TABLE 1.
In vitro and in vivo effects of the main alternative approaches studied.
| In vitro effects | In vivo effects | References | |
| Debridement | |||
| Negative pressure therapy | – | Enhance wound closure | Apelqvist et al., 2017; Liu et al., 2018 |
| Antimicrobial agents | |||
| Calcium sulfate beads with antibiotics | Decreased viability of MRSA strains | No clinical evaluation | Price et al., 2016 |
| Nanoparticles | Silver nanoparticles affect P. aeruginosa biofilm formation | No clinical evaluation | Beyth et al., 2015; Ahmadi and Adibhesami, 2017; Hamdan et al., 2017; Mihai et al., 2018 |
| Oxyclozanide | Enhances aminoglycoside and tetracycline killing in S. aureus biofilms | No clinical evaluation | Maiden et al., 2019 |
| Guanylated polymethacrylates | Effective killing of C. albicans and S. aureus in polymicrobial biofilms | Untested in human DFU | Qu et al., 2016 |
| Guar gum-associated nisin | Reduction of biofilm formation by S. aureus isolates from patients | Evaluation with strains isolated from DFI | Cirioni et al., 2006; Dutta and Das, 2016; Santos et al., 2016; Thombare et al., 2016 |
| Acapsil | – | Shorter hospital stay and faster wound healing | Bilyayeva et al., 2017 |
| Antiseptics | |||
| Cadexomer iodine | – | Reduction (1 log10) of microbial load and biofilm in DFU (11/17 patients) | Schwartz et al., 2013; Malone et al., 2017b |
| Nutraceuticals | |||
| Cranberry | Inhibition of pilus synthesis and prevention of biofilm formation | Decrease of Escherichia coli, S. aureus adhesion | LaPlante et al., 2012 |
| Tannic acid | Inhibition of S. aureus biofilm formation by peptidoglycan cleavage | Acceleration of cutaneous wound healing in rat model | Payne et al., 2013; Orlowski et al., 2018; Chen et al., 2019 |
| Tea-tree oil and Cinnamon oil | Effect on MRSA biofilm | Reduction of the quantity of colonized MRSA and promotion of healing of chronic wounds in a clinical trial | Kwieciński et al., 2009; Lee et al., 2014; Cui et al., 2016; Seyed Ahmadi et al., 2019 |
| Ellagic acid | Limits S. aureus biofilm formation and enhances antibiotic susceptibility | No clinical evaluation | Quave et al., 2012 |
| Propolis and honey | Anti-inflammatory and anti-bacterial properties | Reduction of bacterial load of chronic wounds in combination with antibiotics | Henshaw et al., 2014; Jull et al., 2015; Martinotti and Ranzato, 2015; Minden-Birkenmaier and Bowlin, 2018; McLoone et al., 2020 |
| Probiotics | Lactobacilli antibiofilm activity | Acceleration of wound healing in mice | Vuotto et al., 2014; Vågesjö et al., 2018 |
| Phage therapy | |||
| Reduction of biofilm formation and infection by P. aeruginosa, S. aureus, and A. baumannii | Reduction of bacterial load and wound closure in diabetic mouse wound infections | Mendes et al., 2014; Fish et al., 2018; Hill et al., 2018; Morozova et al., 2018; Taha et al., 2018; Albac et al., 2020; Kifelew et al., 2020 | |
| Action on wound healing | |||
| Photodynamic therapy | – | Increase of reepithelization | Tardivo et al., 2014 |
| Hyperbaric oxygen therapy | – | Improvement of short-term healing | Kranke et al., 2015 |
| Non-thermal plasma | – | Acceleration of wound healing in animal models of ulcers | Chatraie et al., 2018; Cooley et al., 2020 |
| Electrostimulation | Enhanced wound closure time | Evaluation with dressings | Barki et al., 2019 |
| Alternatives for inhibition of adhesion and biofilm | |||
| Inhibition of initial bacterial adhesion | |||
| EDTA and citrate | Prevention of biofilm formation and degradation of pre-existing biofilm (via Mg2+, Ca2+, and iron chelators) | Prevention of infection in a rabbit catheter model (with minocycline) | Raad et al., 2008 |
| Aryl rhodanines | Inhibition of biofilm formation by S. aureus and other Gram-positive bacteria by targeting early stage of adhesion | No clinical evaluation | Opperman et al., 2009 |
| Interaction with biofilm metabolism by QS stimulus modulation | |||
| Furanone | Inhibition of biofilm formation and expression of P. aeruginosa virulence factors | Decrease of P. aeruginosa virulence | Kim et al., 2012; García-Contreras et al., 2013 |
| Sodium ascorbate | Modulation of QS signal in P. aeruginosa | No clinical evaluation | El-Mowafy et al., 2014 |
| Savarin | Inhibition of S. aureus biofilm formation (by targeting agr) | No clinical evaluation | Sully et al., 2014 |
| Azithromycin | Inhibition of biofilm formation and expression of P. aeruginosa virulence factors | Improvement of clinical signs in patients with CF and P. aeruginosa infections | Bala et al., 2011 |
| RNAII inhibiting peptide | Reduction of S. aureus virulence | Healing improvement in a chronic wound mouse model | Giacometti et al., 2003 |
| c-di-GMP | Reduction of biofilm formation in P. aeruginosa and A. baumannii | No clinical evaluation | Romling et al., 2013; Lieberman et al., 2014; Wu et al., 2015 |
| Exo-polysaccharides | Reduction of biofilm formation (P. aeruginosa) by targeting virulence factors + PA01 and S. epidermidis in co-culture | No clinical evaluation | Pihl et al., 2010; Jiang et al., 2011; Rendueles et al., 2013; Limoli et al., 2015 |
| 1,018-peptide and derivates | Disruption of P. aeruginosa and B. cenocepacia mature biofilms | No clinical evaluation | Willcox et al., 2008; de la Fuente-Núñez et al., 2012, 2014 |
| Deferiprone | Activity against coagulase-negative staphylococci | No clinical evaluation | Coraça-Huber et al., 2018 |
| Enzymes enhancing bacterial dispersion | |||
| α-amylase | Disruption of biofilm formed by S. aureus | No clinical evaluation | Kalpana et al., 2012 |
| α-amylase and cellulase | Disruption of biofilm | In vivo disruption but the dispersal can cause systemic infection | Fleming et al., 2017 |
| DNase, dispersin B | Eradication of single and multi-species biofilms | No clinical evaluation | Chen and Lee, 2018; Sharma and Pagedar Singh, 2018 |
| 2-aminoimidazole | Disruption of biofilms formed by S. aureus | No clinical evaluation | Rogers et al., 2010 |
| Lysostaphin | Eradication of P. aeruginosa biofilms | Effective treatment for biofilm disruption on jugular vein catheters in mice | Kokai-Kun et al., 2009 |
| C2DA | Dispersion of S. aureus, Action on MRSA biofilm | No clinical evaluation | Jennings et al., 2012 |
| Next-generation dressings and grafts | |||
| NGAD NGAD + mesenchymal stem cells | Removal of biofilms by S. aureus and antibiotic-resistant P. aeruginosa | Evaluation with clinical strains | Parsons et al., 2016; Pérez-Díaz et al., 2018; Tarusha et al., 2018 |
| Electrospun nanofibers | Prevent biofilm formation and enhance fibroblast development | No clinical evaluation | Ramalingam et al., 2019 |
| Surfactant based gel | – | Reduced bacteria development and biofilm infection | Yang et al., 2017; Percival et al., 2018 |
| Dehydrated amniotic membranes | Faster wound healing in patients with severe comorbidities | Lower extremity wounds | Lullove, 2017 |
| Sucrose octasulfate | – | Significant increase of wound closure rate | Edmonds et al., 2018 |
| Skin substitutes | – | Fish skin offers natural anti-inflammatory properties and promotes growth of new skin. Other wounds and patients with burns | See clinicaltrials.gov NCT01348581 |
| Arenicola marina | This new dressing delivers oxygen to the wound bed, enhancing healing and cell proliferation | No evaluation clinical | Le Pape et al., 2018 |
| Epigel® | This new bioactive hydrogel hydrates the wound bed | No clinical evaluation | See www.epinovabiotech.com |
| Keratinocyte treatment. Skin grafts (epithelial or fetal cells). Stem cells. Collagen I matrix. Human placental tissues. | – | Improve closure time | Kanji and Das, 2017; Lo et al., 2019; Lintzeris et al., 2018; Mao et al., 2018; Momeni et al., 2019; Hassanshahi et al., 2019; Hwang et al., 2019; Oropallo, 2019 |
| 3D-printed scaffolds | – | Shorter healing time | Pushparaj and Ranganathan, 2017; Sun et al., 2018 |
EDTA, ethylene diamine tetra-acetic; EGTA, egtazic acid; MRSA, methicillin-resistant Staphylococcus aureus; QS, quorum sensing; CF, cystic fibrosis; C2DA, cis-2-decenoic acid; DFI, diabetic foot infection; DFU, diabetic foot ulcer; NGAD, next-generation carboxymethylcellulose silver- containing wound dressing.