Enhancing Skin Cicatrization with Natural Sources – The Role of Polyunsaturated Fatty Acids (PUFAs) and Beeswax

Abstract

Objectives: To evaluate the effectiveness and tolerance in patients with RDEB of an ointment with the following active ingredients: petroleum jelly (30%), cod liver oil (10%), beeswax, sunflower oil, BHT, sweet almond oil. The formulation does not contain antibiotics or corticosteroids. Methods: A prospective study was carried out on a cohort of ten patients diagnosed with RDEB confirmed by molecular biology that are followed at the Centre for Research in Genodermatosis and EB. Given the seriousness of the pathology and the difficulties in obtaining good results with the therapeutic resources available, a one-year pilot test was performed with the use of an off-label drug. The therapeutic effectiveness was evaluated as well as the tolerance and safety of the ointment. Patients with infected injuries, anaemic with hemoglobin levels lower than 8 g/dl or albumin levels lower than 3 g/dl were excluded from the study. Before starting the treatment, a complete blood test was carried out. Lesions were evaluated by a grading system considering the compromise, depth and edges of the injury. Photographs of the injuries were taken at the beginning and at weekly controls for the first month and later monthly. The ointment was applied after bathing on sterilised dressings, followed by the placement of secondary dressings that allowed the oxygenation of the lesions. Both applications were changed every 12 or 24 hours. Results: The drug was evaluated for the period of one-year in each patient. No adverse effects were observed. It was well tolerated and blood tests results were not affected. After 48 hours of initiating the treatment the patients reported: absence of pain, increase of average sleep, decrease in the use of analgesic medication, faster healing of blisters in the skin, diminishing the affected areas and significant improvement in life quality. Conclusions: Even though the number of patients in the study was small, the results obtained allow us to conclude that this medication may be beneficial to alleviate the signs and symptoms of patients with RDEB. Subsequent studies on a greater number of patients will allow the confirmation of the seen couraging results.

1. Introduction

Wound healing has become a field of interest for biotechnological developments which have led in the last 10 years to an intense search for new findings in terms of synthetic compounds with healing properties, drug delivery systems and synthetic fibers and polymers, biomaterials, and nanoparticles [1, 2].

Skin cicatrization is a living model of the regenerative tissue process. Many comorbidities for instance bioburden and antibiotic resistance can appear during cicatrization and because of antibiotic abuse, and there is an increasing percentage of antibiotic resistance in developing countries. Another issue is wound bed inflammation which can be a chronic condition and establish a lack of healing timeline.

Despite technological advances and discoveries in the wound healing field, there is a turning back point in which doctors and researchers all over the world are paying attention to natural source agents with skin restorative capacity.

Beeswax for instance can provide antimicrobial peptides, which can prevent local infection at wound sites [3, 4, 5, 6]. Polyunsaturated fatty acids (PUFA’s) from cod liver oil, sunflower oil, and sweet almond oil provide a natural source of omega 3–6 with a local anti-inflammatory action at the wound bed [7, 8]. Recent case reports had reported the benefit of a combination of both PUFAs and beeswax for the topical treatment of sacral sores, burn wounds, and severe skin conditions like epidermolysis bullosa [9, 10, 11, 12].

Natural resources with a medical scope and careful production process should lead to an old and new pathway for skin regeneration. Medicine and Technology should work together to find a balance to use natural molecules capable of reducing local inflammation, and preventing and controlling the local infection.

It is very common for topical wound healing products to provoke contact dermatitis reactions that lead to discontinuing the product.

In this chapter, the authors will make an overview throughout the cicatrization process of the human skin, including frequent causes that alter wound healing like biofilm and local infection, pressure sores and hypoxia, burns, and genetic disorders which share great denuded skin areas. Authors will also describe their clinical experience in both adult and pediatric patients with chronic wounds treated with an ointment rich in PUFAs, ceramides, and antimicrobial peptides, Curefini™.

2. Cicatrization process. Stages

Wound healing is a well-organized process that can be separated into four sequenced and overlapped stages: hemostasis, inflammation, proliferation, and maturation. These can normally occur in acute wounds like in a knife cut for example.

Hemostasis is a coordinated mechanism of preservation to stop hemorrhage and avoid depleting the blood volume. Instantly, blood vessels constrict to restrict blood flow. Next, platelets aggregate to plug in the damage area in the wall of the blood vessel (platelet activation) followed by a coagulation cascade in which participate multiple factors that contribute to definitive fibrin clot formation. The fibrin clot is a provisory matrix that scaffolds the reconstruction of the dermis matrix of the human skin [13].

Even do inflammation has been presented as the second stage of the wound healing process, the presence of the immune system occurs from the very beginning of the injury throughout the granulation phase also. The initial infiltrate is composed of neutrophil cells to remove cellular debris and bacteria and decontaminate the wound bed. Then, neutrophils are replaced after by a mononuclear infiltrate. Celso’s tetrade is often present in this stage: swelling, heat, pain, and redness. Inflammation is a natural part of the wound healing process and is only problematic if prolonged or excessive.

The proliferative or granulation phase is ongoing all the time in the background. By the first week, the fibroblasts have started to deposit new collagen and glycosaminoglycans. These proteoglycans form the core of the wound and help stabilize the wound. Then, reepithelialization starts to occur with the migration of cells from the wound periphery and adjacent edges. The granulation phase not only implies the reconstruction of a new collagen net at the dermis but also the presence of new vessels to provide oxygen and nutrients [14]. In healthy stages of wound healing, granulation tissue is pink or red. When occlusive or semiocclusive dressings are applied within 48 hours after injury, correct tissue humidity and hydration are maintained to optimize epithelialization. Initially, only a thin superficial layer of epithelial cells is laid down, but a thicker and more durable layer of cells will bridge the wound over time. Fibroblasts suffer a phenotype change to myofibroblasts. Myofibroblast-acquired contractile cytoskeleton allows them to cause the wound to contract by gripping the wound edges and pulling them together.

The maturation phase refers to collagen fibers remodelation from type III to type I. This phase also called the remodeling phase starts around week 3 and can last up to 12 months. Collagenases are enzymes that break peptide bonds in collagen and eliminate the excess collagen, and wound contraction also begins. The resulting scar will never have 100% of the original strength of the wound and only about 80% of the tensile strength [15]. Once the proliferative phase has ended, many repairing cells will go under apoptosis. During the maturation phase, collagen fibers will slowly acquire a more parallel and closer disposition since water will be reabsorbed cross-linking of collagen reduces scar thickness and also makes the skin area of the wound strong.

3. Chronic wounds

Wounds generally heal in 4 to 6 weeks. Chronic wounds are those in which the healing process shows no response or a lower time rate of response over 4 or 6 weeks. Hypoxia, bacterial colonization, ischemia, reperfusion injury, altered cellular response, and collagen synthesis defects are factors that lead to impaired wound healing. Also, systemic conditions like diabetes, cancer, malnutrition, and smoking alter proper wound healing.

3.1 Biofilm

All open wounds, because they lack the protective covering of skin, are colonized within the first 24 hours, and they contain microorganisms that can be from the patient own’s flora or from an exogen origin, for example, in hospitalized patients. Normally, these microbes are destroyed by the host’s immune system. But, if microbes attach to the wound surface and proliferate, a biofilm will begin to develop, establish, and exhibit resistance to destruction by the host immune system and antimicrobials. At the wound site, microbes can proliferate exist under two distinct phenotypic states—planktonic (free-living) or biofilm (sessile/attached/aggregated). In the planktonic state, microbes can attach to a suitable surface (biotic or abiotic) and develop into polymicrobial biofilm aggregates. A biofilm can be described as a microbial colony encased in a polysaccharide matrix that can become attached to a wound surface. This biofilm, if proliferates to a critical point for instance more than 10⁶ colony-forming units (CFUs) per tissue grams obtained by biopsy sample, can affect the healing potential due to the production of destructive enzymes and toxins, which can promote a chronic inflammatory state and also local or systemic infection. In the biofilm form, microbes have improved tolerance for antibiotics and host immune defenses [16, 17]. It is estimated that ~80% of the bacteria-producing chronic infections can form biofilms. During the process of biofilm formation, microorganisms can communicate with each other through quorum sensing. Quorum sensing regulates the metabolic activity of planktonic cells, and it can induce microbial biofilm formation and increased virulence [18]. Biofilm infection as defined in vivo based on criteria laid out by Parsek and Singh include i) aggregate embedded in extra polymeric substance (EPS) matrix; ii) adherence to a surface or each other; iii) persistent and localized infection; and iv) resistance to antimicrobial treatments [19].

3.1.1 Prevention and treatment of biofilm

Strategies to manage biofilm infection in wound care settings may be divided into three broad categories based on the aspect of the biofilm life cycle: adhesion inhibitors, biofilm maturation (communication) inhibitors, and promoters of disruption.

The management of invasive wound infection usually includes systemic antimicrobial therapy in combination with debridement. While debridement can be very powerful in debulking hostile biofilm aggregates, the lack of visualization of biofilm aggregates during debridement can inadvertently translocate bacteria into deeper tissue worsening local response and the patient’s clinical condition [20, 21]. Surgical debridement converts biofilm bacteria to planktonic bacteria susceptible to antimicrobial therapy.

Other physical methods include nanomaterials (nanometer or submicron scale) which include nanoparticles made of metal or metal oxide. The membrane cell can be disrupted by the direct action of these nanoparticles or more indirectly by the liberation of free radicals or antiseptical drugs carried by liposomes.

Magnetic nanoparticles can be used to produce irreversible biofilm disruption (such as γFe2O3 maghemite or Fe3O4 magnetite nanoparticles) [22].

Nonthermal or atmospheric cold plasma (ACP) another physical alternative involves the generation of photons, electrons, neutrons, and protons when exposed to the constant supply of energy to a gas. The anti-biofilm effects of ACP are thought to be due to the generation of reactive oxygen species (ROS) and nitrogen species (RNS) (including organic radicals) [23].

Chemical methods are included in traditional strategies against biofilm. Silver-based management: The ionic form of silver (Ag +) has shown effectivity against bacteria (including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant Enterococci (VRE)), viruses, and fungi in planktonic form. Silver-based wound dressings help to control wound biofilm by a controlled liberation of silver ions. This mode of antiseptic delivering to the wound bed is less cytotoxic for the growing cells which can proliferate in a less toxic environment. Silver nanoparticles are less toxic than ionic silver [24, 25].

Iodine is an antiseptic that impacts bacterial cells by multiple mechanisms. The neutral and lipophilic nature of iodine could enhance the penetration of this molecule into biofilms. It can kill planktonic cells rapidly and also inhibit mature biofilms of Staphylococcus aureus and P. aeruginosa when treated over an extended period. The cadexomer-iodine (CI) combinations that sequester iodine without limiting its inhibitory functions have been shown to have anti-biofilm effects [26].

Hypochlorous acid (HOCl) is known to rapidly eradicate pathogenic bacteria and is less toxic to mammalian cells than hydrogen peroxide. Some studies claimed that HOCl was bactericidal against Streptococcus strains but unable to disrupt biofilm, and in vitro efficacy against biofilm-forming Pseudomonas and Staphylococcus strains was demonstrated [27, 28].

Quorum sensing inhibitors: Bacteria can communicate with each other, exchange resistance mechanisms, and adapt their behavior collectively to their environment by a molecular phenomenon called quorum sensing (QS) that involves the synthesis and response to small molecules called autoinducers (AIs). QS drives the synthesis of virulence factors such as pyocyanin (P. aeruginosa), biofilm formation, and other activities. The inhibition of QS is called quorum quenching (QQ). Inhibitors with the QQ effect are numerous and range from natural (e.g., certain types of honey) [29, 30] to synthetic (e.g., furanone) [31].

Antimicrobial peptides: Antimicrobial compounds produced by honey microbiota Lactobacillaceae and Bacillaceae present in honey microbiota are known producers of antimicrobial compounds such as bacteriocins, surfactants, and siderophores. Environments rich in carbohydrates such honey and other beehive products facilitate the proliferation of lactic acid bacteria (LAB) and fructophilic lactic acid bacteria (FLAB) like Lactobacillus and Bacillus [32, 33].

Several LAB and FLAB isolated from pollen, honey, bee bread, and crop displayed antimicrobial activities against bee pathogens, foodborne, and multidrug-resistant human pathogens like multiple antibiotic-resistant Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis, and P. aeruginosa [34, 35].

LAB are well-recognized as the producers of the most active antifungal compounds against filamentous fungi, Aspergillus and Penicillium spp. and yeasts Saccharomyces, Candida, Kluyveromyces, Zygosaccharomyces, and Pichia spp. [36, 37].

Bacillales are another dominant order of Firmicutes-colonizing nectar and honey. Bacillales compound more than 50% of honey microbiota, ranging from 60 to 90% of all bacteria in the honey can. Bacillus strains produce gene-coded and nonribosomally synthesized antimicrobial peptides. Together with LAB, Bacillus spp. comprises an efficient factory that supplies honey with a broad range of antimicrobial compounds [38, 39].

A broad-spectrum activity has been demonstrated in most bacterial strains. There is also a reported bacteriostatic activity against several strains of Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Candida albicans [40, 41].

Honey and its derivates products are usually contaminated with fungus and yeast, which had become adapted to osmolarity changes due to sugar concentration variations and pH acidity changes. These contaminants also require to be resistant to other microbes antagonist interaction like bacteria.

To survive, fungi and yeast produce antimicrobial compounds, siderophores and surfactants, inhibiting bacterial growth and quorum sensing. This compounds result beneficial to human health [42, 43, 44].

The main antimicrobial mechanisms of action of dominant honey microbiota bacteria and fungi are: (a) the change of orientation of the peptide-lipid II complexes from parallel to perpendicular to the membrane, (b) the insertion of the C-terminal of the peptide into the cytoplasmic membrane, and (c) the formation of transmembrane, water-filled pore [45]. The second mode of action includes inhibition of cell wall biosynthesis through the binding to lipid II. Lipid II is the main transporter of a peptidoglycan subunit from the cell interior to the place of cell wall synthesis [46].

3.2 Pressure sores

Pressure ulcers are considered chronic cutaneous wounds caused by sustained pressure over time, deformation, friction, and rubbing. Usually, bed sores appear in bedridden patients who cannot move or change their body positioning by their own will or because their consciousness is altered. Besides, the healing process can be prolonged and slow because of malnutrition, anemia, and the use of vasopressor drugs or anti-inflammatory drugs like corticosteroids. These lesions are usually located in the skin and underlying tissues on bony prominences [47].

Pressure ulcers represent a major problem in the healthcare system, with great epidemiologic, economic, and socio-family impact [48]. Approximately 65% of pressure ulcers originate in hospital stays, affecting mostly patients above 65 years of age and producing a negative impact on their nutritional and metabolic status and alteration in bowel movement, mobility, cognitive, and perceptual capacity, and the skin barrier [49].

Hospital-acquired pressure ulcers are considered one of the healthcare quality indicators, and it is estimated that 55–77% of cases could be avoided [50]. Early detection of patients at risk of developing a pressure injury needs to be implemented from the time of admission. Age, incontinence, and body mass index (BMI) are well-established risk factors. Having a BMI < 19 kg/square meter and an age above 65 are the most significant risk factors [51, 52]. Incidence is lower in overweight (BMI 25–30 kg/square meter) and obese (BMI >30 kg/square meter) patients [53].

The Braden Scale assesses the risk of developing a pressure injury based on criteria related to activity, mobility, skin moisture, nutritional status, friction, and rubbing, as well as the ability to feel pain and discomfort in different parts of the body as a result of pressure [54, 55].

Charlson’s Comorbidity Index permits the assessment of comorbidity factors related to the mortality risk of hospitalized patients. Patients with vascular disease, diabetes, chronic renal or pulmonary disease, and cancer are at a higher risk of developing pressure ulcers [56, 57].

Another important aspect of risk evaluation can be the categorization by related risk groups, for example, clustering groups of surgical patients and nonsurgical patients during hospitalization [58]. Surgical patients are at higher risk of developing pressure ulcers due to factors such as longer immobilization, anesthesia and/or surgery, and pre-existing medical conditions [59, 60].

3.2.1 Pressure sore prevention

The patient’s skin evaluation is fundamental to pressure injury prevention, classification/diagnosis, and treatment. All inpatients should have a skin assessment to determine their general condition and identify factors that increase the risk for pressure ulcer development. This examination should be performed from the initial patient’s admission throughout his route at different hospital units: Urgency, Intensive care, General Unit up to discharge. The initial condition of the patient’s skin at the admission first initial exam, like thin and fragile skin or senile purpura, is the most important early indicator of the skin’s reaction to pressure exposure and the continuing risk of pressure injury [61].

The complete skin assessment should include a general visual check of the entire body’s skin and mucosae surface and identify any characteristics indicative of pressure damage. This first signs include redness, local pain, and blistering. Caregivers should frequently monitor and check the skin beneath dressings, prostheses, and devices, and also areas of localized heat, skin breakdown, edema, areas of redness that do not blanch, and induration of the wound.

Bony prominence areas, which are at an increased risk for pressure injury due to pressure, friction, and shearing forces, should be protected from the very beginning of the admission. High-risk areas include the sacrum, heels, elbows, wrists, temporal region of skull, ears, shoulders, back of the head (especially in children less than 36 months of age), knees, and toes.

The patient’s baseline level of mobility and current level of mobility should be considered to plan an accurate strategy to prevent bed sores. For patients who can move independently or assist in moving themselves, it is recommended that they be encouraged and/or assisted to change their position regularly, either in bed or out of bed (if able). The selection of an appropriate support surface should take into consideration factors such as the individual’s level of mobility within the bed, the patient’s weight, and the need for microclimate control. When a patient’s voluntary movement is altered, changing body position every 2 hours is recommended.

Increased moisture on the skin or excessive dryness can exacerbate pressure injury development due to the risk of skin breakdown and altered skin integrity.

To maintain the skin clean and dry, the skin must be daily cleaned to remove unwanted substances without rubbing or frictioning the patient’s skin; pH neutral or slightly acidic skin cleanser (pH 4–7) is recommended and alkaline products (pH >7) should be avoided. To avoid skin dryness, a fragrance-free moisturizer is recommended.

Caregivers should protect the patient’s skin from incontinence. It is recommended to clean skin promptly after episodes of incontinence and choose appropriately sized incontinence products for maximum absorption. To create a physical barrier between the skin and fecal or urine irritants the use of barrier creams is recommended to prevent the skin breakdown.

Patients in pain are at an increased risk of pressure injury. Analgesia should be adequate during patient hospitalization, and analgesic rescue must be performed if a patient undergoes major mobilization that could expose injured skin areas and cause pain.

Malnourished patients are at increased risk of pressure injury development. Hydration and nutritional support should keep the nitrogen balance and serum albumin levels according to renal and liver function to maintain adequate skin integrity and hydration.

3.2.2 Pressure sores classification and wound management

Pressure injury stages and according to treatment indication.

Pressure injury staging or classification describes the extent of skin and tissue damage. Staging a pressure injury is essential for the development and implementation of a management plan.

Stage 1: Localized área of nonblanchable erythema of intact skin: protects the skin to prevent further injury. Dressing selection: silicone adhesive, nonadherent foam, or transparent hydrocolloid adhesive dressing.

Stage 2 Partial thickness skin loss relieves pressure and protects the wound from further trauma and contamination. Dressing: silicone adhesive or nonadherent foam.

Stage 3 Full-thickness skin loss: relieve pressure and protect the wound from further trauma and contamination. Dressing: alginate, hydrogel, hydrofiber, or silicone dressing.

In the treatment of cavitated wounds, different therapeutic options must focus on stimulating granulation at the dermis level to achieve coverage of underlying structures such as muscles, bones, or tendons.

A critical point from the therapeutic perspective in order to prevent and or treat pressure sores is the capability of healthcare givers to recognize early stages of pressure sores among the different types of skin colors and be skilled in the adequate selection of intelligent dressing and devices. It is also important to prevent fecal or urine prolonged contact to patient’s skin to avoid further irritation and or contamination.

Currently, calcium alginate is frequently used, as well as negative pressure systems or grafts for cavitated wounds.

The choice will depend on the availability of financial and human resources and hospital infrastructure. Advanced wound care, proper diagnostic understanding in each case, and management of the patient and his/her family context are all necessary conditions to achieve good clinical results. The insufficient availability of skilled human resources as well as the high cost of materials required for advanced care of wounds in developing countries call for the development of easy-to-implement, reproducible, and economical strategies that can be supervised by telemedicine.

During the last decade, the therapeutic approach to cavitated pressure ulcers has made great progress with the advancement of new technologies such as negative pressure, which promotes the filling of deep wounds [61]. Negative pressure cannot be applied in the presence of cancer tissue in the wound, to untreated osteomyelitis, in wounds with organ or vessel exposure, or to areas with poor blood flow. In some trials, its use in infected grade IV sacral ulcers has proved advantageous in terms of recovery time as compared to conventional treatments, achieving a recovery time duration of approximately 6 weeks [62]. However, in developing countries, this type of device continues to have a high cost, not only because of the elements required but also because of the skilled staff required for correct application and removal.

Other options are flaps and grafts close to the anal region, but these may lead to complications such as infection and necrosis. Usually, the sacral and perianal regions create difficulties in the adjustment and fixation of any device. Combined techniques and strategies, such as flaps plus a negative pressure system, tend to work well, although they also imply greater therapeutic demands [63].

A low-cost option for the treatment of cavitated wounds is calcium alginate, alone or in combination with micronized silver, with high absorptive and hemostatic capacity and some bactericidal properties. Calcium alginate may be applied in rope dressings that are easily introduced in tunneled wounds and can easily integrate naturally into the tissue. The dressings can be changed every 72 hours. When this product dissolves, it releases a gel-type discharge from the wound bed with a special smell that may be mistaken for infection. It requires a secondary dressing [64].

3.3 Skin genetic disorders: epidermolysis bullosa

Epidermolysis bullosa (EB) is a hereditary genetic skin disorder, classified as a type of genodermatosis, which causes severe, chronic skin blisters associated with painful and potentially life-threatening complications. Currently, there is no effective therapy or cure for EB.

Epidermolysis bullosa (EB) is a rare disease that affects 1 in 40,000 to 50,000 newborns worldwide.

Epidermolysis bullosa is a genetic disease caused by a modification, decrease, or absence of structural proteins in the skin. It is caused by a mutation of the gene that codes for that protein. Genetics has identified over 20 genes that are responsible for this disease, which makes it difficult to cure. It is characterized by lesions and blisters on the skin and mucous membranes (oral cavity, nasal cavity, pharynx, esophagus, digestive tract, respiratory tract, genitourinary tract, perianal area, and conjunctivae) that occur after minimal trauma or even spontaneously.

In epidermolysis bullosa (EB), blisters with serum-hematic fluid content appear on the skin. When these blisters burst, burn-like lesions occur, which then progress into scars and skin retractions that lead to functional disabilities such as pseudosyndactyly, among others. Lesions also occur on mucous membranes causing complications at the gastrointestinal tract level, resulting in malnutrition which further complicates healing.

EB is characterized by a pronounced skin and mucosal frailty that triggers blister and ulcer formation in response to minor trauma. The main affected sites are those exposed to frequent friction and pressure.

Perioral tissues, lip and cheek skin, and mucous membranes are especially affected by constant exposure to the “trauma” of chewing. Ulcers in the perioral region due to minimal trauma during chewing result in scars and tissue thickness which, when retracted, cause microstomia, thus making it difficult to open the mouth.

Localized blisters are the most common feature in all types of EB. However, depending on the EB subtype, the extent of involvement will vary from small vesicles that heal without causing damage to extensive lesions that lead to scarring and subsequent oral deformity, among others.

Vesicles have been identified in 92% of patients with recessive dystrophic EB, the tongue being the most affected area causing lingual depapillation.

Vesicle scarring leads to ankyloglossia (tongue sticking to the floor of the mouth) and obliteration of the buccal vestibule, which results in difficulty in chewing and suction movements. In addition, the lack of normal mobility of the oral cavity causes bone and dental development problems in the maxillae.

As a result of scar tissue formation in the mucosal lining and the skin of the lip region, especially in the commissures, there is a reduced inter-incisive buccal opening.

The reason for the delay in maxillary and consequently craniofacial growth is associated with impaired oral and masticatory movements and malnutrition due to reduced and inadequate food intake.

The formation of intraoral scar adhesions results in the collapse of the maxillae, palatal atrophy, retained teeth, dental misalignment, and dental crowding. Therefore, patients suffer from malocclusion.

Microstomia (limited mouth opening) and ankyloglossia cause muscle function alterations and subsequent craniofacial and dental growth impairment. Although the full spectrum of clinical manifestations is heterogeneous, blistering, pruritus, skin erosions, atrophic scarring, hyperkeratosis, and ulcers are the main cutaneous expression of the disease.

There are three main types of EB plus Kindler’s syndrome:

EB simplex (EBS) comprises all subtypes of EB that have mechanical fragility and blistering localized in the epidermis. There are two subgroups: suprabasal and basal depending on the histopathological site where the blisters originate in the epidermis. The most frequent mutations are found in the genes coding for the proteins Cytokeratin 5 and 14, Plectin, and Transglutaminase 5, among others. Inheritance is mainly autosomal dominant, but there are rare subtypes of recessive inheritance. There are generalized forms with lesions appearing at birth scattered all over the body and others localized mainly on the hands and feet. All EBS forms are exacerbated in hot and humid environments where increased sweat production contributes to blister formation. There is no growth delay, anemia, or esophageal lesions in this type of EB.

Junctional EB (JEB) includes all EB subtypes in which blisters are found in the lamina lucida located in the area where the basement membrane joins the epidermis and dermis and overlying the lamina densa. There are two subgroups: generalized and localized. The most frequent mutations are observed in the genes coding for proteins Laminin 332, Collagen type VIII, and Integrin α6β4. Inheritance is autosomal recessive. JEB is a severe form of the disease. It is characterized by widely distributed blisters, hyperplastic granulation tissue in the perioral, perinasal, and nail regions, or blistering sites. It also involves the mucous membrane of the mouth (intraoral vesicles), larynx, bronchi, esophagus, rectum, and vagina. Extensive denuded areas are observed at friction sites. The combination of chronic infections and iron depletion can lead to chronic anemia; it can be associated with growth delay, malnutrition, and involvement of the oral cavity and dentition.

Dystrophic EB (DEB) includes all DEB subtypes where blistering occurs within the upper dermis just below the lamina densa of the skin. There are two subgroups: dominant (DDEB) and recessive (RDEB). All mutations of this EB type are seen in the gene coding for Collagen type VII protein. Inheritance can be dominant or recessive, with recessive inheritance being more severe. Some DDEB forms may involve hands, feet, knees, nails, and other organs, whereas RDEB shows extensive blisters and lesions all over the body, nail loss, anemia, growth delay, pseudosyndactyly (fusion of the fingers or hands in the form of a cocoon), and wounds in the cornea, mouth, esophagus, and bowel. There is a high probability of bacterial colonization and recurrent infections in wounds. Also, there is a risk of developing skin cancer (spinocellular carcinoma).

In the Kindler syndrome (KS), of autosomal recessive inheritance, mutations are observed in the gene coding for the Kindlin 1 protein. It is the least common form of EB, and it is difficult to diagnose. It is characterized by the presence of phenotypic features unique to EB: photosensitivity, poikiloderma, and scarring.

New scientific advances despite their high cost and complex clinical applicability open up new pads for future treatments. This includes gene therapy, protein replacement therapy, cell therapy with allogeneic fibroblasts, mesenchymal stromal cells, and gene editing/engineering. Tissue engineering materials that mimic skin structure are also now available. However everyday patients´ reality is much closer to standard treatments like nonadherent dressing and ointments.

In addition to this, many intrinsic factors adversely affect patient’s healing process that includes anemia, malnutrition, infection, and itching.

The constant skin detachment leaves numerous body denudated areas that undergo the defective repair process. Incidental pain, pruritus and scarring, and local infections increase the incidence of squamous cell carcinoma, which represents the main cause of death in young adults with RDEB.

Goertz et al. described a solidifying gel that dissolves at room temperature and hardens to a gel consistency at normal body temperature or above. This gel reduces incidental and spontaneous pain.

Another new smart dressing is a gelling dendrite dressing based on hydrogel, which solidifies in few minutes, ensure hemostasis, and provide a balanced moisture environment. It can be dissolved any time [65].

Antibacterial gel dressings based on chitosan (Opticell Ag+) have recently been introduced, which provide a moist, adaptable, highly absorbable antimicrobial dressing to reduce dressing changes and alleviate pain [66].

Honey impregnated dressings and ointments are effective in both the treatment of chronic wounds and in reducing the biological load [67].

Cutimed Sorbact dressings remove bacteria through hydrophobic interactions. They are coated with a fatty acid derivative that attracts bacteria to the dressing, where they are bound [68].

Dressings containing polyhexanide, such as Suprasorb X1 PHMB (Activa Healthcare, Lohmann & Rauscher, UK), provide antimicrobial treatment for critically colonized and infected wounds, and they are recommended for long-term application [69].

The polymer membrane dressing (PolyMem, Ferris, OH, USA) contains a cleaning agent (surfactant), which reduces the biological load and allows the healing of resistant wounds. Polymeric membrane dressings have the advantage of being “self-contained” without the need for a nonadherent primary or secondary dressing to protect or manage exudation [70].

Infected or critically colonized wounds require more frequent dressing changes. Another important aspect to consider is that an ideal dressing should be also usable on oral, ophthalmic, or genital mucosa, especially on this kind of patient.

3.4 Domestic burns

Burns are a global public health problem, accounting for an estimated 180,000 deaths annually. In 2004, nearly 11 million people worldwide were burned severely enough to require medical attention. In India, over 1,000,000 people are moderately or severely burnt every year. The majority of these occur in low- and middle-income countries, and almost two-thirds occur in the WHO African and South-East Asia regions. Burns are among the leading causes of disability-adjusted life-years (DALYs) lost in low- and middle-income countries. Nonfatal burn injuries are a leading cause of morbidity, occur mainly in the home and workplace, and are preventable. Nonfatal burns are a leading cause of morbidity, including prolonged hospitalization, disfigurement, and disability, often with resulting stigma and rejection [71].

A burn is an injury to the skin or other organic tissue primarily caused by heat or due to radiation, radioactivity, electricity, friction, or contact with chemicals. Thermal (heat) burns occur when some or all of the cells in the skin or other tissues are destroyed by: hot liquids (scalds), hot solids (contact burns), or flame (flame burns).

Females have slightly higher rates of death from burns. Open-fire cooking can ignite loose clothing of women suffering major burns areas. Unsafe cookstoves and neglected parent-control environments put also children at risk when they are nearby [71].

Open flames used for heating and lighting also pose risks, and self-directed or interpersonal violence is also a factor. In Argentina, since 2016 there has been an increased number of domestic violence cases against women perpetrated by male partners. These attacks are characterized by flammable body burn injuries. Usually, men spray alcohol against the victim’s body and then light it up with any kind of flammable object, cigars, matches, for instance. In 2016 were registered 256 total cases of femicides, 7% of them were burn injuries [72].

It is mandatory to find accessible and affordable treatments for domestic burns in developing countries. This should be accompanied by educational first-aid strategies. Medically tested natural products like beeswax and cod liver oil combined ointment, constitute a great treatment option for domestic burns.

4. Curefini™ natural ointment

Curefini™ is an OTC product approved by the FDA and is currently in use in pediatric patients with recessive dystrophic epidermolysis bullosa (RDEB). Curefini’s main components are petrolatum, sunflower oil, cod liver oil, sweet almond oil, and medical beeswax. Curefini™ polyunsaturated fatty acids (PUFAs) component gives anti-inflammatory properties that facilitate a controlled wound inflammatory environment, enhance reepithelialization and granulation processes, and allow for autolytic debridement and gentile mechanical detritus removal on each gauze change.

Curefini™ ointment is a formula enriched with PUFAs, omega 3, and omega 6, contained in its pure source oils. PUFAs reduce the local inflammatory process in the wound by inhibiting the production of inflammatory eicosanoids and competitive inhibition of the formation of arachidonic acid. PUFAs also have antibacterial action [8].

Sunflower seed oil contains large amounts of linoleic acid, which has anti-inflammatory and antibacterial properties and promotes the restoration of the skin barrier [73].

Sweet almond oil is restorative to the skin barrier and has anti-pruritic properties [74].

Beeswax is known for its healing, antibacterial, and anti-inflammatory properties [4, 5].

The combination of cod liver oil and medicinal beeswax has been successfully used in wound treatment in veterinary medicine [9, 10].

Curefini® has been previously tested on a porcine model for second-degree burns and showed the ability to control the inflammatory process and promote the development of a more-resistant skin layer in the affected area [75].

4.1 Polyunsaturated fatty acids, PUFAs

Adequate skin response to an injury depends not only on prior skin health but also on many crucial factors of them mentioned before, like nutritional status and optimum tissue oxygen supply, and an equally important factor is a balanced inflammation microenvironment. In the same way, as heat is needed to cook a meal, in the tissue regeneration process, the immune system and free oxygen radicals should be balanced and controlled in time and intensity to restore damaged structures. Bioactive lipids and cytokines regulate the skin’s immune system. They can initiate an immune response with controlled inflammation, followed by efficient resolution.

Unsaturated fatty acids such as linoleic acid (LA), α-linolenic acid, and oleic acid, and most of their bioactive products have shown an effective role as a topical treatment of chronic skin wounds. Their effect, when the treatment starts at day 0, has been observed mainly in the inflammatory phase of the wound healing process. Thanks to their bioactive properties, unsaturated fatty acids (monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs)) enhance the wound healing process in chronic wounds.

A fatty acid chain is monounsaturated if it contains one double covalent bond between the carbon atoms and polyunsaturated if it contains more than one double covalent bond. According to the length of the chain, they can be classified into short chain (2–6 carbon atoms), médium chain (13–21), and long chain (more than 22). The metabolic rate of fatty acid depends on the number of carbons and double bonds, the location of the double-bond position, and its geometric configuration (cis or trans) [76]. The double-bond position in the chain, defined by the number of carbon atoms from the terminal methyl group (omega or ω) (H3C), determines the “metabolic family” to which the fatty acid belongs.

The human body cannot synthesize some PUFAs which are those from the omega-3 (ω-3 or n-3) and omega-6 (ω-6 or n-6) families. They have the first double bond in the third and the sixth carbon, respectively, counting from the terminal methyl group. α-Linolenic acid (ALA) belongs to the ω-3 family and is an important precursor of other fatty acids with bioactive properties, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). On the contrary, linoleic acid (LA) belongs to the ω-6 family and is a precursor of arachidonic acid (AA), an important fatty acid with several metabolic effects, since it originates other eicosanoids from the ω-6 family, such as leukotriene, prostaglandins, and thromboxane.

Even though the human body can produce saturated and unsaturated fatty acids from carbohydrates and proteins, it is not able to synthesize ALA and LA [77].

PUFAs can regulate and modulate inflammation and immune response due to eicosanoid production [78]. Eicosanoids are originated from omega-6 and -3 PUFA metabolism, such as prostaglandins, leukotrienes, thromboxanes, and lipoxins, which modulate the inflammatory response unevenly [79].

Eicosanoids from omega-6 PUFA metabolism, produced by AA oxidation, are potent inflammatory mediators, involved in infection, inflammation, tissue damage, immune system modulation, and platelet aggregation. On the other hand, with a predominant anti-inflammatory role, ALA (omega-3 family) can be converted into EPA and DHA, which compete with AA for the enzymatic pathways of cyclooxygenase (COX) and lipoxygenase (LOX), also giving rise to eicosanoids [80].

During skin wound healing, keratinocyte and fibroblast produce PGE2, which has a pro-inflammatory action, promoting vasodilatation, cell proliferation, and modulating immune response [81, 82]. PGE2 also regulates fibroblast migration and collagen contraction and has an anti-fibrotic effect by increasing the expression of matrix metalloproteinase (MMP) 2 and 9, which are type IV collagenase found at elevated levels in chronic wounds and inhibiting TGF-β1-induced collagen synthesis of dermal fibroblasts [83]. PGE2 is also involved in keratinocyte proliferation and differentiation, the chemotaxis of keratinocytes, and the modulation of dermal fibroblasts [84].

The metabolism of AA (omega 6 family) via COX and LOX pathways generates proinflammatory products, while the metabolism of ALA and LA (omega-3 family) results in anti-inflammatory action products.

Skin macrophages have nuclear receptors called peroxisome proliferator-activated receptors (PPARs) that can regulate their anti-inflammatory state reducing the production of pro-inflammatory cytokines [85].

PUFAs such as 15-hydroxy-eicosatetraenoic acids, 13-hydroxy-octadecadienoic acid, 15-doxy-Δ-12, and 14-prostaglandin J2 (15d-PGJ2) can activate PPAR-γ receptor reducing the levels of proinflammatory cytokines such as IL-1β, TNF-α, and IL-6 in the wound, and slightly increase the levels of pro healing growth factors, such as VEGF, IGF, and TGF-β1 [86].

Topical treatment with polyunsaturated fatty acids (PUFAs) and fatty acids’ analogs as well as their receptors’ agonists has positive effects in wound healing. They have become an interesting treatment option to enhance the wound healing process.

Cod liver oil is rich in the following PUFAs: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), sunflower, and almond oil contain linoleic acid (LA) and gamma-linolenic acid (GLA) all of them present in Curefini™ formula.

4.2 Beeswax

Beeswax is as a complex lipid with organic constituents displayed in a liquid form, produced by the specialized wax glands of the bees. Beeswax changes its glass-clear and colorless appearance after worker bees masticates it and then becomes more brownish with the incorporation of pollen oils and propolis.

Its chemical composition is represented by a combination of almost 300 constituents such as fatty acid esters (approximately 67%), free fatty acids (12–14%), diesters, hydrocarbons (among 12–16%), fatty alcohol (approximately 1%), and exogenous substances (propolis and pollen residues, and a reduced number of floral constituents) [87].

Beeswax also has flavonoids and antioxidants which have positive effects on the wound healing process when applied topically regulating the production of cytokines by skin inflammatory cells [88, 89].

Virgin beeswax was observed to have antibacterial inhibition against different types of bacteria and also C. albicans yeast. The efficiency of beeswax can be detected against some Gram-positive bacteria, including S. epidermidis, Streptococcus pyogenes (S. pyogenes), and S. aureus but also on P. aeruginosa, B. subtilis, and E. coli as part of Gram-negative bacteria. A smaller impact was shown among C. albicans while against Proteus mirabilis and Salmonella typhimurium, beeswax proved to have no effect. The synergy between honey, olive oil, and beeswax was demonstrated to have an important impact on C. albicans and S. aureus [5, 90].

5. Case reports: clinical experience with Curefini™ ointment

5.1 Case 1: grade IV sacral sore treated with Curefini™ ointment

The present Case Report has been published at Case Reports in Dermatological Medicine Journal Open Access publisher CC-By 4.0 license [91].

Fifty-seven-year-old male patient with a history of hypertension, dyslipidemia, obesity, and coronary disease underwent double bypass surgery, with a 27-day-post op interment period during which he developed a sacral pressure ulcer with asymmetrical compromise on both sides of the intergluteal cleft, grade III, and grade IV pressure ulcers on the left and right sides, respectively, according to the NUAP/EUAP classification [92]. The patient’s photographs showed a sacral ulcer involving the intergluteal cleft in a butterfly shape, with necrotic tissue 10 cm diameter on each side. Involvement of the deep tissues was not evident at first sight, but the left side seemed to have more superficial involvement (Figure 1a). The treating physician decided to initiate autolytic debridement with chloramphenicol/collagenase ointment plus secondary gauze dressing with petrolatum, cleaning with polyhexanide solution twice daily. After 10 days of evolution, the first surgical toilette was performed with debridement of necrotized tissue; no swabs or culture specimens were collected. An ulcerative granulation bed was observed in the deep dermis with active borders and some brownish-red areas on both sides. No local erythema, temperature, or purulent discharge was observed (Figure 1b). The patient received prophylactic antibiotic therapy with ciprofloxacin 500 mg PO bid for five days and continued with chloramphenicol/collagenase treatment at home. After 18 days of chloramphenicol/collagenase local treatment, an ulcerative bed was involving sectors up to the hypodermis with fatty tissue exposure and cavitation at the right median and paramedian sacral level, reaching the muscular plane with no evident bone exposure (Figure 1c). Neither the probe to bone nor the lumbosacral IRM was performed. A fetid, purulent discharge was found on the gauze. No fever or shivering was reported. It was decided to schedule a new surgical toilette which was performed on day 20.

Figure 1.

Wound progression before Curefini®treatment. (a) Day 1: the patient is discharged from hospital after 27 days. Chloramphenicol/collagen is initiated as local treatment. (b) Day 10: the first surgical debridement is performed. Chloramphenicol/collagenase local treatment continues. (c) Day 18: topical treatment with chloramphenicol/collagenase continues. (d) Day 20: the second surgical debridement is performed, initiated with iodoform gauze, antibiotics PO, and oral opioids. Wound progression with Curefini®treatment. (e) Day 42: after 12 days of Curefini®local treatment. (f) Day 60: after 30 days of Curefini®. (g) Day 75: after 45 days of Curefini® local treatment.

On day 20, a second surgical debridement was performed. Physical examination showed a left-side grade III pressure sore with granulation tissue at the wound bed and active reepithelialization borders; on the right side, a cavitated grade IV sore was observed, with hypodermis fat exposure, increased depth of the cavity with no bone exposure, and the negative probe to bone test (Figure 1d).

Following the debridement, according to the patient’s medical report, no soft tissue culture specimens were collected and empiric systemic antibiotic treatment was indicated: amoxicillin/clavulanate 875/125 mg PO bid for 10 days and local treatment with iodoform gauze dressings inside the cavity, with the indication to change every 48 hours. The patient complained of an increase in local pain and received tramadol 50 mg PO every 8 hours.

On day 30, the treating physician proposed a skin graft; however, the patient decided to get a second opinion from a wound care specialist. At this point, the authors contacted the patient for the first time. During the interview, the patient was said to be concerned about the evolution of the wound, was said to be unwilling to have a surgical procedure and later hospitalization since his home is located 500 km away from the hospital, and had reported continuous pain and impossibility to sit or find a good position to sleep and regarding his mood, and he seemed to be more depressed.

As independent wound care specialists, we suggested to the patient and his family a new local treatment consisting of gauzes embedded in an ointment made of cod liver oil, sunflower seed oil, sweet almonds, virgin beeswax, and vitamins A and D, Curefini™. One month after being discharged from the Coronary Unit, the patient started topical treatment with a sterile gauze lubricated with Curefini™, filling the cavity. The surface of both buttocks was covered with sterile gauze embedded with Curefini™, with the indication to change it every 12 hours.

On day 42, after 12 days of topical treatment with natural ointment, pain improved significantly, oral opioids were tapered until total discontinuation, and the patient tolerated the sitting position for brief periods. After Curefini™ local treatment was established, the granulation and reepithelialization processes were reactivated and hypodermis fat tissue was covered with new skin (Figure 1e). On day 60, after 30 days of treatment with Curefini, a 50% reduction in transverse wound diameter was observed, along with granulation tissue in the cavity bed and advanced epithelialization border (Figure 1f).

On day 75 after discharge from the hospital, with a 45-day-continuous period of Curefini™ treatment, 95% closure of the lesion was achieved and a large crater ulcer was replaced by a transverse fissure in the right intergluteal fold of only 4 cm in depth, which continued to be treated locally with a gauze impregnated with the ointment (Figure 1g).

At this point, the patient starts to walk without difficulty or pain, maintains a correct diet with normal bowel movements, has restorative sleep, and shows a tranquil mood.

Control after 3 months of Curefini™ treatment showed the cavitation was filled, although a certain degree of scar retraction is observed in the surrounding tissue with some hypertrophy. No remnant fistula trajectory or tunnel is observed.

This case highlights the therapeutic efficacy of treatment with a natural ingredient-based product on cavitated wounds that help to reduce pain and promote granulation and reepithelialization of the skin. We remark that despite the location of a cavitated sacral wound near the anus and patient depositions, no local or systemic infectious events were detected. Its use should be considered a treatment of choice in developing countries where the distance from the hospital, economic limitations, and lack of wound care specialists are key conditions for a successful outcome.

Curefini™ can be used for prevention as a barrier to avoid shearing, friction, and also on early stages pressure sores.

5.2 Case report 2: second-degree burn treated with Curefini™ ointment

The present case report was published in Wounds International Journal [11].

A 51-year-old female patient with no clinical records of health problems consulted for a boiling oil scald of her skilled hand that occurred 4 days previous to consultation. She felt an extreme burning and piercing pain. The color of the skin was initially red, developing a blister of serous content with a size of 7 per 4 centimeters in diameter red on the base and purple surrounding it (Figure 2a). At home, the patient placed her hand under cool running water to relieve pain and covered her hand with a gauze dressing. The blister broke spontaneously, draining part of its content (Figure 2b). She was immediately treated in the Emergency Room where the blister was debrided and the area was treated with silver sulfadiazine and lidocaine, sterile gauze, and gauze dressing. Spontaneous and incidental pain did not improve, so the patient decided to seek cross-consultation with the Dermatology Department 4 days after the incident. On physical examination, there were no infection findings, the wound bed was intense red and there was no tissue fragment or cellular detritus. The mobility of fingers was limited by pain (Figure 2c).

Figure 2.

(a) and (b) The first six hours after burn injury with boiling oil, a serum-filled blister measuring 7×4cm was formed, with purple tissue surrounding it. Initially, the patient had placed her hand under cool running water to relieve pain and covered her hand with a gauze dressing. The blister broke spontaneously. She was then treated in the emergency department, where the blister was debrided (c) and the wound was treated with silver sulfadiazine and lidocaine, with a sterile gauze dressing. Her spontaneous and incidental pain did not improve, so she decided to seek a consultation with the dermatology department on day 4 (d) On physical examination, there were no signs of infection, the wound bed was bright red and there were no tissue fragments or cellular debris. The mobility of her fingers was limited by pain. The treatment protocol was changed to Curefini™ ointment, using a thick layer on a sterile dressing on the wound, and a secondary dressing of PVC clingfilm. (e–g) At 3 weeks, 80% of the wound had reepithelised. At the end of 6 weeks (h), the skin showed normal thickness reporting no scarring, contracture or hypersensitivity. She had recovered her range of motion and could flex and extend her finger and close her hand into a fist. No infection developed at any stage.

The treatment protocol is decided to be modified initiating treatment with Curefini TM ointment extending a thick layer on a sterile dressing to therefore apply it over the area affected covering the hand and forearm with PVC cling film.

A daily wound treatment course was prescribed. About 24 hours after the onset of treatment, the patient experienced significant pain relief which allowed her to sleep and started to move her hand. After subsequent medical control visits, the attenuation of intense red color, which for the days turned pink, could be observed (Figure 2d–f).

At 3 weeks, reepithelization of wound healing (Figure 2g) was achieved by 80%. Wound healing treatment continued for 4 weeks exactly according to the onset of treatment, since the patient still referred skin sensitization to the topical exposure of her hand exposed, daily rubs, and climate change. At the end of the period, skin showed normal thickness reporting no scarring, retractions, or hypersensitivity. The opening and closing hand functions of fingers as well as the closed fist function were achieved (Figure 2h). During the whole process, the wound did not get infected.

Curefini^TM ointment reported the following:

• Decreased spontaneous and incidental pain

• Favored reepithelization.

• Provided natural components with anti-inflammatory and antibacterial capacity offering an alternative to the common use of products containing antibiotics or corticosteroids.

• Resulted effective in wound healing treatment for second-grade burns in human adults. It was previously tested on a porcine model for second-degree burns showing an ability to control the inflammatory process and promote the development of a more resistant skin layer in the affected área

• Maintained skin moisturized and decreased desiccation. Curefini TM has the potential to be used in other inflammatory and desquamated skin states.

• Stimulated the occlusive healing, plus the impermeability of the secondary dressing, PVC cling film by avoiding direct contact with air, and low tension oxygen tension on skin surface [93].

5.3 Case 3: long-term follow-up study of nine (9) years of a female patient diagnosed at birth with recessive dystrophic epidermolysis bullosa, under continuous treatment of skin and oral mucosa with a topical ointment elaborated with petrolatum, cod liver oil, virgin bee wax, sunflower oil, sweet almond oil, and vitamins a, D, and E. Assessment of skin development and quality of life (QoL) impact

Background: Full-term AGA, born by cesarean section on 10/25/11, Apgar 8/10. Clinical diagnosis: Recessive Dystrophic Epidermolysis Bullosa (RDEB) with aplasia cutis in feet, confirmed by molecular biology. Symptoms included the daily occurrence of blood-filled blisters and permanent itching. Wounds were easily infected and necrotic maroon in color. The patient was in severe pain and required frequent use of morphine. Did not respond during the first 6 months of life to topical treatment qualified by the EB international guidelines (moisturizers, antibiotic creams, and dressings.

Method/Intervention: Treatment of skin and oral mucosa with a topical ointment elaborated with petrolatum, cod liver oil, virgin beeswax, sunflower oil, sweet almond oil, and vitamins A, D, and E. Dressings changed every 12 hours: ointment on sterile gauzes covered by dressings to allow for oxygenation; no wound touching or cleaning. The ointment was spread on the lips, oral mucosa, and tongue.

Quality of Life (QoL) first 6 months of life pre-intervention: Pain as dominant symptom treated with opioids. Generalized serohematic blisters in the skin, oral mucosa, and lips; aplasia cutis with repeated infections in feet. Intense pruritus and scratching alter sleep. Frequent crying, feeding difficulty, and sleep alteration. Patient needs specialized nursing assistance every 2–4 hours. (Figure 3a–e, Video 1: https://youtu.be/8kiL-9hrJXU).

Figure 3.

(a–c) New-born conventional treatment. (d, e) 5 month old, conventional treatment. (f, g) 6 ½ month old, 20-days long treatment with Curefini™ ointment. (h, i) after 120 day of treatment with Curefini™ ointment. (j) after 3 years of treatment with Curefini™ ointment.

QoL after 6 months of life post-intervention: - Upon treatment onset: Significant pain relief and reduction of blister number and size, blood-free content, night itching calms down. Sleep regularizes, and feeding improves. After 20 days of treatment, opioids are discontinued. –.

At 6 months of age: cure of aplasia cutis. Cure wounds every 24 hours by the parents to date. The wounds never got infected (Figure 3f,g).

After 120 days of treatment with Curefini™ ointment (Figure 3h,i).

At 3 years of age, continuous positive skin response was observed (Figure 3j).

At 6 years of age: until then, baths with chlorhexidine in water, thereafter she showered independently, with wounded areas covered by dressings. Patient gets dressed with assistance.

Schooling: At age 3 she initiated pre-school, continuing to elementary school with good performance.

First esophageal dilation at the age of 5 years; then 5th and last at the age of 8 years in 2019. Off-label treatment with Losartan potassium since May 2020 (REFLECT), dose 17.5 mg b.i.d. Entertainment: Rides a tricycle, on horseback, and interacts with friends. Current hematological parameters: Anemia, HB levels never below 10 g/dL; HCT: 31.4%. ESR: 27 mm/hrs. (0–20); PCR: 15 mg/L (< 5 mg/L). Treatment: Iron poly maltose 1 mL/d (50 mg). Liver and kidney function: NAD.

At 9 years of age: BMI 14.2 (WHO child growth standards; p 3/15); body weight 23.700 kg; height: 123 cm. No pseudo syndactyly or microstomy, good mouth opening, dentition NAD. Persistent pruritus was informed. (Figure 3k).

Conclusion: During 9 years of observation and treatment, the ointment controlled pain, reduced affected areas, and prevented skin infections and retractile scars. Well, patient compliance to treatment method. Well integrated into school and peers. CDLQI = 5 (Figure 3l, Video 2: https://youtu.be/i2_Myo2VnRY).

6. Conclusions

Natural source combined formula of cod liver oil, sweet almond oil, sunflower oil, and beeswax ointment has clinically proven its efficacy as an enhancer of the wound healing process showing particular efficacy on controlling skin inflammation, thus local pain. Nor clinical dermatitis or skin irritation was detected while it is used. It can be used safely both on skin and mucosa.

If proper sterile application technique is used, no bioburden or wound infection was detected as a complication in any of the three different clinical cases.

Beyond its own properties, the clinical use of this particular balanced natural source formula has reduced the concomitant use of topical and systemic antibiotics, corticosteroids and opioids.

Topical use of PUFA’s and beeswax may lead the way for a new kind of medicine understanding that humans belong to Earth and we are here not only to take care of ourselves but to protect what can heal us.., Nature!

Conflict of interest

The authors declare no conflict of interest.