Bacterial cellulose-based scaffold: synthesis and surface modification for sustained rifampicin release for topic skin infections treatment

doi:10.21203/rs.3.rs-2963863/v1

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Bacterial cellulose-based scaffold: synthesis and surface modification for sustained rifampicin release for topic skin infections treatment

https://doi.org/10.21203/rs.3.rs-2963863/v1

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published 14 Apr, 2024

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The present work aims the production of bacterial cellulose (BC), by Komagataeibacter hansenii, and the surface modifications by methanol treatment to produce membranes with different physical characteristics that allow the use of device for sustained release of the antibacterial drug rifampicin (RIF) with broad spectrum and bactericidal activity against Gram-positive and Gram-negative species, being able to penetrate bacterial biofilms, for potential use as a dressing for the prevention or treatment of SSTIs. Here, BC produced was treated with methanol (BC-MetOH) to obtain optimized membranes for use as sustained release devices for the antibacterial RIF. The parameters evaluated were fiber densities, thickness, and entanglement of BC-MetOH impregnated by RIF in methanolic solution (BC-MetOH-RIF) compared to BC-dH₂O impregnated by RIF in aqueous solution (BC-dH₂O-RIF) in regarding the capacity for sustained release of RIF. BC-MetOH-RIF and BC-dH₂O-RIF were characterized by field emission scanning electron microscopy (FEG-SEM), thermogravimetric analysis, and Fourier transform infrared spectroscopy. The comparison between the sustained release capacity of RIF by BC-RIF-MetOH and BC-RIF-dH₂O were analyzed by disc diffusion technique. Intermolecular interactions between RIF and BC were accounted for in water and methanol solutions using molecular dynamics (MD) simulations. Both FEG-SEM and MD simulations demonstrated that the interaction energy of the BC-RIF-MetOH set related to the RIF-BC is stronger in methanol solution than in water. The results obtained demonstrate that BC-RIF-MetOH can contribute to the increase of the therapeutic arsenal for bacterial infections treatment of the SSTIs.

Bacterial cellulose

sustained drug release

wound infection

Skin constitutes the principal physical barrier for defense of the body against the entry of microorganisms (Rahman et al. 2021). When a disruption occurs, due cutaneous trauma or surgery, the result can be a skin and soft-tissue infections (SSTIs) disorder by microorganisms penetration, which can progress to systemic infections (Watkins and David 2021; Sartelli et al. 2022).

In the same way as SSTI, surgical wound infections (SWI) are also frequent postoperative complications and often lead to prolonged hospital stays, increased healthcare costs, and a deterioration in the overall treatment results (Hartinger et al. 2020; Monahan et al. 2023). Most SSTI and SWI are caused by Gram-positive organisms, particularly Staphylococcus aureus and group A β-hemolytic streptococci. (Stevens et al. 2014; Watkins and David 2021).

S. aureus is known as an important human Gram-positive pathogen, biofilm producer, causative of serious bacterial infections, as skin and soft-tissue infection, bacteremia, pneumonia, further causes metastatic infections such as infective endocarditis, osteomyelitis, through the blood migration (Ma et al. 2020).

Biofilms exist in various infections and have been demonstrated to play an important role in human disease (Zhang et al. 2020). Biofilm-producing S. aureus in skin wound infection contains extracellular polysaccharide adhesion molecules, proteins, teichoic acid, and extracellular DNA. what enables chronic infection by protecting a bacteria from antimicrobials and host immune-cell phagocytosis (Zheng et al. 2022).

In addition, S. aureus can affect healing outcomes because this microorganism is often resistant to different classes of antibiotics, being able to form biofilm with antiphagocytic activities and they produce several virulence factors, including secretion of toxins and enzymes, and penicillinase/beta-lactamase producing and oxacillin resistance (Nomura et al. 2020), which drive further tissue damage (Versey et al. 2021).

Perioperative local antibiotic treatment has been widely clinically studied to date with generally promising results (Hartinger et al. 2020). Studies suggested that the administration of rifampin by systemic pathway decreases the risk of infections in deep sternal wound infections caused by staphylococci following cardiac surgery (Khanlari et al. 2010). Kahramanca et al. demonstrated that local application of 250 mg of rifampicin (RIF) over the mesh was capable significantly reduce the occurrence of infection postoperative surgical site the inguinal hernia without the need for systemic administration (Kahramanca et al. 2013).

RIF, is a semisynthetic antibiotic obtained from rifamycin (Sutradhar and Zaman 2021; Hardie and Fenn 2022), used as a first line treatment for tuberculosis, as well as in the treatment of other infectious diseases (Sutradhar and Zaman 2021) constitute one of the most potent and broad-spectrum antibiotics against others Gram-positive and Gram-negative bacterial pathogens including Staphylococcus epidermidis, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (Honig et al. 2020), being its antibacterial activity of is due to specific inhibition of bacterial RNA polymerase (Politano et al. 2013; Alifano et al. 2014), capable of penetrates readily through the biofilm and the fact that around 80% of surgical site infections are associated with the formation of a poorly permeable biofilm (Edmiston et al. 2015; Shiels et al. 2018), Skin and surgical wounds infected from biofilm-producing microorganisms, including S. aureus, constitute a major healthcare problem that requires new and innovative treatment methods. Thus, RIF for being able to penetrate biofilms, the local administration has the potential to serve as an ideal surgical site infection protection and / or treatment agent (Hartinger et al. 2020).

Wound dressings impregnated with antimicrobial agents have emerged as viable options to reduce colonization and bacterial infections of wounds and to improve the healing process. Dressings currently available for wound care are conventionally applied only to protect the wound from contamination (Negut et al. 2018). Unlike traditional dressings, such as cotton bandages, that have no active role in the healing process, advanced dressings produced by incorporating different classes of antibiotics can be designed (Anjum et al. 2016, 2017; Marius et al. 2016; Ye et al. 2018). These types of dressings are valuable in treating wound infections where high concentrations of antibiotics are needed locally (Da et al. 2017) allowing the maintenance of local moisture, oxygen exchange, adsorb wound exudate, accelerate healing, reduce pain, and prevent or treat infections (Portela et al. 2020), appropriate strength, flexibility (Fan 2021).

Mesoporous silica nanoparticles (MSNs) developed by Aguilar-Colomer et al. (Aguilar-Colomer et al. 2021) demonstrated a burst effect followed by a sustained release of RIF above the minimum inhibitory concentration (MIC) for up to 96 h, showing significant activity on Gram-positive and Gram-negative biofilm-producing bacteria.

Several publications cite the relevant results of topical use of antimicrobials (Anjum et al. 2016, 2017; Marius et al. 2016; Ye et al. 2018; Negut et al. 2018) available in semi-solid forms as base materials for hydrogel dressings like, carboxymethyl cellulose, chitosan, collagen, hyaluronic acid, and alginate (Hamedi et al. 2018; Gupta et al. 2019; Islam et al. 2021), and bacterial cellulose (BC) (Asanarong et al. 2021; Ciecholewska-Juśko et al. 2021; Zhang et al. 2021). However, even with the availability of several semi-solid pharmaceutical forms for topical application in the treatment of skin diseases, such as ointments, creams, gels, that have sustained release characteristics, there is low patient compliance, due to the need for repetitive applications, especially in the treatment of chronic infections (Frederiksen et al. 2015).

BC, as it is a natural polymer, endowed with peculiar characteristics such as similarity to natural fabrics (Pang et al. 2020), high highly porous structure (Salonen et al. 2017; Beekmann et al. 2020), mechanical resistance, hypoallergenicity, biocompatibility and high degree of liquid absorption (Lazarini et al. 2016, 2018b), produced by Komagataeibacter hansenii bacterial specie, are widely studied as controlled drug delivery systems, by our research group and many international groups (Mohd Amin et al. 2014; de Oliveira Barud et al. 2016; Juncu et al. 2016; Lazarini et al. 2016; Ullah et al. 2016; Fontes et al. 2017; Treesuppharat et al. 2017; Badshah et al. 2018; Negut et al. 2018), (Trovatti et al. 2012; Silva et al. 2014), antibiotics as tetracycline, amoxicillin and levofloxacin (Pavaloiu et al. 2014), and antibacterial agents as silver metal complex (Lustri et al. 2017; Aquaroni et al. 2020).

Although pristine BC has peculiar characteristics such as, the inability to resist the free movement of gases, solvents and other small molecules, makes this pristine biopolymer inappropriate for sustained drug delivery systems (Salonen et al. 2017; Beekmann et al. 2020).

The chemical and physical surface and bulk modifications of BC become inevitable for successful applications in controlled drug delivery system (Ul-islam et al. 2015; Salonen et al. 2017; Beekmann et al. 2020). Different physical, chemical and mechanical modification techniques have been reported using polymers, solvents and biosynthetic pathways to prepare advanced BC-based functional materials with superior properties (de Oliveira Barud et al. 2016; Picheth et al. 2017). The reported processes most frequently for chemical modification are related to creating use of free hydroxyl groups (Ullah et al. 2016). Among the reported BC chemical modification procedures, surface acetylation has displayed greater advantages with the ability to maintain a large modified surface area with controlled hydrophobic properties and compatibility with other composite materials (Hu et al. 2014).

Li et al. (Li et al. 2018) reported that using compatible solvents with low surface tension, as alcohols (ethanol, isopropanol and n-butanol), exhibited highly porous structures in foam materials with controllable pore structure prepared from nanofibrillated cellulose. Lazarini et al. (Lazarini et al. 2018a) reported obtaining BC membranes produced by K. hansenii variants obtained after selective pressures (exposure to UV radiation, different temperatures and different pH). The results obtained demonstrate that the membranes synthesized by the variants presented differences in thickness, degree of interlacing of the fibers and in pore size.

The present work had as aims the production of BC, by K. hansenii ATCC 23769 variant obtained after selective pressure Lazarini et al. (Lazarini et al. 2018a), and the surface modifications by methanol treatment to produce membranes with different fiber densities, thickness and entangling that allow the use of device for sustained release of the antibacterial drug RIF in aqueous and methanolic solution after thermal treatment for future application as topical dressing for infected wound. BC membranes produced were characterized by field FEG-SEM, TGA, DTG, and FTIR. Interaction analysis of the RIF and BC in aqueous and methanolic solution through simulations of molecular dynamics were also performed. It was also analyzed the of retention capacity and sustained release of RIF in aqueous and methanolic solution, antibacterial broad-spectrum drug with bactericidal effect impregnated in BC membranes before and after methanolic and thermic treatment.

Materials

Anhydrous glucose and ethanol were purchased from Synth®, yeast extract, bacteriological agar and Müller-Hinton agar were purchased from Kasvi. The bacteria for BC production K. hansenii PS was obtained after isolation in culture incubated at 35° C as described by Lazarini et al. (Lazarini et al. 2018a). Staphylococcus aureus ATCC 25923 was purchased from André Tosello Foundation. RIF (C₄₃H₅₈N₄O₁₂) was purchased from Sigma-Aldrich.

Methods

BC production and processing

K. hansenii PS was reactivated from stock in glycerol stored at -80ºC, in a medium used for maintenance, being kept in a B.O.D. oven at 28ºC until the growth of a BC film, being used as pre-inoculum. BC production was performed using 100 mL of culture medium compost by anhydrous glucose 30g⋅L, yeast extract 5.6 g⋅L and ethanol 50 mL⋅L (G30), and 50 mL of pre-inoculum the cultures were adjusted to McFarland scale 1.0 using a spectrophotometer reading. The cultivation was incubated in a B.O.D. oven at 28ºC for 7 days. After the 7 days the membranes were initially washed in distilled water until cleared and then treated with 0.5M NaOH for 30 minutes in a water bath at 80ºC, for removal of bacterial strains. After treatment with NaOH 0.5M the membranes were kept in a water bath at 65ºC, with periodic water changes until the pH was neutralized. After the treatment and processing the BC membranes were dried, being kept in a ventilated oven at 65°C, until completely dehydration. Posteriorly the dried BC membranes were used for characterization and all tests.

Elemental analysis of carbon and hydrogen was performed using a Perkin-Elmer analyzer, model 2400 CHNS / O. The analytical result determined that the BC membrane produced showed C (%) 42.66 and H (%) 6.92, thus compared with the theoretical calculation analysis for BC (C% = 44.4; H% = 6.72) confirms the pure composition of the BC membrane obtained.

Treatment of BC membranes with Methanol (MetOH)

The BC membranes produced and processed as described on item 2.2.1. were cut into discs as 10mm in diameter and separately placed in 24-well plates, where they were kept submerged in 100 µL of MetOH for 24 hours and kept refrigerated (4ºC). After 24 hours, the membranes were subjected to thermal treatment at 65 ºC in ventilated oven. After thermal treatment the residual methanol was completely removed. The obtained BC-MetOH and BC-dH₂O were used for RIF impregnation. The BC-dH₂O was also produced. BC-MetOH and BC-dH₂O were characterized by TGA / DTG, FEG-SEM, and FTIR.

Determination of volume/area ratio of swelling

The volume/area ratio of swelling was performed using methodology described by Lazarini et al. (2016) (Lazarini et al. 2016). To determine the swelling mass (Sm), membranes with an area of 4 cm² were dehydrated as described on item 2.2.1. and submerged separately in distilled water and 50 µL methanol for 4h at 4ºC to reach swelling equilibrium. The water and MetOH mass of the different BC membranes after swelling was measured in a Shimadzu analytical and calculated applying the Eq. 1.:

(1)\({Sm={M}_{S}-M}_{d }\)

where Sm corresponds to the swelling mass, M_S to the BC membrane swollen mass after 4 hours and M_d to the dry mass of the BC membrane (g)

In the sequence, under the same conditions, 180 µL of RIF solution (20mg⋅mL) using the methanol and deionized water as solvents was weighted. After obtaining the mass of 180 µL of a RIF solution, the corresponding mass of RIF adsorbed on each of the BC membranes was calculated using Eq. 2.:

(2)\(Sv=\frac{180{\mu }\text{L}\text{x} \text{S}\text{m}}{\text{M}\text{r}}\)

where Sv corresponds to the volume of RIF solution (20mg⋅mL^− 1) adsorbed and Mr is the mass of 180 µL of RIF solution.

Determination of the volume/area ratio of swelling was performed using Eq. 3.:

(3)\({V}_{A}=\frac{\text{S}\text{v}}{\text{A}\text{b}\text{c}}\)

where VA corresponds to the volume/area ratio of swelling in the membrane after swelling, and Abc is the area (0.7854 cm²) of BC membranes.

Determination of the mass RIF/disc (RIF_M) was performed using Eq. 4:

(4)\({RIF}_{M}=\frac{{V}_{A}-3.6}{180}\)

Treatment of BC-MetOH and BC-dH₂O with RIF

The BC discs obtained as described on item 2.2.2. were placed in 24-well plates and kept submerged separately in 180 µL of a 20mg⋅mL^− 1 methanolic RIF solution (BC-RIF-MetOH) and 180 µL of a 20 mg⋅mL^− 1 aqueous RIF solution (BC-RIF-dH₂O). BC-MetOH and BC-dH₂O were used as control. The BC-RIF-MetOH and BC-RIF-dH₂O were incubated for 24 hours under refrigeration at 4ºC until complete swelling. After this procedure, BC-RIF-MetOH and BC-RIF-dH₂O were subjected to thermal treatment in a ventilated oven at 35ºC for 8 hours until total removal of the solvents H₂O and MetOH.

Analysis of the RIF sustained release capacity of BC-MetOH-RIF and BC-dH₂O-RIF

BC-RIF-MetOH and BC-RIF-dH₂O were used for disc diffusion analysis using an adapted methodology described by CLSI (CLSI 2019). The discs were placed on Mueller Hinton agar (MH), inoculated with S. aureus ATCC 25923. The plate was incubated in a bacteriological oven at 37ºC for 24 hours. After this period, the inhibition zone was measured, and the BC discs were transferred to a new MH agar plate with S. aureus ATCC 25923. This process was repeated until there was no more formation of inhibition zone. BC-MetOH and BC-dH₂O, subjected to thermal treatment in a ventilated oven at 35ºC for 8 hours until total removal of the solvents H₂O and MetOH, were used as control. All the experiments were performed in triplicate.

Characterization of BC-RIF-MetOH, BC-RIF-dH₂O, BC-MetOH, BC-dH₂O

The characterizations of BC-RIF-MetOH, BC-RIF-dH₂O, BC-MetOH, BC-dH₂O were performed by FEG-SEM were in the JEOL JSM-6360 LV device with carbon coating, vibrational absorption spectroscopy in the infrared region performed on the FTIR spectrophotometer Cary 630 Agilent (ATR). The measurements were performed in ATR (attenuated total reflectance) mode, from 4000 to 600 cm^− 1 scans, and thermogravimetric and derived thermogravimetry (TGA/DTG) analysis using TA Instruments equipment and SDT Q600 cell. The conditions employed were synthetic air atmosphere with continuous flow of 100 mL / min and heating rate of 10° C per minute. The temperature used in the experiment was between 30–600° C, using an alumina crucible as a reference.

Molecular dynamic simulation

All simulated system were molecular dynamic simulated within the NAMD 2.9 program (Kalé et al. 1997) using CHARMM36 force field (Brooks et al. 2012) parameters. Before obtaining the final MD trajectory, systems were energy minimized in NVT ensemble using the following parameters: time step of 2 fs; cutoff: 12 Å for describing short-range interactions as well as particle-mesh Ewald (PME) formalism was applied. To reach 310 K of temperature, the system was gradually warmed up and equilibrated during 1 ns. A 10 ns of MD simulation was sufficient to obtain characterize the interference of the solvent in the studied molecular structures. Hydrogen bonds (H bonds) were computed during the trajectories using H bonds plugin implemented in Visual Molecular Dynamics (VMD) program (Humphrey et al. 1996). Another important analyzed parameter was the number of solvent molecules between RIF and cellulose. In this case, an algorithm was created to be used in VMD to account it using TCL language programming (Nelson 1999). The tridimensional models and interactions between molecules were analyzed with Discovery Studio, version 20.1.0.192955.

FEG-SEM of dry BC membranes treated with methanol (BC-MetOH) and deionized water (BC- dH₂O)

The FEG-SEM comparative analysis dry BC-MetOH and BC-dH₂O discs showed significative difference in relation to fiber interlacing, thickness, arrangement, and pore size as can observed in the Figure 1.

Several authors described different techniques to produce physical, chemical, and mechanical modifications, using polymers, solvents and biosynthetic pathways. This, is to prepare advanced BC-based functional materials with superior properties for drug delivery application (Picheth et al. 2017; de Oliveira et al. 2017; Badshah et al. 2018). However, information regarding methanol usage to produce physical modification in BC membranes to application as drug delivery system is scarce.

FTIR analysis

The FTIR spectra of pristine BC membranes are shown in Figure 2, bands in the range 3350-3500 cm^-1 of pure cellulose are attributed to O–H stretching, while bands from 2800-2900 cm^-1 are assigned to C–H stretching. The band at 1160 cm^-1 is attributed to C–O–C stretching (Leal et al. 2020; Kotcharat et al. 2021).

The FTIR analysis shows a difference between pristine BC and the BC-RIF-MetOH and BC-RIF-dH₂O. However, FTIR spectra curves suggest that there was no change in the chemical composition of RIF, both in BC-RIF-MetOH and BC-RIF-dH₂O, because the absorption peaks of pure RIF were maintained equally in BC-RIF-MetOH and BC-RIF-dH₂O. These results demonstrate the incorporation of RIF into the BC-MetOH and BC-dH₂O.

The FTIR spectrum of the commercial sample of RIF (Figure 2, Panel A) is similar to that published by Agrawal et al. (Agrawal et al. 2004), demonstrating the incorporations of RIF in the BC membranes BC-MetOH and BC-dH₂O using both solvents.

TGA/DTG analysis

According to the TGA / DTG curves (Figure 3), and with the data compiled in Table 1 presented below, the pristine BC curve (Figure 3.A) shows three mass loss events. The first loss event, approximately 2% mass, occurs between 30 °C and 100 °C and is available for loss of water molecules adsorbed on the material surface, subsequently, two significant mass loss events are observed: the first is about 70% in the 160-360°C range; the second is approximately 26% in the range of 360-500°C. These events are associated with the thermal degradation of cellulose, which concerns the depolymerization processes, the decomposition of the glycosidic units and the formation of gaseous residues as already observed by De Salvi et al. (De Salvi et al. 2012).

It is observed that the RIF sample (Figure 3.B) presents the characteristic profile of the drug, with mass loss of about 2% up to 100 °C, another loss between 200-250 °C with about 10%, a third loss in the range 250-450 °C having lost about 29% and finally a fourth loss between 450-600 °C losing about 33% of the mass, as already demonstrated by Alves et al. (Alves et al. 2010). In addition, the RIF sample has about 22% residue at 600°C, demonstrating that its degradation is not complete at this temperature.

The MetOH-treated sample (Figure 3.C) showed a profile like the characteristic profile of BC, with three significant mass loss events and low residue at 600 °C (about 2%). The difference observed between the treated sample and the pure BC sample is that the BC-MetOH sample showed an increase in mass loss in the first event (4%) compared to the pure BC sample (2%). This event, as already presented, refers to the loss of water adsorbed on the surface of the material and is related to the fact that the treatment makes the BC more porous and its fibers less dense, as pointed out in the FEG-SEM analysis, facilitating the evaporation of water molecules.

The samples containing RIF, on the other hand, have different characteristics. The BC-RIF-MetOH (Figure 3.D) sample has an intermediate degradation profile, showing characteristic peaks of BC and RIF. The BC-RIF-dH₂O (Figure 3.E) sample has a profile similar to pure BC, however, the last event of thermal BC loss of mass at approximately 500°C, while the sample with RIF extends to 600°C, thus demonstrating a possible increase in degradation temperature. Furthermore, it is verified that RIF increased the stability of BC-MetOH, passing the initial temperature of the first mass loss event from 30°C for BC-MetOH to 45°C for BC-RIF-MetOH, which may to suggest that the RIF was in fact impregnated on the BC membrane treated with MetOH, thus corroborating the other analyzes presented.

Table. 1. TGA results of the samples, showing mass loss events, their temperatures, and the final residue at 600°C.

Sample	First mass loss event (%)/ temperature range (°C)	Second mass loss event (%)/ temperature range (°C)	Third mass loss event (%)/ temperature range (°C)	Fourth mass loss event (%)/ temperature range (°C)	Residue at 600°C
Pure BC	2/30-100	70/160-360	26/360-500	-/-	2
RIF	3/50-160	13/190-250	25/260-430	32/440-600	22
BC-MetOH	4/30-100	73/230-350	21/360-505	-/-	2
BC-RIF-MetOH	4/45-100	5/160-220	39/230-350	50/355-600	1
BC-RIF-dH₂O	4/30-100	65/150-345	28/350-590	-/-	2

From the data obtained by the DTG curves, it can be confirmed what was said from the TGA curves: the treatment with MetOH increased the thermal stability of the membrane at ~9°C, while the RIF decreased the stability of the membranes, both the MetOH-treated and the untreated membrane. Despite the decrease in thermal stability, there will be no loss in the use of this material in any case, since it will be used at body temperature (~37°C). In addition, it is possible to verify in the BC-RIF-MetOH sample DTG curves (Figure4.D) the appearance of the RIF characteristic curves, confirming again that the RIF was in fact incorporated in the treated sample, corroborating with the other analyses. While this profile is not found in the untreated membrane (BC-RIF-dH₂0), demonstrating that there was not the expected interaction for this material.

Analysis FEG-SEM of BC-RIF-MetOH and BC-RIF-dH₂O

The SEM images of BC-RIF-MetOH and BC-RIF-dH₂O are showed in Figure 4. As can observed It is possible to see that this difference is related to the network interlacing, and density of the fibers. Although the membranes were produced under the same conditions, it is possible to report the structural difference with treatment of BC membrane and the solubilization of the RIF drug using MetOH, as can observed in the Figure 1A, that showed the membrane treated with MetOH.

The Figure 4 demonstrates that, in addition, to the change in the physical characteristics of the BC membrane by treatment with methanol, the solvent also produced chemical and physical changes in the RIF drug, demonstrated by the RIF crystal structure shown in Figure 3B, characteristic of RIF after water dilution and drying (Schianti et al. 2013).

As can be observed, the BC-RIF-dH₂O showed RIF in crystal forms and superficial distribution, while the RIF (amorphous structure) contained in the BC-RIF-MetOH device is more integrated into the BC membrane, which probably promoted greater capacity retention, providing a sustained and controlled release of the antibiotic, when compared to the BC-RIF-dH₂O device.

Determination of volume/area ratio of swelling and RIF/disc mass

The volume / area of swelling allows the approximate calculation of the amount of drug that was adsorbed by the BC discs used in the release test. The results obtained (Table 2) showed that there was a difference of approximately 1mg of incorporated RIF mass between the discs with BC-RIF-MetOH (3.45 mg) and BC-RIF-dH₂O (2.44 mg), considering that, in both conditions, the stock concentration of methanolic and aqueous RIF solutions was 20mg×mL^-1.

Table 2. Determination of volume/area ratio of swelling and RIF/disc mass

Sample	Ms (mg)	Md (mg)	Sm (mg)	Sv (µL)	Mr (mg)	VA (µL×cm²)	(mg)
BC-RIF-dH₂O	86.93	3.39	83.54	95.78	157.00	121.95	2.44
BC-RIF-MetOH	60.30	4.63	55.67	135.41	74.00	172.40	3.45

Ms = BC membrane mass swollen; MD = BC membrane dry mass; Sm = swelling mass; Sv- volume of RIF solution (20mg×mL^-1) adsorbed; Mr = mass of 180 µL of RIF solution; VA volume/area ratio of swelling.

Interaction analysis of the BC-RIF-MetOH and BC-RIF-dH₂O by using molecular dynamic simulations

During the equilibration step, water molecules are capable of separate BC from RIF, while methanol ones not. As a result, the value of the interaction energy in methanol is more favorable than water (Table 3).

Table 3. Average interaction energies and average number of hydrogen bonds formed between RIF and BC and with the solvents.

Interaction Energy (kcal/mol)/ Hydrogen bonds formed	BC-dH₂O	BC-MetOH	H₂O	C₂H₆OH
RIF	-14.9909 (0)	-17.486 (~0.5)	-98.9638 (~1.7)	-52.5644 (~2.5)
BC	+ 0.0000 (0)	-2.818 (~1.0)	-51.1307 (~1.1)	-28.2307 (~2.0)

As can be seen in the above table, the interaction energy related to the BC-RIF interaction is stronger in methanol solution than in water. This fact is attribute to the average hydrogen bond formed during the system trajectory in methanol where at least HB ~0.5 is formed and no HB in water was noticed. Additionally, the distance observed in the last frame of the trajectory shows that cellulose is totally surrounded by water molecules, this fact was not observed in MetOH.

Interactions analysis of BC-RIF in MEtOH (Figure 5) showed that in this solvent hydrogen bonds between RIF and BC molecules are formed, while in water environment, interactions between RIF and the solvent are more likely to occur (Figure 6). Besides, the alignment of RIF structures after MD simulation showed an overlay of 74%, with 1.8 RMSD (Figure 7). In this sense, the difference observed in experimental RIF release, in both environments, are probably due to solvent and RIF interactions, rather than major structural changes in RIF.

Sustained/controlled RIF delivery by disc diffusion methods

The results showed that the BC-RIF-MetOH showed 696 hours of uninterrupted release, and the BC-RIF-dH₂O were able to maintain the release for 120 hours. The Figure 8 show the results of the release with BC-RIF-MetOH. The Figure 9 shows the obtained results using BC-RIF-dH₂O as support of the release.

Although, as described in the results of determination of volume/area ratio of swelling, where there was a mass of about 1mg of incorporated RIF in the BC-RIF-MetOH in relation to BC-RIF-dH₂O, this difference in mass does not justify the maintenance of the RIF release by BC-RIF-MetOH for an additional 576 hours. Thus, it can be inferred that the greater capacity for RIF release by BC-RIF-MetOH is due to changes in the physical characteristics of BC, by MetOH and by the change in the physical and chemical characteristics of RIF impregnated in the BC-RIF-MetOH membrane as can be observed in the Figure 1 and 4.

Results obtained by Demir et al. (Demir et al. 2016) was demonstrated that the topical of RIF was an easy and effective method for reducing surgical site infections SSIs and meningitis/ VP shunt infections related to neural tube defects surgery.

Hartinger et al. (Hartinger et al. 2020) developed two types (homogeneous and sandwich structured) carbodiimide-cross-linked fresh water fish collagen wound dressings for in vivo use as rifampin-release device and were tested by means of a series of incubations in phosphate- buffered saline. The microbiological activity was tested against methicillin-resistant S. aureus employing disc diffusion tests. The results demonstrated that rifampin-release devices delayed the release of rifampin in vitro, which translated into at least 22 hours of RIF release in the rat model.

These results demonstrate that, even the BC-RIF-MetOH containing 1 mg more RIF than BC-RIF-dH₂O the release maintenance for 696 hours was due to the treatment of BC membrane with MetOH and the use of methanolic solution of RIF, also demonstrating that the treatment with MetOH provided an increase in the surface area of the membrane, allowing an increase in the volume of swelling and greater RIF interaction with the BC membrane, as can be seen in Figure 8 and 9.

The Figure 10 and 11 showed the Sustained / controlled release using BC-RIF-dH₂O by disc diffusion assay.

The Figure 12 shows the results of diffusion disc test evaluating the toxicity of BC-MetOH compared to BC-dH₂O after heat treatment (Panel A and Panel B). The results demonstrate that BC-MetOH did not show bacterial growth inhibitory activity, as well as the BC-dH₂O control, compared to discs impregnated with MetOH before heat treatment (Panel C) presence of inhibition halo demonstrates that the treatment promoted the removal of MetOH. The absence of an inhibition zone around the BC-MetOH disc (Panel B) demonstrates that MetOH was completely removed after heat treatment, does not present toxicity risks.

According to Pötzinger et al. (Pötzinger et al. 2017) , the selection of the drug-loading method for a certain application should be based on the physicochemical characteristics of the drug, including molar mass, solubility, stability during each process step, therapeutic dose and the characteristics of BC membranes as pristine wet, semidried, freeze-dried and structural modifications da BC membrane or the drug loading procedure. Despite substantial structural variabilities of the loaded drugs regarding size, hydro-/lipophilicity and stability, the published drug-loading strategies for BC are almost comparable and quite limited up to now.

As described by CLSI 2022 (CLSI 2022), the sensibility of S. aureus for RIF, by disc diffusion, is ³ 20mm, with the RIF concentration per disc being 5 µg. The obtained results showed that the inhibition zone, in triplicate, for each 24 hours were greater than 20 mm, suggesting that the concentration of RIF released, every 24 hours, BC-MetOH-RIF devices were able to maintain the release of concentrations above that considered to be the minimum for inhibiting the growth of S. aureus for 576 hours. These results demonstrate the effectiveness of retention and sustained release of RIF by the BC-MetOH-RIF device, which may increase the therapeutic arsenal in the treatment and prevention of SSTIs and SWI.

The BC with methanol treatment presented physical changes in its structure that allowed a greater volume of swelling, in addition to the use of methanolic RIF solution providing a greater interaction of the antibiotic with the BC membrane (BC-RIF-MetOH). These results showed that methanol treatment and the use of the RIF methanolic solution produced change in the physical and chemical characteristics of RIF better capacity to maintain a sustained / controlled release of antibiotic RIF by 576h uninterruptedly, in concentrations above the MIC, demonstrated by the maintenance of inhibition zone around of the BC-RIF-MetOH membranes. Such results demonstrated that this sustained and controlled release efficiency of the RIF antibiotic is due to the treatment with methanol and impregnation of the membrane with the methanolic RIF solution, to which the BC membrane was subjected, when compared to the membrane without methanolic treatment and impregnated with solution aqueous solution containing the same antibiotic. The interaction analysis of the BC-RIF-MetOH and BC-RIF-dH₂O using MD simulation reinforce the effectiveness of pretreatment of BC membranes with methanol and use of methanolic RIF solution for impregnation but BC membranes.

Thus, the results obtained in this work demonstrate that a product was obtained with a great possibility of adding, in a short period of time, to the therapeutic arsenal for the treatment of bacterial infections of skin and soft tissues, including the biofilm producer, since rifampicin is not available for topical use. Although, there are no formulations topical using the RIF, an antibiotic of broad spectrum, approved by global health agencies for systemic use, with known therapeutic and adverse effects, which would certainly be reduced with topical use and, because BC is a biomaterial known to be hypoallergenic, biocompatible, nanostructured, with staggered and reproducible productivity, including the MetOH treatment procedure, not requiring extensive studies of development phases applied to new drugs.

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: Data available from the authors upon request

Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding: Brazilian Agencies FAPESP (São Paulo Research Foundation, Grants# 2021/07458-9, 2015/09833-0, 2018/12590-0, 2018/25512-8, and 2013/07793. CNPq (National Council of Scientific and Technological Development, PQ Grant # 300968/2016-7, 407822/2018-6; INCT-INFO). Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Finance Code 001. FUNADESP (National Foundation for Development of Private Superior Education - Grant # 2-76/2021).

Authors’ contributions: Caroline Yamada: Investigation, Writing, Validation. Silmara C. Lazarini Frajácomo: Investigation, Writing, Validation. Hernane S. Barud: Investigation, Resources, Funding Acquisition. Nayara C. do Amaral: Investigation, Writing - Review & Editing. Adriano Marques Gonçalves: Investigation of Interaction analysis using molecular dynamic simulations. Guedmiller Souza de Oliveira: Investigation of Interaction analysis using molecular dynamic simulations. Rafael Mariano-Neto: Investigation of Interaction analysis using molecular dynamic simulations. Wilton R. Lustri: Conceptualization, Methodology, Investigation, Validation, Writing - Original Draft, Visualization, Project administration, Supervision and Funding Acquisition.

Acknowledgements

We are grateful to the High-Resolution Scanning Microscope Laboratory of the Chemistry Institute of the State University of Araraquara - IQ-UNESP-Araraquara, São Paulo, Brazil and TA Instruments Brazil and Laboratório de Computação Científica Aplicada e Tecnologia de Informação from the Federal University of Uberlândia (UFU), Campus Pontal, financial supported by FINEP.

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Bacterial cellulose-based scaffold: synthesis and surface modification for sustained rifampicin release for topic skin infections treatment

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Abstract

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Introduction

Materials and Methods

Methods

(1)\({Sm={M}_{S}-M}_{d }\)

(2)\(Sv=\frac{180{\mu }\text{L}\text{x} \text{S}\text{m}}{\text{M}\text{r}}\)

(3)\({V}_{A}=\frac{\text{S}\text{v}}{\text{A}\text{b}\text{c}}\)

(4)\({RIF}_{M}=\frac{{V}_{A}-3.6}{180}\)

Results and discussion

Conclusions

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Additional Declarations

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