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    Topic review

    Porphyrinoid Photosensitizers

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    The use of photodynamic therapy (PDT) to eradicate microorganisms has been regarded as a promising alternative to anti-infective therapies, such as those based on antibiotics, and more recently, is being considered for skin wound-healing. Among the several molecules exploited as photosensitizers (PS), porphyrinoids exhibit suitable features for achieving those goals efficiently. The capability that these macrocycles display to generate reactive oxygen species (ROS) gives a significant contribution to the regenerative process. ROS are responsible for avoiding the development of infections by inactivating microorganisms such as bacteria but also by promoting cell proliferation through the activation of stem cells which regulates inflammatory factors and collagen remodeling. The PS can act solo or combined with several materials, such as polymers, hydrogels, nanotubes, or metal-organic frameworks (MOF), keeping both the microbial photoinactivation and healing/regenerative processes’ effectiveness. 

    1. Introduction

    Porphyrins and analogs are a class of N-heterocyclic macrocycles well-known for their mediation in important biological functions, such as respiration and photosynthesis, but also by their role in a wide range of clinical and non-clinical applications that have high impacts on human life [1][2][3]. Natural tetrapyrrolic macrocycles like heme (iron(II) complex of PP-IX) and chlorophylls (Figure 1), but also the synthetic porphyrins and analogs ones (e.g., benzoporphyrins, chlorins, phthalocyanines) [4][5] are recognized to present unique structural, physicochemical, and photochemical features to be used in the development of dyes for dye-sensitized solar cells (DSSC) [6][7][8][9][10][11][12][13], (chemo) sensors [14][15][16][17][18][19][20], (photo)catalysts [21][22][23][24][25][26][27], biomarkers [14][28][29] or as therapeutic photosensitizers (PS) [30][31][32][33][34][35][36][37][38][39][40], among other applications [1].

    Figure 1. General structure of the porphyrinic nucleus and natural derivatives, such as chlorophyll a and b, and heme.

    The strong absorption usually exhibited by these highly conjugated aromatic compounds in the visible region (Figure 2A) and their ability to generate reactive oxygen species (ROS), such as oxygen singlet (1O2), under light irradiation and in the presence of dioxygen (Figure 2B) are particularly relevant for their success to mediate the photodynamic process in photodynamic therapy (PDT) against tumoral cells [33][36][41][42], but also toward non-oncological pathologies, such as age-related macular degeneration. In the last two decades, porphyrinoids (either as free-base or coordinated with different metals) have been recognized as highly efficient PS to eradicate a broad range of microorganisms including drug-resistant strains using the same concept of PDT [31][37][43][44][45][46][47][48][49][50].

    Figure 2. (A) Electromagnetic spectrum and typical absorption spectrum of porphyrins (blue line), chlorins (green line) and phthalocyanines (red line). (B) Simplified Jablonski diagram and reactive oxygen species (ROS) generation.

    2. PDT

    For the photodynamic process to occur, the PS is first activated with light at an appropriate wavelength, and promoted to an excited singlet state (Figure 2). When returning to its stable ground state, the excess energy can be released by emitting light in the form of fluorescence or by heat production (internal conversion). Alternatively, the excited 1PS* can undergo the so-called “intersystem crossing process”, affording the excited triplet state (3PS*). In this excited state, the PS can transfer their energy directly to dioxygen (3O2) (Type II mechanism), returning to the singlet ground state (1PS) and/or undergoes electron transfer reactions (Type I mechanism) to biological substrate molecules, leading to the formation of radicals and consequently, other reactive oxygen species (ROS), such as hydroxyl radical (OH), superoxide anion radical (O2), and hydrogen peroxide (H2O2) (Figure 2B) [51][52][53]. Such radicals are then responsible for the elimination of undesirable bacteria.

    Recently, the potential of PDT for tissue regeneration has caught the attention of many research groups concerning the role of non-porphyrinoid PS for skin wound healing, as was recently highlighted in our previous review [54]. In that review article, it is discussed that the PDT process not only enhances the mitochondrial activity, respiratory chain, and ATP synthesis [52][55], but also recruits important metalloproteinases (MMP)/growth factors (GF) and activate signal-regulated kinases [56][57] that are critical for the differentiation and proliferation of skin cells (such as fibroblasts) and extracellular matrix (ECM) components (such as elastin and collagen) [53][56][57][58] (Figure 3). However, bacterial infections are still the major issue during skin wound healing, being responsible for unsuccessful regenerative processes [59]. This is the main reason that makes PDT an attractive approach to eradicate bacterial infections in situ, while promoting local proliferation of healthy tissue. One of the major challenges is fine-tuning the structural and photophysical properties of PS to have strong absorption in the ideal “phototherapeutic window” (wavelengths ranging from 600 to 800 nm) where the light penetration in the tissue is high. In fact, most of the porphyrinoid-based PS described as effective for wound healing absorb in this region (Figure 2).


    Figure 3. Schematic representation of tetrapyrrolic macrocycles photosensitizers (PS) contribution for wound healing.

    The PS studies comprised (i) first-generation, consisting of mixtures obtained from natural occurring porphyrins (e.g., hematoporphyrin derivative, Photofrin); (ii) second-generation, such as porphyrins, chlorins, benzoporphyrins and phthalocyanines with pure structures; and (iii) third-generation, resulting from the combination of second-generation PS with specific delivery carriers, such as antibodies, liposomes, polymers, nanoparticles, and micelles to overcome the drawbacks of the other two PS generations, such as low accumulation on the desired site, self-aggregation and low solubility in aqueous media [46][59][60].

    The increasing number of publications embracing tetrapyrrolic macrocycles as PS for skin wound healing prompts us to compile these works separate from our previous publication where the non-porphyrinoids PS were the target [54]. Herein, this review will focus on the use of tetrapyrrolic macrocycles, namely porphyrins, chlorins, and phthalocyanines, as PS for skin wound healing, with some of them clinically approved (e.g., Hematoporphyrin derivative, Photofrin®, Foscan®, Fotoditazin®, Visudyne®) but also on the approved prodrugs 5-aminolevulinic acid (Levulan®) and derivatives (Metvix® (methyl ester derivative) and Hexvix® (hexyl ester derivative)) as precursors of endogenous PP-IX. This review is organized according to the structural features of each PS and, to facilitate the discussion, the macrocycles obtained from natural sources were separated from the synthetic ones.

    3. Final Remarks

    In summary, PDI with porphyrinoids-based photosensitizers exhibits great potential for the treatment of skin wounds, by enhancing healing in bacteria-infected wounds. Noticeably, in recent years, significant efforts were performed by the scientific community to improve the use of tetrapyrrolic macrocycles in skin wound healing. The capability of porphyrinoids to act as efficient PS (Table 1) relies on their capability to generate ROS when irradiated at wavelengths comprised in the “therapeutic window”.

    The different PS can be used solo, modified with appropriate units (ex. chlorin derivatives modified with poly-Lysine or incorporated into micelles to increase their lipophilicity), or incorporated and conjugated with other molecules (ex. immobilization in polymeric templates). In fact, the reported studies show that the pathway to improving the efficiency of porphyrin-based PS in skin wound healing passes throughout the exploitation of using PS immobilized/supported into solid matrixes. This strategy is more advantageous since it allows to merge the features of both PS and matrix.

    The use of (bio)polymers, such as chitosan, collagen, alginate, and polyurethane, allows to match the PS features with the biocompatibility, degradability, and stimulating properties of the polymer. This is a significant input that makes available the use of molecules with low solubility but remarkable ROS production, such as some synthetic meso-tetraarylporphyrins or phthalocyanines.

    Porphyrinoids display high synthetic versatility, allowing the preparation of several different PS delivery systems in the target wound site. Tetrapyrrolic can be directly attached to the matrix through covalent bonds, encapsulated in polymeric nanocarriers, incorporated by a physical mixture with hydrogels, or used to decorate polymeric systems throughout non-covalent approaches.

    The symbiotic effect of PS and biocompatible polymeric systems improve not only the healing rate, but also the PS efficiency against Gram-negative bacteria (bacteria that are less affected by PDI) growth and consequent biofilm formation, the optimization of the PS into the wound, and the PS degradation rates slow down. Moreover, this approach allows topical application at the wound site which is a significant advantage for the regenerative and skin wound healing processes.

    Considering that the limited clinical success of wound healing [101] is associated with the lack of (i) funding, (ii) centers of excellence concerning wound care management, (iii) methodologic consistency in clinical trials, and (iv) the appearance of more complex pathologies due to the populations aging, and too many drugs with limited efficacies, we believe that PDI/healing can have an opportunity to overcome some of these drawbacks. This approach can improve the local asepsis due to its antimicrobial effect, which includes areas with diminished blood irrigation, and where the conventional antimicrobials do not work. Consequently, it will reduce patient pain and increase cosmetic effects due to enhanced cell proliferation. Additionally, it can be performed in ambulatory care environments, requiring low-cost light sources, and demanding easy clinical staff training. Furthermore, the treatment can be repeated without resistance development.

    The entry is from 10.3390/ijms22084121


    1. Kadish, K.M.; Smith, K.M.; Guilard, R. Handbook of Porphyrin Science; World Scientific Publishing Company: Singapore, 2010.
    2. Cavaleiro, J.A.S.; Tomé, A.C.; Neves, M.G.P.M.S. 9 meso-tetraarylporphyrin derivatives: New synthetic methodologies. In Handbook of Porphyrin Science; Kadish, K.M., Smith, K.M., Guilard, R., Eds.; World Scientific: Singapore, 2010; Volume 2, pp. 193–294.
    3. Cerqueira, A.F.R.; Moura, N.M.M.; Serra, V.V.; Faustino, M.A.F.; Tomé, A.C.; Cavaleiro, J.A.S.; Neves, M.G.P.M.S. β-formyl- and β-vinylporphyrins: Magic building blocks for novel porphyrin derivatives. Molecules 2017, 22, 1269.
    4. Shepherd, M.; Medlock, A.E.; Dailey, H.A. Porphyrin metabolism. In Encyclopedia of Biological Chemistry, 2nd ed.; Elsevier Inc.: Amsterdam, The Netherlands, 2013; pp. 544–549. ISBN 9780123786319.
    5. Taniguchi, M.; Lindsey, J.S. Synthetic chlorins, possible surrogates for chlorophylls, prepared by derivatization of porphyrins. Chem. Rev. 2017, 117, 344–535.
    6. Di Carlo, G.; Biroli, A.O.; Tessore, F.; Caramori, S.; Pizzotti, M. beta-Substituted Zn-II porphyrins as dyes for DSSC: A possible approach to photovoltaic windows. Coord. Chem. Rev. 2018, 358, 153–177.
    7. Kundu, S.; Patra, A. Nanoscale strategies for light harvesting. Chem. Rev. 2017, 117, 712–757.
    8. Di Carlo, G.; Biroli, A.O.; Pizzotti, M.; Tessore, F. Efficient sunlight harvesting by A(4) beta-pyrrolic substituted Zn-II Porphyrins: A mini-review. Front. Chem. 2019, 7, 22.
    9. Birel, O.; Nadeem, S.; Duman, H. Porphyrin-based dye-sensitized solar cells (DSSCs): A review. J. Fluoresc. 2017, 27, 1075–1085.
    10. Singhal, A. Meso-linked multiporphyrins as model for light harvesting systems: Review. Nat. Prod. Chem. Res. 2017, 5, 259.
    11. Li, L.L.; Diau, E.W.G. Porphyrin-sensitized solar cells. Chem. Soc. Rev. 2013, 42, 291–304.
    12. Urbani, M.; Grätzel, M.; Nazeeruddin, M.K.; Torres, T. Meso-substituted porphyrins for dye-sensitized solar cells. Chem. Rev. 2014, 114, 12330–12396.
    13. Otsuki, J. Supramolecular approach towards light-harvesting materials based on porphyrins and chlorophylls. J. Mater. Chem. A 2018, 6, 6710–6753.
    14. Guan, W.; Zhou, W.; Lu, J.; Lu, C. Luminescent films for chemo- and biosensing. Chem. Soc. Rev. 2015, 44, 6981–7001.
    15. Lee, H.; Hong, K.I.; Jang, W.D. Design and applications of molecular probes containing porphyrin derivatives. Coord. Chem. Rev. 2018, 354, 46–73.
    16. Paolesse, R.; Nardis, S.; Monti, D.; Stefanelli, M.; Di Natale, C. Porphyrinoids for chemical sensor applications. Chem. Rev. 2017, 117, 2517–2583.
    17. Moura, N.; Núñez, C.; Santos, S.; Faustino, M.; Cavaleiro, J.; Neves, M.G.P.M.S.; Capelo-Martínez, J.L.; Lodeiro, C. Synthesis, spectroscopy studies, and theoretical calculations of new fluorescent probes based on pyrazole containing porphyrins for Zn(II), Cd(II), and Hg(II) optical detection. Inorg. Chem. 2014, 53, 6149–6158.
    18. Monti, D.; Nardis, S.; Stefanelli, M.; Paolesse, R.; Di Natale, C.; D’Amico, A. Porphyrin-based nanostructures for sensing applications. J. Sens. 2009, 2009, 1–10.
    19. Ding, Y.; Zhu, W.H.; Xie, Y. Development of ion chemosensors based on porphyrin analogues. Chem. Rev. 2017, 117, 2203–2256.
    20. Moura, N.M.M.; Núñez, C.; Santos, S.M.; Faustino, M.A.F.; Cavaleiro, J.A.S.; Almeida Paz, F.A.; Neves, M.G.P.M.S.; Capelo, J.L.; Lodeiro, C. A New 3,5-bisporphyrinylpyridine derivative as a fluorescent ratiometric probe for zinc ions. Chem. A Eur. J. 2014, 20, 6684–6692.
    21. Pegis, M.L.; Wise, C.F.; Martin, D.J.; Mayer, J.M. Oxygen reduction by homogeneous molecular catalysts and electrocatalysts. Chem. Rev. 2018, 118, 2340–2391.
    22. Ali, A.; Akram, W.; Liu, H.-Y. Reactive cobalt–oxo complexes of tetrapyrrolic macrocycles and N-based ligand in oxidative transformation reactions. Molecules 2018, 24, 78.
    23. Santos, E.; Carvalho, C.; Terzi, C.; Nakagaki, S. Recent advances in catalyzed sequential reactions and the potential use of tetrapyrrolic macrocycles as catalysts. Molecules 2018, 23, 2796.
    24. Zhang, W.; Lai, W.; Cao, R. Energy-related small molecule activation reactions: Oxygen reduction and hydrogen and oxygen evolution reactions catalyzed by porphyrin- and corrole-based systems. Chem. Rev. 2017, 117, 3717–3797.
    25. Costentin, C.; Robert, M.; Savéant, J.M. Current issues in molecular catalysis illustrated by iron porphyrins as catalysts of the CO2-to-CO electrochemical conversion. Acc. Chem. Res. 2015, 48, 2996–3006.
    26. Costas, M. Selective C-H oxidation catalyzed by metalloporphyrins. Coord. Chem. Rev. 2011, 255, 2912–2932.
    27. Da Silva, E.S.; Moura, N.M.M.; Neves, M.G.P.M.S.; Coutinho, A.; Prieto, M.; Silva, C.G.; Faria, J.L. Novel hybrids of graphitic carbon nitride sensitized with free-base meso-tetrakis(carboxyphenyl) porphyrins for efficient visible light photocatalytic hydrogen production. Appl. Catal. B Environ. 2018, 221, 56–69.
    28. Calvete, M.J.F.; Pinto, S.M.A.; Pereira, M.M.; Geraldes, C.F.G.C. Metal coordinated pyrrole-based macrocycles as contrast agents for magnetic resonance imaging technologies: Synthesis and applications. Coord. Chem. Rev. 2017, 333, 82–107.
    29. Ethirajan, M.; Chen, Y.; Joshi, P.; Pandey, R.K. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 2011, 40, 340–362.
    30. McKenzie, L.K.; Bryant, H.E.; Weinstein, J.A. Transition metal complexes as photosensitisers in one- and two-photon photodynamic therapy. Coord. Chem. Rev. 2019, 379, 2–29.
    31. Mesquita, M.Q.; Dias, C.J.; Neves, M.G.P.M.S.; Almeida, A.; Faustino, M.A.F. Revisiting current photoactive materials for antimicrobial photodynamic therapy. Molecules 2018, 23, 2424.
    32. Dias, C.J.; Sardo, I.; Moura, N.M.M.; Felgueiras, J.; Neves, M.G.P.M.S.; Fardilha, M.; Faustino, M.A.F. An efficient synthetic access to new uracil-alditols bearing a porphyrin unit and biological assessment in prostate cancer cells. Dye. Pigment. 2020, 173.
    33. Kou, J.; Dou, D.; Yang, L. Porphyrin photosensitizers in photodynamic therapy and its applications. Oncotarget 2017, 8, 81591–81603.
    34. Baglia, R.A.; Zaragoza, J.P.T.; Goldberg, D.P. Biomimetic reactivity of oxygen-derived manganese and iron porphyrinoid complexes. Chem. Rev. 2017, 117, 13320–13352.
    35. Wen, X.; Li, Y.; Hamblin, M.R. Photodynamic therapy in dermatology beyond non-melanoma cancer: An update. Photodiagn. Photodyn. Ther. 2017, 19, 140–152.
    36. Van Straten, D.; Mashayekhi, V.; de Bruijn, H.; Oliveira, S.; Robinson, D. Oncologic photodynamic therapy: Basic principles, current clinical status and future directions. Cancers 2017, 9, 19.
    37. Davies, J.; Davies, D. Origins and evolution of antibiotic resistance. Microbiol. Mol. Biol. Rev. 2010, 74, 417–433.
    38. Tanaka, T.; Osuka, A. Conjugated porphyrin arrays: Synthesis, properties and applications for functional materials. Chem. Soc. Rev. 2015, 44, 943–969.
    39. Castro, K.A.D.F.; Moura, N.M.M.; Simões, M.M.Q.; Cavaleiro, J.A.S.; do Faustino, M.A.F.; Cunha, Â.; Paz, F.A.A.; Mendes, R.F.; Almeida, A.; Freire, C.S.R.; et al. Synthesis and characterization of photoactive porphyrin and poly(2-hydroxyethyl methacrylate) based materials with bactericidal properties. Appl. Mater. Today 2019, 16, 332–341.
    40. Moura, N.M.M.; Esteves, M.; Vieira, C.; Rocha, G.M.S.R.O.; Faustino, M.A.F.; Almeida, A.; Cavaleiro, J.A.S.; Lodeiro, C.; Neves, M.G.P.M.S. Novel β-functionalized mono-charged porphyrinic derivatives: Synthesis and photoinactivation of Escherichia coli. Dye. Pigment. 2019, 160, 361–371.
    41. Agostinis, P.; Berg, K.; Cengel, K.A.; Foster, T.H.; Girotti, A.W.; Gollnick, S.O.; Hahn, S.M.; Hamblin, M.R.; Juzeniene, A.; Kessel, D.; et al. Photodynamic therapy of cancer: An update. Cancer J. Clin. 2011, 61, 250–281.
    42. Tian, J.; Huang, B.; Nawaz, M.H.; Zhang, W. Recent advances of multi-dimensional porphyrin-based functional materials in photodynamic therapy. Coord. Chem. Rev. 2020, 420, 213410.
    43. Liu, Y.; Qin, R.; Zaat, S.A.J.; Breukink, E.; Heger, M. Antibacterial photodynamic therapy: Overview of a promising approach to fight antibiotic-resistant bacterial infections. J. Clin. Transl. Res. 2015, 1, 140–167.
    44. Vieira, C.; Gomes, A.T.P.C.; Mesquita, M.Q.; Moura, N.M.M.; Neves, M.G.P.M.S.; Faustino, M.A.F.; Almeida, A.; Neves, G.P.M.S.; Faustino, A.F.; Almeida, A. An insight into the potentiation effect of potassium iodide on aPDT efficacy. Front. Microbiol. 2018, 9, 2665.
    45. Mesquita, M.Q.; Dias, C.J.; Gamelas, S.; Neves, M.G.P.M.S.; Almeida, A.; Faustino, M.A.F. An insight on the role of photosensitizer nanocarriers for Photodynamic Therapy. An. Acad. Bras. Ciênc. 2018, 90, 1101–1130.
    46. De Freitas, L.F.; Hamblin, M.R. Antimicrobial photoinactivation with functionalized fullerenes. In Nanobiomaterials in Antimicrobial Therapy: Applications of Nanobiomaterials; Elsevier Inc.: Amsterdam, The Netherlands, 2016; pp. 1–27. ISBN 9780323428873.
    47. Almeida, A.; Faustino, M.A.F.; Tomé, J.P.C. Photodynamic inactivation of bacteria: Finding the effective targets. Future Med. Chem. 2015, 7, 1221–1224.
    48. Ladeira, B.M.F.; Dias, C.J.; Gomes, A.T.P.C.; Tomé, A.C.; Neves, M.G.P.M.S.; Moura, N.M.M.; Almeida, A.; Faustino, M.A.F. Cationic pyrrolidine/pyrroline-substituted porphyrins as efficient photosensitizers against E. coli. Molecules 2021, 26, 464.
    49. Moreira, X.; Santos, P.; Faustino, M.A.F.; Raposo, M.M.M.; Costa, S.P.G.; Moura, N.M.M.; Gomes, A.T.P.C.; Almeida, A.; Neves, M.G.P.M.S. An insight into the synthesis of cationic porphyrin-imidazole derivatives and their photodynamic inactivation efficiency against Escherichia coli. Dye. Pigment. 2020, 178, 108330.
    50. Castro, K.A.D.F.; Moura, N.M.M.; Figueira, F.; Ferreira, R.I.; Simões, M.M.Q.; Cavaleiro, J.A.S.; Faustino, M.A.F.; Silvestre, A.J.D.; Freire, C.S.R.; Tomé, J.P.C.; et al. New materials based on cationic porphyrins conjugated to chitosan or titanium dioxide: Synthesis, characterization and antimicrobial efficacy. Int. J. Mol. Sci. 2019, 20, 2522.
    51. Yang, B.; Chen, Y.; Shi, J. Reactive oxygen species (ROS)-based nanomedicine. Chem. Rev. 2019, 119, 4881–4985.
    52. Jaber, G.; Dariush, R.; Shahin, A.; Alireza, T.; Abbas, B. Photosensitizers in antibacterial photodynamic therapy: An overview. Laser Ther. 2018, 27, 293–302.
    53. Tedesco, A.; Jesus, P. Low level energy photodynamic therapy for skin processes and regeneration. In Photomedicine—Advances in Clinical Practice; Tanaka, Y., Ed.; IntechOpen: London, UK, 2017; Volume 5, pp. 75–94. ISBN 978-953-51-3156-4.
    54. Vallejo, M.C.S.; Moura, N.M.M.; Ferreira Faustino, M.A.; Almeida, A.; Gonçalves, I.; Serra, V.V.; Neves, M.G.P.M.S. An insight into the role of non-porphyrinoid photosensitizers for skin wound healing. Int. J. Mol. Sci. 2020, 22, 234.
    55. Silva, J.C.E.; Lacava, Z.G.M.; Kuckelhaus, S.; Silva, L.P.; Neto, L.F.M.; Sauro, E.E.; Tedesco, A.C. Evaluation of the use of low level laser and photosensitizer drugs in healing. Lasers Surg. Med. 2004, 34, 451–457.
    56. Jang, Y.H.; Koo, G.-B.; Kim, J.-Y.; Kim, Y.-S.; Kim, Y.C. Prolonged activation of ERK contributes to the photorejuvenation effect in photodynamic therapy in human dermal fibroblasts. J. Investig. Dermatol. 2013, 133, 2265–2275.
    57. Nelson, K.K.; Melendez, J.A. Mitochondrial redox control of matrix metalloproteinases. Free Radic. Biol. Med. 2004, 37, 768–784.
    58. Rosique, R.G.; Rosique, M.J.; Farina Junior, J.A. Curbing inflammation in skin wound healing: A review. Int. J. Inflamm. 2015, 2015, 316235.
    59. Nesi-Reis, V.; Lera-Nonose, D.S.S.L.; Oyama, J.; Silva-Lalucci, M.P.P.; Demarchi, I.G.; Aristides, S.M.A.; Teixeira, J.J.V.; Silveira, T.G.V.; Lonardoni, M.V.C. Contribution of photodynamic therapy in wound healing: A systematic review. Photodiagn. Photodyn. Ther. 2018, 21, 294–305.
    60. Oyama, J.; Fernandes Herculano Ramos-Milaré, Á.C.; Lopes Lera-Nonose, D.S.S.; Nesi-Reis, V.; Galhardo Demarchi, I.; Alessi Aristides, S.M.; Juarez Vieira Teixeira, J.; Gomes Verzignassi Silveira, T.; Campana Lonardoni, M.V. Photodynamic therapy in wound healing in vivo: A systematic review. Photodiagn. Photodyn. Ther. 2020, 30, 101682.
    61. Mendoza-Garcia, J.; Sebastian, A.; Alonso-Rasgado, T.; Bayat, A. Optimization of an ex vivo wound healing model in the adult human skin: Functional evaluation using photodynamic therapy. Wound Repair Regen. 2015, 23, 685–702.
    62. Jayasree, R.S.; Gupta, A.K.; Rathinam, K.; Mohanan, P.V.; Mohanty, M. The influence of photodynamic therapy on the wound healing process in rats. J. Biomater. Appl. 2001, 15, 176–186.
    63. Hamblin, M.R.; O’Donnell, D.A.; Murthy, N.; Contag, C.H.; Hasan, T. Rapid control of wound infections by targeted photodynamic therapy monitored by in vivo bioluminescence imaging. Photochem. Photobiol. 2002, 75, 51–57.
    64. Wang, C.; Chen, P.; Wang, C.; Chen, P.; Qiao, Y.; Kang, Y.; Guo, S.; Wu, D.; Wangd, J.; Wu, H. Bacteria-activated chlorin e6 ionic liquid based on cation and anion dual-mode antibacterial action for enhanced photodynamic efficacy. Biomater. Sci. 2019, 7, 1399–1410.
    65. Luo, Y.; Li, J.; Liu, X.; Tan, L.; Cui, Z.; Feng, X.; Yang, X.; Liang, Y.; Li, Z.; Zhu, S.; et al. Dual metal-organic framework heterointerface. ACS Cent. Sci. 2019, 5, 1591–1601.
    66. Han, D.; Han, Y.; Li, J.; Liu, X.; Yeung, K.W.K.; Zheng, Y.; Cui, Z.; Yang, X.; Liang, Y.; Li, Z.; et al. Enhanced photocatalytic activity and photothermal effects of cu-doped metal-organic frameworks for rapid treatment of bacteria-infected wounds. Appl. Catal. B Environ. 2020, 261, 118248.
    67. Han, D.; Li, Y.; Liu, X.; Yeung, K.W.K.; Zheng, Y.; Cui, Z.; Liang, Y.; Li, Z.; Zhu, S.; Wang, X.; et al. Photothermy-strengthened photocatalytic activity of polydopamine-modified metal-organic frameworks for rapid therapy of bacteria-infected wounds. J. Mater. Sci. Technol. 2021, 62, 83–95.
    68. Sun, L.; Song, L.; Zhang, X.; Zhou, R.; Yin, J.; Luan, S. Poly(γ-glutamic acid)-based electrospun nanofibrous mats with photodynamic therapy for effectively combating wound infection. Mater. Sci. Eng. C 2020, 113, 110936.
    69. Chen, J.; Yang, L.; Chen, J.; Liu, W.; Zhang, D.; Xu, P.; Dai, T.; Shang, L.; Yang, Y.; Tang, S.; et al. Composite of silver nanoparticles and photosensitizer leads to mutual enhancement of antimicrobial efficacy and promotes wound healing. Chem. Eng. J. 2019, 374, 1373–1381.
    70. Hamblin, M.R.; Zahra, T.; Contag, C.H.; McManus, A.T.; Hasan, T. Optical monitoring and treatment of potentially lethal wound infections in vivo. J. Infect. Dis. 2003, 187, 1717–1725.
    71. Sahu, K.; Sharma, M.; Bansal, H.; Dube, A.; Gupta, P.K. Topical photodynamic treatment with poly-l-lysine-chlorin p6 conjugate improves wound healing by reducing hyperinflammatory response in Pseudomonas aeruginosa-infected wounds of mice. Lasers Med. Sci. 2013, 28, 465–471.
    72. Sahu, K.; Sharma, M.; Sharma, P.; Verma, Y.; Rao, K.D.; Bansal, H.; Dube, A.; Gupta, P.K. Effect of poly-L-lysine-chlorin P6-mediated antimicrobial photodynamic treatment on collagen restoration in bacteria-infected wounds. Photomed. Laser Surg. 2014, 32, 23–29.
    73. Fila, G.; Kasimova, K.; Arenas, Y.; Nakonieczna, J.; Grinholc, M.; Bielawski, K.P.; Lilge, L. Murine model imitating chronic wound infections for evaluation of antimicrobial photodynamic therapy efficacy. Front. Microbiol. 2016, 7, 1258.
    74. Xu, Z.; Gao, Y.; Meng, S.; Yang, B.; Pang, L.; Wang, C.; Liu, T. Mechanism and in vivo evaluation: Photodynamic antibacterial chemotherapy of lysine-porphyrin conjugate. Front. Microbiol. 2016, 7, 242.
    75. Wang, D.; Zhang, Y.; Yan, S.; Chen, Z.; Deng, Y.; Xu, P.; Chen, J.; Liu, W.; Hu, P.; Huang, M.; et al. An effective zinc phthalocyanine derivative against multidrug-resistant bacterial infection. J. Porphyr. Phthalocyan. 2017, 21, 205–210.
    76. Simonetti, O.; Cirioni, O.; Orlando, F.; Alongi, C.; Lucarini, G.; Silvestri, C.; Zizzi, A.; Fantetti, L.; Roncucci, G.; Giacometti, A.; et al. Effectiveness of antimicrobial photodynamic therapy with a single treatment of RLP068/Cl in an experimental model of Staphylococcus aureus wound infection. Br. J. Dermatol. 2011, 164, 987–995.
    77. Demidova, T.N.; Gad, F.; Zahra, T.; Francis, K.P.; Hamblin, M.R. Monitoring photodynamic therapy of localized infections by bioluminescence imaging of genetically engineered bacteria. J. Photochem. Photobiol. B Biol. 2005, 81, 15–25.
    78. Dai, T.; Tegos, G.P.; Lu, Z.; Huang, L.; Zhiyentayev, T.; Franklin, M.J.; Baer, D.G.; Hamblin, M.R. Photodynamic therapy for Acinetobacter baumannii burn infections in mice. Antimicrob. Agents Chemother. 2009, 53, 3929–3934.
    79. Carrasco, E.; Calvo, M.I.; Blázquez-Castro, A.; Vecchio, D.; Zamarrón, A.; De Almeida, I.J.D.; Stockert, J.C.; Hamblin, M.R.; Juarranz, Á.; Espada, J. Photoactivation of ROS production in situ transiently activates cell proliferation in mouse skin and in the hair follicle stem cell niche promoting hair growth and wound healing. J. Invest. Dermatol. 2015, 135, 2611–2622.
    80. Dai, T.; Tegos, G.P.; Zhiyentayev, T.; Mylonakis, E.; Hamblin, M.R. Photodynamic therapy for methicillin-resistant Staphylococcus aureus infection in a mouse skin abrasion model. Lasers Surg. Med. 2010, 42, 38–44.
    81. Vecchio, D.; Dai, T.; Huang, L.; Fantetti, L.; Roncucci, G.; Hamblin, M.R. Antimicrobial photodynamic therapy with RLP068 kills methicillin-resistant Staphylococcus aureus and improves wound healing in a mouse model of infected skin abrasion PDT with RLP068/Cl in infected mouse skin abrasion. J. Biophoton. 2013, 6, 733–742.
    82. Mai, B.; Jia, M.; Liu, S.; Sheng, Z.; Li, M.; Gao, Y.; Wang, X.; Liu, Q.; Wang, P. Smart hydrogel-Based DVDMS/bFGF nanohybrids for antibacterial phototherapy with multiple damaging sites and accelerated wound healing. ACS Appl. Mater. Interfaces 2020, 12, 10156–10169.
    83. Lambrechts, S.A.G.; Demidova, T.N.; Aalders, M.C.G.; Hasan, T.; Hamblin, M.R. Photodynamic therapy for Staphylococcus aureus infected burn wounds in mice. Photochem. Photobiol. Sci. 2005, 4, 503–509.
    84. Morimoto, K.; Ozawa, T.; Awazu, K.; Ito, N.; Honda, N.; Matsumoto, S.; Tsuruta, D. Photodynamic therapy using systemic administration of 5-aminolevulinic acid and a 410-nm wavelength light-emitting diode for methicillin-resistant staphylococcus aureus-infected ulcers in mice. PLoS ONE 2014, 9, e105173.
    85. Lyapina, E.A.; Machneva, T.V.; Larkina, E.A.; Tkachevskaya, E.P.; Osipov, A.N.; Mironov, A.F. Effect of photosensitizers pheophorbide a and protoporphyrin IX on skin wound healing upon low-intensity laser irradiation. Biophysics 2010, 55, 296–300.
    86. Rudenko, T.G.; Shekhter, A.B.; Guller, A.E.; Aksenova, N.A.; Glagolev, N.N.; Ivanov, A.V.; Aboyants, R.K.; Kotova, S.L.; Solovieva, A.B. Specific features of early stage of the wound healing process occurring against the background of photodynamic therapy using fotoditazin photosensitizer-amphiphilic polymer complexes. Photochem. Photobiol. 2014, 90, 1413–1422.
    87. Katayama, B.; Ozawa, T.; Morimoto, K.; Awazu, K.; Ito, N.; Honda, N.; Oiso, N.; Tsuruta, D. Enhanced sterilization and healing of cutaneous pseudomonas infection using 5-aminolevulinic acid as a photosensitizer with 410-nm LED light. J. Dermatol. Sci. 2018, 90, 323–331.
    88. Yang, T.; Tan, Y.; Zhang, W.; Yang, W.; Luo, J.; Chen, L.; Liu, H.; Yang, G.; Lei, X. Effects of ALA-PDT on the healing of mouse skin wounds infected with pseudomonas aeruginosa and its related mechanisms. Front. Cell Dev. Biol. 2020, 8, 1471.
    89. Hu, C.; Zhang, F.; Kong, Q.; Lu, Y.; Zhang, B.; Wu, C.; Luo, R.; Wang, Y. Synergistic chemical and photodynamic antimicrobial therapy for enhanced wound healing mediated by multifunctional light-responsive nanoparticles. Biomacromolecules 2019, 20, 4581–4592.
    90. Garrier, J.; Bezdetnaya, L.; Barlier, C.; Gräfe, S.; Guillemin, F.; D’Hallewin, M.A. Foslip ®-based photodynamic therapy as a means to improve wound healing. Photodiagnosis Photodyn. Ther. 2011, 8, 321–327.
    91. Ghaffarifar, F.; Jorjani, O.; Mirshams, M.; Miranbaygi, M.H.; Hosseini, Z.K. Short communication: Photodynamic therapy as a new treatment of cutaneous leishmaniasis. East Mediterr. Health J. 2006, 12, 902–908.
    92. Evangelou, G.; Krasagakis, K.; Giannikaki, E.; Kruger-Krasagakis, S.; Tosca, A. Successful treatment of cutaneous leishmaniasis with intralesional aminolevulinic acid photodynamic therapy. Photodermatol. Photoimmunol. Photomed. 2011, 27, 254–256.
    93. Clayton, T.H.; Harrison, P.V. Photodynamic therapy for infected leg ulcers. Br. J. Dermatol. 2007, 156, 384–385.
    94. Lei, X.; Liu, B.; Huang, Z.; Wu, J. A clinical study of photodynamic therapy for chronic skin ulcers in lower limbs infected with Pseudomonas aeruginosa. Arch. Dermatol. Res. 2015, 307, 49–55.
    95. Mosti, G.; Picerni, P.; Licau, M.; Mattaliano, V. Photodynamic therapy in infected venous and mixed leg ulcers: A pilot experience. J. Wound Care 2018, 27, 816–821.
    96. Arenbergerova, M.; Arenberger, P.; Bednar, M.; Kubat, P.; Mosinger, J. Light-activated nanofibre textiles exert antibacterial effects in the setting of chronic wound healing. Exp. Dermatol. 2012, 21, 619–624.
    97. Cappugi, P.; Comacchi, C.; Torchia, D. Photodynamic therapy for chronic venous ulcers. Acta Dermatovenerol. Croat. 2014, 22, 129–131.
    98. Devirgiliis, V.; Panasiti, V.; Fioriti, D.; Anzivino, E.; Bellizzi, A.; Cimillo, M.; Curzio, M.; Melis, L.; Roberti, V.; Gobbi, S.; et al. Antibacterial activity of methyl aminolevulinate photodynamic therapy in the treatment of a cutaneous ulcer. Int. J. Immunopathol. Pharmacol. 2011, 24, 793–795.
    99. Berking, C.; Herzinger, T.; Flaig, M.J.; Brenner, M.; Borelli, C.; Degitz, K. The efficacy of photodynamic therapy in actinic cheilitis of the lower lip: A prospective study of 15 patients. Dermatol. Surg. 2007, 33, 825–830.
    100. Mills, S.J.; Farrar, M.D.; Ashcroft, G.S.; Griffiths, C.E.M.; Hardman, M.J.; Rhodes, L.E. Topical photodynamic therapy following excisional wounding of human skin increases production of transforming growth factor-β3 and matrix metalloproteinases 1 and 9, with associated improvement in dermal matrix organization. Br. J. Dermatol. 2014, 171, 55–62.
    101. Mahmoudi, M.; Gould, L. Opportunities and challenges of the management of chronic wounds: A multidisciplinary viewpoint. Chron. Wound Care Manag. Res. 2020, 7, 27–36.