Molecular Imaging Assessment of ACL Viability
Phase: NA
Conditions: ACL Injury
Sponsor: University of Cincinnati

Protocol Title: 
Molecular Imaging Assessment of ACL Viability 
 
Protocol Date: 
March 13, 2013 
 
Principal Investigator: 
Michael V. Knopp, MD, PhD 
Professor of Radiology and Novartis Chair of Imaging Research 
Vice Chair of Research, Department of Radiology 
395 West 12th Avenue, 4th Floor 
Columbus, OH 43210 
 
Knopp.16@osu.edu 
 
Office: 614-293-9998 
Fax: 614-293-9275 

Page 2 of 7 
Protocol Date: March 13, 2013 
 
 
I.   Objectives 
 
Primary Research Question: 
1.   Does the appearance of the reconstructed anterior cruciate ligament (ACL) 
vary in appearance on PET/MRI depending on graft type and time after 
surgery? 
 
Secondary Research Question: 
1.   What is the appearance of the native ACL on Positron Emission 
Tomography/Magnetic Resonance Imaging (PET/MRI)? 
 
II. Background and Rationale 
 
The ACL is commonly injured and is the most frequently reconstructed ligament of the 
knee. Reconstructive techniques have evolved over time with variable results.11 Modern 
techniques allow clinically stable ligament reconstruction in the majority of cases; however, 
failed reconstruction continues to be a problem with failure rates for ACL reconstruction 
reported to be between 5 and 20%. 
 
The use of allograft tissue in ACL reconstruction has been associated with increased graft 
failure rates.3 While the etiology increased allograft failure rates is unclear and likely 
multifactorial, different patterns of revascularization and ligamentization may contribute. 
This process typically follows a regular pattern.12 Vascular invasion of the graft is noted 
by three weeks, but the central portion remains poorly vascularized compared to the distal 
and proximal ends.2 By about eight weeks post-operative, the entire graft is generally 
revascularized when autograft is used.1 Numerous animal studies5, 9, 14 have demonstrated 
slower revascularization and a magnetic resonance imaging (MRI) study13 in humans has 
suggested slower ligamentization in allografts. Complete ligamentization of the central 
portion may never occur in some cases.8  In addition, these studies demonstrate that the 
ligamentization process is quite variable among individuals. 
 
The  last  thirty  years  have  also  witnessed  a  significant  shift  in  the  approach  to 
rehabilitation following ACL reconstruction.4 Protocols have moved away from 
immobilization and bracing in favor of early weight-bearing and restoration of range of 
motion and muscle control.4, 17 These changes have resulted in decreased incidence of 
flexion  contractures6,  15   and  earlier  return  of  muscle  strength  and  control.16   These 
protocols have also decreased the time required for athletes’ strength and function to 
return to levels required for return to sport. Returning injured athletes to play as quickly 
as is safely possible following ACL reconstruction has become an area of intense interest 
in recent years. While numerous studies have demonstrated the safety of early mobilization 
and strengthening activities, earlier return to unrestricted sports is supported by significantly 
less data. One retrospective study has shown no difference in objective knee stability or 
patient reported outcome with return to play between 2 and 6 months compared to return 
to play between 7 and 14 months.7  However, in addition to being 

Page 3 of 7 
Protocol Date: March 13, 2013 
 
small and underpowered to address the issue of graft failure, this study utilized older 
surgical and rehabilitation techniques that do not necessarily reflect current practice. 
 
Given the different rates of ligamentization noted among individuals as well as graft 
types and the desire to return athletes to sport as early as possible, a tool that could quantify 
the revascularization and incorporation of an ACL graft would be highly useful. Positron 
emission tomography (PET) scans have the capacity to demonstrate revascularization as 
well as metabolic activity of tissues. Recent technologic advances have improved the 
resolution of PET scans and the imaging of structures such as the anterior cruciate ligament 
is now possible. In addition, advances in ACL imaging techniques such as chemical 
exchange saturation transfer (proteinCEST) have improved the  ability  of  MRI  to  assess  
the  intra-articular  environment.10   We  propose  to  use PET/MRI to evaluate intact and 
reconstructed ACL tissue to assess the utility of this technique in ligament imaging. 
 
III.  Procedures 
 
A.  Research Design 
 
This Phase I feasibility trial will evaluate knee injuries utilizing a standard of care non-
contrast 3 Tesla (T) MRI. In addition, knee injuries will be assessed with a low dose 
(1/5 of the dose given for standard of care PET scans) fluorodeoxyglucose (FDG) PET 
research scan with CEST sequences. Patients enrolled in this study will include both 
those with and without a  history of ACL repair; however, patients receiving the 
standard of care MRI will not be currently suspected of having an ACL injury based 
on physical examination and history. 
 
Patients with and without a history of ACL reconstruction will undergo a low dose 
FDG PET scan in the same setting as their MRI. The PET examination will be 
performed such that the early phase of imaging is performed prior to the MRI and 
the delayed phase is completed immediately following the MRI. This dual-phase 
scanning will allow for both assessment of the vascularity of the graft as well as its 
metabolic activity. 
 
Patients will be asked to provide study personnel with authorization to their medical 
records regarding the outcome of the knee graft. This authorization will be provided 
for 10 years from date of signed consent. 
 
Comparisons  of  the  finding  in  normal  and  reconstructed  ligaments  as  well  as 
between  graft  types  based  on  time  from  reconstruction  will  demonstrate  the 
feasibility of this imaging technique and allow for generation of an imaging based 
hypothesis that will provide metabolic activity of the graft in a post-operative knee. 

Page 4 of 7 
Protocol Date: March 13, 2013 
 
B.  Sample 
 
The study population will include 100 evaluable patients between 18 and 60 years of 
age undergoing a standard of care MRI at OSU. All patients will have no current or 
suspected ACL injuries based on a physical examination and patient history. Five 
patients will not have a history of ACL injury or reconstruction and 95 patients will 
have a history of ACL reconstruction. The 100 patients will be selected to include a 
variety of graft types (autograft and allografts) at a variety of time points after surgery. 
 
Inclusion Criteria: 
• Male and female patients between 18 and 60 years of age. 
• Patients scheduled for a standard of care MRI at OSU. 
 
Exclusion Criteria: 
• Patients with a suspected ACL injury. 
• Patients who are pregnant or lactating. 
• Patients who are prisoners. 
• Patients who are unable to provide consent. 
• Patient  with  significant  renal  insufficiency,  i.e.  an  estimated  glomerular 
filtration rate (eGFR) less than 30 mL/min/1.73m2. 
• Patients who exhibit noticeable anxiety and/or claustrophobia or who exhibit 
sever vertigo when they are moved into the MR. 
• Subjects with any type of bioimplant activated by mechanical, electronic, or 
magnetic means (e.g., cochlear implants, pacemakers, neurostimulators, 
biostimulators, electronic infusion pumps, etc.). 
• Subjects with any type of ferromagnetic bioimplant that could potentially be 
displaced or damaged. 
• Subjects that have vascular or aneurysm clips, or metallic staples from a 
surgical procedure. 
• Subjects with permanent tattoo eye liner (may contain metallic coloring). 
• Subjects that may have shrapnel imbedded in their bodies, such as from war 
wounds, metal workers and machinists (metallic fragments in or near eyes), 
severe auto accident victims. 
 
C.  Detailed Study Procedures 
 
For each participant, written informed consent will be obtained prior to any protocol 
related activities. As part of this procedure, the principal investigator or one of the 
study personnel will explain orally and in writing the nature, duration, and purpose of 
the study as well as all associated risks and benefits. They will inform the patient that 
he/she may withdraw from the study at any time.  At the time of consent, patients will 
complete an MRI Subject Screening that will assess the patient’s compatibility with the 
MR scanner. 

Page 5 of 7 
Protocol Date: March 13, 2013 
 
Patients interested in taking part in the study will undergo a complete standardized knee 
examination by one of the orthopaedic surgeons on the research team. Patients will also 
complete a patient-oriented knee evaluation form that captures prior knee history and 
allows calculation of patient reported knee scores including the subjective International 
Knee Documentation Committee (IKDC) score, the Knee injury Osteoarthritis Outcome 
Score (KOOS), and the Marx activity score. 
 
All patients will undergo a low dose PET scan in the same setting as their MRI. The 
MRI will include standard diagnostic sequences as well as a protein/CEST sequence. 
This additional sequence will add about 15 minutes to the study and carries no additional 
risk. The PET examination will be performed such that the early phase of imaging is 
performed prior to the MRI and the delayed phase immediately following the MRI. This 
dual-phase scanning will allow for both assessment of the vascularity of the graft as 
well as its metabolic activity. 
 
Patients will be asked to lie about 90 minutes in the PET system. The imaging maybe 
interrupted to allow the patient to void the bladder. 
 
Risks: 
Patients will have an intravenous injection of FDG.   There is slight risk of 
inflammation, infection, or hematoma from the i.v. and there is some associated 
discomfort.  This is a standard procedure for many diagnostic tests.  The i.v. will be 
removed prior to the positioning of the patient within the PET scanner.  There is a 
remote possibility of an allergic reaction to FDG, though we are unaware of any reported 
incidents. 
 
Patients will receive radiation exposure as a result of this research project. It is estimated 
that patients will be exposed to an effective dose equivalent of 550 millirem related to 
the F-18 FDG radiotracer (based on 5 mCi estimated dose) per scan, and an effective 
dose equivalent of 20 millirem related to a low dose CT of the knee, for a total effective 
dose equivalent of 570 millirem. 
 
The MRI will include standard diagnostic sequences as well as a protein/CEST 
sequence. This additional sequence will add about 15 minutes to the study and carries 
no additional risk. 
 
Benefits: 
Possible benefits for some participants include insight into the status of their ACL 
graft as determined by the PET results. All scans will contribute to improvements in our 
understanding of graft incorporation and failure mechanisms in ACL reconstruction. 
 
 
 
 
 
 
 
References 

Page 6 of 7 
Protocol Date: March 13, 2013 
 
 
1. 
Alm A, Gillquist J, Stromberg B. The medial third of the patellar ligament in 
reconstruction of the anterior cruciate ligament. A clinical and histologic study by 
means of arthroscopy or arthrotomy. Acta Chir Scand Suppl. 1974;445:5-14. 
PMID: 4528792. 
2. 
Arnoczky SP, Warren RF, Ashlock MA. Replacement of the anterior cruciate 
ligament using a patellar tendon allograft. An experimental study. J Bone Joint 
Surg Am. Mar 1986;68(3):376-385. PMID: 3949832. 
3. 
Borchers JR, Pedroza A, Kaeding C. Activity level and graft type as risk factors 
for anterior cruciate ligament graft failure: a case-control study. Am J Sports Med. 
Dec 2009;37(12):2362-2367. PMID: 19684294. 
4. 
De Carlo MS, McDivitt R. Rehabilitation of Patients Following Autogenic Bone- 
Patellar Tendon-Bone ACL Reconstruction: A 20-Year Perspective. N Am J 
Sports Phys Ther. Aug 2006;1(3):108-123. PMID: 21522223. 
5. 
Dustmann M, Schmidt T, Gangey I, Unterhauser FN, Weiler A, Scheffler SU. The 
extracellular remodeling of free-soft-tissue autografts and allografts for 
reconstruction of the anterior cruciate ligament: a comparison study in a sheep 
model. Knee Surg Sports Traumatol Arthrosc. Apr 2008;16(4):360-369. PMID: 
18183370. 
6. 
Frndak PA, Berasi CC. Rehabilitation concerns following anterior cruciate 
ligament reconstruction. Sports Med. Nov 1991;12(5):338-346. PMID: 1763251. 
7. 
Glasgow SG, Gabriel JP, Sapega AA, Glasgow MT, Torg JS. The effect of early 
versus late return to vigorous activities on the outcome of anterior cruciate 
ligament reconstruction. Am J Sports Med. Mar-Apr 1993;21(2):243-248. PMID: 
8465920. 
8. 
Hulstyn M, Fadale PD, Abate J, Walsh WR. Biomechanical evaluation of 
interference screw fixation in a bovine patellar bone-tendon-bone autograft 
complex for anterior cruciate ligament reconstruction. Arthroscopy. 
1993;9(4):417-424. PMID: 8216573. 
9. 
Jackson DW, Grood ES, Goldstein JD, et al. A comparison of patellar tendon 
autograft and allograft used for anterior cruciate ligament reconstruction in the 
goat model. Am J Sports Med. Mar-Apr 1993;21(2):176-185. PMID: 8465909. 
10. 
Jia G, Takayama Y, Flanigan DC, et al. Quantitative assessment of mobile protein 
levels in human knee synovial fluid: feasibility of chemical exchange saturation 
transfer (proteinCEST) MRI of osteoarthritis. Magn Reson Imaging. Apr 
2011;29(3):335-341. PMID: 21292419. 
11. 
McCulloch PC, Lattermann C, Boland AL, Bach BR, Jr. An illustrated history of 
anterior cruciate ligament surgery. J Knee Surg. Apr 2007;20(2):95-104. PMID: 
17486900. 
12. 
Menetrey J, Duthon VB, Laumonier T, Fritschy D. "Biological failure" of the 
anterior cruciate ligament graft. Knee Surg Sports Traumatol Arthrosc. Mar 
2008;16(3):224-231. PMID: 18183368. 
13. 
Muramatsu K, Hachiya Y, Izawa H. Serial evaluation of human anterior cruciate 
ligament grafts by contrast-enhanced magnetic resonance imaging: comparison of 
allografts and autografts. Arthroscopy. Sep 2008;24(9):1038-1044. PMID: 
18760212. 

Page 7 of 7 
Protocol Date: March 13, 2013 
 
14. 
Nagano J, Shino K, Maeda A, Nakata K, Horibe S. The remodelling process of 
allogeneic and autogenous patellar tendon grafts in rats: a radiochemical study. 
Arch Orthop Trauma Surg. 1996;115(1):10-16. PMID: 8775703. 
15. 
Noyes FR, Barber-Westin SD. A comparison of results in acute and chronic 
anterior cruciate ligament ruptures of arthroscopically assisted autogenous patellar 
tendon reconstruction. Am J Sports Med. Jul-Aug 1997;25(4):460-471. PMID: 
9240979. 
16. 
Shaw T, Williams MT, Chipchase LS. Do early quadriceps exercises affect the 
outcome of ACL reconstruction? A randomised controlled trial. Aust J 
Physiother. 2005;51(1):9-17. PMID: 15748120. 
17. 
Shelbourne KD, Nitz P. Accelerated rehabilitation after anterior cruciate ligament 
reconstruction. Am J Sports Med. May-Jun 1990;18(3):292-299. PMID: 2372081.