A Prospective, Randomized, Controlled, Clinical Trial Evaluating the Non-Inferiority of Bridge-Enhanced Anterior Cruciate Ligament Repair (BEAR) to Anterior Cruciate Ligament Reconstruction With an Autologous Tendon Graft (ACLR)
Phase: NA
Conditions: Anterior Cruciate Ligament Tear
Sponsor: Miach Orthopaedics

BEAR™ Implant,  IDE Number G150268     
Sponsor: Miach Orthopaedics, Inc. 
________________________________________________________________________ 
IDE Number G150268:  BEAR® Implant 
A Prospective, Randomized, Controlled, Clinical Trial Evaluating 
the Non-Inferiority of Bridge-Enhanced ACL Repair (BEAR) to 
ACL Reconstruction with an Autologous Tendon Graft (ACLR) 
Miach Orthopaedics Inc 
69 Milk Street  
Westborough, MA 01581 
Version H 
16Dec2021
NCT02664545

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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TABLE OF CONTENTS 
 
Table of Contents ................................................................................................................ 2 
Investigational Plan ............................................................................................................. 4 
1.1 
List of Abbreviations ............................................................................................ 5 
1.2 
Study Schema ....................................................................................................... 6 
1.3 
Study Summary .................................................................................................... 7 
1.4 
Background and Significance ............................................................................... 8 
1.4.1 
Disease Background...................................................................................... 8 
1.4.2 
Study Device Background and Associated Known Toxicities ..................... 8 
1.4.3 
Summary of non-clinical in vitro/in vivo studies ....................................... 10 
1.4.4 
Rationale ..................................................................................................... 25 
1.5 
Study Objectives ................................................................................................ 25 
1.5.1 
Primary Objective ....................................................................................... 25 
1.5.2 
Secondary Objective(s) ............................................................................... 25 
1.5.3 
Endpoints .................................................................................................... 27 
1.6 
Patient Selection ................................................................................................. 31 
1.6.1 
Inclusion Criteria ........................................................................................ 32 
1.6.2 
Exclusion Criteria ....................................................................................... 33 
1.6.3 
Early Withdrawal of Patients ...................................................................... 34 
1.7 
Treatment Plan ................................................................................................... 34 
1.7.1 
General Study Design ................................................................................. 34 
1.7.2 
Surgical Procedures .................................................................................... 35 
1.8 
Study Procedures ................................................................................................ 38 
1.8.1 
Study Visits ................................................................................................. 41 
1.8.2 
Outcome Measures...................................................................................... 45 
1.8.3 
Post-operative Physical Therapy ................................................................. 48 
1.8.4 
Study Timeline ............................................................................................ 48 
1.9 
Adverse Event Criteria and Reporting Procedures ............................................ 48 
1.9.1 
Adverse Event Monitoring .......................................................................... 48 
1.9.2 
Definitions................................................................................................... 49 
1.9.3 
Eliciting Adverse Effect Information .......................................................... 50 
1.9.4 
Abnormal Test Findings ............................................................................. 50 
1.9.5 
Causality and Severity Assessment ............................................................ 51 
1.9.6 
Recording and Assessment of Adverse Effects .......................................... 51 
1.9.7 
Post-Surgery Procedures for Adverse Events ............................................. 52 
1.9.8 
Reporting Adverse Events .......................................................................... 52 
1.9.9 
Risk Mitigation Strategy ............................................................................. 53 
1.9.10 Justification for the Investigation................................................................ 54 
1.9.11 Stopping Rules ............................................................................................ 55 
1.10 
Device Information ......................................................................................... 55 
1.10.1 BEAR® Implant ......................................................................................... 55 
1.10.2 Return and Retention of Study Device ....................................................... 56 
1.11 
Data Management Methods ............................................................................ 56 
1.11.1 Data Management and Record Keeping ..................................................... 56 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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1.11.2 Source Documents ...................................................................................... 56 
1.11.3 Case Report Forms ...................................................................................... 57 
1.11.4 Confidentiality and Security ....................................................................... 58 
1.11.5 Records Retention ....................................................................................... 58 
1.12 
Quality Control Method.................................................................................. 58 
1.12.1 Data Monitoring .......................................................................................... 58 
1.12.2 Data Monitoring Committee ....................................................................... 59 
1.12.3 Safety Monitoring Plan ............................................................................... 59 
1.12.4 Auditing and Inspecting .............................................................................. 59 
1.12.5 Changes and Amendments to the Protocol ................................................. 60 
1.12.6 Ethical and Legal Considerations ............................................................... 60 
1.13 
Data Analysis Plan.......................................................................................... 60 
1.14 
Statistical Power and Sample Size Considerations ........................................ 62 
1.15 
Study Organization ......................................................................................... 63 
2 
References ................................................................................................................. 64 
 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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INVESTIGATIONAL PLAN 
A Prospective, Randomized, Controlled, Clinical Trial Evaluating the Non-
Inferiority of Bridge-Enhanced ACL Repair (BEAR) to ACL Reconstruction with 
an Autologous Tendon Graft (ACLR) 
 
Study Sponsor:   
Miach Orthopaedics, Inc. 
Sponsor Contact:  
 
  
Study Device:   
Extracellular Matrix Based Scaffold (BEAR® Implant) 
Protocol Short 
Title 
BEAR II Trial 
Bridge-Enhanced ACL Repair II 
 
 
 
 
 
 
Study Device 
Anterior Cruciate Ligament Repair Scaffold/BEAR® Implant 
 
IDE number:  
G150268 
 
 
 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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1.1 
List of Abbreviations 
 
ACL   
Anterior Cruciate Ligament 
 
AOSSM 
The American Orthopaedic Society for Sports Medicine 
 
BCH  
Boston Children's Hospital 
 
BEAR  
Bridge-Enhanced ACL Repair Implant 
 
CRF 
 
Case report forms  
 
EQuIP 
Education and Quality Improvement Program at Boston Children's 
Hospital 
 
IKDC 
International Knee Documentation Committee (validated patient 
questionnaire for assessing knee function) 
 
LCL 
 
Lateral Collateral Ligament 
 
MCL  
Medial Collateral Ligament 
 
MOON  
Multicenter Orthopaedic Outcomes Network (previously established 
prospective cohort of over 3000 patients who have had ACL 
reconstruction) 
 
MOP  
Manual of Operating Procedures   
 
MRI   
Magnetic Resonance Imaging 
 
PCL   
Posterior Cruciate Ligament 
 
REDCap  
Research Electronic Data Capture data management system 
 
ROM    
Range of Motion 
 
SAE 
 
Serious Adverse Event 
 
UADE  
Unanticipated Adverse Event 
 
VAS    
Visual Analog Score for Pain 

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1.2 
Study Schema  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YES 
OR 
NO 
Patients under age 35 with 
an ACL Injury who are 
interested in returning to 
activities that involve 
cutting or pivoting 
Patient consents to participate in 
the BEAR II RCT 
At surgery, patient meets 
criteria for study inclusion 
Patient has 
Standard ACL 
reconstruction 
surgery with 
tendon graft. 
Patient Randomized to 
BEAR or ACLR surgery 
(2:1 Randomization scheme) 
6 months , 1, 2, 6 and 10 years after surgery 
               Screening for adverse events 
               IKDC questionnaire 
               Physical Exam 
               Strength Testing 
               Xray imaging at 2 years 
MRI imaging at 6 mos, 1,2, 6 and 10 years 
NO 
2 weeks, 6 weeks, 3 months after surgery 
 
Screening for adverse events 
 
Questionnaire     Strength Testing  
 
Physical Exam    Lachman Test 
 
Patient undergoes BEAR 
procedure 
YES 
Patient undergoes ACL 
reconstruction procedure 

BEAR® Implant, IDE Number: G150268   
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1.3 
Study Summary 
Title 
Bridge-Enhanced ACL Repair II Trial 
Short Title 
BEAR II Trial 
Protocol Number 
CP-02-001 
Phase 
Pivotal Trial  
Methodology 
Single center, 2-arm, randomized, controlled clinical trial.  2:1 
Randomization Scheme. 
Study Duration 
14 years 
Study Center(s) 
Single-center, Boston Children's Hospital. 
Objectives 
To determine the efficacy of the BEAR® implant and demonstrate its 
non-inferiority to the standard of ACL reconstruction in terms of knee 
stability and patient reported outcomes, as well as its superiority in terms 
of regaining muscle strength at 3, 6, and 12 months after surgery.  
Additional objectives are to determine if safety outcomes including 
infection, graft rejection, and need for further surgical procedures are 
different between patients undergoing the BEAR procedure and those 
undergoing ACL reconstruction, as well as if markers of early 
osteoarthritis are clinically different in the two groups at the two year 
time point. Subjects will be followed up at 6 and 10 years post-surgery to 
evaluate long-term outcomes and osteoarthritis. 
Number of Subjects 
Up to 100 (up to 67 with bridge-enhanced ACL repair, and up to 33 with 
autograft ACL reconstruction) 
Diagnosis and Main 
Inclusion Criteria 
Anterior cruciate ligament injury, within 45 days of injury 
Study Product(s), Dose, 
Route, Regimen 
BEAR® Implant 
Duration of administration 
Single administration at surgery; implant resorbed over approximately 8 
weeks 
Reference therapy 
ACL reconstruction with autograft tendon 
Statistical Methodology 
Noninferiority testing for the Bridge-Enhanced ACL Repair procedure 
vs. the ACL Reconstruction procedure will be performed with the 
primary outcome measures of IKDC patient reported outcome and AP 
knee laxity.  Noninferiority analysis will be based on comparing the 95% 
confidence interval for each primary outcome to pre-specified 
noninferiority margins. 
 
 
 
 
 

BEAR® Implant, IDE Number: G150268   
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1.4 
Background and Significance  
1.4.1 Disease Background 
The annual incidence of anterior cruciate ligament (ACL) injury in the US is estimated at 
1 per 1,000 people [46]. ACL injuries have immediate and long-term effects on the 
quality of life, and are known risk factors for post-traumatic osteoarthritis [47]. In the 
past, surgeons tried to repair the ACL; however, it failed to heal in over 90% of patients 
[48]. The reason for this was unknown. Thus, the current gold standard of treatment, 
ACL reconstruction, which involves removal and replacement of the ligament with a 
tendon graft, has become popular (Figure 1). However, patients treated with ACL 
reconstruction continue to exhibit progressive articular cartilage and joint damage in the 
injured knee. A recent prospective cohort study suggests that 62% of ACL reconstructed 
patients with an isolated ACL injury presented with radiographic evidence of 
posttraumatic osteoarthritis 10–15 years post-surgery [49]. Considering that many 
patients sustain ACL injuries before the age of 16, these injuries may place young 
patients at risk for premature post-traumatic osteoarthritis before age 30 even with our 
current best treatment methods. 
 
Figure 1: Schematic demonstrating an ACL tear (left panel), our current method of 
treatment with removal of the ACL and replacement with a tendon graft (ACL 
reconstruction, middle panel) and the novel treatment of repair and regeneration we have 
developed from this injury ("Bridge-enhanced ACL repair," right panel). 
 
1.4.2 Study Device Background and Associated Known Toxicities 
1.4.2.1 Device Description 
The BEAR® device is a bovine collagen based implant (Figure 2).  The bovine tissue is 
sourced from New Zealand (which is a country free of bovine spongiform 
encephalopathy) and is further treated to remove bovine cell fragments and DNA.  The 
manufacturing process is completed using aseptic conditions and no serum or cells are 
introduced in the process.  The resulting implant is terminally sterilized using electron 
beam irradiation.  Lot testing of the implant has confirmed sterility of the implant after 
sterilization and has also confirmed the absence of bovine viruses.    
 
 

BEAR® Implant, IDE Number: G150268   
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Figure 2: The collagen device prior to implantation (Scale = centimeters). 
 
1.4.2.2 The principle of operation of the device 
The primary device reported above will be implanted at the time of surgical stabilization 
of the ACL with sutures as previously reported.  In brief, surgical stabilization is 
accomplished as previously performed for non-enhanced ACL repair with devices 
previously approved by the FDA for soft tissue repair (sutures and cortical buttons).   
This repair will be accomplished using sutures and two cortical buttons (Endobutton from 
Smith and Nephew or equivalent device as deemed by the FDA).  The sutures to stabilize 
the knee will be made of Ethibond.  Two #2 Ethibond sutures will be used to reconnect 
the femur and tibia, and a #2 Vicryl suture used to pull the tibial ACL remnant toward the 
femoral attachment site.  Once implanted, the patient’s own blood is added to the implant 
and saturates it. The blood clots within the implant and the implant stabilizes the clot in 
the gap between the torn ligament ends. The implant is replaced within 2 to 3 weeks with 
ACL cells and native collagen and blood vessels consistent with fibrovascular repair 
tissue.   
1.4.2.3 Device implantation 
 
 
Figure 3:  Stepwise demonstration of the “bridge-enhanced ACL repair” technique using 
the collagen device (seen first in C where it is threaded onto sutures).  In this technique, 
the torn ACL tissue is preserved (A).  Small tunnels (4 mm) are drilled in the femur and 
tibia and an extracortical button with sutures attached to it is passed through the femoral 
tunnel and engaged on the proximal femoral cortex.  One set of sutures from this 
extracortical button is threaded through the collagen implant, tibial tunnel and secured in 
place with a second extracortical button (red sutures). A second set of sutures (green) 
from the Endobutton were tied to the Kessler suture placed in the tibial stump of the ACL 

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(green sutures).  The collagen device is then saturated with 5 cc of the patient’s blood.  
The collagen device is not load bearing, the initial strength of the repair is dependent on 
the suture repair of the ACL.  The ends of the torn ACL then grow into the collagen 
implant and the ligament reunites.  
 
The implant device works by immobilizing the blood in between the two torn ends of the 
ligament.  It is not load bearing.  The suture repair of the ACL is the load bearing 
structure for the repair, as it has been in past studies of ACL repair.   
1.4.2.4 Device Mechanism 
The device is porous and can absorb blood.  The device immobilizes the autologous 
blood in the ligament wound site and as the blood naturally forms a clot, or provisional 
implant, the device is able to protect the clot and maintain it within the wound site.  The 
blood clot goes on to release the wound healing growth factors and proteins [8, 15] which 
are effective in healing ligaments that are outside the joint (medial collateral ligament) 
and in preclinical models, are able to stimulate the ingrowth of surrounding cells into the 
implant [28, 58, 60]. This scar has been shown to have strength similar to that of an ACL 
tendon graft in the porcine model at 3, 6 and 12 months after surgery [36, 40].  The only 
function of the device is to keep the blood in the wound site and protect it from being 
prematurely washed away by the synovial fluid in the joint. 
1.4.2.5 Other Agents/Devices 
The implant described above is designed to be implanted at the time of surgical 
stabilization of the ACL with sutures as previously reported.  In brief, surgical 
stabilization is accomplished as previously performed for non-enhanced ACL repair with 
devices previously approved by the FDA for soft tissue repair (sutures and cortical 
buttons).   This repair will be accomplished using sutures and two cortical buttons 
(Endobutton from Smith and Nephew or equivalent device as deemed by the FDA.  The 
sutures to stabilize the knee will be made of Ethibond.  Two #2 Ethibond sutures will be 
used to reconnect the femur and tibia, and a #2 Vicryl suture used to pull the tibial ACL 
remnant toward the femoral attachment site.  
 
Once implanted, the patient’s own blood is added to the implant and saturates it. The 
blood clots within the scaffold implant and the implant stabilizes the clot in the gap 
between the torn ligament ends. The implant is replaced within 2 to 3 weeks with ACL 
cells and native collagen and blood vessels consistent with fibrovascular repair tissue.   
1.4.3 Summary of non-clinical in vitro/in vivo studies 
1.4.3.1 Efficacy in Preclinical Models 
Recent ACL bridge-enhanced repair studies in three large animal models have 
demonstrated that placement of the extracellular matrix device in the injury site of the 
ACL can stimulate biological and mechanical healing of the ligament [2, 22, 23, 28, 30, 
31, 58, 59, 94].  With the current treatment model, the mechanical properties of the ACL 
bridge-enhanced repair are equivalent to those of an ACL reconstruction at 3, 6 and 12 
months after surgery (Figure 4). 

BEAR® Implant, IDE Number: G150268   
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Figure 4: Tensile structural properties of the bridge-enhanced stress-protected ACL 
repair (labeled as Repair) were identical to those of ACL reconstruction (labeled as 
ACLR) with a graft in a randomized large animal study (n = 8/group; p > 0.60 for all 
parameters). Both treatment groups had a more functional repair than that of the untreated 
ACL transection.  
 
In addition, it has also been recently reported that the stimulation of ligament repair and 
regeneration using the “bridge-enhanced ACL repair” (BEAR) technique prevents the 
development of post-traumatic osteoarthritis after an ACL injury [40]. In the most recent 
study, 80% of the knees that had a conventional ACL reconstruction developed post-
traumatic osteoarthritis while the knees in the bridge-enhanced ACL repair group 
(BEAR) did not 1 year after surgery (Figure 5).  
 
 
Figure 5: The distal femur cartilage 1-year after (A) an untreated ACL rupture, (B) after 
conventional ACL reconstruction, and (C) after bridge-enhanced ACL repair. Note the 
damage to the medial femoral condyle in the untreated and ACL reconstructed knees 
(black arrows) and the lack of damage in the medial femoral condyle in the bridge-
enhanced ACL repaired knee (white arrow).   

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1.4.3.2 Safety in Preclinical Models 
1.4.3.2.1 Sterility Testing 
Sterility testing was performed for each lot prior to release.  A Sterility Testing 
Qualification study was performed by Microtest, Inc, for the implant and the BEAR® 
implant was successfully validated for USP<71>/EP 2.6.1 Sterility testing.  Subsequent 
lots (071301A/B, 081301B/C, 081302A/B/C) were each tested for sterility according to 
specification USP 36<71>/EP 2.6.1 and no growth was found, thus the implants passed 
the lot sterility testing.  
1.4.3.2.2 Viral testing 
A literature review of our processing methods and the ability of similar methods to 
eliminate the four classes of virus (RNA, DNA, enveloped, non-enveloped) was 
conducted. The three steps of acidic pH, detergent and 15 kGy electron beam terminal 
sterilization are all used in our processing.  In previously published literature, the use of 
an acidic environment results in a reduction in viral load by 103 to 108.  The use of Triton 
X as a detergent results in a reduction in viral load by 105 to 107.  The use of electron 
beam at 13 to 18 kGy for allograft tissue results in a reported reduction by 106.  The 
BEAR™ manufacturing process incorporates all of these steps.  For our investigational 
device exemption studies, we will continue to perform lot testing for the presence of virus 
for the four classes of virus (DNA+, DNA-, RNA+ and RNA-(Charles Rivers 
Laboratories ,Wilmington, MA; STM-V-615.3, In Vitro Test for Bovine Adventitious 
Agents (9 CFR) in Products Other than Bovine Serum).   
 
Prior testing for the presence of bovine virus has been conducted on all lots of implants 
designated for clinical/human use.  In brief, testing was performed at Charles River 
Laboratories under GLP conditions. Samples of our implant were hydrated and portions 
of the resulting solution inoculated in duplicate into cell cultures that are generally 
susceptible to bovine viruses.  The inoculated cultures were maintained for 21 days, with 
subcultures taken at 7 and 14 days post-inoculation.   Spot slides were prepared for the 
detection of the following bovine viruses (Bovine Adenovirus Type 3, Bovine 
Parvovirus, Rabies Virus ERA Strain, Reovirus Type 3, Bovine Viral Diarrhea Virus, 
Blue Tongue Virus Type 10, Bovine Respiratory Syncytial Virus) and fluorescent 
antibody staining used to identify the presence of virus.  Hemadsorption testing of 
parainfluenza virus-inoculated positive controls was also performed on Day 21 samples 
as an additional test.  There was no evidence of bovine virus in the implant material. 
1.4.3.2.3 Biocompatibility 
Biocompatibility testing was performed at NAMSA according to the requirements of the 
International Organization for Standardization 10993-1, Biological evaluation of medical 
devices, Fourth Edition 2009-10-15.  The following tests were performed under GLP 
conditions: 
 Cytotoxicity Study Using the ISO Elution Method (V0014) 
 ISO Maximization Sensitization Study - Extract (T261) 
 ISO Intracutaneous Study with Sponsor Provided Control - Extract (T251) 
 ISO Systemic Toxicity Study - Extract (T0625) 

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 Genotoxicity, Bacterial Reverse Mutation Study (V0023) 
 Genotoxicity, in vitro Chromosomal Aberration Study in Mammalian Cells - 
Extract (V002) 
 Genotoxicity, Mouse Peripheral Blood Micronucleus Study (T0566) 
 ISO Muscle Implantation Study - 2 week (T250) 
 6 week Systemic Toxicity Study in Rats Following Subcutaneous Implant 
(T0118) 
 
The results of the studies are summarized below.   
1.4.3.2.3.1 Cytotoxicity Study:  10993-Part 5 
A single preparation of the test article was extracted in single strength Minimum 
Essential Medium (IX MEM) at 37°C for 24 hours. The negative control, reagent control, 
and positive control were similarly prepared. Triplicate monolayers of L-929 mouse 
fibroblast cells were dosed with each extract and incubated at 37°C in the presence of 5% 
C02 for 48 hours. Following incubation, the monolayers were examined microscopically 
for abnormal cell morphology and cellular degeneration.   
 The test article extract showed evidence of causing slight cell lysis or toxicity.  
 The test article extract met the requirements of the test since the grade was less 
than a grade 2 (mild reactivity). 
1.4.3.2.3.2 Maximization Sensitization Study - Extract (T261; 10993-10).  
The test article, the BEAR™ implant, was evaluated for the potential to cause delayed 
dermal contact sensitization in a guinea pig maximization test. This study was conducted 
based on the requirements of ISO 10993-10, Biological evaluation of medical devices - 
Part 10: Tests for irritation and skin sensitization. The test article was extracted in 0.9% 
sodium chloride USP. The extract was intradermally injected and occlusively patched to 
ten test guinea pigs. The extraction vehicle was similarly injected and occlusively 
patched to five control guinea pigs. Following a recovery period, the test and control 
animals received a challenge patch of the appropriate test article extract and the vehicle 
control. All sites were scored for dermal reactions at 24 and 48 hours after patch removal.  
 The test article extract showed no evidence of causing delayed dermal contact 
sensitization in the guinea pig.  
 The test article was not considered a sensitizer in the guinea pig maximization test 
1.4.3.2.3.3 Intracutaneous Study with Sponsor Provided Control - Extract (T251; 10993-
10)   
The test article, the BEAR™ ACL implant, was evaluated for the potential to cause 
irritation following intracutaneous injection in rabbits.  This study was conducted based 
on ISO 10993-10, Biological evaluation of medical devices - Part 10: Tests for irritation 
and skin sensitization. The test article was extracted in 0.9% sodium chloride USP 
solution (SC). A 0.2 mL dose of the test article extract was injected intracutaneously into 
five separate sites on the right side of the back of each of three animals. Similarly, the 
extract vehicle alone (negative control) and the sponsor provided control article extract 
was injected on the left side of the back of each animal. The injection sites were observed 
immediately after injection. Observations for erythema and edema were conducted at 24 

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hours after injection and continuing daily for 7 days after the injection. The test was 
performed on both our implant as well as a control of SURGIFOAM, another collagen-
based implant which has been FDA approved for clinical use (P990004/S002).   
 Both the test article and SURGIFOAM had an increase over the negative control 
values as would be expected for a collagen-based implant. 
 There was no significant difference between the test article and SURGIFOAM in 
this study.    
1.4.3.2.3.4 Systemic Toxicity Study - Extract (T0625; 10993-11).   
The test article, the BEAR™ implant, was evaluated for acute systemic toxicity in mice 
based on ISO 10993-11, Biological evaluation of medical devices - Part 11: Tests for 
systemic toxicity. The test article was extracted in 0.9% sodium chloride USP solution. A 
single dose of the test article extract was injected into a group of five animals. Similarly, 
a separate group of five animals was dosed with the extraction vehicle alone (vehicle 
control). The animals were observed for signs of systemic toxicity immediately after 
injection and at 4, 24, 48 and 72 hours after injection. Body weights were recorded prior 
to dosing and on days 1, 2 and 3. A gross necropsy was performed after the last 
observation to asses any abnormalities in the viscera. 
 There was no mortality or evidence of systemic toxicity from the extract injected 
into mice. The test article extract met the requirements of the study. There were 
no abnormalities noted at gross necropsy in the viscera. 
1.4.3.2.3.5 Genotoxicity, Bacterial Reverse Mutation Study (V0023, 10993-3). 
A bacterial reverse mutation assay was conducted to evaluate whether a dimethyl 
sulfoxide (DMSO) extract and a saline extract of the BEAR® implant would induce 
reverse mutations at the histidine locus of the Salmonella typhimurium tester strains 
TA98, TA100, TA1535, and TA1537 or at the tryptophan locus of Escherichia coli tester 
strain WP2uvrA.  The assay was conducted in the presence and absence of metabolic 
activation. Tubes containing molten top agar were inoculated with culture from one of the 
five tester strains, along with the DMSO or saline extract.  An aliquot of sterile water for 
injection or rat liver S9 homogenate, providing metabolic activation, was added.  The 
mixture was poured across triplicate plates.  Parallel testing was conducted with negative 
controls (extraction vehicle alone) and positive controls.  The mean number of revertants 
for the test extract plates was compared to the mean number of revertants of the negative 
control plates for each of the five tester strains.  
 The DMSO and saline test article extracts were considered to be nonmutagenic to 
S. typhimurium tester strains TA98, TA100, TA1535, and TA1537, and to E. coli 
tester strain WP2uvrA. 
1.4.3.2.3.6 Genotoxicity, in vitro Chromosomal Aberration Study in Mammalian Cells - 
Extract (V002, OECD Test No. 473).   
The test article, the BEAR™ implant, was extracted in serum free McCoy's medium and 
dimethylsulfoxide (DMSO).  A chromosomal aberration study was conducted to 
determine whether the extract would cause genotoxicity in Chinese hamster ovary (CHO-
WBL) cells in the presence and absence of S9 metabolic activation.   The serum free 
McCoy’s medium extract was supplemented to 10% with fetal bovine serum prior to 

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dosing the cells.  The DMSO test article extract was diluted 1:100 with McCoy's 5A 
complete medium prior to dosing the cells.  A monolayer of CHO-WBL cells was 
exposed to the test article extracts in duplicate and in the presence and absence of S9 
metabolic activation.  Parallel testing was also conducted with a corresponding negative 
and positive control.  The extraction vehicle without the test article served as the negative 
control.  Cells were exposed for 4 hours with and without metabolic activation, and for 
20 hours without metabolic activation.  
 The serum free McCoy's medium test article extract did not produce a statistically 
significant increase in chromosome aberrations as compared to the negative 
control in the presence or absence of S9 metabolic activation.   
 The DMSO test article extract did not produce a statistically significant increase 
in chromosome aberrations as compared to the negative control in the presence or 
absence of S9 metabolic activation. 
1.4.3.2.3.7 Genotoxicity, Mouse Peripheral Blood Micronucleus Study (T0566; OECD Test 
No. 474).    
The test article, the BEAR™ implant, was evaluated for the potential to produce 
cytogenetic damage, resulting in micronuclei formation in the mouse peripheral blood 
micronucleus model. The test article was extracted in 0.9% sodium chloride USP 
solution. For three consecutive days, twelve mice (six per sex) were injected 
intraperitoneally with the test article extract. Similarly, six animals per sex were dosed 
with either the vehicle as the negative control or methyl methanesulfonate as a positive 
control. All animals were observed immediately following dosing and daily for 
assessment of general health. On day 4, blood was collected from the tail veins and 
reticulocytes were evaluated for the presence of micronuclei by flow cytometry. 
 The test article extract did not induce micronuclei in mice. 
1.4.3.2.3.8 Muscle Implantation Study - 2 week (T250; 10993-6).   
Sterile implant test articles were aseptically prepared. Negative control articles were 
sterilized by steam. The test article and negative control were intramuscularly implanted 
and animals were euthanized 2 weeks later. Muscle tissues were excised and the implant 
sites examined macroscopically. A microscopic evaluation of representative implant sites 
from each animal was conducted to further define any tissue response.  
 The macroscopic reaction was slight as compared to the negative control article. 
 Microscopically, the test article was classified as a moderate irritant as compared 
to the negative control article. 
 
The muscle implantation study in rabbits results demonstrated the BEAR™ implant had a 
slight macroscopic reaction as compared to the negative control (High density 
Polyethelene or HDPE).  Microscopically, the BEAR® implant was classified as a 
moderate irritant as compared to the HDPE.  This was due to two things:   
 The presence of some necrotic fibers around the implant 
 A greater concentration of inflammatory cells, including macrophages, 
lymphocytes and plasma cells around the BEAR® implant than around the HDPE 
implant.   
 

BEAR® Implant, IDE Number: G150268   
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16 
 
As the BEAR® implant is designed to stimulate wound healing, and the influx of 
inflammatory cells is a critical part of wound healing in the first two weeks after 
implantation, the influx of inflammatory cells was expected.  The necrosis of the muscle 
fibers was thought to be due to the implantation of the implant in muscle, rather than in 
the fluid environment of the joint where it is designed to be used.  The implant is also 
designed to be hydrated with blood or platelet rich plasma prior to implantation, which 
was not done in this biocompatibility study.   Pathologists from NAMSA and from 
Charter both thought the small amount of muscle necrosis visualized on the slides was 
likely due to the fact there was minimal fluid around to hydrate the material, which 
resulted in drying or dessication of the cells adjacent to the material (see emails from Dr 
Carraway(NAMSA) 12-3-2013 and Dr Kramer (Charter) 12-5-2013).  Dr Kramer went 
back and evaluated the pathologic slides from VIV-001 and VIV-003 and while he did 
see inflammation around the BEAR® implant when implanted in the fluid environment 
of the knee joint, he did not see any necrosis in those studies.   
 The consensus opinion was that the scoring as a moderate irritant was due to the 
implantation in the muscle, rather than the fluid environment of the joint, where 
the implant is designed to be used.   
 The signs of irritation were not seen in the pathologic analyses in the porcine 
model when the scaffold was implanted in the joint. 
1.4.3.2.3.9 6 week Systemic Toxicity Study in Rats Following Subcutaneous Implant 
(T0118; 10993-6, 10993-11). 
The test article, the BEAR® implant, was surgically implanted in the subcutaneous tissue 
of the rat to evaluate potential systemic toxicity and local tissue response at the 
implantation site.  A separate group of animals was similarly implanted with high density 
polyethylene (HDPE) to serve as the control group.  Twelve male and 12 female rats 
were randomly assigned to either the test or control group (6/sex/group).  Animals were 
observed daily for overt signs of toxicity.  Detailed clinical examinations were conducted 
weekly.  Animals were weighed prior to implantation, at weekly intervals, and on the day 
of euthanasia.  At 6 weeks, blood samples were collected for hematology and clinical 
chemistry analysis, and the animals were euthanized.  A necropsy was conducted, 
selected organs were collected and weighed, and implantation sites were excised and 
examined macroscopically.  A microscopic evaluation of the implantation sites and 
collected organs was conducted.   
 Clinical observations, body weights, necropsy results, organ weights, organ/body 
weight ratios and organ/brain weight ratios were not adversely affected by 
implantation of the test or control articles.   
 There were no changes in hematology or clinical chemistry values considered 
related to implantation with the test article.   
 Necropsy observations and microscopic evaluation of collected organs revealed 
no evidence of a test article related response.   
 Microscopic evaluation of the implantation sites indicated no significant 
difference in the local tissue response between the control and test articles.    
 There was no evidence of systemic toxicity from the test article following 
subcutaneous implantation in the rat.   

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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17 
 
 Microscopically, the test article was classified as a nonirritant in males and a 
slight irritant in females.   
 Overall, microscopically the test article was considered as a nonirritant as 
compared to the control. 
1.4.3.3 Clinical Data 
With the preclinical data in a large animal model showing similar ACL strength with the 
bridge-enhanced repair and the ACL graft, we next obtained FDA and IRB approval for a 
first-in-human study to begin to determine if this device is safe in humans as well.  A 2-
arm, single center study was designed to determine if any adverse events occur at a 
higher rate with bridge-enhanced ACL repair than with the gold standard of care, ACL 
reconstruction.  At this time, ten patients have undergone bridge-enhanced ACL repair, 
with no severe adverse events of deep joint infection, inflammation, or implant failure.  
All patients are at least three months out from surgery, and as in vivo resorption time in 
the porcine knee was 6 to 8 weeks, we anticipate much, if not all, of the implant has also 
been resorbed in these patients.  
 
1.4.3.3.1 Safety Outcomes/Adverse Events 
Under IDE G140151, we have started a first-in-human study of the BEAR implant.  This 
controlled cohort study consisted of twenty patients undergoing surgery for an ACL 
injury.  Ten of the patients received the BEAR implant repair technique (BEAR) and ten 
had ACL reconstruction with an autograft hamstring tendon (ACLR).  We have currently 
completed enrollment, and all patients who had the BEAR procedure are between two 
and eight months postoperative.  We currently have data at three months (N=8 BEAR, 
N=5 ACLR) and six months (N=7 BEAR and N=4 ACLR) postoperatively.   
1.4.3.1 Safety Outcomes/Adverse Events 
The adverse events reported (see Table 1 for a complete listing) were similar in both the 
intervention and control groups.  Each safety outcome criteria is detailed below and all 
adverse event data can be found in Table 1.  In addition to the adverse events we 
evaluated specifically for the study, one patient in the intervention group had one day of a 
urticarial reaction 5 weeks after surgery, which resolved without intervention.  Upon 
further questioning, this patient had a pre-operative history of urticaria with stress, which 
would flare for a few hours and then resolve.   In addition, one patient in the intervention 
group was diagnosed with mild frostbite (listed on the AE sheet as a burn) over the knee 
after use of the cooling device.  Protection of the area from cold over the next week 
resulted in complete resolution of the erythema. Lastly, one of the patients in the control 
group sustained a deep venous thrombosis post-operatively.   
 
 
 
 
 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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18 
 
Table 1: All listed adverse events for the patients in the initial safety study.  Of note, 
eight patients have undergone the intervention while only four have undergone the 
control procedure.  The only severe adverse event noted was a deep venous thrombosis, 
which occurred in a patient in the control group. 
Study ID 
Adverse Event 
CTCAE 4.03 
Grade 
(1-5) 
Attribution to 
study device 
Expected 
Outcome 
Control 
Dizziness 
1 
0 - Not related 
0 (No) 
1 - Resolved, no sequelae 
Control 
Fever 
1 
0 - Not related 
0 (No) 
1 - Resolved, no sequelae 
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
 
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
 
Control 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
 
Control 
Joint Range of 
Motion Decreased 
1 
0 - Not related 
1 (Yes) 
 
Control 
Muscle weakness 
lower limb 
1 
0 - Not related 
0  (No) 
1 - Resolved, no sequelae 
Control 
Muscle weakness 
lower limb 
1 
0 - Not related 
0  (No) 
Control 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
1 
0 - Not related 
1  (Yes) 
  
Control 
Pain 
1 
0 - Not related 
1  (Yes) 
  
Control 
Pain 
1 
0 - Not related 
1  (Yes) 
  
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Control 
Pain 
2 
0 - Not related 
1  (Yes) 
 
Control 
Paresthesia 
1 
0 - Not related 
1  (Yes) 
  
Control 
Thromboembolic 
event 
2 
0 - Not related 
1  (Yes) 
 1 - Resolved, no sequelae 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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19 
 
  
 
 
 
 
 
Study ID 
Adverse Event 
CTCAE 4.03 
Grade 
(1-5) 
Attribution to 
study device 
Expected 
Outcome 
Intervention 
Burn 
1 
0 - Not related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Fall 
2 
0 - Not related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
0  (No) 
  
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
2 - Resolved,  with sequelae 
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
  
Intervention 
Joint effusion 
1 
0 - Not related 
1  (Yes) 
 
Intervention 
Muscle weakness  
2 
1 - Possibly 
related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Muscle weakness  
2 
1 - Possibly 
related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Baker Cyst 
2 
0 - Not related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Nausea 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Neutrophil count 
decreased 
1 
0 - Not related 
0 (No) 
 
Intervention 
Neutrophil count 
decreased 
1 
0 - Not related 
0 (No) 
 
Intervention 
Pain 
1 
0 - Not related 
0  (No) 
  
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
 1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
 1 - Resolved, no sequelae 
Intervention 
Pain 
1 
0 - Not related 
1  (Yes) 
  
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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20 
 
 
1.4.3.1.1 Adverse Events: Infection 
No patients in either group were diagnosed with a deep joint infection.   
1.4.3.1.2 Adverse Events: Inflammation 
No patients had signs or symptoms, which would necessitate an arthrocentesis for 
diagnosis of inflammation or infection.  Patients in both groups have had an effusion after 
surgery, consistent with what would be expected after knee surgery (see Table 1 for a 
complete listing).  The majority of the effusions in both groups had resolved by the three 
month time point (Figure 6) and were in the range of what would be considered as 
expected by our medical monitors. 
 
 
 
Figure 6: Effusion scores at baseline, 
two weeks, six weeks, three months and 
six months after both bridge-enhanced 
ACL repair (intervention group) and the 
group undergoing ACL reconstruction 
(control group).  The effusion score 
reports the amount of effusion measured 
in the patient at that clinical visit.   No 
statistically significant difference was 
seen between groups. 
 
 
 
 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
2 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
3 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
3 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
3 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Pain 
3 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Paresthesia 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
Urticaria 
2 
0 - Not related 
0  (No) 
1 - Resolved, no sequelae 
Intervention 
Vomiting 
1 
0 - Not related 
1  (Yes) 
1 - Resolved, no sequelae 
Intervention 
White Blood Cell 
decreased 
1 
0 - Not related 
0 (No) 
 
Intervention 
White Blood Cell 
decreased 
1 
0 - Not related 
0 (No) 
 
Intervention 
White Blood Cell 
decreased 
2 
0 - Not related 
0 (No) 
1 - Resolved, no sequelae 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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21 
 
1.4.3.1.3 Adverse Events:  Muscle Atrophy 
Our pre-established criteria for muscle atrophy was that if at the six week follow-up visit, 
the patient cannot ambulate independently and continues to require crutches for 
ambulation, the patient will be classified as having muscle atrophy and treated 
accordingly.  For 2 patients in the 10 intervention patients who have been evaluated at the 
six week time point, and 2 patient in the 8 control patients that have been evaluated at the 
six week time point, one crutch or a cane was still being used at the six week time point.  
All patients were able to discontinue use of any ambulatory aid by eight weeks post-
operatively.   
1.4.3.1.4 Adverse Events:  Pain 
No patients in either group required re-hospitalization for pain after their surgery.  The 
pain scores for the patients in the two groups have been similar and the averages 
illustrated in Figure 7.  These pain scores were in the range of what would be considered 
as expected by our medical monitors.  
 
 
Figure 7:  Self-reported pain scores at 
baseline, two weeks, six weeks, three 
months and six months after both 
bridge-enhanced ACL Repair 
(intervention group) and the group 
undergoing ACL Reconstruction 
(ACLR group).  The pain score 
reports the highest level of pain the 
patient experienced since the last 
clinical visit.   No statistically 
significant difference was seen 
between groups. 
 
 
 
1.4.3.1.5 Adverse Events:  Implant Failure 
No patient in either group has had a Lachman exam that demonstrated 6mm or greater 
AP knee laxity than the unoperated knee.   
 
1.4.3.2 Efficacy Outcomes 
 
Efficacy outcomes, including IKDC (International Knee Documentation Committee) 
scores, Lachman Testing, MRI imaging, knee range of motion and muscle strength have 
also been collected for these patients are the details are outlined below.  These data are 
presented as of 11-3-2015. 
 

BEAR® Implant, IDE Number: G150268   
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1.4.3.2.1 IKDC scores 
The preoperative IKDC scores were 33+/- 11 points for the BEAR patients and 40 +/- 10 for the 
ACL reconstruction patients.  IKDC scores improved in both groups at three months and again at 
six months (Figure 8).  No statistically significant differences were found between the scores in 
the two groups at in this small number of patients.   
 
 
Figure 8:  IKDC scores pre-operatively and post-operatively at 3 and 6 months for the 
patients in the study as of 11-3-2015. 
 
1.4.3.2.2 Knee Laxity 
The average side-to-side difference in knee laxity at three months post-operatively as 
measured by manual Lachman testing was 1.0 +/- 1.5 for the BEAR group and 0.4 +/- 1.2 
for the ACL reconstructed group.  At six months, the values were 1.5 +/- 1.2 in the 
BEAR group and 0.3 +/- 0.5 in the ACL reconstruction group.    There was no clinically 
or statistically significant difference between the groups in this small number of patients.  
No patient in either group had a Lachman on the operative side which was more than 4 
mm greater than the contralateral knee.   KT-2000 instrumented testing for 
anteroposterior laxity at six months revealed the average side-to-side difference in knee 
laxity at six months was 2.0 +/- 2.0 for the BEAR group and 1.5 +/- 1.8 for the ACL 
reconstructed group.   
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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23 
 
 
Figure 9:  Anteroposterior knee laxity in the two groups as measured by Lachman 
(manual) testing and KT-2000 (instrumented) testing post-operatively.  No significant 
difference was noted between groups. 
1.4.3.2.3 MRI Imaging 
All patients in the bridge-enhanced repair group had the presence of tissue in the region 
of the healing ACL (Figure 10).Using the algorithm from the porcine model for MR 
prediction of the maximum load of the ACL, the average predicted maximum load at 
three months after surgery for the BEAR patients was 730+/- 184N, while that for the 
ACL reconstructed patients was 970 +/- 290N.  There was no significant difference 
between the groups in this small number of patients.  Note this analysis was only on n=8 
of the repair patients and n=5 of the ACL reconstruction patients , all of the patients who 
have had their three month MRI completed as of November 3, 2015. 
 
Figure 10:  MRI appearance in the sagittal plane of an intact ACL (left hand panel) and 
the first bridge-enhanced repair patient.  The second panel is the torn ACL, the third 
panel shows the MR appearance at 11 weeks and the last panel shows the appearance at 
13 weeks post-operatively on the CISS sequence.   
 
1.4.3.2.4 Knee Range of Motion 
The range of motion was restricted both at baseline and at two and six weeks when 
compared to the contralateral side in both groups of patients.  The range of motion was 
Intact ACL  
Torn ACL 
Control 
First Bridge-Enhanced ACL Repair Patient 
11 Weeks  
Post-Operative 
13 Weeks  
Post-Operative 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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24 
 
within 5 degrees of the contralateral side in extension by three months in all patients and 
within 25 degrees of full flexion in the BEAR groups, both of which were considered in 
the expected range (Figure 11).  Range of motion in both flexion and extension had 
returned to within 3 degrees of normal in all patients by six months post-operatively. 
  
 
 
Figure 11:  Active Range of Motion in the bridge-enhanced repair (BEAR) group and the 
ACL reconstruction (ACLR) group at baseline, 2 weeks, 6 weeks, three months and six 
months after surgery.  No significant differences in range of motion in the two groups 
were detected in this early analysis.   
 
1.4.3.2.5 Muscle Strength 
At three months after surgery, for patient data available as of 11/2/2015, the average 
recovery in hamstring strength at three months after surgery (calculated as 
(operative/contralateral) x 100) was 77 +/- 16 percent in the intervention group and 52 +/- 
6 percent in the ACL reconstructed group (means +/- SD).   At six months after surgery, 
it was 87 +/- 12 in the intervention group and 68 +/- 19 percent in the ACL reconstruction 
group (Figure 12).  Using a mixed measures ANOVA, the effect of treatment was 
significant (P< 0.01), with the BEAR patients having improved hamstring recovery when 
compared to the ACL reconstructed patients.   
 
Figure 12: Recovery of hamstring strength 
after the bridge-enhanced ACL repair 
(BEAR) and ACL reconstruction (ACLR).  
The BEAR patients had significantly 
improved hamstring strength recovery at 
these early time points (three and six months, 
0 < 0.01.) 
 
 
 
 
 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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25 
 
 
1.4.4 Rationale 
With the preclinical data in a large animal model showing similar ACL strength with the 
bridge-enhanced repair and the ACL graft, and the feasibility study showing no 
significant adverse events in the intervention group, the next step is to determine if this 
device results in an outcome after ACL surgery that is not inferior to the result obtained 
with autograft ACL reconstruction, the current gold standard of treatment for patients 
thought to benefit from surgical treatment for their ACL injury.  The benefits of the 
bridge-enhanced procedure are that patients do not have to have the extra trauma of an 
autologous graft harvest.  Use of allograft tendon for the ACL graft also avoids the 
trauma of autologous graft harvest; however, use of allograft is no longer recommended 
in patients under 25 years of age due to the relatively high failure rate of allografts (20 to 
30%) and risk of additional surgery on the operative knee (30%) in this age group.  If we 
can show use of the implant leads to similar results as the autograft ACL reconstruction 
procedure, patients will benefit from not having a second area of their leg compromised 
to treat the ACL injury.   This 2-arm, single center study is designed to determine if 
patient reported outcomes after a bridge-enhanced ACL repair are non-inferior to patient 
reported outcomes after the gold standard of care, ACL reconstruction in terms of knee 
laxity and patient reported outcomes at two years and to determine if there is superiority 
for the BEAR procedure in terms of early return of muscle strength.   
1.5 
Study Objectives  
1.5.1 Primary Objective 
 
The overall objective of this study is to determine the non-inferiority of the efficacy of the 
BEAR® Implant when compared with an ACL reconstruction with an autograft 
reconstruction (current gold standard).  The outcomes for evaluating the primary objective 
will include a patient reported score on the International Knee Documentation Committee 
(IKDC) validated outcome measure at two years after surgery and a measure of AP knee 
laxity at two years after surgery.   
 
1.5.2 Secondary Objective(s) 
 
Our secondary objectives are: 
 
1) to determine if patients having ACL surgery with the BEAR Implant recover their 
hamstring or quadriceps strength more quickly than patients undergoing ACL 
reconstruction.  To assess this, we will measure the hamstring and quadriceps strength at 
3 and 6, 12 and 24 months after surgery.   We hypothesize that at 3 and 6 months, 
patients who received BEAR surgery will have superior hamstring strength than those 
who received hamstring autograft. 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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26 
 
2) to determine if markers of early osteoarthritic change are less prevalent in the BEAR 
patients than in patients undergoing ACL reconstruction at two years out from surgery.  
We will collect imaging data, as well as patient reported outcome data using the Knee 
Injury and Osteoarthritis Outcome Score (KOOS) questionnaire, during the course of this 
study. While we think it is unlikely either group will have clinically significant changes 
in the 2 year time frame for this protocol, we will collect this data during the two year 
primary outcome assessment period and again at six and ten years post-surgery.  
 
3)  to determine if there are any increased safety risks associated with use of the BEAR 
Implant. These potential safety risks include loss of range of motion of the knee, 
development of bovine Type I collagen antibodies, infection (superficial or deep surgical 
site infection), graft or repair failure, development or graft/device rejection as evidenced 
clinically or serologically, need for further surgeries, development of prion disease or 
other viral diseases, or occurrence of deep venous thrombosis.  We will also record any 
other adverse events which occur during the course of the trial. 
 
 4) to determine if patients undergoing the BEAR procedure are able to get back to work 
and sports at the same rate as patients undergoing ACL reconstruction, and to determine 
if there is a difference in the rate of meeting the return-to-sport criteria for patients in the 
BEAR and ACL reconstruction groups. 
 
5) to determine whether the patient reported outcomes or graft failure rates can be 
predicted by the surrogate prediction of maximum load and stiffness of the healing ACL 
using a novel MRI technique [38, 41, 95].  This technique provides a non-invasive way to 
assess the healing ACL or ACL graft and will be another imaging modality to assess the 
relative volume, tissue quality and orientation of the ACL after the BEAR procedure and 
autograft ACL reconstruction at 6 months, and 2 years after surgery. 
 
6) to determine whether the volume and orientation of the ACL after the BEAR 
procedure is different from the volume and orientation of the ACL graft after ACL 
reconstruction.  This will also be measured using the MRIs obtained at 6 months and 2 
years after surgery.  
 
Measures of efficacy will be evaluated using physical exam, laxity testing, strength 
testing and imaging.  Specific tests will be performed as noted in  
 
 
 
 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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27 
 
 
Table 3 at time points up to (and including) two years out from surgery.   
 
Table 2: Primary and Secondary Study Objectives. 
Primary Study Endpoints 
 
Secondary Study Endpoints 
 
 Patient Reported 
Outcomes (IKDC) 
 Knee Anteroposterior 
Laxity as measured by 
KT instrumented laxity 
testing 
 Quadriceps and 
Hamstring Strength 
 KOOS patient reported 
outcome score 
 Imaging findings 
associated with early 
osteoarthritis 
 Knee range of motion 
 Bovine Type I collagen 
antibody presence 
 Deep joint infection 
 Incision and drainage of 
a deep surgical site 
infection 
 Evidence of Graft 
Rejection 
 Graft or repair failure 
 Return to work/sports 
 Additional surgeries on 
the operative knee 
 MRI imaging of the 
ACL 
 All adverse events 
 
1.5.3 Endpoints 
The endpoints for the primary and secondary objectives will be measured as follows: 
1.5.3.1 PRIMARY ENDPOINTS 
The primary outcomes for this trial will be the score on the IKDC questionnaire at one 
and two years after surgery and the AP laxity of the knee as measured by KT testing at 
one and two years after surgery.   
1.5.3.1.1 IKDC Outcome 
The IKDC patient-reported outcome measure instrument will be administered to all 
patients at six months, 1, 2, 6, and 10 years after surgery.  For the IKDC outcomes, a 
difference of 11.5 points between control and BEAR groups will be considered clinically 
significant, at the primary analysis at two years, as previously published [34].  

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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28 
 
1.5.3.1.2 Anteroposterior (AP) Laxity 
The anteroposterior (AP) knee laxity will be determined using a KT arthrometer at the 
30lb (130N) setting on both knees of the subject at six months and 1, 2, 6 and 10 years 
after surgery (see Appendix C).  Both sides will be covered with a sleeve so the licensed 
examiner cannot tell which is the operated knee or which procedure the patient had.  
Values for both knees will be recorded. For knee laxity, a difference of 2.0 mm in the 
side-to-side difference measurements at 2 years after surgery, the primary analysis, for 
the patients in the bridge-enhanced repair group vs. the ACL reconstruction group will be 
considered clinically significant.     
 
1.5.3.2 SECONDARY ENDPOINTS  
1.5.3.2.1 Hamstring and Quadriceps Strength 
The strength of the quadriceps, hamstring and hip abductor musculature will be 
determined at three, six, twelve and twenty-four months after surgery.  Both sides will be 
covered with a sleeve so the licensed examiner cannot tell which is the operated knee or 
which procedure the patient had.  The quadriceps testing will be performed in a seated 
position with the knee flexed 90 degrees so as not to stress the repair or healing graft.  
Values for both knees will be recorded.  In addition, Biodex testing will be performed at 
the six, twelve and twenty four month follow-up. Hop testing will also be performed at 
six, twelve and twenty four months if the patients have progressed to hopping as part of 
their rehabilitation with their physical therapist and if the patient feels comfortable doing 
the test.  Lastly, static and dynamic balance testing will be performed at six, twelve and 
twenty-four months after surgery. 
 
1.5.3.2.2 KOOS Score 
The Knee Injury and Osteoarthritis Outcome Score (KOOS) score is another validated 
patient outcome measure with three domains: Pain, Knee Related Quality of Life and 
Sports.  We will collect data for all three domains at twenty four months after surgery.  A 
10 point difference between groups will be considered statistically significant based on  
prior studies validating the KOOS score [96]. 
 
1.5.3.2.3 Xray Imaging  
A semiflexed weight bearing MTP view, as well as a lateral projection, will be obtained 
at baseline and at two years after surgery to assess joint space narrowing and the presence 
of osteophytes suggestive of early OA.  The signs to be identified include peaking of the 
intercondylar tubercles and buttressing osteophytosis [97].  Joint space width changes 
will be measured as previously reported by Jones et al for a large cohort of patients 
undergoing ACL reconstruction at two years post-operatively [98] where joint space 
widening was noted in the ACL reconstruction cohort.  This joint space widening at this 
time point has been reported by others as associated with early osteoarthritis [99] which 
is why it will be measured here. The Kellgren and Lawrence system will be used to 
classify the severity of knee osteoarthritis using five grades: 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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29 
 
 
Grade 0: no radiographic features of OA are present 
 
Grade 1: doubtful joint space narrowing (JSN) and possible osteophytic lipping 
 
Grade 2: definite osteophytes and possible JSN on anteroposterior weight-
bearing radiograph 
 
Grade 3: multiple osteophytes, definite JSN, sclerosis, possible bony deformity 
 
Grade 4: large osteophytes, marked JSN, severe sclerosis and definite bony 
deformity 
At the 2 year time point, we do not anticipate seeing any clinically significant change on 
the K-L scale for either group, but we will plan to collect the data at baseline and 2 years 
in preparation for a longer term follow up of this cohort. 
1.5.3.2.1 Range of Motion 
Active and passive range of motion will be measured using a goniometer at three months, 
six months and one and two years after surgery. Both sides will be covered with a sleeve 
so the licensed examiner cannot tell which is the operated knee or which procedure the 
patient had.  Values for both knees will be recorded.   In addition, a standing active 
flexion angle will be recorded for both knees.   
 
1.5.3.2.2 Bovine Type I Collagen Antibodies 
As prior studies of bovine collagen products have reported a 2-3% rate of patients having 
elevated levels of bovine type I collagen antibodies[79], likely from dietary exposure [80, 
81], we will plan to screen patients pre-operatively for the presence of these using a test 
for levels of IgE antibodies to bovine gelatin (hydrolyzed collagen).Patients with a 
positive test (low, moderate, high, or very high level) for these antibodies will be 
excluded from the study. Preoperative levels of IgG antibodies to type I collagen will also 
be measured, but will not be used to screen for hypersensitive individuals as levels of IgG 
are not thought to correlate with adverse events or hypersensitivity (NIAID Consensus 
statement 2010).   
 
In addition, as 10% or greater of patients receiving other bovine collagen implants can 
develop bovine type I collagen antibodies[84], with the peak antibody detection at 
approximately four to six months, we will test all patients post-operatively at the six 
month time point for the presence  of both IgE and IgG antibodies.   
1.5.3.2.3 Deep Joint Infection/Incision and Drainage of Deep Surgical 
Site Infection 
We will also monitor patients for any signs of a post-operative infection.  If there is 
clinical suspicion for a possible deep joint infection (fever greater than 101 degrees 
Fahrenheit, increasing pain in the knee, presence of an effusion, drainage from the knee), 
a knee arthrocentesis will be performed and if organisms are cultured from the joint fluid, 
the patient will be classified as having a deep joint infection  (according to CDC/NHSN 
Surveillance Definitions for Specific Types of Infections) and treated accordingly.  Any 
patient diagnosed with a deep joint infection or who undergoes incision and drainage of a 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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30 
 
deep surgical site infection will have the event recorded as an adverse event.  These 
adverse event data will be evaluated as a secondary outcome of the study. 
 
1.5.3.2.4 Evidence of Graft Rejection 
If a patient presents with a swollen, warm knee and there is clinical suspicion of marked 
inflammation versus septic joint, an arthrocentesis will be performed.  If the synovial 
fluid culture is negative for organisms, the patient will be classified as having a marked 
inflammatory reaction and treated accordingly.  Bovine Type I collagen antibodies, ANA, 
CBC with differential, CRP and ESR lab tests will be performed as well for all 
symptomatic subjects.  In addition, a urinalysis will be performed and in subjects having 
protein in the urinalysis, a protein electrophoresis will also be performed.  Evidence of 
graft rejection, clinically or by serology, will be recorded as a secondary outcome 
measure, as well graft removal for any reason. 
1.5.3.2.5 Graft or repair failure 
A patient shall be noted to have had a graft or repair failure when one or more of the 
following criteria are met:  positive pivot shift exam, Lachman exam with greater than 6 
mm side to side difference, absence of tissue in the expected ACL location on MRI 
imaging, MR evidence of graft or repair loss of continuity or symptomatic instability 
requiring revision of the ACL surgery. 
 
1.5.3.2.6 Other adverse reactions 
Any adverse reactions, including (but not limited to) deep venous thrombosis, loss of 
function, need for prolonged parenteral pain medication, development of neurologic 
symptoms or additional trauma will also be recorded for all patients in the study.   
 
In addition, if any evidence of prion disease is noted, a workup will be initiated.  
Evidence of prion disease could include:  any rapidly developing dementia, neurologic 
symptoms of difficulty walking and changes in gait (other than those expected after knee 
surgery), hallucinations, confusion or difficulty speaking.  If the patient or clinician are 
concerned prion disease may be developing, the patient will be referred for a neurologic 
consultation and workup may include MRI of the brain, electroencephalogram (EEG), 
blood tests and a complete neurologic and ophthalmologic exam.  These would be 
conducted at the discretion of the examining neurologist. 
 
In addition, prior reports of injectable collagens have reported embolic complications 
including pulmonary embolism[90] and blindness[91] and other complications[92] [93].  
While implantation of a large implant into a joint cavity may have a significantly lower 
risk profile for embolism than an injectable material placed in the vicinity of blood 
vessels, collagen can activate platelets.  The study team will monitor for signs and 
symptoms of a possible deep venous thrombosis in all study patients and patients 
presenting with calf pain, ankle swelling, a positive Homan's sign, shortness of breath or 
clinician concern for possible deep venous thrombosis will be referred for ultrasound 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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31 
 
screening for a DVT, and if positive, a referral to hematology for treatment with 
anticoagulation as indicated.  
 
Any additional surgical procedures that the subject requires on the operative knee, as well 
as any surgical procedures required on the contralateral knee, will also be recorded and 
reported as an additional secondary outcome measure.  These include (but are not limited 
to) additional surgery to address meniscal or cartilage pathology, scar tissue, 
arthrofibrosis, removal of symptomatic hardware or graft removal for any reason. 
1.5.3.2.7 Return to work/sports 
Time for patients to return to full time work or school, as well as sports, will be recorded 
for all patients in the study.  Failure to return to work or sports will be recorded as a 
secondary outcome, and if the failure is due to the operative knee, that will also be 
recorded.  In addition, the length of time for patients to meet return to sport criteria, 
including 90% strength on the operative side for quadriceps and hamstring strength and 
achievement of a hamstring to quadriceps ratio of 0.60, will also be recorded for all 
patients.  All strength testing will be performed with a sleeve over both knees so the 
examiner is blinded to both operative side and the procedure performed.   
 
1.5.3.2.8 MRI  
MRI will be used at six months, 1, 2, 6 and 10 years with the same specific sequence 
previously validated in the porcine model to predict the yield and maximum load of the 
repaired ACL or ACL graft (see Appendix B). In addition, MR imaging will be used to 
measure the volume and orientation of both the ACL repaired using the BEAR technique 
and the ACL reconstruction as well as that of the contralateral knee.   During the course 
of this study, we will determine if the values for maximum load, yield load, stiffness, 
volume or orientation of the healing ACL or graft, as well as the relative value of these 
parameters compared with the contralateral side, are predictive of patient outcomes, 
including patient reported outcomes on the IKDC or KOOS testing, graft or ACL re-
rupture, rate of return to sport/work and muscle strength.    
1.6 
Patient Selection 
Participants in both groups will be screened and recruited during their visit to the Boston 
Children's Hospital Orthopaedic Surgery or Sports Medicine Clinics, with referral to Dr 
Lyle Micheli, Dr Yi-Meng Yen or Dr Dennis Kramer in the event the patient is willing to 
participate in the clinical trial and are thought to be a candidate for ACL reconstruction 
with autograft tendon. Patients will be thought to be a candidate for surgery if they are 
under 35 and active. The most recent AAOS Clinical Practice Guideline states: 
“Moderate evidence supports surgical reconstruction in active young adult (aged 18 to 35 
years) patients with an ACL tear.”   A recent systematic review also concluded that 
surgical stabilization should be considered the preferred method of treatment for 
skeletally immature individuals with complete ACL tears (Vavken and Murray, 
Arthroscopy, 2011 May; 27(5):704-16).   Non-operative treatment is also considered 
reasonable by some surgeons for active adult patients who participate exclusively in non-
cutting athletics (e.g swimming, bicycling, skiing), or non-athletic young adults.  For this 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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32 
 
reason, in this proposed trial, we will only enroll patients where there is moderate 
evidence that surgical reconstruction has benefit (i.e. active young patients younger 
than 35 years of age). 
 
The eligibility criteria (see below) will be the same for both groups. On average, 20 ACL 
reconstructions are performed on patients aged 14 to 35 years, each month, by these 
surgeons in the sports medicine group. This number should be sufficient to consent and 
enroll up to 100 patients over a 14 month period. Patients found to be eligible will be 
offered participation. The treating surgeon and research coordinator will explain the study 
to the patient and answer all questions. The research coordinator will review the consent 
document, obtain required signatures and provide the patient with a photocopy of the 
consent form for his/her records.  
1.6.1 Inclusion Criteria  
1.6.1.1 At Preoperative Exam 
To be eligible for this trial the subjects must meet all of the following criteria: 
 Age:  All patients must be at least 14 years of age and have closed femoral 
and tibial physes.  The upper age limit will be 35 years of age.  
 Sex:  Both male and female 
 ACL:  Complete tear, confirmed by MRI 
 Time from injury to screening: ≤45 days 
 MRI:  ACL tissue present on pre-operative MRI - at least 50% of the ACL 
length must still be attached to the tibial plateau 
 Prior surgery on affected knee: None 
 History of prior infection in knee: None 
 Regular use of tobacco or nicotine in any form: None 
 Use of corticosteroid within last 6 months: None 
 Underwent chemotherapy treatment: Never 
 History of sickle cell disease:  None 
 History of anaphylaxis: None 
 Any condition that could affect healing or infection risk (Diabetes, 
inflammatory arthritis, etc): None 
 Medial collateral ligament injuries: Grade I or II may be included 
 Bovine Type I collagen antibodies: Patient must not have clinically 
significant levels of IgE antibodies to bovine gelatin on pre-operative 
screening or a known history of allergy to beef or bovine derived products.  
 Patients who have selected surgical treatment of their ACL injury and have 
been thought to be surgical candidates by the treating physician 
 Patients along with their surgeon must be willing to undergo either hamstring 
autograft or bone patellar tendon bone autograft, if randomized to the control 
group 
1.6.1.2 Inclusion Criteria at Surgery 
 ACL abnormal on arthroscopic inspection:  Yes 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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33 
 
 Time from injury to surgery: ≤45 days 
 Meniscus: No displaced bucket handle injuries  requiring repair 
 ACL tissue present:  More than 50 percent of the length of the ACL remains 
attached to the tibial insertion site 
 Synovectomy/plica:  All may be included 
 Chondral injury:  Chondral injury on either condyle that is not full-thickness 
may be included. 
 
1.6.2 Exclusion Criteria  
1.6.2.1 At Pre-operative Exam  
To be eligible for this trial the subjects must meet none of the following criteria: 
 Prior surgery on affected knee  
 History of prior infection on affected knee 
 Regular use of tobacco or nicotine in any form  
 Use of corticosteroid within last 3 months 
 Ever underwent chemotherapy treatment  
 History of sickle cell disease  
 History of anaphylaxis 
 Any condition that could affect healing or infection risk (Diabetes, 
inflammatory arthritis, etc) 
 Diagnosis of posterolateral corner injury (LCL complete tear, Biceps femoris 
tendon avulsion, tear of the arcuate ligament, tear of the popliteus ligament)  
 Diagnosis of Grade III medial collateral ligament injury  
 Bovine Type I collagen antibody level deemed clinically significant or a 
known allergy to beef or bovine derived products.  Diagnosis of complete 
patellar dislocation 
 Preference for conventional ACL reconstruction other than hamstring 
autograft or bone patellar tendon bone autograft (e.g., allograft, other 
autografts). 
 
1.6.2.2 Exclusion Criteria at Surgery 
 ACL deemed normal on arthroscopic inspection 
 Time from injury to surgery is >45 days 
 Length of remaining ACL attached to the tibial insertion site less than 50 
percent  
 Displaced bucket handle meniscal injury requiring repair 
 Diagnosis of full-thickness chondral injury on either condyle 
 Grade III medial collateral ligament injury 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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34 
 
1.6.3 Early Withdrawal of Patients 
Patients will be withdrawn from the study, if for any reason their surgery cannot be 
scheduled within 45 days of their injury. Physical examination and imaging will be used 
to assess patient eligibility for the trial; however, the extent of soft tissue damage may not 
be fully appreciated until the time of surgery.  Some patients will be deemed eligible, 
consented, and then later, during surgery, found to meet exclusion criteria and will be 
withdrawn from the trial if they do not want to be part of the ACL reconstruction group.  
Patients will be withdrawn from the trial if initial arthroscopic inspection of the knee 
reveals that the ACL tissue has resorbed so that less than 50% of the length of the ACL 
remains at the tibial insertion site. Patients will also be withdrawn if the surgeon 
discovers during surgery that the meniscus has a displaced bucket handle tear that 
requires repair and/or there is a full-thickness chondral injury on either condyle. Under 
these circumstances, the surgeon will repair all soft tissue damage and perform an ACL 
reconstruction using the technique that s/he believes will be most efficacious for the 
patient. Patients also may choose to withdraw from the study at any time and for any 
reason.  
 
Any patient who has bovine type I collagen antibodies at a level greater than 2 standard 
deviations above that of normal human sera will be excluded from participation in the 
study. 
 
The reason for withdrawal and the circumstances of withdrawal will be documented for 
all patients withdrawn from the study.  Even though patients may be disqualified 
prematurely from the study on one basis (i.e. missing a post-operative evaluation point), 
every effort will be made to obtain permission to continue to follow subjects with a 
protocol deviation to obtain primary outcome data at the final, twelve-month time point.  
These data are critical for the accurate assessment of the integrity of the final study 
analysis since early withdrawal could be related to the safety profile of the study 
procedure or device. 
1.7 
Treatment Plan 
1.7.1 General Study Design 
The protocol will be approved by the Investigational Review Board (IRB) of Boston 
Children's Hospital and by the Food and Drug Administration prior to the start of the 
investigation.   
 
This study is to be conducted in the USA according to ISO 14155:2011 (Clinical 
investigation of medical devices for human subjects – Good clinical practice); United 
States Code of Federal Regulations Title 21 Part 50 (Protection of Human Subjects) and 
Part 56 (Institutional Review Boards); 21 CRF Part 812 (Investigational Device 
Exemptions); and other applicable government regulations and institutional research 
policies and procedures. This is an efficacy study of the BEAR® ACL implant and will 
be carried out in the form of a randomized controlled trial of approximately 100 patients.  
We will recruit patients in two strata: those who, along with their surgeon, would prefer 
hamstring autograft if randomized to conventional ACL reconstruction, and those who 

BEAR® Implant, IDE Number: G150268   
Miach Orthopaedics, Inc 
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35 
 
would prefer bone patellar tendon bone (BPTB) autograft.  Our goal is to recruit 87 
patients in the hamstring-preference stratum.  We expect an additional 10-15 in the BPTB 
stratum for a total of approximately 100.  Randomization will be in 2:1 ratio so there will 
be approximately 67 BEAR and 33 Control patients in total.  
 
After consenting but before randomization, all patients will complete additional testing 
and evaluation including questionnaires, laboratory studies of blood and urine, physical 
exam and imaging.  If a patient has positive antibodies to bovine Type I collagen at a 
level greater than 2 standard deviations from normal, they will not be eligible for the trial.  
Second, if a patient is found to have less than 50% of the length of the ACL remaining at 
the time of surgery, they will be discontinued from the study. 
 
All patients in the trial will have preauthorization for their surgical procedure obtained 
using the diagnosis code for an ACL tear and the procedure code 29888 - 
Arthroscopically assisted ACL repair or reconstruction.  This is an established code and 
the modifier Q1 will be added to the procedure code to notify the insurance carriers that 
the patient is participating in a clinical trial.  Patients will be informed that the billing for 
their surgery will be handled in the same way it would be if they were having ACL 
surgery outside of the trial.  If the patient's insurance refuses to give preauthorization for 
the costs of the surgery because of the patient's participation in the trial, the patient will 
have the option to leave the study at any time.   
 
The length of study participation for each patient will be 24 months from the time of 
surgery, with 6 post-operative visits taking place at 1-2 weeks, 6 weeks, and 3, 6, 12 and 
24 months. The primary endpoints to be monitored are a patient reported outcome (IKDC 
score) and a knee AP laxity measure. The secondary endpoints evaluated for efficacy will 
include muscle strength, KOOS patient reported outcome scores, imaging outcomes, knee 
range of motion, bovine type I collagen antibody presence, incidence of deep joint 
infection or inflammatory/immune reaction, graft or repair failure, time to return to 
work/sports, rates of additional surgery and ACL strength, volume and orientation as 
predicted by MRI (Table 3).  
 
1.7.2 Surgical Procedures 
Participants in the intervention and control groups will be screened and consented by a 
licensed professional during a visit to the Boston Children's Hospital Orthopaedic or 
Sports Medicine Clinics. After consenting to participate in the trial, patients will be 
randomized to either the BEAR (Intervention) procedure or ACL reconstruction 
(Control), as the current gold standard treatment of ACL injuries.  Both treatments are 
based on well-established surgical techniques, long used in suture repair or reconstruction 
of ruptured ACL. The main safety and efficacy related outcomes of ACL surgery will be 
closely monitored over a 24 month period following established protocols and guidelines 
in order to assess the safety and efficacy of the Bridge-Enhanced ACL repair compared to 
the ACL reconstruction.  

BEAR® Implant, IDE Number: G150268   
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1.7.2.1 Control Group; ACL Reconstruction with Hamstring or 
Bone-Patellar Tendon-Bone (BPTB) Autograft  
These patients will undergo a standard arthroscopic ACL reconstruction, with 
surgeon/patient preference dictating what type of graft will be used to stabilize the knee. 
As autologous hamstring tendon and bone-patellar tendon-bone grafts have not been 
found to be statistically different in clinical or biomechanical outcome studies involving 
the primary outcome measures [100-103], both hamstring and bone-patellar tendon-bone 
graft will be used in this study.  Tunnel position will be considered acceptable if the intra-
articular exit of both femoral and tibial tunnels are within the footprint of the original 
ACL.  The general schematic of the procedure is presented in Figure 13 below and a 
detailed description of the surgical procedure is outlined in Appendix A: Surgical 
Procedures. 
 
 
Figure 13: Standard ACL reconstruction procedure. In this procedure, the torn 
ACL is removed from the knee (B) and then large tunnels (10mm) are drilled in 
the femur and tibia. A graft is taken from the back of the patient's thigh, passed 
through the tunnels (C and D) and fixed in place with interference screws. This 
figure illustrates replacing the anterior cruciate ligament with a bone-patellar 
tendon-bone graft using an interference screw.  In this study, the preferred 
femoral fixation technique will be suspensory fixation with a cortical button 
(Endobutton or similar) construct. 
1.7.2.2 Intervention Group; Bridge-Enhanced ACL Repair with 
BEAR® Implant 
Patients will receive anesthesia and undergo surgery under the same conditions as the 
ACL reconstruction group, with two exceptions: 1) the surgical approach utilized to 
perform the repair will be a mini-arthrotomy instead of arthroscopy; and 2) repair of the 
knee joint will be achieved by inserting the extracellular matrix sponge (BEAR™  
scaffold) and suture construct and allowing the ACL to regenerate and repair on its own, 
rather than replacing it with hamstring graft.  A suture stent will be placed across the 
knee for initial stabilization as shown in panel B below.  The tunnel positions for the 
suture stent will be considered acceptable if the intra-articular exit of both femoral and 
tibial tunnels are within 2 mm of the footprint of the original ACL.  The general 
schematic of the procedure is presented in Figure 14 below and a description of the 
surgical procedure is outlined in detail in Appendix A: Surgical Procedures. 

BEAR® Implant, IDE Number: G150268   
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Figure 14: Stepwise demonstration of the “Bridge-Enhanced ACL repair” technique 
using the collagen device (seen first in C where it is threaded onto sutures). In this 
technique, the torn ACL tissue is preserved (A). Small tunnels (4 mm) are drilled in the 
femur and tibia and an cortical button (Endobutton or similar) with sutures attached to it 
is passed through the femoral tunnel and engaged on the proximal femoral cortex.  One 
set of sutures from the button is threaded through the collagen implant, tibial tunnel and 
secured in place with an extracortical button (red sutures). A second set of sutures (green) 
from the Endobutton were tied to the Kessler suture placed in the tibial stump of the ACL 
(green sutures). The collagen device is then saturated with 5 mL of the patient’s blood. 
The collagen device is not load-bearing; the initial strength of the repair is dependent on 
the sutures. The ends of the torn ACL then grow into the collagen implant and the 
ligament reunites. 
 
1.7.2.3 Major differences in the control and interventional 
procedures 
 The intervention group will need to have 20 ml of blood drawn during surgery 
(for a CBC test and to deliver 10 cc of blood to the implant), while the control 
group will only need 10 ml (for the CBC only).  
 The intervention group will need a 2-inch incision at the joint to expose the ACL 
and allow for delivery of the implant. This mini-arthrotomy carries the theoretical 
additional risks of infection and arthrofibrosis; however, a recent study has 
demonstrated no difference in outcomes for ACL surgery performed 
arthroscopically versus with an arthrotomy [104]. 
 The control group includes a 2 inch incision over the hamstring insertion site to 
allow for harvesting of the hamstring tendons for a graft, or a 3 inch incision over 
the front of the knee if a bone-patellar tendon-bone graft is used.  The BEAR 
group requires a 1 cm incision for tunnel creation. The larger incision carries a 
potentially greater risk of bleeding, infection and superficial nerve injury.  
 The control group requires harvesting of two of the medial hamstring tendons or a 
piece of bone from the patella and tibia with the middle third of the patellar 
tendon, the investigational group does not. This may lower the risk of hamstring 
or patellar graft harvest pain and post-operative hamstring or quadriceps weakness 
for the intervention group. 
 

BEAR® Implant, IDE Number: G150268   
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38 
 
1.8 
Study Procedures 
Participants in the intervention and control groups will be screened and consented by a 
licensed professional during their initial visit to the Boston Children's Hospital 
Orthopaedic or Sports Medicine Clinics. Table 3 below is an outline of the visit schedule 
that all patients will follow and the measures performed at each visit.  
 
 
 
 

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Table 3: Visit Schedule and Measures for Intervention (BEAR) and Control (ACLR) 
Patients. 
 

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40 
 
 
Pre-Op 
Intra-
Op 
Post-Op 
 
Measure 
Baseline 
Surgery 
1-2 wks 
(5-15 
days) 
6 wks 
(±1 wk) 
3 mos 
(±2 
wks) 
6 mos 
(±1 mo) 
1 and 2 
years 
(±2 mos) 
6 and 10 
years 
(-6 
mos/+1 
yr) 
 
Screening & 
Eligibility 
X 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
History 
(fever, pain, 
stiffness, VAS 
score) 
X 
 
X 
X 
X 
X 
X 
X 
Clinical Exam 
(wound, thigh 
circ, swelling) 
X 
 
X 
X 
X 
X 
X 
X 
Knee X-ray 
(semiflexed MTP 
view) 
X 
 
 
 
 
 
X (2 yrs 
only) 
X 
MRI 
X1 
 
 
 
 
X2 
X2  
X2 
Biomechanical 
Testing (6 and 10 
years only) 
optional 
 
 
 
 
 
 
 
X 
Knee Range of 
Motion 
X 
X 
X 
X 
X 
X 
X 
X 
Knee Laxity 
(Lachman) 
X 
X 
 
 
X 
X 
X 
X 
Pivot Shift 
 
X 
 
 
 
X 
X 
X 
Knee Laxity (KT-
1000) 
 
 
 
 
 
X 
X 
X 
Strength Testing 
 
 
X 
X 
X 
X 
X 
X 
IKDC 
X 
 
 
 
X 
X 
X 
X 
KOOS 
Questionnaire 
X 
 
 
 
 
X 
X 
X 
MOON 
questionnaire 
X 
 
 
 
 
 
X (2 yrs 
only) 
X 
ACL-Return to 
Sports survey 
 
 
 
 
 
X 
X 
X 
Bovine Type I 
collagen Ab 
X 
 
 
 
 
X 
 
 
CBC and 
Chemistries 
X 
X 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
ANA, CRP, ESR 
X 
 
 
 
 
 
 
 
Protein C and S 
X 
 
 
 
 
 
 
 
Research labs 
(blood and urine) 
 
 
 
 
 
 
X 
X 
Adverse Events 
 
X 
X 
Xx 
X 
X 
X 
X 

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Miach Orthopaedics, Inc 
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1Standard MRI 
2Research MRI 
 
1.8.1 Study Visits 
1.8.1.1 Baseline/Preoperative Assessment:  
Patients will be screened by a licensed professional at the Baseline visit to determine 
eligibility for the study.  If deemed eligible to participate, the patient will be asked if they 
would like to participate in the randomized controlled study.  If informed consent is 
granted for participation, the research coordinator will complete a screening form (FORM 
1), and a pre-operative questionnaire.  The licensed examiner will complete a physical 
exam on both knees (including goniometer range-of-motion for flexion and extension and 
thigh circumference measurements at mid patella and 5 and 10 cm above the joint line) 
and record.  Pre-operative imaging results will also be recorded.  The research 
coordinator will also document the patient has signed the informed consent.   
 
The patient will also complete a pre-operative questionnaire.  The questionnaire contains 
the three KOOS subscales, Marx activity score and SF-36 elements.  This questionnaire 
will also be administered at two years post-operatively. 
 
Patient will also have a standardized knee x-ray series (the semiflexed postero-anterior 
metatarsophalangeal and lateral knee x-ray) performed at that visit.  
 
Patients will also have blood and urine testing performed at this visit.  These tests will 
include: Bovine Type I collagen antibodies, ANA, CBC with differential, protein C and 
S, CRP and ESR.  In addition, a urinalysis will be performed and in subjects having 
protein in the urinalysis, a protein electrophoresis will also be performed.   
 
1.8.1.2 Randomization Procedures 
 
Patients will be randomized in 2:1 (BEAR:ACL Reconstruction) ratio using a stratified 
random permuted-block allocation procedure, with two strata representing 
surgeon/patient autograft preference: 
 
 
1. Hamstring Preference: randomize to BEAR or Hamstring autograft. 
 
2. Bone Patellar-Tendon Bone (BPTB) preference: randomize to BEAR or BPTB 
autograft. 
 
Allocation concealment will be accomplished by using sequentially numbered sealed 
envelopes, separate sets for each stratum. The study statistician will generate the 
allocation sequence using random block sizes that will not be revealed to study staff 
involved in recruitment or randomization.   
 

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After graft preference stratum is determined, the next sequential unopened envelope for 
that stratum will be opened.  If the treatment allocation is to ACL Reconstruction, the 
patient will receive either Hamstring or BPTB autograft according to which stratum they 
are in.  We anticipate that the vast majority (~90%) of patients will be in the Hamstring-
preference stratum. 
 
1.8.1.3 Randomization, Blinding and Unblinding Criteria 
After patients have been enrolled in the study, they will be randomized by the statistician.  
The surgeon and surgical schedulers will be notified of the group assignment; however, 
the patients will not be notified as to which procedure they will have.  We will plan to 
reveal the group assignment to the patients at the two-year post-op time point.  The 
surgeon, research coordinator, research study nurses, medical monitoring committee 
members and statistician will be unblinded as to patient assignment and the interim data 
reports to the medical monitors and statistician will contain information on the patient 
assignments.  All post-operative physical examinations will be performed by an examiner 
who is blinded as to study group, and both knees will be covered with sleeves prior to the 
examiner entering the room to conceal which is the operative knee and which procedure 
was performed.  The physical therapists will not be informed which surgery the patient 
received, just that they had ACL surgery, and patients in both groups will follow an 
identical PT protocol.  Unblinding of the patient will occur in the event of any of the 
following: persistent knee inflammation/effusion requiring removal of implant, deep joint 
infection, graft or repair failure or any evidence of prion disease symptoms.  A patient 
shall be noted to have had a graft or repair failure when one or more of the following 
criteria are met:  positive pivot shift exam, Lachman exam with greater than 10 mm side 
to side difference, absence of tissue in the expected ACL location on MRI imaging, MR 
evidence of graft or repair loss of continuity or symptomatic instability requiring revision 
of the ACL surgery.  Evidence of prion disease could include:  any rapidly developing 
dementia, neurologic symptoms of difficulty walking and changes in gait (other than 
those expected after knee surgery), hallucinations, confusion or difficulty speaking.  If 
the patient or clinician are concerned prion disease may be developing, the patient will be 
referred for a neurologic consultation and workup may include MRI of the brain, 
electroencephalogram (EEG), blood tests and a complete neurologic and ophthalmologic 
exam.  These would be conducted at the discretion of the examining neurologist.  In 
addition, unblinding of the patient will be performed in the event of any Grade 4 or 5 
serious adverse event. 
 
1.8.1.4 Intra-operative Assessment 
Before the day of surgery, the research coordinator will prepare the CRF with the patient 
name, identification number, date of surgery and study arm.  The research coordinator 
will bring the form to the operating room and complete the remaining questions during 
the surgery with the assistance of the surgeon.  A preoperative exam will be performed 
under anesthesia and the results recorded.  During surgery, arthroscopic examination of 
the menisci, chondral surfaces and ACL will be performed and the results recorded.  
Specifically, it will be recorded whether the ACL is abnormal on arthroscopic inspection.  

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For the menisci, it will be recorded whether the meniscus is normal, it is injured but does 
not require repair or has a displaced bucket handle tear that requires repair. For the ACL, 
the length of the ACL remaining (recorded as a percentage of the distance between the 
femoral and tibial insertion sites of the native ACL) will be recorded.  The presence of 
any chondral injury, as well as the area of the injury and the grade of injury, will also be 
recorded.  In addition, the CRF will be completed by the research coordinator in the 
operating room to document additional findings at surgery.   
 
A patient will be excluded from the study if the ACL is noted to be normal on 
arthroscopic exam, if they have a displaced bucket handle meniscal injury requiring 
repair or if a full thickness chondral injury is present.  Patients will be withdrawn from 
the trial if initial arthroscopic inspection of the knee reveals that the ACL tissue has 
resorbed so that less than 50% of the length of the ACL remains at the tibial insertion 
site.  The finding of less than 50% of the ACL length being present will be noted on the 
case report form.   
 
The research coordinator will also bring the following documents to be given to the study 
patient and family regarding post-operative care:   
1. Subject Document:  Post-operative Instructions 
2. Subject Document:  Post-operative Physical Therapy Prescription and Protocol 
 
 
1.8.1.5 Scheduled Post-operative Follow-up:   
The timing of follow-up visits for this study is identical to the clinical schedule (with the 
exception of 6 and 10 year follow up visits) and is identical for both groups (BEAR and 
ACLR). Patients will return to see the surgeon at approximately 1-2 weeks (5-15 days), 6 
weeks (±1 week,) 3 months (±2 weeks,) 6 months (±1 month) 12 and 24 months (±2 
month) and 6 and 10 Year (-6 mos/+1 yr) post procedure.   
 
At the 1-2 week time point, the research coordinator will complete the CRFs with the 
pertinent history and patient questionnaire.  A pertinent physical exam will be performed 
by a licensed professional on both knees (including goniometer range-of-motion for 
flexion and extension and thigh circumference measurements at the superior pole of the 
patella and 5 and 10 cm above the joint line, as well as temperature, wound check and 
standard post-operative knee joint examination – see Table 3) and the results recorded on 
the CRF.  
 
At the 6 week time point, the research coordinator will complete the CRFs with the 
pertinent history and patient questionnaire.  A pertinent physical exam will be performed 
by a licensed professional on both knees (including goniometer range-of-motion for 
flexion and extension and thigh circumference measurements at the superior pole of the 
patella and 5 and 10 cm above the joint line, as well as temperature, wound check and 
standard post-operative knee joint examination – see Table 3) and the results recorded on 
the CRFs.  
 

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At the 3 month time point, the research coordinator will complete the CRFs with the 
pertinent history and patient questionnaire.  A pertinent physical exam will be performed 
by a licensed professional on both knees (including goniometer range-of-motion for 
flexion and extension and thigh circumference measurements at the superior pole of the 
patella and 5 and 10 cm above the joint line, as well as a standard post-operative knee 
joint examination – see Table 3) and the results recorded on the CRFs. The patient will 
then complete an IKDC questionnaire.  Strength testing will also be performed for 
quadriceps, hamstring and hip adductor testing and the results recorded.  
 
At the 6 month time point, the research coordinator will complete the CRFs, with the 
pertinent history and patient questionnaires.  A pertinent physical exam will be performed 
by a licensed examiner on both knees (including goniometer range-of-motion for flexion 
and extension and thigh circumference measurements at the superior pole of the patella 
and 5 and 10 cm above the joint line, standard post-operative knee joint examination - see 
Table 3) and the results recorded on the CRF.  Strength testing will also be performed, as 
well as KT testing and hop testing at this visit and the results recorded. The patient will 
then complete an IKDC questionnaire.  The patient will also undergo an MRI using the 
CISS sequence to evaluate the repair and the contralateral ACL. 
 
At the 12 month time point, the research coordinator will complete the CRFs with the 
pertinent history and patient questionnaires.  A pertinent physical exam on both knees 
(including goniometer range-of-motion for flexion and extension and thigh circumference 
measurements at mid patella and 5 and 10 cm above the joint line, as well as temperature, 
wound check and standard post-operative knee joint examination - see Table 3) will be 
performed by a licensed examiner and the results recorded. Strength testing will also be 
performed as well as KT-1000 testing and hop testing at this visit and the results 
recorded. The patient will then complete an IKDC questionnaire.  The patient will also 
undergo an MRI using the CISS sequence to evaluate the repair and the contralateral 
ACL. 
 
 
At the 24 month, 6 and 10 year time points, the research coordinator will complete the 
CRFs with the pertinent history and patient questionnaires.  A pertinent physical exam on 
both knees (including goniometer range-of-motion for flexion and extension and thigh 
circumference measurements at mid patella and 5 and 10 cm above the joint line, as well 
as temperature, wound check and standard post-operative knee joint examination - see 
Table 3) will be performed by a licensed examiner and the results recorded. Strength 
testing will also be performed as well as KT-1000 testing and hop testing at this visit and 
the results recorded. The patient will then complete an IKDC questionnaire and 
KOOS/MARX/SF-36 questionnaire.  The patient will also have a repeat of the x-ray 
taken at the pre-operative visit, namely a semiflexed MTP x-ray and will have blood and 
urine collected for laboratory testing.  The patient will also undergo an MRI using the 
CISS sequence to evaluate the repair and the contralateral ACL. 
 
Biomechanical Testing to be completed at the 6 and 10 Year Visit (optional): 

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To assess the long-term effect of BEAR vs ACLR in knee function during daily activity 
(i.e. walking) and balance. There is solid evidence on gait changes after ACL surgery 
leading to knee pain and OA. This would be a great addition to current imaging studies to 
evaluate risk of PTOA in BEAR vs ACLR. The primary outcomes are asymmetry in knee 
rotation and loading during walking.  
 
The surgeon will ask about adverse events at each visit, including screening for 
neurologic symptoms, and document any responses. If any adverse events have occurred 
or are potentially occurring, the research coordinator will complete the CRF and follow 
the procedures detailed in Section 9.   
 
1.8.1.6 Unscheduled Visits:   
Patients may return to the clinic at a time point that is not a protocol specified follow-up 
visit. If the Investigator determines that a clinic visit is required in order to evaluate an 
adverse event or patient reported complaint, an “Unscheduled Visit” case report form 
should be completed. The evaluation at an unscheduled visit requires an updated patient 
history since the time of the last patient contact, documentation of complaints/symptoms 
and medications, and description of treatment provided and any changes to post-operative 
care schedule. 
1.8.2 Outcome Measures 
 
Training:  All licensed examiners will be trained in the protocol procedures before using 
these in the study.   
 
Patient Reported Function (IKDC):  This scale was specifically developed to be 
sensitive and responsive to highly active patients with knee injuries [105, 106]. The 
American Orthopaedic Society for Sports Medicine (AOSSM) developed the IKDC and 
recommends it as a primary outcome measure. This scale has been widely used in 
multiple ACL injury related cohorts such as the MOON cohort [107-112]  as one of the 
most commonly utilized validated patient-reported outcome assessment in sports 
medicine [105].  
 
Instrumented Laxity (KT):  Testing will be performed by experienced, certified athletic 
trainers or physician assistants trained using standardized equipment according to the 
MOON protocol, Manual of Operating Procedures (MOP) and instructions by 
MEDmetric (KT device manufacturer).   This testing will be performed at 6, 12 and 24 
months and 6 and 10 years after surgery.  The anterior displacement at 130N (30lbs) will 
be used to obtain a side-to-side difference in millimeters.  Patients will wear a sleeve 
over both knees at the time of examination to minimize potential bias.   
 
Muscle Strength: The strength of the quadriceps, hamstring and hip abductor 
musculature will be determined at three, six, twelve and twenty-four months and 6 and 10 
years after surgery.  Patients will wear a sleeve over both knees at the time of 
examination to minimize potential bias.  The quadriceps testing will be performed in a 

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seated position with the knee flexed 90 degrees so as not to stress the repair or healing 
graft.  Values for both knees will be recorded.  In addition, Biodex testing will be 
performed at the six, twelve and twenty four month follow-up. Hop testing will also be 
performed at six, twelve and twenty four months and 6 and 10 years if the patients have 
progressed to hopping as part of their rehabilitation with their physical therapist and if the 
patient feels comfortable doing the test.  Lastly, static and dynamic balance testing will 
be performed at six, twelve and twenty-four months and 6 and 10 years after surgery. 
 
KOOS Score: The KOOS score is another validated patient outcome measure with three 
domains: Pain, Knee Related Quality of Life and Sports.  We will collect data for all 
three domains at 3, 6, 12 and twenty four months and 6 and 10 years after surgery.  A 10 
point difference between groups will be considered statistically significant based on  prior 
studies validating the KOOS score [96]. 
 
Xray Imaging: A semiflexed weight bearing MTP view, as well as a lateral projection, 
will be obtained at baseline and at two, six and 10 years after surgery to assess joint space 
narrowing and the presence of osteophytes suggestive of early OA.   
 
Range of Motion:  Active and passive range of motion will be measured using a 
goniometer pre-operatively, intra-operatively and at 2 weeks, six weeks, three months, 
six months and one, two, six and 10 years after surgery. Both sides will be covered with 
a sleeve so the licensed examiner cannot tell which the operated knee is or which 
procedure the patient had.  Values for both knees will be recorded.   In addition, a 
standing active flexion angle will be recorded for both knees.   
 
Functional testing:  Hop testing, as well as static and dynamic balance testing and 
Biodex testing for flexion and extension strength will be evaluated at six, twelve and 
twenty four months for all study subjects.  These data will be used to determine the 
percentage of patients meeting return to sport criteria at each time point. At the 1-2 week, 
6 week and 3 month post-operative visits, we will assess whether the patient is able to 
perform a straight leg raise without an extensor lag.  At three, six, 12 and 24 months and 
six and ten years after surgery, for both groups, we will measure quadriceps strength, 
hamstring strength and hip abductor strength using a hand-held dynamometer on both the 
involved and contralateral knees.   Biodex testing for flexion and extension strength will 
be measured at six, 12 and 24 months and six and ten years after surgery.  The ratio of the 
measurement from the surgical leg to the contralateral uninjured knee will be calculated 
and compared between treatment groups. Patients will wear a sleeve over both knees at 
the time of examination to minimize potential bias.   
 
Knee Examination:  An independent examiner (not the operating surgeon) will perform 
the physical exam based on the MOON (Multicenter Orthopaedic Outcomes Network) 
protocol. Patients will wear a sleeve over both knees at the time of examination to 
minimize potential bias.  The exam will include range of motion, presence or absence of 
effusion and crepitus, and a series of tests including the Lachman (at baseline, 3, 6, 12 
and 24 months and 6 and 10 years), anterior drawer, posterior tibial sag, medial and 
lateral joint opening, pivot-shift, and internal and external rotation tests at the designated 
time points. 

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Evaluation of the BEAR or ACL Reconstruction Using MRI:  The experimental MRI 
protocol will be used to estimate the biomechanical properties of the healing ligament or 
graft, as well as these properties in comparison to the contralateral ACL, in the clinical 
trial [113]. In a previous study, we found that using a combination of volume and signal 
intensity could accurately predict the structural properties of a healing ACL at both 15 
and 52 weeks of healing using our minipig model of ACL surgery (yield load, failure 
load, linear stiffness; R2 > 0.68) [113, 114].  MR imaging with the CISS sequence will be 
used to measure the volume and orientation of both the ACL repaired using the BEAR 
technique or  the ACL reconstruction and the contralateral knee.   MRI will be performed 
at 6 months, 2, 6 and 10 years after surgery to help us gain additional information about 
the status of the healing ACL or graft using this new MRI sequence. 
 
Biomechanical evaluation of knee function and lading after ACL Surgery 
 
Rationale: 3D biomechanical evaluation of gait and balance have been widely used to 
asses knee function after ACL surgery.2,8 These studies have direct implications in 
treatment assessment and evaluation of knee osteoarthritis (OA) risk.2,3,9 A poor 
balance, measured as shorter single-leg standing or larger sway, is indicative of inferior 
knee function, higher risk of re-injury and posttraumatic OA. 1,7,8 A higher degree of 
asymmetry in knee motion and loading in sagittal and frontal planes have also been 
consistently linked to higher risk of posttraumatic OA after ACL surgery.2,3,9 Evaluation 
of single-leg standing balance and gait biomechanics will shed light on relative efficacy 
of BEAR to restore normal knee function and biomechanics after surgery. The following 
tests will be conducted at each follow up visit: 
 
Static Balance Test: Subjects will complete an instrumented balance error scoring system 
test. This test has been used to measure static postural stability in those with ankle1,7 and 
knee8 related impairments. Subjects were asked to maintain balance on a single leg with 
closed eyes for as long as they could for up to 20 seconds. Each subject will complete 3 
trials per leg. This test is a way to measure the somatosensory and/or visual information 
processing ability of an individual, which may be affected following a lower extremity 
orthopedic injury. Participants will stand on a pressure-sensing device (Equilibrate, 
Balance Engineering Inc., Henrietta, NY), which will provide objective information 
related to the control of posture in each stance. Tests  
 
Outcomes Measures (measured for each trial) 
1. Balance time 
2. Body sway. 
 
 
Joint kinematic Test: Subjects will be fitted with reflective markers in a validated, reliable 
marker set for motion analysis4,6. Three-dimensional motion capture will be performed 
with a 10 camera (Motion Analysis Corporation, Santa Rosa, CA) Motion Analysis system. 
Neutral tibiofemoral alignment will be defined using the methodology outlined by Kvist et 
al5. Subjects will be instructed to walk for 10 meters at a self-selected speed following a 
pre-defined straight walking path marked on the floor. 

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Outcome Measures (measured for each knee) 
1. Knee flexion angle  
2. External knee flexion moment 
3. External knee adduction moment 
 
 
 
6 Years Visits (<1 hr prep and testing):  
 
1. 3D Motion Capture (joint rotations) + Force Plate (joint loads) data during level 
walking 
a. Outcomes: lower extremity kinetics and kinematics  
 
2. Single-legged Standing balance on force plate 
a. Outcomes: balance time, COP trajectory 
 
1.8.3 Post-operative Physical Therapy 
Prior to hospital discharge from their ACL surgery, Intervention and Control patients will 
be given a prescription for physical therapy.  They will also be given a copy of the trial’s 
standardized Physical Therapy Protocol (Appendix D) to give to the physical therapist 
they choose to see for treatment.  (Because BCH is a large referral center and patients 
come from all over New England, we will not mandate that all subjects receive physical 
therapy at the same location.)  The goal of providing a standardized protocol is to reduce 
the variation in post-operative physical therapy, thus minimizing the likelihood that it is 
responsible for any observed differences in physical function or other outcomes between 
the two groups.  If a patient does not attend at least four physical therapy sessions in the 
first three months after surgery, this will be recorded on the case report form; however, 
they will be kept in the study.   
1.8.4 Study Timeline  
We anticipate completing the twenty four-month follow-up for this study in 3.5 years.  
Each patient will be enrolled and followed for efficacy measures until 24 months.  We 
anticipate requiring 14 months for subject recruitment, an additional two years to 
complete the 2 year follow-up for the efficacy measures and then two months to analyze 
and report the results. We anticipate to complete the long term follow up of 6 and 10 
years within 14 years of study start to account for patient visit windows and to perform 
the study analyses.   
1.9 
Adverse Event Criteria and Reporting Procedures  
1.9.1 Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those who 

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will enroll in future studies using similar devices. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of patient safety 
and care.  
 
All patients experiencing an adverse event, regardless of its relationship to study device, 
will be monitored until:  
1. The adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline; 
2. Any abnormal laboratory values have returned to baseline; 
3. There is a satisfactory explanation other than the study device for the changes; or, 
observed 
4. Death 
 
1.9.2 Definitions 
1.9.2.1 Adverse Event Definitions  
An adverse event is any untoward medical occurrence experienced by a subject that 
occurs in temporal association with the use of an administered investigational 
intervention, whether considered intervention-related or not.  An event can be any sign, 
symptom, laboratory abnormality, or disease temporally associated with the use of an 
experimental intervention, whether or not related to the intervention. 
1.9.2.2 Severity of Adverse Events 
 
The severity of an AE is graded as follows: 
 
 Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
 
 Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
 
 Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or  
significantly affects his/her clinical status. 
 
 Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
 
 Fatal (grade 5): the event caused death. 
 
Unanticipated Adverse Device Effect (UADE): Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if 
that effect, problem, or death was not previously identified in nature, severity, or degree 

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of incidence in the investigational plan or IDE application (including a supplementary 
plan or application), or any other unanticipated serious problem associated with a device 
that relates to the rights, safety, or welfare of subjects. 
 
Associated with the Investigational Device: There is a reasonable possibility that the 
adverse effect may have been caused by the investigational device. 
 
Life-Threatening Adverse Effect: Any adverse effect that places the subject, in the 
view of either the investigator or the sponsor, at immediate risk of death from the effect 
as it occurred.  It does not include a reaction that, had it occurred in a more severe form, 
might have caused death. 
 
Serious Adverse Effect (SAE): An adverse effect is considered “serious” if, in the view 
of either the investigator or the sponsor, it results in any of the following outcomes:  
1. Results in death. 
2. Is life-threatening. 
3. Requires in-patient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. 
4. Results in persistent or significant disability or incapacity. 
5. Is an important medical event which may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the above 
outcomes.  
 
Unanticipated Adverse Effect: Any adverse effect, the nature, specificity, severity, or 
frequency of which is not consistent with the risk information in the clinical study 
protocol or elsewhere in the current IDE application. 
1.9.3 Eliciting Adverse Effect Information 
Study subjects in both groups will be routinely questioned about adverse effects at study 
visits. They will also be instructed about signs and symptoms associated with potential 
adverse effects and will be encouraged to call and report them in between study visits. 
1.9.4 Abnormal Test Findings 
An abnormal test finding will be classified as an adverse effect if one or more of the 
following criteria are met: 
 The test finding is accompanied by clinical symptoms 
 The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional concomitant drug 
or other therapy (Note: simply repeating a test finding, in the absence of any of 
the other listed criteria, does not constitute an adverse effect.) 
 The test finding leads to a change in study dosing or exposure or discontinuation 
of subject participation in the clinical study 
 The test finding is considered an adverse effect by the investigator  

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1.9.5 Causality and Severity Assessment 
The investigator will promptly review documented adverse effects and abnormal test 
findings to determine 1) if the abnormal test finding should be classified as an adverse 
effect; 2) if there is a reasonable possibility that the adverse effect was caused by the 
investigational device or other study treatments; and 3) if the adverse effect meets the 
criteria for a serious adverse effect. If the investigator’s final determination of causality is 
“unknown and of questionable relationship to the investigational device or other study 
treatments,” the adverse effect will be classified as associated with the use of the 
investigational device or other study treatments for reporting purposes.  If the 
investigator’s final determination of causality is “unknown but not related to the 
investigational device or other study treatments,” this determination and the rationale for 
the determination will be documented in the respective subject’s case history. The 
sponsor will ultimately review all events that have been reported by the sites and 
determine if they meet criteria for UADE reporting to the FDA. 
 
The relationship between the treatment type and any adverse event will be determined by 
the investigator, medical monitor, and Data Monitoring Committee using the following 
criteria: 
 Not Related:  The event is clearly related to other factors, such as the subject’s 
clinical state, therapeutic interventions or drugs administered to the subject. 
 Possibly Related:  The event follows a compatible temporal sequence from the 
time of the ACL procedure, but could have been produced by other factors such 
as the subject’s clinical state, therapeutic interventions or drugs administered to 
the subject. 
 Probably Related:  The event follows a reasonable temporal sequence from the 
time of the ACL procedure, and cannot be reasonably explained by other factors 
such as the subject’s clinical state, therapeutic interventions or drugs administered 
to the subject.   
1.9.6 Recording and Assessment of Adverse Effects 
All observed or volunteered adverse effects (serious or non-serious) and abnormal test 
findings, regardless of treatment group, if applicable, or suspected causal relationship to 
the investigational device or, if applicable, other study treatment or diagnostic product(s) 
will be recorded in the subjects’ case histories. Events will be recorded according to the 
date and time of first presenting symptom, severity, and their duration, as well as any 
treatment prescribed.  After the ACL procedure, all new adverse events that were not 
present at enrollment will be recorded.  Any medical condition or abnormal laboratory 
value present at enrollment that remains unchanged or improves, will not be recorded as 
an adverse event.  However, worsening of a medical condition that was present at 
enrollment will be considered a new adverse event and reported.  Abnormal laboratory 
values, if felt by the investigator to be clinically significant, will also be recorded on the 
Adverse Event Form and assessed in terms of severity and relationship to the treatment.  
For all adverse effects, sufficient information will be pursued and/or obtained so as to 
permit 1) an adequate determination of the outcome of the effect (i.e., whether the effect 
should be classified as a serious adverse effect) and; 2) an assessment of the casual 
relationship between the adverse effect and the investigational device or, if applicable, 

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the other study treatment or diagnostic product(s). Adverse effects or abnormal test 
findings felt to be associated with the investigational device or, if applicable, other study 
treatment or diagnostic product(s) will be followed until the effect (or its sequelae) or the 
abnormal test finding resolves or stabilizes at a level acceptable to the investigator. 
 
Serious adverse events will be reviewed by the Data Monitoring Committee who will be 
unblinded as to patient group assignment.  Differences of opinion as to the causality, 
classification, or expectedness of events will be adjudicated by the Data Monitoring 
Committee. All unresolved adverse events will be followed by the investigators until the 
events are resolved or the adverse event is otherwise explained or has stabilized. 
1.9.7 Post-Surgery Procedures for Adverse Events 
At each contact with the patient, the Investigator must seek information on adverse events 
by specific questioning and, as appropriate, by examination.  Information on all adverse 
events should be recorded immediately in the source document, and also in the 
appropriate adverse event module of the case report form (CRF).  All clearly related 
signs, symptoms, and abnormal diagnostic procedure results should be recorded in the 
source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical 
course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up to 
determine the final outcome.  Any serious adverse events that occur after the study period 
should also be recorded, reported promptly and followed. 
1.9.8 Reporting Adverse Events 
Reports of all serious adverse events will be submitted to the local IRB, and the local 
institutional Biosafety Committee by the site investigator in the shortest time possible 
after the notification of the event and per site institutional guidelines. The sponsor will 
report the serious device related adverse events to the Data Monitoring Committee as 
soon as possible and no later than 10 calendar days after the event. For any adverse event 
determined to be an Unanticipated Adverse Device Effect (UADE), the sponsor- will 
submit a safety report to the site to report to their IRB as soon as possible and, in no 
event, later than 10 working days after the sponsor-investigator first receives notice of the 
adverse effect. UADEs will also be reported to the Data Monitoring Committee in the 
same timeframe. Follow-up information to reported adverse effects will be submitted to 
the IRB as soon as the relevant information is available. The safety report will consist of: 
 A completed Form FDA 3500A: 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadF
orms/UCM387002.pdf 
 A cover letter analyzing the significance of the event   
 
Similarly, UADEs will be reported by the sponsor to the FDA by submitting an expedited 
safety report to the FDA’s Center for Devices and Radiological Health as a report to the 
IDE. A copy of this safety report will be provided to all participating study investigators. 

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The completed Form FDA 3500A and cover letter will be submitted to the FDA as soon 
as possible and, in no event, later than 10 working days after the sponsor first receives 
notice of the adverse effect. If, following receipt and investigation of follow-up 
information regarding an adverse effect that was previously determined not to be a 
UADE, the sponsor determines that the event does meet the requirements for expedited 
reporting, the sponsor will submit a completed Form FDA 3500A and cover letter as soon 
as possible, but in no event later than 10 working days, after the determination is made. 
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor will 
submit additional information concerning the reported adverse effect as requested by the 
FDA. 
1.9.9 Risk Mitigation Strategy 
Risks to the patients who have agreed to participate in the study will be minimized to the 
greatest extent possible.  This study is incorporating the following measures: 
 
1. All research staff working on this trial will have completed the required human 
subject protection education/training. 
2. The surgeons who participate in this clinical study will be trained to select the 
qualified patients and perform the proper technique for use of the collagen device. 
The surgeons, Dr. Lyle Micheli, Dr. Yi-Meng Yen and Dr. Dennis Kramer will be 
trained by the PI on proper surgical technique and will practice this technique 
prior to performing the surgery on any study patients.  They each have over 15 
years of surgical experience. 
3. Patient selection is of paramount importance. Patients will be thoroughly screened 
and only those that meet the eligibility criteria will be offered participation in the 
study. The inclusion and exclusion criteria have been carefully chosen to describe 
the best patient for the surgical implant procedure. Patients will have all of their 
questions answered by the licensed professional during the informed consent 
process and it will be made clear that participation is voluntary. The recruitment 
process will be documented by a consent form, which will be signed by the 
patient and/or legal guardian.  Patients will be given a signed, original copy of the 
consent form for their records.   
4. Patients will be placed on a post-operative management plan commensurate with 
their medical history and operative recovery protocol.  
5. The patient will be closely monitored for complications and adverse events using 
case report forms and patient records. Any complaint of symptoms will be 
recorded if it results in an unscheduled visit when a patient presents with new or 
worsening pain, neurological, and/or functional symptoms as compared to a 
previous visit and or when surgical intervention is required to resolve the event.  
6. The PI and research team will review adverse events on an ongoing basis at every 
planned and unplanned clinical visit and report them to the sponsor and other 
appropriate parties, as required, in a timely manner. Investigators will be 
instructed to call in any unexpected or potentially serious adverse events as per 
federal regulation.  

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7. If an unreasonable risk occurs, the PI will terminate the clinical investigation 
within a timely fashion from the date the risk was determined to be unreasonable, 
with consideration given to the risk.   
8. Additional details about risk mitigation are available in the Failure Mode Effect 
Analysis (FMEA) and hazard identification documentation found in section 
1.9.11 Stopping rulesError! Reference source not found. 
1.9.10 Justification for the Investigation 
The annual incidence of ACL injury in the US is estimated at 1 per 1,000 people [46]. 
ACL injuries have immediate and long-term effects on the quality of life, and are known 
risk factors for post-traumatic osteoarthritis [47]. In the past, surgeons tried to repair the 
ACL; however, it failed to heal in over 90% of patients [48]. The reason for this was 
unknown. Thus, the current gold standard of treatment, ACL reconstruction, which 
involves removal and replacement of the ligament with a tendon graft, has become 
popular. However, patients treated with ACL reconstruction continue to exhibit 
progressive articular cartilage and joint damage in the injured knee. A recent prospective 
cohort study suggests that 62% of ACL reconstructed patients with an isolated ACL 
injury presented with radiographic evidence of posttraumatic osteoarthritis 10–15 years 
post-surgery [49]. Considering that many patients sustain ACL injuries before the age of 
16, these injuries may place young patients at risk for premature post-traumatic 
osteoarthritis before age 30 even with our current best treatment methods. 
 
In our preclinical studies, we have found that use of a bridge-enhanced ACL repair 
technique, using the BEAR® Implant, results in improved healing of the ACL, avoidance 
of the need to harvest a graft and a significant decrease in the incidence of post-traumatic 
osteoarthritis.  Biocompatibility and sterilization studies suggest the device is 
biocompatible and sterile.  Thus, this new technique could represent a less invasive 
method of ACL surgery with equivalent mechanical results to the current technique and 
the potential future benefit of cartilage protection.  A clinical study of a small number of 
patients revealed no serious adverse effects with use of this technique in human patients.  
Now a non-inferiority trial of efficacy to show this less invasive technique gives similar 
outcomes to the standard procedure of ACL graft reconstruction is proposed.  
 
The potential benefits of Bridge-Enhanced ACL repair are expected to outweigh the 
potential risks. If the Bridge-Enhanced extracellular matrix sponge (BEAR® Implant) 
allows the ACL to regenerate with outcomes that are non-inferior to that of a 
reconstructed ACL, patients can avoid the more invasive reconstruction that requires 
harvest of a graft from the hamstring tendons to replace the ruptured ACL.  While the use 
of allograft tendon (cadaver graft) also avoids the need for harvesting hamstring or 
patellar tendon for an autologous graft, the use of allograft is not recommended in 
patients under 25 years of age, due to a relatively high failure rate of allograft (reported 
rates of 20 to 30%) and risk of needing additional surgery on the knee within two years of 
surgery (30%).  Therefore, autograft is almost exclusively used in this patient 
demographic.  Furthermore, unlike standard reconstruction where any remaining ACL 
tissue is removed, this new technique preserves the anatomic and physiologic 
characteristics of the ligament. The surgery requires less instrumentation (and thus, less 
potential for contamination), and results in less bone loss for the patient.  Finally, 

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although patients in this study will not be followed long enough to assess development of 
arthritis, earlier work in our pre-clinical large animal models showed a lower rate of post-
traumatic arthritis in bridge-enhanced repairs as compared to standard reconstructions 
[115].    
1.9.11 Stopping Rules 
Early stopping of the trial for safety related reasons will be considered by the Data 
Monitoring Committee consisting of two orthopedists and an immunologist.  The 
committee will be notified after any joint infection and the committee will 
meet/conference call as soon as possible after two such infections have occurred.   They 
will use the following rule as a guideline in consideration of early stopping and the 
committee may deviate from the rule based on clinical expertise, judgment, and a global 
review of trial methodology.  Early stopping will be considered if, in the Intervention 
Group, two or more of the first 20 subjects or if three or more of all Intervention subjects, 
develop a deep joint infection, or experience a serious adverse event of any type thought 
to be related to the BEAR® Implant.   Table 4 shows the probability of triggering this 
rule, as a function of the true underlying (but unknown) event rate assuming a total of 60 
BEAR patients. (The calculations are relatively insensitive to this total sample size.)   
 
Table 4: Stopping rule probabilities as a function of true event rate.  
 
True event rate 
0.01 
0.05 
0.10 
0.20 
0.30 
Probability [ ≥2 
events of first 
20] 
1.7% 
26.4% 
60.8% 
93.1% 
99.2% 
Probability [ ≥3 
events of 60] 
3.3% 
60.7% 
95.1% 
>99.9% 
>99.9% 
 
For example, with a true background event rate of .01, there is a very small chance 
(1.7%) of triggering the stopping rule within the first 20 patients or overall (3.3%), but if 
the true rate is .20, the rule would be triggered with high probability (93.1%  within the 
first 20 patients, >99.9% overall).  This rule is to be considered a guideline and the 
committee may deviate from the rule based on clinical expertise, judgment, and a global 
review of trial methodology and conduct. 
 
1.10 Device Information  
1.10.1 BEAR® Implant 
 
 Other names for the drug(s)/device: In our prior IDE application, the device 
was called the BEAR™ Scaffold. 
 
 Classification – type of agent/device: Experimental Device, Category A, Class 
III 
 

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 Mode of action: Absorbs autologous blood and holds it in the wound site of 
the ACL, allowing the cells in the blood (platelets, white blood cells) to 
stimulate healing of the ligament. 
 
 Storage and stability: Can be stored at room temperature for twenty-four  
months.   
 
 Preparation:  The implant is removed from its double peel pack at the time of 
surgery and sutured into place during surgery. 
 
 Route of administration for this study:  Surgical, via a mini-arthrotomy. 
 
 Incompatibilities: Unknown. 
 
 Availability: Provided by study sponsor. Manufactured using GLP conditions 
with design control at Boston Children’s Hospital. 
 
 Side effects: Unknown, but may include insufficient healing of the ligament, 
infection, inflammation, knee stiffness. 
 
 Nursing implications:  The outer peel pack is not sterile on its outer surface.  
The inner surface of the outer peel pack and entire inner peel pack are sterile, 
as is the device. 
 
1.10.2 Return and Retention of Study Device 
Please return any unused study devices to the MIACH™ Laboratories in the Orthopaedic 
Research Laboratories on Enders 2.  Complete address below: 
 
MIACH™ Laboratories 
 
Enders 216.3 
 
Boston Children’s Hospital 
 
300 Longwood Ave 
 
Boston, MA 02115 
 
1.11 Data Management Methods  
1.11.1 Data Management and Record Keeping 
Information that is typically collected as part of routine care will be stored in the patient’s 
medical record.  Data obtained exclusively for research purposes will be stored in a 
separate research folder, unless it is deemed clinically relevant, in which case it will also 
be placed in the medical record. 
1.11.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  

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Source data are contained in a variety of original documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, patients’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, X-rays, patient files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
1.11.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study 
and will be developed by the research team.  All data requested on the CRF must be 
recorded.  All missing data must be explained.  If a space on the CRF is left blank 
because the procedure was not done or the question was not asked, write “N/D”.  If the 
item is not applicable to the individual case, write “N/A”.  All entries should be printed 
legibly in black ink. If any recording error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and record the correct data above it (“DO 
NOT ERASE OR WHITE OUT ERRORS”.) All such changes must be initialed and 
dated. For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. The case report forms can be found in the study Manual of 
Operations. 
 
Case Report Forms have been created for screening for patients who would meet the 
inclusion criteria, a baseline history and physical examination form, imaging, surgery, the 
history and physical exam at each follow-up appointment, adverse event reporting and 
the conclusion of a patient’s participation in this trial.  The detailed case report forms can 
be found after this section.   
 
 

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1.11.4 Confidentiality and Security 
Information about study patients will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Data will be entered by the clinical sites onto electronic CRFs in a 21 CFR 
Part 11 compliant Electronic Data Capture System (EDC). The database will be 
maintained by a data management group contracted with the Sponsor.  In order to 
maintain confidentiality, each subject will be assigned a unique study identification (ID) 
number which will be recorded on all study documents and used to enter data into the 
system. 
 
All study data will be recorded in source documents and transferred to the official 
electronic case report forms The source  documents will be maintained at each site..  
Identifiable data, such as patient name, contact information and medical record numbers 
will only be stored at the clinical study site.  All study-related documents will be archived 
for the required length of time after completion of the study. Database backup routines 
are automated and executed daily to ensure data safety and reliability.  
1.11.5 Records Retention 
Records will be retained for the maximum length of time necessary, as dictated by the 
sponsor and FDA policies. 
1.12 Quality Control Method  
Data monitoring will be ongoing and focus on study performance with respect to patient 
recruitment, retention and follow-up, completion and flow of data forms, safety reporting, 
protocol adherence and quality of data. Monitoring will also include the ongoing review 
and assessment regarding the incidence, frequency, and severity of adverse events. It is 
the primary responsibility of the sponsor to oversee the safety of the study. This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as 
noted above, as well as adherence to the individual reporting requirements described 
within the protocol and per individual reporting requirements set forth by the IRB. 
1.12.1 Data Monitoring 
Study monitoring functions will be performed by Miach clinical (contract) monitors 
and/or clinical monitors from a qualified independent clinical research organization 
(CRO) in compliance with recognized applicable U.S. regulations (21 CFR Part 812 
[Investigational Device Exemptions], 21 CFR Part 50 [Protection of Human Subjects] 
and 21 CFR Part 56 [Institutional Review Boards]), Good Clinical Practice, and 
recommendations guiding physicians in biomedical research involving human subjects 
adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964. The monitors will 
oversee progress of the investigation at each investigational site and work with site 
research coordinators to ensure adherence to the study protocol and informed patient 
consent obligations, as well as the aforementioned regulations and standards. 
The frequency of monitoring will be adequate to assure the integrity of the study and will 
be defined in the monitoring plan.  For example, initially, data will be reviewed after 
approximately two patients are enrolled and then again after two controls are enrolled.  
Every CRF completed to date and consent form will be reviewed for these subjects.  The 

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same procedure will be followed after approximately the fifth patient and fifth control are 
enrolled.  At this visit, the monitor will review any additional CRFs collected for the two 
patients and controls reviewed initially, as well as the consent forms and adverse event 
forms for every subject enrolled to date.  The final monitoring visit will take place after 
the last patient and last control have completed the trial.  The remaining CRFs for all 
subjects previously reviewed, will be examined, such that their whole research record 
will have been 100% monitored.  The remaining consent documents and AE forms for all 
subjects will also be inspected.  The Investigator will allocate adequate time for such 
monitoring activities.  The Investigator will also ensure that the monitor reviewer is given 
access to all the above noted study-related documents and study related facilities (e.g. 
pharmacy, detailed medical records, diagnostic laboratory, etc.), and has adequate space 
and time to conduct the monitoring visits.  Monitoring reports will be completed for all 
visits. Reports will include the date of the visit, a list of study site personnel, and a 
summary of the findings, problems, and actions taken to correct any deficiencies. The 
Data Monitor may recommend additional record review at any time, if she feels this is 
necessary. 
1.12.2 Data Monitoring Committee 
There will be a Data Monitoring Committee (DMC)made up of three physicians, two 
orthopedists and one immunologist, who will provide safety oversight and give 
consideration to early stopping of the trial.  In the safety monitoring role, the DMC will 
establish a charter including a mission statement, operating procedure and proposed 
monitoring criteria for the study, including any required interim analysis time points for 
assessing safety and proposed study stopping rules. The rule is outlined in Table 4. The 
specific stopping rules shall remain confidential to the sites. Written minutes of all 
meetings shall be developed after each DMC meeting and major conclusions (i.e. the 
assessment for study continuation vs. stopping) shall be documented.  Meeting 
summaries shall be included in reports to the IRB as appropriate.  DMC will include a 
regular assessment of the number and type of adverse device events occurring for each 
patient as well as an aggregate review of the accumulated safety data. For every UADE 
reported to the FDA, the report will also be supplied to the DMC as soon as possible and, 
in no event, later than 10 working days after the sponsor first receives notice and 
determines a UADE has occurred. Any additional clinical information or laboratory 
results requested by the DMC will be provided in a timely manner.    
1.12.3 Safety Monitoring Plan 
A medical monitor will be assigned to review all events and event rates in the trial.  A 
safety plan will be written to document the process for review and reporting of any events 
that meet regulatory reporting requirements. 
1.12.4 Auditing and Inspecting 
The sponsor and investigators will permit study-related monitoring, audits, and 
inspections by the sponsor, the independent data monitor and government regulatory 
bodies, of all study related documents (e.g. source documents, regulatory documents, data 
collection instruments, study data etc.).  The Investigator will ensure the capability for 
inspections of applicable study-related facilities. 

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1.12.5 Changes and Amendments to the Protocol 
No changes will be made to this protocol unless specifically approved by Miach 
Orthopaedics, Inc. and the changes documented in an addendum to the protocol.   
1.12.6 Ethical and Legal Considerations 
 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator must comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. 
 
1.13 Data Analysis Plan  
Baseline characteristics and safety and efficacy outcomes will be summarized 
descriptively within each group using means, standard deviations, percentiles (e.g., 
minimum, median, maximum) for continuous variables and with counts and percentages 
for categorical variables.  Patterns of change over time will be summarized using 
graphical methods and summary statistics. 
 
The difference in means between groups, (BEAR minus control) will be calculated for 
continuous efficacy endpoints as a measure of relative treatment efficacy.  Assuming 
higher scores are better, a positive difference in means will indicate that BEAR is better 
than control and a negative difference that BEAR is worse.  (If lower scores are better, 
this interpretation is reversed.)  95% confidence intervals for the difference in means will 
be used to show a plausible range of relative treatment efficacy. Analyses of 
anteroposterior knee laxity, range of motion and muscle strength measures that are 
performed on both knees will be based on within-patient side-to-side differences 
(involved minus contralateral knee) or percent deficit (side-to-side difference as a percent 
of the contralateral knee). The intervention groups will then be compared with respect to 
these side-to-side differences. 
 

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For the patient-reported functional primary endpoint, IKDC score at 24 months, 
non-inferiority for BEAR will be demonstrated if the entire 95% CI lies to the right of the 
non-inferiority margin of -11.5.  For the biomechanical primary endpoint, knee laxity at 
24 months, a lower side-to-side difference (involved minus contralateral knee) is 
desirable so non-inferiority will be demonstrated if the 95% CI for the treatment group 
difference lies to the left of the non-inferiority margin of +2.0 mm.  Choice of these 
non-inferiority margins is discussed further in Section 14.  Similar analyses will be 
conducted at each visit during which the measurements are made although these will be 
considered secondary analyses.   
 
Overall, demonstration of non-inferiority requires that both primary endpoints meet the 
CI criteria described above.  Although the 95% CIs are two-sided intervals, only one side 
is relevant for demonstrating non-inferiority so the Type I error rate for each endpoint is 
𝛼 =0.025 and the combined statistical procedure is protected at an overall Type I error 
rate of 𝛼≤0.05.  
 
In addition to conducting the non-inferiority analyses for all patients, the hamstring-
preference stratum is a subgroup of special interest and we will conduct the analyses 
within that group as a pre-specified subgroup analysis.  If non-inferiority is demonstrated 
in the hamstring-preference subgroup, then we will test for superiority for the hamstring 
strength endpoint at 3 and 6 months in that subgroup.  We hypothesize superiority of 
BEAR over hamstring graft at these early time points. 
 
Treatment comparisons will be conducted both on an intention-to-treat (ITT) basis, with 
patients included in the treatment group they were randomized to, and on a per-protocol 
(PP) basis, with patients included in the surgical group according to which type of 
surgery they received. Whereas in a superiority trial an ITT analysis generally 
underestimates the treatment difference and is therefore conservative, in a non-inferiority 
trial the ITT analysis generally favors the conclusion of non-inferiority so demonstrating 
consistent conclusions with both ITT and PP approaches lends credibility to the 
conclusions.   
 
In addition, we will use multiple imputation to investigate how robust the results are to 
outcome data that are missing due to attrition or other reasons.  These analyses will 
include a “tipping point” strategy, in which missing data are imputed under a range of 
assumed biases until the p-value changes from significant to non-significant or vice 
versa.  This sensitivity analysis identifies how non-representative the missing data would 
have to be to alter conclusions. 
 
Outcomes measured longitudinally will be compared between treatment groups at each 
time point.  Generally, the intervention groups will be compared using t-tests, Mann-
Whitney tests and Fisher’s exact tests as appropriate and these tests will be interpreted 
carefully taking into account limitations of the design and statistical methods.  

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1.14 Statistical Power and Sample Size Considerations  
Generally, non-inferiority will be tested by constructing a 95% confidence interval for the 
difference between the intervention group means and observing whether or not the 
confidence interval overlaps a pre-specified non-inferiority margin for that endpoint.  
Of the two primary outcomes, the knee laxity endpoint requires the larger sample size.  For 
AP laxity, we used an estimated SD=2.7mm from Fleming et al[116] based on the pooled 
standard deviations of the within-patient side-to-side difference scores for both the low 
tension and high tension groups (personal communication).  Based on the Arneja and 
Leith[117]  recommendation of a 2 to 3 mm threshold as the basis for a diagnostic test, we 
selected a clinically important difference to be 2.0 mm.  Under this assumption, and 
assuming a 2:1 randomization, a sample size of N=69 (46 BEAR, 23 Control) will provide 
80% power to test non-inferiority as described above.  Inflating the sample size to account 
for an anticipated 20% attrition brings the sample size goal to N=87.   
Because of our special interest in the hamstring graft subgroup, we will recruit until we 
have met the target N=87 subjects in the hamstring-preference stratum.  Based on historical 
data at our institution, we expect ~85% of all randomized patients to be in the hamstring-
preference subgroup so we project a total sample size, including subjects in the BPTB-
preference stratum, to be about N=100.  The remainder of the power calculations will be 
based on the smaller number of N=87 and therefore power is slightly underestimated. 
Our second primary endpoint is the IKDC score at 24 months post-surgery.  Irrgang[118] 
concluded that a change in the IKDC of 11.5 points was an optimal threshold with high 
sensitivity for distinguishing those who were or were not improved.  Therefore, we used 
11.5 as the non-inferiority margin.  In a cohort of 69 subjects reported by Reinke[119], the 
SD of IKDC scores at two years was 10.5.  In a systematic literature review of 
reconstruction and non-surgical cohorts with mean 13.9 years follow-up, Chalmers[120] 
reported a mean difference in IKDC scores of 5.8 and an effect size of .73, which implies 
a SD of 7.26.  We used the most conservative of these SD estimates, 10.5.  With that SD 
and the clinically important difference of 11.5 as recommended by Irrgang [118], our 
sample size of 87 patients (minus 20% projected attrition) gives us 99% power to detect 
non-inferiority between the groups for this primary outcome measure.  
 
To project statistical power for some additional secondary endpoints, we considered the 
KOOS scores as a second patient-reported outcome measure.  Roos et al [96] reported 
SDs for the Sports and Knee Related Quality of Life (krQOL) subscales at 6 months post 
ACL reconstruction of 15.8 and 10.1, respectively, and Roos and Lohmander [121] 
concluded that 10 points represented a clinically significant effect for the KOOS. Under 
these assumptions, our sample size of 87 patients will provide 69% and 97% power to 
test non-inferiority for the Sports and krQOL subscales of the KOOS, assuming 20% 
dropout at the two year time point.   
 
For hamstring strength deficits after ACL surgery, Landes et al[122] reported a mean 
hamstring strength side-to-side difference of 17 Nm (a 23% deficit relative to the 
contralateral knee), with a SD of 14 Nm, 2 years after ACL reconstruction with hamstring 
tendon.  Data obtained at Boston Children's Hospital for 235 patients undergoing 

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autologous hamstring grafts showed a mean 29% deficit (SD = ±23%) of hamstring 
strength at six months post-operatively.  From the initial BEAR study, the patients 
undergoing ACL reconstruction had an average 33% deficit of hamstring strength at the 
six month time point, while the BEAR patients had only a 13% deficit, an estimated 20-
point difference.  At 3 months there was a larger treatment effect observed, 25 points.   
Assuming a SD of ±23%, our sample size of 87 patients (minus 20% projected attrition) 
will have 91% power to detect a 20-point difference in percent hamstring strength deficit 
at 3 or 6 months. 
 
For imaging outcomes, we don't anticipate any significant changes in joint space on plain 
radiography at two years, so while we will collect these images at time zero and year two, 
this will be simply for baseline recording in the event the results of this proposed study 
warrant longer term study of these patients at time points when we might anticipate 
seeing joint space narrowing, such as at 6 or 10 years after injury as has been done for 
prior ACL reconstruction cohort studies.   
 
Finally, with the 2:1 randomization, our sample size of N=87 will yield 58 BEAR 
patients, 46 after 20% attrition, for observing rare safety events such as graft removal due 
to an immune response.   Forty-six evaluable patients will provide a 90% chance of 
observing at least one event if the true event rate is .049.  However, such events are likely 
to occur early in follow-up, before potential dropout, so the number of evaluable patients 
could be as high as 58.  In addition, if we consider the 10 BEAR patients in the pilot 
study, we could have a maximum potential of 68 evaluable patients in which to observe 
rare safety events. Therefore, we will plan to consider the safety outcomes for the patients 
in the initial BEAR I trial (IDE  G140151) in addition to those in this current IDE study 
to improve our power to detect any differences between the ACL reconstruction and 
BEAR groups for these relatively rare safety events.  With 58 or 68 evaluable patients, 
we will have a 90% chance of observing at least one event even for events that are more 
rare (event rates .039 or .033, respectively).   
 
1.15 Study Organization  
This will be a single clinical site prospective controlled trial conducted in the Department 
of Orthopaedic Surgery at Boston Children’s Hospital.  Miach Orthopaedics, Inc., will 
serve as the IDE Sponsor.  Patients will be recruited from the practices of and operated 
on by Dr. Lyle Micheli, MD, Director of the Division of Sports Medicine, Dr. Yi-Meng 
Yen, and Dr. Dennis Kramer.  All surgeons are already proficient with ACL 
reconstruction with hamstring tendon and will be trained on the bridge-enhanced repair 
technique prior to performing this operation.  Six-month, 2 year, 6 year and 10 year study 
MRIs and x-rays will be read clinically at Boston Children’s Hospital, and de-identified 
copies will be sent to Braden Fleming, PhD, a bioengineer at Brown University/Rhode 
Island Hospital, who developed and validated the MRI protocol that will be used to 
predict ACL strength for this study.  Dr Fleming, or one of his team members, will be one 
of the readers of the MRIs for the experimental analyses of correlates of MR images with 
patient outcomes, as well as the analysis of the x-rays for radiographic changes consistent 
with osteoarthritis.  Dr Martha Murray’s lab will store the research samples (blood 

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serum/plasma and urine) for future use, to be determined later by Investigators. There 
will be a Data Monitoring Committee made up of three physicians, two orthopedists and 
one internal medicine physician. The committee’s role is to review adverse events as they 
occur, to ensure individual patient safety and safety of the overall trial.   Study 
monitoring functions will be performed by independent contract clinical monitors and/or 
clinical monitors from a qualified independent clinical research organization (CRO) as 
designated by the Sponsor.