Periodic Reporting for period 1 - Net2Gel (Double network hydrogels for topical drug delivery applications)
Reporting period: 2020-09-01 to 2022-08-31
In many applications the use of a single material does not meet the desired properties and can result in material failure. This is often addressed by composite or hybrid materials, i.e. a material made from two or more different materials that, when combined, are higher performing than those individual materials by themselves.
Hydrogels are materials able to retain a large amount of water while keeping shape integrity. The high water content makes them highly suitable for medical applications of which contact lenses is a prominent example. Moreover, the ability to match hydrogel properties to those of the extracellular matrix and biological tissue has also triggered an enormous interest in hydrogels in drug delivery, tissue engineering and wound healing. Polymer hydrogels, either derived from natural or synthetic polymers, are three-dimensional networks which can be covalently cross-linked, physically cross-linked (e.g. by hydrogen bonds or ionic interactions), or both. The type and extent of crosslinking affects the mechanical properties of hydrogels. While physical hydrogels are typically mechanically weak, i.e. they cannot bear any load, chemical hydrogels are stronger but often lack elasticity, i.e. they are brittle and break when stretched. In many applications, the use of hydrogels is severely limited by their mechanical properties. The way to design hydrogels with improved mechanical properties is by the formation of hydrogel hybrids or double networks (DN). DN comprise of an interpenetrating network (IPN) of two chemically different individual networks, and exhibit high toughness and strength compared to a conventional single network (SN) hydrogel. The first network usually consists of a rigid physically or lightly covalently cross-linked network. This network is load bearing and provides stability. A second network is then formed within the first network, which is soft and highly flexible and provides the overall mechanical toughness and elasticity to the material. The resulting hybrid material usually possess a remarkable stretchability and toughness significantly outperforming the properties of the individual networks. By the addition of an adhesive layer, a highly flexible and stretchable wet adhesive tape might be created for wound dressing and tissue repair.
The problem of designing new hydrogel materials is extremely important today, especially for the dressing materials industry. According to a market report, the global transdermal drug delivery systems market is expected to reach 7.1 billion USD by 2023 at a Compound Annual Growth Rate of 4.5%.
The overall research aim of this project is to develop a new biodegradable and bioabsorbable class of double network hydrogels with mechanical properties suitable for the design of drug delivery patches. Specifically:
• To develop and optimize the chemistry and formation of microscopic and macroscopic poly(peptide-acrylate) hydrogel DN and evaluate their physico-chemical properties
• Investigate the biocompatibility as a function of the DN composition.
• Demonstrate applicability of DN hydrogel materials in the transdermal delivery of drugs.
• Develop a DN school experiment for secondary school pupils.
Hydrogels are materials able to retain a large amount of water while keeping shape integrity. The high water content makes them highly suitable for medical applications of which contact lenses is a prominent example. Moreover, the ability to match hydrogel properties to those of the extracellular matrix and biological tissue has also triggered an enormous interest in hydrogels in drug delivery, tissue engineering and wound healing. Polymer hydrogels, either derived from natural or synthetic polymers, are three-dimensional networks which can be covalently cross-linked, physically cross-linked (e.g. by hydrogen bonds or ionic interactions), or both. The type and extent of crosslinking affects the mechanical properties of hydrogels. While physical hydrogels are typically mechanically weak, i.e. they cannot bear any load, chemical hydrogels are stronger but often lack elasticity, i.e. they are brittle and break when stretched. In many applications, the use of hydrogels is severely limited by their mechanical properties. The way to design hydrogels with improved mechanical properties is by the formation of hydrogel hybrids or double networks (DN). DN comprise of an interpenetrating network (IPN) of two chemically different individual networks, and exhibit high toughness and strength compared to a conventional single network (SN) hydrogel. The first network usually consists of a rigid physically or lightly covalently cross-linked network. This network is load bearing and provides stability. A second network is then formed within the first network, which is soft and highly flexible and provides the overall mechanical toughness and elasticity to the material. The resulting hybrid material usually possess a remarkable stretchability and toughness significantly outperforming the properties of the individual networks. By the addition of an adhesive layer, a highly flexible and stretchable wet adhesive tape might be created for wound dressing and tissue repair.
The problem of designing new hydrogel materials is extremely important today, especially for the dressing materials industry. According to a market report, the global transdermal drug delivery systems market is expected to reach 7.1 billion USD by 2023 at a Compound Annual Growth Rate of 4.5%.
The overall research aim of this project is to develop a new biodegradable and bioabsorbable class of double network hydrogels with mechanical properties suitable for the design of drug delivery patches. Specifically:
• To develop and optimize the chemistry and formation of microscopic and macroscopic poly(peptide-acrylate) hydrogel DN and evaluate their physico-chemical properties
• Investigate the biocompatibility as a function of the DN composition.
• Demonstrate applicability of DN hydrogel materials in the transdermal delivery of drugs.
• Develop a DN school experiment for secondary school pupils.
The project consisted of the design of polypeptide-based double hydrogel networks for transdermal drug delivery. These designed materials had to be mechanically flexible so as to allow movement on the skin (or wound) as well as hold drugs. Novel chemistry was developed to achieve materials with enhanced properties validated for a drug delivery application, thereby applying expertise from a variety of disciplines. Two different families of polymers were combined, that is polypeptides derived from the polymerisation of N-Carboxyanydrides (NCA), for the first network, and polyacrylamides obtained as a result of radical polymerization for second network. For crosslinking of the polypeptide first network 1,2,4-triazoline-3,5-dione (TAD) chemistry was employed. TAD groups are reactive towards enophiles with allylic hydrogens and have been applied in reactions on biopolymers and synthetic polymers. During the project a crosslinking was successfully performed on polylysine copolymers. As a next step six double networks were prepared by radical polymerization of acrylamides within the primary polypeptide gels. Obtained DN hydrogels exhibited increased mechanical properties and stability. Additionally, as shown by biological studies, the application of DNs significantly improved biocompatibility of hydrogels. Overall, obtained DN hydrogels outperformed single networks of both components separately.
Those of obtained hydrogels, which proved biocompatible, were subjected to drug loading and delivery studies. Anti-inflammatory drug indomethacin was selected as the model active ingredient. The drug was loaded with very good efficiency. Next the release studies were performed, showing successful drug release over time. The release process was shown to be dependent mainly on diffusion of the drug from the hydrogel into the release media.
The results obtained were presented so far at two international conferences and were used to prepare a manuscript for a publication.
Based on the results obtained, a plan and a full experimental workup manual for secondary school students were prepared, aimed at familiarizing with the concept of DNs and popularizing science among younger generations.
Those of obtained hydrogels, which proved biocompatible, were subjected to drug loading and delivery studies. Anti-inflammatory drug indomethacin was selected as the model active ingredient. The drug was loaded with very good efficiency. Next the release studies were performed, showing successful drug release over time. The release process was shown to be dependent mainly on diffusion of the drug from the hydrogel into the release media.
The results obtained were presented so far at two international conferences and were used to prepare a manuscript for a publication.
Based on the results obtained, a plan and a full experimental workup manual for secondary school students were prepared, aimed at familiarizing with the concept of DNs and popularizing science among younger generations.
The proposed solutions are innovative compared to the current state of art. Until now, there were few literature reports regarding hydrogels based on double polymer networks, which would use polypeptides. The results obtained as part of the project have proved that acrylamides radical polymerization can be successfully performed inside the primary polypeptide network. An important discovery was that the use of DN allows for a significant increase in hydrogel biocompatibility, and thus offers a wide spectrum of applications that go beyond the field of drug carriers. In addition, by effectively loading and releasing the drug from the received polymer matrix, the spectrum of products has been expanded, which can be used as dressing materials or media of drugs.
It is worth noting that the use of polypeptide networks also affects at least partial biodegradability of the proposed materials, and thus is an avenue leading to a reduction in waste production with which society faces.
It is worth noting that the use of polypeptide networks also affects at least partial biodegradability of the proposed materials, and thus is an avenue leading to a reduction in waste production with which society faces.