Task: Create a novel biomaterial for medical use

1. A BIODEGRADABLE IMPLANT FOR CONSTANT PAIN
RELIEF FOLLOWING SURGICAL PROCEDURES
Final Paper-BME 3700
Due Date: April 28, 2016
Group Members: Derek Dodge, Celine Agnes, Ashley Vanaman, Kristen
Campbell and Daniel Evans

2. Abstract
Pain relief drugs are a ubiquitous method of comfort after major surgeries. Many of the
current methods of delivery, like orally taken pills and constant intravenous delivery, have
significant drawbacks. Though the drawbacks vary from method to method, they all stand to be
improved. The idea of an implantable, biodegradable capsule that constantly releases
medication would solve many of these issues. It is a physically feasible idea that can be made
with existing technology and techniques, and would be more effective at treating pain than
current methods. While the device is untested as of now, it is hoped that in vitro and in vivo tests
would be possible in the near future. Several tests that could be run are described below. In
addition, possible modifications and future additions to the design are also listed.

3. Introduction
In the modern medical community today, there is a constant need to improve the field of
surgery and discover new ways to make the surgical procedures more successful and faster.
With this constant improvement of the surgical field, there lacks improvements in the area of
pain relief post surgery. The product that the group of students is looking to develop in this
project does not currently have anything quite like it. In the medical society, there is a critical
and consistent need for pain relief drugs.
There are currently four different ways of controlling pain relief post surgery. The first of
these is the Intravenous Patient Controlled Analgesia. This is a pump that allows the patient to
push a button and the machine then pumps a small amount of pain medicine into the IV line in
your arm. This is a typical and innovative method due to the fact that it provides stable pain
relief and a sense of control over their pain management. As long as family members are not in
control of the button, the dosage of the medication is limited into a safe amount. The second of
these is the Patient Controlled Epidural Analgesia. The epidural uses a PCA pump to deliver the
medicine. The way this method is done is by inserting an epidural catheter through the patient's
back. This could be a cause for concern in the sense of discomfort for the patient. It is also not a
risk free procedure for pain control. The epidural does not always adequately control pain. The
third of these is the Nerve Blocks. The Nerve Blocks have a more specialized capability to
control pain in a small area of the body. This can allow for the amount of medication to be more
reduced. This can help to prevent possible addictions to medication. Finally the most common
method of pain medication delivery is pain medications taken by mouth. These are ordered by
the doctor and must be taken at certain intervals throughout the day. Though this gives the user
a lot of control in the medication and pain relief, it also comes with many disadvantages. These
disadvantages include addiction, patient responsibility, and even overdose.
It can be seen from the disadvantages discussed above, there are definitive issues
facing the current model of delivery, many having to do with user error. A patient is often
unfamiliar with the pills being given to them, and can possibly give incorrect doses to
themselves resulting in more pain than is necessary. This disadvantage can be eliminated by
removing the aspect of self control from the method of delivery.

4. Figure 1: Traditional oral drug delivery versusa constant method, like is suggested. The line with the multiple
peaksisthe traditional methodandoftenleadsto levelsof drug past what is safe or below wha t is necessary to provide
relief. The constant release never crosses the toxicity line or subtherapeutic line. [12]
By having a drug that has a zero-order controlled release, the drug concentration is kept
constant within the therapeutic level. This will eliminate the patient from becoming addicted
where they can potentially overdose and do more damage to their bodies than intended.
Another issue is other people besides the patient taking the pills or the pills being sold. This can
obviously negatively affect other individuals besides the patient. That also ties into the next
issue. Pills tend to have more addictions associated with them than other forms of pain
medication. This is mainly due to the easily abused nature of their ingestion. It is difficult for a
doctor to limit the amount taken once the patient has left the hospital or wants to abuse the
drug. The group of students carefully discussed these disadvantages as a way to design a
proposed solution that meets the needs and improves the disadvantages.
The proposed solution to these disadvantages and need for a more efficient way of
delivering pain medication is a degradable capsule to be filled with drugs and implanted during
surgery. It would be multilayered and as each layer degrades, a constant release of pain
medication is maintained. This would help in limiting the inconsistency of drug dosage
associated with pills as it spikes and falls over preferred levels. There would also be no time
delay for pain relief as the medication is constantly being given, and the patient does not have
to worry about constantly timing their pills and the waiting period before the medication kicks in.
There is also no way for a patient to sell or overuse the drug.

5. Design
This capsule would be made from an easily degradable polymer. The first choice
material would be a polyanhydride. It is a copolymer of the aliphatic and aromatic polymers
PCPP and sebacic acid. The aromatic degrades over years, while the aliphatic degrades within
days. By combining them, it is possible to create a customizable degradation time, based on the
patient’s needs. The window available is anywhere between those two extremes. It also
degrades in a in layers, which is perfect for the group’s purposes. When it does degrade, it
breaks down into compounds easily dealt with by the body. It can already be produced in wafer
form, so it would be a simple modification to produce a multi-laminar vesicle, or a set of hollow,
roughly spherical shells imbedded within each other. [11]
Figure 2: The chemical formula for the polyanhydride suggested. [11]
The first possible method of production would be where the multi-layered shell would be
formed first. Then the empty capsule would be loaded with the drug after the fact. This could be
difficult as the layers have to be resistant to the drugs passage through to prevent early release.
Making them one way acceptors of the drugs could be very difficult. A more reasonable solution
could be making the capsule one layer at a time. As each one is made, it could be loaded with
the drug. This would eliminate the need for the drugs to pass through the layers. Both of these
polymers would be assembled by the layer by layer method.
Figure 3: A simplified example of the layer-by-layer method. A substrate isused asa base for the polyanhydride to bindto.
The drug wouldbe on top of the polymer, thenmore layersof polymer would be addedon top, alternating each layer. [14]

6. However loading each individual layer is very time consuming and difficult. The best
overall option is likely simply binding the drug to the polymer itself. As the polymer degrades, it
cannot hold the drug anymore and it is released into the body at a very regular rate. This also
does not need a specific shape, specifically the shells do not need to be uniform and implanted
within themselves. As long as the polymer is made at the correct porosity to allow the drug to be
attached uniformly throughout, it does not matter the internal structure. The polymer will still
break down in layers regardless.
In regards to size of the capsule, there are many factors to consider. The severity of the
procedure is one of the most major concerns. Larger capsules with more drugs are required for
more painful surgeries. The abdomen can also allow for such larger capsules, so a longer drug
delivery period is possible. If the time period necessary is so long that even increasing the size
and aromatic ratio is no longer viable, it could be a minor outpatient procedure to implant
another. It also would not have to be removed, as the body will dispose of it itself, with no further
surgeries unless more drugs are required. The location within the body, however, is not a major
concern. It can be placed in the abdomen, regardless of what the procedure was. A relatively
small incision can be used to insert a capsule, separate from the initial surgery if the main
incisions were on the extremities. As long as the drug has access to the blood, it can spread to
where it is needed.
The implant also has to be able to bind to multiple kinds of pain relief medications. Many
people are incapable of taking certain kinds of medication due to allergies or types of illnesses.
Every drug is also not able to bind to every type of functional group in a polymer. The functional
groups on the polymer may have to be modified depending on the drug being applied.
Testing
More than 50 million people in the United States have allergies. Allergy testing,
specifically skin testing, is a convenient and accurate way to find effective treatment. The first
type of skin test includes a drop of a suspected allergen pricked or scratched on the surface of
the skin of the back or forearm. The second type of skin test involves a small amount of the
suspected allergen injected into the skin of the arm or forearm. Redness and swelling at the test
spot represents an allergy and multiple suspected allergens can be tested at once. Skin allergy
testing would be ideal for the polyanhydride used in this biomedical device because it is fast,
with reactions usually appearing within 20 minutes, and it is less costly than allergy blood tests.

7. Unfortunately, some medications can interfere with skin tests, unlike with blood tests, which is
why testing is necessary before surgery [8]. Biomaterials, depending upon their site of
application, should be evaluated for possible tissue irritation. This biomaterial was chosen
because no data regarding the hypersensitivity of polyanhydrides has been reported [7].
Effectiveness testing of the biomedical device would be completed via degradation
timing tests and with an oral pill leading up to the procedure. The oral pill would be administered
prior to surgery to ensure no internal patient-specific negative side effects. On a larger scale, it
is important to test how long it takes the polyanhydride to arrive at the site of need. Degradation
timing tests are needed to give information on how the biomedical device would have to be
designed in order to degrade the proper amount of painkiller to the patient over time.
Polyanhydrides are emerging as important biomaterials due to their predictable biodegradation
and drug release in tissue. Degradation is dependent on crystallinity, molecular weight,
copolymer composition, pH of the medium, and uptake of water inside the polymer matrix. The
higher hydrophobicity, the lower water permeability of the matrix. The highly hydrophobic
polyanhydrides exhibit ideal surface erosion, since the rate of hydrolytic degradation at the
surface will be much faster than the rate of water penetration into the bulk of the matrix [7] . The
release rate of incorporated drug in the polymer matrix is affected by the fabrication method,
size and geometry of the polyanhydride matrix, drug solubility, drug loading and particle size of
the incorporated drug [10].
A study from Drexel University, MIT, and MCP-Hahnemann University found that the
degradation rate of polyanhydrides increases 800 times as the composition of sebacic acid in
the copolymer increases to 80%. Matrices of different thickness with the same surface area
were found to have similar erosion rates; thicker devices generally exhibited longer periods of
erosion. The in vivo degradation of these polymers correlated well with the in vitro degradation,
with in vivo degradation rates slightly slower than in vitro. The in vitro and in vivo toxicity data
points to the fact that these polymers are well tolerated by the tissues and can generally be
considered a biocompatible class of polymers [7]
One study from MIT obtained “polymers with degradation rates in the range of 10-1
and
10-4
mg/g/cm2
. Near constant erosion rates were observed with hydrophobic poly[bis(p-
carboxyphenoxy) alkane anhydrides] for periods of up to six months. Copolymerization of these
hydrophobic backbones with sebacic acid gently enhances the degradation rates.” Factors that
affected degradation were pH, with higher stability in acidic environments, and fabrication
procedures, where a dominantly erosion controlled release mechanism was observed in the

8. injection-molded samples. A results table of the physical properties of different polyanhydrides
can be seen below [9]. It is especially important to look at the varying erosion rates.
Table 1: Physical Properties of Different Polyanhydrides [9].
Another MIT study found that neither mutagenicity nor toxicity were associated with polymers of
the breakdown products of poly[bis-(p-carboxyphenoxy) propane anhydride], poly(terephthalic
acid anhydride), and their copolymers with sebacic acid. Further, no inflammatory cells were
observed in biocompatibility tests measuring host responses to the polymers [9].
Lastly, from studies at the University of Regensburg, a general equation for describing
erosion-controlled drug release, which can be applied to polyanhydride spheres, cylinders, and
slabs was derived:
(1)
where Mt and M∞ are the polymer mass at time t and at infinite time, respectively, c0 a uniform
initial drug concentration or in the case of erosion a ‘polymer concentration’, a is the radius of a
cylinder or sphere or the half-thickness of a slab and n is a ‘shape factor’ (n=3 for spheres, n=2
for cylinders and n=1 for slabs) [1]. This equation could aid in the designing of the biomedical
device in question to ensure that the proper dosage of pain killer is being administered to the
patient. Over or underdosing the patient can lead to serious effects in the future. If this device
were fabricated, it would be necessary to conduct tests similar to those previously mentioned to
ensure the functionality and biocompatibility of the drug release capsule. Weening off of the
painkiller at the proper rate is important. When the degradation of the biomaterial is known, the
concentration of the painkiller can be decreased to avoid addiction. Both quantitative and
qualitative tests will be necessary to assess the patient’s pain and monitor the amount of
painkiller in the body.

9. Future Work
Instead of performing a surgery to insert a solid capsule into a patient’s body, an
injectable form of the degradable painkiller could be created. The main idea behind this is the
fact that it would be possible to inject the new material rather than including it post surgery. This
could be done with the injection of solid nanoparticle capsules. This would help to better be able
to control the amount of drug that is being delivered to the patient. The amount can vary based
on the amount of pain the patient is in and can be reassessed as needed. Each individual
nanocapsule could be created similarly to the original idea above. This would eliminate the
need for surgery to implant the drug. Although, layer by layer techniques would probably not
work for creation of these nanoparticles due to the small scale. This means that the dose would
either be determined by the amount of nanoparticles injected or by the concentration of the
drugs infused with the degradable nanoparticles.
Since every person is a different size, body type, etc. they will respond differently to the
same dosage of a painkiller. This means that the correct dosage of the drug will need to be
taken into account for each patient specifically. Factors that could affect the recommended
dose could be gender, weight, age, degradation characteristics of the polymer capsule, and
other factors. These factors would need to be taken into account prior to delivering the drug. In
other words, while planning the surgery, doctors would need to plan the correct dose of this
implantable painkiller for the patient.
Ideally, many polymers would be tested to find the optimal degradable drug delivery
system. Also, many different pain medications would need to be tested to ensure their
effectiveness as an implantable drug. Different combination of each painkiller and each polymer
would need to be tested as to cross test each system and optimize the drug delivery system.
This would also eliminate unknown complications involving combinations of certain polymers
and certain drugs. Results from these combinations would yield the ideal combination of drug
and polymer.
In addition to optimizing the polymer/drug combination, the size of the implant would
need to be optimized to be as small as possible. This could be done by altering the
concentration of drug within the polymer or the degrading properties of the polymer itself.
Making the implant as small as possible will allow for a minimally invasive extension to the
surgery which initially required the pain medication.

10. Healthcare today is moving towards personal medicine so even though an effort to
customize each implantable painkiller would be tasking, it is a viable option for the future.
Considering that almost 15,000 people die every year from overdoses involving prescription
painkillers, the FDA or hospitals would want to use this implantable painkiller method to
increase patient safety. Not only would these future techniques increase patient safety but it
would also increase safety of people who receive prescribed pain medication from patients or
doctors. For instance in 2010, 1 in 20 people in the US, 12 years and older, reported using
prescription painkillers for nonmedical reasons in the past year [13]. Implantable pain killers
could prevent the abuse and drug sales of these medications in the future.
Conclusion
Due to the large amount and wide range of different surgical procedures that are done
daily, the amount of medicine that is administered is large as well. Many households have
several different excess prescription drugs from different past illnesses or surgeries. Having
prescription drugs lying around the house can lead to possible overdoses by children or these
drugs being sold illegally. Due to the fact that this proposed drug delivery mechanism is
implanted within the body and degrades over time, it eliminates having extra medicine lying
around the home that can be misused in the future. The capsule being proposed will have drugs
within the polymer resulting in the release of the drug as the polymer degrades. The polymers
surface will degrade in a layer by layer method which will slowly release a constant amount of
drugs. The benefits of having a constant drug delivery is that the patient will not have pain when
the drug dosage taken begins to wear off. The size of the polymer could vary depending on the
patient and the amount of drug that is needed.
Since the group does not know how each patient will respond to the implanted drug, it is
important and necessary to always test the drug on the patient prior to the implantation. This
testing will help to eliminate the possibility of the patient being allergic or sensitive to the drug
once it is implanted. If the patient was allergic to the drug and there was not prior testing done to
determine this, then it would require another surgery to remove the implant and another drug
would then be needed. In the future, it would ideally be possible to find a way to make each
implant custom for each patients in a mass production way in order to reduce the price of the
implant. It is also possible after a lot of testing to find a polymer that would work the best based
off of in-vivo testing. Based off the research conducted, it appears that the material of
polyanhydride would work well for the polymer. Testing would need to be performed in order to

11. help to prove this. Also the group would ideally like the size of the implant to be as small as
possible. Again testing would need to be completed in order to find the most effective and
smallest implant would be ideal.
This state of the art design would help make sure recovery from different surgeries went
as smoothly as possible and that the patient experienced a minimal amount of pain if any. The
design presented is the first prototype in a long process of testing and changing to make a
device to be able to help fill the gap in advancement in post surgery pain relief. Hopefully one
day this drug release mechanism will be used widely throughout the medical world.
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