Evolution of Crosslinking Methods in Obtaining Alginate Hydrogels for Drug Delivery

Evolution of Crosslinking Methods in Obtaining Alginate Hydrogels for Drug Delivery

• Author
• Expedito Lopes Fernandes Júnior
• Co-authors
• Antônia Carla de Jesus Oliveira , Mônica Felts de La Roca Soares , José Lamartine Soares Sobrinho
• Abstract

• Introduction

  Cross-linking is the formation of cross-links between adjacent polymer chains to form an entangled matrix. When this process takes place without the formation of covalent bonds, but only maintains the architecture of the material by intermolecular forces, it is a physical method. If there are covalent interactions, the method is chemical. In this sense, there are many materials produced from crosslinking, among which hydrogels, biomaterials for application in fields such as drug delivery, tissue engineering, bone regeneration and cancer therapy, are made up of hydrophilic polymers and have a high capacity for water absorption (Soleimani et al., 2021).

       Alginate - a natural polysaccharide composed of mannuronic acid and guluronic acid - is one of the most used polysaccharides in the formulation of hydrogels. Full of hydroxyl and carboxyl groups in its structure, it is classified as a polyanionic polymer, which is why many of the biomaterials made from alginate are obtained physically due to the ease of forming cross-links with Ca2+ and Ba2+ cations (Tan et al., 2019 ). When obtained in this way, however, alginate hydrogels tend to have lower mechanical resistance, despite greater biocompatibility. Meanwhile, those obtained chemically are firm, but toxic thanks to the use of harmful crosslinking agents (Abbasian et al., 2019). In this sense, it is important to optimize each process in order to combine improvements in all parameters of greatest interest in hydrogels, namely: porosity, biocompatibility, mechanical resistance and flexibility (Sood et al., 2021).

   

       Chemical cross-linking methods can be broadly divided into three types: free radical polymerization, macromolecular chemical self-cross-linking and physicochemical double-cross-linking. In the latter, the combination of chemical and physical strategies makes it possible to combine the benefits of both, presenting as the main challenge, however, the difficult conditions to which biomaterials can be subjected, such as high temperatures, incidence of destructive UV radiation and the already mentioned toxic effects of crosslinking agents necessary for the formation of covalent bonds. In the meantime, continuous experimentation to optimize properties and processes in the formulation is essential.

   

  Aims

       Investigate physicochemical crosslinking strategies documented in the literature for alginate hydrogels compared to conventional crosslinking, evaluating trends in mechanical, rheological, thermal, morphological and structural properties, as well as the drug delivery pattern, based on the method used.

   

  Methods

       A literature review was carried out in the Sciencedirect database using the descriptors “dual-crosslinked”, “alginate” and “hydrogel”, obtaining 1872 research articles in English in the last 3 years, with 10 articles selected for the review.

   

  Results and Discussion

   

       From a structural point of view, alginate meets the main requirements for physical cross-linking. In fact, interpenetrating network systems created from the diffusion of calcium ions to the center of the polymeric tangle establish sufficient firmness to obtain a hydrogel that can certainly be chemically improved (Balam, Boztepe & Künkül, 2022). Furthermore, one of the most common modifications in alginate, converting the carboxyl functions into carboxylate salt, further stabilizes the resonance in the functional group and confers greater polarity, enhancing the ionic interaction with divalent cations such as Ca2+. The gulonuronic acid units constitute G chains and the mannuronic acid units constitute M chains. These are linked irregularly by Beta-1,4-glycosidic bonds. The length of the G chains is directly related to mechanical properties, while the length of the M chains to immunogenicity and, therefore, biocompatibility (Tan et al., 2023).

       Although they produce hydrogels with lower mechanical strength, physical crosslinking methods for alginate are still a gamble that often results in good prospects. An example of this are two recent works: in the first, a modified sodium alginate hydrogel produced by photo-crosslinking showed thermal stability, mechanical resistance, acceptable gastrointestinal tolerance and responsiveness to the nitric oxide (NO) release system - a relevant vasodilator in the inflammatory process - modifying its structure in the presence of this chemical messenger and becoming non-toxic to cells and without thrombogenic effect, which opens up space for future research with drug delivery targeted to the NO system (Chen et al., 2020); In the second, polyacrylamide and alginate hydrogel was generated by ionic crosslinking using calcium ions obtained from calcium chloride (CaCl2), forming a double interpenetrating network with high firmness (Houben & Pitet, 2023).

       As can be seen, alginate biomaterials are excellent sources of study for drug delivery when optimizing them. In fact, in addition to boasting a high number of carboxyls, which makes it pH-responsive, the addition of other groups through modification can introduce new properties such as thermal sensitivity, responsiveness to oxidative and reductive processes and even magnetic properties to allow delivery of drugs in a progressively more targeted and selective way (Tan et al., 2023).

  However, prior modification of the structure is not a strategy exclusive to physical methods. In this sense, there are many recent works that investigate the properties of modified alginate hydrogels produced by a mixed method, and it is therefore appropriate to mention some of them, as well as discuss their innovative character and application in health sciences: the alginate hydrogel formed by cross-linking physical-chemistry (ionic with Ca2+ ions and chemistry with glutaraldehyde as a cross-linking agent) tested for carrying sulfanilamide demonstrated adjustable fluid absorption capacity and controlled release of active ingredient, promising material as a wound dressing by combining absorptive potential with antibacterial properties , results superior to those obtained for exclusive ionic crosslinking with Ca2+ ions (Sun et al., 2020); Alginate hydrogel, oxidized alginate and silk fibroin were obtained by double crosslinking (physical by ionic gelation and chemical by Schiff base reaction). Now, the Schiff reaction can occur between primary amine groups and aldehyde at room temperature to form imine groups between polymer chains without a crosslinking agent. Therefore, alginate, having its hydroxyl groups oxidized to carbonyl with sodium metaperiodate, can serve as one of the reactants in this reaction and, in this context, the hydrogel formulated with silk fibroin (containing cellular binding sites and the amine group) demonstrated greater differentiation into bone tissue than that obtained by physical cross-linking alone, as well as a significant increase in the release of alkaline phosphatase as an early marker of bone differentiation (Ghorbani et al., 2023); In a pioneering study, a metal organic structure (MOF) of Copper and 4,4'-azopyridine (AZPY) was encapsulated in methacrylated alginate hydrogel for antimicrobial applications. Encapsulation was carried out by photo-crosslinking induced by visible light, while obtaining the physicochemical hydrogel was completed by the addition of calcium chloride (CaCl2). The biomaterial obtained demonstrated excellent antibacterial properties against two strains, methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus mutans, and antifungal properties against Candida albicans. Furthermore, it has considerable potential in tissue engineering for multiple applications in the biomedical field due to its controllable mechanical properties and excellent antimicrobial effect plus low cytotoxicity with tests in mice (Gwon et al., 2023).
   
  Conclusion
       In this work, a literature review was carried out in order to gather and explain the importance of studies with alginate crosslinking, one of the polysaccharides of greatest interest in the formulation of biomaterials. The structural principles that justify the preference of physical methods for cross-linking alginate were explained, as well as the mechanisms involved. Some work with alternative and even more promising methods for biotechnological applications was also considered, highlighting that of targeted and controlled drug delivery. In view of the above, it is important to continue research with alginate and the biomaterials created from it in order to provide good results and perspectives for future studies, as well as beneficial innovations in health sciences and the treatment of various diseases.

   

  Acknowledgments

  CAPES, Propesqui and the team from the medicine and related quality control center (NCQMC) of the Department of Pharmaceutical Sciences at UFPE, Recife, PE, Brazil. Special thanks to the researcher Antônia Carla de Jesus Oliveira and professors Mônica Felts de La Roca Soares and José Lamartine Soares Sobrinho, members of the mentioned laboratory.

   

  References

  TAN, J. et al., Development of alginate-based hydrogels: Crosslinking strategies and biomedical applications, International Journal of Biological Macromolecules,

  Volume 239, 2023, https://doi.org/10.1016/j.ijbiomac.2023.124275.

   

  CHEN, P. et al., Photo-crosslinking modified sodium alginate hydrogel for targeting delivery potential by NO response, International Journal of Biological Macromolecules, 2023, https://doi.org/10.1016/j.ijbiomac.2023.126454.

   

  SUN, X. et al., Alginate hydrogel fibers based on ionic and chemical crosslinking for wound dressings, International Journal of Biological Macromolecules, Volume 157, 2020, Pages 522-529, https://doi.org/10.1016/j.ijbiomac.2020.04.210.

   

  GHORBANI, M. et al., Dual-crosslinked in-situ forming alginate/silk fibroin hydrogel with potential for bone tissue engineering, Biomaterials Advances, Volume 153, 2023, https://doi.org/10.1016/j.bioadv.2023.213565.

   

  GWON, K. et al., Construction of a bioactive copper-based metal organic framework-embedded dual-crosslinked alginate hydrogel for antimicrobial applications, International Journal of Biological Macromolecules, Volume 242, Part 1, 2023, https://doi.org/10.1016/j.ijbiomac.2023.124840.

   

  TAN, J. et al., Development of alginate-based hydrogels: Crosslinking strategies and biomedical applications, International Journal of Biological Macromolecules, Volume 239, 2023, https://doi.org/10.1016/j.ijbiomac.2023.124275.

   

  BALAN, K.E. BOZTEPE, C. KUNKUL, A. Modeling the effect of physical crosslinking degree of pH and temperature responsive poly(NIPAAm-co-VSA)/alginate IPN hydrogels on drug release behavior, Journal of Drug Delivery Science and Technology, Volume 75, 2022, , https://doi.org/10.1016/j.jddst.2022.103671.

   

  HOUBEN, A. PITET, L.M. Ionic crosslinking strategies for poly(acrylamide) /alginate hybrid hydrogels, Reactive and Functional Polymers, Volume 191, 2023, https://doi.org/10.1016/j.reactfunctpolym.2023.105676.

   

  SOLEIMANI, K. et al., A novel bioreducible and pH-responsive magnetic nanohydrogel based on ?-cyclodextrin for chemo/hyperthermia therapy of cancer, Carbohydrate Polymers, Volume 252, 2021, https://doi.org/10.1016/j.carbpol.2020.117229.

   

  SOOD, A. GUPTA, A. AGRAWAL, G. Recent advances in polysaccharides based biomaterials for drug delivery and tissue engineering applications, Carbohydrate Polymer Technologies and Applications, Volume 2, 2021, https://doi.org/10.1016/j.carpta.2021.100067.

   

   

   
• Keywords
• Crosslinking, hydrogel, polymer, alginate, modification.
• Modality
• Pôster
• Subject Area
• Quimioinformatics, Bioinformatics and TheoreticalChemistry