1. Preprogrammed Pulsatile Delivery System for
Tissue Enginerring Application
Angjela Keci, Ming Dang1
, Peter X. Ma1,2,3,4
1.Macromolecular Science and Engineering Center, 2.Department of Biologic and Materials Sciences, 3.Department of Biomedical Engineering, 4.Department of Materials Science and Engineering,
University of Michigan, Ann Arbor, MI 48109
Abstract
Osteoporosis is a medical condition in which bones become weak and brittle.
Currently, the only effective and FDA-approved treatment is the daily injection
of Parathyroid Hormone (PTH). We are trying to develop a biodegradable, im-
plantable system for pulsatile delivery of PTH that has the ability to release
PTH every 24 hours for a three week period. Recent research has developed a
four-layer pulsatile drug device using polyanhydrides, which delivered four
pulses of drug over four days. However, the four-layer device is inadequate to
cover the 21-day period. PTH therapy lasting 21-days has been shown to
cause a remarkable increase in bone mass. Prior to this, the polyanhydrides
was synthesized from three precursors: polyethylene glycol anhydride
(PEG-AA), sebacic acid anhydride (SA-AA) precursor, and 1,3-bis (p-carboxy-
phenoxy) propane anhydride (CPP-AA) precursor. These precursors underwent
condensation polymerization under high vacuum at 175ºC to form the
three-component polyanhydrides copolymer, poly(SA-CPP-PEG). A hot press
was then used to form the polymer into a film of varying thickness (from
50-300 µm). We confirmed the structure of the polymer by using NMR spec-
trum, and the polymer exhibited typical surface erosion behavior. Our future
work will involve studying the assembly of the device using films of different
thicknesses.
Objectives
• Make an implantable device made of biodegradable materials could be
used to deliver the drug and the treatment is in a pulsatile manner.
• 21 days of PTH administration has been shown to cause a prominent ana-
bolic effect in bone mass growth by Dr. McCauley's research lab.
• A four-layer pulsatile drug device made of polyanhydrides has been devel-
oped that delivers four pulses of PTH over four days, but this would not last the
entirety of the 21-day PTH regimen.
• We want to develop a pulsatile drug device that will deliver PTH every 24
hours over the entirety of 21 days using the polyanhydrides. The thickness of
the copolymer would have to be optimized so that it would degrade in body
conditions over the course of 24 hours.
Method-Chemical Synthesis
• The polyanhydrides copolymer is synthesized from three anhydrous
precursors.
• One is polyethylene glycol anhydride (PEG-AA), which was synthe-
sized from PEG-diacid and acetic anhydride.
• One is sebabic acid anhydride (SA-AA) precursor, which was synthe-
sized from sebacic acid and acetic anhydride at 100ºC.
• The last is 1,3-bis (p-carboxyphenoxy) propane anhydride, which
was synthesized from sodium hydroxide, 4-hydroxybenzoic acid, and
1,3-dibromopropane at 85ºC. Further preparation involves the washing
of the powder with methanol, workup with sulfuric acid, further wash-
ings with water, and a final drying stage in a vacuum freezer.
• These three anhydrous precursors underwent condensation polym-
erization under high vacuum at 175ºC to form the final copolymer,
poly(SA-CPP-PEG).
Results
We were able to successfully synthesize the copolymer, shown in Figure 1. The
structure is verified through the use of NMR spectrum. The NMR graph of the
copolymer is shown in Figure 2. SEM observation showed that the polyanhy-
drides exhibited typical surface erosion behavior (Figure 4). Multilayer pulsa-
tile delivery device was fabricated using lay-by-layer stacking technique (Fig-
ure 3) and the device was able to delivery up to seven pulses of protein (
bovine serum albumin) in vitro (Figure 5)
Conclusion
We were able to successfully synthesize the three-component polyanhy-
drides copolymer, poly(SA-CPP-PEG) and pulsatile device capable of deliv-
ering 7 pulses of drug was fabricated. This device will be implanted in mice
to study the effects of the PTH . If this method of delivering PTH is proven
successful in mice, then it can be tested in larger lab animals, like rats or rab-
bits, with the eventual goal of getting the delivery system into clinical test-
ing. If this delivery system for PTH is successful, it will revolutionize the treat-
ment of osteoporosis, and therefore increase the quality of life for those who
have the disease.
Method- Device Fabrication
• A hot press is then used to press the polymer into films of varying thickness,
from 50-300 µm. The film layers are then alternated with layers of PTH and the
resulting drug delivery device which was then implanted in mice to test the ef-
fects of the PTH.
Fig 4. SEM micrographs of (a) untreated polyanhydrides stored under vacuum and (b)polyanhydrides specimens after ero-
sion in 0.1M PBS at 37 °C for 12 h.
Fig 1. Synthesis route of sebacic acid (SA) anhydride precursor, 1,3-bis(p-carboxy-
phenoxy)propane (CPP）anhydride precursor, poly(ethylene glycol) PEG anhydride
precursor and SA-CPP-PEG polyanhydrides
Fig 5. In vitro release of BSA from pulsatile drug delivery device
Fig 3. Schematic illustration of fabrication process of im-
plantable pulsatile delivery device. (a) PCL (Polycaprolac-
tone) sealant layer, polyanhydrides isolation layers and
drug (PTH) layers were introduced into the ring hole. (b)
Layers compressed. (c) Ring removed. (d) PCL solution
(green) used to seal the edge; (e) Cross-section view of
finished device; (f) macroscopic images of the device (left:
quarter, right device).
Figure 2. (a)Chemical structure and (b)NMR spectrum of poly(SA-CPP-PEG)
b.
a.