Evaluating the durability of bioprinted arteries transplanted into rabbits



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EXPLORING THE ETHICAL IMPLICATIONS OF EXPERIMENTATION ON RABBITS FOR BIOPRINTING RESEARCH THAT MAY IMPROVE TREATMENT FOR ATHEROSCLEROSIS
Isaac Hong Wong (isw4@pitt.edu)



EVALUATING THE DURABILITY OF BIOPRINTED ARTERIES TRANSPLANTED INTO RABBITS
Atherosclerosis is a process where fatty deposits build up on the arterial walls, and is a major underlying cause for most cardiovascular incidents [1]. When atherosclerosis develops in the coronary arteries, which supply oxygenated blood to the heart muscles, blood flow becomes more and more restricted, and risk of heart attack increases. In 2013, an estimated 32% of women and 52.9% of men had prevalent coronary artery atherosclerosis [1]. When atherosclerosis progresses to an advanced stage, the patient undergoes a bypass operation to divert the blood flow through a surgically grafted piece of artery, harvested from the patient’s own body, past the affected site. However, these vessels are unequal in strength and elasticity, and is also likely to be affected by atherosclerosis [2]. Furthermore, any new treatment should also seek to be widely available, since approximately 400,000 coronary artery bypass operations were performed in the US alone [2]. In order to address these limitations of autografted arteries and meet the high volume of operations, my research team and I, through bioprinting, seek to manufacture living arteries for implantation.

In recent years, bioprinting has replaced the traditional method of seeding cells to grow on biocompatible scaffolds due to the ability of bioprinting to produce, with accuracy and high resolution, vascularized 3D structures made of multiple cell types. Bioprinting is a method of organ and tissue biofabrication that applies the principles of additive manufacturing, creating 3D living tissue by depositing living cells or cell spheroids in layers, allowing each layer to harden before depositing the next [3].

In past four years, we have been able to consistently bioprint segments of vascular tissue that mimicked the coronary arteries. Inspired by the work of Norette et al., where they were able to bioprint simple vascular structures by extrusion-type printing, we used extrusion printing, a quick but less precise method, to create the bulk of our vessel, as well as laser-assisted printing, a slower but more precise method, to print the more delicate structures [4,5]. After conducting extensive mechanical stress tests to preliminarily determine the strength and approximate lifespan of our vessels, as well as preliminary simulations to ensure that the inner walls were smooth enough to let blood cells pass without clotting, our team was ready to move onto testing the durability of our vessels in New Zealand rabbits.

The New Zealand rabbit was chosen because it only takes a few days of high-cholesterol diet to induce atherosclerosis in their arteries, it’s large enough to operate on, and both its systolic and diastolic blood pressures correspond to a typical human with normal to high blood pressure, making it a suitable choice to quickly and effectively test the durability of our printed vessels [6,7,8].

However, while going forward with planning for our next stage of testing, I began to question if it was ethical to induce disease in healthy animals, then operate on them, knowing that it was possible for some to die in the process, and others to have to live with the disease, or be euthanized. Even though our research can reasonably be expected to improve the current state of coronary artery bypass operations, as well as provide a stepping stone for more complicated bioprinting research, does the argument that the public stands to benefit from animal experimentation give us the ethical green light to carry on with our research?
Defining the Question
Ethics has been defined in different ways, but in an engineering context, Joseph Wujek and Deborah Johnson from the Institute of Electrical and Electronics Engineers (IEEE) has described ethics as a set of “rules and ideals for human behavior” [9]. The rules and the ideals for human behavior are really two different extremes. The rules can be defined by professional and legal documents, while ideals are more ambiguously guided by our individual and collective values [10]. My decision to continue or politely withdraw from the research would therefore require me to consider both my professional and legal obligations as well as moral inclinations.
PROFESSIONAL GUIDELINES
As a biomedical engineer, I have membership to both the National Society of Professional Engineers (NSPE) as well as the Biomedical Engineering Society (BMES), and thus have professional obligations to adhere to their code of ethics. But my professional obligations do not simply lie with the engineering community, they also lie, in certain respects, with the medical community and their codes of ethics, developed by the American Medical Association (AMA) [11]. It must be said, however, that these codes do not have the authority of law. Established by a society of engineers and doctors, these provisions are more of the engineering and medical society’s expectations than legal boundaries.
National Society of Professional Engineers
The NSPE’s code of ethics has no mention of animal experimentation, but it expects me to “hold paramount the safety, health, and welfare of the public” as well as to “at all times strive to serve the public interest” [12]. This holds a conundrum, for on one hand I should continue my research, because it would improve the health and welfare of the public, but on the other hand, if the public should deem it in their moral interest to denounce animal experimentation, I’m caught between the two clauses.

A possible solution would be to find a different way to carry out our research without experimenting on animals. However, any new implant material must first meet various standards for biocompatibility, mechanical stability, and lack of toxicity [13]. With our current technology, many aspects of the above cannot be tested for in an in vitro environment –mathematical modelling and computer simulations are not very effective because we do not understand enough about biochemical processes and their relationship with the mechanical workings of the human body, or lack the technology to accurately regulate a microclimate similar to that in vivo [14].

With in vivo testing, the inaccuracies of the in vitro methods can be circumvented [14]. However, because human experimentation is mostly illegal and typically morally unacceptable in the eyes of the public, the we resort to animal experimentation. Furthermore, I am to “hold paramount” the health and welfare of the public, which means that serving the public’s moral interest is of secondary importance to my service to the public’s health.
Biomedical Engineering Society
The BMES code of ethics similarly charges me to “enhance the safety, health, and welfare of the public”, but also ask that I consider the “cost, availability, and delivery of health care” [15]. While current technology is unable to accurately simulate chemical and biological processes of the body, if we stop all animal experimentation and focus our time and budgets on creating an accurate simulator for the highly complex workings of the body, two things are likely to follow:

The time required to both research the workings of relevant biochemical and mechanical processes and develop the apparatus that can accurately simulate them, as well as the time dedicated to our particular research on bioprinted arteries, is likely to take much longer than if animal experimentation were carried out. The question of: “Is our convenience worth the lives of dozens of rabbits?” is a reasonable one, yet the question of: “are patients going to be deprived of improved surgical methods for the sake of our apprehension?” is an equally, if not more jarring question.

The costs involved in the above mentioned research and development will be very high. Practically, the costs that go into the development of any medical treatment is partially laid on the shoulders of the patients. Increasing the cost of research means increasing the cost of treatment, making the treatment less widely available, dampening any enhancement to the public’s health.
Professional Expectations
Both the NSPE and BMES codes of ethics can be interpreted to hold the welfare and health of the public over that of animals, and the BMES code also expects me to consider the cost and availability of the treatment option we intend to offer [12,15]. Additionally, the AMA code of ethics also states that “a physician shall support access to medical care for all people” [16]. From the above, it is clear that despite any moral opposition some part of the public may have against animal experimentation, my professional obligations dictate that I should continue with our research on rabbits, and for any research involving animals, the BMES code of ethics expect me to “comply fully with legal, ethical, institutional, governmental, and other applicable research guidelines, respecting the rights of and exercising the responsibilities to… animal subjects” [15].
LEGAL OBLIGATIONS
With regard to legal obligations, the state of Pennsylvania prohibits cruelty to animals, where “any person commits an offense if he…cruelly ill-treats, overloads, beats, otherwise abuses any animal” is found in offense to the statute [17]. However, this law does not apply to any personnel trained in accordance to and complying with the Animal Welfare Act (AWA) [17].

Although I myself am not trained in the AWA, several of my fellow researchers longer have been. After reviewing the AWA and the plans that my colleagues have drawn up for the holding and treatment of the rabbits, I was satisfied that we had met our legal requirements. The rabbits would be transported in safe, comfortable structures with specific microclimates, and then released into holding rooms with specific temperatures, humidity, noise, and light, and provided with sufficient water and ventilation. The food they were to be provided was specifically designed to provide adequate nutrition as well induce the atherosclerosis that we needed for the experiment. In addition, in order for the experiment to as accurate as possible, our rabbits have to be well treated so that they will not be unduly stressed and thus skew the results.

By complying with Pennsylvania state law, and the AWA, the research team and I have met our legal obligations.


MORAL GUIDELINES
However, even as the institutional codes of ethics provides me with what the engineering society expects me to do in this situation, and the AWA provides me with the go-ahead to carry out my experiment without legal consequences, the question of should I is not yet answered. Does society deem it morally acceptable to experiment on animals for society’s benefit?
Morally Wrong
Some believe that animal experimentation is completely objectionable, and should be made illegal in the eyes of the law. Their beliefs can be summed up by a quote from Jeremy Bentham: “The question is not, can they reason? Nor, can they talk? But, can they suffer?”[18]. They believe that we, as humans, have a moral duty to all creatures that are sentient – able to feel pain, to suffer – just like we have a moral duty to other human beings. In that manner, just as it is morally wrong to experiment on another human being without their autonomous consent, it is also morally wrong to experiment on animals without their consent. And since we cannot communicate with our laboratory rabbits to ask for their consent, it is never morally right to experiment on them.
Morally Indeterminate
Others believe that animal experimentation is acceptable only under certain conditions and guidelines, the most common of which is Russell and Burch’s “Principle of 3 R’s” – replacement, reduction, and refinement [19].

The replacement principle applies when first establishing a plan for the experiment [19]. If the experiment could reasonably be performed without the use of animals – for example, by in vitro techniques, mathematical modelling, computer simulations, or experiments on less morally objectionable creatures, like insects, plants, or fungi – then the researcher must choose the alternative [19]. The reduction principle states that if no alternative is found, the experiment should be optimized in such manner that reduces the suffering or the number of animals needed, while still obtaining the necessary data [19]. This is to reduce the total number of suffering animals, but does not mean that a smaller number of animals undergo intense suffering to spare a larger number of animals mild suffering [19]. The refinement principle refers to an improvement of the accommodation and procedural aspects of the experiment in order to minimize pain and stress, and provide for the welfare of the animals [19].

When the 3 R’s are fulfilled, our experimentation on rabbits for the benefit of public health and welfare is acceptable.
Comparing the Two
It is clear that animals can suffer, and thus have sentience. However, it is not so clear that sentience in a different species should justify any moral duty owed to them. That being said, it is also difficult to justify inflicting injury and disease onto animals for our selfish purposes, no matter how many little welfares we grant to them through the AWA. To complicate matters, every individual has a different opinion, and when individuals aggregate, can it justified for the moral “right” to go to the majority? Similarly, can it justified for the moral “right” to go to the group with the most influence? Would the individuals of the group that is less numerous or less influential lay down their moral arms and conform to the moral “right”?
THE PROFESSIONAL, LEGAL, AND MORAL DECISION
An ethical decision involves not only our moral compass, which is different for every individual, but also our legal and professional obligations [10]. For myself, as a bioengineer, my legal obligations with regard to bioprinting research by experimenting on rabbits have been fulfilled, and my professional obligations guide me towards the enhancement of the public’s health and welfare over that of the animals’. In those regards, the ends do justify the means.

When it comes to a moral decision, however, the answer is not as well-defined. Since it is difficult to determine a moral decision by relying on societal trends, the decision is a personal one. In such case, since whether I decide to politely withdraw or continue with the research, there are no theoretical legal or professional consequences, the decision is then motivated by either practical concerns – like the possession of a job, the possibility of a raise, the source of our research funding, threats from interest groups – or by personal values, or a mixture of both.

In the case of an ethical argument, I believe that the above mentioned “practical concerns” should have no bearing on an ethical decision. Assuming that practical influences are non-existent, and despite sympathizing with animal rights supporters’ concept of sentience and belief that animal experimentation is never acceptable, I feel that being able to improve the lives of humans is more important.

Consequently, to be in line with society’s moral direction for acceptable animal experimentation, Russell and Burch’s 3 R’s should be taken into consideration. With regard to replacement, the research team and I had already performed extensive in vitro testing prior to considering in vivo testing on live rabbits. Furthermore, no computer simulation or mathematical model is advanced enough to predict what will happen inside a real body. We use rabbits because the relevant parameters in rabbits – blood pressure and atherosclerosis – are similar to humans. However, it is difficult to reduce the number of rabbits required, since each rabbit can only be tested once. Consequently, we can only refine the procedure to provide welfare and reduce suffering. The rabbits suffer little up till the operation – atherosclerosis is not a painful affliction, and anesthesia will be used for the operation. However, unavoidably, after the operation, they are at risk of suffering if the implant ruptures, is rejected, or other unforeseen circumstances arise.

With the professional codes of ethics and legal obligations adhered to, and the 3 R’s fulfilled, our research of the durability of bioprinted arteries used in bypass operations in rabbits is a go.
REFERENCES
[1] “AHA Statistical Update” (2013). American Heart Association. (Online Article). http://circ.ahajournals.org/content/127/1/e6.full#sec-304

[2] B. Graca, G. Filardo. (2011) “Vascular Bioprinting.” American Journal of Cardiology. (Print Article). Vol. 107, no. 1, pp. 141-142.

[3] C. Ferris, K. Gilmore, G. Wallace, M. Panhuis. (2013). “Biofabrication: an overview of the approaches used for printing of living cells.” Applied Microbiology and Biotechnology. (Print Article). Vol. 97, no. 10, pp. 4243-4258.

[4] C. Norotte, F. S. Marga, L. E. Niklason, and G. Forgacs. (2009) “Scaffold-free vascular tissue engineering using bioprinting.” Biomaterials. (Print Article). Vol. 30, no. 30, pp. 5910–5917.

[5] I. Ozbolat, Y. Yu. (2013). “Bioprinting Toward Organ Fabrication: Challenges and Future Trends.” IEEE Transactions on Biomedical Engineering. (Print Article). Vol. 60, no. 3, pp. 691-699.

[6] A. Yanni. (2004). “The laboratory animal: animal model of atherosclerosis research.” Laboratory Animals. (Print Article). Vol. 38, no. 3, pp. 246-256.

[7] V. Govyrin. (1957). “Measurements of arterial pressures in intact rabbits.” Bulletin of Experimental Biology and Medicine. (Print Article). Vol. 44, no. 1, pp. 896-897.

[8] A. Mortenson. (1996). “The use of rabbits in atherosclerosis research. Diet and drug intervention in different rabbit models exposed to selected dietary fats and the calcium antagonist (-)-anipamil.” Roskilde University Institute of Life Science. (Online Article). http://rudar.ruc.dk/bitstream/1800/489/1/The_use_of_rabbits.pdf

[9] J. Wujek, D. Johnson. (1992). “How to be a good engineer” Online Ethics Center. (Online Article). http://www.onlineethics.org/Topics/LegalIssues/LegalEssays/speakersguide.aspx

[10] B. Ennis Dulin. (2003) “Sharpening the Focus: Legal Context of Engineering Ethics”. J. Prof. Issues Eng. Educ. Pract.. (Print Article) Vol. 129, no. 3, pp. 138–142.

[11] N. Wood, N. Barakat. “Inclusion of bioengineering into existing codes of ethics”. Grand Valley State University School of Engineering. (Online Article). http://claymore.engineer.gvsu.edu/ocs/index.php/aseencs2009/aseencs2009/paper/viewFile/31/11

[12] “Code of Ethics for Engineers” (2007). National Society of Professional Engineers. (Online Article). http://www.nspe.org/resources/pdfs/Ethics/CodeofEthics/Code-2007-July.pdf

[13]S. Saraf, V. Kumaraswamy. (2013). “Basic research: issues with animal experimentations”. Indian Journal of Orthopaedics. (Online Article). http://www.ijoonline.com/article.asp?issn=0019-5413;year=2013;volume=47;issue=1;spage=6;epage=9;aulast=Saraf

[14] G. Lambarti, S. Cascone, M. Iannaccone, G. Titomanlio. (2012). “In vitro simulation of drug intestinal absorption”. International Journal of Pharmaceutics. (Print Article) Vol. 439, no. 1-2, pp. 165-168.

[15] “Biomedical Engineering Society Code of Ethics” (2004). Biomedical Engineering Society. (Online Article). http://bmes.org/files/2004%20Approved%20%20Code%20of%20Ethics(2).pdf

[16] “Principles of Medical Ethics”. (2001). American Medical Association. (Online Article). http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/principles-medical-ethics.page?

[17] “Purdon’s Pennsylvania’s Statutes and Consolidated Statutes” (2013). Animal Legal and Historical Center. (Online Article). http://www.animallaw.info/statutes/stuspa18pacsa_5511.htm

[18] “Jeremy Bentham on the suffering of non-human animals”. (2013). BLTC. (Online Article). http://www.utilitarianism.com/jeremybentham.html



[19] B. Marinescu, C. Coman. “The ethics of animal testing”. (2010). Romanian Journal of Bioethics. (Print Article). Vol. 8, no. 3, pp. 197-204.
ACKNOWLEDGEMENTS:
I would like to thank my parents, Haiperng Wong and Wendy Wee, and my girlfriend, Carolyn Yue, for being a source of support and encouragement throughout my first 6 weeks at college. As one can never have too many proof-readers, another special thanks for helping to proof-read my essays. I would like to thank Kristin Vermilya from the Writing Center for her helpful suggestions about how to structure my paper. I am also ever grateful to my room-mate, Bernard Berger, for being considerate and tidy in his living habits, so much so that I can study and think in peace.

Swanson School of Engineering, University of Pittsburgh

2013/10/29 1

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