Nanotechnology

In the past, and even now to some extent, many medicinal substances were used because they seemed to work, even though the specific mechanism, pharmacology or pharmacodynamics were not precisely understood. That is part of the reason for the lengthy and complex new drug approval process through the U.S. Food and Drug Administration (FDA).

Nanoscience

In the coming years, nanomedical applications for disease diagnosis, therapy, and prevention are expected to change health care in fundamental ways. Of particular interest is application of nanoscience to pharmaceutical research, which promises to make the drug discovery process more one of design. Developments in nanoscale biomedicine include implants to monitor blood chemistry and release drugs on demand, which could be a boon for diabetics and cancer patients; artificial bone, cartilage, skin and other implants that will not be rejected by the human immune system and may never need replacement; more radical forms of human repair that may repair nerve processes and reverse blindness or paralysis; and advances in cancer treatment in the form of improved, cell-directed chemotherapy and radiotherapy, with the possibility of outright cures for some forms of cancer becoming more plausible.

With nanotechnology in its infancy, there are still many unknowns, including the acute and chronic consequences of novel applications of nanomaterials in the human body. The extent of those risks will be unknowable until much more time passes. Still, while regulatory guidelines specific to nanomedical health concerns will not exist anytime soon, medical science continues to move forward. As a result, medical products manufacturers and downstream users of products incorporating nanomaterials ' e.g., health care providers ' are likely to be the unhappy subjects of “regulation by litigation.” It is therefore incumbent upon health care providers and their legal advisers to become acquainted with the potential benefits and risks of nanomedicine and with how it may soon affect the practice of medicine.

Understanding the Terminology

Nanoscience involves structures and substances so small that they are essentially invisible, and challenge our ability to conceptualize their size. One nanometer is one billionth of a meter. A human hair measures 80,000 nanometers wide, and the smallest things visible to the human eye are 10,000 nanometers wide. “Nanomaterials” are molecules or groups of molecules with at least one dimension between one and 100 nanometers. “Nanotechnology” is the fabrication of nanomaterials into useful nanoscale products. As explained by the National Science Foundation, “Nanostructures are at the confluence of the smallest of human-made devices and the largest molecules of living things.” In other words, nanostructures aren't just smaller than anything ever made before, they are the smallest solid things it is possible to make.

At that size, below 50 nm, the laws of classical Newtonian physics give way to quantum effects and material properties change. For example, carbon becomes 100 times stronger than steel and silver takes on biologic properties and becomes a bactericide. Scientists can manipulate individual atoms and molecules, like tiny Lego blocks, to build functional microscopic structures used for specific tasks like drug delivery, in vivo fluorescent imaging, or bone tissue replacement.

'Nanomedicine'

“Nanomedicine” is the application of nanotechnology to health care. It promises profound impacts, through new classes of drugs, cell-specific cancer diagnostics and therapy, advanced medical devices, and tissue engineering. The aim of nanomedicine is the comprehensive monitoring, control, construction, repair, defense, and improvement of all human biological systems, working from the molecular level ' using engineered devices and nanostructures ' to ultimately achieve a medical benefit. Anticipated applications include pharmaceuticals, biopharmaceuticals, drug delivery, diagnostics, implantable devices, and production of new biocompatible materials. How important is nanomedicine? The U.S. National Science Foundation predicts that nanotechnology will produce half of the pharmaceutical industry product line by 2015. See Lux Research, The Nanotech Report, 4th ed. (2006). This report also predicts that by 2014, 2.6 trillion U.S. dollars in global manufactured goods may incorporate nanotechnology (about 15% of total global output).

New Opportunities and New Risks

The exciting promise of nanomedicine is tempered by the sentiment behind that most famous portion of the Hippocratic oath: the admonition to medical professionals to “do no harm.” There is evidence that the characteristics that make nanoscale materials exciting and useful ' creation of matter with novel and unique physical, chemical, and biological properties that do not conform to conventional physics ' create unpredictable biological risks. How do manufactured nano-structures, with molecular structures and physical properties heretofore unknown, behave in living organisms, including humans? No one really knows.

Health Risks

Although only tentative, some early studies suggest that exposure to some nanoparticles may create health risks. See discussion of early studies in Florini, Walsh, Balbus, and Denison, Nanotechnology: Getting It Right the First Time, 3 Nanotechnology L & Bus 39, 41-43, Feb./Mar. 2006. First, there is their size. By gaining access to virtually the entire body, and interacting with biomolecules both on and inside cells, nanoscale devices offer the tremendous opportunity to detect disease and deliver more effective therapeutic treatments. But nanoparticles' size and mobility also raise questions about toxicity and bioaccumulation. Nanoparticles' exceptionally large relative surface area creates increased surface reactivity and enhanced intrinsic toxicity. Moreover, due to their size, nanoparticles have unprecedented mobility. Hundreds or thousands of times smaller than human cells, they are more easily taken up by the human body. They can penetrate cells, cross biological membranes that function as barriers against larger particles, and can biodisperse into tissues and organs more efficiently than larger particles.

In Vivo Behavior

Nanosize is not the only issue. Many of the properties of nanomaterials are fundamentally different from those of their bulk counterparts due to an increased surface area and quantum effects, which can affect their in vivo behavior. Some of the properties that may be relevant to biological toxicity include: size distribution; shape; agglomeration state; biopersistence, durability, and solubility; surface area; surface charge; surface chemistry/coatings; porosity; chemical composition; trace impurities and contaminants; and crystallinity. See, e.g., ASTM Int'l, Standard Guide for Handling Unbound Engineered Nanoscale Particles in Occupational Settings, E2535-07 (2007). Because reducing the size of structures to the nanolevel results in distinctly different properties, experts agree that it is insufficient to rely on knowledge of the classical toxicity testing of larger particle analogs when the risks of nanoparticles and nanostructures have yet to be assessed. See, e.g., Nanoscience and Nanotechnologies: Opportunities and Uncertainties, The Royal Society and the Royal Academy of Engineering, July 2004, at http://www.raeng.org.uk/policy/reports/nanoscience.htm; The Allianz Group and the Organisation for Economic Co-operation and Development (OECD), Small Sizes That Matter: Opportunities and Risks of Nanotechnologies, June 2005.

Simply put, the potential risks of the nanotechnology doors recently opened, as well as what will be found behind the next door, are unknown. (For a more extended discussion of the potential health risks, which are beyond the scope of this paper, see, e.g., B. Barry, The State of the Science ' Human Health, Toxicology, and Nanotechnological Risk, Chapter 4, Nanotechnology: Health and Environmental Risks (2008); Wernette and Nilsen, Nanotorts: The Legal Risks of Nanotechnologies, for the Defense, November 2008; de Jong, Roszek and Geertsma, Nanotechnology in Medical Applications: Possible Risks for Human Health, RIVM Report 265001002, 2005, at http://rivm.openrepository.com/rivm/bitstream/10029/7266/1/265001002.pdf.) The limited understanding of potential toxicological and other biologic effects of various nanomaterials suggests caution.

Potential Uses of Nanopharmaceuticals and Nanodiagnostics

Drug companies in today's global economy face enormous pressure to deliver high-quality products to the consumer while maintaining profitability. They must improve the success rate of new molecular entities (NMEs) while reducing relative research and development (R & D) costs and cycle time associated with producing new drugs. Nanotechnology is expected to reduce the cost of drug discovery, design, and development, and the resulting improved R&D success rate should enable faster introduction of new, cost-effective products to the marketplace. In addition to NMEs, nanotechnology allows pharmaceutical companies to “nanosize” approved drugs and to revisit the feasibility of drugs that had been shelved due to factors such as poor solubility, toxicity issues, low bioavailability, or lack of target specificity (e.g., delivering the drug to a specific tissue site).

Nanodevices can deliver medicinal molecules directly into cells, releasing drugs in targeted and localized fashions, and allowing the controlled release of drug molecules over time. Some nanopharmaceutical examples include topical lotions using nanoemulsion particles to penetrate pores and hair follicles to attack a wide range of microbial pathogens ' bacteria, fungi, and viruses; nanodrug delivery systems that enhance therapeutic effectiveness by targeting certain types of cells, speeding up delivery time, and preventing digestive enzymes from breaking down the medication; advanced delivery systems that can infiltrate cells and detect pre-malignant and cancerous changes in the cells, release a chemical substance to kill the cell, and verify destruction of the cell by becoming fluorescent in the presence of enzymes release by the fatally wounded cells; and implantable devices composed of nanocomposites that hold medicine and can periodically dispense drugs, such as insulin or morphine. See, e.g., Pierstorff et al., Monitoring, Diagnostic, and Therapeutic Technologies for Advanced Medicine at the Intersection of Life Science and Engineering, 7 J. Nanoscience & Nanotechnology 2949, 2007; Lam and Ho, The Coalescence of Nanotechnology with Systems Biology for Optimized Drug Delivery, 5 Nanotechnology L & Bus 125, Summer 2008.

A principal benefit of nanopharmaceuticals will be significantly enhanced bioavailability. Bioavailability refers to the presence of drug molecules where and when they are needed in the body to do the most good. In addition to using microcapsules to deliver time-released molecular drug payloads, nanoscience allows for more complex drug delivery schemes, such as the ability to get drugs through cell walls and into cells. Efficient drug delivery is important both to deliver therapeutics to specific targets in order to minimize side effects, and also because many diseases (e.g., sickle cell anemia) depend upon processes within the cell and can only be interfered with by drugs delivered into the cell. See, e.g., Borm, Drug Delivery and Nanoparticles: Applications and Hazards, 3(2) Int'l J. of Nanomed. 133, 2008; D. Thassu et al, Nanoparticulate Drug Delivery Systems (Informa Healthcare USA 2007).

Conclusion

In addition to improved drugs and drug delivery systems, nanotechnology promises to dramatically improve diagnostic capabilities. Non-invasive nanodevices can be used, for example, to enter the body to determine glucose levels, distinguish between normal and cancerous tissue, and provide genetic screening for multiple diseases. The use of nanosized materials, such as quantum dots that fluoresce, also promises great improvements in diagnostic imaging. For example, new techniques in optical, ultrasonic, and nuclear imaging will allow for cell-specific, noninvasive molecular imaging that should permit detection of cancer cells far earlier than current techniques.

Ronald C. Wernette, a member of this newsletter's Board of Editors, is a partner with Bowman and Brooke LLP in the firm's Troy, MI, office, where he focuses his practice on toxic exposure, product liability, and other personal injury defense. He is a member of the Defense Research Institute Product Liability Committee and ABA Section of Science & Technology Law. He can be reached at [email protected]

In the past, and even now to some extent, many medicinal substances were used because they seemed to work, even though the specific mechanism, pharmacology or pharmacodynamics were not precisely understood. That is part of the reason for the lengthy and complex new drug approval process through the U.S. Food and Drug Administration (FDA).

Nanoscience

In the coming years, nanomedical applications for disease diagnosis, therapy, and prevention are expected to change health care in fundamental ways. Of particular interest is application of nanoscience to pharmaceutical research, which promises to make the drug discovery process more one of design. Developments in nanoscale biomedicine include implants to monitor blood chemistry and release drugs on demand, which could be a boon for diabetics and cancer patients; artificial bone, cartilage, skin and other implants that will not be rejected by the human immune system and may never need replacement; more radical forms of human repair that may repair nerve processes and reverse blindness or paralysis; and advances in cancer treatment in the form of improved, cell-directed chemotherapy and radiotherapy, with the possibility of outright cures for some forms of cancer becoming more plausible.

With nanotechnology in its infancy, there are still many unknowns, including the acute and chronic consequences of novel applications of nanomaterials in the human body. The extent of those risks will be unknowable until much more time passes. Still, while regulatory guidelines specific to nanomedical health concerns will not exist anytime soon, medical science continues to move forward. As a result, medical products manufacturers and downstream users of products incorporating nanomaterials ' e.g., health care providers ' are likely to be the unhappy subjects of “regulation by litigation.” It is therefore incumbent upon health care providers and their legal advisers to become acquainted with the potential benefits and risks of nanomedicine and with how it may soon affect the practice of medicine.

Understanding the Terminology

Nanoscience involves structures and substances so small that they are essentially invisible, and challenge our ability to conceptualize their size. One nanometer is one billionth of a meter. A human hair measures 80,000 nanometers wide, and the smallest things visible to the human eye are 10,000 nanometers wide. “Nanomaterials” are molecules or groups of molecules with at least one dimension between one and 100 nanometers. “Nanotechnology” is the fabrication of nanomaterials into useful nanoscale products. As explained by the National Science Foundation, “Nanostructures are at the confluence of the smallest of human-made devices and the largest molecules of living things.” In other words, nanostructures aren't just smaller than anything ever made before, they are the smallest solid things it is possible to make.

At that size, below 50 nm, the laws of classical Newtonian physics give way to quantum effects and material properties change. For example, carbon becomes 100 times stronger than steel and silver takes on biologic properties and becomes a bactericide. Scientists can manipulate individual atoms and molecules, like tiny Lego blocks, to build functional microscopic structures used for specific tasks like drug delivery, in vivo fluorescent imaging, or bone tissue replacement.

'Nanomedicine'

“Nanomedicine” is the application of nanotechnology to health care. It promises profound impacts, through new classes of drugs, cell-specific cancer diagnostics and therapy, advanced medical devices, and tissue engineering. The aim of nanomedicine is the comprehensive monitoring, control, construction, repair, defense, and improvement of all human biological systems, working from the molecular level ' using engineered devices and nanostructures ' to ultimately achieve a medical benefit. Anticipated applications include pharmaceuticals, biopharmaceuticals, drug delivery, diagnostics, implantable devices, and production of new biocompatible materials. How important is nanomedicine? The U.S. National Science Foundation predicts that nanotechnology will produce half of the pharmaceutical industry product line by 2015. See Lux Research, The Nanotech Report, 4th ed. (2006). This report also predicts that by 2014, 2.6 trillion U.S. dollars in global manufactured goods may incorporate nanotechnology (about 15% of total global output).

New Opportunities and New Risks

The exciting promise of nanomedicine is tempered by the sentiment behind that most famous portion of the Hippocratic oath: the admonition to medical professionals to “do no harm.” There is evidence that the characteristics that make nanoscale materials exciting and useful ' creation of matter with novel and unique physical, chemical, and biological properties that do not conform to conventional physics ' create unpredictable biological risks. How do manufactured nano-structures, with molecular structures and physical properties heretofore unknown, behave in living organisms, including humans? No one really knows.

Health Risks

Although only tentative, some early studies suggest that exposure to some nanoparticles may create health risks. See discussion of early studies in Florini, Walsh, Balbus, and Denison, Nanotechnology: Getting It Right the First Time, 3 Nanotechnology L & Bus 39, 41-43, Feb./Mar. 2006. First, there is their size. By gaining access to virtually the entire body, and interacting with biomolecules both on and inside cells, nanoscale devices offer the tremendous opportunity to detect disease and deliver more effective therapeutic treatments. But nanoparticles' size and mobility also raise questions about toxicity and bioaccumulation. Nanoparticles' exceptionally large relative surface area creates increased surface reactivity and enhanced intrinsic toxicity. Moreover, due to their size, nanoparticles have unprecedented mobility. Hundreds or thousands of times smaller than human cells, they are more easily taken up by the human body. They can penetrate cells, cross biological membranes that function as barriers against larger particles, and can biodisperse into tissues and organs more efficiently than larger particles.

In Vivo Behavior

Nanosize is not the only issue. Many of the properties of nanomaterials are fundamentally different from those of their bulk counterparts due to an increased surface area and quantum effects, which can affect their in vivo behavior. Some of the properties that may be relevant to biological toxicity include: size distribution; shape; agglomeration state; biopersistence, durability, and solubility; surface area; surface charge; surface chemistry/coatings; porosity; chemical composition; trace impurities and contaminants; and crystallinity. See, e.g., ASTM Int'l, Standard Guide for Handling Unbound Engineered Nanoscale Particles in Occupational Settings, E2535-07 (2007). Because reducing the size of structures to the nanolevel results in distinctly different properties, experts agree that it is insufficient to rely on knowledge of the classical toxicity testing of larger particle analogs when the risks of nanoparticles and nanostructures have yet to be assessed. See, e.g., Nanoscience and Nanotechnologies: Opportunities and Uncertainties, The Royal Society and the Royal Academy of Engineering, July 2004, at http://www.raeng.org.uk/policy/reports/nanoscience.htm; The Allianz Group and the Organisation for Economic Co-operation and Development (OECD), Small Sizes That Matter: Opportunities and Risks of Nanotechnologies, June 2005.

Simply put, the potential risks of the nanotechnology doors recently opened, as well as what will be found behind the next door, are unknown. (For a more extended discussion of the potential health risks, which are beyond the scope of this paper, see, e.g., B. Barry, The State of the Science ' Human Health, Toxicology, and Nanotechnological Risk, Chapter 4, Nanotechnology: Health and Environmental Risks (2008); Wernette and Nilsen, Nanotorts: The Legal Risks of Nanotechnologies, for the Defense, November 2008; de Jong, Roszek and Geertsma, Nanotechnology in Medical Applications: Possible Risks for Human Health, RIVM Report 265001002, 2005, at http://rivm.openrepository.com/rivm/bitstream/10029/7266/1/265001002.pdf.) The limited understanding of potential toxicological and other biologic effects of various nanomaterials suggests caution.

Potential Uses of Nanopharmaceuticals and Nanodiagnostics

Drug companies in today's global economy face enormous pressure to deliver high-quality products to the consumer while maintaining profitability. They must improve the success rate of new molecular entities (NMEs) while reducing relative research and development (R & D) costs and cycle time associated with producing new drugs. Nanotechnology is expected to reduce the cost of drug discovery, design, and development, and the resulting improved R&D success rate should enable faster introduction of new, cost-effective products to the marketplace. In addition to NMEs, nanotechnology allows pharmaceutical companies to “nanosize” approved drugs and to revisit the feasibility of drugs that had been shelved due to factors such as poor solubility, toxicity issues, low bioavailability, or lack of target specificity (e.g., delivering the drug to a specific tissue site).

Nanodevices can deliver medicinal molecules directly into cells, releasing drugs in targeted and localized fashions, and allowing the controlled release of drug molecules over time. Some nanopharmaceutical examples include topical lotions using nanoemulsion particles to penetrate pores and hair follicles to attack a wide range of microbial pathogens ' bacteria, fungi, and viruses; nanodrug delivery systems that enhance therapeutic effectiveness by targeting certain types of cells, speeding up delivery time, and preventing digestive enzymes from breaking down the medication; advanced delivery systems that can infiltrate cells and detect pre-malignant and cancerous changes in the cells, release a chemical substance to kill the cell, and verify destruction of the cell by becoming fluorescent in the presence of enzymes release by the fatally wounded cells; and implantable devices composed of nanocomposites that hold medicine and can periodically dispense drugs, such as insulin or morphine. See, e.g., Pierstorff et al., Monitoring, Diagnostic, and Therapeutic Technologies for Advanced Medicine at the Intersection of Life Science and Engineering, 7 J. Nanoscience & Nanotechnology 2949, 2007; Lam and Ho, The Coalescence of Nanotechnology with Systems Biology for Optimized Drug Delivery, 5 Nanotechnology L & Bus 125, Summer 2008.

A principal benefit of nanopharmaceuticals will be significantly enhanced bioavailability. Bioavailability refers to the presence of drug molecules where and when they are needed in the body to do the most good. In addition to using microcapsules to deliver time-released molecular drug payloads, nanoscience allows for more complex drug delivery schemes, such as the ability to get drugs through cell walls and into cells. Efficient drug delivery is important both to deliver therapeutics to specific targets in order to minimize side effects, and also because many diseases (e.g., sickle cell anemia) depend upon processes within the cell and can only be interfered with by drugs delivered into the cell. See, e.g., Borm, Drug Delivery and Nanoparticles: Applications and Hazards, 3(2) Int'l J. of Nanomed. 133, 2008; D. Thassu et al, Nanoparticulate Drug Delivery Systems (Informa Healthcare USA 2007).

Conclusion

In addition to improved drugs and drug delivery systems, nanotechnology promises to dramatically improve diagnostic capabilities. Non-invasive nanodevices can be used, for example, to enter the body to determine glucose levels, distinguish between normal and cancerous tissue, and provide genetic screening for multiple diseases. The use of nanosized materials, such as quantum dots that fluoresce, also promises great improvements in diagnostic imaging. For example, new techniques in optical, ultrasonic, and nuclear imaging will allow for cell-specific, noninvasive molecular imaging that should permit detection of cancer cells far earlier than current techniques.

Ronald C. Wernette, a member of this newsletter's Board of Editors, is a partner with Bowman and Brooke LLP in the firm's Troy, MI, office, where he focuses his practice on toxic exposure, product liability, and other personal injury defense. He is a member of the Defense Research Institute Product Liability Committee and ABA Section of Science & Technology Law. He can be reached at [email protected]