Introduction

Ulcers are classified according to their etiology: vascular, pressure, neuropathic, iatrogenic/traumatic, oncologic and others. Some of them have a slow evolution and a tendency to chronicity.

All ulcers affecting skin and deep tissues are considered as a health problem due to social importance and the great impact on the economy they have.

In the Western Countries between 1-2% of the population suffer from chronical ulcers, for people older than 60 years this share is between 0.6-3%, increasing to 5% for people olderthan 80 years, (Acta Med Croatica. 2014 Oct; 68 Suppl 1:5-7.[Chronic wounds as a public health problem].Situm M, Kolić M, Redzepi G, Antolić S.) overall a recurrence rate of 30%  (Leitlinie:Diagnostik und Therapie des Ulcus cruris venosum) can be observed.

Considering that about 2-4% of the total healthcare budget is spend on the treatment of ulcers and complex wounds. (Sen CK, Gordillo GM, Roy S, et al. Human Skin Wounds: A Major and Snowballing Threat to Public Health and the Economy. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. 2009;17(6):763-771. doi:10.1111/j.1524- 475X.2009.00543.x.)

Only the treatment of pressure ulcers accounts for 461 mln of expenses in Spain, there are between 57 000 and 100 000 patients with that condition treated daily; the estimated annual expenses in the UK are more than 2 bln pounds.

In Germany, according to the study Primärmedizinische Versorgung (PMV) conduced in Cologne, 2.9 mln patients currently suffer from chronical wounds of the following categories:

  • • Decubitus (11% – 320 025)
  • • Ulcus cruris (39% – 1 173 408)
  • • Diabetic foot (13% – 383 561)
  • • Posttraumatic Wounds (21% – 612 229)
  • • Burns (3% – 78 050)
  •  Other Wounds such as infections, abscess, amputation wounds or postoperative wounds at maligned regrowth (14% – 404 139)

Moreover, the occurrence of chronical wounds can be seen as an indicator for the quality of life as well as the healthcare assistance to be received by these patients. In the coming years, there is an expected increase of the cases due to increased life expectancy, the epidemic of Diabetes Mellitus and obesity, as a result of a major change in lifestyle and unhealthy diet. It is a global phenomenon, there are more than 9.7 mln venous ulcers and approximately 10 million diabetic ulcers estimated worldwide.

One of the biggest challenges, the doctors face with in this area, is that the standardized wound treatment is only successful in 30-75% of cases, the rest of them become chronic wounds, and it can take months or years for them to close up, or in worst cases it never happens.

More than 40 mln cases of chronic wounds worldwide don’t close up, 10 mln of them are in Europe. (Maderal AD, Kirsner RS. Clinical and Economic Benefits of Autologous Epidermal Grafting. Muacevic A, Adler JR, eds. Cureus. 2016;8(11):e875.doi:10.7759/cureus.875.)

“The avalanche of medical products for the treatment of complex ulcers and wounds that has flooded the German market in recent years,contrasts with the lack of positive overall results”, wrote Prof. Dr. Gernold Wozniak of Bottrop Knappschaftskrankenhaus Hospital in an article in the Gefäßchirurgie journal.

More and more active dressings appear every day, they generate conditions of suitable moisture for the healing of ulcers, improve the control of exudate and infections, protect their edges, but do not shorten the healing time of chronic wounds.

Most existing therapies are not effective, moreover they are not supported by any scientific basis. Even so-called advanced therapies have not achieved the expected results. Moreover,these therapies are too expensive, and their profitability to effectiveness ratio is still to be evaluated in the coming years.

Research

Taking into account this situation, a research conducted at Ruhr-University Bochum (Germany) became the starting point for the development of a new therapy, scientifically based on findings made by researchers of the Department of Cellular Physiology at this University, where various types of olfactory receptors in skin cells were discovered.

In particular, the so-called OR2AT4 is activated by the synthetic sandalwood odour, and initiates a biochemical signalling pathway mediated by Ca, Kinases and AMPc, favouring a faster proliferation and migration of cells – two fundamental processes which facilitate tissue reparation, as was demonstrated in cultures of human skin.

These findings were published in the scientific journal “Journal of Investigative Dermatology”, 134,2823- 2832(2014).

 

According to the study, cell growth is stimulated by more than 30%. Extrapolating this research to medical practice, we have patented (Nº 201630534) a system and designed a method for the application of this therapy, which allows us to significantly reduce tissue repair time.

In the last two decades, several olfactory receptors have been discovered outside their normal location at the level of the nasal epithelium (Vanderhaeghen et al., 1997;Feldmesser et al., 2006; Zhang et al., 2007; Flegel et al., 2013; Kang and Koo, 2012), they have been described at the small intestine level (Braun et al., 2007), prostate (Neuhaus et al., 2009) and spermatozoa (Spehr et al., 2003).

 

In addition, the presence of several ancestral receptors at the skin level was discovered, unknown up to now, but with preserved functionality. Only now we begin to identify them. In particular, the OR2AT4 receptor, present in the skin, mainly at the level of basal keratinocytes, melanocytes and dendritic cells, is stimulated by “smelling” the aroma of synthetic sandal oil

The presence of airborne Sandalore molecules in a closed environment (i.e. plastic bag) used to apply the therapy, provokes the stimulation of the OR2AT4 receptors, triggering a signalling pathway that opens the CNG channels (Cyclic nucleotide–gated ion channel) (Oda et al., 1997), tripling AMPc levels (Busse et al, 2014), which is bound to the channel protein and stimulates the entry of Calcium 2+ into cells (Sondersorg et al., 2014). This activates the cascade MAPK (Kinases) Erk . and p38 (Stork and Schmitt, 2002), involved in all biological processes of proliferation, differentiation and cell movement, adding phosphate groups to various proteins that serve as substrate and participate in most cellular processes including wound healing (Marshall, 1994; Seger and Krebs, 1995;Sharma et al, 2003; Wang et al, 2006; Shibata et al, 2012).

This acceleration of keratinocyte proliferation by more than 30%, combined with cell migration, is an indicator of wound re-epithelialization (Woodley et al., 1993, Gurtner etal., 2008, Shaw and Martin, 2009, Muller et al, 2012, Plikus et al, 2012). Thus, cell migration was exanimated using agarose gel test to assess chemotactic migration of the cells in the presence of a specific effector. Comparing the migration of keratinocytes stimulated with Sandalore to a control group, there is a significant increase (40% of distance and 50% of area) after 5 days of incubation.

 

Another striking finding is the acceleration in wound closure due to enhanced formation of monolayers of keratinocytes and epithelial pointers, increasing control and interaction between keratinocytes and adjacent sensory nerve cells, thereby stimulating the communication between both cell types; another important mechanism that promotes cicatrization (Roosterman et al, 2006, Scuri et al, 2010, Lebonvallet et al, 2012 and 2013,Sondersorg et al, 2014). Moreover, previous studies demonstrate the antimicrobial effect of Sandalore and the stimulation it causes at the keratinocyte level, increasing the IL-1 alpha production by 10 000%, with an immunoregulatory effect, related to the acute immune and inflammatory response. (Dissertation, Dra. Busse, Olfaktorische Rezeptoren in humanen Keratinozyten-Molekulare Mechanismen und physiologische Bedeutung; Bochum; Juli 2013.)

 

The safety of the product demonstrated for several decades is confirmed, as the histological observations made in the Laboratory demonstrate the viability of the cellsstimulated with Sandalore, there was no alterations in the cellular morphology, norapoptotic changes after applying iodide staining of propidium.

Therapy

The therapy is very easy in application, painless and safe for the patient.

The used formula is based on natural oils rich in polyphenols, vitamins and monounsaturated fatty acids with antioxidant, emollient and protective properties, which favour hydration, resistance and elasticity of the skin.

The synthetic sandalwood aroma has been approved for human use for many years. It forms part of aromas of many famous perfumes, air fresheners, soaps, detergents and other cleaning and personal hygiene products. Being used in the appropriate concentration, it stimulates the OR2AT4 receptors present in the skin, triggering a cascade of reactions, which promote the repair of the skin.

The area on which the treatment is to be applied, is placed in a closed environment (i.e.plastic bag) that is connected to a diffuser, which nebulizes an oil containing synthetic sandalwood aroma (+ Plus Cells Oil), generating a suitable concentration of it in the air surrounding the area to be treated, which aids cellular regeneration.

The ulcer is afterwards covered with the dressing suitable to its condition.

According to research conducted on human skin cultures, the stimulation of cell migration and proliferation begins 20 seconds after a contact with Sandalore.

We have established a protocol requiring treatment sessions of one hour at least 3 days a week, since there is a direct relation between effectiveness and time of exposure. Because this therapy speeds up the cell regeneration process, there is an increased need for nutrients involved in this process. It is advised to use adequate diet and supplements that contain vitamins, minerals, amino acids and coenzymes, enhancing the renewal of the tissue .

+ Plus Cell Oil with a low concentration of Sandalore, can be used to protect the integrity of the skin in order to prevent the appearance of lesions.

Exclusion Criteria

Treatment is not recommended for patients with advanced arterial insufficiency (stages III and IV of the Leriche-Fontaine classification), nor for diabetic foot (stages IV and V of the Wagner classification), who require revascularization, amputation etc., as they would not benefit from this therapy and it would delay the priority treatment.

Once a suitable treatment for critical perfusion situation or in the worth case an amputation has been performed, D.O. Therapy could be applied in order to improve the healing of existing lesions.