A Tiny Glimpse into the Immensity of Nanomedicine

Cynthia Beynon, PhD Student

University of Utah College of Nursing

The Change

After Robert Hooke and Antoni van Leeuwenhoek first saw microscopic fungi, protozoa, and bacteria in the 1660’s, the whole world of medicine was transformed.  This new perspective revolutionized our understanding of illness prevention and intervention, making the previous best efforts of well-meaning individuals not only obsolete, but imprudent (Gest, 2004).  Decades from now, we may compare this change with current discoveries underway in the even more minute world of nanotechnology.

Size

According to nano.gov, “the prefix "nano" means one-billionth, or 10^-9; therefore one nanometer is one-billionth of a meter” (Nano.gov, 2017).

(Paumier, 2003)

For a bit of perspective, watch this video from the World Science Festival (Festival, 2013): How Big is a Nanometer?

Definition

Nanotechnology is manufacturing and manipulation of particles with at least one dimension that measures between 1-100 nm (Nano.gov, 2017).  Components used include nanoparticles, quantum dots, nanotubes, fullerenes, nanowires, etc. (Nanowerk.com, 2017).  This site can even direct you to order these nanoproducts!

Nano-size fragments exponentially increase the surface area available for manipulation and demonstrate unique properties in composition, agglomeration, structure, charge, and solubility (Nikalje, 2015).  Additionally, “Cellular responses are critically different at the nano-scale level” (Banik, 2016, p. 271).

History

Evidence of the use of nanotechnology dates as far back as the 4^th century, but it was not until the late 1800s that scientists began to understand and experiment with nanostructures.  The term “nanotechnology” was first coined by Taniguchi, a professor in Tokyo in 1974.  Nanotechnology companies emerged in the United States in the 1990s, and during the next decade, products that contained nanotechnology began to appear on the market.  Also in 2000, the National Nanotechnology Initiative (NNI) was created, and funding from Congress followed in 2001 (Nano.gov, 2017).

In 2008, Science Daily reported there were 2-4 new products entering the market every single week (ScienceDaily, 2008).  Maintaining a useful Nanotechnology Consumer Products Inventory has proved challenging, in part due to a lack of standardization and measurement in composition and labeling. Additionally, a significant number of products that claimed to use nanomaterials do not appear to be credible. A revised inventory from 2013 listed “1814 consumer products from 622 companies in 32 countries” (Vance, 2015, p. 1769).

Applications

Research in nanotechnology results in an almost incomprehensibly broad range of applications:  fabrics, personal care, household products, computers, vehicles, electronics, transportation, energy, water purification, and environmental sustainability, just to name a few.  Here are some examples of nanotechnology-developed products you may be familiar with ("Discover," 2010).

In the field of Nano medicine, some areas of particular focus have included cancer treatment, antibiotic resistance, drug targeting, diagnosis and imaging, and vaccine delivery.  Current research in immunotherapy is investigating the use of nanoparticles that incorporate peanut extract as an oral agent to desensitize patient and prevent anaphylaxis  (Nowak-Wegrzyn, 2017).  Researchers are working to increase availability and serviceability of the Hepatitis B vaccine by developing a mucosal delivery method utilizing nanotechnology (Eng-Kiong, 2016).  Other scientists concerned with the detrimental effects of ultraviolet radiation on human skin introduced nanoparticles titanium dioxide and zinc oxide to develop a sunscreen that no longer leaves the familiar white cream on the skin (Baron, 2016).  

As of July 18, 2017, ClinicalTrials.gov search results for “nanotechnology AND nano” yielded 185 studies in the following areas: heart failure, hernia, multiple sclerosis, asthma, chronic obstructive lung disease, renal cell carcinoma, prostate cancer, dental caries, Parkinson’s disease, coronary stenosis, metabolic syndrome, diabetes, yeast infection, environmental contamination, cryptococcal infections, leukemia, menopause, and many more (ClinicalTrials.gov, 2017).  

ClinicalTrials.gov - provides patients, their family members, and the public with easy and free access to information on clinical studies for a wide range of diseases and conditions.

Risks and Concerns

Nanotechnology is not without its concerns.  Some researchers have expressed apprehension regarding potential toxicity.  What effect will nanoparticles have when they are percutaneously absorbed (Baron, 2016)?  What effect will breathing nanoparticles have on the respiratory system (Goldman, 2017)?

In Europe, regulators took a more cautious position about the introduction of nanotechnology, while regulation has been minimal in the USA. There is a lack of research regarding long-term implications, and concerns about nominal regulation and limited guidelines  (ScientificAmerica.com, 2009).

Other concerns involve financial and ethical implications of developments in nanotechnology. An article published in The New York Times in July of 2017 announced the approval of a gene-altering leukemia treatment.  The drug, CTL019, was associated with an 82.5 percent remission rate.  The exciting news brings hope, but it is not without misgivings.  Treatment is predicted to cost $300,000 or more (Grady, 2017).  The financial ramifications of nanotechnology are worth consideration.  Who will pay for this treatment?  Will it be available for everyone? Or will physical suffering and life-expectance be directly dependent on economic status?

Additionally, nanotechnology is a booming business.  According to the National Science Foundation, worldwide revenue from Nano-enhanced products was 1 trillion dollars in 2013 ("Market report on emerging nanotechnology now available," 2014). When something is so profitable, how closely do producers look at the long-term ramifications and safety concerns?

To Learn More

1. Order the Big Things from a Tiny World brochure from Nano.gov.
2. Watch a video about nanotechnology.  Here are some options from NBCLearn and YouTube.
3.  Read a journal.  Multiple publications are devoted to nanotechnology research and application, including Nanotechnology; Journal of Nanoscience and Nanotechnology; Nanomedicine: Nanotechnology, Biology, and Medicine; Journal of Nanoparticle Research; Nano Research; NANO.  Check out this link for information about Nanotechnology Journal Impact Factors. (OMICSonline.org, n.d.)
4. Attend a conference.  There are many opportunities to attend a workshop or conference and learn more about nanotechnology.  Here are some conference ideas.  (OMICSonline.org, n.d.)

In Conclusion

This October, celebrate Nano Day!  Since a nano is 10^-9, October 9^th has been designated the day to celebrate all things Nano.  You can participate in films, podcasts, and seminars—and even run the one hundred billion nanometer dash! 

The impact of nanotechnology is reaching into multiple aspects of our lives, and so far we are barely seeing the tip of the iceberg.  Look for exciting things ahead as previously unimaginable things become possible through nanotechnology! 

References

Banik, B. L., Fattahi P., & Brown, J. L. (2016). Polymeric nanoparticles: the future of nanomedicine. WIREs Nanomed Nanobiotechnology, 8, 271-299. doi:10.1002.wnan.1364

Baron, E. D. (2016, December 7, 2016). Selection of sunscreen and sun-protective measures. UpToDate.  Retrieved from https://www-uptodate-com.ezproxy.lib.utah.edu/contents/selection-of-sunscreen-and-sun-protective-measures?source=search_result&search=selection%20of%20sunscreen%20and%20sun-protective%20measures&selectedTitle=1~150

ClinicalTrials.gov. (2017).   Retrieved from ClinicalTrials.gov

Discover. (2010). Science for the the curious; the 9 best nanotechnology-powered products.  Retrieved from http://discovermagazine.com/galleries/zen-photo/n/nanotech-products

Eng-Kiong, T. L., A. (2016, August 9, 2016). Hepatitis B virus vaccination. UpToDate.  Retrieved from https://www-uptodate-com.ezproxy.lib.utah.edu/contents/hepatitis-b-virus-vaccination?source=search_result&search=hepatitis%20b%20virus%20vaccination&selectedTitle=5~150

Festival, W. S. (2013). How Big is a Nanometer?

Gest, H. (2004). The discovery of microorganisms by Robert Hooke and Antoni van Leeuwenhoek, Fellows of The Royal Society. Notes and Records of the Royal Society of London, 58(2), 187-201. doi:10.1098/rsnr.2004.0055

Goldman, R. H. (2017, Feb 21, 2017). Overview of occupational and environmental health. UpToDate.  Retrieved from https://www-uptodate-com.ezproxy.lib.utah.edu/contents/overview-of-occupational-and-environmental-health?source=search_result&search=overview%20of%20occupation%20and%20environmental%20health&selectedTitle=1~150

Grady, D. (2017). F.D.A. panel recommends approval for gene-altering leukemia treatment. The New York Times, p. 5. Retrieved from http://nyti.ms/2ua97p5

Market report on emerging nanotechnology now available. (2014). [Press release]. Retrieved from https://www.nsf.gov/news/news_summ.jsp?cntn_id=130586

Nano.gov. (2017). Size of the nanoscale. National Nanotechnology Initiative.  Retrieved from https://www.nano.gov/nanotech-101/what/nano-size

Nanowerk.com. (2017). Nanomaterials database.   Retrieved from nanowerk.com/nanomaterial-database.php

Nikalje, A. P. (2015). Nanotechnology and its applications in medicine. Medicinal Chemistry, 5, 81-89. doi:10.4172/2161-0444.1000247

Nowak-Wegrzyn, A. (2017, July 10, 2017). Investigation therapies for food allergy: oral immunotherapy. UpToDate.  Retrieved from https://www-uptodate-com.ezproxy.lib.utah.edu/contents/investigational-therapies-for-food-allergy-oral-immunotherapy?source=search_result&search=nanoparticles&selectedTitle=2~12

OMICSonline.org. (n.d.). Nanotechnology journals.   Retrieved from https://www.omicsonline.org/nanotechnology-journals-impact-factor-ranking.php?gclid=CjwKCAjw8IXMBRB8EiwAg9fgMPez-OqVHoBcjU0HqCcxOvQi-RD9yRudfe1EfMiH-qTSJfUKIPrgtxoCe6oQAvD_BwE

Paumier, G., Ronan, P., NIH, Fijalkowski, A. J., Walker, J., Jones, D., Heal, T., & Ruiz, M. (2003). Biological and technological scales compared Biological and technological scales compared-en, CC BY-SA 2.5

 Science Primer (National Center for Biotechnology Information), Liquid_2003, Arne Nordmann & The Tango! Desktop Project.

ScienceDaily. (2008). Project on Emerging Nanotechnologies: new nanotechnology products hitting the market at the rate of 3-4 per week. ScienceDaily. Retrieved from sciencedaily.com/release/2008/04/080424102505.htm

ScientificAmerica.com. (2009). Are nanotech consumer products safe? Scientific American.  Retrieved from https://www.scientificamerican.com/article/are-nanotech-consumer-products-safe/

Vance, M. E., Kuiken, T., Vejerano, E. P., McGinnis, S. P., Hochella, M. F., Jr., Rejeski, D., & Hull, M. S. . (2015). Nanotechnology in the real world: redeveloping the nanomaterial consumer products inventory. Beilstein Journal of Nanotechnology, 6, 1769-1780.

Glucose Control in Intensive Care Unit: Where Innovation and Technology Will Help?

Vanessa De Azevedo, RN - PhD Student
College of Nursing
University of Utah

What is Stress Induced Hyperglycemia?

Stress Induced Hyperglycemia (SIH) is characterized by level of blood glucose of 140 mg/dl or higher in patients receiving treatment in Intensive Care Unit (ICU) from surgery, traumatic injury, and critical or acute medical illnesses. Regarding the reason for admission in ICU, the presence of hyperglycemia is associated with increased morbidity and mortality. Patients with or without previous diagnose of Diabetes are also susceptible to present hyperglycemia when involved in critical scenarios.

Excessive counter regulatory hormones (e.g. glucagon, growth hormone, catecholamine and endogenous or exogenous glucocorticoid), and high circulation or tissue levels of cytokine are the causes of SIH. Such a condition makes insulin incapable of combating hepatic gluconeogenesis (the formation of glycose by the liver) responsible for blood glucose levels, and also makes the absorption of glucose into skeletal muscles impaired. In addition, intravenous nutrition therapy commonly received in critical settings is also responsible for events of hyperglycemia.

It is well known in medicine that controlling SIH in critical patients is a challenge for health care providers. The ideal blood sugar target range is 70-110 mg/dl; however, the high risk of hypoglycemia is eminent when such a target is applied. Researchers are trying to find a safer ways to control patients’ glycemic level without producing adverse hypoglycemia events. Insulin protocols, randomized control trials (RCT), and revision of guidelines have been done to solve such an important issue.

        What happens if a patient presents hyper or hypoglycemia when in ICU?

        Hyperglycemia is characterized by blood sugar level higher or equal to 110 mg/dl in a healthy person. Considering critical patients, high levels of blood sugar (< 140 mg/dl) can result in mitochondrial damage, endothelial dysfunction, and immune suppression, leading to an increased risk of infection. Indeed, SIH can result in polyneuropathy which requires a longer use of mechanical ventilation and longer hospitalization in ICU.      

        

       Hypoglycemia is defined as blood glucose level below or equal to 70 mg/dl. Glucose is not a villain for our body, it is also a metabolic fuel for the brain. Lack of glucose in the human body can be the consequence of a tight glucose control in ICU, in other words, excessive amount of insulin administrated when restrictive insulin protocols are applied. Other causes of hypoglycemia are inadequate nutrition, and insufficient provision of glucose. If untreated, hypoglycemia can result in permanent brain damage and death.

        

       Both hyperglycemia and hypoglycemia if not properly treated can result in poor care outcomes and even death.

        What has been done to avoid SIH in ICU settings?

        After a detection of blood sugar elevated, physicians prescribe an insulin protocol which consists of an intravenous administration of regular insulin (fast acting) through a pump. The dose of insulin is calculated by the level of glucose measured at the moment of administration. Through a simple but reliable glucometer, the blood glucose level is measured. The blood sample can be collect through finger sticks, and venous or arterial line. Arterial blood is the most accurate source for accessing glycemic level. 

       The insulin protocol requires hourly glycemic assessments in order to manage the insulin dose administrated. Such approach causes a delay in treatment which might result in adverse events such as hypoglycemia. The American Diabetes Association (ADA), the American College of Critical Care Medicine (ACCM), and the American Association of Clinical Endocrinologists (AACE) recommend a target glucose range of 140-180mg/dl. They also recommend the use of paper-based or computerized protocols that allow for predefined adjustments in infusion rate based on glycemic fluctuations and insulin dose, and initiation of intravenous insulin protocol at 180 mg/dl. Furthermore, hypoglycemia protocols should be established for each patient. The goal of the guidelines above is to avoid hypoglycemia and hyperglycemia and to mitigate adverse outcomes.

What is the role of nurses taking care of patients with insulin protocol in ICU?

        Nurses play a crucial role in glycemic management. They assess glycemic level from the beginning to the end of the therapy, making critical decisions that will impact the evolution of the therapy, and patient care outcomes.

        

       Such responsibilities require time, attention, dedication, and application of scientific knowledge. Once insulin therapy is initiated, nursing workload will increase.

Why do we need a change?

        Hourly glycemic assessment is not enough when managing insulin protocols. The need for a more tight control is essential to avoid adverse events such as hyper or hypoglycemia.

        

        There is consensus among researchers that the more tight the glucose levels (70 -110 mg/dl) the more benefits patients will have. However, such a tight control is not recommended due to high incidence of hypoglycemia it may cause.

        

         Hourly measurement with glucometers and finger sticks will result in hematomas, and consequently poor quality of a blood sample. Indeed, such an approach will increase nursing workload which can drive nurses away from other critical care conditions that might require special attention.

Where innovation and technology can help?

        Currently in the market we have devices such as continuous glucose monitoring and bionic pancreas that are helping patients with Diabetes types 1 and 2 to self-manage their blood glucose. Even though, critically ill patients are not necessarily in the scope of diabetes, they will certainly be beneficiated with such technology in ICUs.

What is CGM? 

Illustration of a continuous glucose monitoring Dexcom G4, retrieved from: https://diatribe.org/issues/48/test-drive

Continuous Glucose Monitoring (CGM) is a device that was initially designed with the purpose of helping Diabetes Type 1 patients to self-manage their blood sugar. Such an equipment contains a glucose sensor, a transmitter, and a display. The sensor captures and measures in real-time glucose fluid in the subcutaneous tissue. Connected to a transmitter, glucose levels are send wirelessly via radio frequency to the monitor display device.

What is Bionic pancreas? 

Top figure represents a bionic pancreas monitor, retrived from: https://diatribe.org/introducing-beta-bionics-bringing-ilet-bionic-pancreas-market . 

Bottom figure respresents an ilustration of how artificial pancreas works. Retrieved from: http://discovermagazine.com/2016/may/13-priming-the-pump

Bionic pancreas is a device that aims at imitating the human pancreas delivering insulin and glucagon hormones based on a blood sugar result measured every five minutes. The system consists of a dual pump (one for insulin and one for glucagon) that receives information from a separate sensor –CGM- and automatically calculates the exact dose of hormone a patient needs.

What to expect using CGM and Bionic Pancreas in ICU?

In conclusion, the addition of the new technology in ICU settings will lead to a real-time management of glycemic levels, reduction of nursing workload, and more accurate and safe levels of glucose. CGM and bionic pancreas will help prevent/manage SIH by simulating an almost real and effective human pancreas resulting in reduction of incidence of infection, hospital length of stay, and better patient outcomes.

References and suggested links for further reading:

https://www.medtronicdiabetes.com/treatments/continuous-glucose-monitoring

http://www.ndei.org/ADA-diabetes-management-guidelines-in-patient-glycemia-targets-critically-ill.aspx.html

http://inpatient.aace.com/strategies-for-achieving-glycemic-control-management-of-hyperglycemia-in-the-critical-care-setting

http://www.bionicpancreas.org

https://diatribe.org/introducing-beta-bionics-bringing-ilet-bionic-pancreas-market

McCowen,K.C., Malhotra, A., Bistrian, B.R. (2001). Stress-Induced Hyperglycemia. Critical Care Clinics, 17(1), 107-124. Doi http://dx.doi.org/10.1016/S0749-0704(05)70154-8

Harp, J. B., Yancopoulos, G. D., & Gromada, J. (2016). Glucagon orchestrates stress-induced hyperglycaemia. Diabetes, Obesity and Metabolism, 18(7), 648-653. doi: 10.1111/dom.12668

Godinjak, A., Iglica, A., Burekovic, A., Jusufovic, S., Ajanovic, A., Tancica, I., & Kukuljac, A. (2015). Hyperglycemia in Critically Ill Patients: Management and Prognosis. Medical Archives, 69(3), 157-160. doi: 10.5455/medarh.2015.69.157-160

Lacherade, J.-C., Jacqueminet, S., & Preiser, J.-C. (2009). An Overview of Hypoglycemia in the Critically Ill. Journal of Diabetes Science and Technology, 3(6), 1242–1249.

Brunner, R., Kitzberger, R., Miehsler, W., Herkner, H., Madl, C., & Holzinger, U. (2011). Accuracy and reliability of a subcutaneous continuous glucose-monitoring system in critically ill patients. Critical Care Medicine, 39(4), 659-664. doi: 10.1097/CCM.0b013e318206bf2e

De Block, C., Manuel, Y. K. B., Van Gaal, L., & Rogiers, P. (2006). Intensive insulin therapy in the intensive care unit: assessment by continuous glucose monitoring. Diabetes Care, 29(8), 1750-1756.

Harris, D. L., Battin, M. R., Weston, P. J., & Harding, J. E. (2010). Continuous glucose monitoring in newborn babies at risk of hypoglycemia. Journal of Pediatrics, 157(2), 198-202.e191. doi: 10.1016/j.jpeds.2010.02.003