Development, characterization and pre-clinical trials of an innovative wound healing dressing based on propolis (EPP-AF®)-containing self-microemulsifying formulation incorporated in biocellulose membranes.

The considerable role of pristine bacterial cellulose membranes (BC) as ideal dressings have been widely demonstrated to treat wounds and burns. Nevertheless, drawbacks regarding antimicrobial spectrum and frequent dressing replacement are still present. Based on this, the present work proposes an innovative dressing by incorporating a technological self-microemulsifying formulation (SMEF) encapsulating propolis (BC/PP). BC/PP was fully chemically and biologically characterized employing in vitro and in vivo models. Antimicrobial studies demonstrated BC/PP high efficiency against both gran-negative and gran-positive bacteria. Release studies evidenced propolis markers sustained release for up to 7 days. In vivo wound healing activity was assessed by wound healing rate, anti-inflammatory and tissue formation events and the results evidenced the pro-inflammatory activity of BC/PP, which could promote improved healing results. To conclude, BC/PP presented an outstanding antibacterial activity in vitro with weekly replacement and promotion of healing, offering, for the first time, a broad-spectrum biomembrane potential to treat infected wounds.

[1]  G. Caetano,et al.  Chitosan-alginate membranes accelerate wound healing. , 2015, Journal of biomedical materials research. Part B, Applied biomaterials.

[2]  V. Boddu,et al.  Dehydration of 1,4-dioxane by pervaporation using crosslinked calcium alginate-chitosan blend membranes , 2008 .

[3]  J. Grange,et al.  Antibacterial Properties of Propolis (Bee Glue) , 1990, Journal of the Royal Society of Medicine.

[4]  Sidney José Lima Ribeiro,et al.  Bacterial cellulose membrane as flexible substrate for organic light emitting devices , 2008 .

[5]  Simona Martinotti,et al.  Wound healing properties of jojoba liquid wax: an in vitro study. , 2011, Journal of ethnopharmacology.

[6]  Tomaz Velnar,et al.  The Wound Healing Process: An Overview of the Cellular and Molecular Mechanisms , 2009, The Journal of international medical research.

[7]  H. Gwak,et al.  Formulation and Evaluation of Ketorolac Transdermal Systems , 2007, Drug delivery.

[8]  E. Trovatti The Future of Bacterial Cellulose and Other Microbial Polysaccharides , 2013 .

[9]  L. Barcelos,et al.  Brazilian green propolis modulates inflammation, angiogenesis and fibrogenesis in intraperitoneal implant in mice , 2014, BMC Complementary and Alternative Medicine.

[10]  S. Ofoefule,et al.  Mechanisms behind sustained release matrix tablets prepared with poly(acrylic) acid polymers , 2000 .

[11]  J. C. Cardoso,et al.  The incorporation of Brazilian propolis into collagen-based dressing films improves dermal burn healing , 2013 .

[12]  D. C. Cara,et al.  Aqueous Extract of Brazilian Green Propolis: Primary Components, Evaluation of Inflammation and Wound Healing by Using Subcutaneous Implanted Sponges , 2011, Evidence-based complementary and alternative medicine : eCAM.

[13]  S. Ribeiro,et al.  A multipurpose natural and renewable polymer in medical applications: Bacterial cellulose. , 2016, Carbohydrate polymers.

[14]  M. Roesch-Ely,et al.  Bacterial cellulose membrane associated with red propolis as phytomodulator: Improved healing effects in experimental models of diabetes mellitus. , 2019, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[15]  S. Ribeiro,et al.  Draft Genome Sequence of Komagataeibacter rhaeticus Strain AF1, a High Producer of Cellulose, Isolated from Kombucha Tea , 2014, Genome Announcements.

[16]  K. Ghosh,et al.  Tissue engineering for cutaneous wounds. , 2007, The Journal of investigative dermatology.

[17]  D. G. Dixon,et al.  Zero-order release from biphasic polymer hydrogels , 1995 .

[18]  G. Cassali,et al.  Effects of inhibition of PDE4 and TNF‐α on local and remote injuries following ischaemia and reperfusion injury , 2001, British journal of pharmacology.

[19]  G. Caetano,et al.  Hyaluronidase Modulates Inflammatory Response and Accelerates the Cutaneous Wound Healing , 2014, PloS one.

[20]  S. Ribeiro,et al.  Antimicrobial Brazilian Propolis (EPP-AF) Containing Biocellulose Membranes as Promising Biomaterial for Skin Wound Healing , 2013, Evidence-based complementary and alternative medicine : eCAM.

[21]  A. Ramos,et al.  Propolis: a review of its anti-inflammatory and healing actions , 2007 .

[22]  M. Sofian‐Azirun,et al.  Antibacterial activity of propolis and honey against Staphylococcus aureus and Escherichia coli. , 2010 .

[23]  T. Mahmood,et al.  Basics of Self Micro Emulsifying Drug Delivery System , 2012 .

[24]  M. Baesso,et al.  Dynamics of reepithelialisation and penetration rate of a bee propolis formulation during cutaneous wounds healing. , 2009, Analytica chimica acta.

[25]  S. B. Garcia,et al.  Clinical and immunohistopathological aspects of venous ulcers treatment by Low-Intensity Pulsed Ultrasound (LIPUS). , 2013, Ultrasonics.

[26]  M. Fonseca,et al.  Propolis extract release evaluation from topical formulations by chemiluminescence and HPLC. , 2006, Journal of pharmaceutical and biomedical analysis.

[27]  M. Tenenhaus,et al.  Regenerative materials that facilitate wound healing. , 2012, Clinics in plastic surgery.

[28]  John D Stroncek,et al.  Instructional PowerPoint presentations for cutaneous wound healing and tissue response to sutures. , 2009, Journal of biomedical materials research. Part A.

[29]  G. E. El Maghraby Self-microemulsifying and microemulsion systems for transdermal delivery of indomethacin: effect of phase transition. , 2010, Colloids and surfaces. B, Biointerfaces.

[30]  Ashraf Maher,et al.  Colonization of burn wounds in Ain Shams University Burn Unit. , 2003, Burns : journal of the International Society for Burn Injuries.

[31]  V. Jannin,et al.  Development of self emulsifying lipid formulations of BCS class II drugs with low to medium lipophilicity. , 2015, International journal of pharmaceutics.

[32]  C. Enwemeka,et al.  Phototherapy promotes healing of chronic diabetic leg ulcers that failed to respond to other therapies , 2009, Lasers in surgery and medicine.

[33]  S. Werner,et al.  Wound repair and regeneration , 1994, Nature.

[34]  J. M. Marchetti,et al.  Propolis Standardized Extract (EPP-AF®), an Innovative Chemically and Biologically Reproducible Pharmaceutical Compound for Treating Wounds , 2012, International journal of biological sciences.

[35]  Carla Lopes,et al.  Formas farmacêuticas de liberação modificada: polímeros hidrifílicos , 2005 .

[36]  N. Menke,et al.  Biologic therapeutics and molecular profiling to optimize wound healing. , 2008, Gynecologic oncology.

[37]  J. M. Sforcin,et al.  Seasonal effect on Brazilian propolis antibacterial activity. , 2000, Journal of ethnopharmacology.

[38]  WangWeiguang,et al.  3D-Printed Poly(ɛ-caprolactone)/Graphene Scaffolds Activated with P1-Latex Protein for Bone Regeneration , 2018 .

[39]  S. Ribeiro,et al.  Transparent composites prepared from bacterial cellulose and castor oil based polyurethane as substrates for flexible OLEDs , 2015 .

[40]  Marek Kawecki,et al.  The future prospects of microbial cellulose in biomedical applications. , 2007, Biomacromolecules.

[41]  L. Drago,et al.  In Vitro Antimicrobial Activity of Propolis Dry Extract , 2000, Journal of chemotherapy.

[42]  S. B. Garcia,et al.  The inflammatory stimulus of a natural latex biomembrane improves healing in mice. , 2011, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[43]  A. Chaudhry,et al.  ANTI-MICROBIAL ACTIVITY OF CINNAMOMUM CASSIA AGAINST DIVERSE MICROBIAL FLORA WITH ITS NUTRITIONAL AND MEDICINAL IMPACTS , 2006 .

[44]  J. M. Sforcin,et al.  Immunomodulatory action of propolis on macrophage activation , 2000 .

[45]  B. Han,et al.  Preparation and properties of a drug release membrane of mitomycin C with N-succinyl-hydroxyethyl chitosan , 2011, Journal of materials science. Materials in medicine.

[46]  J. M. Sforcin,et al.  Nitric Oxide and Brazilian Propolis Combined Accelerates Tissue Repair by Modulating Cell Migration, Cytokine Production and Collagen Deposition in Experimental Leishmaniasis , 2015, PloS one.

[47]  D. Klemm,et al.  Cellulose: fascinating biopolymer and sustainable raw material. , 2005, Angewandte Chemie.

[48]  Sidney J. L. Ribeiro,et al.  Preparation and characterization of a bacterial cellulose/silk fibroin sponge scaffold for tissue regeneration. , 2015, Carbohydrate polymers.

[49]  Junkal Gutierrez,et al.  Komagataeibacter rhaeticus as an alternative bacteria for cellulose production. , 2016, Carbohydrate polymers.

[50]  S. Ribeiro,et al.  Antimicrobial bacterial cellulose-silver nanoparticles composite membranes , 2011 .

[51]  A. Brown XLIII.—On an acetic ferment which forms cellulose , 1886 .