Periodic Reporting for period 2 - DAHAD (Dual Antibacterial Hydrogel ADhesives)
Reporting period: 2024-06-01 to 2025-05-31
Dual Antibacterial Hydrogel Adhesives (DAHAD) project consists in the development of novel alternatives for skin closure applications, combining biomedical adhesives with smart drug delivery systems. This international and interdisciplinary research project, within the field of materials chemistry, encompass three entities: the Instituto de Nanociencia y Materiales de Aragón (CSIC-UZ, Spain), the Universidad de Zaragoza (Spain) and Purdue University (US).
Nowadays, closure techniques typically employed in medical surgery, such as sutures, staples or screws, still remain highly invasive, painful and may be prone to infections. Surgical site infections are indeed the second most frequent type of nosocomial infections leading to prolonged hospitalization, morbidity and even mortality. Several skin adhesives such as Dermabond or Tisseel have been developed but their limited properties or toxicity are hampering a wider implementation. The main challenges that need to be addressed in order to spread the use of surgical adhesives is to develop adhesives capable to stick organs in a wet environment where physiological medium and blood are present while being fully biocompatible. Moreover, by incorporating drug delivery capability into such adhesives, infections, inflammation and/or pain for examples, could be treated locally and more efficiently reducing the risks associated with surgical trauma.
Within this context and following biomimetics insights, previously published works described the design of new adhesive materials containing mussel-inspired catechol moieties have been designed. Such material showed impressive adhesion in wet conditions and delightful results in biological adhesion, being able to glue several tissues in vitro and in vivo. Within DAHAD project, novel adhesive macromolecules containing catechol groups will be synthesized using a molecular design that combines linear and hyperbranched architectures for improved properties. The influence of such design on the adhesion will be assessed. Then, the same macromolecules will be used to prepare hydrogels with both adhesive and antibacterial properties. Adhesion will be tested on skin and antibacterial activity will be tested against the following bacteria: Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the mechanical properties of the hydrogels will be evaluated and improved by incorporating dynamic bonds, such as H-bonding, within the hydrogel structure.
Nowadays, closure techniques typically employed in medical surgery, such as sutures, staples or screws, still remain highly invasive, painful and may be prone to infections. Surgical site infections are indeed the second most frequent type of nosocomial infections leading to prolonged hospitalization, morbidity and even mortality. Several skin adhesives such as Dermabond or Tisseel have been developed but their limited properties or toxicity are hampering a wider implementation. The main challenges that need to be addressed in order to spread the use of surgical adhesives is to develop adhesives capable to stick organs in a wet environment where physiological medium and blood are present while being fully biocompatible. Moreover, by incorporating drug delivery capability into such adhesives, infections, inflammation and/or pain for examples, could be treated locally and more efficiently reducing the risks associated with surgical trauma.
Within this context and following biomimetics insights, previously published works described the design of new adhesive materials containing mussel-inspired catechol moieties have been designed. Such material showed impressive adhesion in wet conditions and delightful results in biological adhesion, being able to glue several tissues in vitro and in vivo. Within DAHAD project, novel adhesive macromolecules containing catechol groups will be synthesized using a molecular design that combines linear and hyperbranched architectures for improved properties. The influence of such design on the adhesion will be assessed. Then, the same macromolecules will be used to prepare hydrogels with both adhesive and antibacterial properties. Adhesion will be tested on skin and antibacterial activity will be tested against the following bacteria: Staphylococcus aureus and Pseudomonas aeruginosa. Finally, the mechanical properties of the hydrogels will be evaluated and improved by incorporating dynamic bonds, such as H-bonding, within the hydrogel structure.
Objective 1: Synthesis of adhesive macromolecules with terminal catechol groups and study of their adhesion.
A series of biomimetic macromolecules with terminal catechol groups have been synthesized with terminal catechol groups following a design that aimed to ease the synthesis of the adhesive macromolecules while promoting cooperative interactions between the terminal catechol groups. Adhesion on aluminum substrates was assayed using water as a solvent, reducing the use of organic solvents. Adhesion strength was comparable to the one of commercial adhesives and molecular cooperation between the terminal catechol moieties was confirmed.
Objective 2: Preparation of new hydrogel adhesives based on the previous macromolecules.
These biomimetic macromolecules can form thermo-responsive hydrogels at concentrations higher than 20 % (w/v). Sol-gel phase diagrams were established using eye observation; hydrogels formulations were usually in the sol state at low temperature (4 °C) and in the gel state at temperature above 30 °C. The critical gelation concentration increased with the number of terminal catechols. The adhesive properties of the hydrogels were studied on porcine skin as a model. All of them showed adhesive forces around 2-3 kPa, which was similar to the values measured for Tisseel commercial adhesive. To increase adhesion strength, photoreactives macromolecules were added to the hydrogel formulations. After UV-light induced crosslinking, adhesion increased to 4 kPa on porcine skin.
Objective 3: Antibiotics loading within the hydrogel adhesives and antibacterial activity.
Cryogenic scanning electron microscopy revealed that the hydrogel adhesives exhibited a porous structure, idoneous for drug delivery applications. Therefore, two antibiotics were loaded into the hydrogel with the best adhesive properties. Antibiograms revealed that, after being loaded with antibiotics, the hydrogels displayed both adhesive properties and antibacterial activity. This result confirmed the preparation of hydrogels with dual properties: biological adhesion and drug delivery.
Objective 4: Properties tailoring of the hydrogel adhesives by means of H-bonding.
H-bonding donor/receptors groups were included within the adhesive hydrogels to allow a more fine tailoring of the hydrogel properties. The resulting hydrogels showed a higher adhesion onto porcine skin, continued to be able to deliver antibiotics and showed better thermoresponsive properties.
A series of biomimetic macromolecules with terminal catechol groups have been synthesized with terminal catechol groups following a design that aimed to ease the synthesis of the adhesive macromolecules while promoting cooperative interactions between the terminal catechol groups. Adhesion on aluminum substrates was assayed using water as a solvent, reducing the use of organic solvents. Adhesion strength was comparable to the one of commercial adhesives and molecular cooperation between the terminal catechol moieties was confirmed.
Objective 2: Preparation of new hydrogel adhesives based on the previous macromolecules.
These biomimetic macromolecules can form thermo-responsive hydrogels at concentrations higher than 20 % (w/v). Sol-gel phase diagrams were established using eye observation; hydrogels formulations were usually in the sol state at low temperature (4 °C) and in the gel state at temperature above 30 °C. The critical gelation concentration increased with the number of terminal catechols. The adhesive properties of the hydrogels were studied on porcine skin as a model. All of them showed adhesive forces around 2-3 kPa, which was similar to the values measured for Tisseel commercial adhesive. To increase adhesion strength, photoreactives macromolecules were added to the hydrogel formulations. After UV-light induced crosslinking, adhesion increased to 4 kPa on porcine skin.
Objective 3: Antibiotics loading within the hydrogel adhesives and antibacterial activity.
Cryogenic scanning electron microscopy revealed that the hydrogel adhesives exhibited a porous structure, idoneous for drug delivery applications. Therefore, two antibiotics were loaded into the hydrogel with the best adhesive properties. Antibiograms revealed that, after being loaded with antibiotics, the hydrogels displayed both adhesive properties and antibacterial activity. This result confirmed the preparation of hydrogels with dual properties: biological adhesion and drug delivery.
Objective 4: Properties tailoring of the hydrogel adhesives by means of H-bonding.
H-bonding donor/receptors groups were included within the adhesive hydrogels to allow a more fine tailoring of the hydrogel properties. The resulting hydrogels showed a higher adhesion onto porcine skin, continued to be able to deliver antibiotics and showed better thermoresponsive properties.
The adhesive macromolecules synthesized during this project were designed by the combination of a linear polymer with a hyperbranched dendritic part. Such original design allowed to obtain macromolecules with terminal catechol moieties located in a close environment in contrast of being dispersed all along the linear polymer chain. Adhesion tests on aluminum substrates demonstrated the interest of such hyperbranched design since higher adhesion strength was obtained for the macromolecules with more catechol units. Hence, a maximum of adhesive strength of 1.9 ± 0.4 MPa was measured for Pluronic-G0(cat)2. This maximum increased up to 3.0 ± 0.6 MPa for Pluronic-G1(cat)4, and up to 4.9 ± 0.9 MPa for Pluronic-G2(cat)8. This result proved the interest of investigating hyperbranched dendritic architecture to develop novel adhesives that can answer today’s challenges in biological adhesion or to improve recyclability.
Dual activity hydrogels displaying adhesive properties and antibacterial delivery are an emerging hot topic nowadays. Several studies showcasing biological glues with antibacterial properties have been published between DAHAD proposal submission and today. Nevertheless, the hydrogel adhesive formulation based on DAHAD macromolecules with terminal catechol is still innovative and completes the actual library principally based on chitosan derivatives. The variety of encapsulated antibiotics illustrated the versality of such hydrogel adhesives to transport and deliver drugs with diverse structures.
The addition of H-bonding donor/receptor groups within the hydrogel structure allowed to increase the mechanical properties of the hydrogel, enhancing adhesion and thermoresponsiveness of the hydrogel while maintaining the antibiotics delivery capabilities. This is a great advancement in the field since such hydrogels are easier to apply by the healthcare providers.
Dual activity hydrogels displaying adhesive properties and antibacterial delivery are an emerging hot topic nowadays. Several studies showcasing biological glues with antibacterial properties have been published between DAHAD proposal submission and today. Nevertheless, the hydrogel adhesive formulation based on DAHAD macromolecules with terminal catechol is still innovative and completes the actual library principally based on chitosan derivatives. The variety of encapsulated antibiotics illustrated the versality of such hydrogel adhesives to transport and deliver drugs with diverse structures.
The addition of H-bonding donor/receptor groups within the hydrogel structure allowed to increase the mechanical properties of the hydrogel, enhancing adhesion and thermoresponsiveness of the hydrogel while maintaining the antibiotics delivery capabilities. This is a great advancement in the field since such hydrogels are easier to apply by the healthcare providers.