resumo
The use of natural polymers for the development of advanced sustainable materials has gained significant prominence in the last two decades. As the most abundant biopolymer on the planet, cellulose emerges as a promising feedstock for the development of new biobased materials. Given their unique properties, cellulose and its derivatives are well-suited for multiple biomedical applications, including wound healing and drug delivery. The skin stands out as one of the most readily accessible organs in the human body, offering an advantageous route for drug and bioactive compound administration. Dermal administration of these compounds mitigates the adverse symptoms often associated with other administration routes. Moreover, this noninvasive approach is associated with better patient compliance with treatments, contributing to the overall improvement of their health status. In this context, the main objective of the present dissertation is to explore the potential of cellulose and its derivatives in the development of innovative dermal administration systems tailored for specific clinical applications. The first study focused on the development of multilayered patches for the treatment of herpes labialis, using bacterial nanocellulose (BNC). To optimize the effectiveness of the treatment, a skin healing promoter (hyaluronic acid), an antiviral drug (acyclovir), and a humectant and plasticizing agent (glycerol) were selectively incorporated into the three distinct layers of the dressing. To modulate the drug release, patches with two different configurations were prepared, namely one with the drug incorporated only in the central layer of the dressing, and another with the drug divided between the central and bottom layers. The prepared multilayered dressings showed adequate morphology and mechanical properties (Young’s modulus up to 0.9 GPa in the dry state and 0.7 GPa in the wet state, and tensile strength up to 27 MPa in the dry state and 7 MPa in the wet state), irrespective of the configuration. However, patches with the drug divided into two layers showed faster and higher acyclovir release (up to 77 ± 5%, within 10 min, in PBS). Moreover, the in vitro release and permeation profiles in Franz vertical cells closely approximated that of a commercial cream formulation. Combined with the non-cytotoxic nature toward L929 dermal fibroblasts, as well as their ability to promote cell adhesion and wound closure in vitro, the results support the prospective application of these BNC-based materials for the administration of acyclovir and hyaluronic acid in the context of herpes labialis treatment and wound healing. The following studies focused on the exploitation of carboxymethylcellulose (CMC), a water-soluble cellulose derivative with good film-forming properties, for the design of dissolvable microneedle systems (MNs) using a micromolding technique. These minimally invasive systems can pierce the outermost layer of the skin, viz. the stratum corneum, and promptly dissolve upon contact with the surrounding interstitial fluid, thus releasing their therapeutic cargo. One of the main advantages of these systems is the ability to deliver drugs and bioactive macromolecules that otherwise would be unsuitable for dermal administration. Thus, the second study of this dissertation focused on combining CMC (5% w/v) with diclofenac sodium (DCF, 1% w/v), a non-steroidal antiinflammatory drug, to develop a minimally invasive administration system that allows for rapid pain relief. The prepared microneedle patches presented integral bodies and sharp tips with heights of approximately 456 μm. The drug-loaded patches displayed the required mechanical strength for skin insertion, reaching maximum values of 0.75 N per needle. Insertion studies on ex vivo abdominal human skin samples revealed the formation of microconducts in the skin ranging from 133 to 401 μm in depth. The MNs rapidly dissolved and released about 98% of the DCF incorporated into the patch (in vitro). The non-cytotoxic behavior of these MNs toward human keratinocytes (HaCaT) highlights their safety for skin application. In a distinct approach, the third and final study of this dissertation focused on the blend of two biopolymers, CMC and fucoidan (Fuc), a sulfated polysaccharide of marine origin. By taking advantage of the intrinsic antiproliferative properties of fucoidan, this study aimed to explore cellulosebased microneedle systems as minimally invasive adjuvant therapy for aggressive skin cancer (melanoma). The inclusion of fucoidan (5%, relative to the CMC mass) in the MN patches did not impact their mechanical properties, achieving a maximum of 1.07 N per needle, and ensuring skin insertion. Ex vivo penetration tests demonstrated their ability to bypass the stratum corneum, penetrate the epidermis, and reach depths of up to 453 μm, analogous to the height of the projections. The MNs eradicated the majority of A375 melanoma cells after 48 h of exposure (83% reduction in cell viability). To approximate in vivo conditions, the potential of the CMC_Fuc MNs was further assessed in a three-dimensional A375 cell culture model. The presence of fucoidan in the MN patch significantly impacted cell viability (reduction of 56% after 48 h of exposure), evidencing the potential of this system for melanoma treatment. In conclusion, the present dissertation demonstrates the versatility of cellulose-based materials for dermal application in the administration of drugs (acyclovir and diclofenac sodium) and bioactive macromolecular compounds (hyaluronic acid and fucoidan) for minimally invasive administration, in the context of wound healing, pain relief or skin cancer treatment.
autores
Ana C. Q. Silva
nossos autores
Ana Cristina Quintans da Silva
Investigador Júniororientadores
Carmen S. R. Freire, Carla Vilela, Armando J. D. Silvestre