Accountability in Research, 19344–369, 2012Copyright © Tayl.docx

Accountability in Research, 19:344–369, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0898-9621 print / 1545-5815 online
DOI: 10.1080/08989621.2012.728910
Reflexive Research Ethics
in Fetal Tissue
Xenotransplantation Research
Bindu Panikkar, Ph.D.,1 Natasha Smith, B.A.,2
and Phil Brown, Ph.D.1
1Social Science Environmental Health Research Institute,
Northeastern University,
Boston, Massachusetts, USA
2Nelson School for Environmental Health, University of
Wisconsin, Madison,
Wisconsin, USA
For biomedical research in which the only involvement of the
human subject is the
provision of tissue or organ samples, a blanket consent, i.e.,
consent to use the tissue
for anything researchers wish to do, is considered by many to be
adequate for legal
and Institutional Review Board (IRB) requirements.
Alternatively, a detailed informed
consent provides patients or study participants with more
thorough information about
the research topic. We document here the beliefs and opinions
of the research staff on

informed consent and the discussion-based reflexive research
ethics process that we
employed in our fetal tissue xenotransplantion research on the
impact of environmental
exposures on fetal development. Reflexive research ethics
entails the continued adjust-
ment of research practice according to relational and reflexive
understandings of what
might be beneficent or harmful. Such reflexivity is not solely an
individual endeavor,
but rather a collective relationship between all actors in the
research process.
Keywords: bioethics, fetal tissue transplantation, informed
consent, reflexive research
ethics, research ethics
INTRODUCTION
Fetal tissue transplantation offers unique research opportunities
for exploring
fetal development and epigenetic changes that stem from
common environ-
mental exposures and other stressors. However, fetal tissue
transplantation
is controversial with ethical, moral, and sociopolitical
considerations that
are different from other human- and animal-based research.
Fetal tissue
research calls attention to concerns over sentient life, abortion,
religious
Address correspondence to Bindu Panikkar, Northeastern
University, Social Science
Environmental Health Research Institute, 318 IV, 360
Huntington Ave., Boston, MA

02115. E-mail: [email protected]
Reflexive Research Ethics 345
beliefs, ownership of the tissue, and who has the right to decide
to donate tis-
sue. There are, of course, feelings of loss of the fetus. Blanket
informed consent
for tissue donation is preferred by many; however, it does not
require that infor-
mation specific to the use of fetal tissue and transplantation be
provided to the
parents who donate fetal tissue (Beskow et al., 2010, NCI,
2011). How much
should parents who donate fetal tissue be told about the
proposed nature of
research for which the tissue will be used? How should the
researchers dis-
cuss, decide, and address complex ethical issues in fetal tissue
research? This
research reports on the “reflexive research ethics” process
(Cordner et al., 2012)
employed by a multidisciplinary research team that explores
environmental
stressors and their impact on fetal development. We developed
the concept
of reflexive research ethics, which involves the self-conscious,
interactive, and
iterative reflection upon researchers’ relationships with research
participants,
relevant communities, and principles of professional and
scientific conduct.
Reflexive research ethics entails the continued adjustment of
research practice

according to relational and reflexive understandings of what
might be benefi-
cent or harmful. Such reflexivity is not solely an individual
endeavor, but rather
a collective relationship between all actors in the research
process.
THE WORK OF THE RESEARCH TEAM
Environmental health researchers and health professionals from
Brown
University, Rhode Island Hospital, and Women and Infants
Hospital collab-
orated in 2010 to form the Children’s Environmental Health
Center, jointly
funded by the Environmental Protection Agency and the
National Institute of
Environmental Health Sciences. The Center’s research is based
on the “Barker
hypothesis,” which examines the fetal basis of childhood and
adult diseases
(Barker, 1992). The Barker hypothesis looks at how a mother’s
body compo-
sition, diet, and fetal exposure to different pollutants in the
environment can
affect genes and ultimately the future health of the fetus. Fetal
programming
is presumed to be an adaptive response to environmental cues,
acting predomi-
nantly through epigenetic mechanisms that regulate the
expression of genes
via multiple mechanisms, such as DNA methylation, histone
modification,
and microRNA modulation. Epigenetic modifications are
responsible for child-
hood and later life patterns of metabolism, cell proliferation and

growth, and
immune and injury responses that can ultimately act as
predisposing factors
in disease.
The Center is built around four components: an Administrative
Core,
a Tissue Procurement Core, a Xenotranplant Core, and a
Community
Outreach and Translation Core. The larger research team
comprises a multi-
institutional and interdisciplinary group including toxicologists,
pediatricians,
obstetrician-gynecologists, pathologists, transplantation
laboratory scientists,
and sociologists. The Community Outreach and Translation
Core comprises
346 B. Panikkar et al.
a sociologist and a postdoctoral environmental health scientist,
who were
assisted by an undergraduate student. The community outreach
activities
include the translation of laboratory observations and broader
children’s envi-
ronmental health issues to clinically relevant and community
appropriate
responses, with the goal of improving public health. The
sociologist (PB) who
directs the Core has extensive experience in research ethics
issues that involve
alternative approaches to informed consent. He and the postdoc
(BP) have

extensive experience in community-based participatory
research, which pays
much attention to ethical concerns such as patient right-to-
know.
The Tissue Procurement Core facilitates tissue collection and
processing
of biological samples for the study. Human fetal tissues
collected for study
from spontaneous abortions are of 12–22 weeks gestation.
Permission is sought
for the collection and use of these fetal tissues from parents
who donate fetal
tissues. Samples collected include prostate, lung, liver, breast,
and ovary tis-
sue specimens from spontaneous abortions that occur at Women
and Infants
Hospital. The aborted fetus is processed at the hospital as part
of the usual
clinical processing for pathological evaluation within 4–18
hours of delivery
for study purposes. The tissues procured for the purposes of this
study are
considered de-identified residual tissue.
Next, the Xenotransplant Core prepares selected tissues for
immediate
xenotransplantation into immunodeficient rodent hosts, after
which the trans-
planted tissues are exposed to common environmental pollutants
and stressors
(e.g., arsenic, lead, phthalates) to assess the human fetal tissue
responses.
This method of xenotransplantation allows for more realistic
assessment of
human health effects, since it involves experimentation on

human cells in
animal hosts. This differs from the traditional animal model
where high
doses are given to animals and the results extrapolated to human
risk esti-
mates. The projects undertaken by this team investigates human
fetal liver
and the metabolic syndrome, human fetal prostate and endocrine
disruption,
human fetal testis and phthalate exposure, human fetal lung,
arsenic exposure
and tissue remodeling, endocrine disruption effects on ovaries,
and endocrine
disruption effects on mammary gland. These studies look into
the underly-
ing mechanisms of environmentally-induced fetal disease.
Importantly, this
biomedical research offers no direct therapeutic benefits to
participants, and
offers benefits only to science in general.
GRAPPLING WITH ETHICS
As the team was writing the proposal for the Center, a year-long
process, the
question emerged on how much to tell the parents about the
research when ask-
ing for permission to use tissue from their fetuses. Two
approaches to informed
consent were initially considered: one that simply obtained
blanket permission
from parents for any and all uses of the tissue, and the other
approach offered

detailed information on the nature of research to the parents
while seeking
consent, what we term “detailed consent.” It was clear that the
university
and hospital Institutional Review Boards (IRBs) would have
approved the
project with blanket consent. Detailed informed consent was a
new area of
discussion for some of the research team members, though
physicians had expe-
rience in medical ethics. It became clear during research group
meetings on
ethics that the question of informed consent was not just a
logistical issue for
the team, but also an opportunity for ongoing research and
education of the
group, the hospital staff and the participants who donated
tissue. The research
group discussions on research ethics in this case influenced the
team’s decision
to offer detailed informed consent to parents who donated fetal
tissues. The
Community Outreach and Translation Core, which serves to
engage the scien-
tific and general communities in this research, adopted this
issue as a research
project and proceeded to document the discussions on research
ethics among
research participants and further interviewed research team
members and the
parents who donated fetal tissue on their views on detailed
informed consent.
Interviewing the project staff brought to light the various
ethical concerns that

the staff reflected on within the process of seeking detailed
informed consent.
It also provided the Outreach Core with a way to evaluate the
effectiveness of
the team’s approach.
This article reports on the beliefs and opinions of the research
team on how
to engage in informed consent; a later article will report on the
experiences of
the participants who donated fetal tissue. We especially
emphasize the “reflex-
ive research ethics” process used in the team’s discussions on
informed consent.
Reflexivity in this case encourages transparency and reflection
on ethics at
all stages, starting early on in the research design process, and
continuing
as the project unfolds and the team gains experience in
discussing detailed
consent with potential tissue donors and with other hospital
colleagues not
involved in the Children’s Center. Reflexive research ethics
aims to promote
active dialogue on purposes, processes, and outcomes between
the work teams
and participants as an ongoing initiative that facilitates
personal, professional,
and system changes.
ISSUES IN FETAL TISSUE RESEARCH
Use of human fetal tissues for research has been legal since the
1930s
(American Society for Cell Biology, 2001). Polio vaccine was
developed using

human fetal kidney cells that led to the 1954 Nobel Prize in
Medicine. Other
vaccines, such as those for rubella and varicella, which have
greatly controlled
major sources of child morbidity and mental retardation in the
United States,
were also made from fetal tissue cultures (Coutts, 1993). Fetal
tissue research
has also offered valuable insights into birth defects and other
developmental
diseases. Fetal tissue and embryos for research can be obtained
from a vari-
ety of sources including hospitals, non-profit tissue banks, and
in some cases
abortion clinics and fertility clinics.
This project uses fetal tissue transplantation to assess the
environmental
impacts on fetal development and epigenetic changes. Fetal cell
research holds
unique promise for biomedical and environmental health
research to explore
fetal development and epigenetic changes that stem from
common environmen-
tal exposures and other stressors. Fetal cells are less susceptible
to rejection
and they proliferate and adapt much more easily than adult
cells, which is why
fetal tissue is so valuable for such research.
But these benefits come up against key obstacles. Fetal tissue

transplanta-
tion into animal models such as rodents is a highly charged and
controversial
topic, with ethical, moral, and sociopolitical implications that
are more pow-
erful than other human- and animal-based research. The use of
fetal tissue
in research has been highly politicized in the United States,
inflamed by the
highly polarized abortion debate in this country in the wake of
Roe vs. Wade
and the controversial debate on the morality of stem cell
research. Some who
oppose the use of miscarried fetal tissue for research and
transplantation do
so because it is inextricably linked to the controversy over
abortion (Verklan,
1993).
Since 1975, federal law requires permission or accordance with
applicable
state laws regarding fetal tissue research (45 C.F.R. 46. Sec
210). Almost half of
the states in the United States have fetal research statutes; 12
either prohibit
or seriously restrict general scientific research in utero, and 18
prohibit it ex
utero (NCSL, 2008; Andrews, 1994, 1993). In 1988, President
Reagan issued a
moratorium on federal funding for fetal tissue transplantation
research. This
ban, however, did not apply to the use of fetal tissue for other
research pur-
poses. It was in effect for five years until the Clinton
administration lifted the
ban in 1993 under the National Institutes of Health

Revitalization Act (Public
Law 103–43), which amended the Public Health Service Act and
allowed sup-
port for research on transplantation of human fetal tissue for
therapeutic
purposes. This Act also allowed the use of tissue from both
spontaneous and
induced abortions, as well as stillbirth (42 U.S.C. 289 et seq.).
Since 1999,
forces both inside and outside Congress opposed to any
scientific use of fetal
tissue have tried to make an issue of the supply of fetal tissue to
researchers,
denouncing those involved as engaged in “the sale of baby body
parts.” During
the 2000 campaign, candidate George W. Bush was opposed to
any use of
fetal tissue or embryonic stem cells for research. Under the
current law, it is
“unlawful for any person to knowingly acquire, receive, or
otherwise transfer
any human fetal tissue for valuable (profitable) consideration if
the transfer
affects interstate commerce” (Hurd, 1992; American Society for
Cell Biology,
2001; Boonstra, 2001).
Human research involving stem cells derived from human
embryos or
human fetal tissue research must be in accordance with the
Department of
Health and Human Services (HHS) regulations for the

Protection of Human
Subjects (45 CFR, Part 46), FDA regulations (21 CFR 50 and
56) for fetal
tissue based clinical research involving drugs, and the informed
consent reg-
ulations (OHRP, 2001). The use of human fetal tissue and
transplantation is
governed by the Uniform Anatomical Gift Act of 2006 which
allows donation,
provided parental consensus is obtained (Verklan, 1993). This
stems from the
1993 statute’s requirement that the woman donating her human
fetal tissue
must sign a statement declaring that the tissue is being donated
for scien-
tific research. The donation is to be made without disclosing the
identity of
individuals who may be the recipients of the transplantations.
Human fetal
tissue may be used only if the head of the agency or other entity
conducting the
research certifies to the Secretary of Health and Human
Services that those
requirements will be available for audit (NIH, 1993; 45 CFR
46.116).
Biomedical research commonly relies on highly specialized
biorepositories
that allow the secondary use of pathology archives derived from
surgical resec-
tion specimens or from autopsy (Riegman and Veen, 2011).
Most studies using
fetal tissue gather residual tissues that are routinely collected
from these
archives. More than 300 million tissue samples are in storage in
the United

States in both public and private repositories with 20 million
added each year.
Many of these were collected during surgical and clinical
procedures and has
not obtained any consent for research (Eismen and Haga, 1999;
Maschke,
2008). In the case of using stored data or human tissues, the
tissue collec-
tors and repository storage and data management center’s are
subject to IRB
review, informed consent, certificate of confidentiality and
assurance of compli-
ance. Informed consent for repositories include “description on
(i) the operation
of the cell repository; (ii) the specific types of research to be
conducted; (iii)
conditions under which data and specimens will be released to
recipient-
investigators; and (iv) procedures for protecting the privacy of
subjects and
maintaining the confidentiality of data” (OPRR, 1997). In 2004,
the U.S. Office
of Human Research Protections (OHRP) issued a guidance that
coded private
information or human biological specimen that are
unidentifiable private infor-
mation not obtained through intervention or interaction with
living individuals
is not considered human subjects research, in which case IRB
review of the
research is not required (OHRP, 2008; 45 CFR 46.101). This
applies also to
in vitro research cell lines and research in animals using already
derived and
established human cell lines. They are not considered human
subject research

and are not governed by the HHS or FDA human subject
protection regulations
appearing at 45 CFR Part 46 and 21 CFR Parts 50 and 56
(OHRP, 2002).
Blanket consent is at the moment considered sufficient consent
modality
for residual tissue use and the fetal tissues from biobanks if
proper gover-
nance is assured. An opt-out procedure, which allows the use of
residual tissue
unless the patient has objected to such use, is formalized in
many European
countries with the reasonable expectation that the results will
come back as
treatment available to all in the health-care system which
applies more to
counties where patients have equal access to healthcare
(Riegman and Veen,
2011). In the United States, anonymous residual tissue is not
human subject
research, and hence, consent is not required (OHRP, 2008;
Washington, 2011).
In recent years, such research use of stored residual human cells
and tissue
has sparked attention, even if it is only slightly different from
biobanking
for which tissue is specifically collected. The well-known case
of Henrietta
Lacks, described in Rebecca Skloot’s widely-read book,
illustrates the abuses

of using stored samples for research about which the donor or
her surviv-
ing family is unaware (Skloot, 2010). The use or misuse of
these samples
has been regarded as the most fundamental concern in the
procurement of
residual samples, especially with regard to genetic research.
With advances
in molecular biology and the ability to identify the role genes
play in dis-
ease formation, there is an accelerated drive towards creating
new diagnostic
tests, targeted treatments for specific diseases, and possibly
even customized
personalized medicine (NCI, 2011; Maschke, 2008). The
“Genetic Information
Nondiscrimination Act” of 2008 proposes that genetic
information is different
from other types of personal information and requires protection
as the release
of genetic test information may adversely affect patients and
their relatives.
Recommendations to prevent misuse propose that secondary
researchers (i.e.,
those not involved in the collection of tissue) use only coded or
anonymized
samples, which do not require informed consent for the
secondary use (OHRP,
2008; Annas et al., 1995; Clayton et al., 1995). However, the
controversy in the
use of these residual samples include not only informed
consent, which is typ-
ically thought to have minimal risks, but also privacy,
confidentiality, future
use, ongoing medical record access, disclosure of research
results, intellectual

property and biobank governance, and the ability to discontinue
participation
(Maschke, 2008; Beskow et al., 2010).
ISSUES IN INFORMED CONSENT
Informed consent is central to the issue of the ethics of fetal
tissue and
xenotransplantation research (NIH Guide, 1993; 45 CFR
46.116). Since the
Belmont Report, informed consent has been described as a form
of respect-
ing individual autonomy (Silverman, 1989; Davis, 2004;
O’Neill, 2004). Some
studies stress that unlimited autonomy should not be imposed
necessarily, on
the basis that people have limited capacity for completely
autonomous behavior
and that autonomy can be represented by previous or later
preferences (O’Neill,
1984; Davis, 2004). It is difficult to fully satisfy the principles
of beneficence
and autonomy in informed consent in a just and healthy manner
(Silverman,
1989), but a well thought-out process tailored to the specific
research context is
possible.
An informed consent process that includes more information
than the
legal minimum may be the right thing to do, regardless of

specific regula-
tions. As Lidz et al. (1984) argued in their classic work on
informed consent,
even if patients do not grasp the details of what they are told,
they still
have a fundamental right to as much information as the
researchers can
provide. In following such an approach, scholars increasingly
view informed
consent as a process rather than simply a form or a single event
(Gray, 1978;
Kuczewski, 2002; Matsui, 2005). The process should be long-
term, educational,
and based on mutual trust; ethical concerns should trump
scientific needs or
agenda (Matsui, 2005; Prentice, 2007). Challenges in
implementing informed
consent include adequately explaining critical aspects of the
research such as
risks, purpose, and procedures (Prentice, 2007; Pfeffer et al.,
1997; Mechanic,
1984; Gillett, 1989). In particular, research concepts such as
clinical trials and
randomization, as well as technical and scientific language, are
difficult to com-
municate to patients (Pfeffer et al., 1997; Prentice, 2007; Russel
et al., 2005).
Informed consent material has been difficult for participants to
understand
based on background factors such as lower socioeconomic
status, literacy, and
language ability (Kuczewski, 2002).
Researchers often view ethics as “a rather static set of standards
for con-
duct based on a system of moral values” (Smith-Doerr, 2006),

established as
professional codes of conduct and mandated through IRB
protocols that deter-
mine acceptable research practices and their protection of
human subjects.
Such a structure offers a clear and predetermined set of
guidelines for research,
but it does not take into account the ongoing reflexivity
required of researchers
involved in new ethical issues. We propose that reflexive
research ethics offer
a valuable advance to routine ethics.
REFLEXIVE RESEARCH ETHICS IN INFORMED CONSENT
Our concept of reflexive research ethics (Cordner et al., 2012)
proposes that
researchers must move beyond seeing ethics as static,
preconceived standards
or guidelines, to seeing research as a process that is embedded
in social rela-
tionships and full of social consequences. Reflexive practice is
an exploration
of tacit knowledge that becomes clarified with time, experience,
and knowledge
which has the potential to shape future action with better
understanding of
the subject matter, relationship with individuals and the
situations involved
(Schon, 1987). Such an activity is transparent and pays close
attention to
experiential learning of activities carried out as part of one’s
profession and
questions the ethical and social consequences to research
applications. This
requires researchers to identify and establish interactive

discussions with the
full range of parties relevant to their work, including research
group mem-
bers, research participants, local communities, academic
disciplines, and those
potentially impacted by the research. They must ensure that
research par-
ticipants have not only the right to information but also the
capacity to
enhance their participation in research and decision-making.
They must iden-
tify norms and principles that govern their work, evaluate
ethical tensions
which may arise from the research, and respond to emergent
ethical ten-
sions, such as those arising from the study of public engagement
with new
or emerging technologies in science such as next generation
DNA sequenc-
ing as well as advances in communications and social media
such as chat
rooms and tweeting, that influence research participation, data
transmission
and access. Xenotransplantation research is precisely such an
emerging tech-
nology. Reflexivity also includes self-conscious and interactive
reflection on all
the above points, and the continued altering of research practice
according to
new understandings.

This article explores the social process within the fetal tissue
procurement
and xenotransplantation research team in building consensus
and employing
detailed informed consent. The research also explores the
beliefs and opin-
ions of the research team members, the evolution of their
thinking on research
ethics, their tensions, challenges, and potential future
implications of employ-
ing a transparent research methodology. Ultimately, we inquire
if reflexivity
and ethical considerations motivate the adoption of a
transparent research
methodology and detailed informed consent.
METHODS
The research team’s discussions about ethics started early on, at
the proposal
writing stage. We built reflexive practice into the research
process in order
to encourage transparency and develop capacities of reflection
on ethics by
promoting active dialogue on purposes, processes, and outcomes
amongst the
research team members as an ongoing initiative that facilitates
better work
ethics. Reflexivity on informed consent has become an ongoing
topic of discus-
sion at our regular team meetings as well as at our annual
retreats, site visits
with the program officers, and other public talks.
Our data include documentation of discussion on research ethics
at the

research team meetings which were followed by interviews with
each of the
research members at the Center. The notes on research ethics
discussions were
taken during the Children’s Environmental Health Center team
meetings at
multiple points in time: the proposal writing, the period
between when the
grant was awarded and the project procedures were being
devised, at many
ensuing team meetings, at the annual retreat to which the
university and com-
munity were invited, and at a later conference that was held as
part of an
Environmental Protection Agency (EPA) site visit. These
meetings were spread
over two years, a year before the project got funded and a year
after that. Other
notes come from meetings with clinical staff at the hospital,
when the team was
informing hospital clinicians of the project and seeking
referrals.
Further, ten members of the research team were interviewed
regarding
their thoughts on many aspects of the project including the
ethical issues
involved, the group discussions that originally led to detailed
consent, and
their expectations for how hospital staff and parents who donate
fetal tissue

would react to the research. The interviews were conducted in
the summer of
2010, a year after the Center got funded. We interviewed all the
key research
personnel in the Center including project staff from the
Administrative core
(n = 1), Tissue procurement core (n = 3), and xenotransplant
core or lab sci-
entists (n = 6). The Community Outreach and Translation Core
staff were not
interviewed since they were carrying out this research on the
informed consent
process. General consensus on detailed informed consent was
reached before
submitting the proposal for funding and before seeking IRB
approval. However,
as we found out later from our in-person interviews with
research staff, not
all were wholeheartedly supportive of that consensus, even
though they went
along with the decision. The interview process gave team
members the chance
to revisit their original perspectives, in which they were better
able to see that
agreement did not necessarily mean deep support of the
approach. Still, the
consensus agreement was always mentioned in public
presentations, and staff
were comfortable with that presentation of self.
In addition, we interviewed the recruiter and the parents who
agreed to
participate in the research and donated their fetal tissues. These
interviews
were done usually a week or two after their miscarriage. We
will report in

a later paper on these interviews, though we refer to their
findings because
the research team learned important data from our analysis and
discussion
of those interviews. The parents who donated the fetal tissues
were enrolled in
the study after the research team decided on offering detailed
informed consent
to the parents who join the study.
The observations on the research ethics discussions were made
by the
social scientist research on the team. Interviews were conducted
by the three
authors: the social scientist researcher on the team, a staff
person on the
Outreach Core who was not on the project team, and a student
working on her
senior thesis. The interviews were semistructured and were one
hour long on
average. Oral consent to participate were obtained for all
interviews conducted
in this study with research team members, recruiter, and parents
who donated
fetal tissues. The interview questionnaires and all study
procedures for the
research team member interviews and parent informed consent
interviews and
follow-up interviews with the parents who donated the tissues
were reviewed
and approved by the Brown University and Women and Infants
Hospital
IRBs.

Data Analysis
All interviews were recorded, transcribed, and coded in NVivo,
a software
program for analyzing qualitative data. Codes were developed
inductively from
the empirical data as well as common themes and topics that
emerged from the
research team discussions and interviews. Preliminary findings
were shared
with the whole research team in order to check the validity of
our analysis, and
no contradictory responses were found among the rest of the
team.
RESULTS
Reflexive dialogues on ethics played a central role in project
design. Many of
the project staff came into the first discussion with a narrow
focus on their
own perspective and their individual piece of the project, and it
was not until a
variety of opinions were put forth that they realized the ethical
implications of
the research.
Views of the Research Staff before Discussion on Ethics
During the planning stages of the project before any of the
discussions
on ethics, seven of the ten research members had not thought
much about
informed consent. Most of the researchers who preferred

blanket consent were
lab scientists primarily involved in animal research. They were
in some cases
not fully aware of the human subject research protocols, as
some noted:
I just think through our training, actually, the ethics portion is
more about,
you know, what’s ethically correct in publishing your research
and not choosing
data and things like that, and not necessarily where your
samples are coming
from . . . the whole right-to-know is just not addressed. . . . I
deal with the animal
side so I knew everything that went into an IACUC [animal
protection office] but
an IRB was brand new (Lab researcher PS 1).1
I really don’t think too much about the ethical issues, I’m
focused on the sci-
ence. I see enough benefits on the other side, therapeutically,
that has kind of
formed my ethical opinion. (Lab researcher PS 8)
These researchers were also not aware that an informed consent
process was
needed when the study started: “when we started, it didn’t occur
to me that
there would be an informed consent process” (Lab researcher PS
2). Some of
the researchers recounted the situations from their past when
consent was not
needed:
I’d done research on newborns before and, in those cases we
were obtaining

cord blood and placentas and now that goes back to the early
1980’s, and we didn’t
ask any of the parents for obtaining those materials, but we
consented them all so
they’d know about the study and also because we were
extracting data from their
medical records. . . . And standards have changed since then. I
mean, back then,
I am absolutely positive we would have used whatever tissue we
wanted with
impunity and not talked to anybody. We would’ve just gone to
the pathologists.
In fact, I think this would’ve gone through an expedited review
by the IRB. (Lab
researcher PS 2)
It is common practice in biomedical research to get residual
tissues from
pathology archives without seeking any consent. Autopsies are
done all the
time, even with miscarriages and this has been a source to
acquire tissues.
A team member pointed out that he has been involved in an
ongoing project
using human fetal testis transplants without consent by just
collecting resid-
ual tissues from fetuses and deliveries from the pathology
archive which had
received a blanket consent (Lab researcher PS 4). This was
verified by one of
his colleagues:

When somebody goes in to the hospital that’s gonna give birth
at the hospital,
whether it’s a miscarriage or a real birth, they sign some form—
very vague form
that says ’my tissue can be used for research purposes.’ So, for
past couple years,
we’ve received residual tissue.” (Lab researcher PS 5)
For these researchers involved in tissue procurement, two main
arguments
came up with regard to using detailed informed consent: one
that it would com-
promise their sample size, and two that they were already under
IRB rules, so
it was not necessary to do a full informed consent. One
researcher felt that dis-
cussion on ethics was not necessarily just the main focus, but
rather how to
get the samples. They thought that it was sufficient to provide
blanket consent
and perhaps unnecessary to complicate things further by
describing the project
in great detail to participants, as was the norm in their earlier
research work:
“I came from that background. [I] thought, you know, the fetus
is dead, who
cares, let’s make use of it the best way we can, why worry about
confusing the
situation with telling people details about what we’re planning
to do” (PS4).
The emphasis here is that the donated tissue samples will be put
to good use
for scientific advancement, a public good.
Blanket consent is commonly utilized in biomedical research. It

covers all
possibilities and allows any use of the material for scientific
research at any
time in the future. One research staff member defined blanket
consent in lit-
erally two lines, “I mean you just check yes or no and sign the
form, . . . which
gives you zero information . . . I think they lump fetus,
placenta, everything
together into one line. . . . so I’m assuming that’s what they’re
using for a
blanket consent form” (PS1). In some cases, blanket consent is
sought because
the researchers do not have a clear idea of the research protocol,
especially
in the case of biobanks, but in this study the researchers already
have the
research protocol in place, which makes it possible to have this
discussion on
the researchers ethical responsibility towards the participants.
While blanket informed consent is more common in biomedical
research,
not all the lab scientists were against detailed consent. Three
out of the
ten research staff were strong supporters of detailed consent.
Our scien-
tists who routinely deal with fetal autopsies were less inclined
to support
detailed informed consent. Our hospital staff who are involved
with patient

care expected ethical issues to be at the forefront, emphasizing
the importance
of detailed informed consent for the patient as well as for all
family mem-
bers and other significant persons. Their views were partly
formed by working
directly with the bereaved patients.
Shifting Tides: Consensus-Building on Detailed Informed
Consent
The transition from blanket consent to adopting detailed
informed consent
started with open discussions among project staff on the ethics
of fetal tis-
sue research and informed consent. After the initial discussions,
most team
members agreed to a process of full informed consent. This
expansion of
the informed consent beyond the IRB requirement and research
norms was
attributed largely to reflexive group discussions on ethics:
I think that what led to the change was just the discussions, and
under-
standing the broader picture—the context of things, I really—I
think that’s how it
evolved. (Lab researcher PS 2)
I think if you can get a group of people to collaborate like this
everything gets
done better and you share information, and somebody might
know something that
you don’t and, so for me having the whole group together- I
think they already
planned on having informed consent. (Lab researcher PS 5)

It wasn’t until everyone came together that you realized sort of
the magnitude
of what we were doing . . . and then I flipped. . . . I walked out
of that meeting and
went home that night and thought . . . that blanket consent is
really not the best
way given what we are going to do with the tissue, the full
[detailed] informed
consent seemed the appropriate way to go. . . . I think that a lot
of people in my
position may not have thought about it the way that we did once
the whole group
came together. (PS1)
The interdisciplinary background of the researchers, spanning
medical science,
and social science helped broaden these discussions to consider
the ethical
norms in other disciplines. Team members were able to
appreciate the perspec-
tive of potential participants who had just experienced a loss.
This especially
led to pushing the boundaries and designing an approach that is
extraordinary
in the biomedical field. One team member felt that the full,
detailed informed
consent process is not terribly innovative, since it is just
adhering to principles
that people have been talking about for quite a while now. He
felt that the novel
thing here was that, “We’re extending them to an area of
research that does not
require such an informed consent” (PS2).
This larger discussion on ethical implications personally

influenced the
team members and some even sought to deepen their awareness
and under-
standing on bioethics on their own, which shows an ongoing
development of
ethical concerns among the researchers. One of the lab
researchers shared that
she had been reading The Immortal Life of Henrietta Lacks,
Rebecca Skloot’s
(2010) bestselling book on the decades of use of an immortal
cancer cell line for
which the patient and her family never gave permission. She
said that she was
“disgusted with scientists and their views” and it made her think
about the
samples that they are getting, that the sample went far back to a
person, and
their families, not just to the freezer (PS 1). Needless to say that
reflexivity
did encourage ethical considerations in the team members, and a
thoughtful
approach was undertaken for this project, which considered all
the different
points of view.
In addition to the ethical considerations, media coverage
emerged as an
important concern. Although blanket consent is legally
adequate, team mem-
bers still believed that details of the project could be
misconstrued by the media

and result in alarming the public and undermining the science.
The team was
divided on whether the possibility of a negative response to the
animal element
necessitated the detailed informed consent or, conversely,
warranted a lack of
detail so as to not unnecessarily alarm or disturb the patient.
Because there
is a segment of the population that is fervent about issues
surrounding fetal
tissue research, members felt it to be important to be aware of
this audience
and be sensitive and delicate in the presentation of information:
I think people raising concerns about that or concerns about
publishing data
and then having the publicity and then having fallout—potential
fallout from that,
could have swayed judgment. I think, you know, whenever
you’re doing science you
want the science to be good but you also want it to be perceived
well, and you don’t
want to be in the midst of a controversy over how this tissue
was obtained and, I
think for us especially where it’s going to be live, potentially
raises more concern
in the public than it does if the tissue is taken fixed and just
used for pathology
or DNA or RNA just because there’s a lot of precedence for that
and, for us, this
is different, its not like someone’s donating a piece of an organ
to be used to save
someone else’s life. I think it’s . . . the fact that it’s fetal opens
up a broader host
of concerns for the general public . . . who owns the tissue?,
who has the right to

decide? (PS 1)
I have the feeling that if I was living in Texas I might actually
feel unsafe
being a participant in this research. And I don’t feel that way
here at all. (PS 2)
I know in England there was an instance—and this is several
years ago—
where a researcher did perfectly legal work with human fetal
tissues that ended
up being televised in the press for having done what was
perfectly legal. But it
involved a failure to consent. So the rules changed after that, in
England, and
became much more restrictive and that—seemed to me, it’s
important to avoid
that kind of notoriety. (PS4)
I completely go by my feelings in this case, so this is not
about—I don’t even
know what the ethical code is anymore. I can just imagine what
this would look
like on the cover of [local newspaper name]—‘my child’s
kidney is in a rat and I
didn’t know about it.’ (PS 10)
For some members, doing informed consent was a way to guard
against pos-
sible negative response, noting the fear of seeing the headline,
“My child’s
kidney is in a rat and I didn’t know about it.” The project staff

also
recalled the highly publicized exploitative cases of human
tissue use as with
decades of use of cancer cell lines from Henrietta Lacks,
unapproved genet-
ics research on Havasupai Indians, John Moore, and Hagahai
people in the
public media. These cases have gained wide popularity and
media attention
because the patents resulting from research on human genetic
material or tis-
sues were sought from the donors without prior informed
consent (Skloot, 2010;
Washington, 2011).
Another researcher’s views were formed by previous
experiences: “And so
we always wondered whether this was gonna come back to
haunt us—if we
were able to publish, are there gonna be moms out there, dads,
wondering, ‘well
was our son’s testis [tissues] used in this project and we never
approved it?’”
(PS 5) Another researcher added that “I was struck by how
important inform-
ing was to some people, which means that’s gotta be important
to some moms
and parents as well. So it was very clear that for some people, it
was horri-
ble that we didn’t inform [them]” (PS4). The ethical awareness
of the public’s
expectation for transparency was in itself sufficient for ethical
responsibility,
particularly when tied to highly sensitive topics.
While consensus on detailed consent was reached among the

research team
members, interviews conducted a year later revealed that four of
the research
staff still felt that it is unnecessary but supported the majority
view, for exam-
ple: “I’m still not convinced that this should be the way, but
since most of the
colleagues, I think, believe that-, I’m ok with that. I mean, if
most of the col-
leagues believe that, that’s okay” (PS 3). These researchers
were focused on
the practical concerns to overcome with regards to the study,
such as getting
a continuous supply of samples to move the research forward.
The discussion
on blanket consent versus the detailed informed consent
displays the classic
tension between science and ethics, between the goals of
research and the need
to do research ethically.
Research Staff Views on Challenges to Detailed Informed
Consent
Detailed informed consent, has many practical and logistical
concerns.
The team members struggled over many details of this consent
process on how
to communicate the use of fetal tissue, xenotransplantation, the
complexity
of these scientific concepts, timing of consent, countering the
views of the
hospital staff who are taking care of the patients and the
complexity this adds
to the IRB process.

Use of miscarried fetal tissue: Most of the research staff
believed that
this research presents special and sensitive considerations
compared to other
research because of the use of miscarried fetal tissue. The team
felt it to be emo-
tionally laden and a culturally and politically charged topic,
requiring sensitive
and delicate handling. Dealing with fetal tissue opened up
concerns having to
do with sentient life, abortion, religious beliefs, ownership of
the tissue, ques-
tions over who has the right to decide and, of course, feelings of
loss for a child
or pregnancy in which much hope may have been placed. A
researcher noted:
Well, there is a strong attachment to a life that you created, that
you feel is
sacred and shouldn’t be manipulated and- that probably you
would want some
burial for, you know, the tissue. It seems to me that it could be
analogous to
somebody who wouldn’t want to donate their organs to science
after they died,
you know, they would want a proper burial and, you know, it
could be for vari-
ous reasons- for religious reasons, sort of an honoring of a life
that ended that is-
basically for that reason. (PS 6)

Those who work closely with patients and are involved in the
process of mis-
carriage and loss expressed how emotional it can be, and how
parents are very
attached to their offspring, fetal or not. This close experience
with patients
caused some to feel that informed consent is very important,
while another
believed it was better and kinder to spare the parents who
participate in the
study from information and potentially alarming details. In
addition, because
the public holds so many strongly held positions regarding
fetuses, some mem-
bers expected these ethical issues to become a focal point of the
research and
thus present potential repercussions. A key concern was the fact
that the tissue
would be biologically functional, which could be an important
issue for donors,
so they should be aware of that.
Another concern was the importance of explaining to parents
that the aim
of the study was not to discover the reason for their miscarriage
or how to
prevent a future loss. One team member felt that parents might
likely have
“therapeutic misconception” (Applebaum et al., 1987) even
though the consent
form explicitly states that the research cannot offer answers on
why miscar-
riage happened. Researchers believed that parents want to feel
that their loss
is contributing to some good, but they must understand that it is
not for their

own individual good. Three of the six parents that agreed to be
interviewed
believed that they would get individual results on why they
miscarried. This
therapeutic misconception might be due to the highly emotional
state of mind
of the participants, but it might also reflect a shortcoming in the
present way
of seeking detailed consent. This gave the team important
feedback, showing
that no matter how clear the informed consent form and its
verbal presenta-
tion might be, people might still hope for individual causal
information. It also
provided an opportunity for the team to revisit the detailed
consent approach
and reaffirm its commitment to detailed consent.
Xenotransplantation: Team members realized that many people
believe
that animal research is unethical. One researcher put themselves
into the
potential situation: “this is just not acceptable that a piece of
my tissue, my
fetus’ tissue is alive in a rat and you’re going to be
manipulating it and doing
things that potentially kill that piece . . . that may flip their
decision” (PS
1). The team was divided on whether the possibility of a
negative response to
the animal element necessitated the full informed consent or,

conversely, war-
ranted a lack of detail so as to not unnecessarily alarm or
disturb the parent.
One of the team members felt that “you don’t need to go any
further into the
transplantation into a rodent. I felt that was unnecessary . . .
less informa-
tion about that portion of the study was better. And if they had
questions and
concerns, then I would go into more detail during the consent
process” (PS 9).
Another researcher said that this is an uncomfortable process
for even
those in the medical profession, and preferred using the term
“animal model”
rather than rodent, since rodent might cause people to think of
negative con-
notations such as “dirty” or “nasty” (PS 10). Accordingly, the
consent form does
talk about transplantation into an animal model but does not
specify that it is
a rodent. Some of the project staff themselves who were not lab
scientists had
very adverse reaction to rodent transplantation:
Since I’m not a medical type person, I do have, I think, some
aversion to
animal studies- so there is sort of a conflict, on the one hand I
do feel that the
work is meaningful and its not clear that one could actually
investigate this kind
of science in any other way, so I feel like—its mainly a visceral
reaction, rather
than being completely informed. . . . I mean there are people
who feel very strongly

about, just, any type of animal research and, for them to
consent, I think it is kind
of deceiving if you’re just informing them about the intent
rather than the actual
procedure, I think that it would be unethical not to have some
mention about it
(PS 6).
Several research members commented on how their perspective
might change
if they were approached as a patient or family member, rather
than viewing
the issues through a scientist’s lens. Opinions varied from not
wanting to par-
ticipate on account of the rodent transplantation, to wanting to
participate but
not wanting any details about the animal part, to not minding if
their tissue
was used, even under blanket consent.
Complexity of scientific concepts: Several members believed
the research
and information to be too complex for participants to
understand and, thus
thought it unnecessary to go into detail during the consent. One
cited the
difficulty of forming the language of the consent so that it
would be understand-
able to people of diverse educational backgrounds. However,
another member
noted that complexity is no excuse for not helping parents who
join the study
understand it. Team members largely agreed that detailed
consent, results,
or updates provided to parents must be in an understandable
format rather

than anything too detailed, scientific, or “over the head” for
non-science-based
people.
Concerns over views of the hospital staff : Many individuals
involved in
the care of the patients, as well as friends or family members,
could influence
recruitment success. Most team members thought that the
hospital staff would
appreciate the provision of detailed informed consent, but were
concerned that
the project adds more work and more time to their busy
schedules and view
it as a hindrance in that respect: “they [hospital staff] may feel
uncomfort-
able talking to the parents and saying, there’s someone that
wants to talk to
you about a study . . . I don’t know exactly the logistics of that,
but I can see
them feeling awkward being put in that position potentially, you
know, some-
one who’s obviously grieving and now you’re asking for
something from them”
(PS1).
Researchers were concerned that hospital staff might feel
awkward talking
to a grieving parents about research, especially if they
themselves have qualms
with the study. Staff might have concerns as to whether the
parents under-

stands the full impact of the study, or issues regarding the fact
that the study
is not directly benefiting the individual patient. The team
remarked that the
hospital staff is extremely protective of their patients, so they
will be concerned
about the emotions involved and whether it is appropriate to
increase patient
pain by talking about this research. They may be protective of
the sensitivity
and fragility of the patients and not look kindly on anything that
interferes
with patient care and well-being. The staff may be close to the
parents with
whom they may have bonded, and the natural reaction in a
tragic situation is
to comfort and support them, not burden them with scientific
research. These
people could easily advise patients not to take part in the study
because of
their own beliefs, or even affect a patient’s thought process
through simple
body language, eye-rolling, or facial expressions.
Timing of seeking consent: The team realized that the timing of
seeking
consent was an important factor (Hewitt et al., 2009). For two
team members
who work closely with the patients, approaching the patient
during a sensi-
tive time presented more of an ethical concern than discussing
the tissues
themselves. One research team member was concerned about the
immediacy
of having to make that decision by the parents (originally within
18 hours after

miscarriage, now 32 hours) during such a vulnerable time: “it’s
almost like
you’re having to approach these women as they’re in the midst
of, their dis-
tress, it’s like you can’t wait until they’ve been able to process
some of their
own tragedy, it’s almost like you’re being forced” (PS 7). Some
also pointed
out that the need for immediate consent also puts the
responsibility to decide
solely on the mother, with very little time to consult with other
family mem-
bers, and does not take into consideration the kind of support
the participant
needs to make the decision (PS 1). If the father was present and
involved, it
may be appropriate for him to approve of the research as well.
Team members
spoke of the importance of the potential participant’s
relationship, support sys-
tem, and whom she feels she needs to consult on the research
decision. In this
sense, it is not just about consent but about the parent and her
emotional state.
The families—or whoever may be present and close to the
parents—are likely
to be suffering emotionally as well, and may impact the process
of seeking
consent.
IRB issues: As more specificity in consent was discussed, some

feared that
there would be less flexibility in the labs’ ability to change
procedures, as
even small changes (i.e., adding another organ system as a
target for trans-
plantation) would require the bureaucratic work of an IRB
modification, as
experienced in the project. Another believed that some
researchers might feel
resentful that this has set an unnecessary standard and that now
they might
be hindered in their work if they are not taking this approach.
The Center has worked very closely with the IRB since 2009.
The first pro-
tocol for the fetal loss study was obtained in October 2009.
Since then, the study
protocol has been revised a dozen times, sometimes to meet IRB
requirements,
and other times to make changes or add new sections to the
study. Although
the IRB approved requested modifications, the process
significantly increased
paperwork. Even as this article draft was being discussed in a
team meeting,
a new modification was being planned to expand the number of
potential par-
ticipants by allowing the use of tissues from planned abortions
required either
to prevent physiological damage to the mother, or due to a
severely deformed
fetus. While the team initially was opposed to using voluntary
abortion tissue
due to the potential controversy, broader considerations gave
reason for reeval-
uation. The fact that the researchers would not profit from the

tissues, that the
tests would be short-term, and the samples would not be kept
longer than ten
years alleviated some ethical concerns.
Research Staff Views on Overcoming Challenges to Detailed
Informed Consent
Emphasis on the purpose of research: The research staff
believed that
despite the complexities involved in detailed informed consent,
it is possible
to get study participants interested in this research if they
explained the pur-
pose of the research: “If they really got interested in the
purpose of the study
and saw what was needed then, yeah, they may look at it in a
positive light.”
Members believed that a principal reason a woman may
participate in the
study is to feel that her tragedy is contributing towards
something good. This
could also potentially help parents deal with the emotional loss
of a miscar-
riage. Simply talking about the loss could also help women to
process their
tragedy or alleviate feelings of guilt. The opportunity to help
others may also
be viewed as a constructive outlet for their grief. While
participation may help
some women with their loss, it would be disingenuous to
presume that kind of
benefit for all participants. Moreover, it should not be
considered a justification
for doing the study.

Information could reduce prejudices: Team members’ felt that
more infor-
mation could only reduce prejudices. They felt that if the
complicated medical
or scientific concepts were explained correctly in a skillful
manner and if the
information is not too difficult, then patients might be
interested in joining the
study. A lab scientist explained that there is nothing bizarre
here, that this is
not a “Frankensteiny” monster experiment, that it is not about
rats so much
but the use of rodent as a receptacle, a place where tissue can be
viable. It is
about the covering on the rat kidney being a convenient place to
put the tissue
to study the tissue (PS 2), “a box that supports life for a couple
of weeks” (PS 8).
Emphasize the benefits of research: Members noted that those
who under-
stand science would easily see the medical benefits of the
research. A member
expressed that it will be hard for women to see the benefits
initially, and that it
will depend on the team members to explain and convince them
of the benefits
for the community and the greater good (PS 10). By
emphasizing the benefits,
they believe that even the complexities in explaining the
xenotransplantation
could be overcome: “If they are of the belief that most of the

things that have
made our lives better- drugs and procedures, vaccines, you
know, everything
has been tested and improved by using rodents, then I don’t
think it would
matter so much to them” (PS 5). Another view was that a
specific discussion of
the science would lead to the research being seen in a positive
light:
Okay this is gonna lead to something that hasn’t begun and
you’re really
gonna be able to look at effects on tissue and maybe that leads
to things being, you
know, banned . . . phthalates, pesticides, who knows what we’ll
wind up looking
at or, it may change standards for . . . exposures for pregnant
women and fetuses
and really provide data that is just not out there. (PS1)
Another point raised was that “the epigenetic changes induced
by environmen-
tal toxicants is not well studied” and that it is a valuable piece
of science to
know about (PS 2). All members felt that participating could
give women a
sense of contributing to science. For some, this may be a large
benefit and the
only reason they need to participate. A few members noted that
this area is not
well studied and has the potential to be very useful in
environmental health,
toxicology, and disease prevention, one noting that if donors
had a sense of
the incomparable value of this tissue, it may help them to see
the benefits.

To tap such a broad viewpoint on the patient’s part, team
members felt that
the greatest level of detailed consent would help. Some tied this
to developing
a relationship with an unhurried discussion and a compassionate
approach.
Educating the hospital staff : Instructing the staff on how to
communicate
with patients was considered crucial in gaining their support.
This would pro-
vide them with an understanding of the importance and purpose
of the study,
and equip them with tools for properly addressing the concerns
of patients that
may arise after the research team has left. Sharing the results
and successes
of the study with the hospital staff was also considered essential
for their con-
tinued involvement in referring participants. There was also
agreement that
hospital staff should have an ongoing opportunity to voice
concerns, provide
feedback, and be debriefed.
Implications for Team Members’ Future Research
The project staff expressed pride in their approach, believing it
to be a posi-
tive change for research, for individual patients and for the
general public, with

potential to impact the ethics of future research in both fetal
studies and in
research protocols overall. In particular, the team felt that the
reflexive ethical
considerations in this research were novel and should be shared.
One member
noted that if we were successful in recruiting women at such a
difficult time
using full informed consent, this would be a huge contribution,
as investigators
seem to be afraid of using a detailed consent in other difficult
venues.
Most members feel this project and approach has and will
continue to
affect them, admitting that they would think twice now before
using fetal tis-
sues without consent and that their “eyes have been opened” to
the emotional
aspect behind fetal research. Several also commented that,
scientifically, this
could affect their future work, allowing an avenue for
translational research.
If the project is successful and evolves into a long-term study, it
could have far-
reaching impacts and be a model for similar studies and
beneficial for future
research on loss and miscarriage.
Most members expected there to be both favorable and
unfavorable
responses to this ethical approach in the scientific community.
One wondered
if the group will be criticized for making the research harder
and focusing too
much on personal responses rather than on getting data. Another

believed that
some researchers may feel resentful that this has set an
unnecessary standard
and that now they might be hindered in their work if they are
not taking this
approach. It was also noted that researchers may not understand,
had they
not been part of the group discussions, and may just think this
group is wast-
ing their time. However, most team members believed very
strongly that this
project is connected to larger issues surrounding the public’s
right-to-know and
transparency in research, and that in the long term, it helps to
build trust and
confidence between the scientific community and the public.
DISCUSSION AND CONCLUSION
For the research team, employing reflexive research ethics
practice and the
decision to provide detailed, rather than blanket informed
consent, was very
transformative. Reflexive research ethics involves more than
simply a con-
certed discussion of the ethics of the research as it applies to
working with
participants. The reflexive research ethics process captured all
the different
phases of planning and deciding on detailed informed consent.
It challenged

the existing views of the research staff, explored common social
beliefs and
political views on fetal tissue research, it weighed the staff
views on the pros
and cons of adopting a transparent process, demonstrated ways
to overcome
the challenges to adopting a transparent approach, and explored
the future
implications of adopting a transparent research methodology.
Alternatively, one can argue that though detailed informed
consent was the
modality used in this research, there was ambivalence among
the research staff
on if it was essential. Also, one can argue that the shift from
blanket consent
to a more transparent process may not quite necessarily be due
to reflexiv-
ity and ethical considerations but may to a large extent be
motivated by the
sensitive and controversial nature of the topic and how it will
be received pub-
licly. The variety of responses or differences on detailed inform
consent and the
level of information to be provided on the nature of research as
obtained from
our interviews conducted a year after detailed informed consent
was adopted
shows that the reflexive research ethics process necessarily did
not change
research staff’s mind or perspectives on research ethics and
informed consent,
though they agreed to such a modality for this particular
research. This lack
of unanimity also leaves room to explore alternate ways of
seeking consent.

Tiered informed consent is an option that allows more
flexibility to the blan-
ket consent process and gives choice to the human subjects on
the types of
research these biospecimens could be used for or the categories
of future use
for the donated biospecimen (OHRP, 2011; Mascke, 2008). But
a tiered pro-
cess still does not require detailing the nature of research. This,
we thought
was essential in our case as it involved transplantation of fetal
tissue into
animal models, which is potentially a sensitive matter socially
and ethically.
Alternatively, provision could be made to provide supplemental
information to
a tiered or blanket consent for those participates who desire
more information
as demonstrated in Beskow et al. (2010). The discussion on
blanket consent
versus the detailed informed consent displays the classic tension
between sci-
ence and ethics, between science and society, between the goals
of research and
the need to do research responsibly.
Though our researchers had varying views on detailed informed
con-
sent, the reflexive research ethics process still challenged the
researchers
to examine their own understanding and beliefs concerning fetal
loss on a
personal and professional level. This led to greater sensitivity in
interacting
with persons outside of the research team, particularly parents
who join

the study and hospital staff. Reflexive ethical practice also pays
attention
to how the project would be received by science, public, and
governmental
audiences. Environmental health and related biomedical
research benefits
from a continuing process of reflection on ethical concerns.
Since our follow-up
interviews with study participants showed that half held a
misconception
that the research would provide information about their own
miscarriage, it
pressed the team to continually assess their protocol. The team
had to question
whether they were at all misleading people during the
consenting process, or
whether the best-intended informed consent was still prone to
misunderstand-
ing. Also, people might not understand the term
xenotransplantation, since it
is sometimes used to describe transplanting animal organs in
human bodies for
therapeutic purposes. It is conceivable that some people would
confuse the two
uses of the term and be influenced by the concern over having
animal parts in
humans, even though that is not part of this research. Reflexive
process in this
case also aided to conceive of such misconceptions before hand
and to present
such complex information in the detailed informed consent with

better clarity.
Our work demonstrates the delicate nature of this research and
the sen-
sitivity that is required when dealing with miscarriage,
xenotransplantation,
and informed consent. Treating informed consent as an ethical
process, rather
than a means to an end, was an important aspect of this project.
Indeed,
choosing to perform detailed informed consent above and
beyond what was
legally required sends an important message to the community
and to science
about the prominent role of ethics for this group. The group
itself has been
strengthened by the ethical approach and if they use this
feedback to become
self-critical of their own process and improve their methods of
research and
consent, they will continue to pursue ethical practices in
research.
ACKNOWLEDGMENTS
This research is supported by grant 1P20ES018169 from the
National
Institute of Environmental Health Sciences and Environmental
Protection
Agency. Additional support comes from the Brown University
Office of the
Vice President for Research. We are grateful to Kim
Boekelheide, David
Ciplet, Alissa Cordner, Linda Covington, Kristen Delayo,
Monique Depaepe,
Richard Freiman, Leah Greenblum, Philip Gruppuso, Susan

Hall, Mary
Hixon, Elizabeth Hoover, Tania Jenkins, Stefan Kostadinov,
Mercedes Lyson,
Stephanie Malin, Margaret Mulcahy, Maureen Phipps, Jodie
Pietruska,
Jennifer Sanders, Tyson Smith, and Chris Thanos for comments
on various
drafts of the article.
NOTE
1. Respondents are referred to by these identifiers, signifying
“Project staff.”
REFERENCES
American Society for Cell Biology. (2001). Talking Point: Fetal
Tissue Research.
Available at http://www.ascb.org/newsfiles/fetaltissue.pdf Last
accessed September
28, 2012.
Annas, G. J., Glantz, L. H., and Roche, P. A. (1995). The
Genetic Privacy Act and
Commentary. “Guidelines for Protecting Privacy of Information
Stored in Genetic
Data Banks.” February 28. Boston University. Available at:
http://www.ornl.gov/
sci/techresources/Human_Genome/resource/privacy/privacy1.ht
ml Last accessed
September 28, 2012.

Andrews, L. B. (1994). Federal and state regulations of fetal
research: A current
perspective. In Fetal Research Applications: A Conference
Summary. Conference
Committee on Fetal Research and Applications, Institute of
Medicine July 1994,
Washington, D. C. National Academies Press.
Andrews, L. B. (1993). Regulation of experimentation on the
unborn. Journal of Legal
Medicine 14: 25–56.
Beskow, L. M., Friedman, J. Y., Hardy, N. C., Lin, L., and
Weinfurt, K. P. (2010).
Developing a simplified consent form for bio banking. PLoS
ONE 5: e13302.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951917/ Last
accessed September
28, 2012.
Boonstra, H. (2001). Human embryo and fetal research: Medical
Support and
Political Controversy. The Guttmacher Report on Public Policy
February 4.
http://www.guttmacher.org/pubs/tgr/04/1/gr040103.html Last
accessed September
28, 2012.
Clayton, E. W., Steinberg, K. K., Muin, J. K., Thompson, E.,
Andrews, L., Kahn, M. J.
E., Kopelman, L. M., and Weiss, J. O. (1995). Informed consent
for genetic research
on stored tissue samples. JAMA 274: 1786–1792.
Cordner, A., Ciplet, D., Brown, P., and Morello-Frosch, R.

(2012). Reflexive research
ethics for environmental health and justice. Social Movement
Studies 11:
161–176
Coutts, M. C. (1993). Fetal tissue research. Kennedy Institute of
Ethics Journal 3:
81–101.
Davis, J. K. (2004). Precedent autonomy and subsequent
consent. Ethical Theory and
Moral Practice 7: 267–291.
Eisman, E., and Haga, S. B. (1999). Handbook of Human Tissue
Sources: A National
Resource of Human Tissue Samples. Santa Monica, CA: Rand
Corporation.
Gillett, G. R. (1989). Informed consent and moral integrity.
Journal of Medical Ethics
15: 117–123.
Gray, B. H. (1978). Complexities of informed consent. Annals
of the American Academy
of Political and Social Science 437: 37–48.
Hewitt, R., Watson, P. H., Dhir, R, Aamodt, R., Thomas, G.,
Mercola, D., Grizzle, W.
E., and Morente, M. M. (2009). Timing of consent for the
research use of surgically
removed tissue: Is postoperative consenting acceptable? Cancer
115: 4–9.
Hurd, R. E. (1992). Ethical issues surrounding the
transplantation of human fetal
tissues. Clinical Research 40: 661–666.

Kuczewski, M. G., and Marshall, P. (2002). The decision
dynamics of clinical research:
The context and process of informed consent. Medical Care 40:
V45–V54.
Lidz, C., Meisel, A., Zerubavel, E., Carter, M., Sestak, R., and
Roth, L. (1984). Informed
Consent: A Study of Decision Making in Psychiatry. New York:
Guilford.
Maschke, K. J. (2008). Biobanks: DNA and research. In From
Birth to Death and Bench
to Clinic: The Hastings Center Bioethics Briefing Book for
Journalists, Policymakers,
and Campaigns. Crowley, M. ed. Garrison, NY: The Hastings
Center, pp. 11–14.
Matsui, K. (2005). Informed consent, participation in, and
withdrawal from a
population-based cohort study involving genetic analysis.
Journal of Medical Ethics
31: 385–392.
Mechanic, D. (1984). Trust and informed consent to rationing.
The Milbank Quarterly
72: 217–223.
National Cancer Institute. (2011). Best Practices for
Biospecimen Resources. Office of
Biorepositories and Biospecimen Research. U.S. Department of
Health and Human

Services.
National Conference of State Legislatures (NCSL). (2008).
Embryonic and fetal
research laws. Available at
http://www.ncsl.org/IssuesResearch/Health/Embryonic
andFetalResearchLaws/tabid/14413/Default.aspx Last accessed
September 28,
2012.
National Institute of Health (NIH). (1993). Human fetal tissue
characterization for
transplantation. 22 (28). Request for Research Grant
Applications. Available
at http://grants.nih.gov/grants/guide/rfa-files/RFA-HD-94-
006.html Last accessed
September 28, 2012.
Office for Human Research Protections. (2002). Guidance for
Investigators and IRBs
regarding Research Involving Human Embryonic Stem Cells,
Germ Cells and
Stem Cell-Derived Test Articles. U.S. Department of Health and
Human Services.
March 19.
Office for Human Research Protections (OHRP). (2008).
Guidance on Research
Involving Coded Private Information on Biological Specimens.
U.S. Department
of Health and Human Services. Guidelines for Research.
October 16. Available at
http://www.hhs.gov/ohrp/policy/cdebiol.html Last accessed
September 28, 2012.
Office for Human Research Protections. (2011). Secretary’s

Advisory Committee on
Human Research Protection (SACHRP). Appendix D. U.S.
Department of Human
and Health Services. Guidelines for Research. Avialable at
http://www.hhs.gov/
ohrp/sachrp/appendixd.html Last accessed September 28, 2012.
Office for Protection from Research Risks. (1997). Issues to
consider in the research
use of stored data or tissues. U.S. Department of Health and
Human Services.
Guidelines for Research. November 7. Available at
http://www.hhs.gov/ohrp/policy/
reposit.html Last accessed September 28, 2012.
O’Neill, O. (1984). Paternalism and partial autonomy. Journal
of Medical Ethics 10:
173–178.
O’Neill, O. (2004). Informed consent and public health.
Philosophical Transactions:
Biological Sciences 359: 1133–1136.
Pfeffer, N and Alderson, P. (1997). Informed consent. Editors
Note. British Medical
Journal 315: 247–254.
Prentice, K. J., Appelbaum, P. S., Conley, R. R., and Carpenter,
W. T. (2007). Maintaining
informed consent validity during lengthy research protocols.
IRB: Ethics and
Human Research 26: 1–6.
Public Law 103–43. (1993). National Institutes of Health
Revitalization Act of 1993.
Available at http://history.nih.gov/research/downloads/PL103-

43.pdf Last accessed
September 28, 2012.
Riegman, P. H. J., and Veen, E. V. (2011). Biobanking residual
tissues. Human Genetics
130: 357–368.
Russell, F. M., Carapetis, J. R., Liddle, H., Edwards, T., Ruff,
T. A., and Devitt, J. (2005).
A pilot study of the quality of informed consent materials for
aboriginal participants
in clinical trials. Journal of Medical Ethics 31: 490–494.
Schon, D. (1987). Educating the Reflective Practitioner. San
Francisco: Jossey-Bass.
Silverman, W. A. (1989). The myth of informed consent: In
daily practice and in clinical
trials. Journal of Medical Ethics 15: 6–11.
Skloot, R. (2010). The Immortal Life of Henrietta Lacks. New
York: Crown.
Smith-Doerr, L. (2006). Learning to reflect or deflect? U.S.
policies and graduate pro-
grams’ ethics trainings for life scientists. In New Political
Sociology of Science.
Frickel, S., and Moore, K. eds. Madison, WI: University of
Wisconsin Press., pp.
405–431.
Verklan, M T. (1993). The ethical use of fetal tissue for

transplantation and research.
Journal of Advanced Nursing 18: 1172–1177.
Washington, H. (2011). Deadly Monopolies: The Shocking
Corporate Takeover of Life
Itself and the Consequences for Your Health and Our Medical
Future. New York:
Doubleday.
Copyright of Accountability in Research: Policies & Quality
Assurance is the property of Taylor & Francis Ltd
and its content may not be copied or emailed to multiple sites or
posted to a listserv without the copyright
holder's express written permission. However, users may print,
download, or email articles for individual use.
S C I E N T I F I C C O N T R I B U T I O N
Is tissue engineering a new paradigm in medicine?
Consequences
for the ethical evaluation of tissue engineering research
Leen Trommelmans Æ Joseph Selling Æ
Kris Dierickx
Published online: 24 July 2009
� Springer Science+Business Media B.V. 2009

Abstract Ex-vivo tissue engineering is a quickly devel-
oping medical technology aiming to regenerate tissue
through the introduction of an ex-vivo created tissue con-
struct instead of restoring the damaged tissue to some level
of functionality. Tissue engineering is considered by some
as a new medical paradigm. We analyse this claim and
identify tissue engineering’s fundamental characteristics,
focusing on the aim of the intervention and on the com-
plexity and continuity of the process. We inquire how these
features have an impact not only on the scientific research
itself but also on the ethical evaluation of this research. We
suggest that viewing tissue engineering as a new medical
paradigm allows us to develop a wider perspective for
successful investigation instead of focusing on isolated
steps of the tissue engineering process in an anecdotal way,
which may lead to an inadequate ethical evaluation. We
argue that the concept of tissue engineering as a paradigm
may benefit the way we address the ethical challenges

presented by tissue engineering.
Keywords Tissue engineering � Regenerative medicine �
Ethics � Paradigm � Research
Introduction
Ex-vivo tissue engineering (TE) is a quickly developing
medical technology. It can be defined as
the creation of new tissue for the therapeutic recon-
struction of the human body, by the deliberate and
controlled stimulation of selected target cells, through
a systematic combination of molecular and mechan-
ical signals with the aid of extracellular scaffolds.
(Williams 2006a)
The in vitro combination of donated, substantially manip-
ulated and cultured human cells with supporting structures
and biomolecules yields metabolically active constructs:
human tissue engineered products (HTEPs). The constructs
are implanted, fostering and assisting the regeneration of
diseased or degenerated tissue in situ, thereby restoring a

particular function of the body. The HTEP can contain the
patient’s own cells, or it can be constructed from donated
cells. At present, all HTEPs are based on differentiated cells
(allogeneic keratinocytes for tissue engineered skin (Met-
calfe and Ferguson 2008) and autologous chondrocytes for
knee cartilage (Chung and Burdick 2008)), but adult and
embryonic stem cells are increasingly investigated as
possible cell sources (Kolf et al. 2007; Fernyhough et al.
2008; Passier and Mummery 2005; Kim and von Recum
2008, Bajada et al. 2008; Chim et al. 2008; Caplan 2007).
TE is considered to be a form of regenerative medicine.
Both TE and regenerative medicine suffer from a defini-
tional quagmire, and both terms are often used interchange-
ably in literature. However, in this article we will maintain
the distinction that regenerative medicine refers in the first
place to the aim of the intervention (to regenerate) and that
TE primarily refers to the method of the intervention:
creating an ex-vivo product and implanting it afterwards in

L. Trommelmans (&) � K. Dierickx
Centre for Biomedical Ethics and Law, KU Leuven,
Kapucijnenvoer 35/3, Box 7001, 3000 Leuven, Belgium
e-mail: [email protected]
K. Dierickx
J. Selling
Faculty of Theology, KU Leuven, Sint-Michielsstr 6,
3000 Leuven, Belgium
123
Med Health Care and Philos (2009) 12:459–467
DOI 10.1007/s11019-009-9192-0
order to obtain regeneration. From this perspective TE is
part of the wider field of regenerative medicine.
Figure 1 gives an overview of the TE process in general.
Since the early 1990s (Langer and Vacanti 1993) the
field has advanced rapidly. While the proverbial ‘heart-in-
a-box’ (Ferber 1999; Lysaght et al. 2008; Moreno-Borchart

2004; Nerem 2000) may be a long way off—if ever
attainable—the development of smaller HTEPs for appli-
cations where medicine currently fails can be envisaged in
the medium term, and may in time have a profound impact
on the treatment of degenerative diseases, traumata and
congenital defects (Mirensky and Breuer 2008; Panetta
et al. 2008). The range of potential HTEPs is large: every
tissue prone to degeneration or that can suffer irreparable
damage is a candidate for TE. Tissue engineered skin
(MacNeil 2007; Pham et al. 2007) and autologous tissue
engineered cartilage implants for the knee (NICE 2005)
have been applied successfully, while other HTEPs such as
bone (Krampera et al. 2006), bladder and urinary tracts
(Atala et al. 2006; Korossis et al. 2006; Sievert et al. 2007),
heart valves (Mendelson and Schoen 2006; Migneco et al.
2008; Knight et al. 2008), heart muscle (Zimmermann et al.
2006), small-diameter arterial substitutes (Stegemann et al.
2007; Bordenave et al. 2008), vaginal tissue (Panici et al.

2007), intervertebral discs (Zhang et al. 2008; Williams
2007), vocal folds (Ford 2008), lymphatic tissue (Hitch-
cock and Niklason 2008), cornea (Shah et al. 2008), liver
(Fiegel et al. 2006, 2008), maxillo-facial applications (Zuk
2008; Moreau et al. 2007; Panetta et al. 2008) and other
applications are being developed.
Diseases due to tissue or organ degeneration are increas-
ingly common in ageing populations; therefore the thera-
peutic benefits of TE promise to be considerable (Grayson
et al. 2008; Rotter et al. 2007). The demand for HTEPs may
consequently increase significantly once they can be safely
produced at a larger scale, at an affordable price and if their
superiority to other therapies can be demonstrated.
The HTEPs that are available today for therapy are
relatively simple products, containing only a very limited
number of cell types, not interacting with the circulatory
system and not immunologically sensitive. They contain
cells that do not raise much ethical debate, are not used for

life-threatening conditions, and alternatives are available if
the HTEP is not efficient or must be removed. Yet even
these first HTEPs suffer from severe technical difficulties
such as the upscaling of the production of HTEPs and the
transfer of knowledge from one domain to the other, and
from economic and regulatory hurdles (Williams 2006b;
Bock et al. 2003).
As with other biomedical innovations, TE is under
ethical scrutiny (EGE 2004; Gordijn 2004; de Vries et al.
2008, Trommelmans et al. 2007). It has not yet received the
same attention as other advances in regenerative medicine
such as gene therapy and somatic cell therapy, or as
technologies like embryonic stem cell research or nano-
medicine. This may be in spite of—or maybe because of—
the many overlapping issues, and the seeming likeness of
TE with established interventions such as the use of med-
ical devices and transplants. However, we argue that TE
has characteristics that need to be considered carefully

when it is evaluated by ethicists, especially given the large
potential of TE and its possible impact on future health
care (Trommelmans et al. 2007).
A useful starting point for the ethical evaluation could
be to regard TE as a new medical paradigm, as is proposed
by tissue engineers themselves (Petit-Zeman 2001; Slavkin
and Bartold 2006). In this article we investigate if this
proposition may indeed be informative for the ethical
analysis of TE. We will therefore firstly evaluate this
contention as we find it in TE literature. We will then
present a more profound argumentation supporting this
argument. Thinking of TE in terms of a new paradigm may
allow us to more clearly see the features common to all
HTEPs that distinguish them from other interventions and
that may influence the ethical conduct of research and
therapy and subsequently develop appropriate approaches,
methods and standards for ethically responsible investiga-
tion and therapy.

Could TE be considered as a new medical paradigm?
According to T. Kuhn (1996)
the term ‘paradigm’ is used in two different senses.
On the one hand, it stands for the entire constellation
of beliefs, values, and techniques, and so on shared
by the members of a given community. On the other
hand, it denotes one sort of element in that
Cell manipulation
Therapy
Animal trial
Cell expansion
Combination with
extracellular matrix
and biomolecules
Exposure to stress
Packaging and
transport/ control
Clinical trial
Human Tissue
Engineered Product

Cell donor
Fig. 1 The tissue engineering process
460 L. Trommelmans et al.
123
constellation, the concrete puzzle-solution which,
employed as models or examples, can replace explicit
rules as a basis for the solutions of the remaining
puzzles of normal science. (p. 175)
Kuhn also refers to the reasons behind the development of
new paradigms: the inability of existing paradigms to
resolve specific problems, while he acknowledges the fact
that even in new paradigms existing knowledge is retained.
… the new candidate must seem to resolve some
outstanding and generally recognised problem that
can be met in no other way. Second, the new para-
digm must promise to preserve a relatively large part
of the concrete problem-solving ability that has
accrued to science through its predecessors. (p. 169)

Starting from these definitions we investigated whether
the claim that TE is a new paradigm can be substantiated.
Keeping in mind that the terms TE and regenerative
medicine are often used interchangeably we undertook a
Pub-Med search which revealed 83 reviews containing the
combination (paradigm) AND (regenerative medicine) OR
(tissue engineering) in the abstract (search conducted
September 2008; all listed articles: 173). Of those 83, the
word paradigm was explicitly applied to TE and/or
regenerative medicine in 27 articles. We identified in these
articles the following arguments to label TE and/or
regenerative medicine as a new paradigm.
(1) The aim of the intervention is regeneration instead of
restoration and/or repair (Ford 2008; Moioli et al. 2007;
Kwan et al. 2008; Solchaga et al. 2001; Frank et al. 2004;
Scott et al. 2008; Gates et al. 2008; Hutmacher and Cool
2007; Tataria et al. 2006). (2) TE is an improvement to
existing treatments, including an answer to donor shortage

(Moioli et al. 2007; Scott et al. 2008; Behfar and Terzic
2007; Capi and Gepstein 2006). (3) TE is an innovative
process in which stem cells play an essential part (Kwan
et al. 2008; Scott et al. 2008; Gates et al. 2008; Huang et al.
2008; Bolland et al. 2007; Sales et al. 2005; Williams
2008). (4) It is a new paradigm because of the specific
construction of the HTEP and/or the multidisciplinarity of
the technology (Solchaga et al. 2001; Hutmacher and Cool
2007; Williams 2008; Butler et al. 2004, 2008; Gerecht-Nir
et al. 2006; Vunjak-Novakovic et al. 1999; Yang et al.
2006; Kretlow et al. 2007). (5) Successful TE depends on
the understanding and/or mimicking of biological pro-
cesses (Ford 2008; Frank et al. 2004; Tataria et al. 2006;
Williams 2008; Butler et al. 2004, 2008; Gerecht-Nir et al.
2006; Kretlow et al. 2007). (6) One type of HTEP (TE
skin) serves as a paradigm for other TE applications (Auger
et al. 2004; Simpson 2006; Simpson and Bowlin 2006;
Brouard and Barrandon 2003). Many articles combine

several arguments. Unfortunately, most of these articles do
not elaborate on their arguments, but restrict themselves to
a brief statement. This finding suggests that the terms
‘paradigm’ and ‘paradigm shift’ as they were first intro-
duced by T. Kuhn are sometimes used all too easily, giving
‘‘a slight whiff of self promotion to the author’’ (Marris
2008). Being part of a scientific and medical revolution and
creating a new conceptual framework certainly seems more
attractive than filling the gaps of a well known and tested
framework. Speaking of ‘a new paradigm’ with all its
revolutionary connotations where actually nothing truly
revolutionary is taking place, may be tempting for scien-
tists, especially in an environment where competition for
funding and media attention is fierce. Yet paradigms and
paradigm shifts are crucial concepts in science, and it is
therefore necessary to further substantiate this claim. For if
these claims are true, and TE is indeed a new paradigm, the
impact on our view of medicine, e.g. on its aim or on the

standard of care in medicine may change drastically. This
in turn may lead to a recalibration of what is required to
conduct research and medicine in an ethical way.
Both meanings of ‘paradigm’ can be identified in the
articles we analysed. Presenting TE skin as a model for
future TE applications (argument 6) is a clear example of
defining a paradigm as an exemplar. The argument that TE
is an improvement compared to other interventions is a
rather weak argument, as the idea of a paradigm shift
implies that it is not a continuation or improvement of an
existing approach, but on the contrary a new approach
toward a specific problem. It is therefore necessary to
examine the concept and method of TE, to identify its key
characteristics and to investigate how these key features
may influence the ethical evaluation of research ethics
issues in TE. Many retrieved articles do effectively refer to
the conceptual or methodological change that is occurring
through the development of TE, especially those that refer

to the regenerative aim of TE and those that describe TE as
a complex process, mimicking natural processes. As we
will argue further, there is indeed a conceptual and meth-
odological shift in TE research, justifying the idea of a
paradigm shift.
The concept and method of tissue engineering
To assess whether there is a conceptual and methodological
shift from ‘standard’ medicine to TE one has to examine
(1) the knowledge on which it builds, (2) its aim and (3) its
methods (Lysaght et al. 2008).
(1) TE draws on the increasing knowledge of biomateri-
als, the results from (stem) cell research and develop-
mental biology, and the increasing capacity to
intervene in cell development and cell differentiation
Is tissue engineering a new paradigm in medicine? 461
123
(U.S. Department of Health 2006). This quintessential

knowledge was not available until very recently.
Progress in regenerative medicine, including TE, and
stem cell research are strongly interconnected. To
paraphrase T. Dobzhansky’s famous statement: ‘noth-
ing in stem cell research makes sense except in the
light of regenerative medicine’ (Dobzhansky 1973).
(2) Unlike other interventions such as tissue transplants
and the use of prostheses, the goal of TE is explicitly
to coax the body through regeneration into its full
physiological capacity, curing hitherto incurable
diseases (Mummery 2004; Passier and Mummery
2003). Until recently medicine did not aim to
regenerate complex tissues and organs, because it
was considered impossible, due to the loss of
regenerative potential in the course of evolution.
Tissue damage initiates the formation of non-func-
tional, non-specific scar tissue, but does not normally
lead to regeneration in humans. Medicine therefore

makes the best of restoring the functionality of the
body through replacement (for example organ trans-
plants, artificial joint implants), enhancement (for
example braces) or mimicking a particular function of
the tissue or organ (for example the use of skin
dressings to prevent infection and dehydration).
(3) Within the field of regenerative medicine, which also
includes somatic cell therapy and gene therapy, TE
distinguishes itself by its unique method: creating a
complex, viable tissue in vitro and implanting it in the
patient (Williams 2006a). Unlike transplantation med-
icine in which unaltered organs are transferred from
donor to recipient, tissue engineers implant laboratory-
grown tailor-made constructs in the dynamic environ-
ment of the body. Regeneration made possible because
of scientific breakthroughs thus introduces a concep-
tual shift as well as the need for an entirely new set of
methods and approaches to realise this aim. So while

regenerative medicine in general, and TE in particular,
builds on existing knowledge and therapies, it aims to
overcome the known shortcomings of existing thera-
pies by applying specific methods.
One could argue that not TE as we have defined it, but
the more encompassing concept of regenerative medicine
is the new paradigm. Indeed, the concept and the actual
feasibility of regeneration as such is fundamentally dif-
ferent from what was previously the goal of medicine,
namely to restore function or at best to assist the sponta-
neously occurring regeneration of damaged tissues, but
never to deliberately induce regeneration. Yet, if we return
to Kuhn’s definition of a paradigm, it does not only concern
the fact that previously irresolvable problems may be
solved by the new approach, but also that this will be done
through a very specific method. Even compared with other
regenerative medicine approaches such as somatic cell
therapy or gene therapy, TE does have this specific meth-

odology. It is the only application that not only deliberately
induces regeneration, but also uses a complex ex-vivo
product, created by a wide array of techniques. Therefore
we would argue that TE in itself is a new paradigm.
To assess the ethical issues that are attached to this new
approach, it is however necessary to identify its key
characteristics and investigate if and how they may present
us with ethical issues.
Characteristics of the new paradigm
A paradigmatic approach may provide us with an
appropriate framework for the identification and evalua-
tion of the ethical concerns raised by TE research and its
applications. A key element of TE is that it presents a
hitherto unencountered complexity, due to the aim and the
method of TE, in which HTEPs combine properties of
medicinal products, medical devices, biologicals and
transplant surgery. Moreover, the process is continuous,
partly in vitro and partly in vivo. Although often

implicitly and sometimes explicitly acknowledged (Mikos
et al. 2006), this complexity and continuity are seldom
recognised as fundamental features that will deeply affect
the ethically responsible conduct of TE research and
therapy. One can isolate separate steps from the entire
process and treat them as if they were mere variants of
commonly known medical interventions and the ethical
issues they present.
However, the ultimate aim of TE is regeneration. This is
by definition a dynamic and continuous process. It is also a
complex process, which is currently not very well under-
stood. Therefore the starting point for the ethical analysis
of TE should be to explore the implications of these fea-
tures on how we understand and evaluate TE. This inves-
tigation will not only have to address the responsible
conduct of TE research. It may also include an investiga-
tion of conceptual issues underlying TE research, and more
broadly of regenerative medicine, such as the question

when regeneration is deemed ‘complete’. Considering TE
as a new medical paradigm therefore implies that the
continuity and complexity of the process are put at the
centre of the paradigm itself and of our understanding of it,
not as mere complementary characteristics that happen to
follow from the techniques that are developed by tissue
engineers. We will therefore focus in the following section
on these two features of TE and their consequences for a
responsible conduct of TE research and for the application
of HTEPs.
462 L. Trommelmans et al.
123
Complexity
The complexity of HTEPs is the result of three critical
features:
(1) Contrary to medicinal products, medical devices or
biologicals, HTEPs as products will always show

variability due to the presence of metabolically active
cells in the dynamic environment of the extracellular
scaffold (European Commission 2001). There is an
ongoing evolution within the HTEP itself: the cells and
the scaffold on which the cells are seeded interact with
each other. The scaffold, especially if it is combined
with growth factors or other bioactive molecules,
guides the migration of cells, their growth, differen-
tiation and death. The active cells on the other hand
produce extracellular material, and the matrix will
more often than not be biodegradable. Despite a well-
considered cell choice and the purification of the cells
used (European Commission 2001), scaffold architec-
ture, standardisation and upscaling in bioreactors
(Wendt et al. 2005) and the development and enforce-
ment of ‘Good Tissue Practices’, ‘Good Clinical
Practices’ and ‘Good Manufacturing Practices’ (Euro-
pean Parliament 2007; Farrugia 2006), individual

HTEPs will always show some variability. Deciding
on the amount of variability allowed within a HTEP or
even within a batch of HTEPs will have consequences
for the generalisability of trial results, for the product’s
safety and its price: stringent requirements will
inevitably lead to a restricted generalisability, a high
number of disqualified products, and a high price.
Lower standards may lead to inefficacious or even
unsafe products (European Parliament 2007).
(2) Implanted HTEPs initiate interactions between the
HTEP and the recipient’s body which also will vary
to some extent. These are not to be avoided, as in
prostheses or transplants, but to be encouraged
(Williams 2008). Understanding, assessing and guid-
ing these interactions during the entire process of
regeneration is crucial (European Parliament 2007).
Identifying the ideal implant time for the HTEP is but
one example. If the HTEP is too ‘green’ or too far

Accountability in Research, 19344–369, 2012Copyright © Tayl.docx

Recommended

Recommended

More Related Content

Similar to Accountability in Research, 19344–369, 2012Copyright © Tayl.docx

Similar to Accountability in Research, 19344–369, 2012Copyright © Tayl.docx (20)

More from annetnash8266

More from annetnash8266 (20)

Recently uploaded

Recently uploaded (20)

Accountability in Research, 19344–369, 2012Copyright © Tayl.docx