1. Context
1.1. A Concise Introduction to Diabetes
Diabetes Mellitus (DM) can be described by eccentric high levels of blood glucose. The uprising of glucose in the blood triggers the pancreatic cells to release insulin. For the elimination of glucose from the blood, insulin plays its role by stimulating muscle and fat cells and making the liver metabolize it, which brings the blood glucose back to normal levels. High blood glucose in diabetic patients may be due to the lacked or inadequate levels of insulin production or its improper working.
Based on the latest report of the World Health Organization (WHO) in 2016, an estimated 422 million adults have DM, and its prevalence is on the rise (1). Immune dysfunction that weakens the defensive potential of the body, diabetic neuropathy that decreases the ability to feel outer stimulants, and poor circulation, especially at lower sites of the body, will put these patients at high risk of many infections. However, in patients struggling with advanced DM who might have Peripheral Vascular Disease (PVD), any breakdown and tearing in skin integrity pose a great risk of complicated skin and soft-tissue infections (cSSTI) (2).
1.2. Diabetes Mellitus Affects the Skin
The culmination of diabetic skin defections can lead to long-lasting life complications for patients. The large expense may undergo public health organizational resources under significant draining. Plenty of these complications coincide with dry skin resulted from DM (3). Diminished dermal lipids of diabetic skin can increase transdermal water loss, and the reduced capability of moisture release will result in more dryness of the skin. Furthermore, the absence of collagen deters skin elasticity. Some of these conditions make the skin more vulnerable to cuts and bruises, developing infections, delayed wound healing, and skin problems such as itching (4).
1.3. Diabetic Skin Care Monetary is Pricey
Suffice to say, the refinement of diabetic skin conditions dedicates high costs to either health system accommodators or patients. The estimated cost of Diabetic Foot Ulcer (DFU) treatment is about 18.7 billion dollars annually. Moreover, the DM-related amputation cost is estimated at 3 billion dollars per year (5, 6).
2. Diabetic Skin and Wound Care by Topical Products
2.1. Polymeric Components
2.1.1. Dimethicone
Octamethyltrisiloxane is a group of organosilicon polymers, according to PubChem. Some cosmetic formulations use this colorless oil and related siloxane polymers at concentrations of use up to 15% (7). As a cosmetic rule, it is considered as a skin protectant and emulsifier (8). Otherwise, the FDA indicated that it should not be used over lacerations and wounds (9). Dimethicone can be used to protect the skin against ordinary soap cleaners and other dermal irritants due to its insoluble characteristic (10).
2.2. Metal Components
2.2.1. Ferric Chloride
As a matter, it is an orange to dark brown-black solid. On the other hand, the solution is a colorless to light brown aqueous liquid.
Locally acts as an astringent and hemostatic agent. The study of Hirobe et al. demonstrated that it can stimulate the proliferation of human skin fibroblasts and keratinocytes in culture (11). In 2015, the study of Nouri et al. on rats demonstrated a significant reduction in hemostatic time versus the control group (12).
2.2.2. Calamine
Calamine is a mixture of ZnO and 0.5% Fe2O3, which is shown as a Fe2O4Zn formula. It is also considered as Chinese traditional medicine (13). Topical Calamine (for the skin) is used to treat itching and skin irritation and decrease sweat levels while helping prevent skin lesions (14).
2.2.3. Zinc
Generally, knowing as Zinc White, Chinese Zinc, and flowers of zinc, crude zinc oxide is a yellow to grey granular solid inorganic compound insoluble in water. The action is provided by making a physical barrier for damaged skin. The topical applying of zinc oxide increases re-epithelialization in partial-thickness wounds in pigs with normal zinc status (15). Often, it can be used as an adjunctive therapy for treating minor skin irritations, cuts and burns, and baby diaper dermatitis. Chiefly described by Martindale, zinc oxide is a mild astringent used as a soothing and protecting agent in eczema, wounds, and slight excoriations (16).
2.2.4. Aluminum Oxide
The compound is an odorless, white, and water-insoluble powder. Aluminum oxide does not penetrate the skin, but it can alter the epidermal barrier. Aluminum oxide is considered as an indirect additive by the FDA. The anodic aluminum oxide membrane could make a more efficient Nano-porous function for keratinocytes and sufficient membrane size for wound healing (17).
2.2.5. Copper
Indeed, copper is an essential trace element for both plants and animals and is shown by the atomic symbol Cu. It is a reddish metallic solid that could be found in various forms, from powder to liquid. It has wound-healing effects. As a rule, its wound-healing effects accommodate VEGF expression and angiogenesis, which could incorporate into wound contraction, extracellular matrix remodeling, and closure. Copper oxide-impregnated dressings enhance wound healing, as shown in a study by Borkow et al. (18).
2.2.6. Iron Sulfate
Ferrous sulfate is a green or yellowish-brown crystal solid. Iron is an astringent in wound healing (19).
2.3. Chemical Components
2.3.1. Iodine
Extraordinary effects on a wide range of microbes and biofilms, in addition to affecting inflammation, have put it a good choice of wound healing (20).
2.3.2. Petrolatum
Helping the skin heal and retain moisture, petrolatum has an immediate barrier-repairing effect on delipidized stratum corneum (21).
2.3.3. Cetyl Palmitate
It is an ester derived from palmitic acid that increases the formation of anisotropic structures (22). It is also known as a thickener and emollient, which smooth and condition dry skin. It is also used as an emulsifier in cosmetics (23).
2.4. Mineral Oils
2.4.1. Paraffin
Liquid paraffin is used in cosmetics and skincare products to lock moisture into the skin. It is well known as a lubricant and emollient and makes a barrier. Among several indications, liquid paraffin could be found in anti-itching products, as well, especially in treating eczema, dry skin, and skin inflammations, in dermatitis and psoriasis products due to its property in preventing water loss (24).
2.5. Herbal Ingredients
2.5.1. Allantoin
It has been used as a moisturizer and keratolytic in the market (25). Pure solutions of allantoin are used for ulcer treatment. Studies have shown positive effects of allantoin on wound healing alone or in combinations (26).
2.5.2. Palmitic Acid
Palmitic acid has many functions in cosmetics, from detergent cleaning agents to emollients. Palmitic acid is a very good emollient despite the possible irritation as an adverse effect (27). A study in 2018 showed the wound-healing effects of palmitic acid in animal models (28).
2.5.3. Menthol
Chiefly, menthol is used as a cooling topical agent and can be described as a heat analgesic (29). The study of Bromm et al. demonstrated the inhibitory effects of cold-sensitive A-delta fiber activation itch (30).
2.5.4. Sorbitol
As a humectant, sorbitol prevents moisture loss by pulling water by osmosis from the air, hydrating the skin; however, when used in extremely dry conditions, sorbitol can instead take the moisture out of the skin and leave it dry or damaged. Sorbitol often is used in modern cosmetics as a humectant, moisturizer, and thickener (31).
2.5.5. Aloe vera
The botanical name of the plant is Aloe barbadensis Miller being used in preventing skin ulcers, burn wounds, genital herpes, psoriasis, and pressure ulcers (32). Aloe vera significantly increases collagen synthesis after topical use, accelerates wound contraction, and stimulates fibroblasts (33). The active compounds are vitamins, enzymes, lignin, saponin, and salicylic acid (34). The antioxidant effect of aloe vera is due to its A, E, C vitamin content (34).
2.5.6. Avocado Oil
Avocado seeds have also been found to have fungicidal and anti-microbial activities (35). In cosmetics, avocado is valuable for its rejuvenate and moisturizing properties. In the study by Werman et al., avocado increased soluble collagen content of the skin (36). Suppressing fungal growth and helping the penetration of other antifungal agents is another effect of aloe vera plant (33)
2.5.7. Shea Butter
It is an extracted fat from the African shea tree or Vitellaria paradoxa, which is used in cosmetics as a moisturizer, as well as an analgesic in Africa (37). It is an excellent emollient for dry skin (38). In medical ointments, it is used as a base and showed to have anti-inflammatory effects against different inflammatory conditions (37).
2.5.8. Camellia sinensis
Also known as Tea, it is popular for health benefits for healthy skin. Tea has anti-inflammatory effects and can reduce scars and accelerate wound closure (39). The 2013 study of Asadi et al. showed a positive effect on surgical wounds (40).
2.5.9. Olive Oil
Olive oil is rich in vitamins and polyphenols. A study by Zahmatkesh et al. in 2015 showed the positive healing effects of ointment on burn wounds while preventing infections, accelerating tissue repair, and helping smooth debridement (18). Another study in 2016 demonstrated decreases in oxidative damage and wound healing rates (41).
2.6. Biological Ingredients and Cell-based Therapies
2.6.1. Bacitracin
Is an antibiotic widely used by both the medical profession and the general public. It is most commonly found in a variety of topical ointments and creams used after surgical procedures, for acute skin injuries, and chronic wounds. The incidence of allergies to this agent has been increasing over the last 10 years (42). The United States Food and Drug Administration (FDA) approved the application of bacitracin in the short-term to prevent both acute and chronic wounds from infections (17). While considering the reported adverse effects, some studies suggested safe long term use of bacitracin on wounds (43). Some dressing designs are efficient in healing wounds while having patented formulations, such as the combination of bacitracin and zinc oxide (44).
2.6.2. Benzalkonium Chloride
It is an organic salt that serves as a biocide (45). A study showed that BKC-loaded hydrocolloid wound dressing successfully increased the epithelialization rate compared to control groups (46).
2.6.3. Glycerin
It is a trihydroxy alcohol used as solvent, humectant, and vehicle in various pharmaceutical purposes according to the National Cancer Institute (NCI). In addition, glycerin can be used as a moisturizer (47) for dry skin and scars (48). In 2002, Loden et al. demonstrated the efficiency of glycerin in atopic skin (49). Studies showed the positive effects of glycerin on wound healing, indicating that it is a bacteriostatic agent at high concentrations that decrease microbial density in the wound (48). Combining glycerin with wound formulations can be helpful due to its anti-itching effects.
2.6.4. Thrombin
Thrombin is an agent that supplies a mechanical formation to facilitate clotting. It has been clinically applied for topical hemostasis and wound management for more than six decades (50). The study by Ofra et al. bounded thrombin to maghemite (γ-Fe2O3) nanoparticles to stabilize thrombin (50). A study designed by Carney et al. indicated accelerated wound healing while increasing the capillary quantity and decreasing prolonged inflammation (51).
2.6.5. Urea
Urea is a physiological substance and a component of moisturizing skin factors that holds the skin’s hydration and integrity (52). There are many applications for urea in topical formulations. It enhances hydration and ichthyosis, and improves the barrier function of the skin (53). Moisturizers having urea have shown to reduce Transepidermal Water Loss (TEWL) in atopic and ichthyotic patients. By the way, it can make normal and atopic skin less sensitive against irritation to sodium lauryl sulfate (21). Swanbeck et al. used urea to treat dry skin (54).
2.6.6. Keratin
Keratin proteins have been proven to play a fundamental role in wound healing. The expression of the controlled keratin gene promotes cell growth, migration, and differentiation, and the absence of KRT17 has been shown to delay wound closure (55). There are reports of wound healing by using keratin-based dressing in fewer than 100 days (56).
2.6.7. Bone Marrow Mesenchymal Stem Cells (BM-MSCs)
They are heterogeneous cell populations of stromal cells. Direct injection of BM-MSCs to damaged tissues resulted in the amelioration of healing by differentiation accompanied by releasing paracrine factors (57, 58). Bone marrow mesenchymal stem cells can re-epithelize damaged tissue. Nevertheless, being the fundamental source of MSCs, the limitations are conspicuous, i.e., the aspiration method is invasive with fewer quantity of cells where differentiation potential declined with age (59, 60). BM-MSCs could effectively promote corneal alkali burn healing (61).
2.6.8. Umbilical Cord Blood Mesenchymal Stem Cells (UCB-MSCs)
They are more easily obtained than bone marrow with the same angiogenic effects (62) while showing interesting immuno-regulatory properties, which have a key role in treating chronic wounds. In 2016, Qin et al. demonstrated the effective clinical therapy of severe diabetic foot ulcers (63). The 2019 study of Han et al. showed the acceleration of cutaneous wound healing in diabetic rats by HUCB implants (64).
2.6.9. Endometrium Mesenchymal Stem Cells (E-MSCs)
Human endometrium is a possible alternative source of MSCs that can be obtained from menstrual blood or diagnostic curettage after hysterectomy (65). The angiogenesis effect was shown by Murphy et al. (66).
2.6.10. Adipose-Derived Mesenchymal Stem Cells (ADSCs)
Having a fundamental role in basic research and preclinical studies, ADSCs are considered an important source of restorative growth factors (67, 68), homing to the injury sites (69). In comparison with BM-MSCs, ADSCs can be harvested in bigger quantities at low risk. ADSCs have been used for wound healing and tissue renovation both in vivo and in vitro (65).
2.6.11. Platelet-Derived Growth Factor (PDGF)
This factor is produced by many cells like fibroblasts, endothelial cells, and keratinocytes in response to injury as a cellular response inducer in all phases of healing (70). The activation of pathways by PDGF generally leads to enhanced cell migration and proliferation and causes increased Vascular Endothelial Growth Factor (VEGF) and Insulin-like Growth Factor (IGF) production. Importantly, it enhanced growth factor receptor expression and extracellular matrix (ECM) (fibronectin, hyaluronic acid) production (70, 71). PDGF-BB is FDA approved for the treatment of diabetic wounds (72).
2.6.12. Fibroblast Growth Factor 2 (FGF-2)
It is produced by many kinds of tissues. FGF-2 is an angiogenic and neurotrophic factor that leads to complete wound healing (73). It has been used in clinical trials for chronic wounds in many formulations, such as hydrogels (74). The 2018 study of Kinoda et al. showed the protective effects of FGF-2 on impaired wound healing in mice (75). In the study by Wu et al. in 2016, FGF-2 facilitated vascular endothelial growth factor in wound healing (76).
2.6.13. Transforming Growth Factor
It is generally named as Tumor Growth Factor (TGF). TGF-β3 is in use in clinical trials for pressure ulcers (77).
2.6.14. Exosomes
Exosomes are cell-excreted vesicles that could be found in almost all eukaryotic fluids (78). Exosomes have notified the scientific community due to their wonderful features, including their possible function as biomarkers of different diseases and their potential to be used as therapeutic agents. They can carry proteins and nucleic acids to target cells and enhance their uptake through endocytosis (79). They are a novel approach to regenerative medicine and wound therapies. However, the concrete mechanisms that underlie this effect are poorly understood (80). A study done in 2018 reported that ADSC-derived exosomes could rise fibroblast proliferation and migration and hone collagen remodeling via the PI3K/Akt signaling pathway to further accelerate wound healing (80).
3. Results
There is a vast kind of material that is considered for the treatment or healthcare of diabetic wounds and skin conditions. In summary, diabetic skincare is an insurmountable factor in wound prevention. DM wound-healing is a lingering process that has been trapped in repairing phases. This paper discussed different ingredients with the potential of use in formulations as the main components. To design a good formulation, some key points should be considered, including effectiveness, safety, and availability. In conclusion, it can be argued that noticing discrepancies among various components could deter the final result. Due to the chronic nature of DM wounds, complete refinement is usually not achieved, so that investigations for novel treatments are ongoing for accurate and shorter treatment procedures. Hence, this assignment will examine this point of view as a matter of specification in formulations.
4. Conclusions
Diabetes mellitus causes a lot of complications to the skin; hence, choosing the right agents with fewer adverse effects on the body and skin is the main key to designing formulations. The chronic character of diabetic ulcers has made them difficult to manage in a specific way. Cell-based therapies and regenerative medicine are gaining ground in quotidian medical care. They are promising for the repair and/or replacement of damaged tissue and the restoration of lost functionality because they possess many criteria necessary for wound healing. Due to the method and form of application, stem cell therapies could treat the wound in a shorter time and are more effective than other forms of treatment. By the appearance of regenerative medicine, stem cell-based therapies and ingredients can be a novel and helpful way of treatment for diabetic ulcers, and by expanding our knowledge, there is a strong hope to resolve this problem.
