The Application of Nanotechnology to Regenerative Medicine

The Application of
Nanotechnology to
Regenerative Medicine
Heather Goodwin

2
Background
The field of regenerative medicine aims to restore, repair, or replace damaged tissues and
organs through in vivo and ex vitro approaches1
. Unlike most medical disciplines,
regenerative medical therapies target the source of disease, rather than just symptoms
alone. Even though organ transplants and artificial implants are regenerative therapies
much focus has been shifted to stem cell therapy and tissue engineering as a result of
technology advancements2
. These therapies give patients the opportunity to heal and not
just manage the pain or discomfort associated with their disease or disorder.
Embryonic stem cells are of particular interest in the field of regenerative
medicine because they possess unlimited proliferation and unrestricted differentiation
potential3
. Physical and chemical methods can be utilized to direct cell differentiation
into a wide variety of cell types, such as such as bone, immune, cartilage, blood, cardiac,
skeletal, and neural cells4
. In contrast, adult stem cells are less useful because they are
available in minimal quantities and only possess the abilities to create new cells in the
tissues in which they reside. In order for adult, or tissue-specific stem cells, to hold the
same differential potential they must be genetically altered to better resemble an
embryonic cell5
. The use of stem cells would allow for the treatment of any disease
caused from tissue malfunction, damage, or failure because they are capable of self-
renewal and differentiation into any needed cell type.
Figure 1: Process of stem cell differentiation6
.

3
As a result of the ethical implications of steam cell research, the majority of
research and product development in regenerative medicine is based on tissue
engineering. In tissue engineering, healthy cells are isolated from a patient and embedded
into a three-dimensional structure known as a scaffold7
. The scaffold may be composed
of natural or synthetic materials, as long as it is biodegradable, biocompatible, and tissue-
specific. The scaffold, which may also contain growth factors, is placed into a chemical
media that resembles the in vivo environment. The use of bioreactors, such as pH,
temperature, oxygen levels, and mechanical forces are controlled in order to further assist
cell growth. The scaffold is then implanted into the body for the purpose of
reconstruction8
. The native cells have been used successfully in joint replacement,
construction of artificial ligaments and tendons, and bone, heart, and wound repair9
.
Figure 2: Process of tissue engineering10
Regardless of the advances in regenerative medicine, it is often difficult to fully
integrate tissues, especially with enough mechanical support11
. However, the introduction
of nanotechnology has resulted in numerous advances in regenerative medicine.
Conventional therapies and early regeneration approaches often utilize biomaterials with
large surface features, often on the micron scale12
. The issue is that most surfaces and
processes on natural tissues function on the nanoscale. Even though the typical cell is
approximately 10 μm in diameter, the cellular components and proteins are much smaller,
often only 5 nm in diameter13
. The use of nanotechnology and nanoparticles in medicine

4
allows for better assess to small cellular components that may be responsible for
dysfunction and disease.
Medical Need:
The most obvious benefit of regenerative medicine is its wide application to a
variety of diseases and disorders. Some areas of clinical application involving
regenerative medicine techniques include skin replacement for burn victims and
diabetics, bone and cartilage regenerations, bladder repair, repair of heart muscle
following myocardial infarction, restoration of the spinal cord or peripheral nerve
following injury, the regeneration of pancreatic tissue to produce insulin in diabetics, and
preventing tissue deterioration following an injury, burn, or stroke14
. Other areas of
research include improving the biocompatibility between tissues and medical devices,
improving the duration of implant materials with the body, and increasing the interaction
between cells and topography of coatings and surfaces15
.
The increase in life expectancy in many countries has resulted in an increased
incidence of chronic diseases, such as, cancer, renal failure, osteoporosis, cardiovascular
disease, diabetes, and degenerative diseases. According to the Center for Disease Control,
seven out of ten deaths among Americans are a result of chronic disease16
, such as those
listed above. Furthermore, arthritis and osteoporosis leaves nearly nineteen million
Americans disabled and diabetes is the leading cause of kidney failure, amputations, and
blindness among Americans aged 20 to 7417
. Even more surprising, one out of two
Americans was diagnosed with at lease one chronic illness in 200518
. It is estimated that
there will be a 6% increase, or 32 million more, Americans living over the age of 65 by
203019
. With this shift in demographics in the United States, an increase in chronic
disease cases is inevitable.
Even though chronic diseases are often untreatable or difficult to treat numerous
in vivo approaches within the field of regenerative medicine have successfully stimulated
the required healing processes. One benefit of regenerative medicine is the ability to
repair and restore dysfunctional tissues in order to avoid organ transplants20
. The
potential to treat the underlying cause of a disease, rather than the symptoms, would
provide an enormous benefit to Americans. This would not only reduce death rates
among individuals with chronic illness, but also cut healthcare costs significantly.
The American Heart Association recently reported that that treatment related to
heart disease is responsible for 17% of the national healthcare expenditure21
. The
associated estimated that with an increased incidence the cost of heart disease is projected
to increase from $237 billion in 2010 to $818 billion in 203022
. In addition, medical
treatment cost for heart failure and stroke are expected to increase by approximately
238% within the next 20 years23
. In the United States alone, medical cost for late-stage
Parkinson’s disease, spinal cord injuries, heart failure, stroke, and diabetes was
approximately $250 billion in 201024
. The total healthcare cost during 2010 exceeded
$2.6 trillion25
, using 17.6% of the United States’ gross domestic product26
. Medical
techniques that are focused on cure and not symptom management are crucial to cutting
healthcare costs and saving lives.

5
Figure 3: Estimates for healthcare costs as a result of shifting demographics27
For diseases where the organ is beyond repair, the ability to grow organ and
tissues for transplantation and implantation through ex vitro approaches has also provided
additional benefits to patients waiting for organ transplants or compatible donors. The use
of a patient’s own cells, as in tissue engineering, provides other added benefits, such as a
lowered risk of immune responses, tissue rejection, and infection28
. Another serious issue
in cellular therapies and organ transplantation is a lack of donors for patients awaiting
organs. It was reported that over 110,000 people in the United States were placed on the
organ donation waiting list in 2011, with an average death rate of 18 people per day29
.
The field of regenerative medicine has demonstrated potential for creating compatible
artificial organs and cells, reducing the need for organ donors.
Because the biological processes operate on the nanoscale level, nanotechnology
has obvious benefits for restoration and repair. Much of the failure experienced in the
medical field may be a result of using micron-sized products to impact processes that are
on a nanoscale. Nanotechnology advancements may allow medical professions to better
treat disease and more effectively repair and restore normal function.

6
FDA Approved Regenerative Medicine Products:
There are currently 55 approved regenerative products available to consumers on
the market. While these products cover a wide variety of diseases, 14 of the top 15
regenerative products, are products designed for skin repair and regeneration30
. Since the
introduction of the first regenerative product, Apligraf®, to the market in 1998 over
500,000 patients have received some form of regenerative therapy31
. Figure 4
demonstrates the application of commercially available regenerative products to different
branches of medicine.
Figure 4: Application of regenerative medicine products to different medical
disciplines32
.
In 1998, the FDA approved Apligraf®, making it the first commercially available
regenerative product on the market. It was first approved for the treatment of venous leg
ulcers, but the approval later expanded to include diabetic foot ulcers as well33
. Apligraf®
is a bi-layered, cell-based product that is created from cells found in healthy human
skin34
. The lower dermal layer is a combination of type 1 collagen, common skin cell
proteins, and human fibroblasts35
, which assist in the natural healing process. The upper
layer is formed through the multiplication and differentiation of keratinocytes. This layer
is composed of protective skin cells and resembles the structure of human epidermis36
.
While the exact therapeutic mechanism is not completely understood, the therapy does
produce cytokines and growth factors found in healthy skin37
. The comparison of
Apligraf® and human skin are shown in figure 5. It is a circular disc, approximately 75
mm in diameter, which is placed directly on venous leg and diabetic foot ulcers to assist
in the natural healing process38
. A non-adhesive dressing is applied before final wrapping
is performed. Apligraf® typically dissolves into wounds, turning into a gel-like substance
until healing is complete39
. Organogenesis, the developers of Apligraf®, just reported a
revenue exceeding $100 million in 2011, demonstrating the potential commercial success
for regenerative products40
.

7
Figure 5. The comparison of Aligraf® and healthy human skin41
.
More recently, in 2012, the FDA approved a cell-based therapy for the treatment
of metastatic hormone-refractory prostate cancer. Provenge® is developed by isolating
white blood cells from the patient in need and incubating them with a prostatic acid
phosphatase (PAP) and GM-CSF fusion protein42
. This protein functions as a prostate
cancer-associated antigen, which ultimately stimulates the patient’s immune system to
find and destroy prostate cancer cells43
. After successful incubation the mixture is
shipped back to the medical center, where it is administered to the patient44
. The
treatment process usually requires six appointments, all of which can be completed in one
month’s time45
. An article, released in early 2011, estimated that sales of Provenge®
would reach over $1 billion dollars in the United States alone46
.
Other companies have utilized regenerative therapies solely for cosmetic reasons.
In June of 2011, Fibrocell, Inc. became the first company to develop a personalized
cellular therapy strictly for aesthetic use. Their product, Laviv®, received FDA approval
for the treatment of moderate and severe nasolabial fold wrinkles, or “smile lines47
.” The
company eventually hopes to expand this approval to include acne and burn scars. To
develop the product, a person’s fibroblasts are extracted from a small skin sample behind
the ear. Fibroblasts in human skin are responsible for the production of collagen, which in
turn gives the tone and structure of young, healthy skin48
. As a person ages, the number
of fibroblast capable of collagen production decreases, resulting in lost skin tone.
Laboratory techniques involving antibiotics, bovine serum, and dimethyl sulfoxide
eventually result in the multiplication of the fibroblasts into millions of copies49
. The
product is then shipped back to the medical center and injected into the nasolabial folds
of the patient. It is typically administered in three treatments, where injections are
administered six weeks apart50
. The CEO of Fibrocell, David Pernock, predicts that the
sales from Laviv will exceed $500 million within the next few years51
.
Avance Nerve Graft®, produced and manufactured by AxoGen, Inc., is a therapy
used for the reconstruction of peripheral nerve gaps. The allograft is produced after
decellularizing the extracellular matrix of a donor’s peripheral nerve52
. The decellularized
extracellular matrix is then implanted into a patient at the site of injury. The scaffold has
successfully provided the structural support for axonal regeneration in 3,000 patients53
.

8
DentoGen® is one of the FDA-approved regenerative medicine products that
utilizes nanotechnology. The product is developed by OrthoGen and is approved for bone
grafting in dentistry. The company explains that the long-term success of dental implants
is dependent on the presences of vital bone54
. Bone grafting products commonly used in
dentistry are only successful in grafting dead and non-vital bones55
. DentoGen® is
manufactured by converting microcrystalline calcium sulfate into nano-sized grains of
calcium sulfate56
, which is biocompatible, biodegradable, non-toxic, and
osteoconductive57
. The calcium sulfate in implanted into the body, where it dissolves into
calcium and sulfate ions. The calcium ions then combine with phosphate to form calcium
phosphate, which is vital to bone growth. The calcium sulfate also degrades once
implanted as a result of the decrease in local pH. This results in demineralization of the
defective bone, causing the release of bone growth factors, such as bone morphogenetic
protein-2 (BMP-2), BMP-7, TGF-ß, AND PDGF-BB58
.
Other examples of leading commercial cell therapy products are shown below in
figure 6. These products helped contribute to global revenue that reached $55.9 billion in
201059
. It is important to note that none of these regenerative medicine products utilize a
nano-based approach, but there are many products in development or waiting FDA
approval60
.
Figure 6: List of leading commercial cell therapies for regenerative medicine61
.

9
Current Developments:
Regenerative medicine is a rapidly growing medical discipline, which is estimated
to include nearly 700 hundred multinational corporations and smaller organizations62
.
The Alliance for Regenerative Medicine revealed that at the conclusion of 2012, more
than 17,000 patients were enrolled in clinical trials being tested by nearly 250
companies63
. These clinical trials, which are all in different stages, may have a strong
impact on a variety of diseases and disorders, as demonstrated by figure 6. Experts
estimate the addition of tissue engineering and new regenerative products will reach
$40.4 billion by 201664
. The expected revenue is shown in figure 7.
Figure 6: Percentage of clinical regenerative products in the different stages of
clinical testing65
.

10
Figure 7: Estimated revenue for new tissue engineering and regenerative products66
.
There have been numerous advances and accomplishments in regenerative
medicine with the past few years. In January 2012, Advanced Cell Technology, Inc.
released and published Phase I and Phase II data that demonstrated the safety and
efficacy of human embryonic steam cells for the treatment of Stargardt’s macular
dystrophy and dry age-related macular degeneration67
. While this study only enrolled two
patients, both showed significant improvement in vision that extended for over four
months68
.
During the same month, Sangamo BioScience, Inc. began two new phase II
clinical trials for a regenerative treatment that they believe will be the “functional cure”
for HIV and AIDs. The company has used zinc finger nuclease technology to disrupt the
coding of CC5, which is used for HIV entry into the cells, by interfering with the DNA
encoding sequence69
. Sangamo’s approach has resulted in the production of T-cells that
are resistant to HIV infections. The company has just received a $14.5 million CIRM
Disease research grant to continue efforts with their regenerative approach70
.
In February of 2012, Baxter International, Inc. began phase III trials for the
regenerative treatment of chronic myocardial ischemia. This disease is characterized by
reduced blood flow to cardiac muscle due to a blockage in one or more heart arteries71
.
Baxter is using a patient’s own CD34+ stem cells, which have demonstrated potential to
reduce angina and amputation rates in patients, while improving exercise time in patients
and inducing vascularization in other clinical trials72
. This study, which currently has
450 enrolled patients73
, hopes to demonstrate the safety and efficacy of this regenerative
treatment for FDA approval.

11
Even more recently, Harvard Bioscience, Inc. announced that their biomarker and
scaffolding was utilized in the second successful transplantation of a synthetic tissue-
engineered windpipe. The windpipe was grown after isolation of the patient’s own cells74
.
As for the use of nanotechnology in the field of regenerative medicine, most
nanoparticles are being assessed for their use in bone regeneration, skin regeneration,
bladder reconstruction, cell encapsulation, and cardiac function restoration75
. In studies
performed between 2004 and 2008, researchers were able to demonstrate that nano-
materials were more effective in producing osteoblasts, or bone-forming cells when
compared to conventional orthopedic implants. These studies showed that nanoparticles,
such as nano-hydroxyapatite, electro-spun silk, and anodized titanium had a larger
surface energy when compared to the most commonly used products on the market. The
increase surface energy resulted in a lager adsorption of proteins, such as vitonectin,
fibronectin, and collagen, which are essential for bone growth. Other researchers have
shown that nano-phase titanium, such as Ti6AlV4 and CoCrMo, promotes better calcium
crystallization when compared to micro-scale samples of the same material. It has
become evident that bone cell growth is not necessary dependent on the material used,
but the size of the surface area implanted76
.
Regardless of the major advancement in skin generation, made possible through
tissue engineering, these products are extremely expensive because they require such a
long in vitro cell culture time77
. In a 2006 article, Chung et al. was able to demonstrate
that nano-materials can be used to increase cell proliferation time, thus decreasing the
time needed for in vitro cultures. Chung utilized poly (ε-caprolactone) and nano-chitosan
to form a human dermal fibroblast scaffold. The use of these non-materials created a
higher surface roughness when compared to smooth chitosan and poly (ε-caprolactone)
surfaces, ultimately resulting in quicker fibroblast proliferation and better viability78
.
With heart disease being the number one cause of death in the United States, it is
obvious that much effort is directed at regenerating cardiac tissue and reestablishing
normal function. In 2005, Zong et al became the first group to successful develop
cardiac tissue by using cardiac myocytes and scaffolds composed of poly(l-lactide) and
poly(lactic-co-glycolic) acid nano-fibers79
. Researchers found that cells were able to align
with the local orientation of the fibers inside of the scaffold and respond to external pace
rates up to 6 hertz80
. The potential to repair and restore electrical signaling would not
only provide health benefits to millions of people and cut healthcare costs immensely.
Other researchers have been studying the benefits of using nano-materials in
vascular grafts and vascular stent materials. Many groups have found that changing the
surface topography of grafts and stents to operate on the nanoscale allows for better cell
interaction. In 2004 Miller et al. and Lui et al. reported an increase in endothelial and
vascular smooth muscle cell proliferation and adhesion when nanostructured poly(lactic-
co-glycolic) acid, titanium, and nitinol stents when compared to micron scale surfaces81
.
Much work has also been performed on returning disease and nonfunctional
bladder tissue, as in the case of bladder cancer. Even though poly-dl-lactide-co-glycolide
has demonstrated potential to grow and restore function in bladder tissue problems of
poor mechanical stability and adverse tissue and immune responses are often
demonstrated82
. Researchers have found that bladder cell growth differs depending on the
scale and surface features of the materials used. In 2003, Tapa et al. reported that smooth

12
muscle cell growth in the bladder was best when poly-dl-lactide-co-glycolide and
polyurethane with nanoscale surface features were used because extracellular matrix
proteins in the bladder operate on the nanoscale83
. Furthermore, in 2008, a group of
researchers found when rough nanometer polyurethane was used in reconstruction a
significantly lower amount of calcium oxalate stones, which pose serious risks, were
formed when compared to conventional polymers84
.
Another one of the major areas of nanotechnology and regenerative medicine is
cell encapsulation. In the medical disciplines concerning type I diabetes, central nervous
system regenerations, and cancer treatment cell encapsulation is of great interest. The
process involves protecting living, genetically engineered cells, which will be used as
drug delivery systems, immunotherapies, and engineered tissues, with polymeric and
biocompatible layers85
. When these cells are delivered, they can provide an unlimited
drug supply, as long as they are functional. Technologies can be used to nanoscale
coatings to the surface of the cells in order to prevent an immune response that would
destroy the cell’s function. The benefit to using nanocoating, instead of micro-scale
coating, is that oxygen and vital nutrients can diffuse more readily and the smaller
volume of material needed greatly reduces clotting86
.
Key Challenges:
Even though regenerative medicine techniques have the ability to help million of
people suffering from chronic illnesses, untreatable diseases, and severely painful and
debilitating diseases, there are still many challenges to overcome. While this report
primarily focused on cellular therapies and tissue engineering, regenerative therapies that
utilize inanimate implant materials often fail as a result of tissue rejection and lack of
mechanical support87
. Another issue occurs when the implant begins to deteriorate and
degrade, resulting in an immune response and necrosis in tissues surrounding the
implant88
. The use of biocompatible, biodegradable nano-scale products and polymers
has increased tissue bonding and comfort level within a patient, but the process is far
from perfect. Because the biocompatibility of devices and inanimate objects depends on
size, surface, shape, roughness and charge89
, it may be beneficial to look at current
products on the market and ways to alter their surfaces. For example, some researchers
believe that creating minor indents within implants may have some benefit. These
indentations can be coated with materials known to attract healing proteins90
. This could
ultimately decrease healing time required after surgery and reduce the rejection of the
implant during the healing processes.
For products that utilize viable cells, limited proliferation capacity is a major
issue. Researchers have found ways to grow functional cells outside the human body, but
once implanted these cells may not interact with other cells and proteins as they do in a
healthy individual. If these cells cannot interact, they do not offer the regenerative
therapeutic properties because the number of available cells is limited. The problem with
decreased cell interaction may require subsequent or long-term treatments, which are
often extremely expensive.
Additional problems arise when adult stem cells or donor cells are needed. When
adult stem cells are used in a regenerative therapy, they are only available in minimal
quantities91
. Another restriction is that adult stem cells can only differentiate into cells
found within their tissue of origin. For patients that require donor cells, the obvious issues

13
are immune reactions and tissue rejection. One way to overcome these challenges is to
use embryonic stem cells, instead of viable cells, adult stem cells, or donor cells.
Embryonic stem cells are undifferentiated cells that can proliferate into any needed cell
type for long periods of time92
. However, ethical concerns make this solution difficult
because human embryos must be destroyed in order to create a cell line. A number of
pro-life organizations protest the use of these stem cells in research and medicine because
they believe life begins at the moment of conception. They argue that their use in
medicine should be considered murder.
The lack of federal funding also poses a major problem for products in
development. The majority of funding for regenerative products has come from private
capital, totaling $4 billion between 1998 and 200493
. During those years, federal funding
for the regenerative medicine was only $250 million94
. Dependence of private capital,
instead of federal funding, creates the problem of competition between companies.
Because these companies are more focused on developing products faster than other
companies to prevent a huge monetary loss, commercially available products are
limited95
. See figure 8 for the estimates of technology readiness in major areas of
regenerative medicine. In order to overcome this challenge, the federal government must
fully understand the benefit of regenerative techniques and the potential to cut healthcare
costs significantly.
Figure 8. Estimates of the readiness of technology in regenerative medicine as of
2010. Achieved areas are shown in green96
.

14
Unique Opportunities:
Regardless of the number of challenges and improvements needed in the field of
regenerative medicine, there are many opportunities as well. These include new treatment
options and improvements of currently available products. The application of
nanotechnology to both new and already developed products could provide immense
benefits over the conventionally used micron materials.
New Treatments:
The field of regenerative medicine is applicable to nearly every disease and
disorder. There is not one medical discipline that would not benefit from the repair,
restoration, and replacement of damaged organs or tissues. Even still, most of the
regenerative products are for skin or wound repair. By looking at figure 4, there are only
minimal amounts of products on the market for the treatment cancer, cardiac disease, and
diabetes. Heart disease and cancer are among the leading causes of death worldwide, and
diabetes is often difficult to treat and manage. The only positive to these health facts is
that there are many opportunities for students, business people, and researchers to
develop products or companies centered on these medical disciplines.
Improvement of Currently Available Products:
As demonstrated above, there is definitely room for improvement in the currently
available regenerative products. Over the last few years, developers have shown that the
surface modifications on currently available devices and products resulted in better cell
proliferation and regeneration. The use of nanotechnology has increased cell growth and
biocompatibility, making these devices and products more successful. Therefore, for
students and researchers who would prefer to work in a company, instead of developing
new ideas for products, there is potential to still impact the field of regenerative medicine.
Conclusion:
In conclusion, the field of regenerative medicine hopes to repair, restore, and
repair function in damaged tissues and organs. Currently available regenerative products
have helped hundred of thousands of patients suffering from severe and painful diseases
and disorders by stimulating healing processes, immune cells, and growth factors. The
ability to stimulate healing and restore function is a major advancement in medicine,
which is normally focused on symptom management and long-term treatment. However,
even with their potential, the number of regenerative products on the market is still
relatively low. This may be a result of low funding, incompatible devices, and
competition between companies. Therefore, there are many opportunities to develop new
products or improve previous products, which could save the lives of millions of
individuals.

15
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