||by Dr. Grace Lee Picciolo and Dr. David L. Stocum
Everybody hopes for better health and restoration of impaired
bodily function, and now that hope is illuminated by the promise
of powerful biological tools that make human cells grow and replace
human tissue. ASTM Committee F04 on Medical and Surgical Materials
and Devices is taking the lead by defining some of those tools
as standards that can be used for the development, production,
testing, and regulatory approval of medical products.(1)
Medical implants fall into several categories, grouped as synthetic
prostheses, artificial organs, transplants, and others. Historically,
medical devices have been regulated by the U.S. Food and Drug
Administrations Center for Devices and Radiological Health, in
some cases using consensus standards and guidelines. Some of these
documents have been developed and/or adopted by FDA. Several other
categories of products, i.e., those containing biologicals or
drugs, are regulated by the FDAs Center for Biologics Evaluation
and Research and the Center for Drug Evaluation and Research.
Products that combine cells and biomaterials and biomolecules
fall within the areas of responsibility of several centers, and
thus are regulated by interdisciplinary teams. These centers typically
utilize Guidance for Industry documents to describe the regulatory
framework used to regulate their products. Many standards exist
for synthetic prostheses and have been developed with the help
of standards- setting organizations, both national and international.
Advances in the basic and applied sciences over the past decade
have led to an explosion in the research and development of medical
applications for restoring the functions of human tissue/organ
systems. Growth in spending has doubled from an estimated $246
million in 1995 to $504 million in mid 1999 (Lysaght, 1995, 1998).
These efforts have led to promising therapies for tissue/organ
defects and an increase in the number of regulatory applications
for tissue engineered medical products. Thus there is a great
need for standards for use by stakeholders in the field of tissue
What Is Tissue Engineering?
Tissue engineering is used in the new science of regenerative
biology and medicine. Regenerative biology seeks to understand
how some body tissues are replaced naturally, through the study
of a variety of animal models, including lower vertebrates such
as amphibians, which are strong regenerators. Regenerative medicine
seeks to apply this understanding to restore the structure and
function of damaged human tissues that do not naturally regenerate.
Therapeutics for regenerative medicine include three approaches.
The first is the transplantation of replacement cells into sites
of injury or disease (cell therapy). The second is to induce regeneration
in situ by the pharmacological suppression of inhibitory factors
and/or supplying factors that stimulate regeneration (drug/ gene
therapy). Tissue engineering is the third approach, and involves
the construction in vitro of bioartificial tissues by seeding
cells into scaffolds of artificial or natural materials, then
using them as extracorporeal devices or implanting them into the
body (combination device and biologic therapy) (Stocum, 1999).
Regenerative biology and medicine, including tissue engineering,
is not a single discipline. Rather, it requires the multidisciplinary
integration of biology, chemistry, physics, engineering, and clinical
science. Regenerative medicine is currently limited in what it
can do. Cell transplants have had some success in reversing the
symptoms of Parkinsons disease, Huntingtons disease, and diabetes.
Such transplants are also useful in repairing cartilage and reconstituting
the immune systems of cancer patients who have undergone extensive
chemotherapy. Dermis has been successfully regenerated in burns
or venous ulcers by the use of growth factors or artificial dermal
matrices. However, these procedures and their results are far
from ideal. Regeneration is not perfect and cell sources are in
short supply. There is still a need for immunosuppression when
foreign cells are used, and the long-term outcomes of the procedures
have not yet been adequately assessed. Several products have reached
various stages in the pre-market and investigational drug approval
process (see the sidebar on previous page). The future, however,
is promising. Within the next 20 years, we should be able to restore
many more tissues via the transplantation, or stimulation in vivo,
of regeneration-competent cells derived from a variety of sources.
Groundwork for the development of an effort in standards for tissue
engineering proceeded within the U.S. FDA, via the FDA InterCenter
Tissue Engineering Working Group, starting in 1994. Advances in
research and development of tissue engineered products resulted
in increases in product submissions to the FDA. The need for standardized
terminology and test methods was therefore identified to facilitate
Challenges in the Field of Tissue Engineering
Currently, the big roadblocks for the field of tissue engineering
Inadequate understanding of the basic biology of regenerative
processes (Stocum, 1999);
Lack of adequate biomimetic materials to act as scaffolds for
either induction of regeneration in vivo, or to build bioartificial
tissues in vitro;
Inadequate cell sources for transplantation or building bioartificial
The problem of immunosuppressive regimens introduced by allogeneic
and xenogeneic (foreign) cells; and
Bioethical issues associated with the use of fetal and embryonic
stem cells as sources. Recently published National Institutes
of Health (NIH) Stem Cell guidelines will permit federal funding
of human pluripotent embryonic stem cell research, with certain
stipulations (Brower, 2000).
The industrial challenge lies mainly in the manufacture of biomaterials
(Picciolo, 1997), cell culture media and expansion protocols,
drug delivery systems, and gene vectors that are of reproducibly
high quality. The nature of biomaterials varies widely according
to their use, but there are common features all must have:
Reproducible geometry and chemical composition;
The incorporation of enough biological signals and cues to induce
cell migration, proliferation, and differentiation;
A rate of biodegradability that matches the rate of regeneration;
Non-induction of an inflammatory or immune reaction;
Ease of surgical manipulation;
Ease of manufacture from readily available materials; and
The challenge for academic scientists is to understand the basic
biology of tissue embryogenesis and regeneration. What are the
physical and chemical signals that instruct or permit cell proliferation
and differentiation? How widespread are regeneration-competent
cells in the body and what are their characteristics? What is
the differentiative capability of these cells? How can we evade
the immune system when transplanting foreign cells? What distinguishes
regeneration from the formation of scar tissue? What is the effect
of tissue mass and age on regeneration? What can strong regenerators
such as frogs, salamanders, and newts tell us about mechanisms
The major issues for government are maintaining or expanding the
funding base for regenerative biology and medicine and the development
of workable policies on stem cell research. The latter is difficult,
and will require finding a way to pursue the potential benefits
of this research within current moral and ethical codes. Programs
such as the NIST Advanced Technology Program, which is directed
to bring technology to the marketplace, will be instrumental in
identifying promising approaches for expanding funding.
To achieve consistent evaluation across the various FDA centers,
a team approach to product reviews is being used when products
contain components that are appropriate to several centers. Getting
potential therapies into clinical trials and setting reasonable
time frames for successful therapies to be put into clinical practice
is the challenge for the regulatory authorities. Evaluating clinical
efficacy is difficult for these types of products because the
use of sham controls (implantation of an inactive material)
is ethically precluded by many situations. Surrogate endpoints
with validated correlations to positive clinical performance must
The patient needs to understand the nature, risks, and potential
outcomes of a procedure when considering whether or not to be
part of a clinical trial or to undergo a clinically approved procedure,
particularly those involving the new technologies with their great
Major issues for the physician are to thoroughly understand the
science and technology behind a regenerative procedure so as to
be able to recommend or not recommend a procedure, and to inform
patients realistically of potential risks and benefits if recommended.
In addition, physicians should play a major role in the development
of clinical materials and procedures. In summary, the promise
may be bright, however, the path is long and needs careful negotiating
to preserve the Hippocratic oath to do no harm.
Role of Standards in Meeting the Challenges
Standards for tissue engineered medical products (TEMPs) will
assist all of the stakeholders of ASTM Committee F04 in pursuing
the development of safe and effective medical products that restore
tissue function. Industry will benefit by having standardized
procedures for producing and testing the products and the components
that are used in the TEMPs. Academic scientists will be able to
use the standards developed for various components that are used
in their products.
Uniformity in regulatory review and approvals will be improved
and expedited, as the opportunity for standards recognition by
the FDA and self certification by the manufacturer are provided
(Marlowe, et al., 1998). This will improve the quality of the
products and also affords the patient and the doctor information
on the expected performance of the products.
Strategy for Developing Standards
Advances in the field of medical applications of tissue engineering
have come about due in part to understanding the role that the
extracellular matrix plays in supporting cell survival, proliferation,
and differentiation in vivo. Interaction with the extracellular
matrix is an important mechanism for control of phenotypic structure
and function of cells in a bioartificial tissue, resulting in
the desired performance of the product to achieve tissue restoration.
The substitute matrix supplied to the cells enables their maintenance
and proliferation. These substitute materials act as scaffolds
for the support of the cells and deposit of biomolecules, which
signal the cells to migrate throughout the material and replace
the tissue. Scaffolds also can be molded to the exact shape desired
for the regrown tissue. The interplay of each of these components
is necessary for functional tissue restoration. Thus, the development
of standards for characterization, processing, and functionality
of the components of bioartificial tissues will contribute to
the validation of the performance of the product. Each of these,
in turn, will be useful when these same components are used for
Standards for interactions among the components and with the host
tissue are critical to the validation also. The interactive effects
of the product will have to be evaluated and test methods developed
to measure the impact on performance in the long term.
Due to the fact that final products differ from one another, standards
specific to each would be difficult to develop and keep up-to-date,
however, common elements in these products could be standardized.
Thus many products would benefit from a few standards.
Formation of Committee F04 Division IV on Tissue Engineered Medical
Because medical device regulation has been greatly facilitated
by ASTM Committee F04 standards in the past, the marriage of the
tissue engineering effort with that of Committee F04 was sought.
The ASTM process for standards development and publication is
useful and provides for consensus development by all important
constituencies as well as an arm into the international standards
arena. Thus the FDA approached ASTM to host the standards development
effort for TEMPs. Dr. Peter Johnson, formerly of the Pittsburgh
Tissue Engineering Initiative, was known for his effective efforts
in formulating the initiative and accepted the challenge of the
position as chair of what was to become Division IV of Committee
Subcommittees and Task Groups
The organization of the standards effort began with the application
of the Hoisin process to identify the important drivers of this
technology. A group of experts were asked to describe the important
features of TEMPs. These lists were then grouped and condensed
into 10 categories. These categories became the Subcommittees
for Division IV TEMPs of ASTM Committee F04 on Medical and Surgical
Materials and Devices. To date, 40 task groups have initiated
work on drafting standards. Information on the status of the efforts
of each of these task groups can be obtained from the F04 home
Areas that are being developed encompass characterization and
testing of the components used to prepare TEMPs, including the
biomaterials used, the cells seeded on the scaffold biomaterials,
and the other biomolecules needed. Our first approved standards
are a guide to substrates for TEMPs and a guide to characterization
of alginate, a natural material used in TEMPs. Other areas under
draft are a guide to cells and cell processing, enumeration methods
for cell counting, and bone and bone morphogenetic test methods.
Future Plans of Committee F04 Division IV
Efforts within Division IV will emphasize the recruiting of knowledgeable
persons within the specific areas where additional standards are
needed, the identification of which will help Division IV keep
pace with the developments in the field. When more research describes
the interactions among the various components of TEMPs, the ability
to specify combinations that lead to success will enable development
of this level of standard. The goal is to work toward performance
standards for various product types that can be applied to incarnations
of various component combinations (Omstead, et al., 1998; Christenson,
1997). As with any such efforts, the proof will be in the clinical
manifestations of performance. Mapping of the standards against
regulatory needs will be the basis for selecting areas for standards
The importance of the global economy will be driving the need
for standards at the international level. Thus the ASTM efforts
will preferably lead to partnering with the international community
for the development of standards that would then be enabled for
acceptance at the international level. This strategy will enhance
the significance of the standards in varying scientific cultures
as well as stretching the available workforce for this volunteer
effort. Interactions with the International Organization for Standardization
(ISO) as well as the European Commission for Standardization (CEN)
have produced important decisions for the undertaking of standards
On a technical level, the comparative molecular analysis of regenerating
vs. non-regenerating tissues in both mammals and lower vertebrates
will be useful in identifying the differences in gene activity
that distinguish regeneration from scar tissue formation. There
may be novel genes in action that distinguishes these processes,
or the same genes might be deployed in different spatial or temporal
patterns of activity, or both. The human genome database can be
culled for the orthologues of genes involved in the regeneration
of animal tissues and the proteins they encode identified and
tested for their therapeutic properties.
Understanding the biology of stem cells will be of crucial importance
for the replacement of tissues through cell transplantation or
for bioartificial tissue construction. We need to know what signals
and cues are necessary to direct the differentiation of stem cells
into specific phenotypes, the nature and range of plasticity of
stem cells found in adult tissues, and how to avoid immunorejection
of cells, either as transplants, or as part of bioartificial tissues.
Advances are being made on all these fronts, and we can anticipate
substantial breakthroughs in the near future.
With these future possibilities, the importance of the ASTM TEMPs
standards work is accentuated. Persons with appropriate expertise
are encouraged to join us in this exciting and rewarding activity.
(1) G. L. Picciolo, K. B. Hellman and P. C. Johnson, 1998. Tissue
Engineered Medical Products, Standards: The time is ripe! Tissue
Eng. Vol. 4, No. 1, pp. 5-7.
V. Brower, 2000. NIH Stem Cell Guidelines Gen. Engin. News,
Vol. 20, No. 16, Sept. 15, 2000.
M. S. Chapekar, 2000. Tissue Engineering: Challenges and Opportunities
Applied Biomaterials, in press.
L. Christenson, 1997. Outcomes Research Is Crucial for Tissue-Engineered
Products Gen. Engin. News, Jan. 15, 1997; Vol. 17, No. 2, p.
M. J. Lysaght, 1995. Product Development in Tissue Engineering
Tissue Eng., Mary Ann Liebert, Inc. Larchmont, N.Y., Vol. 1, No.
2, pp. 221-228.
M. J. Lysaght, N. A. Nguy, K. Sullivan, 1998. An economic survey
of the emerging tissue engineering industry. Tissue Eng., 1998,
Fall; 4(3): 231-238.
D. E. Marlowe, P. J. Phillips, 1998. FDA Recognition of Consensus
Standards in the Premarket Notification Program Biomedical Instrumentation
& Technology, Hanley & Belfus, Inc., pp. 301-304.
D. R. Omstead, L. G. Baird, L. Christenson, G. Du Moulin, R. Tubo,
D.D. Maxted, J. Davis, F.T. Gentile, 1998. Voluntary guidance
for the development of tissue-engineered products Tissue Eng.
1998 Fall; 4(3): 239-66. Review.
G.L. Picciolo, 1997. Enabling biomaterials technology for tissue
engineering: Introduction Tissue Eng., 1997, 3/1 (67-70).
D.L. Stocum, 1999. Regenerative biology: A millennial revolution.
Seminars in Cell and Developmental Biology 10: 433-440.
Also see footnote above.
Copyright 2001, ASTM