1. Introduction

Electroporation is a nano-based method that is now used in different fields of industry. Irreversible and reversible electroporation can be used as a method for treating different cancers. Also, electroporation can facilitate the synthesis of membrane-coated nanoparticles which are useful in treating infectious diseases [1]. This field can come into cancer treatments too. In the past synthesis based on ultrasound (sono) was used and today electroporation is a better way [1]. Advanced materials such as nanostructures and nanocomposites can be used in various fields such as improving human life and environmental remediation, wastewater treatment, renewable and clean energy production, and storage [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]]. The advanced materials can be used in cancer treatments.

Electroporation is a recent technique for treating cancer [17]. There are two forms of this treatment: reversible [18] and irreversible [19]. Recent research articles have provided evidence of the successful potential of cancer treatment [20]. This method can eliminate tumors within seconds and does not pose any risks [21]. This technique eliminates the need for chemical, radiological, or surgical drugs, all of which require significant time and may cause side effects. Despite being a developing technique, its use in cancer treatment is still restricted [22]. Currently, piezoelectric nanogenerators have advanced significantly, thanks to their lightweight, portable, and recharge-free features [23]. As a result, they are highly appropriate for providing electrical energy, and their usage has considerably risen in the past few years [24]. They can be used as an electrical source for electroporation [25]. Electroporation has so far been effective in treating mouse sciatic nerve and has a promising potential for treating nerve cancer in the future [26]. This study involves a direct application on rat sciatic nerves to investigate the long-term effects of IRE on the nerve and provide evidence of its effectiveness in treating cancers that are situated near or involve critical nerves. Therefore, further research is required to explore the use of electroporation in treating nerve cancer.

2. Nerve cancer

The nervous system comprises two parts: 1) the peripheral nervous system, and 2) the central nervous system. The peripheral nervous system is made up of different parts of the nervous system that are situated beyond the central nervous system, including the cranial nerves, spinal nerves, their roots and branches, peripheral nerves, and neuromuscular junctions. Because it lacks the protection of a solid layer of bone or the blood-brain barrier, the peripheral nervous system is more susceptible to injuries or harm than the central nervous system [27].

PVDF nanofibers have been employed in the treatment of peripheral nerve damage [28,29]. The use of the piezoelectric effect for nerve repair was first introduced in 1987 [30], and in 2011, nanofibers with piezoelectric properties were utilized [31]. These nanofibers can provide conductive pathways for nerve growth due to their piezoelectric properties [28]. Near fields with high makeup degrees have been particularly advantageous [32,33].

MPNSTs are an uncommon form of cancer that originates in the nerve linings extending from the spinal cord to the body. These tumors were previously known as peripheral neural sheaths. Although they can develop in any part of the body, they commonly occur in the deep tissues of the legs, arms, and trunk. People with this type of cancer often experience weakness and pain in the affected area, as well as the appearance of a mass or growth. The primary treatment for malignant peripheral nerve sheath tumors is surgery, and in some cases, chemotherapy and radiotherapy may be advised [34].

The United States has a high incidence of nerve cancer treatment, with malignancy being the most common type. According to statistical analyses, factors such as sex, age, and race play a significant role in the occurrence of this type of cancer. Additionally, this cancer is one of the most lethal forms and requires extensive research. Other sources have also identified Europe as a hub for this type of cancer [35].

Nerve cancer can be treated through various methods, including surgery, chemotherapy, and radiation therapy [36]. It is anticipated that electroporation will also be introduced to this field, as it has been effective in treating sciatic nerves in rats thus far [37]. This topic will be further explored.

Cordycepin is a therapeutic drug utilized in the treatment of nerve cancer [38]. The treatment of nerve cancer is significantly impacted by genes, and gene therapy can be utilized to prevent and treat this type of cancer. Schwann cells are responsible for malignant peripheral nerve sheath tumors, and individuals with neurofibromatosis type 1 (NF1), an autosomal dominant disorder that increases the risk of developing tumors, are at a higher risk of developing MPNSTs, which often arise from benign Schwann cell tumors called plexiform neurofibromas. NF1 is characterized by mutations that result in the loss of function of the NF1 gene, which encodes neurofibromin, a protein that activates Ras GTPase and negatively regulates RasGTP-dependent signaling. To establish the role of specific cancer genes and pathways in different stages of MPNST development, growth, and/or metastasis, it is important to validate them using human cell-based models [39].

3. Piezoelectric materials

Intelligent piezoelectric materials have garnered considerable attention in human health applications during the progression of nanotechnology. As early as 400 BC, electrotherapy was commonly employed in medicine to treat neurological conditions using electrical stimulation. As batteries became available with the advent of nanotechnology, storing electricity became feasible, leading to greater interest in the electrical stimulation of tissues during the 1800s and the advancement of piezoelectric materials. Cells and tissues are highly responsive to electrical fields, even within cells, which is an exciting and novel aspect of piezoelectric materials for clinical use. Nanostructured piezoelectric interfaces are crucial in nanomedicine for stimulating cells and tissues, and piezoelectric devices are increasingly being recognized for their intelligent features, rather than merely serving as carriers for medication. Piezoelectric smart materials that are wearable, flexible, and affordable are promising tools for disease prevention, health monitoring, and the early prediction of diseases. Additionally, piezoelectric materials can promote disease recovery, but further research is necessary to investigate their exact mechanism, biocompatibility, and degradation. Despite the significant potential of piezoelectric nanostructures in the biomedical field, the biocompatibility of nanomaterials, preservation, degradability, and accumulation in complex systems outside of the body must be further evaluated before actual clinical implementation [24].

Interdisciplinary drug delivery involves the fields of polymer chemistry, medicine, materials science, biology, and increasingly, electrical engineering. Electrical engineering can effectively contribute to the design of intelligent and functional drug delivery systems, as recent advancements in nanoelectronicsare expected to bring about an increase in electronic integration in intelligent drug delivery systems in the years ahead. Such systems are electronically and fully controllable, providing dynamic control over drug release profiles and timing. For instance, these systems can synchronize chemotherapy regimens' release intervals with the patient's circadian rhythm. By adding sensory capabilities, fully automated drug delivery devices can be developed, capable of sensing blood content, detecting changes in specific parameters (e.g., sugar levels), and releasing the appropriate payload. The effectiveness of drug delivery systems in delivering therapeutic shipments to target sites is crucial, but drug compliance and adherence are other factors that impact overall therapeutic efficacy. The development of low-cost and highly functional devices that can stay in the human body for extended periods, possibly even a lifetime, has the potential to enhance public health and reduce long-term healthcare expenses. Using digital and electronic systems is a highly optimistic method for achieving these objectives [24].

In the field of drug delivery, sound waves, magnetic fields, electromagnetic radiation, and electric fields can serve as stimulants for intelligent drug carriers. Forinstance, sound waves can activate drug carriers to release drugs. Additionally, electroporation is a technique that employs electric fields, while field cancer treatment uses electromagnetic fields and conductive drug delivery can be stimulated using a source of electric fields [[40], [41], [42], [43], [44]].

By incorporating conductive polypyrrole material, a smart and responsive electrical microneedle has been created. Furthermore, a drug delivery system that can be controlled has been developed using piezoelectric nanogenerators that collect and convert mechanical energy into electrical energy, allowing for the regulation of drug release [45].

A recent study employed a nanotube that contains piezoelectric materials to regulate drug release. This mechanism releases the drug by generating tail regions [46].

For instance, it is anticipated that piezoelectric drugs will be utilizing cordycepin to treat neurodegenerative cancer future, soon.

The integration of electroporation with intelligent drug delivery can be achieved by using a piezoelectric component as an electrical field for electroporation and as a means of activating a drug carrier to release the drug, similar to the mechanism described in source 9 (in this source the nanogenerator in band-aids by applying mechanic pressure on them, they change it to electricity. This electricity can release the drugs which are corporated on the band-aids. If we use this electricity as a source of electroporation, we can have both electroporation and intelligent drug delivery which is a topic for further work.). This is an anticipated novel application of piezoelectric materials.

4. Electroporation

High-voltage electrical pulses can cause membrane electroporation, leading to a transient increase in membrane permeability when cells are exposed to them [47]. In reversible electroporation, the increased permeability is temporary, and the cells can repair their plasma membranes and restore reversible electroporation homeostasis, allowing for the impermeable delivery of molecules. In the field of electrochemistry, the electronic transmission of genes is utilized for cell-to-cell communication, such as nucleic acid chemotherapy [18,48,and49]. Nonetheless, irreversible death can occur when the number of pulses and field amplitude is higher [19]. The effectiveness of electroporation-based therapies may be influenced by cellular death mechanisms due to the use of different electrical pulse parameters and conditions, which are yet to be determined [48].

In Irreversible electroporation, the thermal effects are eligible (due to Joule heat generation during pulsing electricity). This heat increases by higher voltages so, this heat should be controlled for having minimum thermal damage [50]. In electroporation the osmotic balance between the in and out cell disruption, if the disruption is temporary so, reversible electroporation occurs, and if not irreversible one occurs. In electroporation, the heat sink and extracellular damage do not occur [51].

Electric field intensity, duration, amount of high voltage, AC orDCt, number of pulses, the material, and geometry of the electroporation needle are the parameters that should be optimized for each electroporation [25].

5. Cell damage and cell death

Cells possess the ability to adapt and maintain their viability and homeostasis in response to physiological demands. When the stimulus, whether internal or external, becomes excessive, or if the cell is no longer capable of adapting the term “cell damage” is employed. The damage can either be reversible or irreversible, depending on whether it is modifiable and nonfatal or fatal, respectively, without any injury. Irreversible damage leads to cell death, as illustrated in Fig. 1. The “point of no return,” which marks the transition from reversible to irreversible damage, is critical in designing therapeutic approaches to prevent or induce cell death after treatment intervention [52].

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Fig. 1. Illustrates the mechanisms involved in irreversible electroporation, including the A) Application of electricity to the cell, B) Cell death, C) The body's response to cell death, and D) The regeneration of tissue [53]..

Mechanisms of cellular damage encompass DNA and protein degradation, elevated reactive species (RS), entry of calcium ions, degradation of mitochondria and membranes, and increased adenosine triphosphate (ATP) [[52], [54], [55]].

A more recent technique called high-frequency electroporation has been utilized, which does not cause muscle contraction and therefore eliminates the need for anesthesia. Consequently, this method is considered the most favorable approach for electroporation [56].

A novel hybrid technique for electroporation involves combining it with a polymer membrane, which works in conjunction to induce the death of cancer cells [57].

Another study incorporated a potent tumor vaccination strategy in which a tumor antigen inhibitor was employed in conjunction with irreversible electroporation [58].

In a different study, a bipolar electrode was employed, and the outcomes were compared to those obtained with a unipolar electrode through simulation. The findings indicate that bipolar electrodes are highly advantageous since they are less complicated and do not encounter issues with using multiple electrodes [59].

Another study implemented preheating as a means of enhancing electroporation efficacy [60].

Pancreatic cancer treatment has shown chemotherapy to be a more rapid approach than irreversible electroporation. Nevertheless, electroporation has generally been introduced with greater effectiveness [61].

An electroporation technique employing a bipolar electrode was utilized, which demonstrated resistance to corrosion caused by stainless steel and platinum. The findings revealed that this approach is considerably simpler as it eliminates the requirement for multiple electrodes and the impact of the electrode distance parameter, therefore making it highly advantageous [62].

The concept of cell death through electroporation was initially confirmed in 1967 [63].

In 1982, high-voltage electrical pulses were used to demonstrate the electrical transmission of genes, which was the first instance of DNA being passed onto a cell. This was accomplished through reversible electroporation [64].

Another study employed irreversible electroporation and simultaneous stimulation of interferon genes, which yielded excellent outcomes [65].

The combination of electroporation and chemotherapy was utilized for drug delivery in 2016, where reversible electroporation occurred alongside irreversible electroporation. This was the first instance of such a combination, and it demonstrated the potential of combining chemotherapy with electroporation [66].

None of the studies on electroporation have ever focused on the treatment of nerve cancer, and there is a lack of research in this area. However, intelligent drug delivery may be a more beneficial approach to cancer treatment due to the successful implementation of straightforward methodologies. Nonetheless, intelligent drug delivery is still an emerging field, and its efficacy in cancer treatment has yet to be fully realizeded.

6. Conclusions

Current literature on electroporation has highlighted its expanding applications, streamlining of the procedure, and exploration for use in various types of cancer. Electroporation utilizes electric fields that can be applied using triboelectric nanogenerators [67] or combinations of piezoelectric and triboelectric materials [68], which presents an excellent avenue for future research (using nanogenerators as electric sources for electroporation which has not been studied before). ToitsWhen it comes to treating cancer, irreversible electroporation (IRE) is effective in killing cancer cells, while reversible electroporation (RE) can aid in the delivery of drugs to the cells. This combination makes IRE a promising strategy for treating nerve cancer and other forms of cancer. Piezoelectric materials can function as both a source of electricity for electroporation and as an activator for drug carriers. Moreover, artificial intelligence is a promising approach to discovering new drugs [69]. Discovering new drugs which are more useful for treating cancer is important. Also, based on previous studies using electroporaticombineding with drug delivery, showed better results vs dusingooneof the alone. Also, using artificial intelligence for discovering new drugs minimize the cost and time. By utilizing personalized knowledge and learning from the solutions it generates, artificial intelligence can address not only specific but also complex problems. The pharmaceutical industry is currently facing challenges in sustaining its drug development programs due to increased R&D costs and reduced efficiency, and artificial intelligence can potentially overcome these obstacles. Moreover, using nanogenerators as an electrical source for electroporation is a green way which helps the environment and it is a clean energy.

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Funding

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Authors' contributions

Dr. Sedigheh Aghayari (the sole author).