A Future for Regenerative Medicine, While Paper

8/3/2019 A Future for Regenerative Medicine, While Paper

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White Paper

A Future for Regenerative Medicine

The Current State of Tissue Engineering: Federal Funding and its Role in Successful Research

Far from the faulty semblance of a bionic human, the current infantile state of tissue engineering

is at a crossroads between advancement, resource limitations, and gaps in applicable knowledge. However,

through the research done so far, it has been shown that even the central dogma of tissue engineering is

far from reality. To overcome present roadblocks and move closer to the overall goal of tissue

engineering (development of in vitro tissues for transplantation or in vivo tissue regeneration), federal

collaboratives have been formed to ease the problem of funding, which in turn promotes research andadvancement. The two reports discussed below describe two such collaboratives. This is a report written

for the main purpose of acquiring federal funding for research in the field of regenerative medicine. The

report also aims to establish a system for governmental control over such research. The authors hope that

by involving the federal government, the field of regenerative medicine will be propelled toward

delivering the marvels it promises1.

Past experience has shown that governmental input into research programs has skyrocketed the

value and results obtained from such research, and in many cases involved little initial funding. A good

example is Sematech (Semiconductor Manufacturing Technology), a cooperation between the fourteenlargest semiconductor wafer manufacturers in the US, formed in 1987 to combat the vast improvements

made in the field by Japan2. The federal government committed to the project by investing $100 million; a

sum matched by the members2. Although it had to work through a series of pitfalls, the most common one

being an overly optimistic view of progress, Sematech did achieve its final goal of returning the US onto

the forefront in semiconductor manufacturing and is currently estimated at $170 billion1.

To achieve federal involvement in regenerative medicine research, the report proposes the

formation of FIRM, the Federal Initiative for Regenerative Medicine. With FIRM, federal funding will be

divided among two main categories –

general research to advance understanding (cellular interactions,storage and preservation of tissues, mass production techniques), and specified research to produce direct

results (a working organ by 2010, a cure for diabetes in the form of growth and implantation of the islets

of langerhans by 2015, and a cure for paralysis by 2020). All of the information obtained from these two

branches of research will be shared with private investors, who will focus on the creation of products and

therapies to satisfy the needs of patients1.

To facilitate the flow of information between groups participating in research, FIRM proposes the

collaboration of federal agencies currently involved in the field, such as Department of Health and Human



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Services, the Department of Defense, the National Aeronautics and Space administration, and the Food

and Drug Administration. The involvement of the FDA will make future clinical trials clearer and the

approval process more directed and efficient. FIRM will be lead by a council, composed of members from

each of the participating agency. The council will decide upon research priorities and milestones to be

met, as well as allocate funding1.

The overall goal of FIRM is to provide tissues on demand for implantation in vitro or the

regeneration of needed tissues in vivo. The gain of reaching such a goal is the next level of medicinal care,

which focuses on the prevention and cure of chronic and terminal disease, such as diabetes, osteoporosis,

health disease, cancer, and organ failure. However, the success of FIRM does not lie solely on research;

the public must also become excited about and understand the aptitude of the initiative. FIRM must

dedicate some resources to introduce regenerative medicine into the school system, as well as create a

recognized name. Public involvement, is turn, will attract bright researchers to further the cause 1. No

other federal program better demonstrates the role of the public in research than the environmental

initiative. Public involvement not only holds the federal government accountable to making good

decisions, but also adds legitimacy to those decisions, making them more like to be implemented3.

“Advancing Tissue Science and Engineering” is a federally funded publication focused on

establishing the current state of tissue engineering and on presenting eight priorities and roles of federal

agencies designed to advance the field – understanding cellular machinery, identifying biomarkers to be

used in assessments, creating better imaging techniques, understanding cell-environment interactions,

creating advanced computational modeling techniques, assembling complex tissues, improving tissue

storage, and developing applications for engineered tissues. It is important to note that all of these eight

goals are interwoven, as it is impossible to progress in certain areas (such as understanding cellular

machinery) without proper developments in the fields of biomarkers, imaging or computational tools4. It

is also important, however, that fundamentals (such as cellular machinery) are understood before further

technological progress is made5.

The publication outlines three areas for tissue engineering applications – medical treatments

(regenerative medicine), medical research (drug delivery, drug metabolism, pharmacogenomics), andnon-medical research (detection of threat agents, protein manufacturing). As much as tissue development

for transplantation is important, the other two fields should not be ignored as they will allow for much

more accurate clinical trials (as full 3D tissues will be used for testing instead of Petri dish samples) and

the elimination of animal testing5. Funding for such research comes from both federal and private sector

support. It is important that all of the involved agencies work together in order to facilitate the flow of

information, as well as hold public forums to spread the information to the general public. MATES IWG

(Multi-Agency Tissue Engineering Science Interagency Working Group) is a federal collaborative



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specifically established to oversee the collaboration of all other involved groups. All new research must

also be forwarded to proper developers to allow for mass-market product creation4.

The overall goal for the tissue engineering industry is to design and build a fully functional tissue,

and eventually an organ, since some full tissue function is lost when only part of the tissue is reproduced4.

However, to develop functional organs, a better understanding of scaffold and matrix properties is needed,

because it is virtually impossible to create a 3D construct without framework 6. It is imperative to find

materials that better mimic the natural environment, such as the extracellular matrix, as well as are strong,

porous, biodegradable, and compatible with the immune system6. Because of these research needs, four

immediate goals were put in place by MATES to further the advancements in tissue engineering –

understanding and controlling cellular response, creating successful scaffolds and matricies, developing

tools to facilitate research, and promoting the move to mass-production and commercialization4

.

The above-outlined reports contain similarities and differences, both in their context and areas of

focus. Regenerative medicine, the main focus of “2020: A New Vision, A Future for Regenerative

Medicine” is a sub-category of tissue engineering, which in turn is the topic for “Advancing Tissue

Science and Engineering,” which creates a similarity and difference in itself. Both reports asses the need

for further research in their respective fields and establish priorities to be addressed immediately.

The main similarity, and the main difference as well, are the member agencies. As can be seen on

Figure 1, quite a few agencies are part of both initiatives – Department of Health and Human Services,

National Institute of Health, Food and Drug Administration, Defense Advanced Research Projects

Agency, National Institute of Standards and Technology, White House Office of Science and Technology

Policy, National Aeronautics and Space Administration, and National Science Foundation. Certain

agencies, however, are only part of FIRM – Department of Commerce, and Department of Defense; while

others are only a part of MATES – Army Medical Research and Materiel Command, Center for Medicare

and Medicaid Service, Department of Energy, Environmental Protection Agency, Naval Research

Laboratory, Department of Agriculture, and Department of Veteran Affairs.



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Figure 1. A graphical representation of the agencies that are part of FIRM (DOD, DOC), MATES

(USAMRMC, CMS, DOE, EPA, NRL, USDA, VA) or both (HSS, NIH, FDA, DARPA, NIST, OSTP, NASA,

NSF)

The operational standards for both of the agencies, MATES IWG and FIRM, share common

threads. For example, both are funded by federal and private means. Also, the two initiatives consider

public understanding a big priority, and contain plans that both inform about and invite the public to

participate in (through joining the research effort) the respective field of study. Another similarity is that

both groups have set standards for information sharing, so that new knowledge that is acquired through a

collaborative inter-agency effort of the researchers is shared with outside product developers, for the

purpose of creating a product that can suit the needs of the client and be mass produced. However, thetwo initiatives differ in their target audience. FIRM hopes to further research in the field of regenerative

medicine, while MATES focuses on tissue engineering in general, both on its medical and non-medical

applications.

One of the main differences between the two reports comes in the reason for submission. For

MATES IWG, an inter-agency collaboration has already been established, thus the report serves to update

others about the current research being conducted, as well as sets a list of updated goals. For FIRM, even

though a summary of the current state of the field of regenerative medicine and main goals is given, the



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main focus of the report is the acquisition of federal funding for the regenerative research effort. Thus,

MATES is more focused on the science, while FIRM is more concerned with establishing an initiative

and funding.

Tissue engineering of the liver is a sub-focus of current regenerative medicine, and is intricately

intertwined with both private and federal enterprises. Successful private efforts have focused on

bioartificial liver bioreactors (BAL) that have been developed to replace liver function in the laboratory 7.

By circulating plasma extracorporeally through bioreactors that contain hepatocytes, these devices mimic

the metabolic function of the liver8. Circe Biomedical, a private company, has produced arguably the

most successful extracorporeal liver assist devices, the HepatAssist, which utilizes a hollow-fiber

bioreactor lined with porcine cells7. However, commercial products available for wide range public use

are still rare in the field of liver tissue engineering. Federal programs such as FIRM and MATES IWG

show promise in easing current troubles that halter the development of tissue-engineered livers.

Highlighted as a concern in both federal ventures and a particular concern in tissue engineered

livers is cell sourcing. The advantages and limitations, as well as long term functional stability and

efficacy of cell sources, have yet to be completely assessed9. Primary hepatocytes are the most common

and preferred choice for cellular therapies9. However, primary hepatocytes require particular extracellular

signals to maintain the hepatic phenotypes in vitro9. Both FIRM and MATES IWG policies address this

issue by establishing goals towards further research in understanding of cellular response and formulating

biomaterial scaffolds and tissue matrix environments. In particular, MATES IWG lists the production of

appropriate bioreactors that create a proper environment which allows for growth, habituation,

incorporation and testing of the manufactured cells4.

A second category, hepatocyte cell lines, are used to compensate for growth limitations and

availability of primary cells9. Immortalized cell lines are a common approach, but encounters problems

with function, safety, and appropriate response9. The spread of oncogenic factors is a primary concern

with immortalized cells and may hinder effective patient based therapies further reinforcing the need for a

large multifaceted approach towards cell sourcing in tissue engineering (REFERENSE???).

Stem cells are yet another avenue for use in cellular therapies for liver disease. Due to theirundifferentiated form in vitro and their ability to be induced into a number of different cell types, these

cells show great promise for treating damaged tissues10. Understanding this great potential, both FIRM

and MATES IWG recognize the need for further understanding of stem cell biology. MATES IWG

stresses that the rapid expansion of stem cells should be a priority topic. Current liver based therapies

revolve around embryonic stem cells, adult liver progenitors, and transdifferentiated nonhepatic cells 9.

Oval cells app ear to be the b ipotential stem cell that appears in instances of hepatic injur y and the

inability of matur e hepatocytes to under go repair11. Some progenitor cells, described as “multipotent



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hepatic stem cells with self-renewal capabilities”, have also been isolated from adult and fetal liver

tissues9. In liver based cellular therapies, there is an uncertainty about which stem cells will be the best

source. The only certainty is that stem cells provide great potential in future therapies. Regenerative

medicine in Europe has already created a model for lung tissue repair using embryonic stem cells,

coupled with efforts to store and grow embryonic stem cells on the large scale4. If the U.S. fails to initiate

further resources and focus into stem cells, they will surely fall behind international rivals in many areas

of tissue engineering and regenerative medicine including liver based therapies.

Although FIRM predicts a fully functional organ by 2010, currently, the prospect of a fully

functional liver is far from merging. Extensive research is being conducted to reproduce the complex 3-D

microenvironment of hepatocytes in vitro. Structurally, mimicking the closely packed hexagonal shaped

lobules of hepatocytes in the liver has inspired a wide array of 3D cell culture matrix construction

methods including electro-spinning and particulate-leaching for fibrous mesh-like constructs and solid

free-free form fabrication techniques for the production of ordered architectures12. Furthermore, new

biomaterials have further expanded possibilities in cell construct design, enabling researchers to develop

new innovative strategies13. However, further federal support in the form of funding and a direction, as

mentioned in both initiatives, is still required to accelerate progress.

An example of a current process in liver tissue engineering, sprouting as a result of direct federal

funding, involves the large scale manufacturing of consistent micro-scale 3D structures. With the aid of

computer automation, identical models of reproducible 3D scaffolds will standardize the experimental

scaffold variable and enable adequate testing of other parameters12. Despite the current demand, there is

no significant research in this direction except for a few small projects12. One of such projects funded by

NASA (the National Aeronautics and Space Administration) is currently ongoing at Drexel University.

Using an automated syringe guided by CAD (Computer Aided Design), which allows for direct layered

cell deposition, scientists at Drexel are developing enabling technologies in the field of bioprinted 3D

tissue constructs14. Of particular interest to NASA, is the potential for pharmacological and metabolic

research on liver micro-organs14.

To satisfy FIRM’s goal and provide liver tissues and organs for implantation in vivo, the four

immediate goals established by MATES IWG must be met: understanding and controlling cellular

response, creating successful scaffolds and matrices, developing tools to facilitate research, and

promoting the move to mass-production and commercialization. Currently, the process of developing a

completely artificial liver is making slow, yet inspiring, progress in all of these aspects. Regulatory and

resource limitations, however, are a matter of great concern in the future of this science. With adequate

support, communication, and direction, provided by the federal government, tissue engineering of the

liver, and as a whole, will be better prepared to overcome the obstacles that lie ahead.



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References

1. FIRM

2. Comello V. Is Sematech a model for global competitiveness? Research & Development 35, 24, 1993.

3. Larson KL, Lach D. Participants and non-participants of place-based groups: An assessment of

attitudes and implications for public participation in water resource management. Journal of

Environmental Management 88, 817, 2008.

4. MATES

5. Vunjak-Novakovic G, Kaplan DL. Tissue Engineering: The Next Generation. Tissue Engineering 12,3261, 2006.

6. Ingber DE, Mow VC, Butler D, Niklason L, Huard J, Mao J, Yannas I, Kaplan D, Vunjak-Novakovic

G. Tissue Engineering and Developmental Biology: Going Biomimetic. Tissue Engineering 12, 3265,

2006.

7. Lal B, Viola J, Hicks D, Grad O. Emergence of Tissue Engineering as a Research Field. 2003.

8. Strain AJ, Neuberger JM. A bioartificial liver--state of the art. Science 295, 1005, 2002.

9. Allen JW, Bhatia SN. Engineering Liver Therapies for the Future. Tissue Engineering 8, 725, 2002.

10. Neuss S, Apel C, Buttler P, Denecke B, Dhanasingh A, Ding X, Grafahrend D, Groger A, Hemmrich

K, Herr A, Jahnen-Dechent W, Mastitskaya S, Perez-Bouza A, Rosewick S, Salber J, Wöltje M,

Zenke M. Assessment of stem cell/biomaterial combinations for stem cell-based tissue engineering.

Biomaterials, 29, 302, 2008.

11. Petersen BE, Zajac VF, Michalopoulos GK. Hepatic oval cell activation in response to injury

following chemically induced periportal or pericentral damage in rats. Hepatology 27, 1030, 1998.

12. Lee J, Cuddihy MJ, Kotov NA. Three-Dimensional Cell Culture Matrices: State of the Art. Tissue

Engineering Part B 14, 61, 2008.

13. Stupp SI, Donners JJJM, Li LS, Mata A. Expanding frontiers in biomaterials. MRS Bulletin 30, 864,

2005.

14. Chang R, Nam J, Sun W. Computer-Aided Design, Modeling, and Freeform Fabrication of 3D Tissue

Constructs for Drug Metabolism Studies. Computer-Aided Design and Application 5, 363, 2008.

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