**8. Nanotechnology**

One technological field that is gaining increased interest in recent years is nanotechnology. Nanotechnology refers to devices or machines on the scale of microns and encompasses a wide range of technologies, including nanosensors, nanoparticles, and nanobots [119]. Nanotechnology opens doors to new therapeutics for a variety of reasons. Most obviously, the size of these devices allows access to previously inaccessible spaces. Due to the nanoscale size of these machines, they have higher surface area-to-volume ratios, leading to increased reactivity, and quantum effects play a larger role in interactions compared to macroscale sizes [120]. While nanotechnology does not necessarily need to involve artificial intelligence, these two fields may work synergistically to help surgeons in the future provide interventions not previously possible.

Because "nano-machines" operate on a scale much smaller than conventional robots, nanotechnology can allow for better and more selective delivery of drugs, such as chemotherapy agents. For instance, nanoparticle capsules may protect agents from enzymatic degradation or unfavorable pH environments or allow drugs to cross the blood–brain barrier [121, 122]. Additionally, one of the most powerful aspects of nanotechnology is the increased specificity of drug delivery targeting. Attaching specific moieties to nanoparticles can allow for targeted binding and release of encapsulated contents [123]. This application has implications in cancer treatment. Although chemotherapeutic agents are useful in treating cancer, these drugs often cause a wide range of adverse effects due to systemic distribution of these drugs. Various nanoparticle vessels, including nanocrystals, liposomes, and carbon nanotubes, can be fitted with surface coatings allowing cell-specific delivery of cancer therapies, ultimately reducing side effects [121, 124, 125]. AI may further increase the specificity of nanoparticle drug delivery through analysis of patterns of biomarkers. Through the integration of AI in biomarker sensing, the presence of different groups and concentrations of certain biomarkers can allow for classification of disease type and stage, enabling targeted and modifiable release of drugs from nanocapsules [126]. The selectivity of nanoparticles can also be leveraged for targeted ablation therapy for certain cancers. For instance, synthetic high-density lipoprotein nanoparticles were used to facilitate the delivery of photothermal ablative agents to hepatocellular carcinoma cells in mouse models, reducing tumor burden and stimulating local immune response [127]. Similar technologies could be applied to other ablation techniques, including radiation, cryoablation, and electroporation, in a wide variety of cancers [128].

Besides use in surgical oncology, nanotechnology may allow surgeons to operate on a nanoscale. Atomic force microscopy (AFM) may be an integral part of nanosurgery in the future. At its core, AFM consists of a microscopic cantilever fitted with a tip along with a laser and photodetector. As the tip of the AFM traverses along a surface, such as tissue, changes in the surface will move the tip and cause deflections of the laser, which can be detected by the photodetector [129]. The use of AFM enables the detection of several angstroms of change [129]. Furthermore, the force applied by the tip to the surface can be used to touch, push, and cut the surface, providing the ability to manipulate membranes, proteins, and DNA [130– 132]. Some experiments show the viability of using AFM to alter cell morphology and puncture cell membranes of individual cells [133]. Other uses of AFM in the future include signaling pathway identification, targeted drug delivery using specialized AFM tips, and disruption of cellular connections, such as dendrites, without interfering with cell bodies [130, 134]. Other potential "nano-machines" are limited only by human creativity and may include nanopropellors, nanowires, and "nanograbbers" (microscopic machines created by Leong et al. capable of performing *in vitro* biopsies) [134, 135].

Besides the direct manipulation of tissue, nanotechnology also makes possible a wide range of other surgeries. For instance, nanotechnology may increase the feasibility of islet transplantation in diabetes. While the results from the Edmonton protocol show that islet transplantation has promise in long-term glycemic control in type 1 diabetes, practicality of islet transplantation was limited by immune response against exogenous islet cells, causing gradual loss of islet function [136]. These concerns could be addressed by encapsulating islet cells with nanoparticles, with several approaches having been investigated to decrease immunogenicity of exogenous compounds [137–139]. Thus, alongside improving drug delivery, nanoparticle capsules may also be used to shield contents and suppress immune response.

Finally, nanoparticles may play roles in facilitating hemostasis and preventing infection after surgery. Many different hemostatic nanomaterials, such as mesoporous xerogels, polyphosphate-bound gold colloids, titanium dioxide (TiO2) nanotubes, and many others, have peen proposed [140]. While additional properties of each nanomaterial differ, they are thought to function by providing scaffolding for coagulation factors [140]. Antimicrobial nanoparticles may also be used for infection control in surgery. Postoperative infection carries a high rate of morbidity. An estimated 11% of deaths in the intensive care unit (ICU) resulted from surgical site infections [141]. Because of this need, antimicrobial nanoparticles may be able to address postsurgical infection risk. Silver nanoparticles have shown promise in accumulating within bacteria and disrupting various cellular processes, such as DNA replication and protein translation [142]. Silver nanoparticles have the potential to improve infection control, especially in orthopedic surgery. Orthopedic implants are susceptible to colonization of biofilm-forming bacteria, which can lead to high risk of morbidities [143]. One concern is the dose-dependent toxicity on human tissue attributable to silver nanoparticle use [144]. However, studies have indicated that osteocytes may be more resilient to this specific type of toxicity. Though silver nanoparticles initially decrease Saos-2 (human osteosarcoma cell line) survivability, Saos-2 cells seem to adapt to silver nanoparticle exposure over the course of 35 days *in vitro* [143]. Given these findings, it is possible that silver nanoparticles may be used to coat orthopedic implants that reduce the effect of osteoblast function (**Table 6**).




**Table 6.**

*Summary of included studies on nanotechnology.*
