LoftinAH _Smart_ Coatings for Spine Implant-Related Infection
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Transcript of LoftinAH _Smart_ Coatings for Spine Implant-Related Infection
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A novel implant coating to de l i ver an t ib io t ic through an active trigger mechanism in a spine infection mouse model
UCLA Department of
Orthopaedic Surgery
“Smart” Coatings: Amanda
H. Loftin
AALAS Annual Meeting
Wednesday Nov. 4th, 2015
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Despite advances in aseptic surgical technique & perioperative antibiotic use...
Chahound et. al. Front Med. 2014
.5 -18.8% of patients
post- operative infection is
reported to still occur in approximately
Undergoing spine surgeries. �
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Surgical site infection following spine surgery is a dreaded complication with significant:
Negative outcomes for the patient
Detrimental effects on the healthcare system
Economic burden
1
2
3
Stavrakis et. al. Front Med. 2015
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NEGATIVE FOR THE PATIENT
OUTCOMES
Neurological Compromise
Morbidity & Mortality
Disability
Abey DM et al J. Spinal Disord. 1995 Glassman SD et al Spine 1996
Levi ADO et al J. Neurosurg. 1997 Roberts FJ et al Spine 1998
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Several patient hospitalizations
Repeat surgeries
Long course of intravenous
followed by oral antibiotics
1
2
3
Detrimental EFFECTS ON THE HEALTHCARE SYSTEM
Stavrakis et. al. Front Med. 2015
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This amounts to huge costs, with the treatment of a single
implant-associated spinal wound infection potentially costing
more than $900,000
Stavrakis et al. Front Med. 2015
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Clinical Presentation
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1 year post-op
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
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1 year post-op
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
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Staphylococcus aureus remains that leading agent of spine implant
infections, responsible for around 50% of cases1
1. Chahoud et al. Front Med. 2014 2. Stavrakis et. al. Front Med. 2015
Staphylococcus epidermidis & Propionibacterium acnes
are also common pathogens 1-2
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BIOFILM FORMATION 1. Attachment of S. aureus to implanted surface
2. Growth Formation of an extracellular matrix that is not susceptible to antimicrobial killing.
3. Dispersal of further establishes the biofilm making treatment extremely difficult
Biofilms block penetration of immune cells and antimicrobials, promoting bacterial survival
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Orthopedic spinal implant infections are unique in that the implant is typically retained to prevent destabilizing
the spine making treatment more challenging
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
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13
��
Implants provide an avascular
surface for bacteria to form biofilm1-3
1. Cappen DA et al Orthop. Clin North Am 1996 2. Massie JB et al C. O. R.R., 1992 3. Knapp DR et al C. O. R.R. 1988
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from http://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
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��
The use of instrumentation increases the risk
of infection1-3
1. Cappen DA et al Orthop. Clin North Am 1996 2. Massie JB et al C. O. R.R., 1992 3. Knapp DR et al C. O. R.R. 1988
Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved fromhttp://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=3
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�The incidence of
spine implant related infection is:
���
1. Stavrakis et. al. Front Med. 2015 2. Chahoud et a. Front Med. 2014 3. Smith et. al. Spine. 2011.
1% without instrumentation1
3.4-10% with instrumentation1
One study reports a 28% higher infection rate with instrumentation
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Once biofilm is formed,
bacteria are 100-1,000 times less susceptible to
antibiotics1
Olsen et. al. J Neurosurg. 2003
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Prevention and
Treatment
17
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Modification of the host is difficult and often
beyond the surgeons control
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Reduction of preoperative risk factors is: timely, requires extreme patient compliance, and often impossible
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Diabetes ���Malnutrition���Obesity���Steroid therapy���Smoking������
Previous Spine Surgery���Cardiovascular problems Age >65���Steroid use���Immunosuppression���Gender���
Patient Risk Factors
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Some surgical risk factors can be modified by the surgeon to decrease risk of infection,
but this may compromise the intended benefit of the procedure
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In Implant Infection Prevention
21
Antibiotics
Implant
Host
Modifiable Factors
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Current methods of local antibiotic delivery
Short-lived Vancomycin powder
Via passive release from suboptimal loading vehicles
Antibiotic loaded beads
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Bardis, Alexander. (2014). Late Post-operative Spinal Infections [PowerPoint Slide]. Retrieved from ttp://www.slideshare.net/AlexanderBardis/postoperative-spinal-infection-65o-eexot?related=2
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No antibiotic barrier is present on the implant itself to protect it from
bacterial colonization and subsequent biofilm formation
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Develop a novel, non-toxic, biodegradable poly (ethylene
glycol )-propylene sulfide (PEG-PPS) polymer coating that can be used
As a vehicle to deliver antibiotics locally through both a passive and active mechanism. To actively release antibiotic in response to the reactive oxygen cascade initiated by the presence of bacteria, allowing the “smart” polymer to release
antibiotic where it is needed most.
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Existing animal models OUR NOVEL IN VIVO MOUSE MODEL
Inexpensive preclinical screen tool to evaluate the efficacy of treatments
Accurate
Rapid Large animals: 1. Costly 2.
Minimal engineering
options Histology based 1. Significant euthanasia 2. Requires large numbers 3. Labor intensive
EVALUATION OF EXISTING
ANIMAL MODELs
Mouse Surgical model
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Combines the use of bioluminescent bacteria and genetically modified mice with advanced imaging to
noninvasively monitor infection and inflammation in real time, without requiring euthanasia. Provides a rapid, accurate, and inexpensive in vivo
preclinical screening tool to evaluate the efficacy of potential strategies to prevent or treat implant related spine infections.
Strengths of our model
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Postoperative evaluation of infection and inflammation
Bioluminescence and fluorescence
imaging
PODs* 0, 1, 3, 5, 7, 10, 14, 18,
21, 28, 35
POD 35
24 lysEGFP mice (12 wks., male)
POD 35
Evaluation of bacterial burden
& immune response
Visualization of biofilm on implant
Colony forming units (CFUs)
harvested from implant and joint tissues
Variable Pressure Scanning Electron
Microscopy (VP-SEM)
ex vivo confirmation of bacterial
burden
POD 0: Intraoperative inoculation of
S. aureus Xen36
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Provides a rapid, accurate, and
inexpensive in vivo preclinical screening
tool to evaluate the efficacy of potential strategies to prevent or
treat implant related spine infections.
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Discussion & Conclusions
This model has unique elements that may: Complement or provide an alternative to previous
animal models of spine implant infections.
1x103 CFU is the ideal inoculum
of S. aureus Xen 36 to establish
a chronic implant-related infection as higher doses cause wound breakdown and lower doses can be cleared by the immune system.
Replace euthanasia with noninvasive real-time
in vivo imaging and provides a direct measurement
of bacterial burden and host neutrophilic inflammatory
response longitudinally in the same animals in real-time.
Mouse model as a platform to test clinical aims Mechanism- p a t h w a y a n a l y s i s
Applicability-coatings Innovation-new antimicrobials
Evaluation of antibiotic & antimicrobial coatings
Immune response to chronic implant related spine infection
Can we redesign orthopedic antibiotics
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“Smart” Coatings
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PEG-PPS Coating
32
OO
OHm
OO S
SS
S Nm n
NaH
OO
Om
Br
AIBNSH
O
OO
O S
OS
OO S
SS
m n
N S S N
1. 2.
NaOMe
star PEG-PPS
star PEG OHOHOHOH
SHSi
OOOOH
SHSiOCH3
OCH3
H3CO+
Implant
A B
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Polyethylene glycol polymer
33
• Coating of optimal “timed” release • Coating of targeted abx
!
!
S O OOSSPPS PEG
Antibiotic
0.5% Star PEG-PPSsolution at 4°C
Dry coat at 37°C
Implant
Implant
!
!Figure!7.!Antibiotic!loaded!implant!coating!process!using!star!PEG6PPS!polymer.!A!solution!of!star!0.5%!PEG6PPS!with!antibiotic!will!be!used!to!rapidly!coat!the!implant.!Metal!implants!will!first!be!silanized!to!introduce!–SH!(thiol)!groups.!Pictures!show:!(A)!uncoated!metal!implants!and!(B)!coated!implants!with!star!PEG6PPS/Rhodamine,!which!can!be!seen!as!a!purple/red6colored!coating!on!the!implant.!!
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Titanium Pins Uncoated 3% PEG-‐PPS 6% PEG-‐PPS
Polymer is low profile: nano-‐micro scale
Covalent linkage: resistant to wear
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Antibiotic Release
0
5
10
15
20
25
30
0 1 2 3 4 5 6 7
Ti Pins: Cumulative Release Profile
6% PEG-PPS3% PEG-PPS
Days
!Daily Release (µg per pin/mL PBS) 3 % PEG-PPS 6 % PEG-PPS
1d 53.77 ± 25.85 136.89 ± 33.64
2d 2.47 ± 0.42 6.52 ± 3.19
3d 2.66 ± 0.62 2.01 ± 0.33
4d 2.25 ± 0.72 2.04 ± 0.04
5d 2.03 ± 0.17 1.82 ± 0.59
6d 2.32 ± 1.14 1.93 ± 0.07
7d 2.28 ± 1.65 1.08 ± 0.60
Daily release is above the minimum inhibitory concentration (MIC) for S. aureus
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Surgical Procedure
36
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Do “smart” coatings work in vivo?
37
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In vivo efficacy of PEG-PPS coatings
38
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Ex Vivo Bacterial Counts
39
0
1000
2000
3000
4000
5000
6000
Col
ony
Form
ing
Uni
ts
PEG Vanc Tig
Tissue Colony Forming Units Post-Operative Day 21
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PEG-PPS is an optimal vehicle to deliver antibiotics in the setting of spinal implants as it passively delivers antibiotics above the MIC and actively increases drug delivery in the presence of bacteria.
The Vanc impregnated PEG-PPS coating
prevented implant colonization by bacteria and
prevented implant infection completely
This novel coating shows promise in the prevention and/or treatment of orthopaedic spine implant infections and further large animal studies and biosafety studies are warranted.
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Now that we have a vehicle to deliver antibiotics, can we redesign
antibiotics?
41
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Introducing Pentobra
Published in: Nathan W. Schmidt; Stephanie Deshayes; Sinead Hawker; Alyssa Blacker; Andrea M. Kasko; Gerard C. L. Wong; ACS Nano 2014, 8, 8786-8793. DOI: 10.1021/nn502201a Copyright © 2014 American Chemical Society
P. acnes
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Special Thanks
43
Bernthal Lab Alexandra Stavrakis Yan He Erik Dworsky Jannifer Manegold
Los Angeles Orthopaedic Hospital
Fabrizio Billi, PhD
CRUMP INSTITUTE OF MOLECULAR IMAGING
David Stout, PhD
Center for Experimental Medicine, University of Tokyo, Japan
Yoichiro Iwakura, D. Sc,
Cedars-Sinai George Liu, M.D., PhD Moshe Arditi, M.D.
Caliper Life Sciences
Kevin Francis, Ph.D. Department of Biomedical Engineering. UC. Davis
Scott Simon, Ph.D.
UCLA Orthopaedic Hospital Research Center
John Adams, MD Jeff Miller, MD
UCLA Department of Orthopaedic Surgery
Jeffrey Eckardt, MD Gerald Finerman, MD
Department of Microbiology and Immunology. Dartmouth Medical School
Ambrose Cheung, MD