covalently -controlled release biologically active bone

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


Features that make cement strong also make it a challenging platform for bioactivity

(2)(1)



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)



Admixed cements for

local drug deliveryStandard bioinert

PMMA cement

Homogenous cement


(2)(1)



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





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





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



Admixed cements for

local drug delivery

Admixed drugs aggregate,

forming weak points

Standard bioinert

PMMA cement

Homogenous cement


(2)(1)



(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


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


Admixed cements (10 wt% drug)

SMAAMA

BMA

salacebenz

AMA

SMA

BMA

benz

ace

sal


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


SMAAMA

BMA

AMA

SMA

BMA


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

covalently -controlled release biologically active bone

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