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. 2021 Oct 14;13(10):1680.
doi: 10.3390/pharmaceutics13101680.

A Novel Three-Polysaccharide Blend In Situ Gelling Powder for Wound Healing Applications

Chiara Amante  1 , Tiziana Esposito  1 , Pasquale Del Gaudio  1 , Veronica Di Sarno  1 , Amalia Porta  1 , Alessandra Tosco  1 , Paola Russo  1 , Luigi Nicolais  2 , Rita P Aquino  1
Affiliations

A Novel Three-Polysaccharide Blend In Situ Gelling Powder for Wound Healing Applications

Chiara Amante et al. Pharmaceutics. .

Abstract

In this paper, alginate/pectin and alginate/pectin/chitosan blend particles, in the form of an in situ forming hydrogel, intended for wound repair applications, have been successfully developed. Particles have been used to encapsulate doxycycline in order to control the delivery of the drug, enhance its antimicrobial properties, and the ability to inhibit host matrix metalloproteinases. The presence of chitosan in the particles strongly influenced their size, morphology, and fluid uptake properties, as well as drug encapsulation efficiency and release, due to both chemical interactions between the polymers in the blend and interactions with the drug demonstrated by FTIR studies. In vitro antimicrobial studies highlighted an increase in antibacterial activity related to the chitosan amount in the powders. Moreover, in situ gelling powders are able to induce a higher release of IL-8 from the human keratinocytes that could stimulate the wound healing process in difficult-healing. Interestingly, doxycycline-loaded particles are able to increase drug activity against MMPs, with good activity against MMP-9 even at 0.5 μg/mL over 72 h. Such results suggest that such powders rich in chitosan could be a promising dressing for exudating wounds.

Keywords: MMP-9 inhibition; alginate; chitosan; doxycycline; exudate absorbance; in situ forming hydrogel; pectin; wound dressing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
SEM microphotographs of alginate-pectin particles produced by mini spray drying with different polymers ratios: blank particles AP-11 (a), AP-31 (b), AP-13 (c), and doxycycline-loaded particles AP-11-2D (d), AP-31-2D (e), AP-13-2D (f).
Figure 2
Figure 2
SEM microphotographs of alginate-pectin particles produced by mini spray drying with different polymers ratio: blank particles APC-111 (a), APC-113 (b), APC-117 (c), and 2% (w/w) doxycycline-loaded particles APC-111-2D (d), APC-113-2D (e), APC-117-2D (f).
Figure 3
Figure 3
Simulated wound fluid uptake of in situ gelling powder APC-117.
Figure 4
Figure 4
Simulated wound fluid uptake of in situ gelling powders: Panel (A): blank alginate/pectin/chitosan particles in comparison with alginate/pectin particles. Panel (B): alginate/pectin/chitosan powders loaded with different amounts of doxycycline.
Figure 4
Figure 4
Simulated wound fluid uptake of in situ gelling powders: Panel (A): blank alginate/pectin/chitosan particles in comparison with alginate/pectin particles. Panel (B): alginate/pectin/chitosan powders loaded with different amounts of doxycycline.
Figure 5
Figure 5
FTIR spectra alginate/pectin/chitosan particles in comparison with doxycycline-loaded polymeric particles and drug raw material. Panel (A): high M content alginate particles (a), amidated pectin particles (b), low MW chitosan particles (c), and APC-111 (d), APC-113 (e), APC-117 (f). Panel (B): doxycycline raw material (g), APC-111 (h), and APC-111-2D (i).
Figure 5
Figure 5
FTIR spectra alginate/pectin/chitosan particles in comparison with doxycycline-loaded polymeric particles and drug raw material. Panel (A): high M content alginate particles (a), amidated pectin particles (b), low MW chitosan particles (c), and APC-111 (d), APC-113 (e), APC-117 (f). Panel (B): doxycycline raw material (g), APC-111 (h), and APC-111-2D (i).
Figure 6
Figure 6
Release profiles of doxycycline-loaded alginate/pectin/chitosan powders with different polymer ratios.
Figure 7
Figure 7
Modified diffusion assay conducted against Staphylococcus aureus at 24 h by APCs-2D at different ratios in concentrations equivalent to 1.55 µg of pure doxycycline, used as control, on the left; on the right, time-kill assay against Staphylococcus aureus obtained by detaining the wells with acetic acid and measuring the absorbance of the CV at 595 nm.
Figure 8
Figure 8
Bioavailability of in situ gelling powders made by different polysaccharide combinations. Panel (A): Cell viability assessed by MTT test on HaCaT cells after 24 h of treatment with two polymer blends alginate/pectin, alginate/chitosan, pectin/chitosan, and three a polymer blend, APC, with different polysaccharide blends. Data are represented as median ± interquartile range (n = 7). The statistical analysis was determined by one-way ANOVA with the Bonferroni test as a post-test. Panel (B): Pro-inflammatory effect of APCs particles at the various concentrations in terms of release of IL-6, TNFα, and Il-8. The statistical analysis, obtained through the Two-Way ANOVA followed by Tukey’s post-test, was carried out with respect to the basal levels.
Figure 8
Figure 8
Bioavailability of in situ gelling powders made by different polysaccharide combinations. Panel (A): Cell viability assessed by MTT test on HaCaT cells after 24 h of treatment with two polymer blends alginate/pectin, alginate/chitosan, pectin/chitosan, and three a polymer blend, APC, with different polysaccharide blends. Data are represented as median ± interquartile range (n = 7). The statistical analysis was determined by one-way ANOVA with the Bonferroni test as a post-test. Panel (B): Pro-inflammatory effect of APCs particles at the various concentrations in terms of release of IL-6, TNFα, and Il-8. The statistical analysis, obtained through the Two-Way ANOVA followed by Tukey’s post-test, was carried out with respect to the basal levels.
Figure 9
Figure 9
Representative zymograms of pure doxycycline and APC-111-2D. Incubation of the hydrogels containing 0.5, 1, and 5 µg/mL of doxycycline at 72 h.
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