Plants Bioactive Compounds in Wound Healing: Comparison
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Please note this is a comparison between Version 2 by Camila Xu and Version 1 by Iuliana-Mihaela Deleanu.

The skin, as the body’s largest and most exposed organ, can provide a readily accessible delivery route for therapeutic substances. Plants, as an important source of so-called “natural products” with an enormous variety and structural diversity that still exceeds the capacity of present-day sciences to define or even discover them, have been part of medicine since ancient times.

  • bioactive molecule
  • biomaterials
  • transdermal delivery
  • wound dressing
  • natural compounds
  • metabolites

1. Introduction

The skin, as the body’s largest and most exposed organ, can provide a readily accessible delivery route for therapeutic substances. In fact, the topical application of remedies has been practiced for thousands of years. From Galen, the Father of Pharmacy, who introduced herbal ingredients into the formulation of drugs, the evolution of skin wound dressing/healing (WD) and transdermal delivery (TD) took an interesting path, which continues, and grows nowadays with the help of modern scientific techniques [1].
Most topical drug delivery systems (DDSs) were traditionally designed for the local administration of active pharmaceutical ingredients (APIs), with numerous applications in the field of skin tissue healing [2,3,4][2][3][4]. However, the concept of soft (permeable) drugs that can also affect the tissues/organs beneath the skin originates from Ibn Sina (Avicenna), the great Persian physician and philosopher, born in 980 AD in the village of Afshanah [5,6][5][6]. This is now believed to be the oldest conceptualization of transdermal drug delivery (TDD).
Currently, there is a constant search for new materials and new medical devices (wound patches, scaffolds, and transdermal delivery systems) that can provide effective treatment through the unique, controlled, and targeted delivery of APIs. New methods are sought to replace conventional drug delivery routes (gastric, intravenous, intradermal, etc.) with TDs due to their numerous advantages: allowing the direct access of APIs to the bloodstream through the skin and avoiding liver metabolism and the gastrointestinal tract; allowing the homogenous absorption of APIs and increasing pharmaceutical effectiveness; reducing/eliminating drug alterations that can occur in the interaction with patient enzymatic and immune systems; and, equally important, TD is more comfortable, non- or less invasive, and can be easily self-administered [3,7,8,9][3][7][8][9]. Furthermore, through bionanotechnology, sophisticated devices can be designed to allow drug storage and controlled, on-demand delivery for several days [6,9][6][9].

2. Natural Compound Transfer Specifics and API Delivery Methods

Dermal and TDD methods, disregarding the principles and formulations, are directly related to skin and drug/API properties, as already mentioned.

2.1. Skin Properties and Drug Transport Mechanism

The skin is a complex three-layer structure comprised of the epidermis, dermis, and hypodermis. It is a two-way protective barrier preventing any external intrusions (microbial, chemical) and, at the same time, the excessive loss of endogenous material. Skin permeability, determined not only by its structure but also by numerous factors like the anatomic site, gender, age, hydration, or external temperature, is mainly associated with Stratum Corneum (SC, the outermost layer), containing a high amount of keratin [7]. Simplistically, TDD means API penetration through the skin at therapeutic rates, but overall, the process, also called percutaneous absorption, is more complicated, described in five main stages. A “vehicle” (transdermal device, cream, or solvent) is often used to incorporate the drug/API. In the first stage, the active molecule is distributed from the vehicle to the hydrolipidic film based on the partition coefficient and molecule’s mobility [12][10]. The drug is then absorbed into a specific skin layer (penetration step) and partitioned from SC into the aqueous viable epidermis, from where the molecule diffuses to the upper dermis. The permeation from one layer to another further takes place, and finally, the drug enters the bloodstream (the resorption or absorption step) [13,14,15][11][12][13]. Each stage depends on numerous factors and can be differently kinetically characterized, but overall, the transfer is controlled by the molecule’s passive diffusion [12][10]. In the case of skin wound healing, the mechanisms are more or less the same, as the API is also entering into the bloodstream, but the required pharmaceutical effect is local. Two major pathways are known to allow some molecule transfer: transepidermal, when a drug permeates into the cells (intracellular) or through the cellular interspaces (transcellular), and transappendageal (via hair follicles or sweat glands) [15,16][13][14]. Disregarding the mechanism or the pathway, there are certain physicochemical properties that a potential drug/bioactive substance must meet for a TD, such as [6,17][6][15]:
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Non-toxicity.
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Low-dose administration requirements.
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High lipophilicity.
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Molecular weight below 500 Da.
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Hydrophilic/hydrophobic balance corresponding to an n-octanol/water partition coefficient (log P) between 1 and 5 (which corresponds to moderate lipophilicity).
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Acceptable water solubility (0.05 to 1 mg/mL).
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Melting point below 250 °C.
These requirements, which would naturally allow successful TDD, are also known as the main factors associated with the limited usage and commercial applications of bioactive TDDS up until now.

2.2. Conventional and Modern Topical and TDD Methods

Depending on the technique(s) that allows API to permeate and/or cross the skin, TDD methods are classified as passive or active. Passive methods, also known as conventional or chemical methods, which include “passive” patch technology, are based on the passive permeation of bioactive molecules. Often these methods are improved via the implementation of penetration/permeation/skin enhancers (usually a chemical or biochemical substance) or supersaturated systems, or other ways, to enhance the mass transfer driving force or to improve skin permeability, allowing for improving dose control. However, TDDs are not fundamentally changed, and the applicability of passive systems remains limited [12,18][10][16]. Furthermore, additional drawbacks are associated with permeation enhancer usage [17][15]:
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Toxicity and skin irritation.
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Two-way skin permeabilization (increase in transepidermal water loss).
-
Additional pharmacological effects.
-
Specificity towards a certain drug.
Active (physical) methods, as accurately described by Alkilani et al., “involve the use of external energy to act as a driving force for drug transport across the skin or by physically disrupting the SC” [15][13]. There is a need for an enhanced TDD, derived naturally together with biotechnological and bioengineering progress, when new (bio)active substances, macromolecules in general, characterized by a low resistance in the gastrointestinal tract, become available for medical and cosmetic therapies [18][16]. Since the introduction of the first-generation TDDs at the commercial scale in the 1950s, significant advances have been made, and numerous active methods have been tested and/or implemented, as depicted in Figure 1 [16,19][14][17]. Among these, the most applied are electrical techniques like electroporation and iontophoresis, mechanical systems like microneedles, or ultrasound-assisted TDDs. Of course, these techniques are not without disadvantages.
Plants 12 02661 g001
Figure 1. Five main methods to enhance API absorption across the skin: drug–vehicle interaction, vesicles, and analogues; SC modification; energy-driven methods; and SC bypass [16][14]. (Pink color indicates the first generation of SC penetration devices; Yellow—the second generation of SC penetration devices/methods; Blue—the third generation of SC penetration devices/methods).
High costs, large-scale feasibility, limited loading capacity, stability, or other issues in controlling drug delivery are determining the search for even more advanced techniques. Most recent studies involve integrated chemical and physical approaches (hybrid methods) [20,21][18][19].

3. Bioactive Transdermal Patches and Wound Dressing Materials

Transdermal patches (TP) and WD materials are widely used nowadays. These are designed in many forms and configurations. From ancient formulations consisting in ointments bandaged on the skin to state-of-the-art microneedle patches, the evolution can be considered spectacular [22,23][20][21]. One of the first described TDDs, and one of the first studies to prove that the limiting step of drug transfer is the diffusion through the skin layer, was introduced by Wurster and Kramer early in 1960, 10 years before the first patent involving continuous drug-rate-controlling delivery was filled [22,24][20][22]. By definition, bioactive means having a certain effect on living organisms [25][23]. A bioactive transdermal patch (BTP) or a WD material can be a structure of a certain complexity to allow the delivery of a bioactive molecule through the skin, directly to the bloodstream. Disregarding the structural complexity, such a patch consists of the following [22,26][20][24]:
  • The active component/drug, which could be a natural or a synthetic component with bioactive properties; it can be supplied from a reservoir or from another structure of the patch [27][25].
  • Backing material, usually made of elastomers, is used to provide patches’ flexibility and protection from the outer environment and water.
  • Drug-releasing membrane/matrix, made of natural/synthetic polymers/elastomers.
  • Adhesive, to keep the patches’ layers together and adhered to the skin; it may also contain the permeation enhancers and/or the drug.
  • The protective liner.
Countless materials/substances are used as either one of these devices’ structural elements, and natural products of a plant origin are included. In fact, medicinal plants have always been an important part of the global medicinal sector. Traditionally, these were used for their curative properties, but nowadays, there are many other ways to use plant materials in the medical field (in general), and as a TP component (in particular). Many examples can be given regarding the use of cell walls’ structural components or plants’ metabolites as constituents in TP development.

References

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  2. Cao, X.; Sun, L.; Luo, Z.; Lin, X.; Zhao, Y. Aquaculture Derived Hybrid Skin Patches for Wound Healing. Eng. Regen. 2023, 4, 28–35.
  3. Raghav, N.; Sharma, M.R.; Kennedy, J.F. Nanocellulose: A Mini-Review on Types and Use in Drug Delivery Systems. Carbohydr. Polym. Technol. Appl. 2021, 2, 100031.
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  11. Ita, K. Transcutaneous Drug Administration. In Transdermal Drug Delivery; Academic Press: Cambridge, MA, USA, 2020; pp. 1–7.
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  15. Kováčik, A.; Kopečná, M.; Vávrová, K. Permeation Enhancers in Transdermal Drug Delivery: Benefits and Limitations. Expert Opin. Drug Deliv. 2020, 17, 145–155.
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