Clinical trial NCT04993339
Conditions: ACL Injury
Sponsor: University of Miami
Start date: 2016-10-24; Completion date: 2020-02-20
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study is to determine whether the use of injectable osteoinductive/osteoconductive compounds (OOC) during Anterior Cruciate Ligament (ACL) reconstructive surgery, combined with an accelerated rehabilitation protocol (ARP) provides clinical outcomes superior to those attained via traditional ACL reconstruction and delayed rehabilitation protocols.

Detailed description:

Arms: arm 1: Participants in this group undergoing standard of care reparative surgery will not receive additional intervention arm 2: Participants in this group undergoing standard of care reparative surgery will receive OOC as an additional intervention
Interventions: intervention 1: OOC
Intervention descriptions: intervention 1: The OOC will be mixed with autologous 5cc of platelet rich plasma (PRP), and then injected using a syringe into both tibia and femoral tunnels

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Clinical Outcomes of Hamstring ACL Reconstruction 
Augmented by an Injectable 
Osteoconductive/Osteoinductive Compound 
 
 
NCT04993339 
 
Version:7  
 
3/30/2017 
 
 


 
1) 
Protocol Title 
Clincal outcomes of ACL reconstruction augmented by an injectable 
osteoconductive/osteoinductive compound 
 
2) 
Objectives* 
The goal of this study is to determine whether the use of injectable 
osteoinductinve/osteoconsuctive compounds (OOC) during ACL reconstructive 
surgery, combined with an accelerated rehabilitation protocol (ARP) provides 
clinical outcomes superior to those attained via traditional ACL reconstruction and 
delayed rehabilitation protocols. 
 
3) 
Background* 
Injury in anterior cruciate ligament (ACL) is common and often requires 
reconstructive surgery to restore normal stability to the knee [1]. The process of 
rehabilitation after ACL injury can last for several months or even years, and 
represents a significant psychological and economic burden for the athlete [2]. 
Although several surgical techniques are available for ACL reconstruction (see for 
instance [3, 4]) and many rehabilitation protocols have been implemented (see 
reviews [5-7]), there is no unanimous consensus on which types of operative 
procedure and rehabilitation routine can provide the shortest time of recuperation for 
the injured athlete.  
 
Osteoconductive/osteoinductive compounds (OOC) are biomaterials characterized 
by bioactive properties: they provide an appropriate scaffold for bone formation 
(osteoconductivity); also, OOCs are able to bind and concentrate endogenous bone 
morphogenetic 
proteins 
in 
circulation, 
thus 
promoting 
osteogenesis 
(osteoinductivity) [8]. The faster ossification mediated by OOC injected in the bone 
tunnel could improve the structural stability of the graft construct, allowing the knee 
joint to adapt to bearing physiological mechanical loads sooner.  
 
To test our research hypothesis we will perform a longitudinal analysis aimed at 
comparing clinical outcomes in athletes undergoing ACL reconstruction with 
injected OOC followed by either a delayed rehabilitation program (DRP) or ARP to 
that of athletes receiving a standard ACL reconstruction followed by either DRP or 
ARP. During the time frame of one year, tunnel expansion and graft-tunnel 
incorporation attained with the four different treatments administered will be 
periodically assessed via MRI scan.   
 
If our central hypothesis is confirmed by the results of our analysis, we will have 
delineated a new treatment for ACL injury which can guarantee a faster postoperative 
recovery, thus reducing both the economic and psychological burden of the athlete.  
 


4) 
Inclusion and Exclusion Criteria* 
Inclusion criterion is any adult (male or female) undergoing a surgical 
procedure for hamstring ACL reconstruction.        
Note: In this study, subjects belonging to the following populations will be 
EXCLUDED:   
• Adults unable to consent 
• Individuals who are not yet adults (infants, children, teenagers) 
• Pregnant women 
• Prisoners 
 
5) 
Procedures Involved* 
 
Surgical Procedures – Surgical procedures will be performed by Dr. Jan Pieter 
Hommen. 
For all the surgical approaches investigated, 2 different graft options will be utilized 
including 1) the patients’ own hamstrings tendons or an 2) allograft tendon. 
Following standard surgical practices, the graft will be anchored to the bones without 
using cortical fixation buttons. More specifically, a bone tunnel matching the 
diameter of the graft will be reamed in the femur and tibia.  Subsequently, the graft 
will be passed and docked into the femoral and tibia tunnels with suspended fixation 
on the external cortices with Arthrex BTB Tightrope 12mm or 15mm metallic buttons 
(Arthrex, Naples, FL). In procedures involving the use of OOC, the bioactive 
compound (StimuBlast®, Arthrex, Naples, FL) will be mixed with 5cc of platelet 
rich plasma (PRP) harvested from the patient as per Arthrex protocol. Subsequently, 
the mixture will be injected using a syringe into both tibia and femoral tunnels prior 
to the docking of the graft within the femur and tibia tunnels. Note that mixing of 
StimuBlast® and autologous PPR is an FDA approved procedure which is highly 
recommended from Arthrex in order to get best results from the use of their OOC 
(see StimuBlast® brochure). In fact, it has been reported that PRP enhances bonw 
healing and regeneration [9]. 
 
Rehabilitation protocols – Delayed rehabilitation protocol consist in the use of a knee 
brace for the first 3 weeks after procedure, immediate closed chain and isometric 
kinematic strengthening with advancing weight-bearing exercises from partial to full 
weight bearing by 3 weeks postoperatively with the use of crutches until the gait 
normalizes. In contrast, accelerated rehabilitation protocols consist of: a knee brace 
for 3 weeks postoperatively utilized at night time only in full extension; crutches for 
three weeks until gait normalizes; closed chain and isometric kinematic exercises; 
open chain kinematics hamstring strengthening within a range of motion of 60 and 
90 degrees. 


 
Evaluation of clinical outcomes and biomechanical performance – In order to assess 
the effectiveness of the combination of the proposed surgical approach together with 
rehabilitation protocols, clinical, diagnostic and biomechanical relevant outcomes 
pertaining to the four subjects’ groups investigated will be evaluated at several time 
points during the rehabilitation process.  
Radiographic and Magnetic Resonance Imaging (MRI) – Radiographic tunnel 
measurements will be made at the initial post-operative evaluation followed by 3, 6, 
and 12 months postoperatively with digital PACS imaging, standardizing any 
potential image magnification. Bone tunnel measurements will be performed by 
board-certified orthopedic surgeon (Dr. Hommen) using digital measurements.  
Tunnel diameter sizes measured at the widest diameter for the femur and tibia will 
be compared to the size of the tunnels drilled at the time of surgery.  MRI scan 
imaging will be performed at 3 months post-surgically. Grafts will be rated as 1) no 
signs of incorporation, 2) partial incorporation, 3) complete incorporation, 4) signs 
of tunnel cyst formation, 5) no evidence of tunnel cyst formation, 5) evidence of 
tunnel expansion, 6) no evidence of tunnel expansion 7) intact graft, 8) stretched 
graft, 9) evidence of graft failure.  Alongside with these qualitative metrics, a 
quantitative image analysis will be performed to evaluate ACL reconstruction. More 
specifically, to quantify the normalized signal intensity of the ACL graft (related to 
ligament vascularization), the signal/noise quotient (SNQ) will be calculated using a 
region of interest (ROI) technique with the following equation: 
 
SNQ = (signal of ACL graft - signal of quadriceps tendon)/signal of background 
 
A custom-made image analysis software will be used for this analysis. The intra-
articular signal of the ACL grafts will be divided into 3 zones to analyze the signal 
intensity. The distal (tibial), middle, and proximal (femoral) thirds will be defined as 
the first, second, and third zones, respectively. The signal from the tendon of the 
quadriceps femoris will be measured with the ROI in the patellar upper limit level to 
normalize the signal intensity of the ACL graft.  
The MRI will be performed on a single MRI scan machine with the knee placed in 
the neutral position in an extremity coil. No contrast agent will be used. The coronal 
and sagittal images will be acquired using fast spin-echo (FSE) proton density–
weighted imaging (PDWI), sagittal FSE T2-weighted imaging, and axial and ACL 
oblique fat-saturated FSE PDWI. The repetition time (TR) range and echo time (TE) 
values were variable (3000-4000/10-30 milliseconds for PDWI and 3000-5000/100 
milliseconds for T2-weighted imaging). The other imaging parameters will be as 
follows: matrix, 220 3 247 (axial and coronal) and 304 3 301 (sagittal); field of view, 
16 cm; slice thickness, 5 mm; and acquisition number.  
Biomechanical outcomes - Aimed at evaluating patients’ recovery after ACL injury, 
previous studies have investigated gait characteristics and lower limb muscular 
activation during walking and dynamic balance. Similar analyses will be performed 


in this study. More specifically, gait characteristics during walking will be measured 
via lower limbs motion capturing analysis in combination with EMG analysis: 
kinematics, forces, moments, and power at each lower limb joint will be measured 
together with extent of muscular contraction of vastus medialis, vastus lateralis, bicep 
femoris, gluteus maximus, soleus and gastrocnemius. All the biomechanical 
experiments will be performed at the Biomechanics Research Lab of the University 
of Miami, under the supervision of Dr. Travascio (PI) and Dr. Asfour (co-PI) at 3 
weeks, 3 months, 6 months and 12 months after surgery. Note that, in order to 
perform this biomechanical analysis, the already approved IRB protocol 20110778 
(Motion Capture and Clinical Gait Analysis – PI: Dr. Asfour) will be used. 
 
Statistical analysis – The question of interest is whether the uses of OOC will have 
any effect on bone tunnel expansion. We will have two groups:standard surgical 
procedure (control)and OOC-based surgical procedure (treatment). Each tunnel 
measurement will be treated as a paired observation (i.e., postoperative change of 
sclerotic margins of the bone tunnel compared with the initially drilled tunnel size). 
A 2-sample t-test will determine statistical significant differences between treatment 
and control. 
A similar statistical approach will be followed for all the other clinical and 
biomechanical measurements performed in this study (i.e., quantitative image 
analysis of graft incorporation, lower joints kinetics, kinematics, and energetics, and 
activation of lower limb muscles) at the prescribed time points (i.e., at 3 weeks, 3 
months, 6 months, and 12 months). 
 
6) 
Data and Specimen Banking* 
Data collected will include patients’ post-operative MRI images, together with type 
of surgical procedure received and rehabilitation protocol. 
The data collected will be anonymized and recorded in form of DICOM on a portable 
storage device by Dr. Hommen. Subsequently, either Dr. Hommen will personally 
deliver the storage device to Dr. Travascio (PI), who will transfer the data onto a 
remotely accessible computer located in Hungar Building at University of Miami 
(Coral Gables, FL). Only Dr. Travascio and the Co-Investigator (Dr. Asfour) will 
have the credentials for accessing the data, which will be stored for the duration of 
the entire study (estimated to be up to 5 years).  
Access of data for immediate or future use will be only granted by the PI or the Co-
Investigator to their staff members, provided that the intended use is within the scope 
of this study. 
 
7) 
Data Management* 
The question of interest is whether the uses of OOC will have any effect on bone 
tunnel expansion. We will have tunnel expansion measurements divided into two 
groups: standard surgical procedure (control)and OOC-based surgical procedure 


(treatment).. Each tunnel measurement will be treated as a paired observation (i.e., 
postoperative change of sclerotic margins of the bone tunnel compared with the 
initially drilled tunnel size). A 2-samples t-test will determine statistical significant 
differences between treatment and control. 
A similar statistical approach will be followed for all the other clinical measurements 
performed in this study. 
From the location of data collection (Hommen Orthopedic Institute or Orthopaedic 
& Sports Medicine Center of Miami), data will be delivered to the Biomechanics 
Research Laboratory in an anonymized format. Data banking and access will be 
controlled by the PI (Dr. Travascio) and the Co-Investigator (Dr. Asfour) as described 
in section 6 ‘Data and Specimen Banking’, see above. 
 
8) 
Risks to Subjects* 
OOC injection: Adverse effects specific to the use of StimuBlast® have not 
been reported. However, adverse events, such as inflammation or infection, 
have been reported in orthopaedic procedures which involved use of 
osteoconductive/osteoinductive compounds. 
PRP extraction and administration: Minimal risks are associated with PRP 
extraction and administration. A bruise may form at the location where the 
blood sample is extracted. Risks (minimal) associated to its administration are 
no different from those associated with conventional cortisone injections. 
MRI scan: There are some risks associated with MRI. For instance, patients 
with pacemaker cannot get an MRI. In addition, implanted medical devices 
that contain metal could not work well or heat up during the exam. Moreover, 
skin irritations or burn can occur in patients with tattoos or having medication 
patches. Finally, some patients may feel claustrophobic or scared of being in 
a very small space while getting the MRI done.  
 
9) 
Potential Benefits to Subjects* 
Possible benefits include a faster incorporation of the ACL graft into the knee 
if the injection of osteoconductive/osteoinductive compound is performed. This 
may lead to a faster post-operative recuperation of the function of the knee. 
 
10) Vulnerable Populations* 
This research does not involve individuals belonging to vulnerable 
populations. 
 


11) Setting 
Patients’ medical images will be collected by Dr. Hommen’s staff at Hommen 
Orthopedic Institute. Data collected will be analyzed at the Biomechanics 
Research Laboratory of the University of Miami, Coral Gables Campus, 
under the supervision of the PI (Dr. Travascio), and the Co-Investigator (Dr. 
Asfour).  
 
12) Resources Available 
Dr. Francesco Travascio (PI) is Assistant Professor at the Department of Industrial 
Engineering of University of Miami. He has a strong experimental and theoretical 
background in connective tissue biomechanics with specific training in biomedical 
image analysis and articular cartilage. As an R&D engineer in a company producing 
navigation systems for robot assisted orthopaedic surgery (MAKO Surgical Corp.), 
he developed novel techniques for radiographic image analysis to be used for 
intraoperative robot navigation. This acquired expertise will be fundamental for the 
medical image analysis planned in this study. As a PI for this study, Dr. Travascio 
will lead and supervise all the aspects of the data analysis.  
Dr. Shihab Asfour (Co-Investigator) is Professor and Chair of the Department of 
Industrial Engineering and Associate dean of College of Engineering at the 
University of Miami. He has been working for more than 30 years in the field of 
musculoskeletal biomechanics, along with prevention and treatment of sports 
injuries.  Dr. Asfour has an extensive knowledge on statistical data analysis. 
Accordingly, within the scope of this project, he will mainly provide support in the 
analysis and the interpretation data produced in this research.   
Dr. Jan Pieter Hommen, M.D. (Surgeon/Co-Investigator) is the director of the 
Hommen Orthopaedic Institute. He is a surgeon specialized in comprehensive 
injuries and pain of the shoulder, hip, knee and ankle. The Hommen Orthopaedic 
Institute provides a unique scientific environment with a wealth of expertise with 
whom the PI will be able to consult at any time while carrying out the research 
proposed. In addition, within the scope of this study, Dr. Hommen will be in charge 
of performing surgical procedures on patients, and of providing clinical insights.  
 
13) Prior Approvals 
This research is currently supported by funds donated to the Biomechanics 
Research Laboratory. Also, we are currently applying for funding to 
Foundation for PM&R.  


14) Recruitment Methods  
Subjects will be recruited at any time during the next two years, also based on their 
availability.  
 
Subjects will be recruited from both Dr. Hommen’s existing patients.  
 
Potential candidates as subjects for this study will be selected by Dr. Hommen 
according to matching criteria for this study (i.e., subjects must receive surgical 
treatment for ACL reconstruction). 
 
No recruitment material will be used in this study. 
 
There is no remuneration for participation in this study. 
 
15) Local Number of Subjects 
We estimate that, during the course of the duration of the project (up to 5 years, 
depending on funding resources), data form a total of 200 subjects will be collected. 
 
16) Confidentiality 
Data will be archived in a remotely accessible computer located Hungar Building of 
University of Miami (Coral Gables, FL). Only the PI (Dr. Travascio) and the Co-
Investigator (Dr. Asfour) will have the credentials for accessing the data. 
Data will be stored indefinitely. 
Access of data for immediate or future use will be only granted by the PI or the Co-
Investigator. Data access will be only granted to PI’s staff members, provided that 
the intended use of the data is within the scope of this study. 
17) Provisions to Protect the Privacy Interests of Subjects 
We anticipate that there are no foreseeable conflicts of privacy for the individuals 
who participate in this study. Moreover, subjects’ information will remain stored in 


a password-protected computer, as described in detail in section 6 ‘Data and 
Specimen Banking’. Any personal information that could present a conflict to a 
subject’s privacy will not be stored or published since archived data will be 
anonymized, see section 7 ‘Data Management’ for details. 
 
18) Consent Process 
In order to participate to this study, subjects will have to sign a consent form (see 
HRP 502 – Consent Form - Travascio attached). In addition, they will be asked to 
complete a HIPAA Authorization form (see HIPAA Authorization Form attached). 
The signing of both consent form and HIPAA authorization will take place in 
presence of your othopaedic surgeons. 
 
Only English-speaking subjects will participate in this study. 
 
Only adults will participate in this study. 
 
19) Process to Document Consent in Writing 
Experimental research for this study presents no more than minimal risk of harm to 
subjects. In order to participate to this study, subjects are required sign a consent form 
and a HIPAA authorization form (see attached files). 
 
References 
[1] Lyman, S., Koulouvais, P., Sherman, S., Do, H., Mandl, L. A., and Marx, R. G., 
2009, "Epidemiology of Anterior Cruciate Ligament Reconstruction," The Journal of 
Bone & Joint Surgery, 91(10), pp. 2321-28. 
 
[2] Wiese-Bjornstal, D. M., Smith, A. M., Shaffer, S. M., and Morrey, M. A., 1998, 
"An Integrated Model of Response to Sport Injury: Psychological and Sociological 
Dynamics," Journal of Applied Sport Psychology, 10(1), pp. 46-69. 
 
[3] Spindler, K. P., Kuhn, J. E., Freedman, K. B., Matthews, C. E., Dittus, R. S., and 
Harrell, F. E., 2004, "Anterior Cruciate Ligament Reconstruction Autograft Choice: 
Bone-Tendon-Bone Versus Hamstring Does It Really Matter? A Systematic 
Review," The American journal of sports medicine, 32(8), pp. 1986-95. 
 
[4] Crawford, C., Nyland, J., Landes, S., Jackson, R., Chang, H. C., Nawab, A., and 
Caborn, D. N., 2007, "Anatomic Double Bundle Acl Reconstruction: A Literature 
Review," Knee Surgery, Sports Traumatology, Arthroscopy, 15(8), pp. 946-64. 


 
[5] Wright, R. W., Preston, E., Fleming, B. C., Amendola, A., Andrish, J. T., 
Bergfeld, J. A., Dunn, W. R., Kaeding, C., Kuhn, J. E., Marx, R. G., Mccarty, E. C., 
Parker, R. C., Spindler, K. P., Wolcott, M., Wolf, B. R., and Williams, G. N., 2008, 
"Acl Reconstruction Rehabilitation: A Systematic Review Part I," Journal of Knee 
Surgery, 21(3), pp. 217-224. 
 
[6] Wright, R. W., Preston, E., Fleming, B. C., Amendola, A., Andrish, J. T., 
Bergfeld, J. A., Dunn, W. R., Kaeding, C., Kuhn, J. E., Marx, R. G., Mccarty, E. C., 
Parker, R. C., Spindler, K. P., Wolcott, M., Wolf, B. R., and Williams, G. N., 2008, 
"Acl Reconstruction Rehabilitation: A Systematic Review Part Ii," Journal of Knee 
Surgery, 21(3), pp. 225-234. 
 
[7] Saka, T., 2014, "Principles of Postoperative Anterior Cruciate Ligament 
Rehabilitation," World journal of orthopedics, 5(4), pp. 450. 
 
[8] Legeros, R. Z., 2002, "Properties of Osteoconductive Biomaterials: Calcium 
Phosphates," Clinical orthopaedics and related research, 395(pp. 81-98. 
 
[9] Sanchez, M., Anitua, E., Cugat, R., Azofra, J., Guadilla, J., Seijas, R. and Andia, 
I., 2009. Nonunions treated with autologous preparation rich in growth factors. 
Journal of orthopaedic trauma, 23(1), pp.52-59. 
 
[10] Chhabra, A., Kline, A. J., Nilles, K. M., and Harner, C. D., 2006, "Tunnel 
Expansion after Anterior Cruciate Ligament Reconstruction with Autogenous 
Hamstrings: A Comparison of the Medial Portal and Transtibial Techniques," 
Arthroscopy: The Journal of Arthroscopy and Related Surgery, 22(10), pp. 1107-12.