Microbial allies in skin trauma recovery: from immune modulation to engineered probiotic therapeutics

Abstract

Research shows that the microbiome of the skin is present as an active contributor to wound healing processes by moving past its historical infection-related function. The review investigates how commensal and probiotic bacteria affect immunomodulation while accelerating epithelial growth, together with tissue repair processes. Researchers use modern methods to link immunological concepts with material science along with synthetic biological techniques to study engineered probiotics which transform current wound treatments. The research study represents an extensive integration of recent findings concerning probiotic-mediated immunomodulatory operations and engineered approaches that improve probiotic delivery systems and their performance during skin wound healing procedures. Recent genetically engineered Lactobacillus reuteri strains that express chemokines like CXCL12 have been found to promote wound healing to an accelerated rate in animal models, and pre-clinical phases of clinical trials in the setting of diabetic foot ulcers (DFU) has demonstrated safety and therapeutic potential. Simultaneously, another live biotherapeutic product has been validated in terms of regenerative and immunomodulatory properties in animal models and in a clinical trial, a multi-cytokine-integrated strain of Lactococcus cremoris secreting FGF-2, IL-4, and CSF-1 promoted faster wound healing in diabetic mice and healed 83% of subjects in a Phase I DFU study. The range of probiotic therapies for trauma care expands due to advancements in probiotic delivery using materials and membrane vesicles derived from probiotics. This review builds a detailed framework that connects core immune functions with modern engineering methods for developing smart wound healing systems that combine engineered probiotics with bioresponsive materials and real-time monitoring systems. Engineered probiotics promise to become an alternative strategy for treating chronic wounds and infection-related complications that currently create significant medical problems.

Keywords

Microbiome / Probiotics / Engineered probiotics / Immunoregulation / Skin wound healing / Trauma recovery

References

[1] Wang G, Lin Z, Li Y, Chen L, Reddy SK, Hu Z, et al. Colonizing microbiota is associated with clinical outcomes in diabetic wound healing. Adv Drug Deliv Rev 2023; 194:114727. https://doi.org/10.1016/j.addr.2023.114727.

[2] Tomic-Canic M, Burgess JL, O’Neill KE, Strbo N, Pastar I. Skin microbiota and its interplay with wound healing. Am J Clin Dermatol 2020; 21:36-43. https://doi.org/10.1007/s40257-020-00536-w.

[3] Yang Y, Huang J, Zeng A, Long X, Yu N, Wang X. The role of the skin microbiome in wound healing. Burns Trauma 2024; 12:tkad059. https://doi.org/10.1093/burnst/tkad059.

[4] Patel BK, Patel KH, Huang RY, Lee CN, Moochhala SM. The gut-skin microbiota axis and its role in diabetic wound healing-a review based on current literature. Int J Mol Sci 2022; 23:2375. https://doi.org/10.3390/ijms23042375.

[5] Pastar I, Nusbaum AG, Gil J, Patel SB, Chen J, Valdes J, et al. Interactions of methicillin resistant staphylococcus aureus usa300 and pseudomonas aeruginosa in polymicrobial wound infection. PLoS One 2013; 8:e56846. https://doi.org/10.1371/journal.pone.0056846.

[6] Schierle CF, De la Garza M, Mustoe TA, Galiano RD. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen 2009; 17:354-9. https://doi.org/10.1111/j.1524-475X.2009.00489.x.

[7] Roy S, Santra S, Das A, Dixith S, Sinha M, Ghatak S, et al. Staphylococcus aureus biofilm infection compromises wound healing by causing deficiencies in granulation tissue collagen. Ann Surg 2020; 271:1174-85. https://doi.org/10.1097/SLA.0000000000003053.

[8] Dowd SE, Sun Y, Secor PR, Rhoads DD, Wolcott BM, James GA, et al. Survey of bacterial diversity in chronic wounds using pyrosequencing, DGGE, and full ribosome shotgun sequencing. BMC Microbiol 2008; 8:43. https://doi.org/10.1186/1471-2180-8-43.

[9] Kirker KR, Secor PR, James GA, Fleckman P, Olerud JE, Stewart PS. Loss of viability and induction of apoptosis in human keratinocytes exposed to staphylococcus aureus biofilms in vitro. Wound Repair Regen 2009; 17:690-9. https://doi.org/10.1111/j.1524-475X.2009.00523.x.

[10] Ramirez HA, Pastar I, Jozic I, Stojadinovic O, Stone RC, Ojeh N, et al. Staphylococcus aureus triggers induction of mir-15b-5p to diminish DNA repair and deregulate inflammatory response in diabetic foot ulcers. J Invest Dermatol 2018; 138:1187-96. https://doi.org/10.1016/j.jid.2017.11.038.

[11] Pastar I, Sawaya AP, Marjanovic J, Burgess JL, Strbo N, Rivas KE, et al. Intracellular staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression. J Clin Invest 2021; 131:e133727. https://doi.org/10.1172/JCI133727.

[12] Fazli M, Bjarnsholt T, Kirketerp-Moller K, Jorgensen B, Andersen AS, Krogfelt KA, et al. Nonrandom distribution of pseudomonas aeruginosa and staphylococcus aureus in chronic wounds. J Clin Microbiol 2009; 47:4084-9. https://doi.org/10.1128/JCM.01395-09.

[13] Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota. Immunity 2017; 46:562-76. https://doi.org/10.1016/j.immuni.2017.04.008.

[14] Luqman A, Gotz F. The ambivalent role of skin microbiota and adrenaline in wound healing and the interplay between them. Int J Mol Sci 2021; 22:4996. https://doi.org/10.3390/ijms22094996.

[15] Strbo N, Pastar I, Romero L, Chen V, Vujanac M, Sawaya AP, et al. Single cell analyses reveal specific distribution of antibacterial molecule perforin-2 in human skin and its modulation by wounding and staphylococcus aureus infection. Exp Dermatol 2019; 28:225-32. https://doi.org/10.1111/exd.13870.

[16] Zielinska M, Pawlowska A, Orzel A, Sulej L, Muzyka-Placzynska K, Baran A, et al. Wound microbiota and its impact on wound healing. Int J Mol Sci 2023;24:24. https://doi.org/10.3390/ijms242417318.

[17] Canchy L, Kerob D, Demessant A, Amici JM. Wound healing and microbiome, an unexpected relationship. J Eur Acad Dermatol Venereol 2023; 37 Suppl 3:7-15. https://doi.org/10.1111/jdv.18854.

[18] Ersanli C, Tzora A, Voidarou CC, Skoufos S, Zeugolis DI, Skoufos I. Biodiversity of skin microbiota as an important biomarker for wound healing. Biology (Basel) 2023; 12:1187. https://doi.org/10.3390/biology12091187.

[19] Xu Z, Hsia HC. The impact of microbial communities on wound healing: a review. Ann Plast Surg 2018; 81:113-23. https://doi.org/10.1097/SAP.0000000000001450.

[20] Johnson TR, Gomez BI, McIntyre MK, Dubick MA, Christy RJ, Nicholson SE, et al. The cutaneous microbiome and wounds: new molecular targets to promote wound healing. Int J Mol Sci 2018; 19:2699. https://doi.org/10.3390/ijms19092699.

[21] Liu XF, Shao JH, Liao YT, Wang LN, Jia Y, Dong PJ, et al. Regulation of short-chain fatty acids in the immune system. Front Immunol 2023; 14:1186892. https://doi.org/10.3389/fimmu.2023.1186892.

[22] Fusco W, Lorenzo MB, Cintoni M, Porcari S, Rinninella E, Kaitsas F, et al. Short-chain fatty-acid-producing bacteria: key components of the human gut microbiota. Nutrients 2023; 15:2211. https://doi.org/10.3390/nu15092211.

[23] Zhang D, Jian YP, Zhang YN, Li Y, Gu LT, Sun HH, et al. Short-chain fatty acids in diseases. Cell Commun Signal 2023; 21:212. https://doi.org/10.1186/s12964-023-01219-9.

[24] Zhou Y, Li Q, Wu Y, Zhang W, Ding L, Ji C, et al. Synergistic brilliance: engineered bacteria and nanomedicine unite in cancer therapy. Adv Mater 2024; 36:e2313953. https://doi.org/10.1002/adma.202313953.

[25] Xia X, Zhang JW, Zhao B, Zhang M, Chen ZR, Zhang BF, et al. Progress of engineered bacteria for tumour therapy. Int Immunopharmacol 2024; 132:111935. https://doi.org/10.1016/j.intimp.2024.111935.

[26] Qin S, He G, Yang J. Nanomaterial combined engineered bacteria for intelligent tumor immunotherapy. J Mater Chem B 2024; 12:9795-820. https://doi.org/10.1039/d4tb00741g.

[27] Chen H, Zhu Y, Zhang C, Hu L, Yang K. Engineered bacteria in tumor immunotherapy. Cancer Lett 2024; 589:216817. https://doi.org/10.1016/j.canlet.2024.216817.

[28] Shen X, Zhu C, Liu X, Zheng H, Wu Q, Xie J, et al. Engineered bacteria for augmented in situ tumor vaccination. Biomater Sci 2023; 11:1137-52. https://doi.org/10.1039/d2bm01593e.

[29] Liu Y, Yu W, Wang Q, Cao Z, Li J. Artificially engineered bacteria to treat gastrointestinal disease and cancer. Drug Discov Today 2023; 28:103667. https://doi.org/10.1016/j.drudis.2023.103667.

[30] Fan JX, Niu MT, Qin YT, Sun YX, Zhang XZ. Progress of engineered bacteria for tumor therapy. Adv Drug Deliv Rev 2022; 185:114296. https://doi.org/10.1016/j.addr.2022.114296.

[31] Wu J, Ye W, Yu J, Zhou T, Zhou N, D KPN, et al. Engineered bacteria and bacterial derivatives as advanced therapeutics for inflammatory bowel disease. Essays Biochem 2025; 69:169-79. https://doi.org/10.1042/EBC20253003.

[32] Zou ZP, Zhang XP, Zhang Q, Yin BC, Zhou Y, Ye BC. Genetically engineered bacteria as inflammatory bowel disease therapeutics. Eng Microbiol 2024; 4:100167. https://doi.org/10.1016/j.engmic.2024.100167.

[33] Airola C, Severino A, Porcari S, Fusco W, Mullish BH, Gasbarrini A, et al. Future modulation of gut microbiota: from eubiotics to fmt, engineered bacteria, and phage therapy. Antibiotics (Basel) 2023; 12:868. https://doi.org/10.3390/antibiotics12050868.

[34] Tanna T, Ramachanderan R, Platt RJ. Engineered bacteria to report gut function: technologies and implementation. Curr Opin Microbiol 2021; 59:24-33. https://doi.org/10.1016/j.mib.2020.07.014.

[35] Meng X, Liu L, Chen X. Bacterial photosynthesis: state-of-the-art in light-driven carbon fixation in engineered bacteria. Curr Opin Microbiol 2022; 69:102174. https://doi.org/10.1016/j.mib.2022.102174.

[36] Jers C, Kalantari A, Garg A, Mijakovic I. Production of 3-hydroxypropanoic acid from glycerol by metabolically engineered bacteria. Front Bioeng Biotechnol 2019; 7:124. https://doi.org/10.3389/fbioe.2019.00124.

[37] Din MO, Danino T, Prindle A, Skalak M, Selimkhanov J, Allen K, et al. Synchronized cycles of bacterial lysis for in vivo delivery. Nature 2016; 536:81-5. https://doi.org/10.1038/nature18930.

[38] Kuhl GC, Tangney M. Bacterial-mediated in situ engineering of tumour-associated macrophages for cancer immunotherapy. Cancers (Basel) 2025; 17:723. https://doi.org/10.3390/cancers17050723.

[39] Lin L, Zhang D. Unveiling the microbial influence: Bacteria’s dual role in tumor metastasis. Front Oncol 2025; 15:1524887. https://doi.org/10.3389/fonc.2025.1524887.

[40] Jin K, Huang Y, Che H, Wu Y. Engineered bacteria for disease diagnosis and treatment using synthetic biology. Microb Biotechnol 2025; 18:e70080. https://doi.org/10.1111/1751-7915.70080.

[41] Stirling F, Bitzan L, O’Keefe S, Redfield E, Oliver JWK, Way J, et al. Rational design of evolutionarily stable microbial kill switches. Mol Cell 2017; 68:686-97 e3. https://doi.org/10.1016/j.molcel.2017.10.033.

[42] Chan CT, Lee JW, Cameron DE, Bashor CJ, Collins JJ. ‘Deadman’ and ‘passcode’ microbial kill switches for bacterial containment. Nat Chem Biol 2016; 12:82-6. https://doi.org/10.1038/nchembio.1979.

[43] Ohnstedt E, Vagesjo E, Fasth A, Lofton Tomenius H, Dahg P, Jonsson S, et al. Engineered bacteria to accelerate wound healing: An adaptive, randomised, double-blind, placebo-controlled, first-in-human phase 1 trial. EClinicalMedicine 2023; 60:102014. https://doi.org/10.1016/j.eclinm.2023.102014.

[44] Schindler C, Mikosinski J, Mikosinski P, Karkkainen HR, Sanio M, Kurkipuro J, et al. Multi-target gene therapy AUP1602-C to improve healing and quality of life for diabetic foot ulcer patients: a phase I, open-label, dose-finding study. Ther Adv Endocrinol Metab 2024; 15:20420188241294134. https://doi.org/10.1177/20420188241294134.

[45] Vagesjo E, Ohnstedt E, Mortier A, Lofton H, Huss F, Proost P, et al. Accelerated wound healing in mice by on-site production and delivery of cxcl12 by transformed lactic acid bacteria. Proc Natl Acad Sci USA 2018; 115:1895-900. https://doi.org/10.1073/pnas.1716580115.

[46] Ohnstedt E, Lofton Tomenius H, Frank P, Roos S, Vagesjo E, Phillipson M. Accelerated wound healing in minipigs by on-site production and delivery of cxcl12 by transformed lactic acid bacteria. Pharmaceutics 2022; 14:229. https://doi.org/10.3390/pharmaceutics14020229.

[47] Lofton-Tomenius H, Pang Y, Pallin A, Myktybekova Z, Lelham N, Riesbeck K, et al. In vitro elimination of highly multidrug-resistant bacteria by the lactic acid bacterial drug candidate ILP100. Infect Dis Ther 2025; 14:1119-31. https://doi.org/10.1007/s40121-025-01137-y.

[48] Kurkipuro J, Mierau I, Wirth T, Samaranayake H, Smith W, Karkkainen HR, et al. Four in one-combination therapy using live lactococcus lactis expressing three therapeutic proteins for the treatment of chronic non-healing wounds. PLoS One 2022; 17:e0264775. https://doi.org/10.1371/journal.pone.0264775.

[49] Plumet L, Magnan C, Costechareyre D, Sotto A, Lavigne JP, Molle V. Phage therapy: a promising approach for staphylococcus aureus diabetic foot infections. J Virol 2025; 99:e0045825. https://doi.org/10.1128/jvi.00458-25.

[50] Wang B, Du L, Dong B, Kou E, Wang L, Zhu Y. Current knowledge and perspectives of phage therapy for combating refractory wound infections. Int J Mol Sci 2024; 25:5465. https://doi.org/10.3390/ijms25105465.

[51] Zyman A, Gorski A, Miedzybrodzki R. Phage therapy of wound-associated infections. Folia Microbiol (Praha) 2022; 67:193-201. https://doi.org/10.1007/s12223-021-00946-1.

[52] Berkson JD, Wate CE, Allen GB, Schubert AM, Dunbar KE, Coryell MP, et al. Phage-specific immunity impairs efficacy of bacteriophage targeting vancomycin resistant enterococcus in a murine model. Nat Commun 2024; 15:2993. https://doi.org/10.1038/s41467-024-47192-w.

[53] Mobarezi Z, Esfandiari AH, Abolbashari S, Meshkat Z. Efficacy of phage therapy in controlling staphylococcal biofilms: a systematic review. Eur J Med Res 2025; 30:605. https://doi.org/10.1186/s40001-025-02781-3.

[54] Yadegar A, Bar-Yoseph H, Monaghan TM, Pakpour S, Severino A, Kuijper EJ, et al. Fecal microbiota transplantation: current challenges and future landscapes. Clin Microbiol Rev 2024; 37:e0006022. https://doi.org/10.1128/cmr.00060-22.

[55] Porcari S, Benech N, Valles-Colomer M, Segata N, Gasbarrini A, Cammarota G, et al. Key determinants of success in fecal microbiota transplantation: from microbiome to clinic. Cell Host Microbe 2023; 31:712-33. https://doi.org/10.1016/j.chom.2023.03.020.

[56] Yu Y, Wang W, Zhang F. The next generation fecal microbiota transplantation: to transplant bacteria or virome. Adv Sci (Weinh) 2023; 10:e2301097. https://doi.org/10.1002/advs.202301097.

[57] Belvoncikova P, Maronek M, Gardlik R. Gut dysbiosis and fecal microbiota transplantation in autoimmune diseases. Int J Mol Sci 2022; 23:10729. https://doi.org/10.3390/ijms231810729.

[58] Minkoff NZ, Aslam S, Medina M, Tanner-Smith EE, Zackular JP, Acra S, et al. Fecal microbiota transplantation for the treatment of recurrent clostridioides difficile (clostridium difficile). Cochrane Database Syst Rev 2023; 4:CD013871. https://doi.org/10.1002/14651858.CD013871.pub2.

[59] Peng C, Lei P, Qi H, Zhu Q, Huang C, Fu J, et al. Effect of fecal microbiota transplantation on diabetic wound healing through the il-17a-mtor-hif1alpha signaling axis. Appl Environ Microbiol 2025; 91:e0201924. https://doi.org/10.1128/aem.02019-24.

[60] Bucataru C, Ciobanasu C. Antimicrobial peptides: opportunities and challenges in overcoming resistance. Microbiol Res 2024; 286:127822. https://doi.org/10.1016/j.micres.2024.127822.

[61] Adnan SB, Maarof M, Fauzi MB, Md Fadilah NI. Antimicrobial peptides in wound healing and skin regeneration: dual roles in immunity and microbial defense. Int J Mol Sci 2025; 26:5920. https://doi.org/10.3390/ijms26135920.

[62] Haidari H, Melguizo-Rodriguez L, Cowin AJ, Kopecki Z. Therapeutic potential of antimicrobial peptides for treatment of wound infection. Am J Physiol Cell Physiol 2023; 324:C29-38. https://doi.org/10.1152/ajpcell.00080.2022.

[63] Duarte-Mata DI, Salinas-Carmona MC. Antimicrobial peptides immune modulation role in intracellular bacterial infection. Front Immunol 2023; 14:1119574. https://doi.org/10.3389/fimmu.2023.1119574.

[64] Pfalzgraff A, Brandenburg K, Weindl G. Antimicrobial peptides and their therapeutic potential for bacterial skin infections and wounds. Front Pharmacol 2018; 9:281. https://doi.org/10.3389/fphar.2018.00281.

[65] Wang G, Chen Z, Tian P, Han Q, Zhang J, Zhang AM, et al. Wound healing mechanism of antimicrobial peptide cathelicidin-dm. Front Bioeng Biotechnol 2022; 10:977159. https://doi.org/10.3389/fbioe.2022.977159.

[66] Zheng S, Tu Y, Li B, Qu G, Li A, Peng X, et al. Antimicrobial peptide biological activity, delivery systems and clinical translation status and challenges. J Transl Med 2025; 23:292. https://doi.org/10.1186/s12967-025-06321-9.

[67] Gera S, Kankuri E, Kogermann K. Antimicrobial peptides-unleashing their therapeutic potential using nanotechnology. Pharmacol Ther 2022; 232:107990. https://doi.org/10.1016/j.pharmthera.2021.107990.

[68] Xuan J, Feng W, Wang J, Wang R, Zhang B, Bo L, et al. Antimicrobial peptides for combating drug-resistant bacterial infections. Drug Resist Updat 2023; 68:100954. https://doi.org/10.1016/j.drup.2023.100954.

[69] Zhang QY, Yan ZB, Meng YM, Hong XY, Shao G, Ma JJ, et al. Antimicrobial peptides: mechanism of action, activity and clinical potential. Mil Med Res 2021; 8:48. https://doi.org/10.1186/s40779-021-00343-2.

[70] Jo H, Brito S, Kwak BM, Park S, Lee MG, Bin BH. Applications of mesenchymal stem cells in skin regeneration and rejuvenation. Int J Mol Sci 2021; 22:2410. https://doi.org/10.3390/ijms22052410.

[71] Levoux J, Prola A, Lafuste P, Gervais M, Chevallier N, Koumaiha Z, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab 2021; 33:688-90. https://doi.org/10.1016/j.cmet.2021.02.003.

[72] Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, et al. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: roles, opportunities and challenges. Mil Med Res 2023; 10:36. https://doi.org/10.1186/s40779-023-00472-w.

[73] Wang AYL, Loh CYY. Episomal induced pluripotent stem cells: functional and potential therapeutic applications. Cell Transplant 2019; 28:112S-31. https://doi.org/10.1177/0963689719886534.

[74] Wang AYL. Human induced pluripotent stem cell-derived exosomes as a new therapeutic strategy for various diseases. Int J Mol Sci 2021; 22:1769. https://doi.org/10.3390/ijms22041769.

[75] Wang AYL, Kao HK, Liu YY, Loh CYY. Engineered extracellular vesicles derived from pluripotent stem cells: a cell-free approach to regenerative medicine. Burns Trauma 2025; 13:tkaf013. https://doi.org/10.1093/burnst/tkaf013.

[76] Wang AYL, Avina AE, Liu YY, Kao HK. Stromal vascular fraction in canine osteoarthritis: advantages, applications, and insights for veterinary practitioners. Front Vet Sci 2025; 12:1586629. https://doi.org/10.3389/fvets.2025.1586629.

[77] Zhang J, Tang W, Zhang X, Song Z, Tong T. An overview of stimuli-responsive intelligent antibacterial nanomaterials. Pharmaceutics 2023; 15:2113. https://doi.org/10.3390/pharmaceutics15082113.

[78] Lammermann T, Afonso PV, Angermann BR, Wang JM, Kastenmuller W, Parent CA, et al. Neutrophil swarms require ltb4 and integrins at sites of cell death in vivo. Nature 2013; 498:371-5. https://doi.org/10.1038/nature12175.

[79] Fischer A, Wannemacher J, Christ S, Koopmans T, Kadri S, Zhao J, et al. Neutrophils direct preexisting matrix to initiate repair in damaged tissues. Nat Immunol 2022; 23:518-31. https://doi.org/10.1038/s41590-022-01166-6.

[80] Liu Y, Zhang M, Liao Y, Chen H, Su D, Tao Y, et al. Human umbilical cord mesenchymal stem cell-derived exosomes promote murine skin wound healing by neutrophil and macrophage modulations revealed by single-cell RNA sequencing. Front Immunol 2023; 14:1142088. https://doi.org/10.3389/fimmu.2023.1142088.

[81] Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci 2017;18:18. https://doi.org/10.3390/ijms18071545.

[82] Chen C, Liu T, Tang Y, Luo G, Liang G, He W. Epigenetic regulation of macrophage polarization in wound healing. Burns Trauma 2023; 11:tkac057. https://doi.org/10.1093/burnst/tkac057.

[83] Sharifiaghdam M, Shaabani E, Faridi-Majidi R, De Smedt SC, Braeckmans K, Fraire JC. Macrophages as a therapeutic target to promote diabetic wound healing. Mol Ther 2022; 30:2891-908. https://doi.org/10.1016/j.ymthe.2022.07.016.

[84] Hassanshahi A, Moradzad M, Ghalamkari S, Fadaei M, Cowin AJ, Hassanshahi M. Macrophage-mediated inflammation in skin wound healing. Cells 2022; 11:2953. https://doi.org/10.3390/cells11192953.

[85] Caputa G, Flachsmann LJ, Cameron AM. Macrophage metabolism: a wound-healing perspective. Immunol Cell Biol 2019; 97:268-78. https://doi.org/10.1111/imcb.12237.

[86] Krzyszczyk P, Schloss R, Palmer A, Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front Physiol 2018; 9:419. https://doi.org/10.3389/fphys.2018.00419.

[87] Zandigohar M, Pang J, Rodrigues A, Roberts RE, Dai Y, Koh TJ. Transcription factor activity regulating macrophage heterogeneity during skin wound healing. J Immunol 2024; 213:506-18. https://doi.org/10.4049/jimmunol.2400172.

[88] Kim H. The transcription factor mafb promotes anti-inflammatory m2 polarization and cholesterol efflux in macrophages. Sci Rep 2017; 7:7591. https://doi.org/10.1038/s41598-017-07381-8.

[89] Aitcheson SM, Frentiu FD, Hurn SE, Edwards K, Murray RZ. Skin wound healing: normal macrophage function and macrophage dysfunction in diabetic wounds. Molecules 2021; 26:4917. https://doi.org/10.3390/molecules26164917.

[90] Wu X, He W, Mu X, Liu Y, Deng J, Liu Y, et al. Macrophage polarization in diabetic wound healing. Burns Trauma 2022; 10:tkac051. https://doi.org/10.1093/burnst/tkac051.

[91] Louiselle AE, Niemiec SM, Zgheib C, Liechty KW. Macrophage polarization and diabetic wound healing. Transl Res 2021; 236:109-16. https://doi.org/10.1016/j.trsl.2021.05.006.

[92] Gay D, Ghinatti G, Guerrero-Juarez CF, Ferrer RA, Ferri F, Lim CH, et al. Phagocytosis of Wnt inhibitor SFRP4 by late wound macrophages drives chronic Wnt activity for fibrotic skin healing. Sci Adv 2020; 6:eaay3704. https://doi.org/10.1126/sciadv.aay3704.

[93] Direder M, Weiss T, Copic D, Vorstandlechner V, Laggner M, Pfisterer K, et al. Schwann cells contribute to keloid formation. Matrix Biol 2022; 108:55-76. https://doi.org/10.1016/j.matbio.2022.03.001.

[94] Chen CJ, Kajita H, Takaya K, Aramaki-Hattori N, Sakai S, Asou T, et al. Single-cell RNA-seq analysis reveals cellular functional heterogeneity in dermis between fibrotic and regenerative wound healing fates. Front Immunol 2022; 13:875407. https://doi.org/10.3389/fimmu.2022.875407.

[95] Wee WKJ, Low ZS, Ooi CK, Henategala BP, Lim ZGR, Yip YS, et al. Single-cell analysis of skin immune cells reveals an angptl4-ifi20b axis that regulates monocyte differentiation during wound healing. Cell Death Dis 2022; 13:180. https://doi.org/10.1038/s41419-022-04638-7.

[96] Pang J, Maienschein-Cline M, Koh TJ.Enhanced proliferation of ly6c(+) monocytes/macrophages contributes to chronic inflammation in skin wounds of diabetic mice. J Immunol 2021; 206:621-30. https://doi.org/10.4049/jimmunol.2000935.

[97] Pang J, Maienschein-Cline M, Koh TJ.Monocyte/macrophage heterogeneity during skin wound healing in mice. J Immunol 2022; 209:1999-2011. https://doi.org/10.4049/jimmunol.2200365.

[98] Zhang S, Wang Y, Xiong X, Xing J, Jing K. Mechanistic insights into hippo-YAP pathway activation for enhanced DFU healing. Am J Physiol Cell Physiol 2025; 328:C1921-40. https://doi.org/10.1152/ajpcell.01067.2024.

[99] Harrison OJ, Linehan JL, Shih HY, Bouladoux N, Han SJ, Smelkinson M, et al. Commensal-specific t cell plasticity promotes rapid tissue adaptation to injury. Science 2019; 363:eaat6280. https://doi.org/10.1126/science.aat6280.

[100] Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, et al. Commensal-dendritic-cell interaction specifies a unique protective skin immune signature. Nature 2015; 520:104-8. https://doi.org/10.1038/nature14052.

[101] Henn D, Zhao D, Sivaraj D, Trotsyuk A, Bonham CA, Fischer KS, et al. Cas9-mediated knockout of ndrg2 enhances the regenerative potential of dendritic cells for wound healing. Nat Commun 2023; 14:4729. https://doi.org/10.1038/s41467-023-40519-z.

[102] Juarez VM, Montalbine AN, Singh A. Microbiome as an immune regulator in health, disease, and therapeutics. Adv Drug Deliv Rev 2022; 188:114400. https://doi.org/10.1016/j.addr.2022.114400.

[103] Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, et al. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory t cells. Immunity 2021; 54:702-20 e17. https://doi.org/10.1016/j.immuni.2021.03.007.

[104] Loomis KH, Wu SK, Ernlund A, Zudock K, Reno A, Blount K, et al. A mixed community of skin microbiome representatives influences cutaneous processes more than individual members. Microbiome 2021; 9:22. https://doi.org/10.1186/s40168-020-00963-1.

[105] Lukic J, Chen V, Strahinic I, Begovic J, Lev-Tov H, Davis SC, et al. Probiotics or pro-healers: the role of beneficial bacteria in tissue repair. Wound Repair Regen 2017; 25:912-22. https://doi.org/10.1111/wrr.12607.

[106] Sanford JA, Zhang LJ, Williams MR, Gangoiti JA, Huang CM, Gallo RL. Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands. Sci Immunol 2016; 1:eaah4609. https://doi.org/10.1126/sciimmunol.aah4609.

[107] Pastar I, O’Neill K, Padula L, Head CR, Burgess JL, Chen V, et al. Staphylococcus epidermidis boosts innate immune response by activation of gamma delta t cells and induction of perforin-2 in human skin. Front Immunol 2020; 11:550946. https://doi.org/10.3389/fimmu.2020.550946.

[108] Luqman A, Muttaqin MZ, Yulaipi S, Ebner P, Matsuo M, Zabel S, et al. Trace amines produced by skin bacteria accelerate wound healing in mice. Commun Biol 2020; 3:277. https://doi.org/10.1038/s42003-020-1000-7.

[109] Mouritzen MV, Petkovic M, Qvist K, Poulsen SS, Alarico S, Leal EC, et al. Improved diabetic wound healing by LFcinB is associated with relevant changes in the skin immune response and microbiota. Mol Ther Methods Clin Dev 2021; 20:726-39. https://doi.org/10.1016/j.omtm.2021.02.008.

[110] Lai Y, Di Nardo A, Nakatsuji T, Leichtle A, Yang Y, Cogen AL, et al. Commensal bacteria regulate toll-like receptor 3-dependent inflammation after skin injury. Nat Med 2009; 15:1377-82. https://doi.org/10.1038/nm.2062.

[111] Wanke I, Steffen H, Christ C, Krismer B, Gotz F, Peschel A, et al. Skin commensals amplify the innate immune response to pathogens by activation of distinct signaling pathways. J Invest Dermatol 2011; 131:382-90. https://doi.org/10.1038/jid.2010.328.

[112] Rademacher F, Simanski M, Hesse B, Dombrowsky G, Vent N, Glaser R, et al. Staphylococcus epidermidis activates aryl hydrocarbon receptor signaling in human keratinocytes: implications for cutaneous defense. J Innate Immun 2019; 11:125-35. https://doi.org/10.1159/000492162.

[113] Uberoi A, Bartow-McKenney C, Zheng Q, Flowers L, Campbell A, Knight SAB, et al. Commensal microbiota regulates skin barrier function and repair via signaling through the aryl hydrocarbon receptor. Cell Host Microbe 2021; 29:1235-48 e8. https://doi.org/10.1016/j.chom.2021.05.011.

[114] Di Domizio J, Belkhodja C, Chenuet P, Fries A, Murray T, Mondejar PM, et al. The commensal skin microbiota triggers type I IFN-dependent innate repair responses in injured skin. Nat Immunol 2020; 21:1034-45. https://doi.org/10.1038/s41590-020-0721-6.

[115] Wang G, Sweren E, Andrews W, Li Y, Chen J, Xue Y, et al. Commensal microbiome promotes hair follicle regeneration by inducing keratinocyte HIF-1α signaling and glutamine metabolism. Sci Adv 2023; 9:eabo7555. https://doi.org/10.1126/sciadv.abo7555.

[116] Beck LS, Deguzman L, Lee WP, Xu Y, McFatridge LA, Amento EP. TGF-beta 1 accelerates wound healing: reversal of steroid-impaired healing in rats and rabbits. Growth Factors 1991; 5:295-304. https://doi.org/10.3109/08977199109000293.

[117] Yin Z, Wang Y, Feng X, Liu C, Guan X, Liu S, et al. Lactobacillus rhamnosus gg and bifidobacterium animalis subsp. Lactis bb-12 promote infected wound healing via regulation of the wound microenvironment. Microb Biotechnol 2024; 17:e70031. https://doi.org/10.1111/1751-7915.70031.

[118] Sun Y, Liu M, Tang X, Zhou Y, Zhang J, Yang B. Culture-delivery live probiotics dressing for accelerated infected wound healing. ACS Appl Mater Interfaces 2023; 15:53283-96. https://doi.org/10.1021/acsami.3c12845.

[119] Ishi S, Kanno E, Tanno H, Kurosaka S, Shoji M, Imai T, et al. Cutaneous wound healing promoted by topical administration of heat-killed Lactobacillus plantarum KB131 and possible contribution of CARD9-mediated signaling. Sci Rep 2023; 13:15917. https://doi.org/10.1038/s41598-023-42919-z.

[120] Kuhn T, Aljohmani A, Frank N, Zielke L, Mehanny M, Laschke MW, et al. A cell-free, biomimetic hydrogel based on probiotic membrane vesicles ameliorates wound healing. J Control Release 2024; 365:969-80. https://doi.org/10.1016/j.jconrel.2023.12.011.

[121] Chen Y, Huang X, Liu A, Fan S, Liu S, Li Z, et al. Lactobacillus reuteri vesicles regulate mitochondrial function of macrophages to promote mucosal and cutaneous wound healing. Adv Sci (Weinh) 2024; 11:e2309725. https://doi.org/10.1002/advs.202309725.

[122] Dou Z, Li B, Wu L, Qiu T, Wang X, Zhang X, et al. Probiotic-functionalized silk fibroin/sodium alginate scaffolds with endoplasmic reticulum stress-relieving properties for promoted scarless wound healing. ACS Appl Mater Interfaces 2023; 15:6297-311. https://doi.org/10.1021/acsami.2c17168.

[123] Poutahidis T, Kearney SM, Levkovich T, Qi P, Varian BJ, Lakritz JR, et al. Microbial symbionts accelerate wound healing via the neuropeptide hormone oxytocin. PLoS One 2013; 8:e78898. https://doi.org/10.1371/journal.pone.0078898.

[124] Brandi J, Cheri S, Manfredi M, Di Carlo C, Vita Vanella V, Federici F, et al. Exploring the wound healing, anti-inflammatory, anti-pathogenic and proteomic effects of lactic acid bacteria on keratinocytes. Sci Rep 2020; 10:11572. https://doi.org/10.1038/s41598-020-68483-4.

[125] Panagiotou D, Filidou E, Gaitanidou M, Tarapatzi G, Spathakis M, Kandilogiannakis L, et al. Role of Lactiplantibacillus plantarum UBLP-40, Lactobacillus rhamnosus UBLR-58 and Bifidobacterium longum UBBL-64 in the wound healing process of the excisional skin. Nutrients 2023; 15:1822. https://doi.org/10.3390/nu15081822.

[126] Chuang YC, Cheng MC, Lee CC, Chiou TY, Tsai TY. Effect of ethanol extract from lactobacillus plantarum TWK10-fermented soymilk on wound healing in streptozotocin-induced diabetic rat. AMB Express 2019; 9:163. https://doi.org/10.1186/s13568-019-0886-2.

[127] Karimi F, Montazeri-Najafabady N, Mohammadi F, Azadi A, Koohpeyma F, Gholami A. A potential therapeutic strategy of an innovative probiotic formulation toward topical treatment of diabetic ulcer: an in vivo study. Nutr Diabetes 2024; 14:66. https://doi.org/10.1038/s41387-024-00320-3.

[128] Michels M, Corneo E, Rocha LBG, Dias R, Voytena APL, Rossetto M, et al. Paraprobiotics strains accelerate wound repair by stimulating re-epithelialization of nih-3t3 cells, decreasing inflammatory response and oxidative stress. Arch Microbiol 2023; 205:134. https://doi.org/10.1007/s00203-023-03469-0.

[129] Moreira CF, Cassini-Vieira P, Canesso MCC, Felipetto M, Ranfley H, Teixeira MM, et al. Lactobacillus rhamnosus CGMCC 1.3724 (LPR) improves skin wound healing and reduces scar formation in mice. Probiotics Antimicrob Proteins 2021; 13:709-19. https://doi.org/10.1007/s12602-020-09713-z.

[130] Gudadappanavar AM, Hombal PR, Timashetti SS, Javali SB. Influence of Lactobacillus acidophilus and Lactobacillus plantarum on wound healing in male Wistar rats-an experimental study. Int J Appl Basic Med Res 2017; 7:233-8. https://doi.org/10.4103/ijabmr.IJABMR_329_16.

[131] Wang X, Li X, Liu J, Tao Y, Wang T, Li L. Lactobacillus plantarum promotes wound healing by inhibiting the NLRP3 inflammasome and pyroptosis activation in diabetic foot wounds. J Inflamm Res 2024; 17:1707-20. https://doi.org/10.2147/JIR.S449565.

[132] Tagliari E, Campos LF, Campos AC, Costa-Casagrande TA, Noronha L. Effect of probiotic oral administration on skin wound healing in rats. Arq Bras Cir Dig 2019; 32:e1457. https://doi.org/10.1590/0102-672020190001e1457.

[133] Han N, Jia L, Guo L, Su Y, Luo Z, Du J, et al. Balanced oral pathogenic bacteria and probiotics promoted wound healing via maintaining mesenchymal stem cell homeostasis. Stem Cell Res Ther 2020; 11:61. https://doi.org/10.1186/s13287-020-1569-2.

[134] Ming Z, Han L, Bao M, Zhu H, Qiang S, Xue S, et al. Living bacterial hydrogels for accelerated infected wound healing. Adv Sci (Weinh) 2021; 8:e2102545. https://doi.org/10.1002/advs.202102545.

[135] Savitri IJ, Suprarahardiani SA, Ulinnuha LK, Prahasanti C, Wijaksana IKE, Ridwan RD, et al. TNF-alpha expression and plasma cell and macrophage numbers in traumatic ulcers in a rat model treated by topical or systemic probiotic l. Casei shirota Int J Med Sci 2025; 22:318-27. https://doi.org/10.7150/ijms.99156.

[136] Guan W, Gong C, Wu S, Cui Z, Zheng Y, Li Z, et al. Instant protection spray for anti-infection and accelerated healing of empyrosis. Adv Mater 2024; 36:e2306589. https://doi.org/10.1002/adma.202306589.

[137] Dubey AK, Podia M, Priyanka RS, Singh S, Pinnaka AK, et al. Insight into the beneficial role of Lactiplantibacillus plantarum supernatant against bacterial infections, oxidative stress, and wound healing in A549 cells and BALB/c mice. Front Pharmacol 2021; 12:728614. https://doi.org/10.3389/fphar.2021.728614.

[138] Mohtashami M, Mohamadi M, Azimi-Nezhad M, Saeidi J, Nia FF, Ghasemi A. Lactobacillus bulgaricus and lactobacillus plantarum improve diabetic wound healing through modulating inflammatory factors. Biotechnol Appl Biochem 2021; 68:1421-31. https://doi.org/10.1002/bab.2064.

[139] Satish L, Gallo PH, Johnson S, Yates CC, Kathju S . Local probiotic therapy with lactobacillus plantarum mitigates scar formation in rabbits after burn injury and infection. Surg Infect 2017; 18:119-27. https://doi.org/10.1089/sur.2016.090.

[140] Abdollahpour D, Homayouni-Rad A, Nourizadeh R, Hakimi S, Mehrabi E. The effect of probiotic supplementation on episiotomy wound healing among primiparous women: a triple-blind randomized clinical trial. BMC Complement Med Ther 2023; 23:149. https://doi.org/10.1186/s12906-023-03980-3.

[141] Moysidis M, Chorti A, Cheva A, Abba Deka I, Tzikos G, Kosmidis C, et al. L. Plantarum UBLP-40 versus the combined formula of L. Rhamnosus UBLP-58 and B. Longum UBBL-64 in excisional wound healing: a cellular perspective. Pharmaceuticals (Basel) 2024; 17:1414. https://doi.org/10.3390/ph17111414.

[142] Tarapatzi G, Filidou E, Kandilogiannakis L, Spathakis M, Gaitanidou M, Arvanitidis K, et al. The probiotic strains bifidomicronbacterium lactis, lactobacillus acidophilus, lactiplantibacillus plantarum and saccharomyces boulardii regulate wound healing and chemokine responses in human intestinal subepithelial myofibroblasts. Pharmaceuticals (Basel) 2022; 15:1293. https://doi.org/10.3390/ph15101293.

[143] Mohammedsaeed W, Cruickshank S, McBain AJ, O’Neill CA. Lactobacillus rhamnosus gg lysate increases re-epithelialization of keratinocyte scratch assays by promoting migration. Sci Rep 2015; 5:16147. https://doi.org/10.1038/srep16147.

[144] Albuquerque-Souza E, Ishikawa KH, Amado PP, Nicoli JR, Holzhausen M, Mayer MPA . Probiotics improve re-epithelialization of scratches infected by Porphyromonas gingivalis through up-regulating CXCL8-CXCR1/CXCR2 axis. Anaerobe 2021; 72:102458. https://doi.org/10.1016/j.anaerobe.2021.102458.

[145] Peral MC, Rachid MM, Gobbato NM, Huaman Martinez MA, Valdez JC. Interleukin-8 production by polymorphonuclear leukocytes from patients with chronic infected leg ulcers treated with lactobacillus plantarum. Clin Microbiol Infect 2010; 16:281-6. https://doi.org/10.1111/j.1469-0691.2009.02793.x.

[146] Kazemi A, Ataellahi Eshkoor P, Saeedi P, Halabian R. Evaluation of antioxidant and antibacterial effects of lactobacilli metabolites-preconditioned bone marrow mesenchymal stem cells in skin lesions amelioration. Bioorg Chem 2022; 124:105797. https://doi.org/10.1016/j.bioorg.2022.105797.

[147] Lombardi F, Palumbo P, Mattei A, Augello FR, Cifone MG, Giuliani M, et al. Soluble fraction from lysates of selected probiotic strains differently influences re-epithelialization of HaCaT scratched monolayer through a mechanism involving nitric oxide synthase 2. Biomolecules 2019; 9:756. https://doi.org/10.3390/biom9120756.

[148] Kaur Sandhu S, Raut J, Kumar S, Singh M, Ahmed B, Singh J, et al. Nanocurcumin and viable lactobacillus plantarum based sponge dressing for skin wound healing. Int J Pharm 2023; 643:123187. https://doi.org/10.1016/j.ijpharm.2023.123187.

[149] Wang Y, Shi L, Lu J, Wang F, Zhou Z, Wang Y, et al. Probiotic active gel promotes diabetic wound healing through continuous local glucose consumption and antioxidant. J Nanobiotechnology 2025; 23:62. https://doi.org/10.1186/s12951-025-03115-5.

[150] Elmansy EA, Elkady EM, Asker MS, Abdou AM, Abdallah NA, Amer SK. Exopolysaccharide produced by lactiplantibacillus plantarum ro30 isolated from romi cheese: characterization, antioxidant and burn healing activity. World J Microbiol Biotechnol 2022; 38:245. https://doi.org/10.1007/s11274-022-03439-6.

[151] Varian BJ, Poutahidis T, DiBenedictis BT, Levkovich T, Ibrahim Y, Didyk E, et al. Microbial lysate upregulates host oxytocin. Brain Behav Immun 2017; 61:36-49. https://doi.org/10.1016/j.bbi.2016.11.002.

[152] Pinto D, Marzani B, Minervini F, Calasso M, Giuliani G, Gobetti M, et al. Plantaricin A synthesized by Lactobacillus plantarum induces in vitro proliferation and migration of human keratinocytes and increases the expression of TGF-BETA1, FGF7, VEGF-A and IL-8 genes. Peptides 2011; 32:1815-24. https://doi.org/10.1016/j.peptides.2011.07.004.

[153] Soleymanzadeh Moghadam S, Mohammad N, Ghooshchian M, FathiZadeh S, Khodaii Z, Faramarzi M, et al. Comparison of the effects of lactobacillus plantarum versus imipenem on infected burn wound healing. Med J Islam Repub Iran 2020; 34:94. https://doi.org/10.34171/mjiri.34.94.

[154] Ashoori Y, Mohkam M, Heidari R, Abootalebi SN, Mousavi SM, Hashemi SA, et al. Development and in vivo characterization of probiotic lysate-treated chitosan nanogel as a novel biocompatible formulation for wound healing. Biomed Res Int 2020; 2020:8868618. https://doi.org/10.1155/2020/8868618.

[155] Peral MC, Martinez MA, Valdez JC. Bacteriotherapy with lactobacillus plantarum in burns. Int Wound J 2009; 6:73-81. https://doi.org/10.1111/j.1742-481X.2008.00577.x.

[156] Ramos AN, Cabral ME, Noseda D, Bosch A, Yantorno OM, Valdez JC. Antipathogenic properties of lactobacillus plantarum on pseudomonas aeruginosa: the potential use of its supernatants in the treatment of infected chronic wounds. Wound Repair Regen 2012; 20:552-62. https://doi.org/10.1111/j.1524-475X.2012.00798.x.

[157] Li M, Xiao H, Su Y, Cheng D, Jia Y, Li Y, et al. Synergistic inhibitory effect of honey and lactobacillus plantarum on pathogenic bacteria and their promotion of healing in infected wounds. Pathogens 2023; 12:501. https://doi.org/10.3390/pathogens12030501.

[158] Abootaleb M, Mohammadi Bandari N, Arbab SN. Interference of Lactobacillus casei with pseudomonas aeruginosa in the treatment of infected burns in Wistar rats. Iran J Basic Med Sci 2021; 24:143-9. https://doi.org/10.22038/IJBMS.2020.47447.10920.

[159] Szollosi AG, Gueniche A, Jammayrac O, Szabo-Papp J, Blanchard C, Vasas N, et al. Bifidobacterium longum extract exerts pro-differentiating effects on human epidermal keratinocytes, in vitro. Exp Dermatol 2017; 26:92-4. https://doi.org/10.1111/exd.13130.

[160] Ramos AN, Sesto Cabral ME, Arena ME, Arrighi CF, Arroyo Aguilar AA, Valdez JC. Compounds from lactobacillus plantarum culture supernatants with potential pro-healing and anti-pathogenic properties in skin chronic wounds. Pharm Biol 2015; 53:350-8. https://doi.org/10.3109/13880209.2014.920037.

[161] Moysidis M, Stavrou G, Cheva A, Abba Deka I, Tsetis JK, Birba V, et al. The 3-d configuration of excisional skin wound healing after topical probiotic application. Injury 2022; 53:1385-93. https://doi.org/10.1016/j.injury.2022.02.006.

[162] Wang J, Wang L, Wang Q, Liu C, Zheng L. Lacticaseibacillus rhamnosus GG enhances fin regeneration under oxytetracycline exposure via activating Wnt signaling and modulating gut microbiota. Fish Shellfish Immunol 2023; 142:109155. https://doi.org/10.1016/j.fsi.2023.109155.

[163] Chae D, Oh SW, Choi YS, Kang DJ, Park CW, Lee J, et al. First report on microbial-derived polydeoxyribonucleotide: a sustainable and enhanced alternative to salmon-based polydeoxyribonucleotide. Curr Issues Mol Biol 2025; 47:41. https://doi.org/10.3390/cimb47010041.

[164] Wang J, Li X, Zhao X, Yuan S, Dou H, Cheng T, et al. Lactobacillus rhamnosus GG-derived extracellular vesicles promote wound healing via mir-21-5p-mediated re-epithelization and angiogenesis. J Nanobiotechnology 2024; 22:644. https://doi.org/10.1186/s12951-024-02893-8.

[165] Han N, Jia L, Su Y, Du J, Guo L, Luo Z, et al. Lactobacillus reuteri extracts promoted wound healing via pi3k/akt/beta-catenin/tgfbeta1 pathway. Stem Cell Res Ther 2019; 10:243. https://doi.org/10.1186/s13287-019-1324-8.

[166] Kim DY, Lee TS, Lee YJ, Ahn SY, Chu B, Jung DH, et al. Lactobacillus reuteri nchbl-005 improves wound healing by promoting the activation of fibroblasts through tlr2/mapk signaling. Inflamm Regen 2025; 45:10. https://doi.org/10.1186/s41232-025-00370-9.

[167] Shirzad M, Hamedi J, Motevaseli E, Modarressi MH. Anti-elastase and anti-collagenase potential of lactobacilli exopolysaccharides on human fibroblast. Artif Cells Nanomed Biotechnol 2018; 46:1051-61. https://doi.org/10.1080/21691401.2018.1443274.

[168] Miao Y, Wei J, Chen X, Shi J, Zhang L, Wang L, et al. Evaluation of living bacterial therapy assisted by ph/reactive oxygen species dual-responsive sodium alginate-based hydrogel for wound infections. Int J Biol Macromol 2024; 271:132536. https://doi.org/10.1016/j.ijbiomac.2024.132536.

[169] Mei L, Zhang D, Shao H, Hao Y, Zhang T, Zheng W, et al. Injectable and self-healing probiotics-loaded hydrogel for promoting superbacteria-infected wound healing. ACS Appl Mater Interfaces 2022; 14:20538-50. https://doi.org/10.1021/acsami.1c23713.

[170] Han Y, Yin Z, Wang Y, Jiang Y, Chen J, Miao Z, et al. Photopolymerizable and antibacterial hydrogels loaded with metabolites from Lacticaseibacillus rhamnosus GG for infected wound healing. Biomacromolecules 2024; 25:2587-96. https://doi.org/10.1021/acs.biomac.4c00124.

[171] Zhou C, Zou Y, Xu R, Han X, Xiang Z, Guo H, et al. Metal-phenolic self-assembly shielded probiotics in hydrogel reinforced wound healing with antibiotic treatment. Mater Horiz 2023; 10:3114-23. https://doi.org/10.1039/d3mh00033h.

[172] Kim JS, Kim J, Lee SM, Woo MR, Kim DW, Kim JO, et al. Development of guar gum-based dual-layer wound dressing containing lactobacillus plantarum: rapid recovery and mechanically flexibility. Int J Biol Macromol 2022; 221:1572-9. https://doi.org/10.1016/j.ijbiomac.2022.09.049.

[173] Tao S, Zhang S, Wei K, Maniura-Weber K, Li Z, Ren Q. An injectable living hydrogel with embedded probiotics as a novel strategy for combating multifaceted pathogen wound infections. Adv Healthc Mater 2024; 13:e2400921. https://doi.org/10.1002/adhm.202400921.

[174] Harandi FN, Khorasani AC, Shojaosadati SA, Hashemi-Najafabadi S. Living lactobacillus-ZnO nanoparticles hybrids as antimicrobial and antibiofilm coatings for wound dressing application. Mater Sci Eng C Mater Biol Appl 2021; 130:112457. https://doi.org/10.1016/j.msec.2021.112457.

[175] Akhtach S, Tabia Z, Belkhou R, Mabrouk KE. Bacterial exopolysaccharide and metal-doped bioactive glass nanoparticles-based electrospun membranes for chronic wound healing. Int J Pharm 2025; 676:125594. https://doi.org/10.1016/j.ijpharm.2025.125594.

[176] Xin H, Cai Z, Hao J, An J, Li Y, Wen M, et al. Macro/microgel-encapsulated, biofilm-armored living probiotic platform for regenerating bacteria-infected diabetic wounds. Adv Healthc Mater 2025; 14:e2403476. https://doi.org/10.1002/adhm.202403476.

[177] Shahghasempour L, Hosseinzadeh S, Haddadi A, Kabiri M. Evaluation of Lactobacillus plantarum and PRGF as a new bioactive multi-layered scaffold PU/PRGF/gelatin/PU for wound healing. Tissue Cell 2023; 82:102091. https://doi.org/10.1016/j.tice.2023.102091.

[178] Soleymani F, Rahimi HR, Farsiani H, Jalili A. Antimicrobial activity of chitosan scaffold loaded with soluble factors of different probiotic strains against multidrug resistant pseudomonas aeruginosa. Iran J Biotechnol 2024; 22:e3612. https://doi.org/10.30498/ijb.2024.381455.3612.

[179] Khodaii Z, Afrasiabi S, Hashemi SA, Ardeshirylajimi A, Natanzi MM. Accelerated wound healing process in rat by probiotic Lactobacillus reuteri derived ointment. J Basic Clin Physiol Pharmacol 2019; 30. https://doi.org/10.1515/jbcpp-2018-0150.

[180] Zhou C, Cao H, Wang Y, Yao C, Zou Y, Liu J, et al. Anchoring of probiotic-membrane vesicles in hydrogels facilitates wound vascularization. ACS Nano 2025; 19:3325-38. https://doi.org/10.1021/acsnano.4c11986.

[181] Gong C, Guan W, Liu X, Zheng Y, Li Z, Zhang Y, et al. Biomimetic bacteriophage-like particles formed from probiotic extracts and no donors for eradicating multidrug-resistant staphylococcus aureus. Adv Mater 2022; 34:e2206134. https://doi.org/10.1002/adma.202206134.

[182] Brugnoli M, Carvalho JPF, Arena MP, Oliveira H, Vilela C, Freire CSR, et al. Co-cultivation of Komagataeibacter sp. and Lacticaseibacillus sp. strains to produce bacterial nanocellulose-hyaluronic acid nanocomposite membranes for skin wound healing applications. Int J Biol Macromol 2025; 299:140208. https://doi.org/10.1016/j.ijbiomac.2025.140208.

[183] Walivaara DA, Sjogren I, Gerasimcik N, Yucel-Lindberg T, Twetman S, Abrahamsson P. Effects of lactobacillus reuteri-containing lozenges on healing after surgical removal of mandibular third molars: a randomised controlled trial. Benef Microbes 2019; 10:653-9. https://doi.org/10.3920/BM2018.0168.

[184] Twetman S, Pedersen AML, Yucel-Lindberg T. Probiotic supplements containing lactobacillus reuteri does not affect the levels of matrix metalloproteinases and interferons in oral wound healing. BMC Res Notes 2018; 11:759. https://doi.org/10.1186/s13104-018-3873-9.

[185] Gottrup F, Jorgensen B, Karlsmark T. News in wound healing and management. Curr Opin Support Palliat Care 2009; 3:300-4. https://doi.org/10.1097/SPC.0b013e328331d40c.

[186] Tsai WH, Chou CH, Huang TY, Wang HL, Chien PJ, Chang WW, et al. Heat-killed lactobacilli preparations promote healing in the experimental cutaneous wounds. Cells 2021; 10:3264. https://doi.org/10.3390/cells10113264.

[187] Fijan S, Frauwallner A, Langerholc T, Krebs B, Ter Haar Nee Younes JA, Heschl A, et al. Efficacy of using probiotics with antagonistic activity against pathogens of wound infections: an integrative review of literature. Biomed Res Int 2019; 2019:7585486. https://doi.org/10.1155/2019/7585486.

[188] Mayes T, Gottschlich MM, James LE, Allgeier C, Weitz J, Kagan RJ. Clinical safety and efficacy of probiotic administration following burn injury. J Burn Care Res 2015; 36:92-9. https://doi.org/10.1097/BCR.0000000000000139.

[189] Danhof HA, Lee J, Thapa A, Britton RA, Di Rienzi SC. Microbial stimulation of oxytocin release from the intestinal epithelium via secretin signaling. Gut Microbes 2023; 15:2256043. https://doi.org/10.1080/19490976.2023.2256043.

[190] Tsiouris CG, Kelesi M, Vasilopoulos G, Kalemikerakis I, Papageorgiou EG. The efficacy of probiotics as pharmacological treatment of cutaneous wounds: meta-analysis of animal studies. Eur J Pharm Sci 2017; 104:230-9. https://doi.org/10.1016/j.ejps.2017.04.002.

[191] Menni A, Moysidis M, Tzikos G, Stavrou G, Tsetis JK, Shrewsbury AD, et al. Looking for the ideal probiotic healing regime. Nutrients 2023; 15:3055. https://doi.org/10.3390/nu15133055.

[192] Erdman SE, Poutahidis T. Microbes and oxytocin: benefits for host physiology and behavior. Int Rev Neurobiol 2016; 131:91-126. https://doi.org/10.1016/bs.irn.2016.07.004.

[193] Soleymanzadeh Moghadam S, Momeni M, Mazar Atabaki S, Mousavi Shabestari T, Boustanshenas M, Afshar M, et al. Topical treatment of second-degree burn wounds with lactobacillus plantarum supernatant: phase I trial. Iran J Pathol 2022; 17:460-8. https://doi.org/10.30699/ijp.2022.551202.2863.

[194] Twetman S, Keller MK, Lee L, Yucel-Lindberg T, Pedersen AML. Effect of probiotic lozenges containing lactobacillus reuteri on oral wound healing: a pilot study. Benef Microbes 2018; 9:691-6. https://doi.org/10.3920/BM2018.0003.

[195] Chen VY, Siegfried LG, Tomic-Canic M, Stone RC, Pastar I. Cutaneous changes in diabetic patients: primed for aberrant healing? Wound Repair Regen 2023; 31:700-12. https://doi.org/10.1111/wrr.13108.

[196] Giri B, Dey S, Das T, Sarkar M, Banerjee J, Dash SK. Chronic hyperglycemia mediated physiological alteration and metabolic distortion leads to organ dysfunction, infection, cancer progression and other pathophysiological consequences: An update on glucose toxicity. Biomed Pharmacother 2018; 107:306-28. https://doi.org/10.1016/j.biopha.2018.07.157.

[197] Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: the connection in diabetic wound healing. Expert Rev Mol Med 2009; 11:e2. https://doi.org/10.1017/S1462399409000945.

[198] Bhattacharjee S, Gao J, Lu YW, Eisa-Beygi S, Wu H, Li K, et al. Endothelial foxm1 and dab2 promote diabetic wound healing. JCI Insight 2025; 10:e186504. https://doi.org/10.1172/jci.insight.186504.

[199] Luo T, Zhu P, Li S, Qin M, Fang Z, Wu F, et al. DFO-loaded PDA nanoparticles facilitated 3d stem cell spheroids for diabetic wound repair by normalizing the pathological microenvironment. Mater Today Bio 2025; 33:101973. https://doi.org/10.1016/j.mtbio.2025.101973.

[200] Rajab AAH, Hegazy WAH. What’s old is new again: insights into diabetic foot microbiome. World J Diabetes 2023; 14:680-704. https://doi.org/10.4239/wjd.v14.i6.680.

[201] Baig MS, Banu A, Zehravi M, Rana R, Burle SS, Khan SL, et al. An overview of diabetic foot ulcers and associated problems with special emphasis on treatments with antimicrobials. Life (Basel) 2022; 12:1054. https://doi.org/10.3390/life12071054.

[202] Hemmati J, Azizi M, Asghari B, Arabestani MR. Multidrug-resistant pathogens in burn wound, prevention, diagnosis, and therapeutic approaches (conventional antimicrobials and nanoparticles). Can J Infect Dis Med Microbiol 2023; 2023:8854311. https://doi.org/10.1155/2023/8854311.

[203] Roy S, Mukherjee P, Kundu S, Majumder D, Raychaudhuri V, Choudhury L. Microbial infections in burn patients. Acute Crit Care 2024; 39:214-25. https://doi.org/10.4266/acc.2023.01571.

[204] Qin S, Xiao W, Zhou C, Pu Q, Deng X, Lan L, et al. Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics. Signal Transduct Target Ther 2022; 7:199. https://doi.org/10.1038/s41392-022-01056-1.

[205] Ward NS, Casserly B, Ayala A. The compensatory anti-inflammatory response syndrome (cars) in critically ill patients. Clin Chest Med 2008; 29:617-25, viii. https://doi.org/10.1016/j.ccm.2008.06.010.

[206] Chames P, Van Regenmortel M, Weiss E, Baty D. Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol 2009; 157:220-33. https://doi.org/10.1111/j.1476-5381.2009.00190.x.

[207] Gholami A, Mohkam M, Soleimanian S, Sadraeian M, Lauto A. Bacterial nanotechnology as a paradigm in targeted cancer therapeutic delivery and immunotherapy. Microsyst Nanoeng 2024; 10:113. https://doi.org/10.1038/s41378-024-00743-z.

[208] Adepu S, Ramakrishna S. Controlled drug delivery systems: current status and future directions. Molecules 2021; 26:5905. https://doi.org/10.3390/molecules26195905.

[209] Date AA, Hanes J, Ensign LM. Nanoparticles for oral delivery: design, evaluation and state-of-the-art. J Control Release 2016; 240:504-26. https://doi.org/10.1016/j.jconrel.2016.06.016.

[210] Li Z, Wang Y, Liu J, Rawding P, Bu J, Hong S, et al. Chemically and biologically engineered bacteria-based delivery systems for emerging diagnosis and advanced therapy. Adv Mater 2021; 33:e2102580. https://doi.org/10.1002/adma.202102580.

[211] Totter E, von Einsiedel E, Regazzoni L, Schuerle S. Paving the way for bacteria-based drug delivery: biohybrid microrobots emerging from microrobotics and synthetic biology. Adv Drug Deliv Rev 2025; 221:115577. https://doi.org/10.1016/j.addr.2025.115577.

[212] Cai Q, Guo R, Chen D, Deng Z, Gao J. Synbionanodesign: pioneering targeted drug delivery with engineered nanomaterials. J Nanobiotechnology 2025; 23:178. https://doi.org/10.1186/s12951-025-03254-9.

[213] Kick L, Kirchner M, Schneider S. Crispr-cas9: from a bacterial immune system to genome-edited human cells in clinical trials. Bioengineered 2017; 8:280-6. https://doi.org/10.1080/21655979.2017.1299834.

[214] Ansori AN, Antonius Y, Susilo RJ, Hayaza S, Kharisma VD, Parikesit AA, et al. Application of crispr-cas9 genome editing technology in various fields: a review. Narra J 2023; 3:e184. https://doi.org/10.52225/narra.v3i2.184.

[215] Ayanoglu FB, Elcin AE, Elcin YM. Bioethical issues in genome editing by crispr-cas9 technology. Turk J Biol 2020; 44:110-20. https://doi.org/10.3906/biy-1912-52.

[216] Li T, Li S, Kang Y, Zhou J, Yi M. Harnessing the evolving crispr/cas9 for precision oncology. J Transl Med 2024; 22:749. https://doi.org/10.1186/s12967-024-05570-4.

[217] Asmamaw M, Zawdie B. Mechanism and applications of crispr/cas-9-mediated genome editing. Biologics 2021; 15:353-61. https://doi.org/10.2147/BTT.S326422.

[218] Xu Y, Tian N, Shi H, Zhou C, Wang Y, Liang FS. A split crispr/cas13b system for conditional RNA regulation and editing. J Am Chem Soc 2023; 145:5561-9. https://doi.org/10.1021/jacs.3c01087.

[219] Kong X, Zhang H, Li G, Wang Z, Kong X, Wang L, et al. Engineered crispr-oscas12f1 and rhcas12f1 with robust activities and expanded target range for genome editing. Nat Commun 2023; 14:2046. https://doi.org/10.1038/s41467-023-37829-7.

[220] Zhao Z, Shang P, Mohanraju P, Geijsen N. Prime editing: advances and therapeutic applications. Trends Biotechnol 2023; 41:1000-12. https://doi.org/10.1016/j.tibtech.2023.03.004.

[221] Gelsinger DR, Vo PLH, Klompe SE, Ronda C, Wang HH, Sternberg SH. Bacterial genome engineering using crispr-associated transposases. Nat Protoc 2024; 19:752-90. https://doi.org/10.1038/s41596-023-00927-3.

[222] Villiger L, Joung J, Koblan L, Weissman J, Abudayyeh OO, Gootenberg JS. Author correction: Crispr technologies for genome, epigenome and transcriptome editing. Nat Rev Mol Cell Biol 2024; 25:510. https://doi.org/10.1038/s41580-024-00745-9.

[223] Du Y, Liu Y, Hu J, Peng X, Liu Z. Crispr/cas9 systems: delivery technologies and biomedical applications. Asian J Pharm Sci 2023; 18:100854. https://doi.org/10.1016/j.ajps.2023.100854.

[224] Bosco N, Goldberg A, Zhao X, Mays JC, Cheng P, Johnson AF, et al. Karyocreate: a crispr-based technology to study chromosome-specific aneuploidy by targeting human centromeres. Cell 2023; 186:1985-2001 e19. https://doi.org/10.1016/j.cell.2023.03.029.

[225] Lin X, Jiao R, Cui H, Yan X, Zhang K. Physiochemically and genetically engineered bacteria: instructive design principles and diverse applications. Adv Sci (Weinh) 2024; 11:e2403156. https://doi.org/10.1002/advs.202403156.

[226] Leenay RT, Vento JM, Shah M, Martino ME, Leulier F, Beisel CL. Genome editing with crispr-cas9 in lactobacillus plantarum revealed that editing outcomes can vary across strains and between methods. Biotechnol J 2019; 14:e1700583. https://doi.org/10.1002/biot.201700583.

[227] Choi HJ, Ahn JH, Park SH, Do KH, Kim J, Moon Y. Enhanced wound healing by recombinant Escherichia coli Nissle 1917 via human epidermal growth factor receptor in human intestinal epithelial cells: therapeutic implication using recombinant probiotics. Infect Immun 2012; 80:1079-87. https://doi.org/10.1128/IAI.05820-11.

[228] Chen H, Lei P, Ji H, Yang Q, Peng B, Ma J, et al. Advances in Escherichia coli Nissle 1917 as a customizable drug delivery system for disease treatment and diagnosis strategies. Mater Today Bio 2023; 18:100543. https://doi.org/10.1016/j.mtbio.2023.100543.

[229] Neumann A, Vollger L, Berends ET, Molhoek EM, Stapels DA, Midon M, et al. Novel role of the antimicrobial peptide ll-37 in the protection of neutrophil extracellular traps against degradation by bacterial nucleases. J Innate Immun 2014; 6:860-8. https://doi.org/10.1159/000363699.

[230] Zhang H, Zhang X, Liang S, Wang J, Zhu Y, Zhang W, et al. Bactericidal synergism between phage endolysin ply2660 and cathelicidin ll-37 against vancomycin-resistant enterococcus faecalis biofilms. NPJ Biofilms Microbiomes 2023; 9:16. https://doi.org/10.1038/s41522-023-00385-5.

[231] Shaykhiev R, Beisswenger C, Kandler K, Senske J, Puchner A, Damm T, et al. Human endogenous antibiotic ll-37 stimulates airway epithelial cell proliferation and wound closure. Am J Physiol Lung Cell Mol Physiol 2005; 289:L842-8. https://doi.org/10.1152/ajplung.00286.2004.

[232] Yamakami K, Tsumori H, Shimizu Y, Sakurai Y, Nagatoshi K, Sonomoto K. Cationic lipid content in liposome-encapsulated nisin improves sustainable bactericidal activity against streptococcus mutans. Open Dent J 2016; 10:360-6. https://doi.org/10.2174/1874210616021001360.

[233] Duc HM, Son HM, Ngan PH, Sato J, Masuda Y, Honjoh KI, et al. Isolation and application of bacteriophages alone or in combination with nisin against planktonic and biofilm cells of staphylococcus aureus. Appl Microbiol Biotechnol 2020; 104:5145-58. https://doi.org/10.1007/s00253-020-10581-4.

[234] Patrulea V, Borchard G, Jordan O. An update on antimicrobial peptides (amps) and their delivery strategies for wound infections. Pharmaceutics 2020; 12:840. https://doi.org/10.3390/pharmaceutics12090840.

[235] Ko J, Jun H, Chung H, Yoon C, Kim T, Kwon M, et al. Comparison of egf with vegf non-viral gene therapy for cutaneous wound healing of streptozotocin diabetic mice. Diabetes Metab J 2011;35:226-35. https://doi.org/10.4093/dmj.2011.35.3.226.

[236] Tejedor S, Wagberg M, Correia C, Avall K, Holtta M, Hultin L, et al. The combination of vascular endothelial growth factor a (vegf-a) and fibroblast growth factor 1 (fgf1) modified mrna improves wound healing in diabetic mice: An ex vivo and in vivo investigation. Cells 2024; 13:414. https://doi.org/10.3390/cells13050414.

[237] Vinores SA, Xiao WH, Aslam S, Shen J, Oshima Y, Nambu H, et al. Implication of the hypoxia response element of the Vegf promoter in mouse models of retinal and choroidal neovascularization, but not retinal vascular development. J Cell Physiol 2006; 206:749-58. https://doi.org/10.1002/jcp.20525.

[238] Liu Y, Cox SR, Morita T, Kourembanas S. Hypoxia regulates vascular endothelial growth factor gene expression in endothelial cells. Identification of a 5′ enhancer. Circ Res 1995; 77:638-43. https://doi.org/10.1161/01.res.77.3.638.

[239] Xia JB, Wu HY, Lai BL, Zheng L, Zhou DC, Chang ZS, et al. Gene delivery of hypoxia-inducible vegf targeting collagen effectively improves cardiac function after myocardial infarction. Sci Rep 2017; 7:13273. https://doi.org/10.1038/s41598-017-13547-1.

[240] Raheem A, Liang L, Zhang G, Cui S. Modulatory effects of probiotics during pathogenic infections with emphasis on immune regulation. Front Immunol 2021; 12:616713. https://doi.org/10.3389/fimmu.2021.616713.

[241] Pena JA, Rogers AB, Ge Z, Ng V, Li SY, Fox JG, et al. Probiotic lactobacillus spp. diminish helicobacter hepaticus-induced inflammatory bowel disease in interleukin-10-deficient mice. Infect Immun 2005; 73:912-20. https://doi.org/10.1128/IAI.73.2.912-920.2005.

[242] Azad MAK, Sarker M, Wan D. Immunomodulatory effects of probiotics on cytokine profiles. Biomed Res Int 2018; 2018:8063647. https://doi.org/10.1155/2018/8063647.

[243] Chattopadhyay S, Teixeira LBC, Kiessling LL, McAnulty JF, Raines RT. Bifunctional peptide that anneals to damaged collagen and clusters tgf-beta receptors enhances wound healing. ACS Chem Biol 2022; 17:314-21. https://doi.org/10.1021/acschembio.1c00745.

[244] Zhang B, Liu Y, Lan X, Xu X, Zhang X, Li X, et al. Oral Escherichia coli expressing il-35 meliorates experimental colitis in mice. J Transl Med 2018; 16:71. https://doi.org/10.1186/s12967-018-1441-7.

[245] Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science 2000; 289:1352-5. https://doi.org/10.1126/science.289.5483.1352.

[246] Steidler L, Neirynck S, Huyghebaert N, Snoeck V, Vermeire A, Goddeeris B, et al. Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10. Nat Biotechnol 2003; 21:785-9. https://doi.org/10.1038/nbt840.

[247] Gardlik R, Palffy R, Celec P. Recombinant probiotic therapy in experimental colitis in mice. Folia Biol (Praha) 2012; 58:238-45. https://doi.org/10.14712/fb2012058060238.

[248] del Carmen S, Moreno de LeBlanc A, Perdigon G, Bastos Pereira V, Miyoshi A, Azevedo V, et al. Evaluation of the anti-inflammatory effect of milk fermented by a strain of il-10-producing lactococcus lactis using a murine model of Crohn’s disease. J Mol Microbiol Biotechnol 2011; 21:138-46. https://doi.org/10.1159/000333830.

[249] Cui M, Pang G, Zhang T, Sun T, Zhang L, Kang R, et al. Optotheranostic nanosystem with phone visual diagnosis and optogenetic microbial therapy for ulcerative colitis at-home care. ACS Nano 2021; 15:7040-52. https://doi.org/10.1021/acsnano.1c00135.

[250] Benbouziane B, Ribelles P, Aubry C, Martin R, Kharrat P, Riazi A, et al. Development of a stress-inducible controlled expression (SICE) system in Lactococcus lactis for the production and delivery of therapeutic molecules at mucosal surfaces. J Biotechnol 2013; 168:120-9. https://doi.org/10.1016/j.jbiotec.2013.04.019.

[251] Amrofell MB, Rottinghaus AG, Moon TS. Engineering microbial diagnostics and therapeutics with smart control. Curr Opin Biotechnol 2020; 66:11-7. https://doi.org/10.1016/j.copbio.2020.05.006.

[252] Kumar L, Cox CR, Sarkar SK. Matrix metalloprotease-1 inhibits and disrupts enterococcus faecalis biofilms. PLoS One 2019; 14:e0210218. https://doi.org/10.1371/journal.pone.0210218.

[253] Krishnaswamy VR, Mintz D, Sagi I. Matrix metalloproteinases: the sculptors of chronic cutaneous wounds. Biochim Biophys Acta Mol Cell Res 2017; 1864:2220-7. https://doi.org/10.1016/j.bbamcr.2017.08.003.

[254] Vatansever F, de Melo WC, Avci P, Vecchio D, Sadasivam M, Gupta A, et al. Antimicrobial strategies centered around reactive oxygen species-bactericidal antibiotics, photodynamic therapy, and beyond. FEMS Microbiol Rev 2013; 37:955-89. https://doi.org/10.1111/1574-6976.12026.

[255] Gonzalez-Flecha B, Demple B . Genetic responses to free radicals. Homeostasis and gene control. Ann N Y Acad Sci 2000; 899:69-87. https://doi.org/10.1111/j.1749-6632.2000.tb06177.x.

[256] Pomposiello PJ, Demple B. Global adjustment of microbial physiology during free radical stress. Adv Microb Physiol 2002; 46:319-41. https://doi.org/10.1016/s0065-2911(02)46007-9.

[257] Zarur M, Seijo-Rabina A, Goyanes A, Concheiro A, Alvarez-Lorenzo C. Ph-responsive scaffolds for tissue regeneration: in vivo performance. Acta Biomater 2023; 168:22-41. https://doi.org/10.1016/j.actbio.2023.07.025.

[258] Joorabloo A, Liu T. Smart theranostics for wound monitoring and therapy. Adv Colloid Interf Sci 2024; 330:103207. https://doi.org/10.1016/j.cis.2024.103207.

[259] Li L, Wang Y, Huang Z, Xu Z, Cao R, Li J, et al. An additive-free multifunctional beta-glucan-peptide hydrogel participates in the whole process of bacterial-infected wound healing. J Control Release 2023; 362:577-90. https://doi.org/10.1016/j.jconrel.2023.09.010.

[260] Rottinghaus AG, Ferreiro A, Fishbein SRS, Dantas G, Moon TS. Genetically stable crispr-based kill switches for engineered microbes. Nat Commun 2022; 13:672. https://doi.org/10.1038/s41467-022-28163-5.

[261] Tao J, Bauer DE, Chiarle R. Assessing and advancing the safety of crispr-cas tools: from DNA to RNA editing. Nat Commun 2023; 14:212. https://doi.org/10.1038/s41467-023-35886-6.

[262] Barber HM, Pater AA, Gagnon KT, Damha MJ, O’Reilly D. Chemical engineering of crispr-cas systems for therapeutic application. Nat Rev Drug Discov 2025; 24:209-30. https://doi.org/10.1038/s41573-024-01086-0.

[263] Alariqi M, Ramadan M, Yu L, Hui F, Hussain A, Zhou X, et al. Enhancing specificity, precision, accessibility, flexibility, and safety to overcome traditional crispr/cas editing challenges and shape future innovations. Adv Sci (Weinh) 2025; 12:e2416331. https://doi.org/10.1002/advs.202416331.

[264] Lei T, Wang Y, Zhang Y, Yang Y, Cao J, Huang J, et al. Leveraging crispr gene editing technology to optimize the efficacy, safety and accessibility of car t-cell therapy. Leukemia 2024; 38:2517-43. https://doi.org/10.1038/s41375-024-02444-y.

[265] Morshedzadeh F, Ghanei M, Lotfi M, Ghasemi M, Ahmadi M, Najari-Hanjani P, et al. An update on the application of crispr technology in clinical practice. Mol Biotechnol 2024; 66:179-97. https://doi.org/10.1007/s12033-023-00724-z.

[266] Lee J-H, Chin SM, Mach KE, Bobenchik AM, Liao JC, Yang S, et al. Translating microbiota analysis for clinical applications. Nat Rev Bioeng 2024; 2:284-6. https://doi.org/10.1038/s44222-024-00168-3.

[267] U.S. Food and Drug Administration (FDA) . Early clinical trials with live biotherapeutic products: Chemistry, manufacturing, and control information. U.S. Department of Health and Human Services, Silver Spring, MD. 2016.

[268] European Medicines Agency (EMA) . Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells (EMA/CAT/GTWP/671639/2008). European Medicines Agency, London, UK. 2012.

[269] Wang H, Wang J, Zhao X, Ye R, Sun L, Wang J, et al. Discovery of an anti-tnf-alpha 9-mer peptide from a t7 phage display library for the treatment of inflammatory bowel disease. J Med Chem 2023; 66:6981-93. https://doi.org/10.1021/acs.jmedchem.3c00436.

[270] Wang X, Yang G, Li S, Gao M, Zhao P, Zhao L. The escherichia coli-derived thymosin beta4 concatemer promotes cell proliferation and healing wound in mice. Biomed Res Int 2013; 2013:241721. https://doi.org/10.1155/2013/241721.

[271] Pitt N, Morrissette M, Gates MF, Bargabos R, Krumpoch M, Hawkins B, et al. Bacterial membrane vesicles restore gut anaerobiosis. NPJ Biofilms Microbiomes 2025; 11:48. https://doi.org/10.1038/s41522-025-00676-z.

[272] Cucci LM, Satriano C, Marzo T, La Mendola D. Angiogenin and copper crossing in wound healing. Int J Mol Sci 2021; 22:10704. https://doi.org/10.3390/ijms221910704.

[273] Custodio CA, Mano JF. Cell surface engineering to control cellular interactions. ChemNanoMat 2016; 2:376-84. https://doi.org/10.1002/cnma.201600047.

[274] Kim JH, Yang B, Tedesco A, Lebig EGD, Ruegger PM, Xu K, et al. High levels of oxidative stress and skin microbiome are critical for initiation and development of chronic wounds in diabetic mice. Sci Rep 2019; 9:19318. https://doi.org/10.1038/s41598-019-55644-3.

[275] Gao T, Wang X, Li Y, Ren F. The role of probiotics in skin health and related gut-skin axis: a review. Nutrients 2023; 15:3123. https://doi.org/10.3390/nu15143123.

[276] Zhang M, Dong Q, Yang K, Chen R, Zhang J, Xiao P, et al. Hyaluronic acid hydrogels with excellent self-healing capacity and photo-enhanced mechanical properties for wound healing. Int J Biol Macromol 2024; 267:131235. https://doi.org/10.1016/j.ijbiomac.2024.131235.

[277] Chelu M, Calderon Moreno JM, Musuc AM, Popa M. Natural regenerative hydrogels for wound healing. Gels 2024; 10:547. https://doi.org/10.3390/gels10090547.

[278] Jiang L, Ding L, Liu G. Nanoparticle formulations for therapeutic delivery, pathogen imaging and theranostic applications in bacterial infections. Theranostics 2023; 13:1545-70. https://doi.org/10.7150/thno.82790.

[279] Beach MA, Nayanathara U, Gao Y, Zhang C, Xiong Y, Wang Y, et al. Polymeric nanoparticles for drug delivery. Chem Rev 2024; 124:5505-616. https://doi.org/10.1021/acs.chemrev.3c00705.

[280] Anisha BS, Biswas R, Chennazhi KP, Jayakumar R . Chitosan-hyaluronic acid/nano silver composite sponges for drug resistant bacteria infected diabetic wounds. Int J Biol Macromol 2013; 62:310-20. https://doi.org/10.1016/j.ijbiomac.2013.09.011.

[281] Liu X, Peng S, Pei Y, Huo Y, Zong Y, Ren J, et al. Facile fabrication of chitosan/hyaluronic acid hydrogel-based wound closure material co-loaded with gold nanoparticles and fibroblast growth factor to improve anti-microbial and healing efficiency in diabetic wound healing and nursing care. Regen Ther 2024; 26:1018-29. https://doi.org/10.1016/j.reth.2024.10.003.

[282] Bhattacharya M, Spencer BL, Kwiecinski JM, Podkowik M, Putzel G, Pironti A, et al. Collagen binding adhesin restricts staphylococcus aureus skin infection. bioRxiv. [Preprint]2024. https://doi.org/10.1101/2024.11.01.621145.

[283] Fu FS, Chen HH, Chen Y, Yuan Y, Zhao Y, Yu A, et al. Engineered bacillus subtilis enhances bone regeneration via immunoregulation and anti-infection. Bioact Mater 2025; 46:503-15. https://doi.org/10.1016/j.bioactmat.2025.01.003.

[284] Bellis SL. Advantages of rgd peptides for directing cell association with biomaterials. Biomaterials 2011; 32:4205-10. https://doi.org/10.1016/j.biomaterials.2011.02.029.

[285] Zhang D, Chia C, Jiao X, Jin W, Kasagi S, Wu R, et al. D-mannose induces regulatory t cells and suppresses immunopathology. Nat Med 2017; 23:1036-45. https://doi.org/10.1038/nm.4375.

[286] Liu H, Gu R, Zhu Y, Lian X, Wang S, Liu X, et al. D-mannose attenuates bone loss in mice via treg cell proliferation and gut microbiota-dependent anti-inflammatory effects. Ther Adv Chronic Dis 2020; 11:2040622320912661. https://doi.org/10.1177/2040622320912661.

[287] Zhang W, Cheng H, Gui Y, Zhan Q, Li S, Qiao W, et al. Mannose treatment: a promising novel strategy to suppress inflammation. Front Immunol 2021; 12:756920. https://doi.org/10.3389/fimmu.2021.756920.

[288] Tian T, Zhang HX, He CP, Fan S, Zhu YL, Qi C, et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials 2018; 150:137-49. https://doi.org/10.1016/j.biomaterials.2017.10.012.

[289] Carmona-Ribeiro AM, de Melo Carrasco LD . Cationic antimicrobial polymers and their assemblies. Int J Mol Sci 2013; 14:9906-46. https://doi.org/10.3390/ijms14059906.

[290] Sayed MA, El-Rahman T, Abdelsalam HK, El-Souad S, Shady RM, Amen RA, et al. Biosynthesis of silver, copper, and their bi-metallic combination of nanocomposites by staphylococcus aureus: their antimicrobial, anticancer activity, and cytotoxicity effect. Indian J Microbiol 2024; 64:1721-37. https://doi.org/10.1007/s12088-024-01229-2.

[291] Kugler R, Bouloussa O, Rondelez F. Evidence of a charge-density threshold for optimum efficiency of biocidal cationic surfaces. Microbiology (Reading) 2005; 151:1341-8. https://doi.org/10.1099/mic.0.27526-0.

[292] Pfaffenroth C, Winkel A, Dempwolf W, Gamble LJ, Castner DG, Stiesch M, et al. Self-assembled antimicrobial and biocompatible copolymer films on titanium. Macromol Biosci 2011; 11:1515-25. https://doi.org/10.1002/mabi.201100124.

[293] Caro A, Humblot V, Methivier C, Minier M, Salmain M, Pradier CM. Grafting of lysozyme and/or poly(ethylene glycol) to prevent biofilm growth on stainless steel surfaces. J Phys Chem B 2009; 113:2101-9. https://doi.org/10.1021/jp805284s.

[294] Song J, Kang H, Lee C, Hwang SH, Jang J. Aqueous synthesis of silver nanoparticle embedded cationic polymer nanofibers and their antibacterial activity. ACS Appl Mater Interfaces 2012; 4:460-5. https://doi.org/10.1021/am201563t.

[295] Cao H, Liu X. Silver nanoparticles-modified films versus biomedical device-associated infections. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2010; 2:670-84. https://doi.org/10.1002/wnan.113.

[296] Seil JT, Webster TJ. Antimicrobial applications of nanotechnology: methods and literature. Int J Nanomedicine 2012; 7:2767-81. https://doi.org/10.2147/IJN.S24805.

[297] Vijayakumar G, Kim HJ, Rangarajulu SK. In vitro antibacterial and wound healing activities evoked by silver nanoparticles synthesized through probiotic bacteria. Antibiotics (Basel) 2023; 12:141. https://doi.org/10.3390/antibiotics12010141.

[298] Hu C, He G, Yang Y, Wang N, Zhang Y, Su Y, et al. Nanomaterials regulate bacterial quorum sensing: applications, mechanisms, and optimization strategies. Adv Sci (Weinh) 2024; 11:e2306070. https://doi.org/10.1002/advs.202306070.

[299] Wang X, Chen C, Hu J, Liu C, Ning Y, Lu F. Current strategies for monitoring and controlling bacterial biofilm formation on medical surfaces. Ecotoxicol Environ Saf 2024; 282:116709. https://doi.org/10.1016/j.ecoenv.2024.116709.

[300] Dediu V, Ghitman J, Gradisteanu Pircalabioru G, Chan KH, Iliescu FS, Iliescu C. Trends in photothermal nanostructures for antimicrobial applications. Int J Mol Sci 2023; 24:9375. https://doi.org/10.3390/ijms24119375.

[301] Yougbare S, Mutalik C, Krisnawati DI, Kristanto H, Jazidie A, Nuh M, et al. Nanomaterials for the photothermal killing of bacteria. Nanomaterials (Basel) 2020; 10:1123. https://doi.org/10.3390/nano10061123.

[302] Lei L, Pan W, Shou X, Shao Y, Ye S, Zhang J, et al. Nanomaterials-assisted gene editing and synthetic biology for optimizing the treatment of pulmonary diseases. J Nanobiotechnology 2024; 22:343. https://doi.org/10.1186/s12951-024-02627-w.

[303] Hung YP, Chen YF, Tsai PJ, Huang IH, Ko WC, Jan JS. Advances in the application of nanomaterials as treatments for bacterial infectious diseases. Pharmaceutics 2021; 13:1913. https://doi.org/10.3390/pharmaceutics13111913.

[304] Huang Y, Guo X, Wu Y, Chen X, Feng L, Xie N, et al. Nanotechnology’s frontier in combatting infectious and inflammatory diseases: prevention and treatment. Signal Transduct Target Ther 2024; 9:34. https://doi.org/10.1038/s41392-024-01745-z.

[305] Pham SH, Choi Y, Choi J. Stimuli-responsive nanomaterials for application in antitumor therapy and drug delivery. Pharmaceutics 2020; 12:630. https://doi.org/10.3390/pharmaceutics12070630.

[306] Wang Y, Chen L, Wang Y, Wang X, Qian D, Yan J, et al. Marine biomaterials in biomedical nano/micro-systems. J Nanobiotechnology 2023; 21:408. https://doi.org/10.1186/s12951-023-02112-w.

[307] Mei L, Zhang Y, Wang K, Chen S, Song T. Nanomaterials at the forefront of antimicrobial therapy by photodynamic and photothermal strategies. Mater Today Bio 2024; 29:101354. https://doi.org/10.1016/j.mtbio.2024.101354.

[308] He L, Di D, Chu X, Liu X, Wang Z, Lu J, et al. Photothermal antibacterial materials to promote wound healing. J Control Release 2023; 363:180-200. https://doi.org/10.1016/j.jconrel.2023.09.035.

[309] Maldonado-Carmona N, Marchand G, Villandier N, Ouk TS, Pereira MM, Calvete MJF, et al. Porphyrin-loaded lignin nanoparticles against bacteria: a photodynamic antimicrobial chemotherapy application. Front Microbiol 2020; 11:606185. https://doi.org/10.3389/fmicb.2020.606185.

[310] Elashnikov R, Radocha M, Panov I, Rimpelova S, Ulbrich P, Michalcova A, et al. Porphyrin-silver nanoparticles hybrids: synthesis, characterization and antibacterial activity. Mater Sci Eng C Mater Biol Appl 2019; 102:192-9. https://doi.org/10.1016/j.msec.2019.04.029.

[311] Chappell TC, Nair NU. Engineered lactobacilli display antibiofilm and growth suppressing activities against pseudomonas aeruginosa. NPJ Biofilms Microbiomes 2020; 6:48. https://doi.org/10.1038/s41522-020-00156-6.

[312] Liu H, Tang L, Yin Y, Cao Y, Fu C, Feng J, et al. Photoresponsive multirole nanoweapon camouflaged by hybrid cell membrane vesicles for efficient antibacterial therapy of pseudomonas aeruginosa-infected pneumonia and wound. Adv Sci (Weinh) 2024; 11:e2403101. https://doi.org/10.1002/advs.202403101.

[313] Lin X, Zhang X, Wang Y, Chen W, Zhu Z, Wang S. Hydrogels and hydrogel-based drug delivery systems for promoting refractory wound healing: applications and prospects. Int J Biol Macromol 2025; 285:138098. https://doi.org/10.1016/j.ijbiomac.2024.138098.

[314] Huang C, Dong L, Zhao B, Lu Y, Huang S, Yuan Z, et al. Anti-inflammatory hydrogel dressings and skin wound healing. Clin Transl Med 2022; 12:e1094. https://doi.org/10.1002/ctm2.1094.

[315] Vo DK, Trinh KTL. Advances in wearable biosensors for wound healing and infection monitoring. Biosensors (Basel) 2025; 15:139. https://doi.org/10.3390/bios15030139.

[316] Weigelt MA, Lev-Tov HA, Tomic-Canic M, Lee WD, Williams R, Strasfeld D, et al. Advanced wound diagnostics: toward transforming wound care into precision medicine. Adv Wound Care (New Rochelle) 2022; 11:330-59. https://doi.org/10.1089/wound.2020.1319.

[317] Ji H, Peng R, Jin L, Ma J, Yang Q, Sun D, et al. Recent advances in ros-sensitive nano-formulations for atherosclerosis applications. Pharmaceutics 2021; 13:1452. https://doi.org/10.3390/pharmaceutics13091452.

[318] Friedrich RP, Cicha I, Alexiou C. Iron oxide nanoparticles in regenerative medicine and tissue engineering. Nanomaterials (Basel) 2021; 11:2337. https://doi.org/10.3390/nano11092337.

[319] Estelrich J, Escribano E, Queralt J, Busquets MA. Iron oxide nanoparticles for magnetically-guided and magnetically-responsive drug delivery. Int J Mol Sci 2015; 16:8070-101. https://doi.org/10.3390/ijms16048070.

[320] Wang F, Wu Q, Jia G, Kong L, Zuo R, Feng K, et al. Black phosphorus/mno(2) nanocomposite disrupting bacterial thermotolerance for efficient mild-temperature photothermal therapy. Adv Sci (Weinh) 2023; 10:e2303911. https://doi.org/10.1002/advs.202303911.

[321] Chen S, Xie Y, Ma K, Wei Z, Ran X, Fu X, et al. Electrospun nanofibrous membranes meet antibacterial nanomaterials: from preparation strategies to biomedical applications. Bioact Mater 2024; 42:478-518. https://doi.org/10.1016/j.bioactmat.2024.09.003.

[322] Leistikow KR, May DS, Suh WS, Vargas Asensio G, Schaenzer AJ, Currie CR, et al. Bacillus subtilis-derived peptides disrupt quorum sensing and biofilm assembly in multidrug-resistant staphylococcus aureus. mSystems 2024; 9:e0071224. https://doi.org/10.1128/msystems.00712-24.

[323] Huebner C, Ding Y, Petermann I, Knapp C, Ferguson LR. The probiotic escherichia coli nissle 1917 reduces pathogen invasion and modulates cytokine expression in caco-2 cells infected with Crohn’s disease-associated E. coli lf82. Appl Environ Microbiol 2011; 77:2541-4. https://doi.org/10.1128/AEM.01601-10.

[324] Hoque ME, Shafoyat MU. Self-healing polymer nanocomposite films and coatings. Polymer Nanocomposite Films and Coatings 2024;181-217. https://doi.org/10.1016/B978-0-443-19139-8.00010-3.

[325] Smirnov MA, Nikolaeva AL, Bobrova NV, Vorobiov VK, Smirnov AV, Lahderanta E, et al. Self-healing films based on chitosan containing citric acid/choline chloride deep eutectic solvent. Polym Test 2021; 97:107156. https://doi.org/10.1016/j.polymertesting.2021.107156.

[326] Saghazadeh S, Rinoldi C, Schot M, Kashaf SS, Sharifi F, Jalilian E, et al. Drug delivery systems and materials for wound healing applications. Adv Drug Deliv Rev 2018; 127:138-66. https://doi.org/10.1016/j.addr.2018.04.008.

[327] Xue Y, Zhou J, Lu Y, Zhang H, Chen B, Dong S, et al. Advancements in wound management: microenvironment-sensitive bioactive dressings with on-demand regulations for diabetic wounds. Engineering 2025; 48:234-61. https://doi.org/10.1016/j.eng.2025.01.018.

[328] Zhou H, Zhang Z, Liu Z, Sa G, Jiang M, Zou Z, et al. Single-cell analysis reveals fibroblast-derived migrasomes as cxcl12 carriers promoting skin wound repair. J Extracell Vesicles 2025; 14:e70112. https://doi.org/10.1002/jev2.70112.

[329] Marcel, Martínez-Porchas FV-A, Garibay-Valdez E . Genetic improvement of a synthetic microbiota: a step further? Front Microbiol 2025; 16:1619874. https://doi.org/10.3389/fmicb.2025.1619874.

[330] Xu R, Yu Y, Chen T. Exploring the dark side of probiotics to pursue light: intrinsic and extrinsic risks to be opportunistic pathogens. Curr Res Food Sci 2025; 10:101044. https://doi.org/10.1016/j.crfs.2025.101044.

[331] Boumis E, Capone A, Galati V, Venditti C, Petrosillo N. Probiotics and infective endocarditis in patients with hereditary hemorrhagic telangiectasia: a clinical case and a review of the literature. BMC Infect Dis 2018; 18:65. https://doi.org/10.1186/s12879-018-2956-5.

[332] Costa RL, Moreira J, Lorenzo A, Lamas CC. Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series. BMC Complement Altern Med 2018; 18:329. https://doi.org/10.1186/s12906-018-2394-3.

[333] Han C, Song J, Hu J, Fu H, Feng Y, Mu R, et al. Smectite promotes probiotic biofilm formation in the gut for cancer immunotherapy. Cell Rep 2021; 34:108706. https://doi.org/10.1016/j.celrep.2021.108706.

[334] Suez J, Zmora N, Zilberman-Schapira G, Mor U, Dori-Bachash M, Bashiardes S, et al. Post-antibiotic gut mucosal microbiome reconstitution is impaired by probiotics and improved by autologous fmt. Cell 2018; 174:1406-23.e16. https://doi.org/10.1016/j.cell.2018.08.047.

[335] Su J, Wu Y, Wang Z, Zhang D, Yang X, Zhao Y, et al. Probiotic biofilm modified scaffolds for facilitating osteomyelitis treatment through sustained release of bacteriophage and regulated macrophage polarization. Mater Today Bio 2025; 30:101444. https://doi.org/10.1016/j.mtbio.2025.101444.

[336] Su J, Gu H, Huang X, Yuan Y, Zhao Y, Yang F, et al. Probiotic biofilm modified bioceramics for bone defect healing via osteogenesis, angiogenesis, and immune modulation. Front Pharmacol 2025; 16:1588023. https://doi.org/10.3389/fphar.2025.1588023.

[337] Huang B, Xiao F, Chen Z, Hu T, Qiu R, Wang W, et al. Coaxial electrospun nanofiber accelerates infected wound healing via engineered probiotic biofilm. Int J Biol Macromol 2024; 279:135100. https://doi.org/10.1016/j.ijbiomac.2024.135100.

[338] Wright O, Stan GB, Ellis T. Building-in biosafety for synthetic biology. Microbiology (Reading) 2013; 159:1221-35. https://doi.org/10.1099/mic.0.066308-0.

[339] Riglar DT, Silver PA. Engineering bacteria for diagnostic and therapeutic applications. Nat Rev Microbiol 2018; 16:214-25. https://doi.org/10.1038/nrmicro.2017.172.

[340] Tauch A, Gotker S, Puhler A, Kalinowski J, Thierbach G. The alanine racemase gene alr is an alternative to antibiotic resistance genes in cloning systems for industrial corynebacterium glutamicum strains. J Biotechnol 2002; 99:79-91. https://doi.org/10.1016/s0168-1656(02)00159-1.

[341] Whitford CM, Dymek S, Kerkhoff D, Marz C, Schmidt O, Edich M, et al. Auxotrophy to xeno-DNA: An exploration of combinatorial mechanisms for a high-fidelity biosafety system for synthetic biology applications. J Biol Eng 2018; 12:13. https://doi.org/10.1186/s13036-018-0105-8.

[342] Kato Y. An engineered bacterium auxotrophic for an unnatural amino acid: a novel biological containment system. PeerJ 2015; 3:e1247. https://doi.org/10.7717/peerj.1247.

[343] Chacon O, Feng Z, Harris NB, Caceres NE, Adams LG, Barletta RG. Mycobacterium smegmatis d-alanine racemase mutants are not dependent on d-alanine for growth. Antimicrob Agents Chemother 2002; 46:47-54. https://doi.org/10.1128/AAC.46.2.47-54.2002.

[344] Stirling F, Bitzan L, O’Keefe S, Redfield E, Oliver JWK, Way J, et al. Rational design of evolutionarily stable microbial kill switches. Mol Cell 2018; 72:395. https://doi.org/10.1016/j.molcel.2018.10.002.

[345] Gamper M, Kast P. Strategy for chromosomal gene targeting in reca-deficient escherichia coli strains. Biotechniques 2005; 38:405-8. https://doi.org/10.2144/05383ST03.

[346] Kingston AW, Roussel-Rossin C, Dupont C, Raleigh EA. Correction: novel reca-independent horizontal gene transfer in escherichia coli k-12. PLoS One 2015; 10:e0143991. https://doi.org/10.1371/journal.pone.0143991.

[347] Guo P, Wang S, Yue H, Zhang X, Ma G, Li X, et al. Advancement of engineered bacteria for orally delivered therapeutics. Small 2023; 19:e2302702. https://doi.org/10.1002/smll.202302702.

[348] Salmikangas P, Schuessler-Lenz M, Ruiz S, Celis P, Reischl I, Menezes-Ferreira M, et al. Marketing regulatory oversight of advanced therapy medicinal products (atmps) in Europe: the ema/cat perspective. Adv Exp Med Biol 2015; 871:103-30. https://doi.org/10.1007/978-3-319-18618-4_6.

[349] Renner M, Anliker B, Sanzenbacher R, Schuele S. Regulation of clinical trials with advanced therapy medicinal products in Germany. Adv Exp Med Biol 2015; 871:87-101. https://doi.org/10.1007/978-3-319-18618-4_5.

[350] Zhou Y, Han Y. Engineered bacteria as drug delivery vehicles: principles and prospects. Eng Microbiol 2022; 2:100034. https://doi.org/10.1016/j.engmic.2022.100034.

[351] Sun X, Zhang Y, Ma C, Yuan Q, Wang X, Wan H, et al. A review of recent advances in flexible wearable sensors for wound detection based on optical and electrical sensing. Biosensors (Basel) 2022; 12:10. https://doi.org/10.3390/bios12010010.

[352] Cheng S, Gu Z, Zhou L, Hao M, An H, Song K, et al. Recent progress in intelligent wearable sensors for health monitoring and wound healing based on biofluids. Front Bioeng Biotechnol 2021; 9:765987. https://doi.org/10.3389/fbioe.2021.765987.

[353] Tang N, Zheng Y, Jiang X, Zhou C, Jin H, Jin K, et al. Wearable sensors and systems for wound healing-related ph and temperature detection. Micromachines (Basel) 2021; 12:430. https://doi.org/10.3390/mi12040430.

[354] Pusta A, Tertis M, Cristea C, Mirel S. Wearable sensors for the detection of biomarkers for wound infection. Biosensors (Basel) 2022; 12:1. https://doi.org/10.3390/bios12010001.

[355] Patel S, Ershad F, Zhao M, Isseroff RR, Duan B, Zhou Y, et al. Wearable electronics for skin wound monitoring and healing. Soft Sci 2022; 2:9. https://doi.org/10.20517/ss.2022.13.

[356] Bao S, Wang Y, Yao L, Chen S, Wang X, Luo Y, et al. Research trends and hot topics of wearable sensors in wound care over past 18 years: a bibliometric analysis. Heliyon 2024; 10:e38762. https://doi.org/10.1016/j.heliyon.2024.e38762.

[357] Kalasin S, Sangnuang P, Surareungchai W. Intelligent wearable sensors interconnected with advanced wound dressing bandages for contactless chronic skin monitoring: artificial intelligence for predicting tissue regeneration. Anal Chem 2022; 94:6842-52. https://doi.org/10.1021/acs.analchem.2c00782.

[358] Mimee M, Nadeau P, Hayward A, Carim S, Flanagan S, Jerger L, et al. An ingestible bacterial-electronic system to monitor gastrointestinal health. Science 2018; 360:915-8. https://doi.org/10.1126/science.aas9315.

[359] Liu B, Kim E, Meggo A, Gandhi S, Luo H, Kallakuri S, et al. Enhanced biocompatibility of neural probes by integrating microstructures and delivering anti-inflammatory agents via microfluidic channels. J Neural Eng 2017; 14:026008. https://doi.org/10.1088/1741-2552/aa52dc.

[360] Roslan MAM, Omar MN, Sharif NAM, Raston NHA, Arzmi MH, Neoh HM, et al. Recent advances in single-cell engineered live biotherapeutic products research for skin repair and disease treatment. NPJ Biofilms Microbiomes 2023; 9:95. https://doi.org/10.1038/s41522-023-00463-8.