In the current landscape of personalized medicine, one of the main challenges is the adverse effects of drugs, which can vary significantly from person to person, limiting the overall effectiveness of therapies. Conventional administration methods, such as tablets, injections, and capsules, often result in the distribution of the active ingredient to areas other than the target site. This dispersion leads to reduced bioavailability, fluctuations in plasma drug levels, and an inability to achieve sustained release over time.
Targeted drug delivery, with controlled and site-specific release, is therefore a crucial aspect of optimizing therapeutic processes. The goal is to achieve maximum efficacy and safety while minimizing the toxicological impact on healthy cells.
A revolution in progress
Drug delivery systems (DDS) are designed to ensure efficient transport of therapeutic agents to the cellular target, improving aqueous solubility, chemical stability, and pharmacological activity. Over the past few decades, significant advancements have been made in this field, with the development of systems based on macro- and nanoscale structures, up to the most recent intelligent systems.
Since 1950, when the first controlled-release formulation of dextroamphetamine (Dexedrine) was introduced, numerous DDS have been developed to enhance drug efficacy and patient well-being. The first generation of these systems, developed between 1950 and 1980, focused on oral and transdermal delivery. Subsequently, attention shifted toward the use of so-called "smart polymers" and hydrogels, which are particularly sensitive to environmental stimuli such as pH, temperature, and glucose levels. More recently, bioresponsive nanosystems have gained significant interest for applications in tissue engineering, imaging, and biosensors.
The importance of biomaterials
Biomaterials play a key role in tissue engineering, mimicking the natural environment of tissues through engineered structures that promote cell growth and provide structural support for the release of cells and therapeutic factors. The choice of the most suitable biomaterial must be based on the formulation and the intended route of administration. Biocompatibility, biodegradability, good mechanical properties, and bioavailability are important criteria in selecting the ideal material to achieve the desired response.
Over the past two decades, various polymeric drug delivery systems have been developed, based on natural or synthetic materials. Although synthetic polymers have attracted numerous studies, they have some limitations related to limited control over their structure and, in some cases, low biocompatibility. Their degradation products can sometimes be toxic.
Biopolymers, on the other hand, offer numerous alternatives in the design and fabrication of DDS. This is because they ensure complete biodegradability with excellent biocompatibility and absence of toxicity. They do not exhibit carcinogenic or thrombogenic properties, are easily extractable and processable, and have minimal environmental impact. These advantages have led to increased attention toward biopolymers, with sales in the sector growing by 20-30% annually.
Silk fibroin, the excellent biopolymer
For some time now, the progress of silk fibroin has been well-documented. This protein has attracted intense research activity, particularly in the field of wound healing, thanks to promising results obtained both in vitro and in vivo.
Advances in processing technologies have expanded the possibilities of combining and functionalizing fibroin with other biomaterials for specific purposes. Over the past 20 years, fibroin has inspired nearly 10,000 scientific publications in the field of tissue engineering and has been employed in the development of a wide range of materials with customized properties and architectures.
Today, it is recognized as one of the most interesting biomaterials due to its exceptional characteristics. This is because it exhibits superior biocompatibility, being naturally accepted by human tissues without provoking significant inflammatory responses. Its biodegradability is tunable, allowing the degradation rate to be adjusted according to the specific needs of the application. It offers high mechanical strength, ensuring structural stability to formulations. Additionally, it possesses intrinsic bioactivity that promotes healing and tissue regeneration processes. Lastly, it boasts remarkable processing versatility, as it can be transformed into multiple physical forms.
Furthermore, it can be processed into various forms, including hydrogels, thin films, three-dimensional porous aerogels, nanofibers, nanoparticles, and textiles, starting from organic or aqueous solutions through different processing techniques.
Binding and release mechanisms
The binding mechanism between drugs and fibroin, along with the microstructure of silk, plays a fundamental role in the release of the active ingredient. A strong electrostatic bond between silk and bound molecules can prevent significant initial burst release, while an increase in β-sheet structures in the protein is responsible for slowing the release rate.
A conformational transition from random coil to β-sheet structure, which results in physical crosslinking, can be induced in fibroin by physical factors such as pH, temperature, solvents, cations, and vorticity. This physical crosslinking is highly promising for biomedical applications due to its low cost, safety, and absence of toxic chemical agents.
Transdermal release
The skin epidermis, with its five anatomical layers, is considered the ideal organ for drug delivery. The ease of administration, avoidance of first-pass metabolism, the large surface area of the skin, low costs, and patient compliance are some of the advantages associated with transdermal release. However, the skin barrier, particularly the stratum corneum, poses a challenge for drug penetration. To overcome this barrier, microneedle-based devices have gained increasing interest in transdermal drug delivery, offering efficient and well-tolerated methods for patients.
Microneedles are small needles (50-900 µm in length) arranged in arrays that can effectively penetrate the stratum corneum, creating reversible microchannels in a minimally invasive manner, releasing drugs without involving blood vessels and nerves in the dermis.
Silk fibroin has been used in the fabrication of microneedles through polydimethylsiloxane (PDMS) molds, demonstrating swelling capacity to facilitate drug release, excellent biocompatibility, and adequate mechanical strength. An example of application is a modified silk fibroin microneedle capable of swelling for transdermal release. The system, composed of 2-ethoxyethanol and fibroin, was designed to penetrate porcine skin in a dry state to a depth of about 200 µm and swell into a hydrogel state through the absorption of interstitial fluid.
