Influence of the chemical composition and structure design of electrospun matrices on the release kinetics of Aloe vera extract rich in aloin
Graphical abstract
Introduction
Electrospinning is a relevant option to produce new materials with therapeutic effects and useful for both direct lesion coverage and transdermal devices to deliver drugs to sites other than those of the biomaterial application. Electrospun materials have aroused interest and are promising for use in the administration of bioactive agents, as they have important characteristics capable of filling and overcoming gaps observed in the use of traditional therapeutic agent delivery devices. In general, the high surface area resulting from the electrospinning process results in greater drug bioavailability even for small doses of therapeutic compounds, with concomitant dose reduction and adverse effects, enabling the drug administration at better planned times and intervals [1]. Besides, the use of electrospinning to produce therapeutic materials can be advantageous also because the biomaterials have microstructures that can mimic the extracellular matrix (ECM).
Different approaches can be used to treat severe acute and chronic skin lesions, such as the combination of wound dressings with local or systemic administration of drugs. The main advantage of localized therapy is that it can eliminate the need to administer the bioactive agent systemically, minimizing the total dose needed to reach the site to be treated, and consequently reduce adverse effects. In this sense, proper design of the delivery device to ensure sustained release in between dressing exchanges coupled to characteristics such as adequate mechanical resistance, good exudate absorption, and capacity to act as a barrier to protect the lesion from environmental contaminants are relevant properties to be expected from a wound dressing.
Electrospun structures encompass many of the attractive characteristics of ideal bioactive wound dressings, such as high surface area and microporous structure, and can be effective tools in the topical administration of a large range of bioactive agents both to avoid and control skin infections and to mediate the healing process [2]. For this reason, their use was considered in the present work in association with compounds extracted from Aloe vera, a plant with widely known beneficial effects to skin lesions of different etiologies, considered as the most popular herb in wound healing [3].
Many of the components of Aloe vera have hydrophilic character and show outstanding therapeutic activity. The plant itself is made up of over 98% water [4], and its leaves have over seventy-five different components including vitamins, minerals, enzymes, simple and complex sugars, anthraquinones, flavonoids, lignin, saponin, sterols, amino acids, and salicylic acid, among others [5].
In the skin, Aloe vera is used to slow cell aging and to treat acne, psoriasis, UV radiation and chemotherapy-associated lesions, as well as for wound healing, since it shows antiseptic, antibacterial, anti-inflammatory, antioxidant, anticancer and immunomodulatory effects [6,7]. Aloin is the main component of Aloe vera, consisting of a mixture of two diastereoisomers, aloin A and aloin B [8,9], as indicated in Fig. 1. It has the ability to reduce pain and inflammation and to stimulate the development and regeneration of skin cells. Specifically for wound healing, aloin can be used as an antibacterial, antioxidant and anti-inflammatory agent [6,7,10]. In addition, several types of cancer cells, such as ovarian, breast and colorectal, are susceptible to the action of aloin [10] and other relevant characteristics on this compound include its laxative properties [8,9], and its use as a dietary supplement to treat stomach ulcers and diabetes [11].
Several polymeric matrices have been developed for the release of Aloe vera extract and aloin. The use of alginate [12], chitosan [13], blends of alginate and polyvinyl alcohol [14], as well as of polyelectrolyte complexes obtained by combining chitosan with alginate or xanthan [10] for this purpose has been reported in the literature.
In the present work, aloin extract was incorporated into three matrices produced by electrospinning solutions with different polymer compositions and using two different biomaterial designs. Aiming to apply the biomaterial directly to the skin lesion bed, polymers with different in vivo degradation rates were used to control aloin release kinetics, and formulations consisting solely of PCL and PCL blended with PLLA or PDLG were analyzed.
Due to the high surface area of the electrospun materials, burst release of bioactive compounds is often observed. This type of kinetic behavior can lead to a reduction in pharmaceutical effectiveness, since when the amount of drug released is too high, the concentration of the bioactive agent in the device quickly lowers to critical levels at which no therapeutic activity is observed.
A strategy to overcome this limitation is to use coaxial electrospinning, which produces core-shell structures, with the core having the bioactive agent and the shell enclosing the inner structure containing the drug to control its release kinetics [17,18]. However, coaxial electrospinning can produce defects in fiber structures, resulting in flaws such as delamination and holes in the shell encapsulating the drug, both favoring drug burst release.
The production of sandwich-like structures using uniaxial electrospinning consists of an effective way to get around these drawbacks, allowing to physically confine the drug between multiple layers and modulate its release kinetics [15], while also considering aspects of relevance in scaling up the fiber mats production process.
Recently, different approaches have been explored to make available technologies to scale up the electrospinning process. According to their working principle, the technologies may be considered nozzle-type or free surface methods [19]. In both groups, improving the number of liquid jets leaving the solution is the main goal. In the first group, increasing the number of needles is a common practical solution that increases process throughput, and the use of different arrangements in needle distribution may improve fiber uniformity and diameter regularity. In the second group, fiber production occurs without nozzles, being based on the distribution of the fiber jets on a surface as a result of a static wave of surface tension and electrostatic forces [17]. In addition to these aspects, several other factors are of paramount importance to define electrospinning equipment choice and the final fiber architecture, such as polymer solution formulation and flow rate, solvent type, electrical charge intensity, the influence of environmental perturbations, number of spinning jets per unit area and the method of fiber collection, among others [20].
In fact, electrospun nanofibers have been indeed gradually transferred to industrial products [21,22]. Many industrial electrospinning setups are available to meet specific demands, e.g. those provided by companies such as Inovenso Inc. (USA), Elmarco s. r.o. (Czech Republic), Tong Li Tech (China), E-Spin Nanotech (India), Linari Engineering s. r.l. (Italy), Kato Tech Co. Ltd. (Japan), Bioinica s. l. (Spain), Mecc Co. Ltd. (Japan), Toptec Co. Ltd. (Republic of Korea), Dienes Apparatebau GmbH (Germany), Electrospunra (Singapore), IME Technologies (Netherlands). Some industrial electrospinning setups allow mass production of nanofibers around 5000 m2 daily, other allows annual throughput up to 50 million m2.
From the commercial perspective, materials containing electrospun nanofibers may offer high-performance while adding value to the final product. Among companies that are currently developing or manufacturing electrospun-based products for the biomedical field, a few examples include BioSurfaces Inc (USA), Espin Technologies Inc (USA), Japan Vilene Company Ltd (Japan), Nanofiber Solutions LLC (USA), NanoSpun Technologies (Israel), Soft Materials and Technologies s. r.l (Italy), and SNS NanoFiber Technology LLC (USA) [23]. The increase in the number and type of products available in the market lately certainly stimulates further developments in the area.
Hence, in this work, single-layered uniaxial electrospun mats of different compositions were compared to sandwich-like structures composed of PCL incorporating the plant extract only in the middle layer. The uniaxial electrospinning strategy was chosen due to being simpler than coaxial processing, easier to be upscaled by the use of multiple nozzles, and because it allows the production of micro and nanofibers in random or aligned arrangement with specific morphologies, hierarchical structure and even with morphology gradients. All structures obtained were characterized regarding their physicochemical properties, mechanical resistance and release kinetics of the bioactive agent with the purpose to analyze their performance gain due to changes in polymer composition and to increased structural complexity.
Section snippets
Materials
Curaçao aloe extract (Aloe barbadensis Miller), a type of Aloe vera that contains 50% alloin and 70–90 kg/mol poly(ε-caprolactone) (PCL) were obtained from Sigma-Aldrich (USA). Poly(l-lactic acid) (PLLA) with an inherent viscosity of 1.8 dL/g and 50/50 poly(D, l-lactic acid-co-glycolic acid) (PDLG) with inherent viscosity equal to 0.2 dL/g) were obtained from Purac Biomaterials (Netherlands).
Electrospinning of the solutions
The polymer and the Aloe vera extract solutions were prepared as described in Table 1, using a 5: 1
Results and Discussion
The success in using electrospun matrices as controlled release devices is related to the efficiency in the incorporation of bioactive agents and with the distribution of the bioactive agent within the fibers. The release kinetics of bioactive agents from a polymer-based matrix is mainly dictated by the physicochemical properties of the system and the interaction between polymer, solvent and the bioactive agent. If there is an uneven distribution of the bioactive agent in the polymer solution,
Conclusions
The materials formulated using the same design but with different chemical compositions of the polymeric matrices showed statistically similar results for aloin release kinetics in vitro. However, the chemical composition of the controlled release matrix significantly influences many of the physicochemical aspects studied, such as in vitro PBS absorption capacity, mass loss, and mechanical properties.
On the other hand, the change in the number and distribution of layers of the device impacts
Author statement
Lonetá L. Lima: Conceptualization, Validation, Investigation, Writing - review & editing, Writing - original draft, Visualization, Andréa C. K. Bierhalz: Conceptualization, Validation, Writing - original draft, Writing - review & editing, Visualization, Ângela M. Moraes: Conceptualization, Resources, Writing - review & editing, Writing - original draft, Visualization, Supervision, Project administration
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq, Brazil, grant numbers 400125/2017-0, 150991/2017-7, 307139/2015-8 and 307829/2018-9). We would like to thank Chiu Chih Ming for the support on the mechanical properties analysis.
Data will be made available on request.
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