Artificial intelligence for regular monitoring of diabetogenic wounds and exploring nanotherapeutics to combat the multifaceted pathophysiology

Authors

• Pooja Yadav ¹
• Priyanka Singh ¹
• Monika Yadav ¹
• Kapil Dangi ¹
• Kapinder Kumar ²
• Anita Kamra Verma * ^{1, 3}

1. Nano-Biotech Lab, Kirori Mal College, University of Delhi, India
2. Associate Professor, Department of Zoology, Allahabad University, Allahabad, India
3. Fellow, Delhi School of Public Health, Institution of Eminence, University of Delhi, India

Abstract

The multifaceted pathophysiology of diabetic wounds coupled with impaired diabetic wound healing remains a significant challenge for the medical community in the 21st century. Possibility of bacterial infections, insufficient vascular supply, increment in levels of oxidative stress, and abnormalities in defenses mechanism of antioxidant causes diabetic foot ulcers (DFU) that leads to significant morbidity. An effective treatment for diabetic wounds is still lacking. Chronic wounds are taking epidemic proportions, leading to an increased interest in exploring novel therapies to meet the challenges. Evaluating the progression in diabetic ulcers poses a major threat for the patients and clinician owing to logistics as irregular visits to the clinics. Unique properties of nanoparticles contain ultra-small size, increased surface-to-volume ratio, low cytotoxicity, enhanced cellular uptake, improved antibacterial activity, biocompatibility and biodegradability making their applications attractive against DFUs. Their potential for healing can be due to their superior antioxidant and anti-inflammatory activities. Further, nanoparticles are effective delivery vehicles for various small molecules, exosomes, metallic molecules, or conjugated with numerous biomaterials- chitosan (CS), hyaluronic acid (HA) and smart hydrogels (HG) to enhance their healing efficacy against diabetic wounds. This review focuses on the futuristic and potential viewpoints of nanoparticles for the therapeutics of diabetic wounds/DFUs. Artificial intelligence (AI) tools and optical sensors can further contribute effectively for the monitoring procedures. Software based on AI technology plays crucial role in assessment and provide continuous care throughout the treatment. AI also helps to connect healthcare experts with larger number of patients at the same time. Nanotherapeutics represents a promising innovative strategy for targeted treatment that can change the landscape of wound healing, by providing a physiologically stable micro-environment for the thorough wound-healing process.

Graphical Abstract

Keywords

• Nanoparticles
• DFUs
• Diabetic/chronic wound
• Optical sensors
• Wound healing

References

[1] Ansari, M. A., Ali, K., Farooqui, Z., Al-Dossary, H. A., Zubair, M., & Musarrat, J., (2021), Nanotechnology and Diabetic Foot Ulcer: Prospects. Diabetic Foot Ulcer: An Update springer. 331-357. DOI: https://doi.org/10.1007/978-981-15-7639-3_20

[2] Clements, J. M., West, B. T., Yaker, Z., Lauinger, B., McCullers, D., Haubert, J., Everett, G. J., (2020), Disparities in diabetes-related multiple chronic conditions and mortality: The influence of race.  Diabetes Res. Clin. Pr. 159:107984. DOI: 10.1016/j.diabres.2019.107984

[3] Al Wahbi, A., (2019), Operative versus non-operative treatment in diabetic dry toe gangrene. Diabetes Metab. Synd. 13(2): 959-963. DOI: 10.1016/j.dsx.2018.12.021

[4] Tan, C. T., Liang, K., Ngo, Z. H., Dube, C. T., & Lim, C. Y., (2020), Application of 3D bioprinting technologies to the management and treatment of diabetic foot ulcers. Biomedicines. 8(10): 441. DOI: 10.3390/biomedicines8100441

[5] Mascharak, S., desJardins-Park, H. E., Davitt, M. F., Guardino, N. J., Gurtner, G. C., Wan, D. C., & Longaker, M. T. (2022), Modulating cellular responses to mechanical forces to promote wound regeneration. Adv. Wound CarefAD. 11(9): 479-495. DOI: 10.1089/wound.2021.0040

[6] Litany, R. J., & Praseetha, P. K. (2022), Tiny tots for a big-league in wound repair: Tools for tissue regeneration by nano techniques of today. J Control Release .349: 443-459. DOI: 10.1016/j.jconrel.2022.07.005

[7] Declue CE, Shornick LP., (2015), The cytokine milieu of diabetic wounds. Diabetes Management. 5(6): 525–37. DOI: 10.2217/dmt.15.44.

[8] Qiu, Z., Kwon, A. H., & Kamiyama, Y., (2007), Effects of plasma fibronectin on the healing of full-thickness skin wounds in streptozotocin-induced diabetic rats. J. Surg. Res. 138(1): 64-70. DOI: 10.1016/j.jss.2006.06.034

[9] Abou El-ezz, D., Abdel-Rahman, L. H., Al-Farhan, B. S., Mostafa, D. A., Ayad, E. G., Basha, M. T., ... & Abdalla, E. M. (2022), Enhanced in vivo wound healing efficacy of a novel hydrogel loaded with copper (II) schiff base quinoline complex (CuSQ) solid lipid nanoparticles. Pharmaceuticals.15(8): 978. DOI: 10.3390/ph15080978

[10] Kwiatkowska, A., Drabik, M., Lipko, A., Grzeczkowicz, A., Stachowiak, R., Marszalik, A., & Granicka, L. H. (2022), Composite membrane dressings system with metallic nanoparticles as an antibacterial factor in wound healing. Membranes. 12(2):215. DOI: 10.3390/membranes12020215

[11] Anisuzzaman, D. M., Wang, C., Rostami, B., Gopalakrishnan, S., Niezgoda, J., & Yu, Z. (2022), Image-based artificial intelligence in wound assessment: A systematic review. Adv. Wound CarefADV .11(12): 687-709. DOI: 10.1089/wound.2021.0091

[12] Gonzalez, A. C. D. O., Costa, T. F., Andrade, Z. D. A., &Medrado, A. R. A. P., (2016), Wound healing-A literature review. An. Bras. Dermat. B. 91: 614-620. DOI: 10.1590/abd1806-4841.20164741

[13] Matar, D. Y., Ng, B., Darwish, O., Wu, M., Orgill, D. P., & Panayi, A. C. (2023), Skin inflammation with a focus on wound healing.  Adv. Wound CarefADV. 12(5): 269-287. DOI: 10.1089/wound.2021.0126

[14] Iqbal, A., Jan, A., Wajid, M. A., & Tariq, S., (2017), Management of chronic non-healing wounds by hirudotherapy. World J. Plast. Surg. 6(1): 9. PMCID: PMC5339604

[15] Cañedo-Dorantes, L.&Cañedo-Ayala, M., (2019), Skin acute wound healing: a comprehensive review. Int. J. Infla. 3706315.  DOI: 10.1155/2019/3706315

[16] Yang, F., Bai, X., Dai, X., & Li, Y., (2021), The biological processes during wound healing. Regen. Med.16(04):373-390. DOI: 10.2217/rme-2020-0066

[17] Pickup, M. J., Pathophysiology of Wound Healing. J. Forensic Leg. Med.( (pp. 103-107). CRC Press. DOI: https://doi.org/10.4324/9780429318764

[18] Yadav, J. P., (2023), Based on clinical research matrix metalloprotease (MMP) inhibitors to promote diabetic wound healing. Horm. Metab. Res.HO. DOI: 10.1055/a-2171-5879

[19] Knoedler, S., Knoedler, L., Kauke-Navarro, M., Rinkevich, Y., Hundeshagen, G., Harhaus, L., Panayi, A. C., (2023), Regulatory T cells in skin regeneration and wound healing. Mil Med Res. 10(1): 49.  DOI: 10.1186/s40779-023-00484-6

[20] Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H. P., &Longaker, M. T., (2018), Cutaneous scarring: basic science, current treatments, and future directions.  Adv. Wound Care. 7(2): 29-45. DOI: 10.1089/wound.2016.0696

[21] Joshi, N., Pohlmeier, L., Ben‐Yehuda Greenwald, M., Haertel, E., Hiebert, P., Kopf, M., & Werner, S., (2020), Comprehensive characterization of myeloid cells during wound healing in healthy and healing‐impaired diabetic mice. Eur. J. Immunol .50(9):1335-1349. DOI: 10.1002/eji.201948438

[22] Cho, H., Blatchley, M. R., Duh, E. J., & Gerecht, S., (2019), Acellular and cellular approaches to improve diabetic wound healing. Adv. Drug Deliv. Rev. 146: 67-288. DOI: 10.1016/j.addr.2018.07.019

[23] Maimon, N., Zamir, Z. Z., Kalkar, P., Zeytuni-Timor, O., Schif-Zuck, S., Larisch, S., & Ariel, A., (2020), The pro-apoptotic ARTS protein induces neutrophil apoptosis, efferocytosis, and macrophage reprogramming to promote resolution of inflammation. Apoptosis. 25: 558-573. DOI: 10.1007/s10495-020-01615-3

[24] Nguyen, T. T., Mobashery, S., & Chang, M., (2016), Roles of matrix metalloproteinases in cutaneous wound healing. Wound healing-new insights into ancient challenges. Springer. 37-71. DOI: http.//dx.doi.org/10.5772/64611

[25] Monika, P., Waiker, P. V., Chandraprabha, M. N., Rangarajan, A., & Murthy, K. N. C., (2021), Myofibroblast progeny in wound biology and wound healing studies. Wound Repair Regen. 29(4): 531-547. DOI: 10.1111/wrr.12937

[26] Solarte David, V. A., Güiza-Argüello, V. R., Arango-Rodríguez, M. L., Sossa, C. L., & Becerra-Bayona, S. M., (2022). Decellularized tissues for wound healing: Towards closing the gap between scaffold design and effective extracellular matrix remodeling. Front. Bioeng. Biotechnol. 10:821852. DOI: 10.3389/fbioe.2022.821852

[27] Maharajan, S, Dua, R., Saini, L. K., Kumar, N., & Gupta, R., (2024). Prevalence and predictors of restless legs syndrome among patients having stable chronic obstructive pulmonary disease. Sleep Med. DOI: https://doi.org/10.1016/j.sleep.2024.03.041Get rights and content

[28] Shao, M., Hussain, Z., Thu, H. E., Khan, S., de Matas, M., Silkstone, V., ... & Bukhari, S. N. A., (2017), Emerging trends in therapeutic algorithm of chronic wound healers: recent advances in drug delivery systems, concepts-to-clinical application and future prospects. CRIT Rev. Ther. Drug. 34:(5). DOI: 10.1615/CritRevTherDrugCarrierSyst.2017016957

[29] Naik, K., Singh, P., Yadav, M., Srivastava, S. K., Tripathi, S., Ranjan, R., ... Anita K Verma & Parmar, A. S., (2023), 3D printable, injectable amyloid-based composite hydrogel of bovine serum albumin and aloe vera for rapid diabetic wound healing. J. Mater. Chem. B. 11(34): 8142-8158. DOI: 10.1039/d3tb01151h

[30] Gaspar-Pintiliescu, A., Stanciuc, A. M., & Craciunescu, O., (2019), Natural composite dressings based on collagen, gelatin and plant bioactive compounds for wound healing: A review. Int. J. Biol. ... 138:854-865. DOI: 10.1016/j.ijbiomac.2019.07.155

[31] Nethi, S. K., Das, S., Patra, C. R., & Mukherjee, S., (2019), Recent advances in inorganic nanomaterials for wound-healing applications. Biomater Sci. 7(7): 2652-2674.  DOI: 10.1039/c9bm00423h

[32] Bai, Q., Han, K., Dong, K., Zheng, C., Zhang, Y., Long, Q., & Lu, T., (2020), Potential applications of nanomaterials and technology for diabetic wound healing.  Int. J. NanomedicineI . 9717-9743. DOI: 10.2147/IJN.S276001

[33] Ezhilarasu, H., Vishalli, D., Dheen, S. T., Bay, B. H., & Srinivasan, D. K. (2020), Nanoparticle-based therapeutic approach for diabetic wound healing. Nanomaterials. 10(6): 1234. DOI: 10.3390/nano10061234

[34] Marshall, C. D., Hu, M. S., Leavitt, T., Barnes, L. A., Lorenz, H. P., &Longaker, M. T., (2018), Cutaneous scarring: basic science, current treatments, and future directions. Adv. Wound care. 7(2): 29-45. DOI: 10.1089/wound.2016.0696

[35] Niveria, K., Yadav, M., Dangi, K., & Verma, A. K., (2022), Overcoming challenges to enable targeting of metastatic breast cancer tumour microenvironment with Nano-therapeutics: current status and future perspectives. Opennano. 100083. DOI: https://doi.org/10.1016/j.onano.2022.100083

[36] Bai, Q., Han, K., Dong, K., Zheng, C., Zhang, Y., Long, Q., & Lu, T., (2020), Potential applications of nanomaterials and technology for diabetic wound healing. Int. J. NanomedicineI. 9717-9743. DOI: 10.2147/IJN.S276001

[37] Ezhilarasu, H., Vishalli, D., Dheen, S. T., Bay, B. H., & Srinivasan, D. K.,(2020), Nanoparticle-based therapeutic approach for diabetic wound healing. Nanomaterials. 10(6):1234. DOI: 10.3390/nano10061234

[38] Das, A. K., & Gavel, P. K., (2020), Low molecular weight self-assembling peptide-based materials for cell culture, antimicrobial, anti-inflammatory, wound healing, anticancer, drug delivery, bioimaging and 3D bioprinting applications. Soft MatterSOFT MA. 16(44):10065-10095.  DOI: 10.1039/d0sm01136c

[39] Yazdi, M. K., Vatanpour, V., Taghizadeh, A., Taghizadeh, M., Ganjali, M. R., Munir, M. T., ... & Ghaedi, M., (2020), Hydrogel membranes: A review Mater. Sci. Eng. C. 114:111023. DOI: 10.1039/d0sm01136c

[40] Bairagi, D., Biswas, P., Basu, K., Hazra, S., Hermida-Merino, D., Sinha, D. K., ... & Banerjee, A., (2019), Self-assembling peptide-based hydrogel: Regulation of mechanical stiffness and thermal stability and 3D cell culture of fibroblasts. ACS Appl. Bio Mater. 2(12): 5235-5244.  DOI: 10.1021/acsabm.9b00424

[41] Agarwal, G., Agiwal, S., & Srivastava, A., (2020), Hyaluronic acid containing scaffolds ameliorate stem cell function for tissue repair and regeneration. Int J Biol Macromol. 165:388-401. DOI: 10.1016/j.ijbiomac.2020.09.107

[42] Garbayo, E., Pascual‐Gil, S., Rodríguez‐Nogales, C., Saludas, L., Estella‐Hermoso de Mendoza, A., & Blanco‐Prieto, M. J., (2020), Nanomedicine and drug delivery systems in cancer and regenerative medicine. Wiley Interdisciplinary Reviews: WIRES NANOMED NANOBI. 12(5): e1637. DOI: 10.1002/wnan.1637

[43] Yang, S., & Jiang, L., (2020), Biomimetic self-assembly of subcellular structures. ChemComm. 56(60): 8342-8354. DOI: 10.1039/d0cc01395a

[44] Liang, K., Bae, K. H., & Kurisawa, M., (2019), Recent advances in the design of injectable hydrogels for stem cell-based therapy. J Mater Chem BJ MA. 7(24): 3775-3791. DOI: https://doi.org/10.1039/C9TB00485H

[45] Ding, X., Zhao, H., Li, Y., Lee, A. L., Li, Z., Fu, M., ... & Yuan, P., (2020), Synthetic peptide hydrogels as 3D scaffolds for tissue engineering. Adv. Drug Deliv. Rev. 160:78-104. DOI: 10.1016/j.addr.2020.10.005

[46] Cui, L., Liang, J., Liu, H., Zhang, K., & Li, J., (2020), Nanomaterials for angiogenesis in skin tissue engineering.  Tissue Eng Part B Rev, 26(3): 203-216. DOI: 10.1089/ten.TEB.2019.0337

[47] Taha, M. S., Padmakumar, S., Singh, A., & Amiji, M. M., (2020), Critical quality attributes in the development of therapeutic nanomedicines toward clinical translation. Drug Deliv. Transl. Res. 10: 766-790.  DOI: 10.1007/s13346-020-00744-1

[48] Ashammakhi, N., Darabi, M. A., Kehr, N. S., Erdem, A., Hu, S. K., Dokmeci, M. R., Khademhosseini, A., (2019), Advances in controlled oxygen generating biomaterials for tissue engineering and regenerative therapy. Biomacromolecules.J. 21(1): 56-72. DOI: 10.1021/acs.biomac.9b00546

[49] Badv, M., Bayat, F., Weitz, J. I., & Didar, T. F., (2020), Single and multi-functional coating strategies for enhancing the biocompatibility and tissue integration of blood-contacting medical implants. Biomaterials 258: 120291. DOI: 10.1016/j.biomaterials.2020.120291

[50] Olmo, J. A. D., Ruiz-Rubio, L., Pérez-Alvarez, L., Sáez-Martínez, V., & Vilas-Vilela, J. L. (2020). Antibacterial coatings for improving the performance of biomaterials. Coatings. 10(2) 139. DOI: https://doi.org/10.3390/coatings10020139

[51] Guhathakurta, S., & Galla, S., (2019), Progress in cardiovascular biomaterials. Asian Cardiovasc Thorac Ann. 27(9):744-750. DOI: 10.1177/0218492319880424

[52] Agarwal, K. M., Singh, P., Mohan, U., Mandal, S., & Bhatia, D., (2020), Comprehensive study related to advancement in biomaterials for medical applications. Sens. Int. 1:100055. DOI: https://doi.org/10.1016/j.sintl.2020.100055

[53] Crabbe-Mann, M. R., (2019), Electrospinning of Cellulose Based Wound Dressing (Doctoral dissertation, UCL (University College London)). https://discovery.ucl.ac.uk/id/eprint/10082026

[54] Nandhini, J., Karthikeyan, E., & Rajeshkumar, S., (2024), Nanomaterials for wound healing: Current status and futuristic frontier. Biomed tech. 6:26-45. DOI: https://doi.org/10.1016/j.bmt.2023.10.001

[55] Youssef, F. S., Ismail, S. H., Fouad, O. A., & Mohamed, G. G., (2024), Green synthesis and Biomedical Applications of Zinc Oxide Nanoparticles. Review. Egyp. j. vet. sci. 55(1): 287-311. DOI: 10.21608/ejvs.2023.225862.1576

[56] Hmingthansanga, V., Singh, N., Banerjee, S., Manickam, S., Velayutham, R., & Natesan, S., (2022), Improved topical drug delivery: Role of permeation enhancers and advanced approaches. Pharmaceutics. 14(12): 2818. DOI: 10.3390/pharmaceutics14122818

[57] Pino, P., Bosco, F., Mollea, C., & Onida, B., (2023), Antimicrobial nano-zinc oxide biocomposites for wound healing applications: A Review. Pharmaceutics, 15(3): 970. DOI: 10.3390/pharmaceutics15030970

[58] Lallo da Silva, B., Abuçafy, M. P., Berbel Manaia, E., Oshiro Junior, J. A., Chiari-Andréo, B. G., Pietro, R. C. R., & Chiavacci, L. A., (2019), Relationship between structure and antimicrobial activity of zinc oxide nanoparticles: An overview. Int. J. NanomedicineI. 9395-9410. DOI: 10.2147/IJN.S216204

[59] Shimizu, K., Kashiwada, S., & Horie, M., (2022), Cellular Effects of Silver Nanoparticle Suspensions on Lung Epithelial Cells and Macrophages.  Appl. Sci. 12(7):3554. DOI:  https://doi.org/10.3390/app12073554

[60] Yang, W., Wang, L., Mettenbrink, E. M., DeAngelis, P. L., & Wilhelm, S., (2021), Nanoparticle toxicology. Anne Joutel 61: 269-289. DOI: 10.1146/annurev-pharmtox-032320-110338

[61] Al-Musawi, S., Albukhaty, S., Al-Karagoly, H., Sulaiman, G. M., Alwahibi, M. S., Dewir, Y. H., ... & Rizwana, H., (2020), Antibacterial activity of honey/chitosan nanofibers loaded with capsaicin and gold nanoparticles for wound dressing. Molecules, 25(20): 4770. DOI: 10.3390/molecules25204770

[62] In vitro studies of the toxic effects of silver nanoparticles on HeLa and U937 cells. DOI: 10.2147/NSA.S78134

[63] Rahman, M. A., Abul Barkat, H., Harwansh, R. K., & Deshmukh, R., (2022), Carbon-based nanomaterials: carbon nanotubes, graphene, and fullerenes for the control of burn infections and wound healing. Curr. Pharm. Biotechnol. 23(12): 1483-1496. DOI: 10.2174/1389201023666220309152340

[64] Hassan, D., Farghali, M., Eldeek, H., Gaber, M., Elossily, N., & Ismail, T., (2019), Antiprotozoal activity of silver nanoparticles against Cryptosporidium parvum oocysts: New insights on their feasibility as a water disinfectant. J. Microbiol. Methods. 165: 105698.  DOI: 10.1016/j.mimet.2019.105698

[65] Muenraya, P., Sawatdee, S., Srichana, T., & Atipairin, A., (2022), Silver nanoparticles conjugated with colistin enhanced the antimicrobial activity against gram-negative bacteria. Molecules. 27(18): 5780. DOI: 10.3390/molecules27185780

[66] Singh, B. R., Singh, B. N., Singh, A., Khan, W., Naqvi, A. H., & Singh, H. B., (2015), Mycofabricatedbiosilver nanoparticles interrupt Pseudomonas aeruginosa quorum sensing systems. Sci. Rep. 5(1): 13719.  DOI: 10.1038/srep13719

[67] Acharya, D., Pandey, P., & Mohanta, B., (2021), A comparative study on the antibacterial activity of different shaped silver nanoparticles. Chem. Zvesti . 75(9): 4907-4915. DOI: https://doi.org/10.1007/s11696-021-01722-8

[68] Rodriguez-Garraus, A., Azqueta, A., Vettorazzi, A., & Lopez de Cerain, A., (2020), Genotoxicity of silver nanoparticles. Nanomaterials. 10(2): 251.  DOI: 10.3390/nano10020251

[69] Rajendran, N. K., Kumar, S. S. D., Houreld, N. N., & Abrahamse, H., (2018), A review on nanoparticle-based treatment for wound healing. J. Drug Deliv. Sci. Techn. 44: 421-430. DOI: https://doi.org/10.1016/j.jddst.2018.01.009

[70] Dahm, H. (2020). Silver nanoparticles in wound infections: present status and future prospects. Nanotech. (SSBI). 151-168. DOI: https://doi.org/10.1007/978-3-030-35147-2_9

[71] Mittal, D., Narang, K., Leekha Kapinder, A., Kumar, K., & Verma, A. K., (2019), Elucidation of Biological Activity of Silver ‎Based Nanoparticles Using Plant ‎Constituents of Syzygium cumini. Int. J. Nano. Nanotech. 15(3): 189-198.

[72] Yusuf, M., (2019), Silver nanoparticles: synthesis and applications. Handbook of Ecomaterials. 2343. DOI: 10.1007/978-3-319-68255-6_16

[73] Rezvani, E., Rafferty, A., McGuinness, C., & Kennedy, J., (2019), Adverse effects of nanosilver on human health and the environment. Acta biomaterialia. 94:145-159.  DOI: 10.1016/j.actbio.2019.05.042

[74] Vijayakumar, V., Samal, S. K., Mohanty, S., & Nayak, S. K., (2019), Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int. J. Biol. Macromol. 122: 137-148. DOI: 10.1016/j.ijbiomac.2018.10.120

[75] Yang, T., Wang, D., & Liu, X., (2019), Assembled gold nanorods for the photothermal killing of bacteria. Colloids Surf. B. 173: 833-841. DOI: 10.1016/j.colsurfb.2018.10.060

[76] Hossain, M. M., Polash, S. A., Saha, T., & Sarker, S. R., (2022), Gold nanoparticles: a lethal nanoweapon against multidrug-resistant bacteria. In Nano-strategies for addressing antimicrobial resistance: nano-diagnostics, nano-carriers, and nano-antimicrobials (pp. 311-351). Cham: Springer International Publishing. DOI: https://doi.org/10.1007/978-3-031-10220-2_9

[77] Chen, X., Laurent, A., Liao, Z., Jaccoud, S., Abdel-Sayed, P., Flahaut, M., ... & Hirt-Burri, N., (2023), Cutaneous Cell Therapy Manufacturing Timeframe Rationalization: Allogeneic Off-the-Freezer Fibroblasts for Dermo-Epidermal Combined Preparations (DE-FE002-SK2) in Burn Care. Pharmaceutics. 15(9): 2334. DOI: 10.3390/pharmaceutics15092334

[78] de Souza, T. A. J., Souza, L. R. R., & Franchi, L. P. (2019). Silver nanoparticles: An integrated view of green synthesis methods, transformation in the environment, and toxicity. Ecotoxicol. Environ. Saf.E. 171: 691-700.  DOI: 10.1016/j.ecoenv.2018.12.095

[79] Ezhilarasu, H., Vishalli, D., Dheen, S. T., Bay, B. H., & Srinivasan, D. K., (2020), Nanoparticle-based therapeutic approach for diabetic wound healing. Nanomaterials. 10(6): 1234. DOI: 10.3390/nano10061234

[80] Arriagada, F., Nonell, S., & Morales, J., (2019), Silica-based nanosystems for therapeutic applications in the skin. Nanomed.14(16): 2243-2267.  DOI: 10.2217/nnm-2019-0052

[81] Jafari, S., Derakhshankhah, H., Alaei, L., Fattahi, A., Varnamkhasti, B. S., & Saboury, A. A., (2019), Mesoporous silica nanoparticles for therapeutic/diagnostic applications.  Biomed. pharmacother.  109: 1100-1111. DOI: 10.1016/j.biopha.2018.10.167

[82] Chen, L., Zhou, X., & He, C., (2019), Mesoporous silica nanoparticles for tissue‐engineering applications.  Nanomed. Nanobiotechnol. 11(6): e1573.  DOI: 10.1002/wnan.1573

[83] Bellet, P., Gasparotto, M., Pressi, S., Fortunato, A., Scapin, G., Mba, M., ... & Filippini, F., (2021), Graphene-based scaffolds for regenerative medicine. Nanomaterials. 11(2): 404. DOI: 10.3390/nano11020404

[84] Mallaiah, D., (2020), Antibacterial activity by functionalized carbon nanotubes. Nanostructures for Antimicrobial and Antibiofilm Applications 63-77. DOI: https://doi.org/10.1007/978-3-030-40337-9_3

[85] Aggarwal, M., Husain, S., & Kumar, B., (2023), Role of Functionalized Carbon Nanotubes in Antimicrobial Activity: A Review. Functionalized carbon nanotubes (CNTs). 377-411. DOI:10.1002/9781119905080.ch15

[86] Cui, F., Sun, J., Ji, J., Yang, X., Wei, K., Xu, H., ... & Sun, X., (2021), Carbon dots-releasing hydrogels with antibacterial activity, high biocompatibility, and fluorescence performance as candidate materials for wound healing. J. Hazard. Mater. 406: 124330. DOI: 10.1016/j.jhazmat.2020.124330

[87] Saleemi, M. A., Kong, Y. L., Yong, P. V. C., & Wong, E. H., (2022), An overview of antimicrobial properties of carbon nanotubes-based nanocomposites. Adv Pharm Bull. 12(3), 449. DOI: 10.34172/apb.2022.049

[88] Karyel, M., & Akcelik, N., (2022, August). Antimicrobial wound dressing materials. In proceedings of IV of international agricultural, biological & life science conference AGBIOL 2022 (p. 421).

[89] Saadh, M. J., (2023), Green synthesis of silver nanoparticles using Piper betle exhibit high antimicrobial activity against Salmonella enteritidis and E. coli. Iraqi J. Vet. Sci. DOI:10.33899/ijvs.2023.136475.2585

[90] Lavaee, F., Yousefi, M., & Haddadi, P., (2020), Comparison of the fungicidal efficacy of photodynamic therapy with methylene blue, silver nanoparticle, and their conjugation on oral Candida isolates using cell viability assay. Curr. Med. Mycol. 6(4): 35. DOI: 10.18502/cmm.6.4.5332

[91] Puccetti, M., Donnadio, A., Ricci, M., Latterini, L., Quaglia, G., Pietrella, D., ... & Ambrogi, V., (2023), Alginate Ag/AgCl nanoparticles composite films for wound dressings with antibiofilm and antimicrobial activities. J. Funct. Biomater. 14(2): 84. DOI: 10.3390/jfb14020084

[92] Afjoul, H., Shamloo, A., & Kamali, A., (2020), Freeze-gelled alginate/gelatin scaffolds for wound healing applications: An in vitro, in vivo study. Mater. Sci. Eng. CMAT SCI. 113: 110957.  DOI: 10.1016/j.msec.2020.110957

[93] Pappachan, J. M., Cassidy, B., Fernandez, C. J., Chandrabalan, V., & Yap, M. H., (2022), The role of artificial intelligence technology in the care of diabetic foot ulcers: the past, the present, and the future. World J. Diabetes. 13(12): 1131. DOI: 10.4239/wjd.v13.i12.1131

[94] Ploderer, B., Brown, R., Seng, L. S. D., Lazzarini, P. A., & van Netten, J. J., (2018), Promoting self-care of diabetic foot ulcers through a mobile phone app: user-centered design and evaluation. JMIR diabetes. 3(4): e10105. DOI: 10.2196/10105

[95] Golledge, J., Fernando, M., Lazzarini, P., Najafi, B., & G. Armstrong, D., (2020), The potential role of sensors, wearables and telehealth in the remote management of diabetes-related foot disease. Sensors, 20(16), 4527.  DOI: 10.3390/s20164527

[96] Najafi, B., & Mishra, R., (2021), Harnessing digital health technologies to remotely manage diabetic foot syndrome: a narrative review. Medicina (Kaunas)ME. 57(4): 377  DOI: 10.3390/medicina57040377

[97] Cabal Mirabal, C. A., Berlanga Acosta, J., Fernández Montequín, J., Oramas Díaz, L., González Dalmau, E., Herrera Martínez, L., ... & Armstrong, D. G., (2019), Quantitative Studies of Diabetic Foot Ulcer Evolution Under Treatment by Digital Stereotactic Photography. J. diabetes Sci. Techno. 13(5): 821-826. DOI: 10.1177/1932296819853843

[98] van Netten, J. J., Clark, D., Lazzarini, P. A., Janda, M., & Reed, L. F. (2017). The validity and reliability of remote diabetic foot ulcer assessment using mobile phone images. Sci. Rep. 7(1), 9480. DOI: 10.1038/s41598-017-09828-4

[99] Jeong, Y. W., Chang, H. J., & Kim, J. A., (2020), Development and feasibility of a safety plan mobile application for adolescent suicide attempt survivors. Comput Inform Nurs. 38(8), 382-392. DOI: 10.1097/CIN.0000000000000592

[100] Foltynski, P., Ladyzynski, P., & Wojcicki, J. M., (2014), A new smartphone‐based method for w] Pak, C., In Jeon, J., Kim, H., Kim, J., Park, S., Ahn, K. H., ... & Heo, C. Y., (2018), A smartphone‐based teleconsultation system for the management of chronic pressure injuries. Wound Repair Regen. W. 26: S19-S26. DOI: 10.1111/wrr.2

[101] Kim, R. B., Gryak, J., Mishra, A., Cui, C., Soroushmehr, S. R., Najarian, K., & Wrobel, J. S., (2020), Utilization of smartphone and tablet camera photographs to predict healing of diabetes-related foot ulcers. Comput. Biol. Med.CO. 126: 104042. DOI: 10.1016/j.compbiomed.2020.104042

[102] Wang, L., Pedersen, P. C., Strong, D. M., Tulu, B., Agu, E., & Ignotz, R., (2014), Smartphone-based wound assessment system for patients with diabetes. IEEE. Trans. Biomed. Eng. 62(2): 477-488. DOI: 10.1109/TBME.2014.2358632

[103] Yap, M. H., Kendrick, C., Reeves, N. D., Goyal, M., Pappachan, J. M., & Cassidy, B., (2021), Development of diabetic foot ulcer datasets: an overview. Diabetic Foot Ulcers Grand Challenge. Springer. 1-18. DOI: https://doi.org/10.1007/978-3-030-94907-5_1

[104] Cassidy, B., Kendrick, C., Reeves, N. D., Pappachan, J. M., O’Shea, C., Armstrong, D. G., & Yap, M. H., (2021), Diabetic foot ulcer grand challenge 2021: evaluation and summary. In Diabetic Foot Ulcers Grand Challenge. Springer. 90-105. Wound area measurement Arti.f Organs. 38(4): 346-352. DOI: https://doi.org/10.1007/978-3-030-94907-5_7