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Optometric Study Center: August 2006
 
Is Nanotechnology The Next Frontier
In Eye Care?
Using 21st century engineering, scientists are seeking ways to target drug delivery, improve corneal wound healing and possibly reverse presbyopia.
By Marc D. Myers, O.D., and Andrew S. Gurwood, O.D.

Self-Assessment Examination Print Version
 

Release Date: August 2006

Expiration Date: August 31, 2007
Goal Statement: Scientists are using nanotechnology to find ways to deliver medication to patients that will increase targeted administration and practically eliminate side effects. Nanotechnology also may eliminate bacteria and fungal buildup on contact lenses, change how we treat corneal wounds and perhaps offer a way to reverse presbyopia. This course will provide optometrists with an understanding of nanotechnology and explain its potential applications in eye care.
Faculty/Editorial Board: Marc D. Myers, O.D., Andrew S. Gurwood, O.D.
Credit Statement: This course is COPE qualified for 2 hours of CE Credit. COPE ID 16893-GO. Please check with your state licensing board to see if this approval counts towards your CE requirement for relicensure.
Joint-Sponsorship Statement: This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Disclosure Statement: Drs. Myers and Gurwood have no relationships to disclose.

In 1959, Nobel Prize-winning physicist Richard Feynman presented his vision of “tiny nano-robots and related machines that could be designed, manufactured and introduced into the human body to perform cellular repairs at the molecular level.”1 While this may have sounded less like science and more like science fiction, Dr. Feynman essentially predicted the development of nanotechnology.

His predictions are likely to become reality in health care, with ophthalmic practice included. Using 21st century engineering, scientists are using nanotechnology to find ways to deliver medication to patients that will increase targeted administration and practically eliminate side effects. Nanotechnology also may eliminate bacteria and fungal buildup on contact lenses, change how we treat corneal wounds, offer a possible way to reverse presbyopia and perhaps help power an artificial retina.

Building Blocks

Nanotechnology refers to engineering and manufacturing at the molecular or nanometer (nm) scale (10-9 meters, or one-billionth of a meter).2 To understand the significance, consider that 1nm is smaller than a living cell and that a human hair measures 80,000nm.3 The nanoparticle serves as the building block of nanotechnology.

Nanomedicine refers to the monitoring, repair, construction and control of biological systems at the molecular level using engineered nanodevices and nanostructures.2 Nanomedicine consists of three overlapping and progressively more powerful molecular technologies:1,2,4

Nanoscale-structured materials and devices, including biosensors, systems to target drug delivery, smart drugs and immunoisolation techniques.

Biotechnology, which offers molecular medicine through genomics, proteomics and artificially engineered microbes.

Molecular machine systems and medical nanorobots that offer the potential for instant recognition of pathogens for diagnosis and extermination. This includes chromosome replacement and individual cell surgery in vivo along with the efficient augmentation and improvement of natural physiological function.1,2,4

R.A. Freitas Jr. and his colleagues have presented tutorials describing how bionanoelectronics and molecular machines are used to operate at atomic scales in the production of nanorobots.4 The essence of their work is microassembly with microscopic parts carried out by microscopic tools. These machines derive their functional capability through complex programming, just as any larger programmable machine would.4

Once these particles and machines are assembled and provided with instructions, they may be inserted generally or locally into the system via injection, inhalation, ingestion, or topical application of drops or ointments to be absorbed into the organism through tissue membranes.4

image1
Nanostructured materials and devices, such as biosensors, are among the technologies that make up nanomedicine. This biosensor is made from an array of silver nanoparticles deposited on glass. The nanoparticles are surrounded by strong electric and magnetic fields that change when molecules from the environment bind to the sensor. This work was performed at the Northwestern University Nanoscale Science and Engineering Center, a National Science Foundation Engineering Research.

In short, the goal of nanotechnology is to provide diagnostic and therapeutic tools that use highly portable and intelligent intermediaries to gather and interpret data. Another of its goals is to provide expeditious repair and perhaps ongoing maintenance in a convenient, non-invasive manner.

Nanotechnology research is not dedicated solely to medicine. Some other potential applications:5-9

• Researchers at the University of Arkansas have assembled nano-wires that may lead to improved flame-retardant fabrics.

• Nanotechnology research in textiles may change the structure and effectiveness of body armor and may lead to advances in the fabrication of bacterial filters.

• Nanotechnology may also provide new systems to decompose pollutants.

• Nanotechnology may help defend against chemical warfare agents. Researchers are considering strategies that would allow these particles to bind to and neutralize agents, such as anthrax toxin. Nanoscale sensors may one day be used to detect chemical, biological, radiological, and explosive agents with extreme sensitivity (potentially as little as a single-agent entity) and selectivity (microfabricated sensor suites and molecular recognition).

• Nanotubules being developed may one day be able to strengthen wood or prevent its breakdown over time.

• The technology may even supply new cost effective methods for desalinization (removing salt from salt water).

In the medical arena, the National Nanotechnology Initiative is funding research for alternative drug delivery in areas such as cancer, cardiovascular and neurologic care. (For more on funding, see “Budgeting for Nanotechnology,” below.) For example, newly engineered medicines may one day be programmed to only attack cancer cells and not those uninvolved cells adjacent to tumors.5 Also, nano-engineered molecules known as nanolipidblockers are being developed to reverse the effects of cardiovascular disease.

Meanwhile, nanodentistry will one day make possible the maintenance of comprehensive oral health by involving the use of nanomaterials, biotechnology (including tissue engineering) and, ultimately, dental nanorobotics (nanomedicine) that will allow precisely controlled oral analgesia, dentition replacement therapy using biologically autologous whole replacement teeth manufactured during a single office visit, and rapid nanometer-scale precision restorative dentistry.10

Budgeting for Nanotechnology

In 1996, several agencies within the U.S. government began meeting regularly to discuss and organize plans to develop programs in nanotechnology. Those informal meetings resulted in the formation of the Interagency Working Group on Nanotechnology (IWGN) in 1998.

IWGN, under the auspices of the National Science and Technology Council, generated many of the early publications that revealed the vision and importance of nanotechnology, thus making it a national initiative.5

In 2001, the IGWN filed a budget with the U.S. Congress. The successful promotion of its advances and potential allowed the IGWN to gain popular support of the Bush administration, raising nanoscale science and technology to the level of a federal initiative.5 The approval of that initiative resulted in the National Nanotechnology Initiative (NNI).

That 2001 administrative approval granted the NNI a budget of more than $450 million to be dispersed among its agencies. Also, the Nanoscale Science, Engineering and Technology (NSET) Subcommittee was established to coordinate leadership and budget guidance for the federal government’s nanoscale research and development programs. The NSET membership includes representatives of departments and agencies currently involved in the NNI and officials from the Office of Science and Technology Policy (OSTP).5

The estimated 2006 budget of the NNI is $1.3 billion. Today, 11 agencies are eligible for inclusion under the NNI’s financial umbrella, with the largest allocations received by the Department of Defense (approximately $436 million), the National Science Foundation (approximately $344 million), the Department of Energy (approximately $207 million) and the National Institutes of Health (approximately $175 million). The NNI reportedly has requested a budget of approximately $1.3 billion for 2007.5

image2

Internationally, annual nanotechnology investing, from both the public and private sector, reached $3 billion in 2003.5-8 The European Commission allocated approximately 1.3 billion euros for nanotechnology research between 2003 and 2006.8

Analysts estimate that worldwide spending will continue to grow at a rate of more than 25% through 2007 as revenues grow at rates of upwards to 35% for biomedical nanoscale devices.7 Global nanotechnology industry revenues are expected to surpass $1 trillion between 2010 through 2015.

Not all organized science is in favor of the advances of nanotechnology. In a 2002 New York Times article, “Opposition to Nanotechnology,” the action group Erosion, Technology, and Concentration (ETC), along with the Science and Environmental Health Network, composed a position paper in which they advocated a “go-slower approach” to nanoscience and supported a moratorium on spending, citing the risks known to be associated with rapid advances in technology.6

The concerns expressed by national and international environmental groups are also constantly being considered and monitored as the potential usages, risks and applications of nanotechnology are recognized.6

Drug Delivery

Nanotechnology also may have several possible ophthalmic applications. Targeted drug delivery is one such application.

For decades, delivery of ophthalmic preparations has come in the form of drops, ointments and injectable agents. One problem with these methods of administration, however, is that they produce incidental contact with tissues that do not require treatment. One study reported that as little as 5% of a medication given as a drop penetrated the cornea and reached its intended target inside the eye, leaving the remaining 95% of the medicine to be absorbed by the cells adjacent to the site of contact.11 Also, depending on an agent’s solubility and penetration, medications may induce unwanted toxic effects to the affected and surrounding tissues.11-13 Compounding factors include undesirable side effects, cost and, in some instances, difficulty of administration.13,14

So, researchers are looking for ways to improve agent potency and to develop delivery systems that target only diseased tissue and parcel out medication in order to titrate the dose over time. Alternative drug delivery systems, capable of resolving most of these issues, are being researched both in the general biomedical industry as well as in nanomedicine.13,14

In 1970, S.R. Waltman and H.E. Kaufman first described soaking soft hydrophilic contact lenses in medication and placing them on the eye to improve ocular penetration of topical drugs, provide increased contact time and remove the burden of administering drops.12 Other researchers, however, say that the amount of available drug that diffuses from the lens during the first few hours of wear limits the length of continuous treatment to that period. Also, the lens might require soaking for several hours to achieve the maximum medicinal load.13

So, researchers continue to search for more creative and efficient ways to deliver medications.13,15 That’s where nanotechnology comes in.

In 2004, for example, a team of nano-engineers at the Institute of Bioengineering and Nanotechnology in Singapore developed contact lenses that release controlled doses of drugs to treat ocular diseases such as glaucoma. Specifically, the researchers said they developed a simple way of making a new lens polymer that could have the medication added directly into the material which would eventually become the lens. Because the drug is part of the lens material, it can be released from the matrix into channels to slowly filter onto the eye surface.

image3
Schematic of a nanoparticle-laden contact lens. Anuj Chauhan, Ph.D., and colleagues at the University of Florida are attempting to integrate nanoparticles into a currently available contact lens material so that all drug classes could be delivered through the contact lens.

Research into using contact lenses for drug delivery is ongoing. For example, at the University of Florida, Anuj Chauhan, Ph.D., and colleagues are conducting trials using a nanoparticle-laden contact lens for drug delivery.

Specifically, Dr. Chauhan is attempting to integrate nanoparticles into currently available contact lens material so that all categories of drug classes could be delivered through the contact lens. The nanoparticles would allow for a programmed time-release of drugs.

Dr. Chauhan has completed a pilot study that employed the use of a poly-2-hydroxyethyl methacrylate (p-HEMA) hydrogel lens laden with nanoparticles that encapsulated lidocaine, a hydrophobic drug.13,14 The contact lenses made up of the nanoparticle-laden hydrogels released therapeutic doses of lidocaine for several days creating levels that approached nearly 100%. Further studies, including animal trials, are ongoing.

Dr. Chauhan’s goal: delivery of at least 50% to 60% of medication to the intended target tissue. His ultimate goal is to deliver close to 100% of the medication.16 Dr. Chauhan hopes to have these lenses available for commercial use within five to 10 years.16

Presbyopia Reversal

Looking beyond drug delivery, Matthew O’Donnell, Ph.D., and his colleagues at the University of Michigan are in the early stages of developing a material to reshape the crystalline lens and restore its flexibility and focusing ability, thus reversing presbyopia.

A new application of technology, known as microscale bubbles, has shown some promise in accomplishing this.17 Microscale bubbles were previously applied experimentally in the area of alternative drug delivery for tumor destruction.

Dr. O’Donnell’s team has applied ultrafast laser pulses to create tiny gas bubbles within the crystalline lens. Before the bubbles diffuse, they are hit with high-frequency sound waves that push the bubbles against lens fibers.

As with ultrasound imaging, vibrating a lens fiber can identify its vulnerablility. Finding these areas will permit directed treatment by laser with the goal of correction to that fiber.

Measuring the movement of the microscale bubbles also helps indicate the current pliability of the lens. In the future, surgeons may use this technique to determine the necessary flexibility a patient may desire or require.17

Bacteria Elimination

Nanotechnology also has resulted in a contact lens material that has natural antibacterial and antifungal properties. Nanoscientists have produced nanosilver particles that measure approximately 25nm.18,19

Silver has been used to treat medical ailments for more than 100 years.19 The large relative surface area of nanosilver particles increases their contact with bacteria and/or fungi, vastly improving bactericidal and fungicidal effectiveness.19

One example of how nanosilver is used: Marietta Vision Specialty Contact Lenses, Marietta, Ga., distributes a contact lens case that has incorporated nanosilver. The case is designed so that these particles, which carry positive charges, collide with the cells of microorganisms, which carry negative charges.18

Once contact is made, the nanosilver adversely affects the microorganism’s cellular metabolism by inhibiting cell growth, suppressing respiration, reducing basal metabolism of the electron transfer system and shutting down transport of substrate in the microbial cell membrane. The nanosilver helps inhibit multiplication and growth of those bacteria and fungi that may cause infections or may otherwise threaten the integrity and health of the cornea.18,19

image5

Marietta Vision Specialty Contact Lenses distributes a contact lens case that has incorporated nanosilver. The lens case is designed so that these particles, which carry positive charges, collide with the cells of microorganisms, which carry negative charges.

Corneal Wound Healing

Nanotechnologists are researching the use of dendrimers for alternative methods of drug delivery, diagnostic imaging, and as carriers of genetic material.18,19

A dendrimer is a synthetic, 3-D molecule that consists of branching parts that are formed using a nano-scale, multistep fabrication process.20 Each step of the process results in a new “generation” of dendrimer that has twice the complexity of the previous generation.20

At Boston University, Mark Grinstaff, Ph.D., and his team have developed a dendritic polymer that has applications as an adhesive for corneal wound repair.21 This dendrimer is composed entirely of two biocompatible products: glycerol and succinic acid.

Potential situations in which the adhesive would be advantageous over sutures include repair of corneal lacerations, securing of unstable LASIK flaps and closure of leaky cataract surgical incisions.21-23 Other potential uses for the adhesive include ocular emergencies that involve perforation of tissue due to trauma or infections and using it to strengthen or build up weak areas that have been compromised by destructive processes associated with inflammation.21-23

Artificial Retina

Researchers from Sandia National Laboratories of Albuquerque, N.M., are part of a multi-institutional, multidisciplinary team that is developing a nanosize battery. This battery may one day be implanted in the eye to power an artificial retina.

image4
Diagrammatical representation of an implantable retina and a biobattery. Researchers from Sandia National Laboratories are part of a multi-institutional, multidisciplinary team that is developing a nanosize battery that may one day be implanted in the eye to power an artificial retina.

The team has received a five-year, $6.5 million grant from the National Eye Institute to establish the National Center for Design of Biomimetic Nanoconductors.24 The center’s goal: to design, synthesize and fabricate nanomedical devices that utilize principles of natural and synthetic ion transporters.

The first challenge is to design a device that can generate electric power via “bio-batteries” for implantable devices. An artificial retina, which has already been developed at the Doheny Eye Institute at the University of Southern California, Los Angeles, may become the first implantable device to benefit from the development of the nanosized battery.24 The ultimate goal for this technology is to reduce severe vision loss from diagnoses such as macular degeneration.24

 

The development of nanotechnology has placed the future, as envisioned by Dr. Feynman, at our doorstep. Parallel to the explosion that fueled the rapid development and advances of computer science, nanotechnology is in its gestational stages, awaiting birth and rapid growth.

Nanotechnology offers the promise of assistance in areas considered previously unreachable to either man or machine and has the potential to directly benefit every living thing on the planet. It is perhaps the next horizon that will forever change the viewpoint from which we see the world—or at least change everyday eye care practice. ■

Dr. Myers is in private practice in Vineland, N.J. He is a clinical examiner for the National Board of Examiners in Optometry and a contributing lecturer of integrative ocular systems and disease and anterior segment disease at Pennsylvania College of Optometry (PCO). Dr. Gurwood is an associate professor of clinical sciences at PCO and a primary care attending physician at the The Eye Institute of PCO.

References

1. Freitas RA Jr. What is nanomedicine? Dis Mon 2005 Jun;51(6):325-41.
2. Freitas RA Jr. The future of nanofabrication and molecular scale devices in nanomedicine. Stud Health Technol Inform 2002;80:45-59.
3. National Nanotechnology Initiative. Frequently asked questions. www.nano.gov/html/facts/faqs.html. (Accessed July 11, 2006)
4. Freitas RA Jr. Nanomedicine, Volume I: Basic Capabilities. Georgetown, Texas: Landes Bioscience, 1999.
5. National Nanotechnology Intiative. About the NNI. www.nano.gov/html/about/home_about.html. (Accessed July 10, 2006)
6. Feder BJ. Opposition to Nanotechnology. The New York Times. www.nytimes.com/2002/08/19/technology. August 19, 2002.
7. Edwards S. B-162 Biomedical applications of nanoscale devices. www.bccresearch.com/biotech/B162.html. (Accessed July 10, 2006)
8. Nanomedicine: grounds for optimism, and a call for papers. Lancet 2003 Aug 30;362(9385):673.
9. National Nanotechnology Initiative. Nanotechnology research in support of homeland security: chemical, biological, radiological, and explosive (cbre) detection and protection. www.nano.gov/html/news/SpecialPapers/Nanotechnology%20Research%20in%20support%20of%20Home-land%20Security_cbre.htm. (Accessed July 10, 2006)
10. Freitas RA Jr. Nanodentistry. J Am Dent Assoc 2000 Nov;131(11):1559-65.
11. Lang JC. Ocular drug delivery–conventional ocular formulations. Adv Drug Delivery Rev 1995;16:39-43.
12. Waltman SR, Kaufman HE. Use of hydrophilic contact lenses to increase ocular penetration of topical drugs. Invest Ophthalmol 1970 Apr;9(4):250-5.
13. Gulsen D, Chauhan A. Ophthalmic drug delivery through contact lenses. Invest Ophthalmol Vis Sci 2004 Jul;45(7): 2342-7.
14. Gulsen D, Li CC, Chauhan A. Dispersion of DMPC liposomes in contact lenses for ophthalmic drug delivery. Curr Eye Res 2005 Dec;30(12):1071-80.
15. Hehl EM, Beck R, Luthard K, et al. Improved penetration of aminoglycosides and fluoroquinolones into the aqueous humour of patients by means of Acuvue contact lenses. Eur J Clin Pharmacol 1999 Jun;55(4):317-23.
16. Personal communication with Anuj Chauhan, Ph.D., June 23, 2006.
17. University of Michigan. Cure for reading glasses may be in view. www.yubanet.com/artman/publish/article_36379.shtml. (Accessed July 10, 2006)
18. Marietta Vision, Specialty Contact Lenses. www.mariettavision.com.
19. JR Nanotech Plc. What is nanotechnology and nano-silver? www.jrnanotech.com/acatalog/More_Info.html. (Accessed July 10, 2006)
20. Azonano.com. Dendrimers: definition, dendrimers in medicine, other industry applications and examples of products. www.azonano.com/details.asp?ArticleID=1372. (Accessed July 10, 2006)
21. Luman NR, Kim T, Grinstaff MW. Dendritic polymers composed of glycerol and succinic acid: synthetic methodologies and medical applications. Pure Appl Chem 2004;76(7-8):1375-85.
22. Wathier M, Jung PJ, Carnahan MA, et al. Dendritic macromers as in situ polymerizing biomaterials for securing cataract incisions. J Am Chem Soc 2004 Oct 13;126(40):12744-5.
23. Kang PC, Carnahan MA, Wathier M, et al. Novel tissue adhesives to secure laser in situ keratomileusis flaps. J Cataract Refract Surg 2005 Jun;31(6):1208-12.
24. Sandia National Laboratories. Sandia researchers to model nano-size battery to be implanted in eye to power artificial retina. January 12, 2006. www.sandia.gov/news-center/news-releases/2006/comp-soft-math/eye.html. (Accessed July 10, 2006)


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