Monday

DermMinute With Dr. Adam Friedman

By James J. Gormley
Adam Friedman MD
 Adam Friedman, MD is Director of Dermatologic Research and Clinical Instructor at the Unified Division of Dermatology of Albert Einstein College of Medicine. In line with his research interests, Dr Friedman currently serves as Vice President of the Nanodermatology Society. On January 16th, 2011, at the 8th Annual Orlando Dermatology Aesthetic and Clinical conference (ODAC), he is presenting "Nanotechnology and Dermatology: What the Clinician Should Know." With gratefully appreciated additional content by Adnan Nasir, MD (founder of the NDS and clinical assistant professor of dermatology at UNC Chapel Hill), Dr. Friedman now speaks to DermMatters about all things nano.

1. On January 16th, 2011, at the 8th Annual Orlando Dermatology Aesthetic and Clinical conference (ODAC), you are presenting "Nanotechnology and Dermatology: What the Clinician Should Know." So, to start off with: What is nanotechnology and what are nanomaterials? 
Dr. Friedman: Nanotechnology is the science of both understanding and controlling matter at dimensions between 1 and 100 nanometers. A nanometer is one-billionth of a meter (1 x 109 meters!). To better appreciate this scale, a sheet of paper is about 100,000 nanometers thick, the diameter of a single hair is on the magnitude of tens of thousands of nanometers, and a single red blood cell is approximately 5000 nanometers wide.
http://www.futureforall.org/
     Nanomaterials is a term that includes all nanosized materials, including both engineered nanoparticles, nanoemulsions, nanopigments, etc as well as randomly or incidentally occurring nano-objects, like those that exist in nature. In fact, nanoscale materials are nothing new. Many important biological take place at the nanoscale. Proteins used by the human body to regulate and maintain homeostasis exist on the nanoscale. Probably one of the best known naturally occurring nanomaterials is hemoglobin, which carries oxygen through the bloodstream, is 5 nms in diameter.
     When particles are purposefully manufactured with nanoscale dimensions, we call them engineered nanoparticles. There are two other ways nanoparticles are formed. Nanoparticles can occur as a byproduct of combustion, industrial manufacturing, and other human activities; these are known as incidental nanoparticles. Natural processes, such as sea spray, can also create nanoparticles.
     Nanotechnology requires not only that matter be small, but that its properties be purposefully engineered and utilized. At the nanoscale, unusual physical, chemical, and biological properties can emerge, enabling novel applications. The properties of these nanomaterials may differ in important ways from their bulky, macromolecular counterparts. For example, a small fragment of carbon is not nanotechnology, but carbon rolled into a small nanotube designed to conduct electricity or to serve as a cage for a drug is nanotechnology.
     Therefore, through nanotechnology, it is possible to develop structures, techniques and systems with completely new properties and functions. Industry, medicine, science and consumers hope that this potential will lead to beneficial applications in robotics, sensory and diagnostic technology, biotechnology and medicine as well as for the further development of consumer products and cosmetics.

2. While K. Eric Drexler, in his prescient 1986 book, Engines of Creation: The Coming Era of Nanotechnology, outlined many areas in which nanotechnology could revolutionize progress, there have also been doomsday or worst-case prognostications and imaginings as well, such as Michael Crichton's novel, Prey (2002). Which vision are you inclined to hold, and why? 

Dr. Friedman: A sci-fi “doomsday” vision is highly unlikely for several reasons. Firstly, the technology barriers required to make nanomaterials are high. Secondly, the quantities of nanomaterials that can be made are limited. Thirdly, most nanomaterials degrade, making a 'grey goo' scenario unlikely. Fourthly, we are a long way from making smart machines that are tiny and capable of replicating themselves to nefarious ends (as suggested in Crichton’s Prey or on Star Trek). Fifth, and finally, we will need to make sure that safeguards are in place to minimize the dangers of nanotechnology, to prevent any potential harmful sequelae associated with this science.

3. Matter behaves differently at nano scale. Therefore, is permeation through the human body's membranes and tissues (including organs) a real concern? Is bioaccumulation of nanomaterials a concern as well, or does the tendency of nano particles to disperse, rather than aggregate, forestall that problem?
Dr. Friedman: Lets start by looking at naturally occurring nanoparticles to answer these questions, such as volcanic ash and viruses. Ash particles can permeate the body's tissues through the lungs. Viruses can penetrate the body through a variety of mechanisms, from direct penetration to being carried along host cells or the bloodstream.
     Artificial nanoparticles therefore also have the potential to permeate the human body. Artificial nanoparticles may get into the body by several means: injection (as in nanoparticles tagged for chemotherapy or for radiologic imaging), inhalational (as in attenuated vaccines in intranasal sprays), by mouth (nanomaterials in foods or used for self-cleaning utensils) and topically (through liposomal and hydrogel drug carriers, or microneedle patches). Nanoparticles are more likely to penetrate skin that is damaged or flexed. 

PMMA microspheres (Yongxing Hu, University of California, Riverside)

     Furthermore, nanoparticles that are dispersed are more likely to penetrate than those that are aggregated or clumped. Scientists believe that the greatest risks stem from the inhalation of nanoparticles, though the risk associated with gastrointestinal uptake has yet to be fully elucidated. The latest scientific findings largely rule out the possibility of nanoparticles extensively and deeply penetrating the human skin. The majority of this work has been performed on nano-sized sunscreen components, titanium dioxide and zinc oxide.      Recently and in concert with these findings, a study by Gulson et al. demonstrated that tiny, insignificant amounts of zinc were absorbed into the bloodstream following repeated topical applications of nano-zinc oxide containing sunscreens. Based on the technique used, it was not possible to conclude whether this minute increase was actually the zinc nanoparticle that got through the skin or rather zinc dissolved in the skin and formed soluble zinc ions. Regardless, the increase in systemic zinc concentrations was not considered harmful.
Georgia Tech's Dr. Zhong Lin Wang prepares to load a sample into a furnace
used to create the new zinc oxide nanohelix structures (NSF)
     In addition, nanoparticle penetration may also be altered by the surface properties of particles (charge, polarity, etc.) and the addition of penetration enhancers. The health of the host can also determine if nanoparticles accumulate or become harmful. An example is nephrogenic systemic fibrosis, caused by nanoparticlate injected gadolinium contrast dye; the disorder is more likely in hosts with poor renal function.
     If nanoparticles stay on the skin or within the epidermis, the natural shedding of the stratumcorneum is likely to reduce the body burden attributed to them. If nanoparticles are biodegradable, biocompatible, or readily excreted, accumulation is not likely to be a problem. However, nanoparticles which are indestructible, and not biocompatible may accumulate and either cause direct damage by crowding out vital organs/tissues/cells, or by inducing a damaging host response.
     In order to truly estimate whether nano products constitute specific health risks, as you mentioned, it is important to know whether the nanomaterials used are aggregated, such as in a matrix, or are present in the product in an unbound, free form. Individual, free nanoparticles, nanotubes or nanofibres could lead to health risks through their small size, form, high mobility and higher reactivity.
     For the most part, current nano products consist of nanoparticles that are incorporated into solid matrices such as hydorgels or liquid suspensions.
     Even if unbound, nanoparticles are predicted to aggregate into larger unions which are generally larger than 100 nm. If this is the case, the toxic effects of nanoparticles linked to their small size and higher reactivity are then no longer as concerning. However, there are currently still many questions that have yet to be answered. There is minimal data available on human exposure to nanoparticles; most research presented is in cell lines or animals. Work is currently underway to develop effective and demonstrative test strategies to determine possible health risks in order to answer these burning questions.

4. What are some examples of nanomaterials used in topical products?
Dr. Friedman: Consumers may be surprised to hear that they already come into contact with multiple products whose components have been developed or generated with the help of nanotechnology. These range from cosmetics, foods or even textiles. In dermatology, the most obvious example is sunscreen, which can contain nano-sized titanium dioxide and zinc oxide. Fullerenes (football-shaped caged molecules made of carbon atoms) are being used in cosmetic products to protect and transport active ingredients and enhance their effect. Other
examples include make-ups with iridescent or vivid hues and emollients with biomimetic lipids. Products in development include perfumes with slower release of scent and insect repellants with longer persistence of active ingredient on the skin.
     The market for nano products is growing at an exponential pace. The unique properties afforded by the nanoscale make it possible to produce substances with completely new properties: paint that is scratch resistant, clothing that is dirt repellent, or, as mentioned above, sunscreens that offer both better protection against UV light and improvedcosmesis.
     A database of nano products which are currently on the market is available onlineThe database "A Nanotechnology Consumer Products Inventory" is a project of the Woodrow Wilson International Centre for Scholars.

5. What are the main current dermatologic and pharmaceutical applications of nanomaterials? Is acne an example?
Dr. Friedman: There are numerous active areas of interest with respect to “nanodermatology.” These include the treatment of acute and chronic inflammatory diseases, infectious diseases, inherited skin diseases and neoplasia. Inflammatory diseases include psoriasis, atopic dermatitis, and contact dermatitis.
     Nanoencapsulated steroids have been developed which remain in the epidermis and have shown anti-inflammatory activity; by not penetrating the dermis, these show less side effects associated with deeper penetration and absorption such as atrophy and HPA axis suppression.
     Infectious diseases being targeted include multi-drug resistant gram positive (Ex: Staphylococcus species, Group A Streptococcus) and gram negative (Ex: Acinetobacter, Pseudomonas) infection with nanosized silver and soy, nanoparticles that release nitric oxide, and superhydrophobic antimicrobial surfaces which can be activated with ambient or ultraviolet light.
     Nanosized topical antifungals which penetrate the nail plate or the sebaceous gland are being used for the treatment of onychomycosis and P. acnes.
     Genetic diseases are being targeted with small inhibitor RNAs. This has been investigated for the treatment of pachyonychia congenita, a series of rare inherited skin diseases resulting in characteristic dystrophic, thickened nails and focal palmoplantar keratoderma. The use of small inhibitor RNAs for the treatment of a broad range of diseases ranging from infectious (genital warts) to neoplastic (melanoma) is being vigorously explored.
     Prevention of skin cancer through more efficacious and cosmetically acceptable nanosunscreens is probably the most common example of nanotechnology in dermatology. The treatment of neoplastic diseases, such as melanoma, are being targeted with nanoscopic gold particles bearing MSH receptors. These particles can be selectively irradiated in the near-infrared range to ablate coated tumor cells. Nanosized magnetic and antibody labeled chemotherapy nanoparticles are also being investigated for targeted and improved treatment of a broad range of malignancies ranging from melanoma to breast cancer.

6. Are there unique pharmacokinetics of nano about which dermatologists should be aware?
Dr. Friedman: The pharmacokinetics of “nano” is a very new area and highly dependent on the materials used to make the nanoparticles. Clearly, not all nanoparticles are created equal as the products used for generation can be quite varied. Yet, one of the proposed benefits of nano does revolve around pharmacokintetics, specifically in dermatology.
     Substances that have specific break down patterns, whether based on acidity, lipid/water content, or temperature, can be used to form nanomaterials that allow for enhanced, site specific delivery as well as controlled/sustained release of the encapsulated therapy payload.
     As there are many forms of nanomaterials, even within the subgroups, i.e. nanoparticles versus nanoemulsions, and there are no specific FDA guidelines for demonstrating pharmacokinetics of cosmetics employing nanotech (which encompasses the majority of nanomaterials in dermatology), little is known regarding this area of nanotechnology. Therefore, it is ripe for research and discovery.

7. Are most dermatologists familiar with nanotechnology? In the July 2010 issue of JDD you introduced the Nanodermatology Society to the dermatology community. Can you update DM readers on the society and why it will beneficial for dermatologists to join it? 
While other areas of medicine, such as oncology and diagnostic radiology incorporate nanotechnology teaching, education, and research in their curricula, dermatology has lagged in this area. In a recent survey based study, which will be presented at the upcoming winter American Academy of Dermatology (AAD) meeting in New Orleans (P1807: Nanotechnology and dermatology education in the United States: Data from a pilot survey), a striking gap in education was noted with respect to nanotechnology in dermatology. Participants indicated a need for more training and education in the area of nanotechnology, as well as called for more research to both evaluate the potential pitfalls associated with these materials as well as seek out new means to advance diagnostic and therapeutic modalities.
     The Nanodermatology Society (NDS) was first and foremost founded to fill this void in dermatology training and provide relevant and practical information regarding nanotechnology
research/development as it relates to the field of dermatology. One of the fastest growing areas of medical research is nanomedicine. Nanomedicine combines a broad array of disciplines, including chemistry, physics, engineering, materials science, and computer science to develop innovative diagnostic and therapeutic tools.
     The fact that dermatology lags behind its peers in this arena is paradoxical in that a significant proportion of new developments in nanotechnology have been in http://www.nanodermsociety.org/skin care. As this field is quite vast, it is of the utmost importance that dermatologists are provided with pertinent, consolidated information regarding these developments which can be easily incorporated into their everyday knowledge and armament of information for patients. In order to accomplish this, the NDS will monitor nanotechnology, study new developments in the field, and evaluate their potential. The NDS will focus on potential beneficial uses of this new technology, as well as potential dangers within its purview.
     Active NDS members have the opportunity to participate in all activities associated with the NDS. These include, attendance at the annual meeting (the 1st annual meeting will be held on February 4th 2011 during the AAD meeting in New Orleans), opportunities to network with peers who share a common interest, and participation in governance of the society. As the society grows and develops, newsletters and a journal will also be available to members. Members of the NDS will also have opportunities to advise academia, the business community, industry, other specialty societies, and lawmakers on the potential pitalls of nanotechnology and provide the media with accurate findings and concerns in order to relay this information to the public.
     For more information regarding the Nanodermatology Society, please visit our website.

About Dr. Friedman: Dr. Friedman is currently investigating novel nanotechnologies that allow for controlled and sustained delivery of a wide spectrum of physiologically and medicinally relevant molecules, with an emphasis on treating infectious diseases, accelerating wound healing, immune modulation, and correcting vascular dysfunction. Dr. Friedman holds several patents derived from these investigations, and has published over 30 papers on both his research as well as a variety of clinical areas in dermatology with an emphasis on emerging medical therapies. He has presented his research in both national and international forums, and has received awards from multiple organizations such as the American Academy of Dermatology and American Society for Dermatologic Surgery. Dr. Friedman is also committed to resident and medical education, and is chair of the leadership workgroup of the American Academy of Dermatology Resident/Fellows Committee and is the Senior Editor of the Dermatology In-Review Online Workshop. 

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