Swimming microorganisms acting as nanorobots versus artificial nanorobotic agents: A perspective view from an historical retrospective on the future of medical nanorobotics in the largest known three-dimensional biomicrofluidic networks

Abstract

The vascular system in each human can be described as a 3D biomicrofluidic network providing a pathway close to approximately 100 000 km in length. Such network can be exploited to target any parts inside the human body with further accessibility through physiological spaces such as the interstitial microenvironments. This fact has triggered research initiatives towards the development of new medical tools in the form of microscopic robotic agents designed for surgical, therapeutic, imaging, or diagnostic applications. To push the technology further towards medical applications, nanotechnology including nanomedicine has been integrated with principles of robotics. This new field of research is known as medical nanorobotics. It has been particularly creative in recent years to make what was and often still considered science-fiction to offer concrete implementations with the potential to enhance significantly many actual medical practices. In such a global effort, two main strategic trends have emerged where artificial and synthetic implementations presently compete with swimming microorganisms being harnessed to act as medical nanorobotic agents. Recognizing the potentials of each approach, efforts to combine both towards the implementation of hybrid nanorobotic agents where functionalities are implemented using both artificial/synthetic and microorganism-based entities have also been initiated. Here, through the main eras of progressive developments in this field, the evolutionary path being described from some of the main historical achievements to recent technological innovations is extrapolated in an attempt to provide a perspective view on the future of medical nanorobotics capable of targeting any parts of the human body accessible through the vascular network.

FIG. 1.

The history of medical nanorobotics being represented through several eras—As depicted, the pre-translational era shows a significant increase in the number of demonstrations and proofs of concepts that are directly aimed towards medical interventions (identified in boxes having a thicker frame). This fact suggests that medical nanorobotics may soon begin to influence specific medical practices. Notice that further proofs of concepts were done during the pre-translational era, and further proofs of concepts will likely be demonstrated beyond the pre-translational era. These overlaps show that each era reflects more the level of maturity of the research efforts, while other activities from previous eras continue to be pursued.

FIG. 2.

Simplified representation of the vascular network that must be travelled to reach a tumor—Larger artificial or synthetic agents under closed-loop navigation control from feedback data gathered from a medical imaging modality are likely to dominate in larger blood vessels (left of the approximately limit of imaging blood vessels depicted in the figure). Gathering feedback information to navigate nanorobotic agents beyond the spatial resolution of existing medical imaging modalities will most likely require more autonomous nanorobotics agents. Although artificial agents designed to move more effectively in low Reynolds number conditions will challenge microorganism-based agents in the microvasculature and the interstitial spaces, the capability of some microorganisms to sense and find their ways in such complex networks under the influence of an external stimulus or from an appropriate embedded sensory capability will mostly yield superior targeting ratios, at least in the shorter term. To deliver payloads deep in the tumor, physiological routes such as the tumor interstitial microenvironment would need to be accessed mostly by transiting through the holes (having a maximum diameter of 2 μm) in the leaky vessels of the angiogenesis network that brings nutrients and oxygen to the tumor.