Sergey Nikulin 1,2,3,6, Alexander Aliper 1,2,3,6, Andrey Garazha 1,2,3,6, Dmitry Kamenskiy 1,2,6,
Nadezhda Zhdanovskaya 1,4,6, Sergey Roumiantsev, MD, PhD, DSc 2,3, Anton Buzdin, PhD,
DSc 2,3,5,6, Andrey Ivashenko, PhD 2,7, Alex Zhavoronkov, PhD *1,2,3,6,8
* correspondence should be addressed to: alex@biogerontology.org
* published on http://www.biogerontology.ru
1. Biogerontology and Regenerative Medicine Center (Center of Excellence in Aging Research at MIPT)
2. Moscow Institute of Physics and Technology
3. D. Rogachev Federal Research and Clinical Center for Pediatric Hematology, Oncology and Immunology
4. The Faculty of Basic Medicine, M.V. Lomonosov Moscow State University
5. The Institute of Bioorganic Chemistry, RAS
6. First Open Institute for Regenerative Medicine for Young Scientists
7. BioPharmaceutical Cluster “Nothern” at MIPT
8. The Biogerontology Research Foundation
TABLE OF CONTENTS
Glossary
4
Introduction
6
Regenerative Medicine Landscape
7
Segmentation
9
1. Services
9
A. Biobanks
9
B. Clinical trials
10
C. Contract Research Organizations (CROs)
11
D. Contract manufacturing (CM)
11
E. Clinics/Hospitals
12
F. Aesthetic medicine
12
G. Consulting/Legal certification
12
2. Enabling technologies
13
A. Equipment suppliers
13
B. Reagents and materials
13
C. Implants
13
D. Cell and tissue sources
14
E. Information Systems
14
3. Molecular induction technologies
14
A. Gene therapy (vectors)
15
B. Small molecules and proteins
16
C. Combination of gene therapy and small molecules and/or proteins
17
4. Cells
18
A. Embryonic stem cells (ESCs)
18
B. Induced pluripotent stem cells (iPSCs)
19
C. Adult stem cells (ASCs)
21
D. Artificial cells (ACs)
26
5. Tissues
27
A. With scaffold
28
B. Without scaffold
29
6. Organs
29
A. Kidney
29
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B. Liver
30
C. Bladder
30
D. Cardiovascular system
30
E. Skin
30
F. Pancreas
30
G. Trachea
31
H. Teeth
31
I.
Bones and cartilages
31
7. Diseases
31
A. Cardiovascular diseases
32
B. Cancer
32
C. Blood diseases
33
D. Wounds
33
E. Reproductive system diseases
33
F. Neurological diseases
34
G. Ocular diseases
34
H. Gastrointestinal diseases
35
I.
Urinary system diseases
35
J. Muscular and skeletal disorders and injuries
35
K. Diabetes
36
L. Immunological diseases
37
Examples of analytics using ARMIF
38
1. BioTime, Inc
38
2. Osiris Therapeutics, Inc
41
3. Stratatech, Inc
43
References
45
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GLOSSARY
3D-bioprinting: layer-by-layer approach to create tissue and organ architecture using bio-ink
and structure materials.
Bio-ink: multicellular building blocks for bioprinting.
Adult stem cells: multipotent stem cells that can be found in juvenile and adult organism.
Allogenic: taken from the same species but genetically different.
Autologous: taken from the same organism.
Biomaterial: biocompatible material interacting with the body to improve biological functions
and replace faulty cellular structures.
Cells: basic structural, functional and biological unit of all living organisms except viruses.
Cell therapy: administration of cells into the body in order to treat a disease or improve the
function of the existing cells.
Clinical trial: stage of medical research that gives information of safety and efficacy for health
interventions (drugs, therapy protocols, diagnostics etc.).
Phase 0 trial: first in-human trials in small groups of patients to investigate the response
of a new intervention in humans (e.g. drug pharmacodynamics and pharmacokinetics).
Phase 1 trial: trials in a small group of patients to screen the method of intervention for
safety.
Phase 2 trial: experimental treatment of larger groups of people to investigate the safety
and effectiveness of new intervention against a placebo.
Phase 3 trial: final confirmation of the safety and efficacy for a new intervention.
Phase 4 trial: post-marketing studies of the risks and benefits of the new intervention as
well as the determination of optimal usage for the intervention.
Embryonic stem cells (ES cells): pluripotent stem cells derived from an early-stage embryo.
Implant: non-biological medical device destined to improve or replace a biological structure.
Expression: realization of information from a gene within the cell.
Extracellular matrix: tissue material between cells.
Ex vivo: outside the living organism.
In silico: performed on a computer or via computer simulation.
In vitro: performed in laboratory conditions rather than within a living organism.
In vivo: within the living organism.
Induced pluripotent stem cells (iPSC or iPS cells): pluripotent stem cells derived from non-
pluripotent cells by reprogramming of genes.
Isogenic: taken from another organism but genetically identical.
Gene therapy: introduction of genetic material into cells to treat a disease.
Genetic vector: DNA or RNA molecule used for the introduction of foreign genetic material
into the cells for research or medical treatment.
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Medical tourism: movement of patients from one country to another to access medical care
facilities.
Multipotent stem cells: stem cells that can differentiate into a family of related cells.
Oligopotent stem cells: stem cells that can differentiate into a few cell types.
Plasmid vector: small circular double-stranded bacterial DNA that can replicate independently
within of the chromosomal DNA in a cell.
Pluripotent stem cells: stem cells that can differentiate into all cells except embryonic cells.
Regenerative medicine: field of medicine referring to approaches for replacing or regenerating
human cells, tissues or organs to improve or restore biological functions.
Reprogramming: deriving less differentiated cells from more differentiated ones by forced
expression of specific genes.
Scaffold: artificial structure capable of supporting the formation of a three-dimensional tissue.
Stem cells: undifferentiated biological cells that have ability for self-renewal and a capacity to
differentiate into specialized cell types.
Tissue: group of similar cells from the same origin that together carry out specific function in the
body.
Totipotent stem cells: stem cells that can differentiate into all embryonic and extra embryonic
cell types.
Tissue engineering: use of cells, engineering, materials, factors and methods to manufacture
tissues and organs ex vivo in order to improve or replace biological functions.
Transcription: copying of DNA into RNA by the enzyme RNA polymerase.
Transcription factor: protein that specifically binds to a known DNA sequence in the gene and
controls the transcription of genes.
Translation: The process of protein synthesis by ribosomes, using the code from the RNA
sequence within the cell.
Transplant: biological material placed into recipient organism to improve or replace a
biological structure.
Viral vector: genetically engineered viruses carrying noninfectious modified viral DNA or
RNA.
Retroviral vector: RNA-containing viral vectors that can integrate only into the genome
of dividing cells.
Lentiviral vector: RNA-containing viral vectors that can integrate into genome of non-
dividing and dividing cells.
Adenoviral vector: DNA-containing viral vector that does not integrate into the genome
and does not replicate during cell division.
Xenogenic: originating from foreign substance.
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INTRODUCTION
The field of regenerative medicine encompasses many areas of scientific research and clinical
applications. While many attempts have been made to compare various companies, research
organizations and research projects, few models account for the whole industry supply chain and
the fact that many companies participate in multiple industry segments. For example, some of the
companies supply reagents, equipment and cells and may have a conservative growth projection
and are less risky from the cash flow and clinical trials perspective, may also have basic research
or translational medicine projects that may serve as major sources of growth. Likewise,
companies engaged in lengthy, expensive and risky clinical trials may have research divisions
working on novel research projects that may be out-licensed to other industry participants and
provide stable sources of funding. There are a vast number of biotechnology companies and
healthcare organizations which are not classically classified as players in the regenerative
medicine field, but are either providing services to the industry acting as suppliers or deploying
regenerative medicine technologies in the clinic, thereby contributing to the creation of demand.
Some of the large biopharmaceutical companies often have research or translational medicine
divisions that occupy leadership positions in certain industry segments are insignificant
compared to the rest of the company, but have leadership positions in certain industry segments.
To address these issues we developed a comprehensive Analytical Regenerative Medicine
Industry Framework (ARMIF), which incorporates many segments of the regenerative medicine
industry and includes services, enabling technologies, technologies for manipulation at the
cellular and tissue level, diseases and highlights the focus on the level of organismal organization
such as cells, tissue and organs.
The presence of the company and level of activity in each segment is visualized using the color
codes: low, medium and high. For example, if the company’s main business is supplying
reagents and cells, the appropriate segments are highlighted in red. If the company is engaged in
research of multiple cell types, but is mostly focusing on autologous cells, but it also has projects
using allogenic cells and is just starting the induced stem cell program, each one of these fields
will be color coded by the level of activity in the field.
While ARMIF is currently limited in both, granularity and scale, it is one of the most
comprehensive models for analyzing the organizations and projects in regenerative medicine that
not only allows to analyze the positioning, but also evaluate the level of participation and track
multiple parameters in each segment. It is a scalable and flexible platform that allows for new
parameters to be added.
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REGENERATIVE MEDICINE LANDSCAPE
Regenerative medicine is rather big industry with an extremely complex structure due to the
involvement of not only the primary companies involved directly in the regenerative medicine
business, but also the services industry associated with diverse fields like bioengineering,
chemical industry, pharmaceutical industry as well as clinics and hospitals involve in trials. We
have developed a map which can help understand what regenerative medicine is. The projection
of this map is in the form of a table, which is divided into several levels (horizontal rows). Each
level in this table represents a separate part of regenerative medicine industry, but some of these
levels are strongly connected. There may be some segments in a level which describe specific
technologies or services. This table can also be used for the description of the companies
working in regenerative medicine. Each company shall have its own copy of the table. If a
company develops a particular technology or provides a particular service the respective table
cell will be marked with a color code, otherwise it will remain white.
The first two levels in this table are represented as the ‘Services’ and ‘Enabling technologies’.
Services form a vital part of any industry and Enabling technologies provide an innovative thrust
for future developments in the field of regenerative medicine.
The next four levels in the table are very similar to the levels of the biological organization in
humans.
Molecular level of the organization of the body is the simplest one but it is not less important
than the others. Molecular induction technologies are a very important part of regenerative
medicine.
Cellular level of the organization in the body has a higher complexity than a molecular level.
Cells are a part of this level form the basis of regenerative medicine as they are the primary unit
involved in the regenerative process. A large number of current treatment modalities in the field
of regenerative medicine are based on cells or cell-derived products.
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Table 1 : Segmentation of regenerative medicine industry
The organization at a tissue level is strongly connected to the cellular level. The source of cells
and/tissues can be classified into four different groups based on the source of the cell/tissue
material and immunogenic capacity.
1. Autologous. Cells and/or tissues derived from the same person who is undergoing a
treatment. Autologous cells/tissues have a very low probability of rejection after
transplantation.
2. Allogenic-Cells and/or tissues derived from a person for treatment another person.
Allogenic cells/tissues have a large probability of rejection after transplantation.
3. Isogenic- cells and/or tissues derived from a person with the same genetic make-up as the
patient (for example from a twin). Isogenic cells and tissues also have a rather low
probability of rejection after transplantation.
4. Xenogenic-cells and/or tissues derived from an animal. Xenogenic cells and tissues have
a large probability of rejection after transplantation.
The next level of complexity in an organism is the organ level organization. Each organ consists
of different types of tissues, which in turn are composed of different cell types. Bio-engineered
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organs have already been produced and some of them have already been successfully
transplanted.
And the final level is the level of diseases where some particular treatments are discussed.
Every table cell is described in the next chapter which is called Segmentation.
SEGMENTATION
1. SERVICES
Services form an important part of any industry. In the field of regenerative medicine, their role
can hardly be overstated, because it is a new area and all stakeholders face a lot of problems. A
well-organized services sector supporting the regenerative medicine industry can undoubtedly
make a great contribution to the development of the field. Some of the associated services
industry caters to the needs of the companies while other provide services to the final consumers.
A. BIOBANKS
Biobank is a repository of different biological materials such as blood, umbilical cord, cells and
tissues, where these materials are collected, processed and stored. The bio-specimens can be used
for different purposes such as scientific research and transplantation. In this section, we shall
cover biobanks which are focused on storage of different cells and tissues for future
transplantation as they are of significant relevance in the regenerative medicine industry.
The present day technology makes it possible to collect a large number of different cell and
tissue types from the human body. For example it can be adipose tissue, cord blood, amniotic
stem cells, and skin and so on.
Biobanks can be public and privately controlled. Public banks collect cells and tissues and make
them available for anyone who needs a transplantation. In such cases, donors are not assured that
their donated specimens will be available to them in future, in a case of a disease. Public banks
are non-profit organizations. Private biobanks are commercial organizations which offer their
clients a possibility to store their tissues and cells for private use at a cost.
Cord blood banks are an example of the most successful biobanks. According to the Alliance for
regenerative medicine (http://alliancerm.org/), more than 30000 cord blood transplants have been
performed until the year 2012. The popularity of private cord blood banks is rising sharply but
there is a strong opinion that the probability of usage of the transplant material by its donor is too
low, giving an advantage to the public banks are better.
According to FundingTrends.org funding of biobanks rose sharply since the year 2003 and
reached a plateau in 2009.
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Chart 1: Funding* received by Biobanks.
B. CLINICAL TRIALS
Clinical trials are an extremely important but cost and time intensive step towards bringing a
research product into the market and to evaluate its safety and efficacy. The process of
conducting clinical trials can face many challenges that is the precise reason that small scale
companies engaged in the development of therapeutics prefer to use the services provided by
companies specialized in getting approvals for and conducting clinical trials. One example of
such a company is PAREXEL, with its presence across continents. According to Yahoo Finance
(http://finance.yahoo.com/ ) market cap of this company is about 2.84 billion dollars.
Such specialized companies provide services that can be very helpful for development of
regenerative medicine field as a large number of small companies, incapable of conducting such
trials independently, can use the expertise and know-how of the professional companies
specialized in clinical trials. FundingTrends.org cites that the funding of clinical trials related to
the regenerative medicine field has sharply increased since 2003.
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Chart 2: Funding* for clinical trials in regenerative medicine.
C. CONTRACT RESEARCH ORGANIZATIONS (CROS)
Contract research organization is an organization which provides different research services to
the pharmaceutical and biotechnological companies on a contract basis. For example, it can be
biological assays, preclinical trials etc. These CROs have a strong connection with the
regenerative medicine field. Firstly, their services can be very helpful for the companies which
are focused on development of a particular regenerative technology. Secondly, these CROs are
often the first clients using the models developed by the regenerative medicine industry. For
instance, the new 3D tissue models are gaining popularity in the field of drug testing.
The annual growth of this segment of the market in the Unites States is 12.1 % and the revenue is
about $15 billion (http://www.ibisworld.com/industry/contract-research-organizations.html).
D. CONTRACT MANUFACTURING (CM)
Contract manufacturer is an organization which manufactures a product on a contract basis. Of
the many manufacturers in biomedical industry, some contract manufacturers provide specialized
manufacturing services for the regenerative medicine industry. Again, as mentioned in the case
of Cos, CM can be beneficial for small innovative companies which may have a breakthrough
product but do not have the manufacturing facilities. The list of products which can be produced
by such organizations is rather extensive. It includes different reagents, vectors for gene therapy,
induced pluripotent stem cells etc.
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E. CLINICS/HOSPITALS
Clinics and hospitals are considerable stakeholders in the regenerative medicine industry. In any
case all clinical trials and fully developed therapies are connected with them. They also
participate in the development of different regenerative technologies as they have their own
research facilities. In future, the role of clinics shall be increasingly important as it is often easier
to produce stem cell products in hospitals rather than in separate laboratories. The delivery of a
stem cell product is a complex process involving legal restrictions. Moreover, some products
have to be used immediately after preparation as they have a short shelf life and may be
subjected to damage upon storage and /or transportation. Hospitals and clinics can be used as a
source of the material from the donors and at the same time provide facilities to deliver the
product to the recipient. Hence, in future, big hospitals and clinics are expected to play a major
role in regenerative medicine.
F. AESTHETIC MEDICINE
The technologies of regenerative medicine can make a serious contribution to aesthetic medicine.
Regeneration and protection of the skin is one of the most important aims of cosmetic
procedures. Several technologies which are currently used for the treatment of connective tissue
and skin related problems are also relevant for cosmetic purposes. For example, the company
Anika Therapeutics manufacture and market some products which can be used for correction of
facial
wrinkles,
scar
remediation
and
lip
augmentation
(http://www.anikatherapeutics.com/products/dermal/index.html ).
G. CONSULTING/LEGAL CERTIFICATION
Consulting and legal certification is an extremely important part of services in regenerative
medicine. The rules and regulations for products as well as services in regenerative medicine are
different depending on the country. Moreover, the regulations are often not easy to interpret and
the innovator often requires professional legal and regulatory personnel to get through the
process of legal certifications and regulatory boards.
Consulting and analytics are also important as regenerative medicine is a very dynamic industry
and all stakeholders need up-to-date information about all events in the field for the decision
making process.
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2. ENABLING TECHNOLOGIES
Enabling technology, as the name suggests, is a driving innovation or technology that can
radically change the capabilities to the benefit of the end user. These organizations may not be
directly involved in the development of a specific treatment using approaches of regenerative
medicine.
A. EQUIPMENT SUPPLIERS
There is a group of companies which are specialized in the production of equipment for cells and
tissues culturing. The range of necessary equipment is rather wide. It includes cell culture hoods,
incubators, microscopes, centrifuges, refrigerators, freezers, etc. The laminar flow hoods provide
aseptic work area, which is necessary for the process of carrying out manipulations with cells
and tissues. Incubators are needed for maintaining special conditions
(gas composition,
temperature, etc.) for proper cell growth. Moreover, some incubators contain special
microscopes which allow real time imaging of cell development and to correct it when it is
needed
(http://www.olympusamerica.com/seg_section/seg_presscenter_headline.asp?pressNo=750).
Refrigerators are used for storage of some reagents. Freezers can be used for different purposes.
There are three types of them (-20°C, -80°C and liquid nitrogen freezers with the temperature of
-196°C). The first two ones are primary used for storage of reagents but the third one is used for
preservation of biomaterials (cells, tissues, etc.).
Other equipment (centrifuges, shakers, pipettes, etc.) is used for different manipulations with
cells and tissues.
B. REAGENTS AND MATERIALS
Another segment of enabling technologies is the production of different reagents and materials.
There are a lot of reagents used in regenerative medicine. The list of them includes cell culture
media, different solutions, growth factors, cytokines, antibodies and other chemical compounds.
Companies such as Life Technologies Corporation, STEMCELL Technologies Inc. and others
provide a wide range of such reagents.
Another important part of the market is production of different biomaterials. These materials are
used for tissue engineering and provide proper environment for cell growth and differentiation.
They also have special mechanical properties depending on their purpose.
C. IMPLANTS
A medical implant is a device introduced into the body to replace a missing biological structure,
and/or to support or enhance the function of a damaged biological structure. Implants are
composed of biomaterials but they should be described separately due to their importance.
Surgeons have used different metal implants for a long time. However, these implants do not
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mimic human tissues as metals have properties that are different from biological material. At
present, it is possible to construct metal implants which can be used as a scaffold for the
attachment and growth of human cells. It has now became possible to combine stem cells and
metal implants to derive an implant with mechanical properties that are better than the metal
implant alone. These implants are also less susceptible to rejected by an organism (Smith et al,
2012).
D. CELL AND TISSUE SOURCES
The source of donor cells, specimens and other biological material is a necessary tool used in the
development of regenerative medicine products. Companies specialized in providing reliable
biological material which is well characterized and meets the required regulatory standards also
form a part of enabling technologies. These characterized biomaterials can be used for different
purposes such as clinical and scientific research or pharmaceutical assays. The list of the bio-
specimens includes donor cells, cell lines, frozen tissue etc. All biological samples should be
well characterized and obtained from reliable sources.
E. INFORMATION SYSTEMS
In present day life science industry, information systems play a vital role. For example, the
whole branch of bioinformatics could not exist without such systems. Regenerative medicine is
not an exception to this rule. Handling of large scale data regarding gene sequences, signaling
pathways and mechanisms of actions of drugs on specific pathways, all utilize the knowledge of
information systems to comprehend this data. Companies involved with the management and
interpretation of large volumes of such data related to biological processes are an extremely
important component for the development of regenerative medicine. Information systems help
integrate and update the research on biological processes, which then forms the basis of research
and development for new products in the life science industry.
3. MOLECULAR INDUCTION TECHNOLOGIES
One possibility for the regeneration of damaged human cells in case of a disease is to transform
them to circumvent this damage. For example, if a cell produces a faulty protein which results in
a specific disease type, we can inject the gene coding for the correct protein. Another possibility
is to transform the stem cells from a patient’s own body and allow them to differentiate into a
specific subtype, replacing the damaged cells. In this chapter, we shall discuss different factors
that can be used to induce the transformation of damaged/diseased cells. All transforming factors
can be divided into two groups. The first group is that of the different vectors used in gene
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therapy. The second group is classified as the small molecules and different biological proteins
which can be introduced into the cells, resulting in a specific transformation.
A. GENE THERAPY (VECTORS)
Gene therapy addresses the correction or an improved regulation of a mutated or defective gene
by introducing nucleic acids (DNA or RNA) as therapeutic molecules for the correction of a
specific defect. Gene therapy can be used to add a new gene to human genome or to replace,
correct or knock out a damaged gene. Nucleic acids, which are used as therapeutic agents should
be packaged within a specialized carrier called as the vector in order to reach the cell nucleus and
express a desired protein product. Finally all delivered DNA and RNA transform into functional
proteins or RNA which can change behavior of the treated cells.
There are several types of vectors which can be classified into two subtypes: the viral
vectors and the non-viral vectors.
a. Viral vectors
The first possibility to deliver nucleic acids into a cell is through the use of different
viruses. Viruses can penetrate into the cell and nucleic membrane and deliver genetic material
which then expressed. If a part of viral genome is replaced with a gene of interest, this gene will
be expressed in cells instead of viral genes. Different types of viruses such as the adenoviruses,
retroviruses and lentiviruses are widely used for human gene therapy.
b. Non-viral vectors
Non-viral vectors comprises of small molecules including naked DNA, liposomes,
inorganic nanoparticles and other structures such as the dendrimers. The efficiency of these
methods has been enhanced since they were first discovered and their main advantage lies in low
immunogenicity and an ease of large scale production.
There therapy can be classified as somatic cell gene therapy, where only somatic cells in
the body are manipulated and the gene defect is still passed on to the future generations. The
second type is the germ line gene therapy where the human germ cells are modified and the
genetic defect is corrected and the corrected gene is passed on to the future generations.
Unfortunately, germ line gene therapy has not yet been completely validated for safety and
remains forbidden in several countries.
Gene therapy is suited for diseases caused by single-gene defects. There are a large
number of gene therapy trials targeting cancer and hereditary diseases. Targeting genetic defects
resulting from several faulty genes is still deemed difficult and has not been widely investigated.
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Until 2012, more than 1800 clinical trials involving gene therapy have been successfully
completed (Ginn, Alexander, Edelstein, Abedi, & Wixon, 2013) in more than 31 countries. There
a number of ongoing clinical trials evaluating the potential of gene therapy methods
(http://www.genetherapynet.com/clinical-trials.html ). For example, the first gene therapy trial
was conducted on a 4 year old girl at the NIH center in the USA on 14 September 1990 for the
treatment of adenosine deaminase deficiency (http://history.nih.gov/exhibits/genetics/sect4.htm ).
Although there are a number of clinical trials reporting success, the method has some serious
disadvantages. The efficacy of many gene therapies is not long lasting, especially for somatic
cell gene therapy. The second disadvantage is the immune response to the treated cells as they
carry fragments of DNA which are recognized as ‘non-self’ by the host. The Furthermore, the
use of viruses can also elicit an immune response, at times making the mode of delivery
incapacitated. The use of integrating viruses, which integrate the DNA into the host DNA can be
tumorigenic as the site of DNA integration is unpredictable and might affect the normal cellular
processes and functioning of cells. Several strategies to overcome these potential disadvantages
are currently being investigated.
Chart 3: Funding* for projects in gene therapy.
The funding of projects on gene therapy has seen a sharp increase since the year 2007 and the
funding reached almost $ 5 billion for the year 2010
(http://www.fundingtrends.org/?keywords=gene+therapy ).
B. SMALL MOLECULES AND PROTEINS
Another promising approach for the treatment of diseases is to introduce small molecules such as
growth factors or other specific proteins in the body to allow for the regeneration of a damaged
or diseased tissue. Different proteins and small molecules can be used for these purposes.
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For example platelet growth factor (biological protein which is contained in platelets) can be
used for treatment non-healing wounds and for regeneration of bones (Burnouf et al, 2013).
Small molecules have also been used for the regeneration of bones (Lo, Ashe, Kan, & Laurencin,
201 2). Recently, scientists have discovered that small molecules and proteins can be used to
reprogram mature cells into stem cells. These stem cells are called induced pluripotent stem cells
(iPSCs) and have the potential to revolutionize the field of regenerative medicine and shall be
discussed separately.
Chart 4: Funding* received by projects in regenerative medicine exploring growth factors and small molecules.
The funding of projects on regeneration which use small molecules and growth factors has also
seen a sharp rise since 2007. However, the funding for projects which use small molecules for
regeneration
is
much
less
than
those
using
growth
factors
(http://www.fundingtrends.org/?keywords=+growth+factors%2C+small+molecules ).
C. COMBINATION OF GENE THERAPY AND SMALL MOLECULES AND/OR PROTEINS
Combination of gene therapy and small molecules or proteins can reduce the side effects of the
first one and improve its efficacy. For example, when adenoviruses are used as vectors, they
have a strong hepatic tropism, strongly reducing the safety and efficacy of the therapy. Recently,
scientists have discovered several small molecules which can circumvent this side effect and
make the therapy safer (Duffy et al, 2013). This approach is very promising and will probably
have widespread applications in the future.
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4. CELLS
The human body consists of more than 1013 cells of several different types. These differences in
different cell types are both, morphological and functional. Different cell types have stark
differences in cell signaling pathways although they have a structurally identical composition.
All cells in a human body are derived from a single fertilized egg cells. Most of the cells in an
adult human body are mature cells without the capacity to proliferate but can perform a
specialized function in the body. After a certain number of cell cycles, a mature cell cannot
divide any further and hence, is unable to regenerate when afflicted by damage or disease. Stem
cells have two main features that make them suitable to replenish the lost adult cells. Stem cells
can proliferate and generate a large number of identical daughter cells, making them suitable to
be used for the regenerative purposes. Secondly, stem cells are capable of being transformed into
many specialized cell types. Stem cells in general can also be classified into several subtypes
depending on their lineage. For example, mesenchymal stem cells, cardiac stem cells, embryonic
stem cells and so on. Each subtype of stem cells has its own advantages and disadvantages which
will be discussed in later sections. The regenerative capacity of cell therapy using stem cells
undoubtedly makes them the most important field in regenerative medicine as they have
enormous medical and economic potential.
A. EMBRYONIC STEM CELLS (ESCS)
As is mentioned before, cells in a human body are derived from the zygote, formed after
fertilization of an egg and a sperm. After fertilization, the zygote divides to form an embryo. At
this stage, the embryonic cells can form all cell subtypes found in a human body along with the
cells forming the placenta, for the attachment of the embryo to the mother’s uterus. After several
days, the cells in an embryo divide and form a blastocyst. At this stage, the embryo consists of a
trophoblast and an embryoblast. The trophoblast is an outer layer of ancillary cells which provide
nutrients and form the placenta. The embryoblast or the inner cell mass contains cells which are
capable of differentiating into all cell subtypes in a human body. Due to their potential to
differentiate, these cells are called as the Embryonic Stem Cells (ESCs) and they are very
valuable because they can help to restore any type of human cells.
In order to get ESCs, the blastocyst is destroyed and the inner cell mass is extracted. Thereafter,
the cell are cultivated to generate a stable cell line. The process of cultivating stem cells is rather
difficult and time intensive and often, additional cells are added into the medium to support the
growth of these ESCs. These additional cells can be of a xenogenic origin and thus, the clinical
usage of derived ESCs is limited because of a high risk of rejection. In order to get specifically
differentiated cells
(for example fibroblasts), the ESCs are placed into a special medium
containing chemicals which help the ESCs differentiate into the necessary cell type.
As ESCs are pluripotent i.e. they can transform into any type of human cells, they are promising
for clinical purposes. They can be transformed into cells such as cardiomyocytes, fibroblasts,
chondrocytes, hepatocytes, etc., paving way for treatment of diseases such as cardiovascular
diseases, diabetes, neurological diseases, etc. FDA approved the first clinical trial of ESCs in
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2009 for the treatment of spinal cord injury developed by Geron Corporation. Unfortunately, the
company had to stop the trial due to financial problems (Falco, 2009).
Although ESCs are promising, there are several technical and ethical issues related to the
development of stem cell therapies. As one has to destroy an embryo to retrieve ESCs, their
usage for research raises a number of ethical and legal problems. In some countries, stem cell
research using human embryos is forbidden. However now there is a way to get ESCs without
destruction of an embryo and it can help to solve such kind of problems. Earlier, xenogenic
components were used during the cultivation of ESCs, which could result in a rejection of the
induced stem cells and, at the same time was a risk for transmission of diseases from a foreign
animal source. However, it is now possible to generate ESCs without the use of xenogenic
elements. The third major problem associated with the use of ESCs is the development of tumors
in the patients, as not all the cells introduced into the body have been specifically differentiated
and the non-differentiated cells result in the formation of tumors. New methods of cultivation of
ESCs and clinical use of ESCs are underway and a breakthrough is expected in near future.
According to FundingTrends.org, the funding of projects using ESCs sharply increased since
2007 (http://www.fundingtrends.org/?keywords=embryonic+stem+cells ).
Chart 5: Funding* received by projects dealing with embryonic stem cells.
B. INDUCED PLURIPOTENT STEM CELLS (IPSCS)
Induced pluripotent stem cells are stem cells artificially derived from mature human cells by
inducing an overexpression of several specific genes. The possibility of transforming mature
somatic cells into stem cells was demonstrated by Shinya Yamanaka and his team in 2006 and
they managed to produce human iPSCs in 2007. In 2012 Shinya Yamanaka was awarded
the Nobel Prize in Physiology or Medicine for his discovery. iPSCs are produced from somatic
cells and it paves way for a novel method of deriving stem cells without destroying an embryo.
This method therefore doesn’t raise any ethical issues. Another important of iPSCs lies in the
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fact that they can be directly derived from a patient’s own cells and consequently the chances of
rejection after transplantation is unlikely.
The process of reprogramming of mature cells to derive iPSCs initially was reported using four
genes. It has now been shown that all the four genes may not be required for successful
reprogramming. This finding is extremely significant as some of the genes reported are
oncogenes and could cause cancer. There are several ways to start the transformation process
with each of the methods having its own advantages and disadvantages. First of all different
types of vectors can be used to deliver the genes for reprogramming. A vector delivers the
necessary genes into a cell and makes it transform into a stem cell. Some of delivered genes can
be oncogenes and that’s why usage of such iPSCs in clinic is dangerous. Moreover, some of the
vectors used (such as plasmids and retroviruses) can integrate into the human genome and result
in unpredictable mutations.
Another approach is to use microRNAs which are small RNA molecules with an ability to bind
to specific mRNA sequences, primarily at the 3’ end and thus regulate gene expression (Bao et
al, 2013) or proteins and small molecules (Science daily, 2009; Cyranoski, 2013). These methods
for reprogramming are relatively safer as there is no modification of the genome and as a result,
mutations are unlikely. Moreover, the efficacy of these methods can be similar or higher than
that reported for the other methods.
iPSCs have properties very similar to embryonic stem cells
(although there are some
differences). For example if one replaces the embryonic stem cells in a mouse embryo with
iPSCs, the embryo grows into a normal mouse. This implies that iPSCs can be used to derive
cells of a specific subtype i.e. for the treatment of cardiovascular diseases, diabetes, neurological
diseases and a number of other diseases with any type of damaged cells. The first clinical trial of
iPSCs was approved in Japan on 19 July 2013 (Cyranoski, 2013). The investigators shall be
transforming human cells from the skin into retinal pigment epithelial cells to be used for the
treatment of age-related macular degeneration. Although iPSCs hold a promise for the future of
regenerative medicine, there is a high risk of developing mutations and cancer with them. The
efficacy of reprogramming adult cells into iPSCs is rather low and the process of transformation
is rather difficult and can sometimes result in an incomplete
According to FundingTrends.org, funding of projects using iPSCs has dramatically increased
since the year 2007.
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Chart 6: Funding* volume index for induced pluripotent stem cells.
C. ADULT STEM CELLS (ASCS)
Adult stem cells (or somatic stem cells) are stem cells found in a juvenile or an adult human
body. These cells are multipotent with a capacity to differentiate into limited number of cell
types, rather than all types of human cells. Usually they differentiate into the cells of the same
germ layer. But sometimes they can transform into the cells of another germ layer. This
phenomenon is referred to as trans-differentiation or plasticity.
The function of ASCs in the body is to regenerate specific tissues (they regenerate the tissue
where they are presented). There are a classified into different types of ASCs i.e. hematopoietic
stem cells, umbilical cord blood stem cells, intestinal stem cells, mesenchymal stem cells, neural
stem cells, olfactory adult stem cells and others. Some are widely used in clinic while others are
at present being evaluated for safety and efficacy of usage. The most important types of adult
stem cells will be discussed in later sections.
Most ASCs are rare and therefore it is difficult to isolate them. Moreover, cultivating ASCs in
the laboratory has proven to be rather difficult. Another drawback is the method of obtaining
these stem cells often involves serious damage to the organs and tissues (for example isolation of
heart stem cells). It is possible to transplant ASCs from one individual to another but it is
obligatory to use immunosuppressive therapy in order to avoid rejection.
According to FundingTrends.org funding of projects using ASCs sharply increased since 2007.
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Chart 7: Funding* volume index for adult stem cells.
a. Mesenchymal stem cells
Mesenchymal stem cells (MSCs) were originally found in the bone marrow. Thereafter they
were also isolated from the fat tissue, muscle tissue and other places. However, there is no
evidence that the cells from other sources are similar to the cells from bone marrow.
Bone marrow is a source of several different cell types (amongst them are the hematopoietic
stem cells which shall be discussed later), but only 0.001-0.01% of them are MSCs, making their
isolation process time intensive and difficult.
MSCs from the bone marrow can differentiate only into three cell types i.e. adipocytes (fat),
chondrocytes (cartilages) and osteocytes (bones). Differentiation of MSCs into other cell types is
not validated or the derived cells are often non-functional.
MSCs can be used in treatment of local skeletal defects. They also have the potential to repair
cartilages. Another area where MSCs can be helpful is treatment of heart and blood vessels.
MSCs can induce neovascularization, which is the process of formation of new vessels. MSCs
themselves do not form new vessels but they activate the precursors of endothelial cells which
form the inner layer of all blood vessels. There are a number of early stage clinical trials
validating the ability of MSCs to induce neovascularization. There are also some reports
indicating that MSCs can be transplanted from one patient to another without any risk of
rejection and moreover it has been demonstrated that MSCs can be used as immunosuppressant.
All these reported studies are in the preliminary stages and require further evidence to prove the
efficacy of MSCs.
According to FundingTrends.org funding of projects using MSCs considerably increased since
2007.
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Chart 8: Funding* of projects on mesenchymal stem cells (MSCs)
b. Hematopoietic stem cells
Hematopoietic stem cells (HSCs) have the capacity to form all types of blood cells. The
population of hematopoietic stem cells contain different cells some of which are multipotent and
others are oligopotent and unipotent. The main source of hematopoietic stem cells is the bone
marrow. HSCs can be also harvested from umbilical cord blood, peripheral blood and amniotic
fluid. HSCs can be frozen and stored for years in special cryofreezers.
Hematopoietic stem cells are used for transplantation. This procedure often performed on
patients with cancer of blood or bone marrow. Before transplantation, radiation and
chemotherapy are used to destroy the immune system of a recipient (in order to avoid rejection)
and to kill malignant cells. The graft can be autologous or allogenic. In case of an autologous
graft, HSCs are collected from the patient before complete or partial destruction of his bone
marrow and then the transplantation is performed. The advantage of this method is a low risk of
rejection. But the risk of relapse (as the graft can contain malignant cells) rises. The allogenic
graft can be safer in some cases but is associated with issues such as the graft-versus-host disease
when the immune cells of the graft begin to attack donor’s tissues. It’s also difficult to find a
suitable donor with similar human leucocyte antigen (HLA). HLA is a molecule expressed on
cell surface (also referred to as the major histocompatibility complex MHC). HLA of the donor
and HLA of recipient should be similar in order to avoid immune conflict.
More than 50000 hematopoietic stem cell transplantations (HSCTs) are performed annually, of
which more than half are autologous and others are allogenic and the number of HSCTs
continues to increase at a rate of 10-20% every year (Perumbeti , 2013).
Although HSCTs are common, they are they have been associated with a risk of infection and
graft-versus-host disease. They are commonly used only for the treatment of life-threatening
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diseases such as leukemia. Improved outcomes have been attributed to better safety standards
and a reduction in the number of infections and other negative outcomes.
According to FundingTrends.org funding of projects using HSCs steadily grew since 1991 up to
2010.
Chart 9: Funding* for hematopoietic stem cells
c. Umbilical cord blood stem cells
Umbilical cord blood stem cells (UCBSC) are derived from the cord blood in the umbilical cord
and placenta after a baby is born. It can be easily collected with no risk to the baby or mother.
Cord blood contains hematopoietic stem cells along with other types of stem cells but additional
studies are required to confirm this finding.
Although the process of collecting an umbilical cord is rather easy, the amount of blood
harvested from the cord is small. Usually this amount is enough to threat a child but not enough
to threat an adult person. To solve this problem, it is possible harvest cells from two umbilical
cords or from the placenta. There is also an opportunity to cultivate UCBSCs in vitro.
Cord blood is used to treat with different types of blood cancer or with genetic blood diseases
like Fanconi anemia. About 20000 umbilical cord blood transplants have been performed until
2013 (Gupta, 2012). Several attempts to use UCBSCs in the treatment of other diseases have not
been successful. For example, a clinical trial studying cord blood treatment for diabetes failed to
show any improvements. At present, there is an active clinical trial exploring the benefits of
UCBSCs in the treatment of child brain disorders and traumatic brain injury but the results have
been controversial.
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Cord blood banks provide the facilities to freeze and store the umbilical cord blood over long
periods of time. There are two types of cord blood banks: public and private. Public cord blood
banks work for the benefit of the general public while the private cord blood banks are usually
profit-making organizations and cord blood stored in these banks is used exclusively by donor or
donor’s relatives. The benefits of private cord blood banks is a controversial issue because the
probability of using cord blood by the donor is too low. According to FundingTrends.org,
funding of projects using UCBSC reached a peak in 2009.
Chart 10: Funding* in the field of umbilical cord blood stem cells.
d. Amniotic stem cells
Amniotic stem cells are derived from the amniotic fluid. Amniotic fluid is a protective liquid
surrounding a fetus. Amniotic stem cells are primarily composed of mesenchymal stem cells
with a capacity to differentiate into various types of human cells.
Amniotic stem cells can be collected without destroying an embryo but there is a very little risk
of pregnancy loss. Overall, the use of amniotic stem cells has not been associated with any
ethical problems. Many banks now provide the facility to store amniotic stem cells.
According to FundingTrends.org funding of projects using amniotic stem cells reached a peak in
2009.
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Chart 11: Funding* for amniotic stem cells.
D. ARTIFICIAL CELLS (ACS)
Artificial cells are engineered constructs which mimic some cell functions and are non-living
entities. An example of an artificial cell is a liposome. Liposomes have a lipid membrane like
living cells and can be used to mimic cells and deliver molecules such as nucleic acids, proteins
and small molecules.
Chart 7: Funding* related to artificial cells.
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As the surface of these artificial cells lacks antigens, they can be useful where immunogenicity is
a problem the can help to avoid immune respond. For example it is possible to encapsulate stem
cells into artificial cells and use them as carriers. Artificial cells can also be used for transporting
different drugs and nucleic acids (DNA and RNA). According to FundingTrends.org funding of
projects using artificial cells reached a peak in 2008.
5. TISSUES
Tissue is the next level of organization of our body after cells. Every tissue consists of a group of
specialized cells and an extracellular matrix supporting these cells in a 3-dimensional structure.
Extracellular matrix is produced by the cells and plays a very important role providing cell
communication, nutrition and special mechanical features to the tissue. All tissues are classified
into four types, i.e. the connective tissue, the muscle tissue, the epithelial tissue and the nervous
tissue.
Regeneration of tissues is an important and challenging issue as one has to recover not only cells
but also the extracellular matrix. Today it is possible to regenerate bones, cartilages, skin,
muscles and other tissues. There are several approaches to tissue engineering which shall be
discussed in later sections.
According to FundingTrends.org funding of projects on tissue engineering considerable grew
since 2007.
Chart 8: Funding* in tissue engineering.
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A. WITH SCAFFOLD
The most popular technique used in tissue engineering is scaffold-based tissue regeneration.
There are three main components to this approach. The first one is a scaffold. Scaffold is defined
as a biologic, synthetic or semi-synthetic matrix with special mechanical properties and provides
a necessary microenvironment for cell growth and differentiation. The second component is the
stem cells and the third component is formed by different molecular induction factors which are
necessary for cell growth and differentiation.
The process of regeneration of any tissue consists of several stages.
1. Harvesting of stem cells from a donor. (It also can be induced pluripotent stem cells.)
2. Cultivating of the derived stem cells.
3. Combining of the scaffold, stem cells and induction factors.
4. Tissue organization.
5. Transplanting of the graft.
There are some modifications of this method. For example, tissue can be formed in vivo rather
than ex vivo. One can introduce a scaffold in the place where regeneration is required and treat it
with stem cells and induction factors. The tissue grows inside the body and the results of this
technique are very promising and probably will be widely used in future.
Chart 9: Funding* in the field of scaffolds.
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Another modification of scaffold-based method is 3D bioprinting. This technique utilizes special
3D printers to form the tissues from biomaterials and cells. At present, scientists are developing
3D bioprinting facilities aimed at printing whole organs rather than tissues.
According to FundingTrends.org funding of projects using scaffolds increased in 2007.
B. WITHOUT SCAFFOLD
There is an alternative method to 3D printing without the use of scaffolds. In this method, small
bio blocks are used as three-dimensional pixels. These blocks consist of different cells derived
from a donor and their composition can be precisely controlled. Once they are put together they
fuse to form a new tissue (Mironov et al, 2009).
6. ORGANS
Organ level is the next level of organization in the human body. Every organ consists of different
tissues and has a higher level of structural complexity than observed at a tissue level. Due to a
higher level of complexity in organization, regeneration of whole organs is a much more
complicated task than regeneration of tissues. There are a number of promising results on animal
experiments relating to tissue engineering of complete organs and this field is believed to
contribute to the growth of regenerative medicine in future.
A. KIDNEY
At present, there is no data on a complete lab-grown human kidney but scientists have attempted
to combine conventional renal filters with bioreactors seeded with renal cells. Renal epithelial
cells have the ability to provide metabolic, endocrine and immune functions and the renal filters
produce urine. Stem cells can have a significant role in compiling an artificial kidney as an
unlimited source of renal cells (Tasnim et al, 2010).
Animal experiments have also shown promising results in experiments attempting to create a
new kidney using decellularized kidneys from a xenogenic source or a donor (Yong, 2013). This
process encompasses the stripping of cells from a donor kidney using specialized detergents to
get a connective tissue scaffold. The decellularized scaffold is then seeded with human umbilical
cord blood stem cells (for the development of vessels) and with the kidney cells from newborn
rats. The transplant can grow in a special incubator and was shown to be functional after
transplantation, although not as efficiently as a normal kidney.
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B. LIVER
A lab-grown human liver has made considerable progress using decellularized scaffolds and
stem cells, as described in the previous section (Uygun & Yarmush, 2013). In a recent study,
scientists created a vascularized and functional human liver using iPSCs to derive specific
hepatic cells, human umbilical endothelial cells
(for development of vessels) and human
mesenchymal stem cells (for the development of connective tissue matrices). All these cells were
combined in a dish and they self-organized into macroscopic cell clusters. Upon transplantation,
these clusters were functional and showed good vascularization (Takebe et al, 2013).
C. BLADDER
Bio-engineered bladder has already been created and successfully transplanted using a
biodegradable scaffold and cells from the bladder and muscle cells to generate a new bladder
(Khamsi, 2006). However, there are several problems concerning the functionality of the
transplanted bladder that are currently being worked upon (Horst et al, 2013).
D. CARDIOVASCULAR SYSTEM
In successful rat experiments scientists used decellularized hearts as scaffolds (Maher, 2013). In
these experiments. In order to construct a new heart, one needs at least two types of cells. These
are endothelial precursor cells (for the development of vessels) and heart muscle precursor cells.
In the experiments these cells were derived from iPSCs. The engineered hearts were shown to be
functional but their efficacy was too low for a successful transplantation. At present, it is also
possible to construct blood vessels and heart valves using decellularized scaffolds.
E. SKIN
Tissue-engineered skin is already available and widely used in clinic, for example, for the
treatment of non-healing wounds. These transplants can mimic all layers of the skin or just one
of the layers, as desired. They can be cellular or acellular. Some of them are derived from
autologous sources while others are of allogenic or even xenogenic origin.
F. PANCREAS
Animal experiments on lab-grown pancreas are rather promising
(Science daily,
2012).
Researchers have succeeded in growing small functional parts of pancreas with the ability to
produce insulin after transplantation. They used special scaffolds and pancreatic cells from a
healthy donor. They also used umbilical cord blood cells for the development of vessels. It was
found from these studies that vascularization is a key to a successful transplantation of the
pancreatic tissue.
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G. TRACHEA
The first bio-engineered trachea has already been constructed and successfully transplanted. It
was performed by Paolo Macchiarini in 2008 using adult stem cells from bone marrow, which
were transformed into cartilage cells. A decellularized segment of a cadaveric trachea was used
as a scaffold in these experiments. In these experiments, the vascularization of the trachea was
observed one month after transplantation.
H. TEETH
Usage of stem cells for the regeneration of teeth is relatively new approach but currently there
are some advances in this field. For example, studies on animal models are being conducted in
order to understand the mechanism of the regeneration of teeth (Wu et al, 2013). Most likely, in
future this research would help the development of a translational therapy for humans. At
present, the most interesting experiments on teeth regeneration are aimed at using induced
pluripotent stem cells (iPSCs) (Cai et al, 2013). Usage of iPSCs is not connected with any ethical
issues and with problems of rejection, making the approach extremely attractive for many
investigators.
I. BONES AND CARTILAGES
Different types of grafts are already used in clinic. It can be allografts or autografts. Special
scaffolds and adult stem cells are used for these purposes. Nowadays scientists try to create the
whole bones using 3D bioprinters.
7. DISEASES
The main goal of regenerative medicine is to treat different diseases, some of some of which are
extremely severe and seriously affect patients’ life. An effective treatment of such diseases can
bring benefits not only to patients but also to global economics as it can seriously reduce
healthcare cost. According to the Alliance for regenerative medicine, healthcare cost in the USA
alone is expected to increase tremendously by 2030, especially for the elderly population. In this
chapter we highlight several important diseases and the role of regenerative medicine in their
treatment.
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A. CARDIOVASCULAR DISEASES
Cardiovascular diseases (CDVs) are diseases which affect cardiovascular system, including the
heart and blood vessels. The list of cardiovascular diseases includes coronary heart disease,
cerebrovascular disease, rheumatic heart disease and congenital heart diseases amongst many
others. According to World Health Organization, cardiovascular diseases are the leading cause of
death in the world and it is estimated that by the year 2030, more than 23 million people will die
of cardiovascular diseases annually
(http://www.who.int/cardiovascular_diseases/en/). Often
there are no symptoms associated with cardiovascular diseases until the occurrence of acute
events (for example a heart attack). After such events, patients need life-changing treatment such
as a surgical operation. After the treatment, a number of patients suffer from long-term
disabilities, loss of productivity and a low quality of life.
Regenerative medicine can bring a lot of benefits in treatment of cardiovascular diseases and
there are a number of products in the market catering to the branch of cardiovascular diseases.
Some available products:
1. Amorcyte (a NeoStem company) is an autologous bone marrow derived stem cell product
designed for the treatment of damaged heart tissue following acute myocardial infarction.
A Phase 2 clinical trial of the product has already begun.
2. The company VentriNova uses small molecules and gene therapy to induce heart cells
and to make them repair the damaged heart tissue. Their lead product, which targets the
Cyclin-A2 gene is currently in the preclinical stage of development.
According to Alliance for regenerative medicine, total inpatient hospital costs in the USA for
CDVs care were
$71.2 billion in
2005. Overall medical costs, which include medical
interventions, healthcare services, medications and lost productivity of the patients was reported
to be $ 316 billion (http://alliancerm.org/disease/cardiovascular-and-regenerative-medicine ).
B. CANCER
Cancer is comprises of a large group of diseases which are characterized by an uncontrollable
cell growth. They invade and damage nearby tissues and can spread or metastasize to distant
parts of the body forming secondary tumors. According to World Health Organization cancer is
the third cause of death in the world.
Transplantation of hematopoietic stem cells is widely used in clinic for the treatment of blood
cancer. Scientists also try to use adult stem cells for the regeneration of lost tissue after a surgical
resection of tumor. There are also a large number of gene therapies at a preclinical or clinical
testing stage for different types of cancers.
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Cancer is associated with huge economic burden to the society. According to the American
Cancer Society in the USA, overall annual costs of cancer were $201.5 billion in the year 2008.
Direct medical costs were estimated to be $77.4 billion and indirect costs (cost of loss in
productivity because of premature death) were $ 124 billion.
C. BLOOD DISEASES
Blood diseases include different types of anemia, cytopenias, coagulopathies and other
associated diseases of the blood. Regenerative medicine has a huge potential in the treatment of
different blood diseases as all blood cell types originate from a dingle progenitor, the pluripotent
hematopoietic stem cell. These cells have been widely used in clinic. For example, bone marrow
transplantation is used for the treatment of several forms of anemia.
D. WOUNDS
Application of regenerative medicine for wound healing forms a large part of the regenerative
medicine industry. Non-healing wounds are a focus of attention in the regenerative medicine as
these wounds do not undergo the normal healing process. They can be caused by burns or are
associated with the presence of other medical conditions such as diabetes. Conventional methods
for the treatment of such wounds are often ineffective and regenerative medicine can bring
considerable benefits.
Some available products:
1. Organogenesis has developed a cellular product which is called Apligraf. It is a bi-
layered graft composed of a layer of mature keratinocytes and a layer of fibroblasts in a
collagen matrix. The efficacy of Apligraf has been proven and in 2012 the company sold
more than 500000 units.
2. Avita Medical has developed a product which is called ReCell Spray-On Skin. It is an
autologous cell technology where the product can be sprayed onto a wound. This product
is proven to accelerate the healing process and minimize scar formation. It is already
available in Europe, Canada and Australia.
According to Alliance for regenerative medicine in the USA, the annual costs associated with the
treatment of non-healing wounds is about $35 billion, which is expected to increase to $200
billion by 2020.
E. REPRODUCTIVE SYSTEM DISEASES
Stem cell therapy has a huge potential in the reproductive medicine as it was discovered that
ovaries contain stem cells, which can differentiate into new oocytes. Previously it was believed
that ovaries contain a limited number of oocytes. Extraction and cultivation of ovarian stem cells
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can be used for the treatment of infertility and there have also been attempts to use bone marrow
derived stem cells for the regeneration of endometrium (Duke & Taylor, 2013).
F. NEUROLOGICAL DISEASES
Neurological diseases encompass diseases which affect various parts of nervous system. Often
these diseases are hard-to-cure and very expensive for the health care system. The list of
neurological diseases includes Alzheimer’s disease, Parkinson’s disease, spinal cord injuries etc.
Regenerative medicine could significantly improve the life of the patients suffering from
neurological diseases.
Alzheimer’s disease (AD) is the most common disease associated with the loss of memory and
intellectual abilities. The majority of patients are above 65 years of age. Scientists have managed
to create a human disease model of AD using reprogrammed donor cells. This model could help
to find clues for the treatment of this disease. According to the Alliance for regenerative
medicine in the USA, annual costs associated with providing care for people with AD are about
$200 billion and these costs are expected to increase to $1.1 trillion by 2050.
Parkinson’s disease (PD) is a neurodegenerative disease associated with the degeneration and
death of neurons. Patients with PD suffer from tremors, poor balance and loss of movement
control. Although this disease is not lethal, it seriously affects the quality of life of the patients
and their families. Scientists succeeded in constructing a model of PD and now they are trying to
use regenerative technologies to replace the dying neurons and to improve the tropism of healthy
neurons. According to the Alliance for regenerative medicine in the USA, annual combined
direct and indirect costs associated with PD are about $23 billion.
Spinal cord injuries often lead to quadriplegia or paraplegia and have a strong negative impact on
the life of the patients. At present, there are several commercial products which could help in
treatment of spinal cord injuries. Some of them are based on the use of stem cells, which can
differentiate into the cells of nervous system; others use special scaffolds to provide appropriate
conditions for the regeneration of spinal cord. According to the Alliance for regenerative
medicine in the USA, annual costs for the treatment of one patient after a spinal cord injury is
more than $320,000 for the first year after the injury and more than $39,000 for subsequent
years.
G. OCULAR DISEASES
Ocular diseases are affect human vision system and include diseases such as age-related macular
degeneration (AMD), cataracts and glaucoma amongst others. Some of these diseases can be
treated by conventional methods but regenerative medicine can bring a lot of benefits into this
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field. There are a number of promising animal experiments which can lead to treatment of the
diseases which cannot be treated now.
Some available products:
1. Advanced Cell Technology has developed a treatment of degenerative retinal disease.
This technology uses retinal pigment epithelial cells derived from human embryonic stem
cells.
2. StemCells Inc. has developed a product which can preserve the visual acuity and protect
the retina from progressive degeneration in rats. This product uses neural stem cells.
Phase 1/2 of clinical trials of this product began in 2012.
According to Alliance for regenerative medicine in the USA annual cost of care for patients
suffering from different ocular diseases is about $51.4 billion.
H. GASTROINTESTINAL DISEASES
A number of regenerative technologies are aimed at the treatment of different parts of digestive
tract. Some of them are associated with the regeneration of large parts of our gastrointestinal
system such as the liver and the pancreas. Others are targeted towards the treatment of different
intestinal diseases such as Familial Adenomatous Polyposis (FAP) and Crohn’s disease.
I. URINARY SYSTEM DISEASES
There has been some research on technologies for regeneration of different parts of the urinary
system. For example, scientists have already succeeded in the synthesis and transplantation of
bio-engineered bladder
(Khamsi,
2006). Presently, there are several companies aimed at
treatment of urological diseases. For instance, the company Tengion has a technology for the
treatment of the patients after removal of bladder. They have also developed a stem cell
technology
for
augmenting
and
repairing
the
kidneys
(http://www.tengion.com/pipeline/kidneys.cfm ).
J. MUSCULAR AND SKELETAL DISORDERS AND INJURIES
Musculoskeletal disorders (MSDs) result from injuries of joints, tendons, bones, cartilages and
muscles. They are generally a result of a sudden trauma or by the action of various prolonged
physical factors. Common symptoms of MSDs are pain, inflammation and stiffness. The list of
MSDs includes such diseases as arthritis, tendonitis, bursitis etc. According to Centers for
Disease Control and prevention In the USA more than 20 million people suffer from arthritis.
Some available products for musculoskeletal disorders include:
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1. The company Mesoblast has developed a treatment for degenerative disc disease using
mesenchymal precursor cells. The company is currently testing its technology in clinic.
2. MiMedix Group, Inc. has developed a product which act as a scaffold assisting the body
in the generation of new tissue. Unfortunately, this product has not yet been approved in
the USA.
According to Alliance for regenerative medicine in the USA annual healthcare costs of MSDs
are about $850 billion.
K. DIABETES
Diabetes is a group of metabolic diseases in which a patient suffers from high blood sugar levels
accompanied with several secondary factors. It is a chronic condition which can lead to many
different complications. For example, it can lead to cardiovascular problems, nerve damage,
kidney failure, blindness and diabetic ulcers.
Diabetes is classified into two types:
Type 1 (or insulin-dependent) diabetes is caused by insufficient insulin production resulting in
elevated levels of blood glucose. Insulin is a hormone which regulates the level of glucose in the
blood and is produced by special cells in pancreas. If a patient has type 1 diabetes, these cells are
attacked by patient's immune system and as a result are non-functional. A decrease in the number
of insulin producing cells results in insufficient production of insulin, resulting in increased
levels of blood glucose. Currently this type of diabetes is treated by injections of insulin.
Type 2 (or noninsulin-dependent) diabetes is characterized by insulin resistance and relative
insulin deficiency. Type 2 diabetes is treated by injecting insulin and by some other medications.
Balanced diet and regular exercise have been shown to have a positive impact in alleviating this
condition.
Regenerative medicine can offer a more radical treatment of diabetes. Some technologies are
aimed at the regeneration of insulin producing cells while others try to mediate immune system
and prevent its attack on the insulin producing pancreatic cells. Gene therapy can also be helpful
in the treatment of diabetes.
Some available products targeting diabetes include:
1. Athersys Inc. has launched preclinical trial of their product which is called MultiStem.
This product should mediate the immune system and protect pancreatic cells.
2. Mesoblast has developed a product derived from mesenchymal progenitor cells. This
product can be helpful in both type 1 and type 2 diabetes. Mesoblast is currently in Phase
2 clinical trial of their product.
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According to the Alliance for regenerative medicine in the USA, annual costs of caring for
patients suffering from diabetes was more than $174 billion in 2007 and is expected to increase
to $336 billion by 2034.
L. IMMUNOLOGICAL DISEASES
The list of immunological diseases is huge and includes several autoimmune disorders, host
versus graft disease etc. Autoimmune disorders are conditions when immune system begin to
attack healthy tissues and destroy them, resulting in an inflammatory response. Usually, the
immune system attacks the connective tissues, blood vessels, joints, muscles and endocrine
glands. The list of autoimmune disorders includes lupus, rheumatoid arthritis, thyroiditis, type 1
diabetes amongst many others. The causes of autoimmune disorders are unknown. There are
some technologies using stem cells which can prevent such conditions.
Some available products:
1) Celgene has developed a product aimed at treatment of different autoimmune disorders.
Placenta-derived stem cells are used in this technology. The company has already
launched a Phase 2 clinical trials of their product for the treatment of Crohn’s disease and
rheumatoid arthritis. They also plan Phase 1 clinical trials for their products targeting
multiple sclerosis and sarcoidosis.
2) Tigenix has two products derived from the adipose tissue stem cells, which are designed
for the treatment of autoimmune disorders. The first product Cx601 is for the treatment of
Crohn’s disease. This product is currently in the Phase 3 trial. The second product Cx611
is targeted for the treatment of rheumatoid arthritis and is in Phase 2 trial.
According to the Alliance for regenerative medicine in the USA, annual direct costs for
treatment of autoimmune disorders are about $100 billion.
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EXAMPLES OF ANALYTICS USING ARMIF
1. BIOTIME, INC.
Ticker symbol: BTX
Year of foundation: 1990
Address: 1301 Harbor Bay Parkway, Suite 100, Alameda, CA 94502, United States
Phone number: (510) 521-3390
Fax number: (510) 521-3389
Web-site: http://www.biotimeinc.com/
Profile: BioTime is an internationally operating biotechnology company focused on the
emerging field of regenerative medicine. Leading products of BioTime include blood plasma
volume expander Hextend, PureStem™ cell lines, HyStem® hydrogels, culture media, and
differentiation kits. Through its specialized subsidiaries, the company develops and markets
products based on human embryonic stem cell and induced pluripotent stem cell technology.
BioTime’s subsidiary Cell Cure Neurosciences Ltd. is involved with the development of
products derived from stem cells for the treatment of retinal and neural degenerative diseases.
OrthoCyte Corporation is a BioTime subsidiary, developing stem cells based therapeutic
solutions to treat orthopedic diseases and injuries. Another subsidiary, OncoCyte Corporation,
focuses on the diagnostic and therapeutic applications of stem cell technology in cancer and
includes the diagnostic product PanC-Dx™, currently being developed for the detection of
cancer in blood samples. One of the major BioTime subsidiary ReCyte Therapeutics, Inc. is
developing products based on induced pluripotent stem cell technology to reverse the
developmental aging of human cells and to treat cardiovascular and blood cell diseases. ReCyte
Therapeutics owns the license to use ACTCellerate technology developed by Advanced Cell
Technology, Inc. (ACT) to produce and market its human embryonic progenitor cells (hEPCs),
called PureStem cell lines. Commercial distribution of PureStem hEPCs is realized through
LifeMap Sciences, Inc. (LifeMap Sciences). LifeMap Sciences, Inc. also markets GeneCards, the
leading human gene database and MalaCards, the human disease database. Another subsidiary,
ES Cell International Pte. Ltd
(ESI), has develops and markets hES cell lines. ESI has
agreements the California Institute of Regenerative Medicine (CIRM) and the University of
California to distribute its hES cell lines to research institutes in California. In September 2012,
BioTime established Asterias Biotherapeutics, Inc. (formerly known as BioTime Acquisition
Corporation (“BAC”)), a subsidiary created to acquire the stem cell assets of Geron Corporation
(NASDAQ: GERN). In October and November 2012, Asterias Biotherapeutics, Inc. approached
Geron with two consecutive proposals. And in July 2013, Asterias Biotherapeutics, Inc. entered
into a definitive Asset Contribution Agreement with Geron to acquire the intellectual property,
including over
400 hES-related patents and patent applications; biological materials and
reagents; lab equipment, and other assets related to Geron’s human embryonic stem (hES) cell
programs, including the Phase I clinical trial of human embryonic stem (hES) cell-derived
oligodendrocytes in patients with acute spinal cord injury, and an autologous cellular
immunotherapy program and the Phase II trial of the therapy in acute myeloid leukemia (as well
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as the related INDs for both). Geron will own 21.4% of Asterias Biotherapeutics, Inc. (BioTime
owns the majority, 71.6%, and a private investor the rest) will receive a 4% royalty. Separately
BioTime is contributing to Asterias Biotherapeutics, Inc. $5mm in cash, 8.9mm of its common
stock (valued at $30mm), five-year warrants to buy 8mm shares for $5, rights to use certain
clinical-grade hES cell lines, a nonexclusive global sublicense on stem cell differentiation
patents, and minority stakes, 10% and 6%, in two of its subsidiaries OrthoCyte and Cell Cure
Neurosciences, respectively. Asterias Biotherapeutics, Inc. also received $5mm from the private
investor.
The company has a commercial license and option agreement with Wisconsin Alumni Research
Foundation (WARF) to use 140 patents and patent pending technology belonging to WARF, as
well as certain stem cell materials. The company also has a license agreement with Cornell
University for the worldwide development and commercialization of technology developed at
Weill Cornell Medical College for the differentiation of hES cells into vascular endothelial cells.
At the moment, the company owns or licenses more than 400 US patents and US patent
applications.
The major customers of BioTime, Inc. are Hospira, Inc.; CJ CheilJedang Corp.; and Summit
Pharmaceuticals International Corporation.
Top management:
Michael D West, PhD, Pres. & CEO
Robert W Peabody, SVP, COO & CFO
Hal Sternberg, PhD, VP, Research
William. P. Tew, PhD, VP, Bus. Dev. & Chief Commercial Officer
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Company's ARMIF
Source: Yahoo Finance (http://biz.yahoo.com/e/130809/btx10-q.html)
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2. OSIRIS THERAPEUTICS, INC.
Ticker symbol: OSIR
Year of foundation: 1990
Address: 7015 Albert Einstein Drive, Columbia, MD 21046-1707, United States
Phone number: (510) 521-3390
Fax number: (510) 521-3389
Web-site: http://www.osiris.com/
Profile:
Osiris Therapeutics is a biotechnology company that develops and commercializes products to
treat medical conditions in inflammatory, cardiovascular, orthopedic and wound healing markets.
Osiris operates in two main segments: therapeutics and biosurgery. The therapeutics segment
offers biologic stem cell drug candidates from bone marrow derived MSCs. Osiris Therapeutics
was the first company to receive marketing clearance for its stem cell drug Prochymal for the
treatment of acute graft-vs.-host disease (GvHD) in children. It was the world’s first regulatory
approval of a manufactured stem cell product and the first therapy approved for GvHD. Osiris
partnered with the Juvenile Diabetes Research Foundation (JDRF) for the development of
Prochymal as a treatment for patients with newly diagnosed type 1 diabetes mellitus. And also
company joined JCR Pharmaceutical Corporation to produce and market Prochymal in Japan.
Another product in the therapeutic segment is called Chondrogen and aimed at osteoarthritis and
cartilage protection.
Biosurgery segment develops, manufactures and markets products orthopedic, wound healing,
and surgical procedures. Three-dimensional cellular repair matrix Grafix was developed for the
treatment of acute and chronic wounds, including diabetic foot ulcers and burns. It demonstrated
a very high efficacy in the recent multicenter, randomized, controlled clinical trial comparing the
safety and effectiveness of Grafix to standard of care in patients with chronic diabetic foot ulcers.
Another product manufactured in this segment, named Ovation, is a cellular repair matrix
designed for bone repair. In October 2013, Mesoblast LTD acquired Osiris' culture-expanded
mesenchymal stem cell (ceMSC) business, including Prochymal, in a transaction worth up to
$100mm in initial consideration and milestone payments. Additionally, Osiris will receive
royalty payments on sales of Prochymal and other products utilizing the acquired ceMSC
technology.
At the moment Osiris has an extensive intellectual property portfolio, including 162 foreign
patents, 45 issued U.S. patents and 13 filed U.S. patent applications.
Top management.
C. Randal Mills, PhD, Pres. & CEO
Philip R Jacoby, CFO
Michelle LeRoux Williams, PhD, CSO
Lode Debrabandere, PhD, COO
Stephen W Potter, SVP, Ops. & Corp. Dev.
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Company's ARMIF
Source: Yahoo Finance (http://finance.yahoo.com/q?s=OSIR)
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3. STRATATECH, INC.
Ticker symbol: private
Year of foundation: 2000
Address: 505 South Rosa Road, Suite 169, Madison, WI 53719, United States
Phone: (608) 441-2750
Fax: (608) 441-2757
Web-site: www.stratatechcorp.com
Profile:
The company is using this progenitor cell line to create a portfolio of therapeutic skin substitutes
to treat severe burns, non-healing ulcers, and other complex skin defects, as well as create novel
three dimensional cellular models that researchers can use as an alternative to animal testing to
evaluate the effects of new chemicals and compounds on human skin. The company was founded
in 2000 to commercialize the discovery of NIKS cells - a human keratinocyte cell line that
produces living tissue nearly identical to native human skin-made at the University of
Wisconsin-Madison. Its proprietary product StrataGraft tissue, is a viable, full-thickness human
skin substitute being developed as a treatment for severe burns and other complex skin defects.
In June
2012, StrataGraft was designated an orphan drug by the U.S. Food and Drug
Administration for the treatment of partial and full thickness skin burns. In January 2013, the
Company has successfully finished proof-of-concept clinical trial of StrataGraft in severe burns.
And in July 2013, Stratatech was awarded a contract valued at up to $47.2 million by the U.S.
Department of Health and Human Service’s Biomedical Advanced Research and Development
Authority (BARDA) for the advanced clinical and manufacturing development of StrataGraft
skin tissue.
The company is also developing another class of products called ExpressGraft, which is
genetically enhanced tissues that produce elevated levels of natural wound healing and anti-
microbial factors. Clinical development for ExpressGraft products will focus on large,
underserved markets in chronic, non-healing ulcers, including diabetic foot ulcers, venous leg
ulcers and sclerotic digital ulcers. It is anticipated that the ExpressGraft antimicrobial product
will enter a Phase I clinical study in diabetic foot ulcers in late 2013.
Company’s intellectual property portfolio comprises nearly 50 US and international patents and
patent applications.
Top management:
B. Lynn Allen-Hoffmann, PhD, CEO & CSO
Russell R. Smestad, President
Robert T. Barnard, CPA, VP & Treasurer
Allen R. Comer, PhD, Director, R&D
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Company's ARMIF
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