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Conference Session A3 Paper #62 Disclaimer—This paper partially fulfills a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering. This paper is a student, not a professional, paper. This paper is based on publicly available information and may not be provide complete analyses of all relevant data. If this paper is used for any purpose other than these authors’ partial fulfillment of a writing requirement for first year (freshman) engineering students at the University of Pittsburgh Swanson School of Engineering, the user does so at his or her own risk. THE APPLICATION OF PH SENSING NANOPROBES TO CARCINOMA DETECTION AND IMAGING Rachel Lau, [email protected], Mahboobin 10:00, Chloe Feast, [email protected], Mahboobin 10:00 Abstract---Current methods of tumor imaging fall short in producing a distinct representation of cancerous cells. A recent technological advance that addresses the shortcomings of previous methods of tumor imaging is the pH sensing nanoprobe. The topic of this paper is the use of pH sensing nanoprobes, such as the PINS nanoprobe, to detect and image epithelial cancer cells exhibiting acidosis. These nanoprobes detect tumor sites more accurately than other methods of cancer detection, providing doctors with an intricate internal map of a patient’s case before and during surgery. By examining journal articles that focus on carcinomas and pH detecting nanoprobes, as well as recent research in this field, we will detail the specific mechanisms of this technology that give doctors an upper hand when compared to previously used detection and imaging technologies. After explaining the current and future applications of this pH sensing nanoprobes, we will examine the limitations of this technology and the questions it raises with regards to sustainability in the areas of public health and biodegradability of byproducts. Through this objective lens, we will prove that pH sensing nanoprobes provide an effective method of detecting cancerous epithelial cells and guiding surgeons through operations on malignant tumors that will significantly and sustainably benefit the oncological field. Key Words—Carcinoma detection, Fluorophores, NIR Fluorescence Imaging, pH sensing nanoprobe, PINS nanoprobe, Tertiary amine groups, Tumor acidosis INTRODUCTION TO PH SENSING NANOPROBES PH sensing nanoprobes represent the intersection of technological innovation and practical, real-world application. Capitalizing on an abnormal pH balance between the intracellular fluid of a cancer cell and its surroundings, pH sensing nanoprobes offer a new method of imaging tumors precisely. An article by Tian Zhao, Gang Huang, Yang Li, Shunchun Yang, Saleh Ramezani, Zhiqiang Lin, Yiguang Wang, Xinpeng Ma, Zhiqun Zeng, Min Luo, Esther de Boer, Xian-Jin Xie, Joel Thibodeux, Rolf A. Brekken, Xiankai Sun, University of Pittsburgh, Swanson School of Engineering 1 Submission Date: 03.31.2017 Baran D. Sumer, and Jinming Gao, all of the Biomedical Engineering News section of the scientific journal Nature details the behaviors and possibilities of pH sensing nanotechnology [1]. The same article asserts that once administered in the body, the nanoprobes fluoresce in regions where pH levels have fallen below the normal homeostatic range, allowing for more accurate visualization of cancerous growths and improvements in real time guided surgery. Such benefits are best reaped when the nanoprobe is applied to skin cancer patients, as pH sensing nanoprobes are most effective when used to identify and image epithelial cancer cells [1]. Given that skin cancer is a highly common form of cancer, yet also easily treatable when found early enough, it can be seen that pH sensing nanoprobes have the potential to greatly improve the way the medical field currently addresses this disease. Even in light of the numerous benefits of pH sensing nanoprobes compared to other methods of carcinoma detection, the sustainability of this technology must be taken into account to provide a holistic evaluation of pH sensing nanoprobes. The potential improvements to quality of life of cancer patients and biodegradability of byproducts are offset by uncertainties about public health in the future which make the sustainability of pH sensing nanoprobes another important aspect to consider. A thorough analysis of the benefits and drawbacks of this new technology will shed light on the net positive gain that we can expect from continued development of pH sensing nanoprobe technology going forwards. THE IMPORTANCE OF SKIN CANCER AS A FOCUS Few people will find their lives untouched by cancer at some point. Cancer is a disease well-known to most, perhaps because there are such a broad range of cancer types that affect upwards of 14.5 million people in the United States alone, according to the National Cancer Institute [2]. While there are many different forms of this disease, this paper addresses the most common and easily treated type where a new technology would have the greatest impact—skin cancer. According to the Skin Cancer Foundation website, in recent years, skin cancer has become the most prominent cancer diagnosis throughout the United States. Common types of skin cancer such as basal cell and squamous cell carcinomas Rachel Lau Chloe Feast affect around half of Americans by the time they reach retirement age [3]. In addition, the American Cancer Society asserts that basal and squamous cell cancers “can be cured with fairly minor surgery or other types of local treatments” [4]. While these types of carcinomas are common in the United States today, with proper detection, they are usually treated and cured successfully, speaking to the need for precise carcinoma detection that pH sensing nanoprobes can provide. extracellular environment is known as cellular acidosis [5]. pH sensing nanoprobe technology operates using the principles of acidosis, detecting and imaging tumors based on the body’s own indicators of cancerous cells. Shortcomings of Previous Detection Methods Numerous processes of tumor detection and imaging have been developed to capitalize on the characteristics that set normal and cancer cells apart. Knowledge of the drawbacks of other cancer detection and imaging technologies is essential to understanding the significance of pH sensing nanoprobes as a precise method of carcinoma detection. Until recently, the most common methods of tracking cancer cells included biomarker tracking and Positron Emission Tomography (PET) scans. The aforementioned article by T. Zhao et. al., in the scientific journal Nature details both technologies. Biomarker based detection traces biomarkers, or biological molecules, that are specific to cancer cells. These include receptors on the membranes of cells, and certain antigens that exist in the presence of tumors [1]. Each type of body tissue displays variations of cell biomarkers [1]. Additionally, the Nature article states that biomarkers vary throughout a population because of phenotypic and genetic differences [1]. For this reason, imaging based solely on cell-biomarkers is not the most effective method of cancer detection because it does not account for such tissue and individual differences. In response to discrepancies in genetic display of cellbiomarkers, other researchers have focused on imaging using PET scans which track increased glucose consumption in cancerous cells. According to T. Zhao et. al. PET scans take advantage of the Warburg effect, a tendency for cancerous tissue producing lactic acid to exhibit a high glucose uptake [1]. The PET scans capture areas of the body demonstrating elevated glucose consumption levels. One drawback of this method, however, is the naturally high consumption of glucose in some bodily tissues gives rise to false positives. This causes extra areas to light up on the PET scan. In addition to false positives, T. Zhao explains that PET detection also produces relatively unclear pictures which are little help during surgery of delicate areas [1]. In light of the drawbacks of other cancer detection methods, pH sensing technology for carcinomas is a worthwhile focus for the healthcare field. CHARACTERIZATION AND DETECTION OF CANCER The prevalence of cancer in our society strengthens a demand for new methods of cancer detection and imaging. Cancer imaging techniques rely upon a variety of biological indicators of cancer cells to image tumors, however potential for false positives and imprecision of the final image render some of these methods undesirable. Before a comparison can be drawn between pH sensing nanoprobes and pre-existing forms of tumor imaging, the basic biological indicators of cancer cells must be examined. This knowledge allows for the development of a basic understanding of cancer detection technology. Identifiable Characteristics of a Cancer Cell On a cellular level, cancerous cells can be identified by unusual pH levels, and the abnormal behaviors induced by those pH levels. Specifically, an article on tumor hypoxia by Johanna Chiche, Ph.D. in cellular biology, reports that “recent techniques using nuclear magnetic resonance 31P spectroscopy…have confirmed the capacity of tumor cells to acidify the extracellular environment and to maintain a rather neutral/alkaline pH” [5]. Thus, this tumor acidosis process serves as an indicator for cancer-cell detection, as stated by Chiche [5]. In sum, the consistent trend towards an acidic environment around cancer cells allows for successful tumor detection via pH levels. As a tumor develops it begins to exhibit hypoxia, or oxygen deficiency, which increases the acidity of the environment around the malignant cells. Chiche explains this phenomenon in detail. Consumption of resources in blood surrounding tumors, glycolysis, and lactic acid production all contribute to a decrease in oxygen concentration near the cancer cell. In response to decreased oxygen content, a proton gradient forms [5]. The high concentration of H+ ions outside of the cell is what decreases the pH of the extracellular fluid. The body attempts to respond to the imbalance in pH by producing other acidic or basic compounds, but this results in the malfunction of cellular proteins. Na+/H+ exchangers in the cell membrane work overtime to prevent the cell’s concentration of H+ ions from increasing, which would lower pH and acidify the cell. Chiche states that this process of neutralizing the intracellular fluid while acidifying the Improved Detection Using pH Sensing Technology Nanotechnology has risen to the top of the hotlist of scientific research, and its specific application to the field of cancer is of great interest. Tuan Vo-Dinh of the Departments of Biomedical Engineering and Chemistry at Duke University explains in his article “Nanosensing at the Single Level” that nanoprobes and nanosensors can be injected into the bloodstream to carry out processes in vivo, or in the body. Equipped with bioreceptors on fiber tips, much like nerve 2 Rachel Lau Chloe Feast endings on finger-tips, sensors can seek out varying pH levels indicative of cancer cells [6]. The probes can cause on-site fluorescence once cancerous tissue is located, and deliver a clear image of the affected area. Delving into deeper applications of this technology is the successful development of the PINS nanoprobe. The PINS nanoprobe has been proven by T. Zhao and his colleagues to be most effective when applied to superficial tissues [1]. Carcinomas such as skin cancer include defective basal and squamous cell groups that turn into tumors inside superficial tissues [1]. Herein lies the connection between pH sensing nanoprobes and a focus on skin cancer. In sum, the PINS nanoprobe is most effective when dealing with skin cancers, see Figure 1 below. understanding both the administrative procedures and functional components of this type of nanotechnology. With the applications of precision carcinoma imaging and real-time guided surgery in mind, the specific details of pH sensing nanoprobes will be addressed to explain why these significant benefits are possible. Specific examination of the PINS nanoprobe, a new near infrared resonance fluorescence imaging probe, will provide a view of this pH sensing nanotechnology in operation. Introducing pH Sensing Nanoprobe Technology to the Body Before examining how pH sensing nanoprobes activate and fluoresce in response to low extracellular pH, it is important to address how they are administered. To be able to properly image cancerous growths in the body, pH sensing nanoprobes must be introduced to the bloodstream via an intravenous injection. According to the article published in Nature by T. Zhao et al., this injection must take place twentyfour hours prior to the imaging process [1]. This provides sufficient time for the nanoprobes to circulate throughout the body and activate in areas of abnormally low pH. After the twenty-four-hour period, T. Zhao et al. report that the fluorescent response of pH sensing nanoprobes can be picked up by clinical cameras such as the SPY Elite [1]. Thus, hospital technology on the market can be used in conjunction with these nanoprobes, increasing their appeal as a method of precise imaging. In addition to a twenty-four-hour time restriction, Quentin le Masne de Chermont, Ph.D. in nanotechnology applied to biology, addresses the steps that must be taken in response to auto fluorescence when administering a nanoprobe. He asserts that the nanoparticles must also be treated with ultraviolet light prior to injection to protect against the interference of auto fluorescence in the body [7]. Furthermore, in an article examining tissue auto fluorescence, Monica Monici of the Centre of Excellence in Optronics in Florence, Italy explains that auto fluorescence is a natural occurrence within cells whereby external radiation excites molecules within lysosomes and mitochondria, causing body cells to fluoresce [8]. In other words, organelles within body cells absorb energy and emit light, preventing the formation of a clear image using nanoprobes. However, treatment of probes prior to injection protects against the impeding effects of auto fluorescence. FIGURE 1 [1] Comparisons of PET Scans of Tumors This image from the article by T. Zhao et al., published in the respected scientific journal Nature, compares PET scans of tumors based on glucose consumption and fluorescence scans based on abnormal pH levels. While these images depict non-superficial tumors, they serve as an effective comparison to human superficial tumors because mice are so small. On the left of the above figure is a white light photo as the human eye would see tumors of two sizes in subject mice. The middle set contains PET scans of the same mice. At first glance, these shots are incredibly blurry in comparison to the photos on either side. Additionally, extra tissues light up as indicated by the overlaying black arrows, displaying false positives in areas that also consume high amounts of glucose. The right panel consists of images taken after injection of the PINS nanoprobe. One can see that the tumors glow in high definition, and that no excess areas fluoresce [1]. Therefore, PINS and the group of pH sensing nanoprobes it represents stands as the imaging method in this test that produces the most useful results. TECHNOLOGY UNDERLYING THE PH SENSING NANOPROBE PH sensing nanoprobes evidently present a unique and precise new method of imaging tumors in comparison to previously used glucose consumption or biomarker tracking strategies. As such, attention should be devoted to 3 Rachel Lau Chloe Feast and any activated nanoprobe occurs because of an abnormally low pH. FIGURE 2 [9] Effect of Auto Fluorescence on Performance of Fluorophores The leftmost image from an article in the journal Biophotonics International shows a fluorescent probe with no auto fluorescence correction [9]. The right image shows a fluorescent probe that has been corrected for the auto fluorescence of the cells it is imaging [9]. The difference between images produced with unexcited and excited nanoprobes seen in Figure 2 highlights the importance of treating the probes to maintain the clarity and the precision benefits of pH sensitive tumor detection. Components of the PINS Nanoprobe In addition to understanding the administrative and corrective procedures associated with this nanotechnology, it is important to understand the parts of the nanoprobe and their respective functions. One of the important characteristics of this technology according to the article by T. Zhao et. al. is its ability to “transform pH from an analogue biologic signal to a discrete exponentially amplified output” [1]. The two components of the pH sensing nanoprobe essential to this function are the fluorescent dye and tertiary amine group. Tertiary amine groups detect the “biologic signal” discussed in the Nature article by turning on and off in response to irregular extracellular pH values [1]. What sets this technology apart is that once detected, pH irregularities produce a local, traceable response via the excitation of a fluorescent dye molecule. This fluorescence reaction allows external imaging devices such as clinical cameras to be used to image cancerous growths based on extracellular pH. FIGURE 3 [1] Graph of the PH Sensitivity of PINS Nanoprobe The above graph from T. Zhao and his colleague’s experiment on the PINS nanoprobe highlights the sensitivity of the probe to pH. As environmental pH drops below 6.9 there is a rapid shift in the nanoprobe from no fluorescence to complete fluorescence. As can be seen in Figure three, there are two distinct active and inactive states of the PINS nanoprobe that mimic “transistor like responses,” as identified by T. Zhao et. al. in the experiment [1]. Thus, the nanoprobe exhibits either an off or on state based on environmental pH, allowing for precise imaging that responds to very small changes in these pH values. Imaging with Fluorophores Detection with pH Responsive Amines The pH sensing capabilities of these nanoprobes would be wasted without a mechanism to track and express the observed pH variations. This mechanism comes in the form of a fluorophore, otherwise known as a fluorescent molecule. Fluorophores operate on the basis of excitation and emission of electrons. As expressed in an article on fluorescent probes from the Thermo Fisher corporate website, once in the body, an external source of energy must be applied to the fluorescent probe to excite fluorophore electrons [11]. This external energy source causes the probe’s fluorophore electrons to jump to a higher energy level. In the time before the electrons decay back down to ground state, the same Thermo Fisher article asserts that “energy is dissipated by molecular collisions” [11]. In other words, the electrons lose energy through interactions with other molecules in their excited state. This loss may be observed in Figure 4 where the energy of the electron in its excited state is portrayed as a downward sloping curve. As discussed previously, hypoxia in cancerous cells induces an acidic extracellular pH that may be detected by pH sensitive nanoprobes. In looking at the range of pH values sensed by the PINS nanoprobes in specific, an appreciation for the precision of pH sensing nanoprobes in general may be obtained. It is important to note that the amine groups included in pH sensing nanoprobes are responsible for responding to changes in pH that delve below a certain transition pH value. Given that pH sensing nanoprobes are injected into the bloodstream, the pH of blood is a significant consideration when evaluating the range of pH values that activate the nanoprobe. One key detail that allows for proper function of this nanotechnology is that, according to an article on bodily pH by Rich Rodriguez M.D., the typical pH of blood is 7.4 [10]. This is significantly higher than the pH of 6.9 at which the PINS nanoprobe is activated [1]. Thus, the normal pH conditions of the body will not activate the PINS nanoprobe, 4 Rachel Lau Chloe Feast FIGURE 5 [1] Survival Rates of Mice Receiving Various Types of Guided Surgery Figure 5 from an article published by T. Zhao et.al presents survival rates of mice operated on with different methods over 160 days. The Tumor Acidosis Guided Surgery (TAGS) in red demonstrated the highest survival rates of mice over the 160 day period when compared with white light surgery and other debulking methods [1]. In Figure 5, it can be seen that TAGS using the PINS nanoprobe generated the highest survival rates in the mice of the experiment. This particular experiment from the journal Nature using the PINS nanoprobe with mice found “13 out of 18 animals (72%) showing cures 150 [days] post-operatively” with a p value of less than 0.0001 [5]. According to author Stanley E. Lazic in his publication on Experimental Design for Laboratory Biologists, a p value below 0.05 indicates a statistically significant difference between two sets of data [12]. As such, because evaluation of this experiment’s data produced a p value lower than 0.05, it can be concluded that TAGS statistically significantly increases survival rates in mice in the period following surgery when compared with other methods of guided surgery. Experiments such as these are an important early step in analyzing the effectiveness of pH sensing nanoprobes. Though the subjects of this experiments were mice, the insight gained from the results allows projections to be made on the future effectiveness of this technology in humans. Evidence that this technology provides a significant benefit when compared to other forms of guided surgery is important to consider when assessing whether or not to bring this technology to market. FIGURE 4 [11] Diagram of Electron Excitation in Fluorophores Figure 4 diagrams the process of excitation and emission of fluorophore electrons. The energy dissipation that occurs in the excited electron is important because it allows scans to distinguish between the light applied to the system and the light emitted by the system [11]. As can be seen in Figure 4, The light emitted by the decaying electron has less energy than the light applied to the system, and therefore may be isolated when performing a scan. The production of precise images with pH sensing nanoprobes is possible because only nanoprobes activated by regions of abnormally low pH will emit this lower energy light in this process APPLICATIONS OF THE PINS NANOPROBE With its unique pH sensing and fluorescing mechanisms, the PINS nanoprobe serves as an excellent example highlighting the potential of pH sensing nanoprobes. Looking at the success of the PINS nanoprobe in animal trials so far, the future prospects of pH sensing nanoprobes in the healthcare market may be extrapolated. Guided Surgery in Animal Trials One of the major benefits of using pH sensing nanoprobes to image tumors is the potential for real time guided surgery with higher postoperative survival rates. The precise images produced with this technology help surgeons identify and remove all parts of a tumor, leaving no traces that would facilitate a return of the cancer in question. To observe these higher postoperative survival rates that accompany guided surgery with pH sensing nanoprobes, we must look to animal trials. In the experiment performed by T. Zhao et. al., pH sensing nanoprobes were shown to increase survival rates in experiments on mice with head and neck cancer [1]. Future Applications in Human Trials While pH sensing nanoprobes such as the PINS nanoprobe have demonstrated considerable success in animal trials with mice, there are still many steps that must be taken before this technology may be used to image tumors and guide surgery in humans. One of the most significant barriers at present is the approval of the Food and Drug Administration (FDA). Ultimately, pH sensing nanoprobes need to be deemed safe for human use. The purpose of this technology is to help with the detection and treatment of individuals with 5 Rachel Lau Chloe Feast cancer, and if the technology produces net negative effects in the body then it is unfit for medical application. According to the FDA’s website, a biologic like pH sensing nanoprobes must be approved by the Center for Biologics Evaluation and Research branch, a multi-step process that starts with the technology submitting an “Investigational New Drug application (IND)” [13]. This must occur before any clinical trials may be performed on humans to ensure the safety and wellbeing of participants in such trials. Thus, the next step for this technology would be obtaining an IND to move into a phase of clinical trials. In this process, the benefits, including tumor acidosis guided surgery and more accurate imaging, must be weighed against the risks of this technology. For example, in the article by T. Zhao et. al., one of the risks presented in the PINS nanoprobe animal trials were “temporary body weight loss and an acute toxicity response at high doses” [1]. In addition, according to an article on effect of nanomaterials on public health from the University of Plymouth by R.D. Handy and B.J. Shaw, some studies have identified an association between “manufactured nanomaterials” and oxidative stress, or the alteration of a cellular response to injury by the presence of oxygen radicals [15]. Thus, the harmful effects of high concentrations of nanoprobes and a potential link between nanomaterials and oxidative stress in cells are two of the largest public health concerns raised when evaluating this technology. An IND will determine whether these risks are small enough to allow for clinical trials, or whether the technology is unsafe for human use. In sum, significant investigation must still be performed on pH sensing nanoprobes before human clinical trials even become an option. Medicine’s Medline Plus website, PET scans have a degree of risk resulting from the usage of x-ray scans that expose the body to potentially cancer causing radiation [16]. If the risk of imaging with pH sensing nanoprobes is smaller or equal to such a risk of PET scans, and there are significant advantages of precision imaging and guided surgery that accompany pH sensing nanoprobes, then pH sensing nanoprobes can be considered sustainable. Unfortunately, this risk contextualization will only be possible as continued research is performed on pH sensing nanoprobes. Clearly, there is much additional research needed before pH sensing nanoprobe technology can become available on the market. Despite this, the promise that pH sensing nanoprobes have shown in animal trials prompts continued investigation into the benefits of human use moving forwards. Sustainability of Nanoprobes with Respect to Public Health One of the most substantial limitations of pH based cancer detection is a restriction on the types of cancer that may be imaged. According to T. Zhao et. al., regions of the body that normally demonstrate a pH lower than the 7.4 of most bodily fluids will fluoresce under pH sensing nanoprobes even if there is no cancer present [1]. As such, pH sensing nanoprobes cannot be used to detect or image cancers in areas of the body with a naturally low pH, which Rich Rodriguez M.D identifies as the stomach or small intestine [10]. While pH sensing nanoprobes produce significantly clearer and more focused images of tumors in areas of the body with a normal pH of around 7.4, they cannot be used with respect to acidic areas of the body. Another restriction on the use of pH sensing nanoprobes is the depth to which the light needed for activation of the nanoprobes will penetrate. One of the reasons that T. Zhao et. al. asserts that pH sensing nanoprobes are best used for carcinoma or skin cancer detection is that the light used in the fluorescing procedure does not need to penetrate many layers of bodily tissue to reach the areas in which cancer is being identified [1]. While this method is successful for skin cancer detection, in subjects larger than the mice specimen used in ANALYZING THE BENEFITS AND LIMITATIONS OF PH SENSING NANOPROBES When compared with methods of imaging such as PET scans or biomarker detection, pH sensing nanoprobes demonstrate a significant improvement boasting clearer images and the opportunity for applications such as guided surgery in the future. Though these are some obvious benefits, certain biological limitations and ethical considerations must also be taken into account to produce a holistic understanding of all sides of this nanotechnology. Limitations of PH Sensing Nanoprobes in Cancer Detection For pH sensing nanoprobes to be considered sustainable, their long-term effects on public health have to be evaluated beyond the standards required for the initiation of clinical trials with an IND. In this context, sustainability is maximizing the improvements to quality of life of skin cancer patients through more precise imaging and guided surgery possibilities, while minimizing future health risks that could be incurred by insufficient investigation into long term bodily effects. There are undeniable concerns about public health that must be addressed before pH sensing nanoprobes can be proclaimed sustainable. To satisfy this definition, the risk of using pH sensing nanoprobes must be minimized. It is important to recognize, however, that there is always an inherent risk associated with introducing a foreign device to the body. Therefore, an accurate measure of risk in this situation is a comparison between the risks of imaging with pH sensing nanoprobes and an alternate imaging technology such as a PET scan. According to an article from the U.S. National Library of 6 Rachel Lau Chloe Feast trials so far, it is important to recognize that the light required to cause fluorescence in pH sensing nanoprobes cannot penetrate deep enough into the body to image certain organs. Thus, even in light of the advantages of pH sensing nanoprobes, there are still significant limitations on the types of cancer that can be imaged based on location in the body and pH of the region in question. As briefly mentioned earlier, concerns about oxidative stress and temporary body weight loss in mice receiving the probes are significant concerns about the sustainability of pH sensing nanoprobes with respect to public health. On the other hand, increased environmental safety supports the sustainable application of pH sensing nanoprobes. In an environmental context, the term sustainability is the capacity for such a technology to exist without detrimentally affecting the environment around it because of its “green” characteristics. An article by Adah Almutairi, Steven J. Guillaudeu, Mikhail Y. Berezin, Samuel Achilefu, and Jean M. J. Frechet, all of the College of Chemistry at University of California, Berkeley, highlights such environmental benefits of a nanoprobe nearly identical to PINS, apart from some structural differences [18]. The article details another nearinfrared (NIR) nanoprobe that operates by activating fluorophores and is “especially promising for imaging applications because of [its] … biodegradable structure” [18]. The article explains the process which creates a completely biodegradable nanoprobe in a form resembling that of a dendrite, for effective outreach into isolated areas. A core structure consisting of pentaerythritol, a biodegradable organic compound, composes the backbone of this specific nanoprobe [18]. The environmentally friendly capabilities of this technology stem from its organic structure, allowing pH sensing nanoprobes to be environmentally sustainable. With future implementation of this technology, this biodegradable structure assures that pH sensing nanoprobes will not contribute to the production of additional biohazard waste in hospitals, thereby sustaining the cleanliness of medical byproducts. In sum, while there are potential health concerns associated with this technology that necessitate additional research, many positive aspects exist with respect to biodegradability which provide grounds for sustainable development. Social Impact and Ethical Considerations In addition to the drawbacks regarding imaging potential for different cancer types, there are many issues within the social realm that complicate uses of nanotechnology. While the technology behind pH sensing nanoprobes yields copious amounts of benefits, Patrick Lin, an author for “The Scientist,” asserts that it can lead to conflicts between religion, society, and personal backgrounds in a population [17]. These conflicts shall be considered in accordance with the overall positive impact of cancer detection. With advancing cancer detection, the biggest social impact is what Lin calls “personal” issues [17]. Members of the public may oppose the use of such technology because of resulting increases in population as well as assimilation of unnatural processes into the body. The article describes an increase in population as negatively affecting social security, retirement, and other types of general welfare [17]. In summation, Lin points out that some may disagree with the development of pH sensing nanotechnology for cancer cells because of worries that increased population will put strain on the world’s resources. In addition to population concerns, the use of such technology raises questions about the extent to which medicine should be allowed to interfere in the body. Lin suggests that in the long term, new nanotechnology devices are paving the road towards doctors “playing the hand of God” [17]. With a technology as in need of further development as pH sensing nanoprobes, social barriers stemming from opinions on the correct allocation of government funds for such research could be a problem moving forwards. As the world becomes more technologically advanced, those wary of losing touch with natural processes will always exist. However, equally as steadfast is the presence of skin cancer and a demand for new technology to improve patients’ lives. The American Cancer Society, a large cancer research organization, states that “Different approaches might be used to treat basal cell carcinoma, and squamous cell carcinoma… Fortunately, most of these cancers...can be cured with fairly minor surgery or other types of local treatment” [4]. The ease of treating skin cancer is a reason to look for more accurate means of detection, regardless of minor social backlash that might occur. Benefits Prove Importance to Health-Care Field on a Global Scale As earlier discussed, cancer is a worldwide phenomenon, and skin cancer is one of the most prevalent varieties. Developing pH sensing nanoprobes for imaging and guided surgery is important even if the same technology cannot trace all cancers universally. To actualize these goals, members of the engineering and health fields must develop new technologies affordably. Unfortunately, little information exists at present on the cost for specific nanosensors such as PINS. However, a better understanding of the cost sources of using this imaging method can be achieved by analyzing components behind the technology. In regards to the cost of implementing pH method imaging in hospitals, the new SPY Elite camera appears as a promising product. T. Zhao et. al. mention SPY Elite cameras in reference to detailed analysis of nanosensor injection levels in their article on the PINS nanoprobe [1]. The corporate Nanoprobe Byproducts and Environmental Impact 7 Rachel Lau Chloe Feast website for NOVADAQ, a fluorescence imaging company, states that “SPY Elite is the first and most advanced fluorescence imaging system that enables surgeons performing open procedures...to visualize...tissue intraoperatively” [19]. As such, many sources suggest this camera as a necessary requirement for imaging with pH sensing nanoprobes, making it an additional cost to take into account. Like the nanoprobes, there is little listed on the cost of SPY Elite, but hospitals would need to invest in the camera to properly apply pH sensing nanoprobe technology. However, the investment would soon pay off. This imaging system would make surgery significantly safer due to the clarity of the images produced. Safer surgery is also cheaper surgery, as costs arising as a result of complications are minimized. Therefore, this system in combination with the proved efficiency of pH nanosensors makes for an extremely successful imaging process. While new cameras pose a potentially respectable initial cost, the use of SPY Elite and nanosensors such as PINS should lower the cost to patient on the average. This occurs because PINS nanoprobes can produce such a detailed image that receiving patients would require less additional testing. Additionally, the nanoprobes themselves are relatively inexpensive. An article by multiple researchers of the University of California, L.A. Nanosystems Institute analyzes data recorded using plasmonic nanosensors, and references them as being very low-cost [20]. Furthermore, the visual produced in combining SPY Elite cameras with PINS nanoprobes should decrease surgical complications. NOVADAQ’s website for SPY Elite advertising cites that these avoidable surgical complications lead to mass cell death in localized regions [19]. These complications cause longer term expenses, but can be avoided via improved healthcare [19]. Therefore, application of pH sensing nanoprobes would admittedly require an initial expense, but overall would make detection and treatment more affordable, and more easily implemented for many affected with skin cancer. environment. Biodegradable nanoprobe structures mean that helping people does not come at the cost of hurting the environment—rather it contributes to environmental sustainability while simultaneously improving the lives of those affected with skin cancer. Given the opportunity to improve detection and imaging of skin cancer, one of the most common forms of cancer that affects individuals worldwide, it is logical to employ such technologies. Overall, pH sensing nanoprobes are a worthwhile pursuit. Though they are still in early stages of development, the potential to improve the lives of so many individuals affected with skin cancer justifies many, if not all, of the costs going forward. SOURCES [1] T. Zhao et al. “A transistor-like pH nanoprobe for tumour detection and image-guided surgery.” 12.19.2016. Accessed 1.11.2017. http://www.nature.com/articles/s41551-016-0006 [2] “Cancer Statistics.” National Cancer Institute. 3.14.2016. Accessed 3.3.2017. https://www.cancer.gov/aboutcancer/understanding/statistics [3] “Skin Cancer Facts and Statistics.” Skin Cancer Foundation. 6.8.2016. Accessed 1.11.2017. http://www.skincancer.org/skin-cancer-information/skincancer-facts#indoor [4] “Basal and squamous cell skin cancer treatment.” American Cancer Society. 5.10.2016. Accessed 1.11.2017.http://www.cancer.org/cancer/skincancerbasalandsquamouscell/detailedguide/skin-cancer-basal-andsquamous-cell-treating-general-info [5] J. Chiche et. al. “Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer.” NCBI. 12.8.2009. Accessed 1.11.2017. https://www.ncbi.nlm.nih.gov/pubmed/20015196 [6] T. Vo-Dinh. “Nanosensing at the single cell level.” NCBI. 2.2008. Accessed 1.11.2017. https://www.ncbi.nlm.nih.gov/pubmed/24839348 [7] Q. le Masne de Chermont et. al. “Nanoprobes with nearinfrared persistent luminescence for in vivo imaging.” University of Pittsburgh. 03.26.2007. Accessed 2.9.2017. http://www.pnas.org/content/104/22/9266.full [8] M. Monici. “Cell and Tissue Autofluorescence Research and Diagnostic Applications.” US National Library of Medicine National Institutes of Health. 2005. 3.3.2017. https://www.ncbi.nlm.nih.gov/pubmed/16216779 [9] A. Knight , N. Billinton. “Distinguishing GFP from Cellular Autofluorescence.” Biophotonics International. 9.2001. 3.3.2017. https://www.microscopyu.com/pdfs/Knight_and_Billinton_ Biophotonics_International_8-42-2001.pdf [10] R. Rodriguez. “The Overall pH of Body Fluid.” LiveStrong Foundation. 9.14.2015. Accessed 3.2.2017. PH SENSING NANOPROBES MOVING FORWARD Throughout this paper the various pros and cons of pH sensing nanoprobes for carcinoma detection have been addressed to present a complete assessment of this technology. While bringing pH sensing nanoprobes to a hospital setting means much additional research, new equipment costs, and a lengthy process of FDA approval, the potential improvements in the detection and imaging of skin cancer justify this investment of time, effort, and money in the long run. When compared with other methods of carcinoma detection, there is no doubt that pH sensing nanoprobes provide an element of precision and potential for guided surgery that will vastly improve the lives of skin cancer patients when applied in the medical field. Yet, even while helping cancer patients, this technology does not hurt the 8 Rachel Lau Chloe Feast http://www.livestrong.com/article/442195-the-overall-ph-ofbody-fluid/ [11] “Fluorescent Probes.” Thermo Fisher Scientific. 2017. Accessed 1.26.2017. https://www.thermofisher.com/us/en/home/lifescience/protein-biology/protein-biology-learningcenter/protein-biology-resource-library/pierce-proteinmethods/fluorescent-probes.html [12] S. Lazic. “What exactly is a p-value?” Experimental Design for Laboratory Biologists. 10.3.2016. Accessed 3.1.2017. http://labstats.net/articles/pvalue.html [13] “Development & Approval Process (CBER).” U.S. Food & Drug Administration. 1.19.2017. Accessed 3.2.2017. https://www.fda.gov/BiologicsBloodVaccines/Development ApprovalProcess/default.htm [14] “Investigational New Drug (IND) Application.” U.S. Food & Drug Administration. 08.01.2016. Accessed 3.2.2017. https://www.fda.gov/Drugs/DevelopmentApprova lProcess/HowDrugsareDevelopedandApproved/ApprovalAp plications/InvestigationalNewDrugINDApplication/ [15] R.D. Handy, B.J. Shaw. “Toxic effects of nanoparticles and nanomaterials: Implications for public health, risk assessment and the public perception of nanotechnology.” Health, Risk & Society. 06.2007. Accessed 3.31.2017. http://web.b.ebscohost.com/ehost/pdfviewer/pdfviewer?vid= 1&sid=8f7c7410-2270-4f37-880ae2c3e25d643a%40sessionmgr101 [16] J. Levy, D. Zieve, I Ogilvie. “PET scan.” MedlinePlus. 7.3.2016. Accessed 3.29.2017. https://medlineplus.gov/ency/article/003827.htm [17] P. Lin. “Nanotechnology’s Dilemmas.” 12.5.2005. Accessed 1.11.2017. http://www.thescientist.com/?articles.view/articleNo/16865/title/Nanotechn ology-s-Dilemmas/ [18] A. Almutairi et. al. “Biodegradable pH-Sensing Dendritic Nanoprobes for Near-Infrared Fluorescence Lifetime and Intensity Imaging.” Journal of the American Chemical Society. 12.19.2007. Accessed 3.26.2017. http://pubs.acs.org/doi/abs/10.1021/ja078147e. [19] “SPY ELITE.” NOVADAQ Technologies Inc. Accessed 3.2.2017. http://novadaq.com/products/spy-elite/. [20] Z. Ballard et. al. “Computational Sensing Using LowCost and Mobile Plasmonic Readers Designed by Machine Learning.” ACS Publications. 1.27.2017. Accessed 3.3.2017. http://pubs.acs.org/doi/abs/10.1021/acsnano.7b00105. ACKNOWLEDGEMENTS We would like to thank Grace Bova, our co-chair, for all of her help. We would also like to thank the Swanson School of Engineering for providing us with the knowledge to undertake our project. Lastly, we would like to thank our friends for supporting us throughout our long, collaborative process. 9