1. =
Improved drug delivery incorporating the degradation of
poly(β-amino ester) polymerized hydrogels
Curtis Bethel
Dr. David Puleo
Department of Biomedical Engineering
Methods
Results DiscussionIntroduction
Synthesis of poly(β-amino esters)
• Tissue regeneration is a natural occurrence, but can be greatly
hindered by abnormally traumatic tissue injury or inheritable tissue
degenerative diseases2.
• Specific drugs can be administered to treat these special cases and aid
in the regeneration process based on their pharmacological properties.
• Simvastatin possesses osteogenic, anti-inflammatory, anti-microbial
and angiogenic properties, but is a small molecule drug and therefore
prone to rapid release rates4.
• Drug delivery is a potential area of improvement in the biomedical
engineering field. Oral dosage is subject to first-pass metabolism while
injections deliver a bolus of drug at high concentration4.
• Poly(β-amino ester) (PBAE) biodegradable hydrogels are easily
synthesized, relatively inexpensive, do not require purification, and
have a variety of tunable properties5.
• PBAE hydrogels provide an intriguing alternative to traditional drug
delivery methods for tissue regeneration. Loaded with drug, the
hydrogels may act as a delivery vehicle and achieve an ideal release
rate.
References
1. Anderson, D. G., et. al., 2006. A combinational library of photocrosslinkable and
degradable materials. Advanced Materials.
2. Badylak, S. F., Dearth, C. L., Sicari, B. M., 2014. Tissue engineering and regenerative
medicine approaches to enhance the functional response to skeletal muscle injury.
The Anatomical Record.
3. Baoge, L., et. al., 2012. Treatment of skeletal muscle injury: a review. Hindawi
Publishing Corporation.
4. Fisher, P. D., et. al., 2014. Improved small molecule drug release from in situ forming
poly(lactic-co-glycolic acid) scaffolds incorporating poly(β-amino ester) and
hydroxyapatite microparticles. J Biomater Sci Polym Ed.
5. Hawkins, A. M., et. al., 2013. Tuning biodegradable hydrogel properties via synthesis
procedure. Polymer Communication.
• The high-performance liquid chromatography (HPLC) retention time for
pure simvastatin is approximately 3.05 minutes. The relatively low
cumulative mass could be due to impurities in the simvastatin that display
varying retention times.
• Although mass degradation was visibly accelerated at lower pHs, the
accelerated systems initially released simvastatin at a slower rate. After
several days, the release became more accelerated. This could be due to
the low solubility of simvastatin in water.
• Hydrogel samples at a lower pH displayed more shrinkage, cracking, and
opacity at earlier time points than samples at pH 7.4.
• AH6 3:1 hydrogels displayed shrinkage, cracking, and opacity at earlier
time points than AH6 5:1 hydrogels. These observations began at the
same point that the release rate increased. This could be due to the
stronger bonds formed in the 5:1 hydrogels during UV polymerization.
• Degradation profile and release profile may be related, but release profile
is not necessarily dependent on degradation due to the fact that the
system could reach equilibrium concentration without all simvastatin
permeating the hydrogel and entering the supernatant solution.
Conclusions
• Decreasing pH is not a valid method of accelerating release profiles of
simvastatin in AH6 5:1 polymer or AH6 3:1 polymer.
• The release profile of simvastatin is more accelerated in AH6 3:1 polymer
than in AH6 5:1 polymer.
• The cumulative release of simvastatin of AH6 3:1 and AH6 5:1
biodegradable hydrogels is gradual and does not release a initial bolus of
high concentration.
References
Figure 1: Cumulative Release of Simvastatin in
PBS Solution at pH 7.4
(Blue = AH6 5:1, Red = AH6 3:1)
Isobuytlamine (6)
+ +
Poly(ethylene glycol)
Diacrylate (PEGDA) (H)
Di(ethylene glycol)
Diacrylate (DEGDA) (A)
Time (days)
MassofSimvastatinReleased(mg)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 2 4 6 8 10
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 2 4 6 8 10
Figure 2: Cumulative Release of Simvastatin in
PBS Solution at pH 6
(Blue = AH6 5:1, Red = AH6 3:1)
Time (days)
MassofSimvastatinReleased(mg)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
0 2 4 6 8 10
Figure 3: Cumulative Release of Simvastatin in
PBS Solution at pH 5
(Blue = AH6 5:1, Red = AH6 3:1)
Time (days)
MassofSimvastatinReleased(mg)
0
0.02
0.04
0.06
0.08
0.1
0.12
0 2 4 6 8 10
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 2 4 6 8 10
Time (days)
Time (days)
Time (days)
Concentration(mg/mL)Concentration(mg/mL)Concentration(mg/mL)
Figure 4: Instantaneous Release of Simvastatin in
PBS Solution at pH 7.4
(Blue = AH6 5:1, Red = AH6 3:1)
Figure 6: Instantaneous Release of Simvastatin in
PBS Solution at pH 5
(Blue = AH6 5:1, Red = AH6 3:1)
Figure 5: Instantaneous Release of Simvastatin in
PBS Solution at pH 6
(Blue = AH6 5:1, Red = AH6 3:1)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 2 4 6 8 10
AH6 X:Y biodegradable hydrogel
(X:Y molar ratio of A:H)
• AH6 3:1 and AH6 5:1 biodegradable hydrogels were synthesized via UV
polymerization using photoinitiator DMPA.
• The PBAE samples were loaded with simvastatin by allowing them to
soak in a simvastatin solution with solvent ethanol.
• A phosphate buffered saline (PBS) solution was used to emulate the
environment of the body.
• Five samples of AH6 3:1 and AH6 5:1 are placed in PBS solution at
three pHs, pH 7.4 to emulate the body and pH 6 and pH 5 to
accelerate the release profile. Each sample is at 37°C.
• Supernatant solution is collected and analyzed through high-
performance liquid chromatography.