Search Results (23)

Hyaluronic acid (HA) fillers represent the most frequently performed minimally invasive procedures for facial rejuvenation, yet their overall safety profile is critically influenced by the cross-linking technology employed. Polyethylene glycol diglycidyl ether (PEGDE) has recently been introduced as an alternative to 1,4-butanediol diglycidyl ether (BDDE). The present prospective observational study was undertaken to evaluate the safety of a PEGDE-crosslinked HA filler for the correction of severe nasolabial folds. A total of 60 patients received bilateral injections of 1 mL per side and were monitored over a six-month period. Safety assessment included systematic documentation of adverse events and non-invasive biophysical and imaging techniques, specifically corneometry, sebumetry, and high-frequency ultrasound (HFUS). The treatment was well tolerated: 15% of patients reported only mild and transient adverse events, such as pain, swelling, bruising, or discomfort, while no serious adverse events, vascular compromise, or ocular complications were observed. Corneometry demonstrated a statistically significant increase in cutaneous hydration, sebumetry confirmed stability of sebaceous activity, and HFUS documented correct placement, homogeneous distribution, and progressive integration of the filler without nodules or granulomatous reactions. These findings support the favorable short-term safety and local tolerance of PEGDE-crosslinked HA fillers in the treatment of severe nasolabial folds. Full article

A quaternized and phenyl-functionalized hyperbranched PEI-based sponge (S_HPEI-QP) was successfully prepared, and its adsorption performance was investigated to evaluate its potential for removing the anionic non-steroidal anti-inflammatory drug (ibuprofen (IBU)). We reported that the synthesis of polyethyleneimine-based sponges was achieved through cryo-polymerization using 1,4-butanediol diglycidyl ether (BDDE) as the crosslinking agent. Subsequent functionalization with resorcinol diglycidyl ether (RDGE) and trimethylamine introduced quaternary ammonium cations, imparting strong basicity and hydrophilicity, as well as phenyl groups, conferring hydrophobic characteristics, respectively. The aforementioned sponge material, S_HPE-QPI, primarily facilitates the efficient adsorption of IBU in aqueous solutions through the anion exchange properties of quaternary ammonium groups and the π-π interactions associated with oxygen-activated benzene rings. Various characterizations, such as scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), and specific surface area determination method (BET), confirmed the successful synthesis of the bifunctionalized S_HPEI-QP adsorbent. This adsorbent features a porous structure (specific surface area of 77.2 m² g⁻¹ and pore size distribution of 25–100 nm) and an isoelectric point (pH_pzc) of 9.38. The adsorption kinetics of the adsorbent for IBU were extremely rapid and conformed to a pseudo-second-order kinetic model, and the adsorption isotherm aligned with the Langmuir isotherm model. Noteworthily, S_HPEI-QP demonstrated an exceptionally high adsorption capacity for IBU, achieving a maximum uptake of 905.73 mg g⁻¹ at pH 7.0, which surpassed that of most of the previous reported adsorbents. Moreover, the sponge material can be chemically regenerated. After eight cycles of use, the adsorption efficiency decreased by only 4%. These findings suggest that the synthesized dendritic anion exchange adsorbent represents a promising candidate for the removal of IBU from contaminated water sources. Full article

In this study, promising compositions of cross-linked gelatin-based scaffolds were tested in vitro and in vivo. Our aim was to utilize a solid matrix that is suitable for medical applications, and to be regulated as a medical device as a soft tissue implant. Three different cross-linkers were used in vitro, and the optimal composition was chosen for in vivo testing. The surfaces of the scaffolds were observed with SEM, and, in the case of divinyl sulfone (DVS), small cracks appeared, and the structure was rigid. With the use of poly(ethylene glycol) diglycidyl ether (PEGDE), the surface was found to be uneven, but generally, the appearance was similar in each case. The optimal scaffold contained 5 v/v % 1,4-butanediol diglycidyl ether (BDDE), and was implanted for either one month or three months in the back of BL6 mice. The explants were assessed using analytical techniques, including microscopic imaging and histological analysis, and it was found that cells, connective tissue, and extracellular matrix (ECM) were all able to successfully infiltrate the scaffolds and did not induce any inflammation. In summary, these novel implants seem to promote blood vessel formation and support the adherence of adipose tissue, as confirmed by optical microscopy and histological evaluations. Full article

Background/Objectives: This Phase 3, randomised, double-blind, multicentre trial evaluated the efficacy and safety of a novel hyaluronic acid hydrogel cross-linked with hexamethylenediamine (HMDA-HA) compared to a conventional 1,4-butanediol diglycidyl ether cross-linked HA (BDDE-HA) in patients with mild-to-moderate knee osteoarthritis (OA). Methods: A total of 223 adults (mean age 63.5 years; 167 women) with Kellgren–Lawrence (KL) grade I–III knee OA were randomised 1:1 to receive two intra-articular injections of HMDA-HA or BDDE-HA at baseline and at 24 weeks. The primary endpoint was changes from baseline in weight-bearing pain (WBP) on a 100 mm visual analogue scale (VAS) at Week 12, assessed in the per-protocol population. A non-inferiority margin of 10 mm was predefined. Secondary outcomes included global assessments, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index scores, responder rates, and rescue medication use [ClinicalTrials.gov: NCT06307847]. Results: At Week 12, least squares mean change (standard error [SE]) in WBP was −23.72 (1.88) mm in the HMDA-HA group (n = 83) and −25.99 (1.76) mm in the BDDE-HA group (n = 95), yielding a difference of 2.26 mm (95% confidence interval [CI]: −2.83 to 7.34; p = 0.3825), thus demonstrating the non-inferiority of HMDA-HA to BDDE-HA. Secondary outcomes were comparable between groups. A total of 136 adverse events were reported: 44 (41.1%) in the HMDA-HA group and 32 (28.1%) in the BDDE-HA group, with no treatment-related adverse drug reactions. Conclusions: A single-injection intra-articular regimen of HMDA-HA was effective and safe for the treatment of adult patients with mild-to-moderate knee OA. Full article

This study proposes a new and simple process that improves the quality of a hyaluronic acid (HA) filler crosslinked with 1,4-butanediol diglycidyl ether (BDDE) using solution dispersion at a low temperature. This process involves the solvent being dispersed among the solute naturally after the mixing process. The process used in this study involved two reactions. First, the solution was dispersed among HA molecules (Mw = ~0.7 MDa) creating a well-homogenized mixture. Second, the decomposition and synthesis of HA occurred naturally in an aqueous alkaline solution (>pH 11), the weight average molar mass (Mw) was adjusted (Mw = ~143,000), and the crosslinking surface area was expanded, allowing for a high degree of crosslinking. Therefore, the viscoelasticity and cohesion of the filler increased with the new method compared to the previous process both at the lab scale (previous process:new process, viscosity (cP) = 24M:43M, storage modulus (Pa) = 306:538, loss modulus (Pa) = 33:61, and tack (N) = 0.24:0.43) and at the factory scale (previous process:new process, complex viscosity (cP) = 19M:26M, storage modulus (Pa) = 229:314, loss modulus (Pa) = 71:107, and tack (N) = 0.35:0.43). Full article

Potential disruptions in the biocompatibility of hyaluronic acid (HA) fillers can arise with mono-linked 1,4-butanediol diglycidyl ether (BDDE) or unreacted (pendant) 1,4-butanediol di-(propan-2,3-diolyl) ether. Assessing the filler’s degree of modification involves evaluating improperly cross-linked BDDE. This study analyzed commercially available HA fillers using nuclear magnetic resonance (NMR), focusing on key parameters, such as the degree of modification (MoD), the cross-linker ratio (CrR), and the degree of cross-linking. We assessed thirteen commercially available HA fillers using NMR. The samples were placed in an NMR instrument, and each sample was analyzed for 26 h, including MoD and CrR assessments. MoD ¹H ranged from 17.065% to 2.239%, MoD ¹³C ranged from 12.567% to 1.947%, and CrR ¹³C ranged from 0.394 to 0.014. Significant distinctions were observed in the CrR ¹³C values when the MoD values of the products were similar. This study underscores the importance of considering the MoD and the CrR together to ensure optimal cross-linking and minimize the risks associated with residual BDDE impurities. Utilizing NMR for HA gel characterization provides valuable insights regarding product quality control, safety assessments, and clinical performance evaluations for esthetic interventions, contributing to filler product improvements. Further studies correlating NMR findings with real-world outcomes are essential for ensuring safety and efficacy. Full article

Hydrogel features can be designed and optimized using different crosslinking agents to meet specific requirements. In this regard, the present work investigates the physico-chemical features of cellulose-based hydrogels, designed by using different epoxy crosslinkers from the same glycidyl family, namely epichlorohydrin (ECH), 1,4-butanediol diglycidyl ether (BDDE), and trimethylolpropane triglycidyl ether (TMPTGE). The effect of the crosslinker’s structure (from simple to branched) and functionality (mono-, bi- and tri-epoxy groups) on the hydrogels’ features was studied. The performances of the hydrogels were investigated through the gel fraction, as well as by ATR-FTIR, DVS, SEM, DSC, and TG analyses. Also, the swelling and rheological behaviors of the hydrogels were examined. The advantages and limitations of each approach were discussed and a strong correlation between the crosslinker structure and the hydrogel properties was established. The formation of new ether bonds was evidenced by ATR-FTIR spectroscopy. It was emphasized that the pore size is directly influenced by the crosslinker type, namely, it decreases with the increasing number of epoxy groups from the crosslinker molecule, i.e., from 46 ± 11.1 µm (hydrogel CE, with ECH) to 12.3 ± 2.5 µm (hydrogel CB, with BDDE) and 6.7 ± 1.5 µm (hydrogel CT, with TMPTGE). The rheological behavior is consistent with the swelling data and hydrogel morphology, such as CE with the highest Q_max and the largest pore size being relatively more elastic than CB and CT. Instead, the denser matrices obtained by using crosslinkers with more complex structures have better thermal stability. The experimental results highlight the possibility of using a specific crosslinking agent, with a defined structure and functionality, in order to establish the main characteristics of hydrogels and, implicitly, to design them for a certain field of application. Full article

Cross-linking chitosan at room and subzero temperature using a series of diglycidyl ethers of glycols (DEs)—ethylene glycol (EGDE), 1,4-butanediol (BDDE), and poly(ethylene glycol) (PEGDE) has been investigated to demonstrate that DEs can be a more powerful alternative to glutaraldehyde (GA) for fabrication of biocompatible chitosan cryogels with tunable properties. Gelation of chitosan with DEs was significantly slower than with GA, allowing formation of cryogels with larger pores and higher permeability, more suitable for flow-through applications and cell culturing. Increased hydration of the cross-links with increased DE chain length weakened intermolecular hydrogen bonding in chitosan and improved cryogel elasticity. At high cross-linking ratios (DE:chitosan 1:4), the toughness and compressive strength of the cryogels decreased in the order EGDE > BDDE > PEGDE. By varying the DE chain length and concentration, permeable chitosan cryogels with elasticity moduli from 10.4 ± 0.8 to 41 ± 3 kPa, toughness from 2.68 ± 0.5 to 8.3 ± 0.1 kJ/m³, and compressive strength at 75% strain from 11 ± 2 to 33 ± 4 kPa were fabricated. Susceptibility of cryogels to enzymatic hydrolysis was identified as the parameter most sensitive to cross-linking conditions. Weight loss of cryogels increased with increased DE chain length, and degradation rate of PEGDE-cross-linked chitosan decreased 612-fold, when the cross-linker concentration increased 20-fold. Full article

In this present study, the material science background of crosslinked gelatin (GEL) was investigated. The aim was to assess the optimal reaction parameters for the production of a water-insoluble crosslinked gelatin matrix suitable for heat sterilization. Matrices were subjected to enzymatic degradation assessments, and their ability to withstand heat sterilization was evaluated. The impact of different crosslinkers on matrix properties was analyzed. It was found that matrices crosslinked with butanediol diglycidyl ether (BDDE) and poly(ethylene glycol) diglycidyl ether (PEGDE) were resistant to enzymatic degradation and heat sterilization. Additionally, at 1 v/v % crosslinker concentration, the crosslinked weight was lower than the starting weight, suggesting simultaneous degradation and crosslinking. The crosslinked weight and swelling ratio were optimal in the case of the matrices that were crosslinked with 3% and 5% v/v BDDE and PEGDE. FTIR analysis confirmed crosslinking, and the reduction of free primary amino groups indicated effective crosslinking even at a 1% v/v crosslinker concentration. Moreover, stress–strain and compression characteristics of the 5% v/v BDDE crosslinked matrix were comparable to native gelatin. Based on material science measurements, the crosslinked matrices may be promising candidates for scaffold development, including properties such as resistance to enzymatic degradation and heat sterilization. Full article

The use of fillers for soft tissue augmentation is an approach to restore the structure in surgically or traumatically created tissue voids. Hyaluronic acid (HA), is one of the main components of the extracellular matrix, and it is widely employed in the design of materials with features similar to human tissues. HA-based fillers already find extensive use in soft tissue applications, but are burdened with inherent drawbacks, such as poor thermal stability. A well-known strategy to improve the HA properties is to reticulate it with 1,4-Butanediol diglycidyl ether (BDDE). The aim of this work was to improve the design of HA hydrogels as fillers, by developing a crosslinking HA method with carboxymethyl cellulose (CMC) by means of BDDE. CMC is a water soluble cellulose ether, whose insertion into the hydrogel can lead to increased thermal stability. HA/CMC hydrogels at different ratios were prepared, and their rheological properties and thermal stability were investigated. The hydrogel with an HA/CMC ratio of 1/1 resulted in the highest values of viscoelastic moduli before and after thermal treatment. The morphology of the hydrogel was examined via SEM. Biocompatibility response, performed with the Alamar blue assay on fibroblast cells, showed a safety percentage of around 90% until 72 h. Full article

Hyaluronic acid is one of the most important ingredients in dermal fillers, where it is often cross-linked to gain more favorable rheological properties and to improve the implant duration. Poly(ethylene glycol) diglycidyl ether (PEGDE) has been recently introduced as a crosslinker because of its very similar chemical reactivity with the most-used crosslinker BDDE, while giving special rheological properties. Monitoring the amount of the crosslinker residues in the final device is always necessary, but in the case of PEGDE, no methods are available in literature. Here, we present an HPLC-QTOF method, validated according to the guidelines of the International Council on Harmonization, which enables the efficient routine examination of the PEGDE content in HA hydrogels. Full article

The cross-linking of polysaccharides is a universal approach to affect their structure and physical properties. Both physical and chemical methods are used for this purpose. Although chemical cross-linking provides good thermal and mechanical stability for the final products, the compounds used as stabilizers can affect the integrity of the cross-linked substances or have toxic properties that limit the applicability of the final products. These risks might be mitigated by using physically cross-linked gels. In the present study, we attempted to obtain hybrid materials based on carbon nonwovens with a layer of cross-linked hyaluronan and peptides that are fragments of bone morphogenetic proteins (BMPs). A variety of cross-linking procedures and cross-linking agents (1,4-butanediamine, citric acid, and BDDE) were tested to find the most optimal method to coat the hydrophobic carbon nonwovens with a hydrophilic hyaluronic acid (HA) layer. Both the use of hyaluronic acid chemically modified with BMP fragments and a physical modification approach (layer-by-layer method) were proposed. The obtained hybrid materials were tested with the spectrometric (MALDI-TOF MS) and spectroscopic methods (IR and 1H-NMR). It was found that the chemical cross-linking of polysaccharides is an effective method for the deposition of a polar active substance on the surface of a hydrophobic carbon nonwoven fabric and that the final material is highly biocompatible. Full article

The present research aimed to characterize soft tissue implants that were prepared with the use of crosslinked hyaluronic acid (HA) using two different crosslinkers and multiple reagent concentrations, alone or in combination with fibrin. The effect of the implants was evaluated in an in vivo mouse model, after 4 weeks in one group and after 12 weeks in the other. The explants were compared using analytical methods, evaluating microscopic images, and a histology analysis. The kinetics of the degradation and remodeling of explants were found to be greatly dependent on the concentration and type of crosslinker; generally, divinyl sulfone (DVS) resists degradation more effectively compared to butanediol diglycidyl ether (BDDE). The presence of fibrin enhances the formation of blood vessels, and the infiltration of cells and extracellular matrix. In summary, if the aim is to create a soft tissue implant with easier degradation of the HA content, then the use of 2–5% BDDE is found to be optimal. For a longer degradation time, 5% DVS is the more suitable crosslinker. The use of fibrin was found to support the biological process of remodeling, while keeping the advances of HA in void filling, enabling the parallel degradation and remodeling processes. Full article

Here, we present a one-pot procedure for the preparation of hyaluronic acid (HA) sulfonated hydrogels in aqueous alkaline medium. The HA hydrogels were crosslinked using 1,4-butanedioldiglycidyl ether (BDDE) alone, or together with N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (Bes), as a safe sulfonating agent. Conditions for the simultaneous reaction of HA with BDDE and Bes were optimized and the resulting hydrogels were characterized under different reaction times (24, 72, and 96 h). The incorporation of sulfonic groups into the HA network was proven by elemental analysis and FTIR spectroscopy and its effect on water uptake was evaluated. Compared with the non-sulfonated sample, sulfonated gels showed improved mechanical properties, with their compressive modulus increased from 15 to 70 kPa, higher stability towards hyaluronidase, and better biocompatibility to 10T1/2 fibroblasts, especially after the absorption of collagen. As main advantages, the procedure described represents an easy and reproducible methodology for the fabrication of sulfonated hydrogels, which does not require toxic chemicals and/or solvents. Full article

BDDE (1,4-butanediol-diglycidylether)-crosslinked hyaluronan (HA) hydrogels are widely used for dermo-aesthetic purposes. The rheology and stability of the gels under physiological conditions greatly affect their clinical indications and outcomes. To date, no studies investigating how these features are related to the chemistry of the polymeric network have been reported. Here, four available HA-BDDE hydrogels were studied to determine how and to what extent their rheology and stability with respect to enzymatic hydrolysis relate to the type and degree of HA structural modification. ¹H-/¹³C-NMR analyses were associated for the quantification of the “true” HA chemical derivatization level, discriminating between HA that was effectively crosslinked by BDDE, and branched HA with BDDE that was anchored on one side. The rheology was measured conventionally and during hydration in a physiological medium. Sensitivity to bovine testicular hyaluronidase was quantified. The correlation between NMR data and gel rheology/stability was evaluated. The study indicated that (1) the gels greatly differed in the amounts of branched, crosslinked, and overall modified HA, with most of the HA being branched; (2) unexpectedly, the conventionally measured rheological properties did not correlate with the chemical data; (3) the gels’ ranking in terms of rheology was greatly affected by hydration; (4) the rheology of the hydrated gels was quantitatively correlated with the amount of crosslinked HA, whereas the correlations with the total HA modification level and with the degree of branched HA were less significant; (5) increasing HA derivatization/crosslinking over 9/3 mol% did not enhance the stability with respect to hyaluronidases. These results broaden our knowledge of these gels and provide valuable information for improving their design and characterization. Full article