Bacterial cellulose biomaterials for the treatment of lower limb ulcers

ABSTRACT Chronic ulcers of the lower limbs are common and recurrent, especially in the elderly population, they are disabling injuries that generate a great socioeconomic burden. This scenario encourages the development of new, low-cost therapeutic alternatives. The present study aims to describe the use of bacterial cellulose in the treatment of lower limb ulcers. This is an integrative literature review, carried out in the PubMed and Science Direct databases by associating the descriptors, with the inclusion criteria being clinical studies in the last 5 years, available in full in English, Portuguese and Spanish. Five clinical trials were analyzed and the main therapeutic effects obtained in the experimental groups that used bacterial cellulose dressings were a reduction in the area of the wounds, one of the studies showed a reduction of 44.18cm2 in the area of the wound, the initial lesions measured on average 89.46cm2 and at the end of the follow-up, they had an average of 45.28cm2, since the reduction in pain and the decrease in the number of exchanges were advantages described in all groups that used the BS. It is concluded that BC dressings are an alternative for the treatment of lower limb ulcers, their use also reduces operational costs related to the treatment of ulcers.


INTRODUCTION
C hronic wounds or wounds that are difficult to heal are those that do not heal properly over a normally acceptable period of time 1 .The mean annual cost of a non-healing wound has been predicted to be US$ 23,300 per affected patient, ranging from US$ 1,800 to US$ 61,500 2 .The humanistic and economic burden of chronic wounds is underestimated and is increasing due to an aging population and the early onset of chronic diseases 3 .Among chronic wounds, ulcers of the lower limbs stand out because they are an important public health problem, both in Brazil and in the world, with physiological, psychosocial, and cultural implications 4 .
According to the Wound Healing Society, about 15% of the elderly in the USA are affected by chronic wounds, predominantly venous stasis ulcers, pressure ulcers, and diabetic foot ulcers 5 .
The most common etiology of these lesions is chronic venous insufficiency (CVI), applicable to approximately 80% of leg ulcer cases, occurring due to abnormal function of the venous system caused by valvular insufficiency, which may be related to obstruction of blood flow 6,7 .Up to two thirds of all leg ulcers will be of venous origin, with a prevalence of 1% to 3% in the general population 8 .
Ischemic wounds, on the other hand, arise because of the most severe manifestation of peripheral arterial disease (PAD) of the lower limbs, which frequently affects the foot and leg, and is associated with a high risk wounds" or "bacterial cellulose and ulcers venous" or "cellulose biomembrane and ulcer venous".Include work comprised clinical studies published between 2017 and 2022 that represent the applicability and recent advances in the use of cellulose-based biomaterials, available in full, in Portuguese, English, and Spanish.We excluded preclinical studies, reviews, abstracts, incomplete texts, and gray literature.Terms were combined in PubMed and Science Direct databases, resulting in the search strategy shown in the flowchart.

RESULTS
We found 17 articles through the search strategies in the databases.After reading the titles, 14 studies remained, of which five were clinical trials and met the inclusion criteria.Table 1 brings the studies' characteristics.
Of the analyzed studies, three (75%) used bacterial cellulose synthesized through the Zoogloea SP biodigestor and one (25%) used the bacteria Gluconacetobacter xylinus.In one (25%), ibuprofen was incorporated.The number of participants in each study ranged from 14 to 39.When analyzing clinical trials of lower limb UVC, three (75%) addressed venous ulcers (VU) and one (25 %), ulcers due to ischemic complications resulting from PAD.
As for the sociodemographic profile of the population, in the study by Silva et   9 .The high cost associated with the treatment does not favor obtaining an effective cure for the disease, which can be explained by the lack of therapeutic standardization 10 .
Several polymeric materials are used for the treatment of chronic wounds and have advantages such as promoting growth factors, moisture retention, increased neovascularization, protection against microbial agents, and tissue adhesiveness.Their role as good wound healing agents essentially depends on their biodegradability, biocompatibility, non-immunogenicity, and mechanical properties 11 .Bacterial cellulose (BC) has recently drawn greater attention as the focus of numerous studies.BC is biosynthesized by various strains of bacteria from glucose monomers that generate a three-dimensional network of interconnected nanostructured cellulose fibers.It can be produced on a large scale by controlled fermentation 12 .
BC is a non-toxic, biocompatible biomaterial made from biotechnological synthesis 11,13 .It has been studied in several areas of medicine and gained prominence for having adequate characteristics and promising results when used as a dressing and biological graft [14][15][16] .It has wide biomedical applicability, such as nail prosthesis, tympanic graft, in the postoperative period of hypospadias correction, in the treatment of pressure injuries, also presenting ideal properties as a dressing [15][16][17][18] .This integrative review (IR) aims to describe the healing effect of bacterial cellulose in the treatment of lower limb ulcers.

METHODS
This study is about an Integrative Review (IR), which is a method that provides opportunities for the synthesis of knowledge through a systematic and rigorous process.The IR should be based on the same recommended principles of methodological rigor in research development 19 .For the synthesis of the study, we defined the objective, determined the inclusion and exclusion criteria, analyzed the studies found, and discussed the results.The research's guiding question was, "Are bacterial cellulose-based biomaterials effective for the treatment of lower limb ulcers?".
We searched the US Public National Library of Medicine (PubMed) and Science Direct databases by associating the terms "bacterial cellulose" and "ischemic and pure arterial insufficiency causes 4-7% of chronic leg ulcers 20 .Most lower limb ulcers are difficult to heal 6 .Their high incidence and morbidity cause severe socioeconomic consequences and burden health services 10 .

Sociodemographic profile
The

Wound characteristics
The adherent VU dressing demonstrated a similar result, without difference in the reduction of the ulcerated area between the treatment groups.However, pain was reduced, and autolytic debridement was faster and more efficient in the biocellulose group than in the standard treatment one 24 .
The presumed objectives of topical VU treatment are to reduce pain and discomfort, eliminate infection and biofilm, help, and promote healing, reduce wound care costs, and improve patients' quality of life 8 .
Pain reduction was reported in all studies.The decrease in pain indicates a lower risk of infection, also allowing the person with the injury to have more freedom, simplifying self-care, and reducing the high operational cost 15 .The post-marketing surveillance study with BCbased epicite hydro dressing obtained through static cultivation of Komagataeibacter xylinus also revealed promising results regarding wound cleansing and pain reduction 25 .
A decrease in the number of dressing changes was also reported, reducing wound handling, and thus avoiding physical injury on the wound bed, a finding also presented in a study using bacterial cellulose as a post-surgical dressing to correct hypospadias 17 .However, reductions in ulcer size and pain were favored by bacterial cellulose.
As observed in the present review, the scarcity of clinical studies that use bacterial cellulose for the treatment of lower limb ulcers makes it difficult to carry out integrative literature review studies that answer questions about the efficiency of this biomaterial.

CONCLUSION
Bacterial cellulose presents promising results when used as a dressing, favoring the proliferation of granulation tissue, reduction of exudate and, decrease in pain.It should be associated with compression therapy to help venous return in cases of venous insufficiency and can also be used for the treatment of ischemic wounds after revascularization of the lower limbs.The application of BC dressings in humans can be expanded in further studies, benefiting patients, and reducing operational costs associated with the treatment of ulcers.

Figure 1 .
Figure 1.Flowchart of the study inclusion process.
main therapeutic effects of the experimental groups were reduction of the wound area, reduction of pain, and decrease in the number of exchanges.The study Zanoti et al. (2019), which used the cellulose membrane cultivated with Gluconacetobacter xylinus bacteria and with the incorporation of Ibuprofen, demonstrated a reduction in the wound area at the end of follow-up from 11.94cm to 11.34cm.The experimental groups that used bacterial cellulose synthesized by Zoogloea sp also showed a reduction in the wound area when compared with the control group.Silva et al. (2021) showed a reduction of 44.18cm 2 in the wounds' area, the initial lesions measuring an average of 89.46cm 2 and, at the end of the follow-up, presented an average of 45.28cm 2 .These results are like a study that used bacterial cellulose dressing for the treatment of pressure injuries, observing a reduction in the mean area of the PI (-14.7cm²) after 30 days of follow-up 15 .Colenci et al. (2019) found no significant results between the groups regarding decrease in ulcer areas.However, lesions treated with biomembranes showed advantages, such as an improvement in the appearance of the wound bed and reduced exudate, properties that promote faster healing.A clinical trial that compared a biocellulose dressing with a non-Oliveira Bacterial cellulose biomaterials for the treatment of lower limb ulcers

Table 1 -
OliveiraBacterial cellulose biomaterials for the treatment of lower limb ulcers Selected studies Characteristics.
21e averages shown in the trials are like what is already described in the literature.There is evidence that the occurrence of lower limb ulcers is common among the elderly, usually affecting patients over 65 years of age21.Venous leg ulcers that are difficult to heal affect approximately 0.3% to 1% of the general adult population and 3% to 4% of patients aged between 65 and 80 years21.
OliveiraBacterial cellulose biomaterials for the treatment of lower limb ulcers

Table 2 -
Comparison of initial and final wound areas