Biomedical instrumentation and nanotechnology for image-guided cancer surgery
Mancini, Michael C.
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Once diagnosed, cancer is treated by surgical resection, chemotherapy, radiation therapy, or a combination of these therapies. It is intuitive that physically and completely removing a solid tumor would be an effective treatment. A complete resection of the tumor mass, defined by surgical margins that are clear of neoplasia, is prognostic for a decreased chance of cancer recurrence and an increased survival rate. In practice, complete resection is difficult. A surgeon primarily has only their senses of touch and sight to provide "real-time" guidance in the removal of a tumor while in the operating room. Preoperative imaging can guide a surgeon to a tumor but does not give a continuous update of surgical progress. Intraoperative pathology is limited to a few slides worth of samples: a product of its time-consuming nature and the limited time a patient can remain under general anesthesia. Technologies to guide a surgeon in effecting complete resection of a tumor mass during the surgical procedure would greatly increase cancer survival rates by lowering rates of cancer recurrence; such a technology would also reduce the need for follow-up chemotherapy or radiation therapy. Here, we describe a prototype instrumentation system that can provide intraoperative guidance with exogenous optical contrast agents. The instrumentation combines interactive point excitation, local spectroscopy, and widefield fluorescence imaging to enable low-cost surgical guidance using FDA-approved fluorescent dyes, semiconductor quantum dots (QDs), or surface-enhanced Raman scattering (SERS) nanoparticles. The utility of this surgical system is demonstrated in rodent tumor models using an FDA-approved fluorescent dye, indocyanine green (ICG), and is then more extensively demonstrated with a pre-clinical study of spontaneous tumors in companion canines. The pre-clinical studies show a high sensitivity in detecting a variety of canine tumors with a low false positive rate, as verified by pathology. We also present a fundamental study on the behavior of quantum dots. QDs are a promising fluorophore for biological applications, including as a surgical contrast agent. To use QDs for in vivo human imaging, toxicity concerns must be addressed first. Although it is suspected that QDs may be toxic to an organism based on the heavy-metal elemental composition of QDs, overt organism toxicity is not seen in long-term animal model studies. We have found that some reactive oxygen species (ROS) generated by the host inflammatory response can rapidly degrade QDs; in the case of hypochlorous acid, optical changes to the QDs are suggestive of degradation occurring within seconds. It is well-known that QDs are sequestered by the immune system when used in vivo---we therefore believe that QD degradation through an inflammatory response may represent a realizable in vivo mechanism for QD degradation. We demonstrate in an in vitro cell culture model that immune cells can degrade QDs through ROS exposure. Knowledge of the degradative processes that QDs would be subject to when used in vivo informs on adaptations that can be made to the QDs to resist degradation. Such adaptations will be important in developing QD-based contrast agents for image guided surgery.