Assigment .Apa seven . All instructions attached.

1  

GETTING NANO TATTOOS RIGHT—A CHECKLIST OF LEGAL AND

ETHICAL HURDLES FOR AN EMERGING NANOMEDICAL TECHNOLOGY

Michael G Bennett, J.D., PhD and R. John Naranja, Jr., M.D.

Northeastern University School of Law

Corresponding Author:

Michael G Bennett, J.D., PhD

40 Cargill Hall

400 Huntington Avenue

Boston, MA 02115

1.850.212.7786 (m)

1.617.373.3048 (o)

1.845.373.5056 (f)

[email protected]

Word Count Abstract: 141

Word Count Manuscript Body: 1499

Reference Count: 10

Figure Count: 0

The authors have no commercial associations that might pose a potential, perceived or real conflict of

interest. Accordingly, the authors have no disclosures to declare.

2  

GETTING NANO TATTOOS RIGHT—A CHECKLIST OF ETHICAL AND

LEGAL HURDLES FOR AN EMERGING NANOMEDICAL TECHNOLOGY

Abstract

The nano tattoo represents a nascent technology designed to be implanted in the skin to provide

continuous and reliable glucose detection for diabetics. Its potential benefits are compelling not

only for its ability to prevent diabetic complications and decrease related social costs, but also for

its ease of use and relative patient-user comfort. This Note aims to articulate a checklist of

fundamental intellectual property, bioethical and system design issues that are appropriately

considered in the pre-clinical, pre-commercialization phase of nano tattoo development. Early

and regular consideration of these factors can increase the odds of a societally beneficial

dissemination of this device by engaging relevant researcher, medical, patient-user and patient-

advocate communities concerned with its appropriate application, as well as policymaking

communities focused on effectively managing diabetes-related healthcare costs. The checklist of

factors includes fundamental issues and is generally applicable to nanomedical inventions.

Keywords

Nano tattoo; bioethics; intellectual property; system design; commercialization

Introduction

The nano tattoo is an intradermally embedded array of biosensors, functionalized to emit visible

color changes corresponding to target chemical markers in the blood stream. Much of the

technology's development has focused on glucose detection and the potential transformation of

3  

diabetic care. This device is poised to obsolesce the current glucose measuring standard of

fingersticks, a method widely considered suboptimal in diagnostic efficiency and patient

comfort. In the long term, the nano tattoo has the potential to decrease diabetic complications

and its associated economic costs.1 Despite these potential benefits, intellectual property,

bioethical and system design hurdles have yet to be rigorously considered. These matters are best

addressed upstream2 —in the pre-clinical, pre-commercialization phase— before design choices

lock innovators and patient-users into device configurations that can lead to unintended, negative

outcomes.

Technological Development

Nano tattoo technology represents a significant refinement of the current diagnostic method for

detecting glucose levels in diabetics. Historically, a patient applied a small fingerstick sample of

blood to a sensor strip and then inserted the strip into a portable monitor where an

electrochemical reaction provided the basis for measuring blood glucose.3 Subsequent

integration of carbon nanotubes in the sensors led to greater sensitivity, more efficient electron

transfer from enzyme to electrode, and the capability of increased catalytic modifications of this

                                                                                                                          1  Within  five  years  of  onset,  in  the  absence  of  proper  care,  diabetes  can  lead  to  neuropathy,  retinopathy  and  other  

complications.  If  diagnosed,  the  diabetic  patient  typically  turns  to  “fingersticks”  to  monitor  glucose  levels,  a  

technology  that  calls  for  extracting  blood  from  a  finger  tip  as  many  as  four  times  daily.  

2  Sarewitz  D,  Guston  D.    Real-­‐Time  Assessment  of  Nanotechnology:    Theory,  Practice,  Prospects.    Conference  on  

Nanotechnology  in  Science,  Economy,  and  Society  2004;  1-­‐9.  

3  Wang  J.  Electrochemical  Glucose  Biosensors.    Chem.  Rev.  (Washington,  DC,  U.S.)  2008;  108:814-­‐825.  

4  

external sensing process.4 The capacity for continuous internal glucose monitoring arose with

the development of an implantable, fluorescence-based nano-biosensor.5 Later research

addressed biosensor degradation, improved visualization of color changes and minimized host

immune response.6 Combined, these developmental innovations represent the state of the art.

Factor Checklist

As the technology moves towards commercialization, we propose a checklist of factors designed

to preemptively address potential legal, bioethical and system design issues that have historically

threatened to impede the societally beneficial market introduction of novel medical devices. The

non-exclusive list of seven factors includes: patent scope, patent thicket potential7, patient

                                                                                                                          4  Zhu  ZG,  Wenhui  S,  Krishna  B,  Francis  M,  Ya-­‐Li  L  and  Xiao-­‐Hua  Z.  Nano-­‐yarn  carbon  nanotube  fiber  based  

enzymatic  glucose  biosensor.    Nanotechnology  2010;  21:1-­‐10.  

5  Clark  H,  Hoyer  M,  Philbert  M,  Kopelman  R,  Optical  Nanosensors  for  Chemical  Analysis  inside  Single  Living  Cells.  1.  

Fabrication,  Characterization,  and  Methods  for  Intracellular  Delivery  of  PEBBLE  Sensors.    Anal.  Chem  1999;  

71(21):4831–4836.  

6  Srivastava  R,  Brown  J,  Zhu  H,  McShane  M.    Stable  Encapsulation  of  Active  Enzyme  by  Application  of  Multilayer  

Nanofilm  Coatings  to  Alginate  Microspheres.    Macromolecular  Bioscience    2005;  5  (8):  717–727;  Cash  K,  Clark  H.    

Nanosensors  and  nanomaterials  for  monitoring  glucose  in  diabetes.  Trends  in  Molecular  Medicine    2010;  16(12):  

584–593;  Srivastava  R,  Jayant  R,  Chaudhary  A,  McShane  M.    Smart  Tattoo”  Glucose  Biosensors  and  Effect  of  

Coencapsulated  Anti-­‐Inflammatory  Agents.    J  Diabetes  Sci  Technol.  2011;  5(1):  76–85.  

7  Bawa,  Raj.    Nanotechnology  Patent  Proliferation  and  the  Crisis  at  the  U.S.  Patent  Office.  Alb  L.J.  Sci.  &  Tech.  2007;  

17:699-­‐736.    

5  

autonomy, beneficence, multi-dimensional justice8, privacy and system design. We explain and

apply each factor to nano tattoos below.

Patent Scope

It is not uncommon for nanotechnology-related patents to claim a broad area of functionality

within the radius of their legal rights to exclude non-inventors’ uses. In order to avoid chilling

experimentation for fear of patent infringement, as well as to safe-guard against post-

commercialization invalidation of over-broad patents, nano tattoo patents should be narrowly

tailored. Presently, patents covering this technology are not overbroad in scope, but our analysis

suggests monitoring this art field as developments continue.9

Patent Thicket Potential

Since nanotechnologies are often transdisciplinary, encompassing such fields as physics,

chemistry, engineering and/or biology, it is not unusual for a single nano-enabled invention to be

covered by multiple overlapping patents. By increasing ownership determination costs, these

“patent thickets” exert a retarding effect on rates of technological development and

dissemination. That fewer than ten U.S. patents have been issued covering fundamental nano

tattoo-related inventions suggests that, currently, this area of innovation does not present a high

probability of a patent thicket.

                                                                                                                          8  Beachamp  T,  Childress  J.  Respect  for  Autonomy,  Beneficence,  Justice.  Beachamp  T,  Childress  J.    editors.    Principles  

of  Biomedical  Ethics,  5th  ed.  Oxford:  Oxford  University  Press,  2001,  p.57-­‐103,  165-­‐214,  225-­‐272;  Roco,  M.  

Nanoscale  Science  and  Engineering:    Unifying  and  Transforming  Tools.    AIChE  Journal  2004;  50(5):  896-­‐897.  

9  Databases  used  for  this  search  include  the  United  States  Patent  and  Trademark  Organization,  Web  of  Science,  

Pub  Med,  LexisNexis  and  Westlaw;  the  keywords  were  “nano  tattoo”  and  “smart  tattoo.”  

6  

Autonomy

Patient autonomy requires delivery of relevant and understandable information that enables

patients to make informed decisions regarding diagnostic and treatment alternatives. Avoiding

paternalism and upholding a patient’s right to self-determination necessitates not only

articulation of a device’s benefits, but also disclosure of attendant risks. Nano tattoo-enabled

management of glucose levels can lead to reduced instances of altered states of consciousness

brought on by hyper- or hypoglycemia. We predict increased autonomy in the form of more

opportunities for patient-users to make informed treatment decisions with clear minds.

Beneficence

Beneficence concerns improving quality of life or life expectancy, and can be assessed through

clinical trials. A device should be more than merely technically innovative; the user should

receive a tangibly beneficial result. Based on existing studies indicating that avoidance of

hyperglycemic episodes results in decreased diabetic complications, nano tattoos will likely

improve both quality of life and life expectancy, but this likelihood must be clinically confirmed

to assure beneficence.

Justice

The principle of justice has meaning in at least three registers: socio-economic justice,

distributive justice and environmental justice. Socioeconomic justice recognizes fair treatment of

individuals and classes independent of their social position or material wealth. Relatedly,

distributive justice is achieved when those who reap the benefits of an activity also bear its costs,

instead of outsourcing the latter to the less powerful. And environmental justice aims to

safeguard the ecosphere against spent nanoparticles whose transport paths and fates are presently

7  

poorly understood. Nano tattoo commercialization will likely encounter hurdles related to justice

issues in all three registers, since large portions of the estimated 25.8 million people constituting

the U.S. diabetic community —children, African-Americans, Native-Americans, Asian-

Americans, Hispanic/Latino Americans, pregnant women, the obese, the extremely ill— are also

historically disadvantaged groups who have born the brunt of environmental costs of

technological developments, who continue to receive sub-standard medical services, and who

seldom share equitably in the fruits of medical technology innovation.10

Privacy

The power to control dissemination of personal information is of critical concern in the context

of nanomedicine. Since nano tattoos will visually reflect glucose concentrations, third parties

may intercept a patient-user's personal medical information. Such an unintended disclosure of

health status would constitute a direct violation of patient confidentiality, presuming a traditional

patient-doctor relationship. This type of unintended disclosure might be even more harmful to a

patient once nano tattoos are designed to generate information concerning other socially

stigmatized conditions, such as cancer, HIV-AIDS, or other infectious diseases.

System Design

Technologies are not apolitical artifacts that merely achieve their stated functional goal. Rather,

through their designs, they tend to encourage certain types of behaviors and effects, while

discouraging others. There are often multiple designs capable of achieving the main goal of a                                                                                                                           10  National  Diabetes  Fact  Sheet:  National  estimates  and  general  information  on  diabetes  and  prediabetes  in  the  

United  States,  2011  US  Department  of  Health  and  Human  Services,  Centers  for  Disease  Control  and  Prevention    

2011;  9  http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf  ;  Elsaesser  A,  Howard,  V.    Toxicology  of  

Nanoparticles.    Advanced  Drug  Delivery  Reviews  2012;  64  :129-­‐137.  

8  

technology, each of them entailing different cost/benefit ratios for users and society at large.

Possible, and possibly competing, nano tattoo designs will likely implicate varied outcomes for

patient-users and society. And all the other factors of the checklist will be touched by the

technology's design: greater or lesser rates of subsequent innovation, more or less patient

autonomy, beneficence, and realized justice. Important questions will likely be addressed by

nano tattoo design decisions: Who will be capable of using the device? Who will monitor

possible human and/or environmental impacts? Most fundamentally, which groups will be able

to contribute to discussions about appropriate designs? Accordingly, the nano tattoo design

process should be open to input from all communities that are likely to be impacted by its

introduction: patient-users, the medical community, marginalized community advocates,

scientific researchers, legal advocates, and policy makers.

Conclusion

The checklist factors implicate one another and occasionally overlap in their scope of concern.

Though not exhaustive, they do address fundamental upstream intellectual property, bioethical

and system design issues of nano tattoos, as well as other nanomedical devices. And the more

promising the potential societal benefits of an emerging nanomedical device are, the more

important does this upstream assessment checklist become.

1  

GETTING NANO TATTOOS RIGHT—A CHECKLIST OF LEGAL AND

ETHICAL HURDLES FOR AN EMERGING NANOMEDICAL TECHNOLOGY

Michael G Bennett, J.D., PhD and R. John Naranja, Jr., M.D.

Northeastern University School of Law

Corresponding Author:

Michael G Bennett, J.D., PhD

40 Cargill Hall

400 Huntington Avenue

Boston, MA 02115

1.850.212.7786 (m)

1.617.373.3048 (o)

1.845.373.5056 (f)

[email protected]

Word Count Abstract: 141

Word Count Manuscript Body: 1499

Reference Count: 10

Figure Count: 0

The authors have no commercial associations that might pose a potential, perceived or real conflict of

interest. Accordingly, the authors have no disclosures to declare.

2  

GETTING NANO TATTOOS RIGHT—A CHECKLIST OF ETHICAL AND

LEGAL HURDLES FOR AN EMERGING NANOMEDICAL TECHNOLOGY

Abstract

The nano tattoo represents a nascent technology designed to be implanted in the skin to provide

continuous and reliable glucose detection for diabetics. Its potential benefits are compelling not

only for its ability to prevent diabetic complications and decrease related social costs, but also for

its ease of use and relative patient-user comfort. This Note aims to articulate a checklist of

fundamental intellectual property, bioethical and system design issues that are appropriately

considered in the pre-clinical, pre-commercialization phase of nano tattoo development. Early

and regular consideration of these factors can increase the odds of a societally beneficial

dissemination of this device by engaging relevant researcher, medical, patient-user and patient-

advocate communities concerned with its appropriate application, as well as policymaking

communities focused on effectively managing diabetes-related healthcare costs. The checklist of

factors includes fundamental issues and is generally applicable to nanomedical inventions.

Keywords

Nano tattoo; bioethics; intellectual property; system design; commercialization

Introduction

The nano tattoo is an intradermally embedded array of biosensors, functionalized to emit visible

color changes corresponding to target chemical markers in the blood stream. Much of the

technology's development has focused on glucose detection and the potential transformation of

3  

diabetic care. This device is poised to obsolesce the current glucose measuring standard of

fingersticks, a method widely considered suboptimal in diagnostic efficiency and patient

comfort. In the long term, the nano tattoo has the potential to decrease diabetic complications

and its associated economic costs.1 Despite these potential benefits, intellectual property,

bioethical and system design hurdles have yet to be rigorously considered. These matters are best

addressed upstream2 —in the pre-clinical, pre-commercialization phase— before design choices

lock innovators and patient-users into device configurations that can lead to unintended, negative

outcomes.

Technological Development

Nano tattoo technology represents a significant refinement of the current diagnostic method for

detecting glucose levels in diabetics. Historically, a patient applied a small fingerstick sample of

blood to a sensor strip and then inserted the strip into a portable monitor where an

electrochemical reaction provided the basis for measuring blood glucose.3 Subsequent

integration of carbon nanotubes in the sensors led to greater sensitivity, more efficient electron

transfer from enzyme to electrode, and the capability of increased catalytic modifications of this

                                                                                                                          1  Within  five  years  of  onset,  in  the  absence  of  proper  care,  diabetes  can  lead  to  neuropathy,  retinopathy  and  other  

complications.  If  diagnosed,  the  diabetic  patient  typically  turns  to  “fingersticks”  to  monitor  glucose  levels,  a  

technology  that  calls  for  extracting  blood  from  a  finger  tip  as  many  as  four  times  daily.  

2  Sarewitz  D,  Guston  D.    Real-­‐Time  Assessment  of  Nanotechnology:    Theory,  Practice,  Prospects.    Conference  on  

Nanotechnology  in  Science,  Economy,  and  Society  2004;  1-­‐9.  

3  Wang  J.  Electrochemical  Glucose  Biosensors.    Chem.  Rev.  (Washington,  DC,  U.S.)  2008;  108:814-­‐825.  

4  

external sensing process.4 The capacity for continuous internal glucose monitoring arose with

the development of an implantable, fluorescence-based nano-biosensor.5 Later research

addressed biosensor degradation, improved visualization of color changes and minimized host

immune response.6 Combined, these developmental innovations represent the state of the art.

Factor Checklist

As the technology moves towards commercialization, we propose a checklist of factors designed

to preemptively address potential legal, bioethical and system design issues that have historically

threatened to impede the societally beneficial market introduction of novel medical devices. The

non-exclusive list of seven factors includes: patent scope, patent thicket potential7, patient

                                                                                                                          4  Zhu  ZG,  Wenhui  S,  Krishna  B,  Francis  M,  Ya-­‐Li  L  and  Xiao-­‐Hua  Z.  Nano-­‐yarn  carbon  nanotube  fiber  based  

enzymatic  glucose  biosensor.    Nanotechnology  2010;  21:1-­‐10.  

5  Clark  H,  Hoyer  M,  Philbert  M,  Kopelman  R,  Optical  Nanosensors  for  Chemical  Analysis  inside  Single  Living  Cells.  1.  

Fabrication,  Characterization,  and  Methods  for  Intracellular  Delivery  of  PEBBLE  Sensors.    Anal.  Chem  1999;  

71(21):4831–4836.  

6  Srivastava  R,  Brown  J,  Zhu  H,  McShane  M.    Stable  Encapsulation  of  Active  Enzyme  by  Application  of  Multilayer  

Nanofilm  Coatings  to  Alginate  Microspheres.    Macromolecular  Bioscience    2005;  5  (8):  717–727;  Cash  K,  Clark  H.    

Nanosensors  and  nanomaterials  for  monitoring  glucose  in  diabetes.  Trends  in  Molecular  Medicine    2010;  16(12):  

584–593;  Srivastava  R,  Jayant  R,  Chaudhary  A,  McShane  M.    Smart  Tattoo”  Glucose  Biosensors  and  Effect  of  

Coencapsulated  Anti-­‐Inflammatory  Agents.    J  Diabetes  Sci  Technol.  2011;  5(1):  76–85.  

7  Bawa,  Raj.    Nanotechnology  Patent  Proliferation  and  the  Crisis  at  the  U.S.  Patent  Office.  Alb  L.J.  Sci.  &  Tech.  2007;  

17:699-­‐736.    

5  

autonomy, beneficence, multi-dimensional justice8, privacy and system design. We explain and

apply each factor to nano tattoos below.

Patent Scope

It is not uncommon for nanotechnology-related patents to claim a broad area of functionality

within the radius of their legal rights to exclude non-inventors’ uses. In order to avoid chilling

experimentation for fear of patent infringement, as well as to safe-guard against post-

commercialization invalidation of over-broad patents, nano tattoo patents should be narrowly

tailored. Presently, patents covering this technology are not overbroad in scope, but our analysis

suggests monitoring this art field as developments continue.9

Patent Thicket Potential

Since nanotechnologies are often transdisciplinary, encompassing such fields as physics,

chemistry, engineering and/or biology, it is not unusual for a single nano-enabled invention to be

covered by multiple overlapping patents. By increasing ownership determination costs, these

“patent thickets” exert a retarding effect on rates of technological development and

dissemination. That fewer than ten U.S. patents have been issued covering fundamental nano

tattoo-related inventions suggests that, currently, this area of innovation does not present a high

probability of a patent thicket.

                                                                                                                          8  Beachamp  T,  Childress  J.  Respect  for  Autonomy,  Beneficence,  Justice.  Beachamp  T,  Childress  J.    editors.    Principles  

of  Biomedical  Ethics,  5th  ed.  Oxford:  Oxford  University  Press,  2001,  p.57-­‐103,  165-­‐214,  225-­‐272;  Roco,  M.  

Nanoscale  Science  and  Engineering:    Unifying  and  Transforming  Tools.    AIChE  Journal  2004;  50(5):  896-­‐897.  

9  Databases  used  for  this  search  include  the  United  States  Patent  and  Trademark  Organization,  Web  of  Science,  

Pub  Med,  LexisNexis  and  Westlaw;  the  keywords  were  “nano  tattoo”  and  “smart  tattoo.”  

6  

Autonomy

Patient autonomy requires delivery of relevant and understandable information that enables

patients to make informed decisions regarding diagnostic and treatment alternatives. Avoiding

paternalism and upholding a patient’s right to self-determination necessitates not only

articulation of a device’s benefits, but also disclosure of attendant risks. Nano tattoo-enabled

management of glucose levels can lead to reduced instances of altered states of consciousness

brought on by hyper- or hypoglycemia. We predict increased autonomy in the form of more

opportunities for patient-users to make informed treatment decisions with clear minds.

Beneficence

Beneficence concerns improving quality of life or life expectancy, and can be assessed through

clinical trials. A device should be more than merely technically innovative; the user should

receive a tangibly beneficial result. Based on existing studies indicating that avoidance of

hyperglycemic episodes results in decreased diabetic complications, nano tattoos will likely

improve both quality of life and life expectancy, but this likelihood must be clinically confirmed

to assure beneficence.

Justice

The principle of justice has meaning in at least three registers: socio-economic justice,

distributive justice and environmental justice. Socioeconomic justice recognizes fair treatment of

individuals and classes independent of their social position or material wealth. Relatedly,

distributive justice is achieved when those who reap the benefits of an activity also bear its costs,

instead of outsourcing the latter to the less powerful. And environmental justice aims to

safeguard the ecosphere against spent nanoparticles whose transport paths and fates are presently

7  

poorly understood. Nano tattoo commercialization will likely encounter hurdles related to justice

issues in all three registers, since large portions of the estimated 25.8 million people constituting

the U.S. diabetic community —children, African-Americans, Native-Americans, Asian-

Americans, Hispanic/Latino Americans, pregnant women, the obese, the extremely ill— are also

historically disadvantaged groups who have born the brunt of environmental costs of

technological developments, who continue to receive sub-standard medical services, and who

seldom share equitably in the fruits of medical technology innovation.10

Privacy

The power to control dissemination of personal information is of critical concern in the context

of nanomedicine. Since nano tattoos will visually reflect glucose concentrations, third parties

may intercept a patient-user's personal medical information. Such an unintended disclosure of

health status would constitute a direct violation of patient confidentiality, presuming a traditional

patient-doctor relationship. This type of unintended disclosure might be even more harmful to a

patient once nano tattoos are designed to generate information concerning other socially

stigmatized conditions, such as cancer, HIV-AIDS, or other infectious diseases.

System Design

Technologies are not apolitical artifacts that merely achieve their stated functional goal. Rather,

through their designs, they tend to encourage certain types of behaviors and effects, while

discouraging others. There are often multiple designs capable of achieving the main goal of a                                                                                                                           10  National  Diabetes  Fact  Sheet:  National  estimates  and  general  information  on  diabetes  and  prediabetes  in  the  

United  States,  2011  US  Department  of  Health  and  Human  Services,  Centers  for  Disease  Control  and  Prevention    

2011;  9  http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf  ;  Elsaesser  A,  Howard,  V.    Toxicology  of  

Nanoparticles.    Advanced  Drug  Delivery  Reviews  2012;  64  :129-­‐137.  

8  

technology, each of them entailing different cost/benefit ratios for users and society at large.

Possible, and possibly competing, nano tattoo designs will likely implicate varied outcomes for

patient-users and society. And all the other factors of the checklist will be touched by the

technology's design: greater or lesser rates of subsequent innovation, more or less patient

autonomy, beneficence, and realized justice. Important questions will likely be addressed by

nano tattoo design decisions: Who will be capable of using the device? Who will monitor

possible human and/or environmental impacts? Most fundamentally, which groups will be able

to contribute to discussions about appropriate designs? Accordingly, the nano tattoo design

process should be open to input from all communities that are likely to be impacted by its

introduction: patient-users, the medical community, marginalized community advocates,

scientific researchers, legal advocates, and policy makers.

Conclusion

The checklist factors implicate one another and occasionally overlap in their scope of concern.

Though not exhaustive, they do address fundamental upstream intellectual property, bioethical

and system design issues of nano tattoos, as well as other nanomedical devices. And the more

promising the potential societal benefits of an emerging nanomedical device are, the more

important does this upstream assessment checklist become.