covalently -controlled release biologically active bone
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Zoe Wright / ORCID 0000-0003-2090-1538
Therapeutic methacrylic (TMA) comonomers transform standard medical adhesives into
mechanically robust platforms for tunable, covalently-controlled local drug delivery
Zoe Wright
Carnegie Mellon University, Department of Chemistry.
Sydlik lab
ACS Spring 2020
Slide 1
Zoe Wright Team Sydlik April 2020
Biologically active bone cements via covalently-controlled release
ORCID 0000-0003-2090-1538
Millions of people in the US are currently living with an orthopedic implant.
My research focuses on creating materials to improve the longevity and function of these
implants, especially by creating new methods for controlled release based on principles of
organic chemistry.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 2
Many orthopedic implants are anchored with bone cement, which serves as a “grout”
2 / ORCID 0000-0003-2090-1538 (1) Berry, DJ et al. J Bone Joint Surg Am. 2015, 97 (17), 1386–1397.
DMPT
activator
MMA
monomer
PMMA
filler
BPO
initiator
Liquid Solid
Many orthopedic implants are anchored with bone cement. Bone cement typically has two
components, a liquid component (which contains Methyl Methacrylate, MMA, monomer and an
activator) and a solid component (which contains a polymeric filler, often PMMA, and a radical
initiator). Combining the two components initiates a free radical polymerization, which is
responsible for the cement cure.
Bone cement relies on mechanical interlock to create adhesion to bone.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 3
Up to 15% of implants fail(1) because the interface between cement and bone is static
3 / ORCID 0000-0003-2090-1538
(1) Katz, J. N. et al. PLOS ONE. 2010, 5 (10), e13520; Hungerford, D. S. et al. J. Biomed. Mater. Res. 1999, 48 (6), 889–898.
(2) Mann’s Surgery of the Foot and Ankle: Expert Consult. Elsevier Health Sciences, 2013. p 1081
(3) Koob, S., Essler, M. et al. Oncotarget. 2019, 10 (22), 2203–2211.
18F PET/CT Fusion
(2) (3) (3)
A significant number of orthopedic implants fail at the interface between the cement and the
surrounding bone. Cement is static, while bone is dynamic, which eventually leads to
degradation of that interface and loosening of the implant.
In these cases, cement begins as a snug fit, but over time, loosening occurs. Bone eventually
pulls away from cement.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 4
Interfacial loosening is related to the biological inertness of PMMA cement
4 / ORCID 0000-0003-2090-1538
(1) Miller, MA et al. Comput Methods Biomech Biomed Engin. 2014, 17 (16), 1809–1820.
(2) Ellison, P et al. Acta Orthopaedica. 2018, 89 (1), 77–83.
(3) Saha et al. Prog Biomater. (2012).
(1)
(2)
(3)
(1)
▪ Not tissue-adhesive
▪ Unresponsive to dynamic bone
▪ Wear debris is persistent
Interfacial loosening is related to the fact that PMMA-based bone cement is inert in the
biological environment. PMMA cement is not inherently tissue adhesive, and is unresponsive to
bone, which is dynamic. Over time, bone will change around the cement, leaving pockets in the
cement that are especially susceptible to physical wear damage. The resulting wear particles
are chemically resistant to degradation in the biological environment, and so tend to persist in
the tissue around the implant, where they cause inflammation. Inflammation can further push
this cycle along.
Finding ways to incorporate bioactivity into PMMA cement could help break this cycle.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 5
5 / ORCID 0000-0003-2090-1538 (1) US Patent Application No. 16/332,511;
Strength derived from
densely entangled chains
Standard bioinert
PMMA cement
Homogenous cement
distributes force evenly
Features that make cement strong also make it a challenging platform for bioactivity
(1)
The features that make cement mechanically strong also make it a challenging platform for
bioactivity. Standard PMMA cement derives its strength from densely entangled polymer chains,
and a bulk material that is homogenous and can distribute mechanical forces evenly.
But if you try to incorporate bioactivity by mixing drugs into PMMA cement…
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 6
6 / ORCID 0000-0003-2090-1538 (1) US Patent Application No. 16/332,511; (2) Saha et al. Prog Biomater. (2012)
Drug must diffuse through
dense hydrophobic matrix
Admixed cements for
local drug delivery
Drug particles aggregate,
forming weak points
Standard bioinert
PMMA cement
Homogenous cement
distributes force evenly
Features that make cement strong also make it a challenging platform for bioactivity
(2)(1)
Strength derived from
densely entangled chains
Bioactive additives to bone cement face many challenges. When admixing bioactive additives
(like drugs) into bone cement, these additives tend to aggregate, forming weak points that
compromise the strength of the cement. Also, these additives then become trapped within the
dense, hydrophobic matrix of the cement, leading to low release efficiency and limited biological
effect.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 7
7 / ORCID 0000-0003-2090-1538
(1) US Patent Application No. 16/332,511; (2) Saha et al. Prog Biomater. (2012)
(3) Meyer, PR et al. J. Biomed. Mater. Res. 1976, 10 (6), 929–938.;
(4) Rashid et al. JBJS Essential Surgical Tech. (2007),
Bioactive cements often end up being temporary – only for worst-case scenarios
(4)
Drug must diffuse through
dense hydrophobic matrix
Admixed cements for
local drug deliveryStandard bioinert
PMMA cement
Homogenous cement
distributes force evenly
(2)(1)
Strength derived from
densely entangled chains
Drug particles aggregate,
forming weak points
(3)
Ultimately, “bioactive cements” are limited to worst case scenarios (like implant loosening
caused by severe infections) or to smaller, less severe injuries in non-loadbearing parts of the
body.
When implant loosening is caused by a severe bone infection, the standard of care involves
admixing antibiotics into bone cement to provide local delivery of the antibiotics. But, antibiotic
eluting bone cements face a serious trade-off: they must achieve sufficient dose for therapeutic
effect, but this severely compromises mechanical strength – so much so that these materials
are not load-bearing. Treatment involves multiple surgeries, and in the recovery period between
surgeries, patients have severely limited mobility.
You encounter similar problems if try to incorporate osteoconductive materials into bone
cements to help cells adhere to cements.
So, to address this need for a load-bearing bioactive cement, we have designed a platform for
delivering therapeutics that prevents aggregation and facilitates drug release…
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 8
Our Therapeutic Methacrylic (TMA) comonomers
provide a robust platform for controlled release
8 / ORCID 0000-0003-2090-1538Wright, ZM; Sydlik, SA et al. J Mater Chem Part B (2017)
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
Rather than mix the drug payload as a solid into the solid component, we designed a new family of therapeutic monomers that can be added to the reactive liquid component of the cement. These Therapeutic Methacrylic (TMA) comonomers carry a drug payload via a covalent tether that links it to a polymerizable double bond. The covalent tether is designed to undergo hydrolysis in biological conditions, which releases the drug payload.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 9
Our Therapeutic Methacrylic (TMA) comonomers
provide a robust platform for controlled release
9 / ORCID 0000-0003-2090-1538Wright, ZM; Sydlik, SA et al. J Mater Chem Part B (2017)
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
Conventional
monomer MMA
TMA
comonomers
I synthesized three TMA monomers with different drug payloads and different carbonyl tethers. These monomers should have different reactivities to hydrolysis, providing different profiles of drug release.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 10
Our Therapeutic Methacrylic (TMA) comonomers
provide a robust platform for controlled release
10 / ORCID 0000-0003-2090-1538Wright, ZM; Sydlik, SA et al. J Mater Chem Part B (2017)
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
MMA
R·
MMA
R·
MMA
R·
TMAs copolymerize with matrix monomers
to form statistical copolymersTether bond ‘X’ controls
drug release covalently
These TMA comonomers are designed to copolymerize with the matrix monomer of bone
cement (methyl methacrylate, MMA), creating statistical copolymers decorated with drug side
groups. This technology essentially enables the creation of a polymeric prodrug in situ during
cement cure, and distributes the drug payload throughout the cement rather than allowing it to
aggregate.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 11
Therapeutic Methacrylic (TMA) comonomers are
a more robust platform for controlled release
11 / ORCID 0000-0003-2090-1538(1) US Patent Application No. 16/332,511; (2) Saha et al. Prog Biomater. (2012)
(3) Wright, ZM; Sydlik, SA et al. Macromol. (2019)
TMA tethered payload is
exposed at surface
Bioactive
TMA cement
TMAs distribute drug
payload homogenously
200 µm
Drug must diffuse through
dense hydrophobic matrix
Admixed cements for
local drug delivery
Admixed drugs aggregate,
forming weak points
Standard bioinert
PMMA cement
Homogenous cement
distributes force evenly
(2)(1)
Strength derived from
densely entangled chains
(3)
TMA cements distribute drug payload throughout the cement, creating materials that are
homogenous and without aggregate pockets. Further, TMAs are unique in that they allow a
greater fraction of the drug payload to be exposed at the surface of the cement and available for
controlled release over the course of days (rather than hours) compared to typical admixed
cements.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 12
TMA cements release drug efficiently compared to admixed cements
12 / ORCID 0000-0003-2090-1538
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25
mg
dru
g r
ele
ase
dp
er
g c
em
en
t
time (d)
0
0.5
1
1.5
2
2.5
0 5 10 15 20 25
mg
dru
g r
ele
ase
dp
er
g c
em
en
t
time (d)
TMA cements (3 wt% TMA)
Admixed cements (10 wt% drug)
SMAAMA
BMA
salacebenz
AMA
SMA
BMA
benz
ace
sal
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
When we examine the release of drugs from TMA cements compared to cements that contain
the same drug payload incorporated via admixing (no covalent tether), we see that a greater
percentage of the payload is released from TMA cements than admixed cements.
TMAs offer a different release pattern than admixed cements, which provides more tools for
achieving precise patterns of drug release.
And even with a lower loading of drug (3 vs 10 wt %), our TMA cements release comparable or
greater doses of the drug per g of cement than the admixed cements.
Note that the AMA cement releases acetaminophen more than 6 times as efficiently as the
admixed acetaminophen cement.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 13
TMA cements release drug efficiently without losing mechanical integrity
13 / ORCID 0000-0003-2090-1538
0
25
50
75
100
125
150
fresh aged
Com
pre
ssiv
e
str
en
gth
(M
Pa
)
10
100
1,000
fresh aged aged
E' (M
Pa
)
(acidic) (neutral)
(neutral)
PMMAControl cement
SMATMA cements AMA BMA
ASTM minimum compressive strength
salAdmixed cements ace benz
TMA cements (3 wt% TMA)
Admixed cements (10 wt% drug)
SMAAMA
BMA
salacebenz
AMA
SMA
BMA
benz
ace
sal
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
The compressive strengths of TMA cements are unchanged after aging in PBS buffer at 37°C
for four months. All TMA cements outperform all admixed cements, fresh and aged. Thus, TMA
comonomers provide a platform for drug release from bone cements that does not compromise
the mechanical strength of the cements.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 14
Release pattern isn’t what we first expected – could cure behavior influence release?
14 / ORCID 0000-0003-2090-1538
TMA cements (3 wt% TMA)
SMAAMA
BMA
AMA
SMA
BMA
Wright, ZM; Sydlik, SA et al. Macromol. (2019)
More susceptible to
hydrolysis than AMA,
but releases more slowly
Position of TMAs in cement copolymer may influence release
The patterns of release we observed for the two ester-tethered TMAs are not exactly what we
first expected. SMA, which uses an electron-deficient ester tether, should be more susceptible
to hydrolysis than AMA, which uses a more electron-rich ester tether; however, the SMA cement
showed slower release of its drug tether than the AMA cement.
Secondary to the susceptibility of each TMA to hydrolysis, we hypothesized that differences in
cure behavior between the three TMAs might affect the release profile.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 15
1H NMR was used to study the kinetics of how TMAs and MMA might react during cure
15 / ORCID 0000-0003-2090-1538
TMA
(slow)
MMA
(fast)
monomer
(MMA)
polymer
(PMMA)
t = 0 min
t = 60 min
DMSO-d6
KPS, 50°C
We used in situ 1H Nuclear Magnetic Resonance (NMR) Spectroscopy to track the kinetics of
copolymerization between each TMA and the matrix monomer MMA. We used the
disappearance of signals in the vinyl region to quantify consumption of monomer over time.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 16
Copolymer architecture likely influences drug release by TMAs
16 / ORCID 0000-0003-2090-1538 Wright, ZM; Sydlik, SA et al. Macromol. (2019)
From the in situ 1H NMR data, I calculated reactivity ratios for each TMA/ MMA pair, and
determined that each TMA/ MMA pair should produce a different type of copolymer architecture.
For example, the reactivity ratios for SMA/ MMA suggest an alternating-type architecture, where
there are no adjacent SMA units. By contrast, the reactivity ratios for BMA/ MMA suggest a
blockier architecture, where MMA units are preferentially consumed first, and BMA units are
consumed later. The reactivity ratios for AMA/ MMA are intermediate, suggesting a statistical
architecture where AMA units may neighbor each other. Secondary to the susceptibility of
individual TMAs to hydrolysis, these differences in copolymer architecture may influence the
profiles of drug release from TMA cements.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 17
TMAs make cement more uniform without compromising working time
17 / ORCID 0000-0003-2090-1538 Wright, ZM; Sydlik, SA et al. Macromol. (2019)
0
100
200
300
400
3 min 10 min
Mn
(kD
a)
0
100
200
300
400
3 min 10 min
Mw
(kD
a)
1.00
1.25
1.50
1.75
2.00
2.25
3 min 10 min
Ð
PMMA SMA AMA BMA
PMMA polymer filler
MMA
R·
MMA
R·
MMA
R·
I also examined the evolution of molecular weight in TMA cements over time by sampling
cements at two points during cure and performing Gel Permeation Chromatography (GPC).
Early in cure, TMAs are similar to PMMA in molecular weight. The values reported by GPC at
the 3 minute mark are dominated by the cement’s polymer filler, which is the same for all
cements, rather than the newly growing polymers responsible for cure.
But later, TMA cements achieve higher molecular weights – and lower dispersities, meaning the
polymers formed when TMA cements cure are more uniform in size than standard PMMA
cement.
Also, there is no major effect on dough time or working time for TMA cements, so surgeons could incorporate these materials into standard operating room procedures seamlessly.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 18
TMAs are a promising tool for adding bioactivity to bone cement
18 / ORCID 0000-0003-2090-1538
SMAAMA
BMA
0
25
50
75
100
125
150
fresh aged
Com
pre
ssiv
e s
tre
ng
th
(MP
a)
200 µm
In conclusion, TMAs offer:
• Modular payload,
• Tunable, efficient, local drug release,
• No disruption to mechanical strength,
• And seamless integration into current medical practices.
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 19
Thanks!
The Pittsburgh News Company. "Tichnor Quality Views,“ Tichnor Bros., Inc.
19 / ORCID 0000-0003-2090-1538
Zoe Wright / ORCID 0000-0003-2090-1538
Slide 20
Acknowledgements
20 / ORCID 0000-0003-2090-1538
Committee Members
• Professor Newell Washburn
• Professor Krzysztof Matyjaszewski
Team Sydlik!
Kwolek Fellowship
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