Bone Regeneration and Synthetic Materials
Lindsey Dougal
The purpose behind tissue engineering is to replace dead dysfunctional tissue
with new synthetic tissue to alleviate pain and disease. There are three types of
treatments used for tissue regeneration: autogenous grafts, allografts, and synthetic
materials called alloplasts. In this paper, we will be analyzing bone regeneration using
synthetic materials by describing different types of bone tissue engineering, how these
tissues are applied, and why we use certain materials over others.
First, we will analyze the bone, and how it repairs itself. There are three phases
in bone repair as seen in figure 1.1 (PEMF Bone Growth Stimulation). The first phase is
the reactive phase. The site of the injury will get flooded with blood, and then blood
vessels constrict. This leads to restriction of blood flow in to the area, which causes a
hematoma (a big scab) to form around the injured site. The next phase is the
reparative phase. A cartilage callus forms where the break is. Once it has filled in the
injured site, the cartilage is replaced by lamellar bone which is formed from osteoblasts.
The last phase is the remodeling phase. In this phase, osteoclasts absorb abscess
formations and model the new bone to the shape the bone had before.
There are many causes that can lead to defects in bone repair. Some examples
are disease or illness and complex fractures. Also, bone density can be an obstacle to
conquer when it comes to repair. Procedures involving autogenous grafts, allografts,
and synthetic materials help heal bones that are impossible to heal on their own. A
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majority of tissue engineering involve dental implants through enhancement surgeries.
Some people have problems or defects with their teeth causing them to need to be
replaced with implants. Another use of bone tissue engineering has to do with complex
fractures that are too large to heal by itself. This is where the three types of bone
tissue engineering come to play.
The first of the three bone tissue procedures are autogenous grafts. Basically,
you take your own bone tissue from another part of your body (usually your hip in
cases of larger bone replacement or from the jaw for smaller bone replacement for
teeth) and insert it in the place in need of repair. The benefit is your body is less likely
to reject your own tissue. However, the cost is having an extra surgical site and more
pain during the recovery.
The second of the three bone tissue procedures are allografts. This procedure
involves taking the bone tissue from a donor whether it be a cadaver or a live donor. It
is perfectly safe because the Food and Drug administration screens for potential risk
factors for the person that receives the bone transplant. They check for HIV and
Hepatitis A and B. They also check the spleen or lymph nodes of the donor to make
sure there are no impending diseases in the tissues. A benefit of this procedure is there
are no extra surgical sites, but the costs are that you have a higher chance of your
body rejecting the tissue, and donations are limited. Since donations are limited there is
always a chance one might not receive a donation in a timely manner.
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The third of the three bone tissue procedures are regeneration through synthetic
materials. A cost would be your body rejecting the material. However, the benefit is
there is always a shortage of donors of tissues. Thankfully, synthetic materials help
solve this problem. There are no limitations on synthetic materials used for bone tissue
regeneration. This means there is virtually less waiting time for a patient whom
originally would have had to put their name on a list for a donor. Finally, this procedure
also does not require an extra surgical site, so recuperation from surgery is not as
uncomfortable or painful.
The basic procedure of bone regeneration through synthetic materials is to start
out with a bone graft. This is basically a matrix that will hold our synthetic material in
place. Next, the synthetic material is inserted. The point behind synthetic materials is to
stimulate bone regenerating cells while also to provide nourishment for the bone. A lot
of these materials are usually Calcium or Phosphate based, and have ceramic
characteristics. As the bone heals, the synthetic material gets reabsorbed leaving brand
new bone.
With this procedure, there are a lot of variables that are currently being
manipulated and experimented with in order to enhance or speed up the procedure.
“Key problems with synthetic scaffold materials are shrinkage and fast
degradation of the scaffolds, a lack of blood supply and nutrition in the central scaffold
volume and the absent or the scarce development of bone tissue along the scaffold to
bridge the bone defect”(Endes, 2011). In the paper, Laser processing of ormosils for
tissue engineering applications, Matei speaks about how he experimented on grafting
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for tissue engineering. “Cells morphology, adhesion, and alignment were studied on
polymeric structures with different shapes, obtained in various experimental
conditions”(Matei,2012). Matei was observing different shapes with different tissue
types to see which tissues respond to certain types of grafts. “Grids of 20 × 20 lines
and 20 lines systems with different distances between lines were built. Such simple
structures can be promising scaffolds for cell cultures, since compact structures without
defects can be processed over large areas” (Matei,2012). One of the bigger variables he
looks at is the distance between each line in a scaffold. This is important because this
could mean bigger structures that can cover larger areas of injured tissues like bone
tissue.
Endes also researched different grafts to solve some of the key problems listed
above. He used “composite scaffolds made of biopolymers like polylactidglycolid acid
(PLGA) coated and loaded with calcium phosphates (CaP) revealed promising
therapeutical options for the regeneration of critical sized bone defects.” Unlike Matei,
Endes used polymers that basically made up the grid and added calcium phosphates to
these polymers which provide nutrition to help stimulate bone growth. These two
findings are substantial because they allow for larger scaffolds, which allows greater
success in repair of larger and more complex breaks.
Another variable that is manipulated is the synthetic material that is used. In his
paper, Teixeira describes how he experimented on the synthetic materials, and how
adding a chemical changes the effect of the synthetic tissue. “The incorporation of
heparin leads to a reduced initial burst phase when compared to the non-heparinized
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materials” (Teixera,2012). The heparin controls the rate of growth in tissue. This is
beneficial because one can isolate tissues and speed up or slow down tissue growth.
Chaudhari also experiments with different materials. Chaudhari used three
different types of synthetic materials and analyzed how efficient each was. The three
materials used were titanium, silica and glass. In this experiment, Chaudhari used
twenty rabbits and he and randomly implanted one of these three materials in each of
the rabbits. After two to four weeks the rabbits were put and down and analyzed for
results. Chaudhari found that” glass is highly osteogenic at a distance from the implant.
The porous titanium coatings didn’t stimulate bone regeneration, but allowed bone
growth into the pores. Although the Silica didn’t stimulate higher bone response, it has
a potential of faster bone growth in the vicinity compared to further away from the
surface. Bone to implant data was inconclusive to understand the bone adaptation”
(Chaudhari, 2011). The benefit of this experiment was Chaudhari found an agent
(Silica) that has potential in expanding how large a graft can get. Even though some of
Chaudhari’s results were inconclusive, they paved way to new experiments. Both
Teixera and Chaudhari have benefited patients by helping minimize recovery time and
being able to heal larger fractures through the use of different materials.
A material that is commonly used in tissue engineering are stem cells. Nair whom
wrote a paper that involved experimentation with rats analyzed two procedures. One
procedure was with stem cells and the other procedure was without. Some variables
they wanted to analyze were the osteogenesis and vascular growth. As a result, the
procedure that had stem cells showed “the implantation site was well vascularized with
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profuse in growth of blood capillaries in Stem cell groups, with preference for tissueengineered Stem cell groups. Similarly, neo-osteogenesis studies were shown only by
tissue-engineered Stem cell groups” (Nair,2009). This means Nair saw that the use
stem cells were very beneficial. The stem cells help promote growth and repair where
they were applied. This is important because stem cells could very well be the next
most efficient material to use in bone regeneration.
Another variable is the different dosages of growth factors that are applied
depending on the health status of a patient. In the paper, PDGF-B gene therapy
accelerates bone engineering and oral implant osseointegration, Chang analyzed
Platelet-derived growth factor (PDGF-B) genes on rats. He realized with rats that are
diseased, for example diabetic, these growth factors weren’t as effective in vivo (in the
body). In Chang’s experiment, he analyzed the effects of different dosage amounts, and
compares PDGF-B with Ad-Luc. “In summary, gene delivery of Ad-PDGF-B shows
regenerative and safety capabilities for bone tissue engineering and osseointegration in
alveolar bone defects comparable with rhPDGF-BB protein delivery in vivo” (Chang,
2012). So basically, Chang discovered that a higher dosage of PDGF has the desired
effect of bone growth in vitro and is also safe for the patient.
Another variable that we can take into the procedure is how we are going to
stimulate growth. In the paper, Human dental pulp cells exhibit bone cell-like
responsiveness to fluid shear stress, Evar Kraft’s purpose “was to determine whether
human dental pulp-derived cells (DPC) are responsive to mechanical loading by
pulsating fluid flow (PFF) upon stimulation of mineralization in vitro” (Kraft, 2012).
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What this means is that they are pulsating fluid at the site to help stimulate tissue. This
is important because stimulation is the initiative of the whole process. If there is no
stimulation, bone regeneration will fail to occur. The results of this experiment were
that “human DPC, like osteogenic cells, acquire responsiveness to pulsating fluid shear
stress in mineralizing conditions. Thus DPC might be able to perform bone-like functions
during mineralized tissue remodeling in vivo, and therefore provide a promising new
tool for mineralized tissue engineering to restore, for example, maxillofacial defects.”
Evar Kraft’s experiment showed us that you don’t always need chemicals to stimulate
growth factors, but pulsating fluids are also influential.
Aciole also stimulates bone regeneration without chemicals. Aciole wanted ”to
evaluate, through the analysis of histomorfometric, the repair of complete tibial fracture
in rabbits fixed with osteosynthesis, treated or not with infrared laser light” (Aciole,
2012). Unlike Kraft whom used pulsating fluids to stimulate bone regeneration, Aciole
uses light in laser form. Aciole experimented on fifteen rabbits. He would surgically
fracture the rabbit’s tibia. He divided these rabbits up into five groups. In groups three
and five, Aciole used the normal technique of grafting to help repair their broken tibia.
Groups one, two, and four received the laser light treatment. As a result, the rabbits
that were healed with the laser, healed quicker than the rabbits that had grafts. This is
important because some patients may be ill or may not be able to use these chemicals
for stimulation, so the fact that there are alternatives benefits these people because it
gives them an opportunity they didn’t have open to them before.
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So far, all these variables were all involved in an in vitro (in the body) procedure.
However, there are alternatives to in vitro procedures. These alternatives are called ex
vitro procedures. These procedures are a lot alike except for the fact that tissue growth
is stimulated outside of the body. The paper, Transcriptome Analysis of MSC and MSCDerived Osteoblasts on ResomerH LT706 and PCL: Impact of Biomaterial Substrate on
Osteogenic Differentiation, gives a great example of this procedure. “Mesenchymal
stem cells (MSC) represent a particularly attractive cell type for bone tissue engineering
because of their ex vivo expansion potential and multipotent differentiation capacity”
(Neuss, 2012). Neuss points out that a common material in ex vitro procedures are
stem cells. However, like in vitro procedures, “tissue engineering frequently involves
three-dimensional scaffolds which (i) allow for cell adhesion in a spatial environment
and (ii) meet application-specific criteria, such as stiffness, degradability and
biocompatibility.” Neuss also describes how scaffolds have to fit certain parameters for
tissue growth.
The problem with so many parameters is that it makes it very hard to produce
tissue. Neuss led an experiment to determine alternative scaffolds for ex vitro
procedures. He “analyzed two synthetic, long-term degradable polymers for their
impact on MSC-based bone tissue engineering.” In the end he found a new polymer
that favored bone regeneration.
Endes also worked ex vitro. As mentioned previously, Endes worked on the
development of an enhanced scaffold that had increased success in larger bone
fractures. He performed his experiment in two different manners. “Interconnectively
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macroporous PLGA scaffolds loaded with microporous and coated with nanoporous
calcium phosphates were either seeded in fixed bed bioreactors with allogenic
osteogenically induced mesenchymal stem cells (ex vitro) and implanted or implanted
unseeded into critical sized femoral bone defects (in vitro).” This is an advantage
because this opens up options for patients. If the patient’s body doesn’t “take” to the in
vitro procedure, the patient still has the option of the ex vitro procedure which involves
stem cells that are grown outside of the body and then implanted into the patient.
Having more options helps lead to customization of each procedure to each patient.
There are many different choices when it comes to regenerating bone growth.
Autogenous grafts and allografts are simple and are very limited in flexibility of their
procedures. There is very little room for improvement for both of these procedures.
However, alloplasts (synthetic material procedures) have many opportunities in
the manipulation of the procedure to enhance outcomes. Variables looked at were
different types of grafts, synthetic materials, different dosages of growth chemicals,
different ways to stimulate bone regeneration, and where to apply initiation of growth
(in vitro vs. ex vitro). These variables all enhance the procedure whether it be bigger
scaffolds to treat larger fractures or different chemicals used to help control the rate of
recovery. These variables also open up more opportunities to different patients. Some
procedures can be done both in vitro and ex vitro. As a whole, all these modifications
help customize bone regeneration for each patient. Not every patient has the same
illness, bone density, size of fracture, or immune response. By having so many variables
manipulated more patients will have successful bone regeneration.
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Overall, we can still rely on allografts and autogenous grafts, but with further
research, synthetic materials will soon become the dominant procedure through these
enhancements.
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Pictures and Charts
Figure 1.1
(PEMF Bone Growth Stimulation).
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Works Cited
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Osteosynthesis, Ir Laser, Bone Graft and Guided Bone Regeneration:
Histomorfometric Study." AIP Conference Proceedings 1364.1 (2011): 60-65.
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Chang, P-C. "PDGF-B Gene Therapy Accelerates Bone Engineering and Oral Implant
Osseointegration." Gene Therapy 17.1 (2010): 95-104. Academic Search
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Chaudhari, Amol. "Bone Tissue Response to Porous and Functionalized Titanium and
Silica Based Coatings." plosone.org. PLos ONE, n.d. Web. 2 Dec 2012.
Endes, S. Hiebl, B. "Angiogenesis and Healing with Non-Shrinking, Fast Degradeable
PLGA/Cap Scaffolds in Critical-Sized Defects in he Rabbit Femur with or
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Nair, Manita B. "Tissue-Engineered Triphasic Ceramic Coated Hydroxyapatite Induced
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