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Review Article

Challenges with Wound Infection Models in Drug Development

Author(s): Sandeep K. Shukla*, Ajay K. Sharma, Vanya Gupta, Aman Kalonia and Priyanka Shaw

Volume 21, Issue 13, 2020

Page: [1301 - 1312] Pages: 12

DOI: 10.2174/1389450121666200302093312

Price: $65

Abstract

Wound research is an evolving science trying to unfold the complex untold mechanisms behind the wound healing cascade. In particular, interest is growing regarding the role of microorganisms in both acute and chronic wound healing. Microbial burden plays an important role in the persistence of chronic wounds, ultimately resulting in delayed wound healing. It is therefore important for clinicians to understand the evolution of infection science and its various etiologies. Therefore, to understand the role of bacterial biofilm in chronic wound pathogenesis, various in vitro and in vivo models are required to investigate biofilms in wound-like settings. Infection models should be refined comprising an important signet of biofilms. These models are eminent for translational research to obtain data for designing an improved wound care formulation. However, all the existing models possess limitations and do not fit properly in the model frame for developing wound care agents. Among various impediments, one of the major drawbacks of such models is that the wound they possess does not mimic the wound a human develops. Therefore, a novel wound infection model is required which can imitate the human wounds.

This review article mainly discusses various in vitro and in vivo models showing microbial colonization, their advantages and challenges. Apart from these models, there are also present ex vivo wound infection models, but this review mainly focused on various in vitro and in vivo models available for studying wound infection in controlled conditions. This information might be useful in designing an ideal wound infection model for developing an effective wound healing formulation.

Keywords: Infection model, wound healing, drug development, anti-infective agent, in vivo models, in vitro models.

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[1]
Ashrafi M, Novak-Frazer L, Bates M, et al. Validation of biofilm formation on human skin wound models and demonstration of clinically translatable bacteria-specific volatile signatures. Sci Rep 2018; 8(1): 9431.
[http://dx.doi.org/10.1038/s41598-018-27504-z] [PMID: 29930327]
[2]
Kumar S, Chandra N, Singh L, Hashmi M Z, Varma A. Biofilms in Human Diseases: Treatment and Control. Springer 1st Edition. (November 19, 2019).
[3]
Saleemi MA, Palanisamy NK, Wong EH. 2018.Alternative Approaches to Combat Medicinally Important Biofilm-Forming Pathogens. In: Antimicrobials, Antibiotic Resistance, Antibiofilm Strategies and Activity Methods. Intech Open.
[4]
Emmert-Buck MR. Translational research: From biological discovery to public benefit (or not). Adv Biol 2014; 2014.
[http://dx.doi.org/10.1155/2014/278789]
[5]
Cattò C, Cappitelli F. Testing anti-biofilm polymeric surfaces: Where to start? Int J Mol Sci 2019; 20(15): 3794.
[http://dx.doi.org/10.3390/ijms20153794] [PMID: 31382580]
[6]
Li J, Xie S, Ahmed S, et al. Antimicrobial activity and resistance: influencing factors. Front Pharmacol 2017; 8: 364.
[http://dx.doi.org/10.3389/fphar.2017.00364] [PMID: 28659799]
[7]
Manner S, Goeres DM, Skogman M, Vuorela P, Fallarero A. Prevention of Staphylococcus aureus biofilm formation by antibiotics in 96-Microtiter Well Plates and Drip Flow Reactors: critical factors influencing outcomes. Sci Rep 2017; 7: 43854.
[http://dx.doi.org/10.1038/srep43854] [PMID: 28252025]
[8]
Bahamondez-Canas TF, Heersema LA, Smyth HDC. Current status of in vitro models and assays for susceptibility testing for wound biofilm infections. Biomedicines 2019; 7(2): 34.
[http://dx.doi.org/10.3390/biomedicines7020034] [PMID: 31052271]
[9]
Balouiri M, Sadiki M, Ibnsouda SK. Methods for in vitro evaluating antimicrobial activity: A review. J Pharm Anal 2016; 6(2): 71-9.
[http://dx.doi.org/10.1016/j.jpha.2015.11.005] [PMID: 29403965]
[10]
Brackman G, Coenye T. In vitro and in vivo biofilm wound models and their application Advances in Microbiology, Infectious Diseases and Public Health. Cham: Springer 2015; pp. 15-32.
[http://dx.doi.org/10.1007/5584_2015_5002]
[11]
Gabrilska RA, Rumbaugh KP. Biofilm models of polymicrobial infection. Future Microbiol 2015; 10(12): 1997-2015.
[http://dx.doi.org/10.2217/fmb.15.109] [PMID: 26592098]
[12]
Keogh D, Tay WH, Ho YY, et al. Enterococcal metabolite cues facilitate interspecies niche modulation and polymicrobial infection. Cell Host Microbe 2016; 20(4): 493-503.
[http://dx.doi.org/10.1016/j.chom.2016.09.004] [PMID: 27736645]
[13]
Azeredo J, Azevedo NF, Briandet R, et al. Critical review on biofilm methods. Crit Rev Microbiol 2017; 43(3): 313-51.
[http://dx.doi.org/10.1080/1040841X.2016.1208146] [PMID: 27868469]
[14]
Filloux A, Ramos JL, Eds. Pseudomonas methods and protocols. NJ: Humana Press 2014.
[http://dx.doi.org/10.1007/978-1-4939-0473-0]
[15]
Lajhar SA, Brownlie J, Barlow R. Characterization of biofilm-forming capacity and resistance to sanitizers of a range of E. coli O26 pathotypes from clinical cases and cattle in Australia. BMC Microbiol 2018; 18(1): 41.
[http://dx.doi.org/10.1186/s12866-018-1182-z] [PMID: 29739319]
[16]
López S, Zea S, Gómez-León J. Evaluation in vitro of biofilm formation with marine bacteria from Colombian Caribbean. Boletín de Investigaciones Marinas y Costeras-INVEMAR 2019; 48(2): 71-93.
[17]
Aslantürk ÖS. In Vitro Cytotoxicity and Cell Viability Assays. Principles, Advantages, and Disadvantages 2018; 2: 64. InTech.
[18]
Haney EF, Trimble MJ, Cheng JT, Vallé Q, Hancock REW. Critical assessment of methods to quantify biofilm growth and evaluate antibiofilm activity of host defence peptides. Biomolecules 2018; 8(2): 29.
[http://dx.doi.org/10.3390/biom8020029] [PMID: 29883434]
[19]
Shukla SK, Rao TS. An improved crystal violet assay for biofilm quantification in 96-well microtitre plate. bioRxiv 2017. 100214.
[20]
Abouelhassan Y, Yang Q, Yousaf H, et al. Nitroxoline: a broad-spectrum biofilm-eradicating agent against pathogenic bacteria. Int J Antimicrob Agents 2017; 49(2): 247-51.
[http://dx.doi.org/10.1016/j.ijantimicag.2016.10.017] [PMID: 28110918]
[21]
Ommen P, Zobek N, Meyer RL. Quantification of biofilm biomass by staining: Non-toxic safranin can replace the popular crystal violet. J Microbiol Methods 2017; 141: 87-9.
[http://dx.doi.org/10.1016/j.mimet.2017.08.003] [PMID: 28802722]
[22]
Peterson S. Irie, Yasuhiko & Borlee, Bradley & Murakami, Keiji & Harrison, Joe & Colvin, Kelly &Parsek, Matthew Different methods for culturing biofilms in vitro. Biofilm Infections 2011.
[23]
Kragh KN, Alhede M, Kvich L, Bjarnsholt T. Into the well—A close look at the complex structures of a microtiter biofilm and the crystal violet assay. Biofilm 2019. 1100006.
[http://dx.doi.org/10.1016/j.bioflm.2019.100006]
[24]
Sun Yan, SDowd Scot, Smith Ethan, Rhoads Dan, Wolcott Randall. 2008; In vitro multispecies Lubbock chronic wound biofilm model. Wound repair and regeneration: official publication of the Wound Healing Society and the European Tissue Repair Society 16: 805-13.
[http://dx.doi.org/10.1111/j.1524-475X.2008.00434.x]
[25]
Ganesh K, Sinha M, Mathew-Steiner SS, Das A, Roy S, Sen CK. Chronic wound biofilm model. Adv Wound Care (New Rochelle) 2015; 4(7): 382-8.
[http://dx.doi.org/10.1089/wound.2014.0587] [PMID: 26155380]
[26]
Clinton A, Carter T. Chronic wound biofilms: pathogenesis and potential therapies. Lab Med 2015; 46(4): 277-84.
[http://dx.doi.org/10.1309/LMBNSWKUI4JPN7SO] [PMID: 26489671]
[27]
Donelli Schwarz. Advances in Microbiology, Infectious Diseases and Public Health. Springer 2016; 1.
[28]
Dowd SE, Sun Y, Smith E, Kennedy JP, Jones CE, Wolcott R. Effects of biofilm treatments on the multi-species Lubbock chronic wound biofilm model. J Wound Care 2009; 18(12): 508-512, 510- 512.
[http://dx.doi.org/10.12968/jowc.2009.18.12.45608] [PMID: 20081576]
[29]
Slade EA, Thorn RMS, Young A, Reynolds DM. An in vitro collagen perfusion wound biofilm model; with applications for antimicrobial studies and microbial metabolomics. BMC Microbiol 2019; 19(1): 310.
[http://dx.doi.org/10.1186/s12866-019-1682-5] [PMID: 31888471]
[30]
Pompilio A, Galardi G, Verginelli F, Muzzi M, Di Giulio A, Di Bonaventura G. Myroides odoratimimus Forms Structurally Complex and Inherently Antibiotic-Resistant Biofilm in a Wound-Like in vitro Model. Front Microbiol 2017; 8: 2591.
[http://dx.doi.org/10.3389/fmicb.2017.02591] [PMID: 29312264]
[31]
Sim CPC, Dashper SG, Reynolds EC. Oral microbial biofilm models and their application to the testing of anticariogenic agents. J Dent 2016; 50: 1-11.
[http://dx.doi.org/10.1016/j.jdent.2016.04.010] [PMID: 27131496]
[32]
Pereira MO, Kuehn M, Wuertz S, Neu T, Melo LF. Effect of flow regime on the architecture of a Pseudomonas fluorescens biofilm. Biotechnol Bioeng 2002; 78(2): 164-71.
[http://dx.doi.org/10.1002/bit.10189] [PMID: 11870607]
[33]
Magana M, Sereti C, Ioannidis A, et al. Options and limitations in clinical investigation of bacterial biofilms. Clin Microbiol Rev 2018; 31(3): e00084-16.
[http://dx.doi.org/10.1128/CMR.00084-16] [PMID: 29618576]
[34]
Goeres DM, Hamilton MA, Beck NA, et al. A method for growing a biofilm under low shear at the air-liquid interface using the drip flow biofilm reactor. Nat Protoc 2009; 4(5): 783-8.
[http://dx.doi.org/10.1038/nprot.2009.59] [PMID: 19528953]
[35]
Gomes IB, Meireles A, Gonçalves AL, et al. Standardized reactors for the study of medical biofilms: a review of the principles and latest modifications. Crit Rev Biotechnol 2018; 38(5): 657-70.
[http://dx.doi.org/10.1080/07388551.2017.1380601] [PMID: 28954541]
[36]
Duckworth PF, Rowlands RS, Barbour ME, Maddocks SE. A novel flow-system to establish experimental biofilms for modelling chronic wound infection and testing the efficacy of wound dressings. Microbiol Res 2018; 215: 141-7.
[http://dx.doi.org/10.1016/j.micres.2018.07.009] [PMID: 30172300]
[37]
Kim J, Park HD, Chung S. Microfluidic approaches to bacterial biofilm formation. Molecules 2012; 17(8): 9818-34.
[http://dx.doi.org/10.3390/molecules17089818] [PMID: 22895027]
[38]
Pousti M, Zarabadi MP, Abbaszadeh Amirdehi M, Paquet-Mercier F, Greener J. Microfluidic bioanalytical flow cells for biofilm studies: a review. Analyst (Lond) 2018; 144(1): 68-86.
[http://dx.doi.org/10.1039/C8AN01526K] [PMID: 30394455]
[39]
Zhang XY, Sun K, Abulimiti A, Xu PP, Li ZY. Microfluidic system for observation of bacterial culture and effects on biofilm formation at microscale. Micromachines (Basel) 2019; 10(9): 606.
[http://dx.doi.org/10.3390/mi10090606] [PMID: 31547458]
[40]
ASubramanian S, Huiszoon R C, Chu S, Bentley W E, Ghodssi Ghodssi. 2019.
[41]
Buhmann MT, Stiefel P, Maniura-Weber K, Ren Q. In vitro biofilm models for device-related infections. Trends Biotechnol 2016; 34(12): 945-8.
[http://dx.doi.org/10.1016/j.tibtech.2016.05.016] [PMID: 27344424]
[42]
Burmølle M, Ren D, Bjarnsholt T, Sørensen SJ. Interactions in multispecies biofilms: do they actually matter? Trends Microbiol 2014; 22(2): 84-91.
[http://dx.doi.org/10.1016/j.tim.2013.12.004] [PMID: 24440178]
[43]
Siddiqui EA, Jagdale P, Ahire K, Jadhav S, Khan SA, Bhosle S, et al. Relevance of small laboratory animals as models in translational research: challenges and road ahead. J Appl Pharm Sci 2016; 6(05): 198-209.
[http://dx.doi.org/10.7324/JAPS.2016.60531]
[44]
Trøstrup H, Thomsen K, Calum H, Hoiby N, Moser C. Animal models of chronic wound care: the application of biofilms in clinical research. Chronic Wound Care Mangament Res 2016; 3: 123-32.
[http://dx.doi.org/10.2147/CWCMR.S84361]
[45]
Swearengen J R. Choosing the right animal model for infectious disease research Animal models and experimental medicine 2018; 1(2): 100-8.
[46]
Doke SK, Dhawale SC. Alternatives to animal testing: A review. Saudi Pharm J 2015; 23(3): 223-9.
[http://dx.doi.org/10.1016/j.jsps.2013.11.002] [PMID: 26106269]
[47]
Trinder M, Daisley BA, Dube JS, Reid G. Drosophila melanogaster as a High-Throughput Model for Host-Microbiota Interactions. Front Microbiol 2017; 8: 751.
[http://dx.doi.org/10.3389/fmicb.2017.00751] [PMID: 28503170]
[48]
Lee YJ, Jang HJ, Chung IY, Cho YH. Drosophila melanogaster as a polymicrobial infection model for Pseudomonas aeruginosa and Staphylococcus aureus. J Microbiol 2018; 56(8): 534-41.
[http://dx.doi.org/10.1007/s12275-018-8331-9] [PMID: 30047081]
[49]
Singkum P, Suwanmanee S, Pumeesat P, Luplertlop N. A powerful in vivo alternative model in scientific research: Galleria mellonella. Acta Microbiol Immunol Hung 2019; 66(1): 31-55.
[http://dx.doi.org/10.1556/030.66.2019.001] [PMID: 30816806]
[50]
Peterson ND, Pukkila-Worley R. Caenorhabditis elegans in high-throughput screens for anti-infective compounds. Curr Opin Immunol 2018; 54: 59-65.
[http://dx.doi.org/10.1016/j.coi.2018.06.003] [PMID: 29935375]
[51]
Kong C, Eng SA, Lim MP, Nathan S. Beyond traditional antimicrobials: A Caenorhabditis elegans model for discovery of novel anti-infectives. Front Microbiol 2016; 7: 1956.
[http://dx.doi.org/10.3389/fmicb.2016.01956] [PMID: 27994583]
[52]
Rendueles O, Ferrières L, Frétaud M, et al. A new zebrafish model of oro-intestinal pathogen colonization reveals a key role for adhesion in protection by probiotic bacteria. PLoS Pathog 2012; 8(7) e1002815.
[http://dx.doi.org/10.1371/journal.ppat.1002815] [PMID: 22911651]
[53]
Gomes MC, Mostowy S. The case for modeling human infection in zebrafish. Trends Microbiol 2019.
[PMID: 31604611]
[54]
Ignacio G, El-Amin I, Mendenhall V. Animal models for wound healingSkin tissue engineering and regenerative medicine Albanna M JH Holmes IV. New York: Academic Press/Elsevier 2016; pp. 387-400.
[55]
Gyssens I C. 2019; Animal models for research in human infectious diseases. CMI editorial policy Clinical microbiology and infection: the official publication of the European Society of Clinical Microbiology and Infectious Diseases 25(6): 649.
[56]
Masopust D, Sivula CP, Jameson SC. Of mice, dirty mice, and men: using mice to understand human immunology J Immunol 2017; 199 383e8.
[57]
Grada A, Mervis J, Falanga V. Research techniques made simple: animal models of wound healing. J Invest Dermatol 2018; 138(10): 2095-2105.e1.
[http://dx.doi.org/10.1016/j.jid.2018.08.005] [PMID: 30244718]
[58]
Trøstrup H, Thomsen K, Calum H, Høiby N, Moser C. Animal models of chronic wound care: the application of biofilms in clinical research. Chronic Wound Care Manage. Res 2016.
[59]
Klein P, Sojka M, Kucera J, et al. A porcine model of skin wound infected with a polybacterial biofilm. Biofouling 2018; 34(2): 226-36.
[http://dx.doi.org/10.1080/08927014.2018.1425684] [PMID: 29405092]
[60]
Woodburn KW, Jaynes JM, Clemens LE. Evaluation of the antimicrobial peptide, RP557, for the broad-spectrum treatment of wound pathogens and biofilm. Front Microbiol 2019; 10: 1688.
[http://dx.doi.org/10.3389/fmicb.2019.01688] [PMID: 31396193]
[61]
Dai T, Kharkwal GB, Tanaka M, Huang Y-Y, Bil de Arce VJ, Hamblin MR. Animal models of external traumatic wound infections. Virulence 2011; 2(4): 296-315.
[http://dx.doi.org/10.4161/viru.2.4.16840] [PMID: 21701256]
[62]
Kraft WG, Johnson PT, David BC, Morgan DR. Cutaneous infection in normal and immunocompromised mice. Infect Immun 1986; 52(3): 707-13.
[http://dx.doi.org/10.1128/IAI.52.3.707-713.1986] [PMID: 3710582]
[63]
Marto J, Duarte A, Simões S, et al. Starch-based pickering emulsions as platforms for topical antibiotic delivery: in vitro and in vivo studies. Polymers (Basel) 2019; 11(1): 108.
[http://dx.doi.org/10.3390/polym11010108] [PMID: 30960092]
[64]
Dijksteel GS, Ulrich MMW, Vlig M, et al. Potential factors contributing to the poor antimicrobial efficacy of SAAP-148 in a rat wound infection model. Ann Clin Microbiol Antimicrob 2019; 18(1): 38.
[http://dx.doi.org/10.1186/s12941-019-0336-7] [PMID: 31796055]
[65]
Santus W, Mingozzi F, Vai M, Granucci F, Zanoni I. Deep Dermal Injection As a Model of Candida albicans Skin Infection for Histological Analyses JoVE. (Journal of Visualized Experiments) 2018; (136): e57574.
[66]
Brandenburg KS, Weaver AJ Jr, Qian L, et al. Development of Pseudomonas aeruginosa biofilms in partial-thickness burn wounds using a Sprague-Dawley rat model. J Burn Care Res 2019; 40(1): 44-57.
[http://dx.doi.org/10.1093/jbcr/iry043] [PMID: 30137429]
[67]
Porumb V, Trandabăț AF, Terinte C, et al. Design and testing of an experimental steam-induced burn model in rats. BioMed Res Int 2017. 20179878109.
[http://dx.doi.org/10.1155/2017/9878109] [PMID: 29159185]
[68]
Stieritz DD, Holder IA. Experimental studies of the pathogenesis of infections due to Pseudomonas aeruginosa: description of a burned mouse model. J Infect Dis 1975; 131(6): 688-91.
[http://dx.doi.org/10.1093/infdis/131.6.688] [PMID: 805812]
[69]
Qian L-W, Fourcaudot AB, Leung KP. Silver sulfadiazine retards wound healing and increases hypertrophic scarring in a rabbit ear excisional wound model. J Burn Care Res 2017; 38: e418-22.
[http://dx.doi.org/10.1097/BCR. 0000000000000406]
[70]
Ud-Din S, Bayat A. Non-animal models of wound healing in cutaneous repair: In silico, in vitro, ex vivo, and in vivo models of wounds and scars in human skin. Wound Repair Regen 2017; 25(2): 164-76.
[http://dx.doi.org/10.1111/wrr.12513] [PMID: 28120405]
[71]
Sami DG, Heiba HH, Abdellatif A. Wound healing models: A systematic review of animal and non-animal models. Wound Medicine 2019; 24(1): 8-17.
[http://dx.doi.org/10.1016/j.wndm.2018.12.001] [PMID: 30621698]
[72]
Nichols WW, Stone GG, Newell P, et al. Ceftazidime-avibactam susceptibility breakpoints against Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 2018; 62(11): e02590-17.
[http://dx.doi.org/10.1128/AAC.02590-17] [PMID: 30061279]
[73]
Silva ON, de la Fuente-Núñez C, Haney EF, et al. An anti-infective synthetic peptide with dual antimicrobial and immunomodulatory activities. Sci Rep 2016; 6: 35465.
[http://dx.doi.org/10.1038/srep35465] [PMID: 27804992]
[74]
He S, He H, Chen Y, Chen Y, Wang W, Yu D. In vitro and in vivo analysis of antimicrobial agents alone and in combination against multi-drug resistant Acinetobacter baumannii. Front Microbiol 2015; 6: 507.
[http://dx.doi.org/10.3389/fmicb.2015.00507] [PMID: 26074898]
[75]
Kong C, Yehye WA, Abd Rahman N, Tan MW, Nathan S. Discovery of potential anti-infectives against Staphylococcus aureus using a Caenorhabditis elegans infection model. BMC Complement Altern Med 2014; 14(1): 4.
[http://dx.doi.org/10.1186/1472-6882-14-4] [PMID: 24393217]
[76]
McCarthy M W. 2019.Teixobactin: a novel anti-infective agent
[http://dx.doi.org/10.1080/14787210.2019.1550357]
[77]
Lancellotti P, Musumeci L, Jacques N, et al. Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant gram-positive bacteria. JAMA Cardiol 2019; 4(6): 596-9.
[http://dx.doi.org/10.1001/jamacardio.2019.1189] [PMID: 31066863]
[78]
Tong C. 2018.Screening for inhibitors of Staphylococcal Sortase A as novel anti-infective agents
[79]
World Health Organization WHO publishes list of bacteria for which new antibiotics are urgently needed 2017 2018.

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