulphone derivative of inulin, under physiological conditions. The influence of the presence of OXA moieties on the mechanical properties of the obtained hydrogels as…

Hyaluronic acid and alpha-elastin based hydrogel for three dimensional culture of vascular endothelial cells

Abstract The aim of this work was to demonstrate that employing a copolymer of hyaluronic acid and α-elastin (HA-EDA-g-α-elastin) is possible to produce a scaffold able to support the adhesion and growth of human vascular endothelial cells (HUVEC) thanks to its ability to incorporate and control the diffusion of vascular endothelial growth factor (VEGF). HA-EDA-g-α-elastin was crosslinked with low molecular weight hyaluronic acid (HALMW) to obtain a hydrogel that gives rise to the formation of three dimensional sponge after the freeze drying process. The physicochemical features the obtained material along with its ability to act as a support for the three dimensional culture of endothelial…

Dexamethasone dipropionate loaded nanoparticles of α-elastin-g-PLGA for potential treatment of restenosis.

A graft copolymer of α-elastin with poly(lactic-co-glycolic) acid (PLGA) has been synthesized and successfully employed to produce nanoparticles. Exploiting the known biological activity of α-elastin to promote the maintenance of smooth muscle cells (SMCs) contractile phenotype and the antiproliferative effect of glucocorticoids, the aim of this research was to produce drug-loaded nanoparticles suitable for potential treatment of restenosis. In particular, nanoparticles of α-elastin-g-PLGA with a mean size of 200 nm have been produced and loaded with dexamethasone dipropionate (10% w/w), chosen as a model drug that inhibits proliferation of vascular SMCs. These nanoparticles are able to pro…

Hyaluronic acid and beta cyclodextrins films for the release of corneal epithelial cells and dexamethasone

In this work we prepared hydrogels based on hyaluronic acid and β-cyclodextrins to sustain the release of both corneal epithelial cells and dexamethasone. This steroid is administered as eye drops several times per day to reduce the risk of rejection in the post operative period after the cornea transplantation and cell release techniques. Hydrogels were produced by crosslinking an amino derivative of hyaluronic acid, with the divinyl sulfone derivative of β-cyclodextrins, this last employed as a crosslinker and solubilizing agent. Drug release studies revealed that dexamethasone containing samples are able to extend the release of this drug for at least five days. Biological studies, condu…

Polycations based on polyasparthylhydrazide for gene therapy

Photothermal nanofibrillar membrane based on hyaluronic acid and graphene oxide to treat Staphylococcus aureus and Pseudomonas aeruginosa infected wounds.

Here we reported the fabrication of an electrospun membrane based on a hyaluronic acid derivative (HA-EDA) to be used as a bandage for the potential treatment of chronic wounds. The membrane, loaded with graphene oxide (GO) and ciprofloxacin, showed photothermal properties and light-triggered drug release when irradiated with a near-infrared (NIR) laser beam. Free amino groups of HA-EDA derivative allowed autocrosslinking of the elec- trospun membrane; thus, a substantial enhancement in the hydrolytic resistance of the patch was obtained. In vitro antibacterial activity studies performed on Staphylococcus aureus and Pseudomonas aeruginosa revealed that such electrospun membranes, due to the…

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic durgs

The topical route is the ideal way to release drugs to the eye. Unfortunately, the low ocular drug bioavailability associated with this route of administration, makes not very efficient the treatment of several ocular diseases. Nowadays, polymeric micelles occupy a significant role in the field of ocular drug delivery thanks to the advantages that they offer in comparison with the administration of drugs in the free form. Indeed, polymeric micelles are suitable for delivering hydrophobic drugs and they seem to be very promising in ocular drug delivery for their high kinetic and thermodynamic stability. Also, micellar systems are able to give a controlled drug release and to act as absorptio…

Microfibers of a Hyaluronic Acid Derivative to Mimic Blood Vessels

PHOTOCROSSLINKING OF DEXTRAN AND POLYASPARTAMIDE DERIVATIVES: A COMBINATION SUITABLE FOR COLON- SPECIFIC DRUG DELIVERY.

The aim of this study was to prepare and characterize novel hydrogels with polysaccharide–polyaminoacid structure, able to undergo an enzymatic hydrolysis in the colon and potentially useful for treating inflammatory bowel diseases (IBD). Starting materials were methacrylated dextran (DEX-MA) and methacrylated α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHM). These polymers were photocrosslinked by exposure of their aqueous solutions at 313 nm without photoinitiators. Different samples, shaped as microparticles, were obtained as a function of polymer concentration and irradiation time. FT-IR analysis confirmed the occurrence of a co-crosslinking between DEX-MA and PHM in all experimental con…

Injectable in situ forming microgels of hyaluronic acid-g-polylactic acid for methylprednisolone release

Abstract A hydrophobic derivative of hyaluronic acid (HA), obtained by grafting polylactic acid (PLA) to the polysaccharide, has been exploited to produce injectable in situ forming microgels. First of all, self assembling properties of HA-g-PLA copolymer have been evaluated by determining the critical aggregation concentration (CAC) value, then this copolymer has been dissolved in a mixture water/NMP 5:2 v/v with a concentration greater than CAC. When solutions at 1% or 2% w/v were injected into Dulbecco phosphate buffer solution (DPBS) pH 7.4, microgels promptly are formed. Their stability in DPBS pH 7.4 in the absence or in the presence of hyaluronidase and cell compatibility have been e…

AMPHIPHILIC GRAFT COPOLYMER OF HYALURONIC ACID AND POLYLACTIC ACID FOR PULMONARY DELIVERY OF AMPHOTERICIN B

ANTIBACTERIAL HYDROGEL AND USE THEREOF IN ORTHOPEDICS.

Double-Network-Structured Graphene Oxide-Containing Nanogels as Photothermal Agents for the Treatment of Colorectal Cancer.

Here, we reported the production of hyaluronic acid/polyaspartamide-based double-network nanogels for the potential treatment of colorectal carcinoma. Graphene oxide, thanks to the huge aromatic surface area, allows to easily load high amount of irinotecan (33.0% w/w) and confers to the system hyperthermic properties when irradiated with a near-infrared (NIR) laser beam. We demonstrate that the release of antitumor drug is influenced both by the pH of the external medium and the NIR irradiation process. In vitro biological studies, conducted on human colon cancer cells (HCT 116), revealed that nanogels are uptaken by the cancer cells and, in the presence of the antitumor drug, can produce a…

Microfibers and Nanoparticles with Controlled Dimensions of a Hyaluronic Acid Derivative

Microfluidics is defined as the technology that deals with the precise control and manipulation of small quantities of fluids constrained in micro-channels of small cross-sectional dimensions [1]. Microfluidics has recently emerged as a very promising route for the production of polymeric fibers at the micro and nanoscale, providing a fine control over fiber shape, size, chemical anisotropy and biological activity [2]. Furthermore, the ability to manipulate nanoliter volumes of liquid and to control mixing and reaction precisely, opens up the possibility of creating smart targeted drug delivery systems as nanoparticles, especially with uniform and narrow size distribution [3]. This work des…

Injectable in situ forming hydrogels based on natural and synthetic polymers for potential application in cartilage repair

In this work we prepared two new hyaluronic acid (HA) based in situ forming hydrogels for the potential treatment of articular cartilage damages. In particular the amino derivative of HA (HA-EDA) and its graft copolymer with α-elastin (HA-EDA-g-α-elastin) were crosslinked, in mild physiological conditions via Michael-type addition, with α,β-poly(N-2-hydroxyethyl)-dl-aspartamide (PHEA) derivatized with divinylsulfone (DV). The swelling and degradation profile of the obtained hydrogels as well as the metabolic activity of incorporated bovine articular chondrocytes were investigated. Histological analysis and scanning electron microscopy (SEM) were performed to analyze the morphology of cells …

Biocompatible Hydrogels Based on Hyaluronic Acid Cross-Linked with a Polyaspartamide Derivative as Delivery Systems for Epithelial Limbal Cells

A Fibrillar Biodegradable Scaffold for Blood Vessels Tissue Engineering

In recent years there has been a growing interest for the development of tubular scaffolds employed to assist the replacement of small blood vessels. Materials designed for this purpose need to be biodegradable, have good mechanical properties and improve cell adhesion, proliferation and differentiation. To obtain biomaterials with these properties, electrospinning seems to be one of the most useful technique. Several biodegradable synthetic polymers or constituents of the extracellular matrix (ECM) have been electrospun showing optimal mechanical properties and biodegradability. However, such polymers are lacking in versatile chemical structure affordable to immobilize growth factors or ch…

Sintesi di nuovi copolimeri graft di acido ialuronico,polietilenglicole ed acido lattico

Heparin functionalized polyaspartamide/polyester scaffold for potential blood vessel regeneration

An interesting issue in tissue engineering is the development of a biodegradable vascular graft able to substitute a blood vessel and to allow its complete regeneration. Here, we report a new scaffold potentially useful as a synthetic vascular graft, produced through the electrospinning of α,β-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide-graft-polylactic acid (PHEA-EDA-g-PLA) in the presence of polycaprolactone (PCL). The scaffold degradation profile has been evaluated as well as the possibility to bind heparin to electrospun fibers, being it a known anticoagulant molecule able to bind growth factors. In vitro cell compatibility has been investigated using human vascular e…

Photo-Cross-Linked Hydrogels with Polysaccharide−Poly(amino acid) Structure:  New Biomaterials for Pharmaceutical Applications

The aim of this work has been the preparation and characterization of novel hydrogels with polysaccharide-poly(amino acid) structure having suitable physicochemical properties for pharmaceutical applications. In the first step, hyaluronic acid (HA) and alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) have been derivatized with methacrylic anhydride (AMA), thus obtaining HA-AMA and PHM derivatives, respectively. In the second step, aqueous solutions of both these derivatives have been irradiated at 313 nm to obtain chemical hydrogels. The hydrogel obtained by irradiating for 15 min an aqueous solution containing 4% w/v of HA-AMA and 4% w/v of PHM resulted in the highest yield. Its swe…

SMART HYDROGELS FOR DRUG DELIVERY

HYALURONAN/POLYASPARTAMIDE BASED BIOMATERIALS AS GENE ACTIVATED MATRICES

Correlating Rheological Properties of a Gellan Gum-Based Bioink: A Study of the Impact of Cell Density.

Here, for the production of a bioink-based gellan gum, an amino derivative of this polysaccharide was mixed with a mono-functionalized aldehyde polyethyleneglycol in order to improve viscoelastic macroscopic properties and the potential processability by means of bioprinting techniques as confirmed by the printing tests. The dynamic Schiff base linkage between amino and aldehyde groups temporally modulates the rheological properties and allows a reduction of the applied pressure during extrusion followed by the recovery of gellan gum strength. Rheological properties, often related to printing resolution, were extensively investigated confirming pseudoplastic behavior and thermotropic and io…

Nano-structured myelin: new nanovesicles for targeted delivery to white matter and microglia, from brain-to-brain

Neurodegenerative diseases affect millions of people worldwide and the presence of various physiological barriers limits the accessibility to the brain and reduces the efficacy of various therapies. Moreover, new carriers having targeting properties to specific brain regions and cells are needed in order to improve therapies for the brain disorder treatment. In this study, for the first time, Myelin nanoVesicles (hereafter defined MyVes) from brain-extracted myelin were produced. The MyVes have an average diameter of 100–150 ​nm, negative zeta potential, spheroidal morphology, and contain lipids and the key proteins of the myelin sheath. Furthermore, they exhibit good cytocompatibility. The…

Multifibrillar bundles of a self-assembling hyaluronic acid derivative obtained through a microfluidic technique for aortic smooth muscle cell orientation and differentiation

A hyaluronic acid derivative that is able to physically crosslink in a saline aqueous environment was employed for the production of fibers with a mean diameter of 50 μm using a microfluidic technique. The microfibers were collected in a tailored rotating collector and assembled to form multifibrillar bundles. The orientation of the microfibers on the collected bundles was evaluated by microCT analysis. The bundles were biofunctionalized by physical addition of fibronectin or chemical tethering of a cyRGDC peptide to achieve control of Aortic Smooth Muscle Cell (AoSMC) attachment, elongation and alignment. The mechanical performances of these bundles were evaluated by elongation tests, rela…

Electrospun PHEA-PLA/PCL Scaffold for Vascular Regeneration: A Preliminary in Vivo Evaluation

Abstract Background There is increasing interest in the development of vessel substitutes, and many studies are currently focusing on the development of biodegradable scaffolds capable of fostering vascular regeneration. We tested a new biocompatible and biodegradable material with mechanical properties similar to those of blood vessels. Methods The material used comprises a mixture of α,β-poly(N-2-hydroxyethyl)- d,l -aspartamide (PHEA) and polylactic acid (PLA), combined with polycaprolactone (PCL) by means of electrospinning technique. Low-molecular-weight heparin was also linked to the copolymer. A tubular PHEA-PLA/PCL sample was used to create an arteriovenous fistula in a pig model wit…

Hyaluronic acid, elastin and heparin containing scaffolds for the treatment of skin chronic wounds

Attachement and spreading of fibroblasts on an RGD peptide-modified injectable hyaluronan hydrogel

Hyaluronan (HA) hydrogels resist attachment and spreading of fibroblasts and most other mammalian cell types. A thiol-modified HA (3,3'-dithiobis(propanoic dihydrazide) [HA-DTPH]) was modified with peptides containing the Arg-Gly-Asp (RGD) sequence and then crosslinked with polyethylene glycol (PEG) diacrylate (PEGDA) to create a biomaterial that supported cell attachment, spreading, and proliferation. The hydrogels were evaluated in vitro and in vivo in three assay systems. First, the behavior of human and murine fibroblasts on the surface of the hydrogels was evaluated. The concentration and structure of the RGD peptides and the length of the PEG spacer influenced cell attachment and spre…

Self-assembling and auto-crosslinkable hyaluronic acid hydrogels with a fibrillar structure

Abstract A hyaluronic acid derivative bearing pendant l -benzoyl-cysteine portions (with a derivatization degree equal to 10 mol.%) was synthesized by linking N,N′-dibenzoyl- l -cystine to the polysaccharide and then reducing its disulfide bridge to thiol groups. The formation of π–π stacking interactions between the benzoyl moieties was studied by fluorescence spectroscopy as a function of polymer concentration and oxidation time. The efficiency of oxidation of thiol groups to disulfide bridges occurring in phosphate buffer pH 7.4, was determined by colorimetric assays. The hydrogel formed by means of oxidative crosslinking has shown the presence of fibrillar aggregates as detected by ligh…

Photocrosslinking of dextran and polyaspartamide derivatives: a combination suitable for colon-specific drug delivery.

Abstract The aim of this study was to prepare and characterize novel hydrogels with polysaccharide–polyaminoacid structure, able to undergo an enzymatic hydrolysis in the colon and potentially useful for treating inflammatory bowel diseases (IBD). Starting materials were methacrylated dextran (DEX-MA) and methacrylated α,β-poly(N-2-hydroxyethyl)- dl -aspartamide (PHM). These polymers were photocrosslinked by exposure of their aqueous solutions at 313 nm without photoinitiators. Different samples, shaped as microparticles, were obtained as a function of polymer concentration and irradiation time. FT-IR analysis confirmed the occurrence of a co-crosslinking between DEX-MA and PHM in all exper…

HYALURONAN CROSS-LINKED WITH alpha,beta-POLYASPARTYLHYDRAZIDE BASED SCAFFOLDS FOR TISSUE ENGINEERING

PRODUCTION OF MICELLES FROM HYALURONIC ACID AMPHIPHILIC DERIVATIVES FOR TARGETED RELEASE OF DOXORUBICIN

Self assembling in the production of Biomimetic matrices for regenerative medicine

Medicated hydrogels of hyaluronic acid derivatives for use in orthopedic field

NEW AMPHIPHILIC HYALURONIC ACID COPOLYMERS BEARING PEG AND PLA CHAINS

Heparin functionalized polyaspartamide/polyester scaffold for potential blood vessel regeneration

A hyaluronic acid/cyclodextrin based injectable hydrogel for local doxorubicin delivery to solid tumors

Localized delivery of anticancer drugs is often the most useful therapeutic approach for the treatment of solid tumors. The use of injectable polymeric systems that maximize drug concentration in the proximal area of the tumor represents an extremely advantageous therapeutic strategy. Here, the development of an injectable in situ forming hydrogel was accomplished by exploiting the azo-type Michael reaction between an amine derivative of hyaluronic and vinylsulfone functionalized -cyclodextrins complexing doxorubicin. This injectable system can be easily prepared and administered with timelines compatible with normal operating room procedures, as demonstrated by rheological tests. In vitro…

SYNTHESIS OF NOVEL GRAFT COPOLYMERS OF HYALURONAN, POLYETHYLENEGLYCOL AND POLYLACTIC ACID

SCAFFOLDS BASED ON HYALURONIC ACID AND POLYAMINOACIDS AS ARTIFICIAL ECM SUBSTITUTES

Production of hyaluronic acid derivative microfibers with controlled dimension as potential drug delivery system

Spray dried hyaluronic acid microparticles for adhesion controlled aggregation and potential stimulation of stem cells

Spray-dried microparticles of a derivative of hyaluronic acid (HA) have been engineered to obtain a controlled aggregation with Human Mesenchymal Stem Cells (hMSCs) into 3D constructs. We demonstrated the utility of chemical functionalization of a native constituent of the extracellular matrix to improve processing performances and to control on stem cell adhesion and differentiation. Native hyaluronic acid (HA), cell adhesive peptides (RGD), transforming growth factor β3, dexamethasone are biological agents potentially suitable for chondrogenic stimulation of hMSCS. However unmodified HA suffers of drawbacks in terms of stability and versatility of processing. Functionalization strategies…

New hyaluronic acid based brush copolymers synthesized by atom transfer radical polymerization.

Abstract In this work, an efficient method for the synthesis of hyaluronic acid based brush copolymers using atom transfer radical polymerization (ATRP) has been reported. At first, two different hyaluronic acid (HA) based macroinitiators have been prepared and then they have been used for the polymerization via ATRP of hydrophilic or hydrophobic molecules carrying vinyl portions. In particular, by linking 2-bromo-2-methylpropionic acid (BMP) to the primary hydroxyl groups of tetrabutyl ammonium salt of HA (HA–TBA) or to amino groups of the ethylenediamino derivative of HA–TBA (HA–TBA–EDA), two macroinitiators (HA–TBA–BMP and HA–TBA–EDA–BMP) have been obtained. Then they have been used for …

Chemical hydrogels based on a hyaluronic acid-graft-α-elastin derivative as potential scaffolds for tissue engineering

In this work hyaluronic acid (HA) functionalized with ethylenediamine (EDA) has been employed to graft α-elastin. In particular a HA-EDA derivative bearing 50 mol% of pendant amino groups has been successfully employed to produce the copolymer HA-EDA-g-α-elastin containing 32% w/w of protein. After grafting with α-elastin, remaining free amino groups reacted with ethylene glycol diglycidyl ether (EGDGE) for producing chemical hydrogels, proposed as scaffolds for tissue engineering. Swelling degree, resistance to chemical and enzymatic hydrolysis, as well as preliminary biological properties of HA-EDA-g-α-elastin/EGDGE scaffold have been evaluated and compared with a HA-EDA/EGDGE scaffold. T…

MODIFIED PEPTIDE RELEASE FROM NEW IN SITU GEL FORMING COPOLYMERS BASED ON POLYLACTIDE AND POLYASPARTAMIDE

Physicochemical and Rheological Characterization of Different Low Molecular Weight Gellan Gum Products and Derived Ionotropic Crosslinked Hydrogels

A series of four different low molecular weight gellan gum products was obtained by alkaline hydrolysis with the aim to investigate the impact of the molecular weight on the rheological properties of the polysaccharide aqueous dispersions and on the physicochemical characteristics of derived ionotropic crosslinked hydrogels. In particular, thermo-rheological analysis was conducted on aqueous dispersions to study the influence of molecular weight on the thermogelation properties typical of the native polysaccharide while strain sweep experiments were conducted to establish if aqueous dispersion shows a viscoelastic behavior. The effect of different Ca2+ on the rheological properties of hydro…

Micelles of hyaluronic acid-hexadecylamine derivatives for ocular release of hydrophobic drugs

Dexamethasone Dipropionate Loaded Nanoparticles Of -Elastin-G-Plga For Potential Treatment Of Restenosis

Synthesis, mechanical and thermal rheological properties of new gellan gum derivatives

New derivatives of gellan gum (GG) were prepared by covalent attachment of octadecylamine (C18- NH2) to polysaccharide backbone via amide linkage by using bis(4-nitrophenyl) carbonate (4-NPBC) as a coupling agent. The effect of the alkyl chain grafted onto hydrophilic backbone of high molecular weight GG was investigated in terms of physicochemical properties and ability of new derivatives to form hydrogels. A series of hydrogels was obtained in solutions with different kind and concentration of ions and their stability and mechanical properties were evaluated. The obtained derivatives resulted soluble at temperature lower than starting GG and physicochemical properties of obtained hydrogel…

Synthesis and evaluation of thermo-rheological behaviour and ionotropic crosslinking of new gellan gum-alkyl derivatives.

Abstract This paper reports the synthesis and the physicochemical characterization of two series of gellan gum (GG) derivatives functionalized with alkyl chains with different number of carbon, from 8 to 18. In particular, low molecular weight gellan gum samples with 52.6 or 96.7 kDa, respectively, were functionalized with octylamine (C8), dodecylamine (C12) and octadecylamine (C18) by using bis(4-nitrophenyl) carbonate (4-NPBC) as a coupling agent. Thermo-rheological and ionotropic crosslinking properties of these gellan gum-alkyl derivatives were evaluated and related to the degree of derivatization in alkyl chains. Results suggested as length and degree of derivatization differently infl…

In situ forming hydrogels of hyaluronic acid and inulin derivatives for cartilage regeneration.

An in situ forming hydrogel obtained by crosslinking of amino functionalized hyaluronic acid derivatives with divinylsulfone functionalized inulin (INU-DV) has been here designed and characterized. In particular two hyaluronic acid derivatives bearing respectively a pendant ethylenediamino (EDA) portion (HA-EDA) and both EDA and octadecyl pendant groups (HA-EDA-C18) were crosslinked through an azo-Michael reaction with INU-DV. Gelation time and consumption of DV portions have been evaluated on hydrogel obtained using HA-EDA and HA-EDA-C18 derivatives with a concentration of 3% w/v and a ratio 80/20 w/w respect to the crosslinker INU-DV. The presence of pendant C18 chains improves mechanical…

Mechanical Characterization of Polysaccharide/polyaminoacid Hydrogels as Potential Scaffolds for Tissue Regeneration

The mechanical properties of hydrogel scaffolds based on hyaluronic acid (HA) that were chemically crosslinked with α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) were investigated. Variation of these properties as a function of three different PHEA-EDA amounts used to crosslink HA has been related to the reaction efficiency evaluated using a colorimetric assay. Moreover, the amount of unreacted amino groups that was still present in the hydrogels was related to the attachment behavior of human dermal fibroblasts to the hydrogel surface. The mechanical data and biological results suggest the suitability of the investigated hydrogels as scaffolds for the regener…

Developing Antibiofilm Fibrillar Scaffold with Intrinsic Capacity to Produce Silver Nanoparticles

The development of biomedical systems with antimicrobial and antibiofilm properties is a difficult medical task for preventing bacterial adhesion and growth on implanted devices. In this work, a fibrillar scaffold was produced by electrospinning a polymeric organic dispersion of polylactic acid (PLA) and poly(α,β-(N-(3,4-dihydroxyphenethyl)-L-aspartamide-co-α,β-N-(2-hydroxyethyl)-L-aspartamide) (PDAEA). The pendant catechol groups of PDAEA were used to reduce silver ions in situ and produce silver nanoparticles onto the surface of the electrospun fibers through a simple and reproducible procedure. The morphological and physicochemical characterization of the obtained s…

Synthesis, characterization and foaming of PHEA-PLLA, a new graft copolymer for biomedical engineering

Abstract In this study a chemical grafting procedure was set up in order to link high molecular weight poly L-lactic acid (PLLA) chains to the hydrophilic α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) backbone. A graft copolymer named PHEA-g-PLLA (or simply PHEA–PLLA) was obtained bearing a degree of derivatization of 1.0 mol.% of PLLA as grafted chain. This new hybrid derivative offers both the opportune crystallinity necessary for the production of scaffolds trough a thermally induced phase separation (TIPS) technique and the proper chemical reactivity to perform further functionalizations with bio-effectors and drugs. PHEA–PLLA porous scaffolds for tissue engineering applications were…

Using Polymeric Scaffolds for Vascular Tissue Engineering

With the high occurrence of cardiovascular disease and increasing numbers of patients requiring vascular access, there is a significant need for small-diameter (<6 mm inner diameter) vascular graft that can provide long-term patency. Despite the technological improvements, restenosis and graft thrombosis continue to hamper the success of the implants. Vascular tissue engineering is a new field that has undergone enormous growth over the last decade and has proposed valid solutions for blood vessels repair. The goal of vascular tissue engineering is to produce neovessels and neoorgan tissue from autologous cells using a biodegradable polymer as a scaffold. The most important advantage of …

Medicated hydrogels of hyaluronic acid derivatives for use in orthopedic field.

Physical hydrogels have been obtained from hyaluronic acid derivatized with polylactic acid in the presence or in the absence of polyethylene glycol chains. They have been extemporarily loaded with antibacterial agents, such as vancomycin and tobramycin. These medicated hydrogels have been used to coat titanium disks (chosen as simple model of orthopedic prosthesis) and in vitro studies in simulated physiological fluid have been performed as a function of time and for different drug loading and polymer concentration values. Sterilization process performed on the hydrogels does not change their rheological behavior and release properties as well as the chemical structure of starting copolyme…

CROSSLINKED HYALURONAN WITH A PROTEIN-LIKE POLYMER: NOVEL FILMS FOR BIOMEDICAL APPLICATION

Chemical stiffening of constructs between polymeric microparticles based on a hyaluronic acid derivative and mesenchymal stem cells: rheological and in vitro viability studies

Hyaluronan alkyl derivatives-based electrospun membranes for potential guided bone regeneration: Fabrication, characterization and in vitro osteoinductive properties

Item does not contain fulltext The aim of the work was to determine the effects of the chemical functionalization of hyaluronic acid (HA) with pendant aliphatic tails at different lengths and free amino groups in terms of chemical reactivity, degradation rate, drug-eluting features, and surface properties when processed as electrospun membranes (EM) evaluating the osteoinductive potential for a possible application as guided bone regeneration (GBR). To this end, a series of HA derivatives with different aliphatic tails (DD-Cx mol% ≈ 12.0 mol%) and decreasing derivatization of free amino groups (DD(EDA) mol% from 70.0 to 30.0 mol%) were first synthesized, namely Hn. Then dexamethasone-loaded…

Construction and evaluation of sponge scaffolds from hyaluronic acid derivatives for potential cartilage regeneration

A two or one pot synthesis has been used for the reaction of hyaluronic acid (HA) with octadecylamine (C-18) and hydrazine (Hy). In both cases, the chemical derivatization involved primary hydroxyl groups of hyaluronic acid and not its carboxyl groups, whose presence is important for receptor interaction. In this way, Hy-HA-C-18 derivatives have been obtained with appropriate hydrophobic and hydrophilic character. Their ability to form homogeneous physical hydrogels has been evaluated as well as the possibility to obtain porous sponges through salt leaching technology. Sponges showing the highest porosity, potentially compatible with cell entrapment, have been characterized with regard to t…

Hepatocyte-targeted fluorescent nanoparticles based on a polyaspartamide for potential theranostic applications

Abstract Here, the synthesis of a galactosylated amphiphilic copolymer bearing rhodamine (RhB) moieties and its use for the preparation of polymeric fluorescent nanoparticles for potential applications in therapy and diagnosis are described. To do this, firstly, a fluorescent derivative of α,β-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA) was synthesized by chemical reaction with RhB, and with polylactic acid (PLA), to obtain PHEA-RhB-PLA. Then, the derivatization of PHEA-RhB-PLA with GAL-PEG-NH 2 allows obtaining PHEA-RhB-PLA-PEG-GAL copolymer, with derivatization degrees in -PLA and -PEG-GAL equal to 1.9 mol% and 4.5 mol%, respectively. Starting from this copolymer, liver-targeted f…

ATRP AS AN EFFICIENT METHOD TO PRODUCE BRUSH COPOLYMERS OF HYALURONIC ACID

COMPOSITE BIOMATERIALS OF HYALURONIC ACID AND A PROTEIN-LIKE POLYMER FOR TISSUE ENGINEERING

Microfibers obtained by electrospinning of alpha, beta poly(N-2-hydroxyethyl)-DL-aspartamide-g-polylactic acid for potential use in tissue reconstruction

Electrospinning of α,β-poly(N-2-hydroxyethyl)-dl-aspartamide-graft-polylactic acid to produce a fibrillar scaffold

Abstract α,β-Poly( N -2-hydroxyethyl)- dl -aspartamide grafted with polylactic acid (PHEA- g -PLA) is a biocompatible and biodegradable amphiphilic copolymer that has been already employed to prepare a drug delivery system. In this study we have prepared for the first time a fibrillar scaffold from PHEA- g -PLA by the electrospinning of a solution of this copolymer in a mixture of N , N -dimethyl formamide (DMF) and acetone (80:20 vol/vol). The average diameter and the morphology of electrospun fibers were detected by scanning electron microscopy. Chemical degradation studies in phosphate buffer solution pH 7.4 have been performed until 15 days in order to obtain a preliminary information a…

Polysaccharide/polyaminoacid composite scaffolds for modified DNA release.

Abstract In this work composite polymeric films or sponges, based on hyaluronic acid (HA) covalently crosslinked with α,β-poly(N-2-hydroxyethyl)(2-aminoethylcarbamate)- d , l -aspartamide (PE), have been prepared and characterized as local gene delivery systems. In particular, HA/PE scaffolds have been loaded with PE/DNA interpolyelectrolyte complexes, employing PE as a macromolecular crosslinker for HA and as a non-viral vector for DNA. In vitro studies showed that HA/PE films and sponges have high compatibility with human dermal fibroblasts and they give a sustained DNA release, whose trend can be easily tailored by varying the crosslinking ratio between HA and PE. Electrophoresis analysi…

Microfluidic production of hyaluronic acid derivative microfibers to control drug release

"Available online 4 July 2016"

CROSSLINKED HYALURONAN WITH A PROTEIN-LIKE POLYMER: NOVEL BIORESORBABLE FILMS FOR BIOMEDICAL APPLICATIONS

In this work, novel hydrogel films based on hyaluronan (HA) chemically crosslinked with the alpha,beta-poly(N-2-hydroxyethyl) (2-aminoethylcarbamate)-D,L-aspartamide (PHEA-EDA) were produced by solution casting method. The goal was to exploit both the biological key role of HA in tissue repair and regeneration, and the versatility of a synthetic protein-like polymer as the PHEA-EDA, in order to obtain biomaterials with physicochemical and biological properties suitable for a clinical use. By varying the molar ratio between the PHEA-EDA amino groups and HA carboxyl groups, three different films were obtained and characterized. Particularly FTIR, swelling, hydrolysis, and enzymatic degradatio…

ANTICANCER RELEASING FILMS AND POROUS SCAFFOLDS BASED ON PHYSICALLY ASSEMBLED HYALURONIC ACID DERIVATIVES

Procedimento per la produzione di derivati funzionalizzati dell'acido ialuronico e relativi idrogeli

POROUS SCAFFOLDS BASED ON PLLA/FUNCTIONALISED POLYMERS BLENDS PRODUCED BY THERMALLY INDUCED PHASE SEPARATION

Microfluidic Fabrication of Physically Assembled Nanogels and Micrometric Fibers by Using a Hyaluronic Acid Derivative

The employ of a hyaluronic acid (HA) derivative, bearing octadecyl (C18) and ethylenediamine (EDA) groups, for microfluidic fabrication of nanogels and microfibers is reported in this study. Two HA-EDA-C18 derivatives (125 and 320 kDa) having ionic strength sensitive properties are synthesized and characterized. The control of the rheological properties of HA-EDA-C18 aqueous dispersions by formation of inclusion complexes with hydroxypropyl-β-cyclodextrins (HPCD) is described. Reversibility of C18/HPCD complexation and physical crosslinking is detected in media with different ionic strength through oscillation frequency tests. HA-EDA-C18 125 kDa is employed for nanogel fabrication. Control …

Hydrogels of methacrylic hyaluronic acid derivatives for oral enzyme therapy in celiac disease

Hyaluronic acid, celiac disease

Disulfide-crosslinked hyaluronan-gelatin hydrogel films: a covalent mimic of the extracellular matrix for in vitro cell growth

A new disulfide crosslinking method was developed for the preparation of blended hyaluronan (HA)-gelatin hydrogels to form a synthetic, covalently linked mimic of the extracellular matrix (ECM). The HA and gelatin were chemically modified using 3,3′-dithiobis(propionic hydrazide) (DTP). After reduction with dithiothreitol (DTT), the thiol derivatives of HA (HA-DTPH) and gelatin (gelatin-DTPH) were obtained and characterized. To minimize interference with biological function, the degree of substitution of HA-DTPH and gelatin-DTPH was kept below 50%. Solutions of HA-DTPH and gelatin-DTPH in varying blends (20%, 40%, 60%, 80% gelatin) were prepared in 1% w/v NaCl and crosslinked by disulfide b…

Polyaspartamide-polylactide electrospun scaffolds for potential topical release of Ibuprofen.

In this work, the production and characterization of electrospun scaffolds of the copolymer α,β-poly(N-2-hydroxyethyl)-DL-aspartamide-graft-polylactic acid (PHEA-g-PLA), proposed for a potential topical release of Ibuprofen (IBU), are reported. The drug has been chemically linked to PHEA-g-PLA and/or physically mixed to the copolymer before electrospinning. Degradation studies have been performed as a function of time in Dulbecco phosphate buffer solution pH 7.4, for both unloaded and drug-loaded scaffolds. By using an appropriate ratio between drug physically blended to the copolymer and drug-copolymer conjugate, a useful control of its release can be obtained. MTS assay on human dermal fi…

A hyaluronic acid derivative as a coating film for an electrospun cell releasing system in the treatment of corneal wounds

The transparency of the cornea is maintained by the stem cells of the corneal epithelium in the limbal region; damage to the limbus may cause partial or total limbal stem cell deficiency that, may lead to blindness. The transplantation of cells is crucial to regenerate the damaged areas. The techniques currently employed consist in cadaveric corneal transplantation or in the use of amniotic membrane as a carrier for delivering cultured limbal stem cells to the cornea. Both these approaches show severe drawbacks such as the potential reject of the transplanted cornea and the risk of viral disease transmissions. Here we report the production of an electrospun device that could be exploited as…

PHEA‐PLLA: A New Polymer Blend For Tissue Engineering Applications

One of most important features that a material should have in order to be utilized for tissue engineering applications is its biocompatibility and its chemical surface. These properties are required for a high degree of cell adhesion on the scaffold. Poly‐L‐lactid acid (PLLA) is a biocompatible synthetic polymer approved by the Food and Drug Administration for human clinical applications. It has been largely employed, in the last years, as a constituent of surgical and implantable devices. PHEA is a biocompatible water‐soluble synthetic polymer, with a protein‐like structure, whose use as a drug carrier and as starting material for many other biomedical and pharmaceutical applications has b…

NEW IN SITU FORMING HYALURONIC ACID SCAFFOLDS WITH A FIBRILLAR STRUCTURE

Metallic core nano-devices as drug delivery systems

FIBRILLAR SCAFFOLD BASED ON ELECTROSPUN alpha,beta-POLY(N-2-HYDROXYETHYL)-DL-ASPARTAMIDE-GRAFT-POLYLACTIC ACID COPOLYMER.

New hyaluronic acid based brush copolymers synthesized by atom transfer radical polymerization

Drug delivery devices based on mesoporous silicate.

A mesoporous material based on aluminosilicate mixture was studied to investigate its ability to include drugs and then release them. Nonsteroidal anti-inflammatory agents such as diflunisal, naproxen, ibuprofen and its sodium salt have been used in this study. The preparation of the mesoporous material and its characterization by X-ray, N2 absorption-desorption isotherm, and thermogravimetry analysis have been described. Drug loading was performed by a soaking procedure. Drug-loaded matrices were characterized for entrapped drug amount, water absorption ability, and thermogravimetric behavior. Drug release studies also were performed at pH 1.1 and 6.8 mimicking gastrointestinal fluids. Exp…

Polyaspartamide-polylactide electrospun scaffolds for potential topical release of ibuprofen

Fabrication of silver nanoparticles by a diethylene triamine-hyaluronic acid derivative and use as antibacterial coating

In this work a synthetic protocol for the functionalization of hyaluronic acid with diethylenetriamine (DETA) was standardized. HA-DETA derivatives were characterized by NMR and proton carbon correlation analysis HSQC and HMBC to confirm chemical structure. A selected derivative was used to set up a green fabrication procedure for HA-DETA capped silver nanoparticles with the aim to achieve a polymeric based coating with potential application in the treatment of medical devices associated infections. Data from UV-visible spectroscopy, electron scanning and transmission microscope (STEM), photoelectric spectroscopy (XPS) and rheological characterization were combined to characterize the HA-DE…

Hyaluronic Acid-Based Micelles as Ocular Platform to Modulate the Loading, Release, and Corneal Permeation of Corticosteroids

The aim of this work is to prepare hyaluronic acid-based micelles as a platform to load corticosteroid drugs and to improve their corneal permeation after administration on the ocular surface. Three amphiphilic derivatives of hyaluronic acid (HA) are synthesized using different amounts of hexadecylamine (C16 -NH2 ). HAC16 a, HAC16 b, and HAC16 c derivatives are able to form micelles by the cosolvent evaporation method and to entrap corticosteroids (dexamethasone, triamcinolone, triamcinolone acetonide). HAC16 a and HAC16 b micelles show the best results in terms of drug loading and particle size. They are also able to improve drug release compared to free drug solution or suspension. In add…

COMPOSITE SCAFFOLD FOR TISSUE ENGINEERING

Novel cationic copolymers of a polyasparthylhydrazide: synthesis and characterization.

Alpha,beta-poly(asparthylhydrazide) (PAHy), a water soluble synthetic polymer, was functionalized by using EDCI chemistry with 3-(carboxypropyl)trimethyl-ammonium chloride (CPTACl) obtaining carboxypropyltrimethyl ammonium copolymers (PAHy-CPTA). Three PAHy-CPTA copolymers at increasing derivatization degrees (38%, 48%, 58%) were chosen for subsequent investigations. The capability of these copolymers to bind, neutralize, and protect DNA against degradation by DNase II was evalued by gel retardation assay and DNA degradation test at pH 5.5. Zeta potential measurements show that all studied polymers are able to neutralize the anionic charge of DNA at polymer/DNA weight ratio in the range of …

IDAC: production of resorbable hyaluronic acid hydrogels

A new biodegradable and biocompatible hydrogel with polyaminoacid structure

The preparation and physicochemical and biological characterization of a novel polyaminoacid hydrogel have been reported. The ,-poly(N-2- hydroxyethyl)-dl-aspartamide (PHEA) has been used as a starting polymer for a derivatization reaction with methacrylic anhydride (MA) to give rise to the methacrylate derivative named PHM. Photocrosslinking of PHM has been performed in aqueous solution at 313 nm and in the absence of toxic initiators. PHM-based hydrogel has been characterized by scanning electron microscopy, X-ray diffractometry, swelling measurements in aqueous media; the degradation of PHM-based hydrogel has been evaluated as a function of time in the absence or in the presence of ester…

Interpenetrated 3D porous scaffolds of silk fibroin with an amino and octadecyl functionalized hyaluronic acid

An ethylenediamine (EDA) and octadecylamine (-C18) hyaluronic acid (HA) derivative, named HA-EDA-C18, has been used for the production of interpenetrated composite biomaterials with silk fibroin. The peculiar ionic strength sensibility of this HA derivative allows the production of porous matrices without the need for chemical crosslinking. Scaffolds have been produced through a salt leaching procedure by exploiting the properties of silk fibroin and HA-EDA-C18 to physically crosslink when forced through a syringe loaded with NaCl. The porosity of the sponges, comprised between 70-80%, was dependent on the amount of each polymer and NaCl size distribution. Moreover, through FT-IR analysis, …

Biodegradable hydrogels obtained by photocrosslinking of dextran and polyaspartamide derivatives

The functionalization of dextran with glycidyl methacrylate (GMA) leads to the formation of a derivative that generates hydrogels for irradiation at 365nm. The effects of various polymer concentrations and irradiation times on the yield and the properties of the obtained hydrogels are reported. The networks have been characterized by FT-IR spectra, dimensional analysis and swelling measurements carried out at different pH values. In vitro studies suggest that all samples undergo a partial chemical hydrolysis, whereas the incubation with dextranases causes a total degradation whose rate depends on the degree of crosslinking. In addition, aqueous solutions of functionalized dextran have been …

New gellan gum-graft-poly(D,L-lactide-co-glycolide) copolymers as promising bioinks: Synthesis and characterization

This research focused on the aim of tackling the urgent demand of printable biomaterials, hence we synthetized and characterized three gellan gum-graft-poly(d,l-lactide-co-glycolide) copolymers (GGm-PLGA a, b and c) which differed in the graft substitution degree. We investigated the effect of the polyester chain grafted onto hydrophilic backbone of gellan gum in terms of physicochemical properties and the ability of the system to print 3D cell laden constructs. In particular, we evaluated thermo-rheological, ionotropic crosslinking, shear thinning, swelling and stability properties of these copolymers and their derived biomaterials and findings related to the degree of functionalization. M…

Hyaluronic acid based hydrogel and use thereof in surgery

Inulin-iron complexes: a potential treatment of iron deficiency anaemia.

The aim of this work was that to synthesize macromolecular derivatives based on inulin able to complex iron and useful in the treatment of iron deficiency anaemia. Carboxylated or thiolated/carboxylated inulin derivatives were obtained by single or double step reactions, respectively. The first one was obtained by reaction of inulin (INU) with succinic anhydride (SA) alone obtaining INU-SA derivative; the second one was obtained by the reaction of INU with succinic anhydride and subsequent reaction of INU-SA with cysteine; both derivatives were treated with ferric chloride in order to obtain the INU-SA-Fe(III) and INU-SA-Cys-Fe(III) complexes. Both complexes showed an excellent biodegradabi…

METHOD TO PRODUCE HYALURONIC ACID FUNCTIONALIZED DERIVATIVES AND FORMATION OF HYDROGELS THEREOF

Production of a Double-Layer Scaffold for the “On-Demand” Release of Fibroblast-like Limbal Stem Cells

The production and characterization of a double layer scaffold, to be used as a system for the “on demand” release of corneal limbal stem cells are here reported. The devices used in the clinics and proposed so far in the scientific literature, for the release of corneal stem cells in the treatment of limbal stem cell deficiency, cannot control the in vivo space-time release of cells since the biomaterial of which they are composed is devoid of stimuli responsiveness features. Our approach was to produce a scaffold composed of two different polymeric layers that give the device the appropriate mechanical properties to be placed on the ocular surface and the possibility of releasing the stem…

Modulation of physical and biological properties of a composite PLLA and polyaspartamide derivative obtained via thermally induced phase separation (TIPS) technique.

Abstract In the present study, blend of poly l -lactic acid (PLLA) with a graft copolymer based on α,β-poly(N-hydroxyethyl)- dl -aspartamide and PLA named PHEA-PLA, has been used to design porous scaffold by using Thermally Induced Phase Separation (TIPS) technique. Starting from a homogeneous ternary solution of polymers, dioxane and deionised water, PLLA/PHEA-PLA porous foams have been produced by varying the polymers concentration and de-mixing temperature in metastable region. Results have shown that scaffolds prepared with a polymer concentration of 4% and de-mixing temperature of 22.5 °C are the best among those assessed, due to their optimal pore size and interconnection. SEM and DSC…

Composite Hydrogels of Alkyl Functionalized Gellan Gum Derivative and Hydroxyapatite/Tricalcium Phosphate Nanoparticles as Injectable Scaffolds for bone Regeneration

An alkyl functionalized gellan gum derivative was here used to produce hydrogels containing hydroxyapatite and tricalcium phosphate nanoparticles as injectable nanostructured scaffolds for bone regeneration. The amphiphilic nature of the polysaccharide derivative along with its thermotropic behavior and ionotropic crosslinking features made possible to produce injectable bone mimetic scaffolds that can be used to release viable cells and osteoinductive biomolecules. The influence of different nanoparticles concentration on the rheological and physicochemical properties of the injectable systems was studied. We found that the presence of inorganic nanoparticles reinforces the three-dimension…

idrogelo a base di acido ialuronico e suo uso in ortopedia

CHEMICALLY CROSSLINKED HYALURONAN AND alpha,beta-POLYASPARTYLHYDRAZIDE AS NANO-COMPOSITE PARTICLES

Hyaluronic Acid-g-Copolymers: Synthesis, Properties, and Applications

Scaffolds based on hyaluronan crosslinked with a polyaminoacid: Novel candidates for tissue engineering application

New porous scaffolds, with a suitable hydrolytic and enzymatic degradation, useful for tissue engineering applications have been obtained by a carbodiimide mediated reaction between hyaluronan (HA) and a synthetic polymer with a polyaminoacid structure such as α,β-polyaspartylhydrazide (PAHy). Scaffolds with a different molar ratio between PAHy repeating units and HA repeating units have been prepared and characterized from a chemical and physicochemical point of view. Tests of indirect and direct cytotoxicity, cell adhesion, and spreading on these biomaterials have been performed by using murine L929 fibroblasts. The new biomaterials showed a good cell compatibility and ability to allow ce…

Electrospun Polyhydroxyethyl-Aspartamide-Polylactic Acid Scaffold for Biliary Duct Repair: A Preliminary In Vivo Evaluation

Abstract Tissue engineering has emerged as a new approach with the potential to overcome the limitations of traditional therapies. The objective of this study was to test whether our polymeric scaffold is able to resist the corrosive action of bile and to support a cell's infiltration and neoangiogenesis with the aim of using it as a biodegradable tissue substitute for serious bile duct injuries. In particular, a resorbable electrospun polyhydroxyethyl-aspartamide–polylactic acid (90 mol% PHEA, 10 mol% PLA)/polycaprolactone (50:50 w/w) plate scaffold was implanted into rabbit gallbladder to assess the in vivo effects of the lytic action of the bile on the scaffold structure and then as a tu…

A methacrylic hyaluronic acid derivative for potential application in oral treatment of celiac disease.

Objective: Aim of this work was the synthesis of a methacrylic hyaluronic acid (HA) derivative and the production, via photocrosslinking, of related hydrogels loaded with an endopeptidase intended for a potential oral treatment of celiac disease. Methods: The methacrylic derivative of HA was prepared through a one-pot procedure involving the reaction with ethylenediamine (EDA) and methacrylic anhydride (MA). The obtained derivative, named HA-EDA-MA, was used to prepare photocrosslinked hydrogels loaded with a prolyl endopeptidase derived from Flavobacterium meningosepticum (PEP FM) able to detoxify gliadin. Obtained hydrogels were recovered as gels or freeze-dried powders. Results: Hydrogel…

MICELLES OF AMPHYPHLIC HYALURONIC ACID DERIVATIVES FOR TARGETED DELIVERY OF DOXORUBICIN

Preparation and characterization of new hydrogels based on hyaluronic acid and α,β-polyaspartylhydrazide

Abstract Hyaluronic acid (HA) has been crosslinked with α,β-polyaspartylhydrazide (PAHy). The crosslinking reaction has been performed in acidic medium in the presence of various amounts of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC). All obtained samples have been characterized by FT-IR analysis and swelling measurements in double distilled water that have confirmed the occurrence of a chemical linkage between two polymers and the affinity towards aqueous medium of HA–PAHy networks, respectively. In vitro degradation assays have been performed in simulated physiological conditions as well as in the presence of hyaluronidase. Experimental data evidenced that HA–PAHy …

PHARMACEUTICAL NANODEVICES FOR BIOMEDICAL APPLICATIONS

NEW GRAFT COPOLYMERS OF HYALURONIC ACID AND POLYLACTIC ACID: SYNTHESIS AND CHARACTERIZATION

Abstract New graft copolymers have been synthesized, using hyaluronic acid (HA) as a hydrophilic backbone and polylactic acid (PLA) as an aliphatic polyester in order to obtain new polymeric derivatives of HA able to hydrophobically associate in an aqueous medium. Hyaluronic acid with low molecular weight was made soluble in organic solvent by transformation to its tetrabutylammonium (TBA) salt. Using the HA–TBA derivative, the reaction was performed in dimethylsulfoxide adding as a reagent the N -hydroxysuccinimide derivative of PLA. Two HA–PLA graft copolymers have been synthesized and characterized by FT-IR, 1 H NMR spectroscopy and gel permeation chromatography. The interaction between …

BIODEGRADABLE POLYASPARTAMIDE-GRAFT-POLYESTER COPOLYMER FOR VASCULAR REGENERATION

A POLYCARBOXYLIC/AMINO FUNCTIONALIZED HYALURONIC ACID DERIVATIVE FOR THE PRODUCTION OF pH SENSIBLE HYDROGELS IN THE PREVENTION OF BACTERIAL ADHESION ON BIOMEDICAL SURFACES

A graft copolymer derivative of hyaluronic acid bearing pendant amino and short polymethacrylate portions (HA-EDA-BMP-MANa) has been employed for the production of a pH sensible vancomycin releasing hydrogel and studied in vitro to test its potential anti adhesive property against Staphylococcus aureus colonization. The copolymer obtained through atom transfer radical polymerization bears chargeable (carboxyl and amino groups) portions and it could be formulated as a hydrogel at a concentration of 10% w/v. The HA-EDA-BMP-MANa hydrogels, produced at three different pH values (5, 6 and 7, respectively), were formulated with or without the addition of vancomycin (2% w/v). The vancomycin releas…

HYDROGELS OF HYALURONIC ACID-GRAFT-alfa-ELASTIN AS EXTRACELLULAR MATRIX SUBSTITUTES

MATRICES OF A HYDROPHOBICALLY FUNCTIONALIZED HYALURONIC ACID DERIVATIVE FOR THE LOCOREGIONAL TUMOUR TREATMENT

A hyaluronic acid (HA) derivative bearing octadecylamine and acylhydrazine functionalities has been here employed for the production of a paclitaxel delivering matrix for locoregional chemotherapy. Through a strategy consisting in a powder compression and a plasticization with a mixture water/ethanol, a physically assembled biomaterial, stable in solutions with physiologic ionic strengths, has been produced. Two different drug loading strategies have been adopted, by using paclitaxel as chemotherapic agent, and obtained samples have been assayed in terms of release in enhanced solubility conditions and in vitro and in vivo tumoural cytotoxicity. In particular sample with the best releasing …

SELF-ASSEMBLED AMPHIPHILIC HYALURONIC ACID GRAFT COPOLYMERS FOR TARGETED RELEASE OF ANTITUMORAL DRUG

Polymeric micelles obtained by self-assembling of amphiphilic hyaluronic acid (HA) graft copolymers have been prepared and characterized. In particular, hyaluronic acid (HA) has been grafted to polylactic acid (PLA) and polyethylenglycol chains (PEG), then the copolymers able to form micelles in aqueous medium have been chosen to entrap the antitumoral drug Doxorubicin. The critical aggregation concentration of HA-g-PLA or HA-g-PLA-g-PEG micelles has been determined by using pyrene as a fluorescent probe, whereas their shape and size have been evaluated by light scattering measurements, scanning and transmission electron microscopies. The selective cytotoxicity of drug loaded micelles towar…

Hyaluronic Acid Derivative with Improved Versatility for Processing and Biological Functionalization

A hydrophobic/amino functionalized derivative of hyaluronic acid (HA-EDA-C18 ) has been processed by salt leaching technique as porous scaffold without need of chemical crosslinking. Aim of this work is to demonstrate the improved versatility of HA-EDA-C18 in terms of processing and biological functionalization. In particular, the chemical procedure to tether thiol bearing RGD peptide has been described. Moreover, the possibility to load and to control the release of slightly water soluble effectors has been demonstrated by using dexamethasone. First, the swelling and degradation profiles of the scaffolds have been investigated, then the evaluation of metabolic activity of bovine chondrocyt…

HYALURONIC ACID BASED-MICELLES FOR OFF-LABEL USE OF IMATINIB IN RETINOPATHIES TREATMENT

The aim of this work was to obtain polymeric micelles able to cross corneal barrier and to improve the permeation of imatinib free base. Micelles were prepared by using hyaluronic acid (HA) derivatives containing ethylenediamine (EDA), chains of hexadecyl (C16), polyethylene glycol (PEG) and/or L-carnitine (CRN). The resulting samples, named as HA-EDA-C16, HA-EDA-C16-PEG and HA-EDA-C16-CRN micelles, were designed to allow a non-invasive way of administration, i.e. topical ocular instillation. These nanocarriers showed an optimal particle size in aqueous media and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal…

SELF ASSEMBLED AND CROSSLINKED FIBRILLAR SCAFFOLDS FOR CARTILAGE REGENERATION.

Hydrogels dell’Acido Ialuronico come Scaffold per la rigenerazione tissutale in situ

Development of stimulus-sensitive electrospun membranes based on novel biodegradable segmented polyurethane as triggered delivery system for doxorubicin

In this work, redox-sensitive polyurethane urea (PUU) based electrospun membranes have been exploited to chemically tether a pH-sensitive doxorubicin derivative achieved by linking a lipoyl hydrazide to the drug via a hydrazone linkage. First, the lipoyl-hydrazone-doxorubicin derivative labelled as LA-Hy-Doxo has been syn- thesized and characterized. Then, the molecule has been tethered, via a thiol-disulfide exchange reaction, to the redox-sensitive PUU (PolyCEGS) electrospun membrane. The redox-sensitive PolyCEGS PUU has been produced by using PCL-PEG-PCL polyol and glutathione-tetramethyl ester (GSSG-OMe)4 as a chain extender. The LA-Hy- Doxo tethered electrospun membrane has showed a du…

Imatinib-Loaded Micelles of Hyaluronic Acid Derivatives for Potential Treatment of Neovascular Ocular Diseases

In this work, new micellar systems able to cross corneal barrier and to improve the permeation of imatinib free base were prepared and characterized. HA-EDA-C-16, HA-EDA-C-16-PEG, and HA-EDA-C-16-CRN micelles were synthesized starting from hyaluronic acid (HA), ethylenediamine (EDA), hexadecyl chains (C-16), polyethylene glycol (PEG), or L-carnitine (CRN). These nanocarriers showed optimal particle size and mucoadhesive properties. Imatinib-loaded micelles were able to interact with corneal barrier and to promote imatinib transcorneal permeation and penetration. In addition, a study was conducted to understand the in vitro imatinib inhibitory effect on a choroidal neovascularization process…

Mucoadhesive PEGylated inulin-based self-assembling nanoparticles: In vitro and ex vivo transcorneal permeation enhancement of corticosteroids

Abstract As transcorneal drug delivery is still a challenge, the scope of the present study was to prepare useful nanosystems able to enhance transcorneal permeation/penetration of drugs. Moreover, this work aims to evaluate the effectiveness of inulin-based nanosystems in the specific field of ocular drug delivery and the effect of PEG chains to promote mucoadhesion, stability and transcorneal penetration/permeation enhancer effect of self-assembling nanoparticles in vitro (transwell systems and HCE) and ex vivo (Franz cells and bovine cornea). In particular, inulin was chosen as the starting natural polysaccharide polymer to design a novel amphiphilic derivative named INU-EDA-RA-PEG capab…

In situ gel forming graft copolymers of a polyaspartamide and polylactic acid: Preparation and characterization

Abstract In situ gel forming systems have been prepared by linking polylactic acid (PLA) to a water soluble and polyfunctional polymer, such as α,β-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA). Three graft copolymers PHEA–PLA with a different derivatization degree in PLA, have been synthesized and characterized. PHEA–PLA graft copolymer with the highest amount in PLA has been used to prepare solutions in organic solvents able to give rise to gel-like matrices when injected into phosphate buffered saline solution. The chemical degradation of these gels has been evaluated and in vitro tests have been performed to evaluate the cell compatibility of the hydrolysis products. The possibili…

UV-photocrosslinking of inulin derivatives to produce hydrogels for drug delivery application.

In this work, INU, a natural polysaccharide, has been chemically modified in order to obtain new photocrosslinkable derivatives. To reach this goal, INU has been derivatized with MA thus obtaining four samples (INU-MA derivatives) as a function of the temperature and time of reaction. An aqueous solution of the derivative INU-MA1 was irradiated by using a UV lamp with an emission range from 250 to 364 nm and without using photoinitiators. The obtained hydrogel showed a remarkable water affinity but it underwent a partial degradation in simulated gastric fluid. To overcome this drawback, INU-MA 1 was derivatized with SA thus obtaining the INU-MA1-SA derivative designed to produce a hydrogel …

Biocompatibility and staining properties of CdSe\CdS\SiO2 nanoparticles for in-vitro biomaterials characterization

Semiconductor nanocrystals, known as quantum dots (QDs) display well-tuned emission spectra from ultraviolet to the infrared region. Their photostability is greatly enhanced compared to fluorophores making them suitable for optical bio-imaging. In this work we have studied the cytocompatibility of CdSe\CdS\SiO2 QDs towards bovine articular chondrocytes in order to establish if these nanoparticles could be used as staining system forcells in tissue engineering purposes. Studies of QDs uptake and cell viability were conducted through morphology evaluation and MTS test. The adhesion behavior of chondrocytes deposited onto scaffolds of a derivative of hyaluronic acid functionalized with octadec…

A New Hyaluronic Acid Derivative Obtained from Atom Transfer Radical Polymerization as a siRNA Vector for CD44 Receptor Tumor Targeting

Two derivatives of hyaluronic acid (HA) have been synthesized by atom transfer radical polymerization (ATRP), starting from an ethylenediamino HA derivative (HA-EDA) and by using diethylaminoethyl methacrylate (DEAEMA) as a monomer for polymerization. Both samples, indicated as HA-EDA-pDEAEMA a and b, are able to condense siRNA, as determined by gel retardation assay and resulting complexes show a size and a zeta potential value dependent on polymerization number, as determined by dynamic light scattering measurements. In vitro studies performed on HCT 116 cell line, that over express CD44 receptor, demonstrate a receptor mediated uptake of complexes, regardless of their surface charge.

Electrospun biodegradable materials for vascular regenerative medicine

Objectives: There is a rising interest for the development of small-sized blood vessels substitutes. Several studies have been focused on the development of a biodegradable graft temporarily able to substitute the blood vessels and allow their complete regeneration after a certain time. We tried to develop a biodegradable material, with optimal mechanical characteristics and the capacity to allow cells adhesion, differentiation and proliferation by electrospinning to obtain a nano-fibrillar scaffold starting from a polymeric solution. Methods: We report the in vivo application on rats of two new electrospun biodegradable materials, specifically designed to create tubular structures. Both bi…