The main aim of this review is to assess the potential use of natural cross-linking agents, such as genipin, citric acid, tannic acid, epigallocatechin gallate, and vanillin in preparing chemically cross-linked hydrogels for the biomedical, pharmaceutical, and cosmetic industries. Chemical cross-linking is one of the most important methods that is commonly used to form mechanically strong hydrogels based on biopolymers, such as alginates, chitosan, hyaluronic acid, collagen, gelatin, and fibroin. Moreover, the properties of natural cross-linking agents and their advantages and disadvantages are compared relative to their commonly known synthetic cross-linking counterparts. Nowadays, advanced technologies can facilitate the acquisition of high-purity biomaterials from unreacted components with no additional purification steps. However, while planning and designing a chemical process, energy and water consumption should be limited in order to reduce the risks associated with global warming. However, many synthetic cross-linking agents, such as N,N′-methylenebisacrylamide, ethylene glycol dimethacrylate, poly (ethylene glycol) diacrylates, epichlorohydrin, and glutaraldehyde, are harmful to both humans and the environment. One solution to this problem could be the use of bio-cross-linking agents obtained from natural resources, which would eliminate their toxic effects and ensure the safety for humans and the environment.

In this paper, the preparation method of bio-hybrid hydrogels incorporated into a system of salicylic acid-pH/thermosensitive nanocarriers to speed up the wound-healing process was developed. This combination creates a dual drug delivery system, which releases the model hydrophobic active substance—salicylic acid—in a gradual and controlled manner for an extended time. Our research team has determined the various properties of bio-hybrid hydrogels based on their physicochemical (swelling degree, and degradation), structural (FT-IR), morphological (SEM), and mechanical (elongation tests) traits. Moreover, empty pH/thermosensitive nanocarriers and their salicylic acid-containing systems were characterized using the following methods: DLS, TG/DTG, and DSC. Additionally, salicylic acid release profiles directly from thermosensitive nanocarriers were compared to the bio-hybrid matrix. These studies were conducted in PBS (pH = 7.4) for 7 days using the USP4 method. To evaluate the antibacterial properties of the obtained materials, the inhibition of growth of Staphylococcus aureus, Escherichia coli, Candida albicans, and Aspergillus niger—as the main microorganisms responsible for human infections—were tested. The obtained results indicated that the pH/thermosensitive nanocarrier–salicylic acid system and bio-hybrid hydrogels are characterized by antibacterial activity against both S. aureus and E. coli.

Gelatine hydrogels can be prepared using different cross-linking methods, such as enzymatic, physical or chemical. Unfortunately, in the case of chemical cross-linking, the typically utilized synthetic cross-linkers are harmful to human health and the environment. Therefore, in accordance with the principles of green chemistry and sustainable development, we have obtained compounds for the chemical cross-linking of hydrogel polymers from the processing of spent coffee grounds. In this study, gelatin/κ-carrageenan hydrogels are cross-linked using a bio-cross-linking agent from spent coffee grounds. Their physicochemical and thermal properties are compared with those of standard physical gels. The chemical cross-linking was confirmed based on FT-IR spectra, which demonstrated the formation of new covalent bonds between the oxidized polyphenols included in the extract from the spent coffee grounds and the amide groups present in the gelatine structure. Significant differences were also observed in morphology (SEM images) and other physico-chemical characteristics (gel fraction, swelling ability, hardness). The chemically cross-linked hydrogels in comparison to physically ones are characterized by a better developed porous network, a slightly higher gel fraction (64.03 ± 4.52% as compared to 68.15 ± 0.77%), and a lower swelling ratio (3820 ± 45% as compared to 1773 ± 35%), while TGA results show that they have better thermal stability. The research confirmed the possibility of using the developed natural cross-linking agent in the process of obtaining hydrogel materials based on bio-polymers.

Currently, there is a tendency for new forms of carrier-drug systems to appear with prolonged and controlled release. However, in order to design medical or pharmaceutical devices, which have to be characterized by high quality and the assumed parameters in real conditions, it is necessary to analyze this process based on in vitro release (IVR) testing methods. For this purpose, extracorporeal studies are carried out, which enable the determination of the release profiles of active substances using a simulated tissue-like environment. Here, we focused on the release tests of poorly water-soluble compounds (salicylic acid and fluocinolone acetonide) from the dual drug delivery system using the flow-through cell method (USP4). Additionally, bio-hybrid hydrogel matrix containing the system of thermosensitive nanocarrier with salicylic acid and fluocinolone acetonide was subjected to the following investigations: physicochemical (swelling ability, gel fraction), morphological (SEM analysis) and structural using FT-IR spectroscopy. On the basis of results, we can conclude that the USP4 method may be suitable, especially for the release tests of poorly water-soluble components introduced into modern forms of drug administration, such as polymeric matrices, hydrogels, nano- and microcarriers as well as hybrid systems.