The Comparative Efficacy of the Masquelet Versus Titanium Mesh Cage Reconstruction Techniques for the Treatment of Large Long Bone Deficiencies
Phase: NA
Conditions: Segmental Long Bone Defects
Sponsor: The University of Texas Medical Branch, Galveston

NCT 02015390
The Comparative Efficacy of the Masquelet versus Titanium Mesh Cage 
Reconstruction Techniques for the Treatment of Large Long Bone Deficiencies 
PI:  Zbigniew Gugala, MD, PhD 
Ronald W. Lindsey, MD  
The University of Texas Medical Branch;  Galveston, TX  
Jun 22, 2020 

 
 
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THE STUDY PROTOCOL  
  
The proposed study is a single-center, prospective, two-arm, randomized clinical trial. The study is conducted and 
coordinated by the University of Texas Medical Branch (UTMB) and its affiliated John Sealy Hospital; Galveston, 
TX as a study site. Patients who present to these hospitals with a traumatic segmental bone loss (high-energy 
trauma, gunshot injury) or a medical condition (infection, nonunion, tumor)  which requires iatrogenic segmental 
bone resection will be enrolled into the study after inclusion/exclusion criteria have been met and signed informed 
consent obtained. Routine patient management (standard of care) will be performed prior to the Masquelet or the 
cylindrical titanium mesh cage (CTMC) reconstruction in accordance with the patient’s bone defect characteristics 
and overall health status. Post enrollment, the study subjects will be randomized into either the Masquelet (Arm 
I) or the CTMC defect treatment technique (Arm II). All aspects of pre-, intra-, and postoperative patient and 
defect management will strictly adhere to the IRB-approved study research protocol. Within each study arm, two 
distinct options of bone graft will be available for use in combination with the Masquelet or the CTMC defect 
reconstruction, and they include: autogenous RIAharvested bone graft (Option A) obtained from reaming of either 
the intramedullary femoral or tibial canal, or fresh-frozen cancellous allograft in combination with demineralized 
bone matrix (Option B). The decision on graft option is made by the patient following an in-depth review by a 
treating physician (study PI).   
  
STUDY DESIGN:  
The proposed randomized clinical trial aims to determine the comparative efficacy of the Masquelet versus the 
CTMC technique in combination with RIA-harvested autogenous bone graft or allogeneic cancellous bone 
croutons-DBM composite as reconstructive modalities of segmental bone defects. The Masquelet technique can 
be regarded as a new standard treatment option in the orthopedic practice as frequently indicated and supported 
by the literature. The CTMC technique will be considered as experimental defect treatment option, which utilizes 
the titanium mesh cage in an innovative manner, although originally approved and cleared by the FDA for such 
use. Because both the Masquelet and the CTMC treatment techniques have potentially similar clinical indications, 
randomization will be performed to assign the enrolled patients to a specific treatment group (Arm I or Arm II) 
to ensure bias-free selection process. The choice of graft type (Option A versus Option B) to be used in 
combination with either the Masquelet or the CTMC technique will be nonrandomized and made by the enrolled 
patient following an in-depth review and explanation of each graft option by the treating physician. Since many 
patients have subjective preference as to whether their own bone or bone from the bone bank should be used as 
graft material, such a study design will not exclude the eligible patients because of that preference, thereby 
enhancing study accrual and enrollment. Furthermore, the merits and justification supporting the specific graft 
selection will be treated as significant covariate in the subsequent analysis of the treatment outcome and resource 
expenditure.  
Treatment Arm Randomization   
The assignment of patients to treatment groups (Arm I versus Arm II) will be done using the nQuery Advisor 
random assignment generation algorithm. The software options in nQuery allow for random block sizes to be 
generated, allowing for a better guarantee of balance while making the assignment largely unpredictable. Our 
biostatistician will use the nQuery software to generate 30 random numbers linked to 15 Arm I and 15 Arm II 

 
 
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labels. An additional random sequence listing 10 Arm I and Arm II will be created as a backup in case of 
randomization irregularities. The Arm I and Arm II sequence will be used to consecutively designate the specific 
treatment arm for the enrolled patients. Randomized treatment arm assignments will be kept in sealed opaque 
envelopes and will not be known to the treating orthopedic surgeons (R.W.L.; N.L.C.) and the patients prior to 
the enrollment. The PI (Z.G.) and the study coordinating team will maintain a randomization confidential 
throughout the study. After a patient has been successfully enrolled to the study, the envelope will be opened and 
the treatment arm designation revealed. The defect treatment will follow exactly as revealed. Any randomization 
irregularities (ie, lost envelopes, envelopes opened but not used, numbers inadvertently skipped) will be reordered 
and reported to the institutional IRB.   
Course of Action  
Patients who present to the study site with a segmental defect or medical condition (nonunion, infection, 
neoplasm) to be treated with a segmental bone resection will be routinely admitted and the PI (Z.G.) notified. The 
patient and his/her medical condition will be reviewed in accordance with the study inclusion/exclusion criteria. 
If eligible, the patient will be enrolled in the study subsequent to discussing and explaining in detail the study 
protocol and obtaining a signed informed consent. The patient will then be randomized and assigned into one of 
the two treatment groups, ie the Masquelet or the CTMC technique (Arm I or Arm II). Next, following a thorough 
explanation of the defect graft options by the treating physician, the patients will select the graft type to be used 
with the randomly assigned treatment arm. The pre-operative data will be collected as per the study protocol, and 
necessary imaging/studies obtained. The required routine (standard of care) surgical procedure(s) preceding the 
defect treatment technique will be performed. Only if and when the defect is suitable for reconstruction, the first 
of two-stage surgery of the Masquelet technique (cement spacer application) or the single-stage CTMC procedure 
will be performed. The select orthopedic surgeons specializing in the Masquelet technique (N.L.C.) or CTMC 
technique (R.W.L.) will perform the specific defect reconstructive surgery (both cement spacer and grafting stages 
of the Masquelet or the entire single-stage cage with grafting of the CTMC technique) for all of the enrolled 
patients to ensure the consistency in the defect reconstruction and the postoperative patient management. For the 
Masquelet technique, there will be a routine 6-8 week period between the two stages of defect management. The 
type of definitive defect stabilization (eg, IM nail, platescrew construct) will be selected by the treating orthopedic 
surgeon. All the intraoperative data will be collected by the PI (Z.G.) or study staff. The patient’s post-surgical 
course will be performed as mandated by the technique of defect treatment. For the Masquelet, the limb weight 
bearing protocol will be strictly followed depending on the consolidation status of the graft. For patients 
undergoing the CTMC postoperative course, weight bearing will be permitted as tolerated. Subjective data (patient 
questionnaire), objective functional data (outcome scores), and imaging data will be collected pre-, and post-
defect reconstruction as designated in the study protocol (pre-hospital, inpatient period, and outpatient follow-up 
visits at 2 weeks, 6 weeks, 12 weeks, and 18 weeks post defect reconstruction).   
Throughout the entire post-operative study period (18 months), the patient’s status will be monitored for 
complications and adverse events. If a complication or adverse events occurs, they will be reviewed by the PIs, 
the study staff, and key personnel and reported to the UTMB IRB according to regulatory and institutional 
policies. In addition, the study documents will be monitored by the UTMB’s Research Services, Monitoring and 
Quality Assurance department for Clinical Research at 3-month-intervals. For the duration of the study, the PIs 
will routinely meet with the study coordinating staff to discuss the study progress, review the enrolled patients, 
and discuss all complications and/or adverse events as they occur. At 6 month intervals the PIs will meet with the 
study’s biostatistician to perform preliminary statistical analysis of the collected data. The investigators will use 

 
 
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these meetings to make adjustments in the course of the study in case of enrollment issues and/or other logistic 
problems occur.   
 
 
Study Variables  
All study preoperative, intraoperative and postoperative variables will be recorded to construct a database of 
patients presenting with segmental bone defects and treated with the Masquelet or the CTMC technique in 
combination of auto- or allograft.   
Preoperative variables are defined as all the patients- and their health-related data that are collected prior to the 
Masquelet or the CTMC reconstructive procedure (to include surgeries performed prior to the first stage of the 
Masquelet or the index CTMC surgical procedure). Preoperative variables to be collected will include:  
• Patient (baseline):   
A) Demographics (age, gender, ethnicity; social functioning/background);  
B) Overall health status;    
C) Risk factors (tobacco, alcohol, recreational drugs);  
D) Co-morbidities  
E) Concomitant medications (past 60 days prior to enrollment)  
F) Past (last 10 years) medical history  
• Defect:   
A) Etiology:   
Traumatic: Systemic and specific extremity injury characteristics to include Injury Severity Score (ISS) 
(Baker 1974); Gustilo-Anderson classification (Gustilo 1976) for open fractures, gunshot 
injury characteristics, type of firearm, bullet/missile retention; nature and extent of blast 
injury, limb neurovascular status.  
Iatrogenic: Specific diagnosis, details on disease (infection, tumor) course and history; type of nonunion 
(hyper-, oligo-, atrophic, septic).  
B) Characteristics: Location, size, degree of contamination, and adjacent soft tissue status.  Imaging: plain 
radiography, CT (in select cases).  
• Affected Limb Function:   
A) Ambulation (passive, active, range of motion);  
B) Pain;  
C) Weight bearing status;  
D) Functional assessment (DASH for the upper extremity, and AAOS Lower Limb Core Scale for the lower 
extremity).  
• Pre-Masquelet or pre-CTMC treatment:   
A) Nature, number, timing of all treatment interventions, specifically data on all surgical procedures 
performed prior to the defect reconstruction;  
B) Provisional defect stabilization;  
C) Soft tissue coverage (type of closure/flap, timing).  

 
 
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Intraoperative variables are defined as those that are recorded during the first and the second stage of the 
Masquelet or the index CTMC reconstructive procedure. These include data pertaining to:  
• Iatrogenic resection: the defect size, geometry, location; determination of healthy margins; (if segmental 
resection is performed on the same operative setting); quality of soft tissue envelope.  
• Masquelet:   
1st stage: spacer cement type, volume, if with antibiotics (types/concentration), in situ or  
 
  
ex vivo cement polymerization.  
2nd stage: time between the stages; quality and patency of biomembrane; technique of the 
cement spacer extraction.    
• CTMC: cage type, manufacturer, dimensions (diameter, length).  
• Bone graft:   
A) RIA-harvested autograft (Option A): location, technique, volume, timing;  
B) Allograft-DBM (Option B): allograft tracking number; allograft/DBM provider; volume; cancellous 
croutons to DBM ratio;  
• Definitive defect fixation: IM nail, plate-screws type, manufacturer, dimensions.  
  
• Reconstruction Surgery:   
A) Quality of reduction, alignment;  
B) Type of definitive stabilization;  
C) Intraoperative plain radiography;  
D) Tourniquet time;  
E) Fluoroscopy time;  
F) Surgery time;  
G) Intraoperative blood loss / transfusions;  
• Complications and/or adverse events encountered intraoperatively.  
Postoperative variables are defined as those that are recorded after the second stage of the Masquelet or the index 
CTMC defect reconstructive procedure. They include clinical examination, imaging, pain and limb function 
assessment, and the overall treatment outcome (questionnaires). The followup data are collected at hospital 
discharge, at 2 weeks, 6 weeks, 3 months, 6 months, 12 months and 18 months post defect reconstruction surgery. 
Postoperative complications and/or adverse events will be documented and reported.  
Defect Healing Assessment  
The radiographic determination of defect healing will consist of a 5-grade scale (ranging from no healing to 
completely healed) in quarter defect length increments (ie, 0%, 24%, 50%, 75%, 100% defect healed). The 
radiographic review will be conducted by the PIs and 2 independent reviewers. Inter- and intrarater agreement 
will be calculated for the final determination of the defect healing status.   
CT imaging will be performed routinely at 12 months post defect reconstruction surgery to visualize the new bone 
formation/graft reconstitution within the defect using two- and three-dimensional reconstructions. Spatial 
determination of new bone formation will be carried out in relation to the defect, the hardware, and the local 

 
 
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anatomic landmarks. The quantitative (bone volume) and qualitative (mineral density) will be calculated 
following a metallic hardware (cage, nail, plate-screws) subtraction algorithm.   
Questionnaires  
Questionnaires will be used in the study as outcome instruments for defining the safety characteristics of the 
enrolled subjects; determining the longitudinal impact on health changes, function and satisfaction; delineating 
the effectiveness of the Masquelet versus CTMC technique of defect reconstruction; developing of specific 
evidence-based medicine clinical pathways and guidelines.  
The following questionnaires will be used in the study as outcome instruments:  
Brief Pain Inventory Short Form (Cleeland 1994);   
• Disabilities of the Arm, Shoulder, and Hand (DASH) for the upper extremity (Hudak 1996);   
• Lower Limb Core Scale (LLCS) for the lower extremity (Johanson 2004);   
• Medical Outcomes Survey Short-Form 36 (SF-36) (Ware 1996);   
• Time Trade-Off to assess Quality-Adjusted Life Years (QALY) (Torrance 1987).   
All these questionnaires have been validated as valuable outcome measure instruments. Furthermore, they are 
endorsed by the American Academy of Orthopaedic Surgeon as recommended reliable and valid tools in the 
assessment of musculoskeletal treatment outcome. The enrolled patients will complete the questionnaires at the 
initial, midcourse, and final follow-up visits. The time burden to complete the questionnaires is approximately 30 
minutes.  
Statistical Methodology  
Descriptive statistics will be used to analyze the collected data specifically to:   
• characterize the patient with segmental bone deficiency;   estimate the proportion of healing with/without 
complications;   cross-compare the recorded variables.   
Paired Student t-test will be used to test the effects of the Masquelet versus the CTMC defect reconstruction on 
the outcome measures.   
Analysis of covariance (ANCOVA) will be used for pair-wise comparison within the two treatment arms (graft 
Option A vs. Option B).  
A mixed model for repeated measures will be conducted to evaluate:  
• 
the effect of the Masquelet versus CTMC defect reconstruction on the outcome measures, adjusting for 
patient demographics and clinical characteristics;   
• 
the effect of the specific defect characteristics (etiology, size, location, adjacent soft tissue involvement, etc) 
on the treatment outcome;  
• 
the possible interaction effects between treatment and defect characteristics.  
Multiple models will be used in case the proposed sample size would not have enough power to produce an 
accurate predictive model which accounts for all possible morbidities and interactions. Simple models using 
modern penalty function techniques (lasso, elastic net, boosted trees, etc.) to control model complexity should 
provide a useful initial predictive tool for each clinical and quality of life outcome.  
Both receiver operating curve (ROC) analysis and clinical judgment will be used in determining the optimal 
clinical indications and timing for defect reconstitution with the definitive defect reconstruction using the 
Masquelet versus the CTMC technique.  

 
 
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Sample Size Justification   
Based on the data from the PIs’ preliminary clinical series of 20 patients, it can be assumed that 75% of patients 
with segmental bone defects reconstructed with the CTMC technique will heal without complications. In the 
present study we propose to enroll and follow-up on 30 patients throughout 4 years of the clinical trial duration. 
This sample size of 30 is largely determined by clinical feasibility. For the sample size 30, a two-sided 95% 
confidence interval for a single proportion using the large sample normal approximation will extend 0.134 from 
the observed proportion for an expected proportion of 0.75.  
Our past experience with prospectively investigating 20 patients with traumatic segmental defects presented to 
our institution (single site) within 2.5-year period suggests that the 30 patients to be enrolled in the proposed study 
within the anticipated time frame is very feasible considering broader inclusion criteria.  
 
Data Analysis   
Prospectively collecting pertinent pre-, intra-, and postoperative study variables will establish a database of 
patients with segmental bone defects reconstructed with CTMC in combination with bone graft of bone graft 
substitute. A series of multivariate models will be constructed to model sizeable complex interactions between 
the patient, defect etiology and characteristics, process of care variables and surgical outcomes. Specific analyses 
will be performed to address the following questions:  
• 
What are the characteristics of the patients who present with segmental bone deficiency warranting surgical 
reconstruction that achieve superior functional and quality of life outcomes when treated with the Masquelet 
versus the CTMC technique?  
• 
What is the nature of a segmental bone defect and its related variables that determine superior outcomes 
after the Masquelet versus the CTMC reconstruction?  
• 
What are the aspects of pre-, intra-, and postoperative care that differ for patients who:  
A) achieve poor outcomes;  
B) 
sustain treatment related complications;  
C) 
incur resource usage well in access of the average?  
Resources Expenditure and Cost-Effectiveness Analysis  
The treatment cost calculations for patients treated with the Masquelet (Arm I) or the CTMC technique (Arm II) 
in combination with auto- (Option A) or allograft (Option B) will include the length of hospital stay, overall 
treatment cost, and the comparative cost-efficiency assessment. The clinical characteristics of the study arms will 
be reported with means and standard deviations, frequencies, or percents, when appropriate. All analyses of 
outcomes will be performed both as "intent-to-treat" and as "efficacy." Average charges in the two groups will be 
compared with a Student t-test or Wilcoxon rank sum test. The progression of defect healing based on imaging 
evaluation (using both qualitative and quantitative measures) and functional recovery assessment (both subjective 
questionnaire, and objective outcome scores) will be compared with the log-rank test and proportional hazards 
model. Frequencies of repeat surgical intervention and complications will be compared with chi-square tests. 
Because there are two designated expert surgeons who will each be performing a single study arm, consistency 
could be expected within each treatment arm as it relates to the specifics of the surgical intervention and the post-
surgical course of patient management.  
The standard economic evaluation approach to assessing the difference between the two defect treatment arms is 
to construct a comparative cost-effectiveness ratio for each arm. This will include determining the incremental 

 
 
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progress in defect healing and/or functional restoration in relation to the treatment time and finally to the costs 
and/or resources allocated to achieve that. Our expectation is that clinical outcomes will favor the CTMC 
technique because of its single stage surgery, shorter treatment time, efficacious defect healing, and early 
unrestricted functional restoration. It is important to emphasize that the primary determination in the study is to 
establish whether applying one of the treatment arms versus the other is associated with clinically- and/or 
statistically-significant improvement in outcome, and secondarily assess the time, cost, and resources that enabled 
that improvement. Both the estimated outcome and cost differences can exhibit some variation, however, 
accounting for uncertainty in estimates has become an important component of economic evaluation. Derived 
from the joint distribution of costs and effects, cost-effectiveness acceptability curves (CEACs) will be established 
to summarize the uncertainty in cost-effectiveness estimations. This is particularly important if the study arm is 
found to be cost-effective rather than cost-saving.  
  
 
HUMAN SUBJECT RECRUITMENT AND SAFETY PROCEDURES  
  
Patients with segmental long bone defects or conditions requiring a segmental bone resection will be reviewed 
for study eligibility as per protocol inclusion/exclusion criteria. Potential study participants will be identified after 
they are admitted to the UTMB John Sealy Hospital; Galveston, TX. The selection of this hospital can offer access 
to a diverse patient population not only in terms of the nature of the study medical problem (segmental bone 
defects) but also demographic, social, health care accessibility characteristics. The hospital specializes in distinct 
areas of orthopeadic care and thereby can provide eligible patients with bone defects of various etiologies 
(posttraumatic vs iatrogenic resections; acute vs chronic) and anatomic locations (lower- and upper extremity). 
The diverse patients recruited to the study will represent study subjects with different treatment outcome 
expectations, thereby reinforcing the study’s validity as being more representative of the entire US society. This 
type of approach will also promote equity in social status by permitting all patients to incur the burdens as well 
as the benefits of the segmental bone defect treatment. The recruitment of patients eligible for the study will be 
equitable; there will be no limitations regarding age (except for skeletal maturity), gender, race, ethnic and cultural 
factors.  
Because of the unique nature of the defect etiology (trauma, iatrogenic resections due to nonunion, infection, 
tumor), and to avoid unanticipated delays and/or a slow accrual in study subject enrollment, an active physician’s 
referral program will be implemented.   
 Study Inclusion Criteria:   
All eligible patients will be screened and enrolled as they present for treatment without consideration of race, 
gender, or cultural/religious consideration.  
• 
Male or female;  
• 
Skeletal maturity (defined by the absence of epiphyseal plate and/or age > 18 years);  All ethnic 
backgrounds;  
• 
Presence of segmental bone defect requiring surgical reconstruction with at least one of the following 
etiologies:  
A) traumatic segmental bone defect that warrants surgical reconstruction;  

 
 
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B) acquired bony nonunion (not congenital) treatable by segmental resection and reconstruction; C) 
local osteomyelitis (dormant or active) treatable by segmental bone resection and reconstruction;  
D) localized, nonmalignant tumor with involvement of bone diaphysis treatable by segmental bone 
resection and reconstruction.  
E) suffiecint comprehension of the English language to understand the consenting process and study 
procedures  
Protected Eligible Patient Groups  
• 
Eligible patient has a mental disorder or medical condition/s that reduces his/her ability to make 
an informed decision and has the consent of his/her legal guardian and/or health care surrogate; 
are you going to remove this bullet?  There is a different explanation under vulnerable pop below.  
• 
Eligible patient is illiterate and has  a non-party observer present during the reading of the informed 
consent AND the non-party observer witnesses the subject’s consent to participate;  
 
 
Defect Eligibility Characteristics  
To be eligible for the study the study inclusion criteria mandates that a patient presents with a segmental bone 
deficiency requiring surgical reconstruction.   
• 
Size: Typical size of a defect that warrants surgical reconstruction (beyond functional limb 
shortening) eligible for the study inclusion is:  
A) greater than 5 cm in length for the humerus;  
B) greater than 2 cm in length for the tibia, femur, radius, ulna.  
• 
Etiology: The eligible defects can be of the following etiology:  
A) traumatic, typically as a result of high-energy injury or gunshot injury;   
B) iatrogenic, resection of nonunion, infection, or tumor.   
• 
Onset/Duration: Eligible defects can be defined as:  
A) acute (time from the injury or resection  less than 2 weeks);  
B) subacute (time from the injury or resection  greater than 2 weeks but  less than 3 months);  
C) chronic (time from injury or resection greater than 3 months).   
According to this designation, typical acute defects include those that are reconstructed during or 
immediately after irrigation and debridement. Typical subacute defects are those that require staged soft 
tissue coverage prior to the reconstruction. All defects that result from previously failed treatment are 
designated as chronic, and those typically comprise nonunions and infections.  
• 
Location: The eligible defect must be located in proximal, mid or distal shaft of the following 
major extremity long bones:  
A) Humerus;  
B) Radius/Ulna; C)   Femur;  
D)   Tibia.  

 
 
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• 
Microbiology: The sterility of the defect needs to be confirmed using routine microbiology (wound 
cultures) and/or pathology histologic evaluation. Infected defects will undergo routine treatment 
which will consist of systemic and locally applied antibiotics (antibiotic-impregnated cement 
spacer or beads) until wound sterility is confirmed by microbiology/pathology evaluation.   
• 
Adjacent soft tissue status: Eligible defects must have adjacent soft tissue that is suitable for 
surgical reconstruction. Thereby, wound coverage can be achieved following defect reconstruction 
by either the closure of viable wound margins or the placement of soft tissue flaps (local or free).  
Wound coverage may be done as a staged surgical procedure (soft tissue coverage typically as 
much as 6 weeks prior to definitive defect reconstruction), or as a single stage procedure 
(performed at the same time as the definitive defect surgical procedure).   
  
Study Exclusion Criteria:  
• 
Non-segmental defects (e.g., defect in continuity involving only single cortex);  
• 
Inability or contraindications to achieve stabilization with an IM nail;  
• 
Insufficient defect size (humerus defects less than 5 cm; femur or tibia defect less than 2 cm in 
length);  
• 
Extremity unsuitable for salvage;  
• 
Patients with inadequate neuro-vascular status;  
• 
Defect and/or soft tissue status ineligible for surgical reconstruction;   
• 
Ipsilateral extremity defect (e.g., tibia and femur ipsilateral defects);  
• 
Skeletal immaturity (open growth plate and/or age less than 18 years);  
• 
Known allergic reaction to titanium implants;  
• 
Disseminated osteomyelitis throughout the bone;  
• 
Active systemic infection at time of surgery;  
• 
Congenital / genetic etiology of nonunion (congenital pseudoarthrosis, osteogenesis imperfecta,  
etc.);  
• 
Women who are pregnant or nursing;  
• 
Women who intend to become pregnant during the study follow-up (i.e., 2 years);  
• 
Disseminated and/or nonresectable malignant tumor involving bone;  
• 
Patients with active compartment syndrome;  
• 
Prisoners;  
• 
Patients considered as non-compliant with medical and follow up care;  
• 
Patients using narcotics, abusing prescription drugs (within last 2 years);  
• 
Patients with alcohol abuse;  
• 
Patients deemed incapable of following instructions pertaining to post operative care due to mental 
or medical condition;  
• 
Patients deemed ineligible due to medico-social concerns.  
   
Study Termination or End Point:   
Consideration for termination of the subject participation in the study after the subject has been enrolled and/or 
study end point includes:  

 
 
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• 
Intraoperative determination of need for surgical procedure outside the study scope or protocol;  
• 
Identifying any valid exclusion criterion after the subject’s enrollment;  
• 
Secondary procedure disrupting or preventing implementation of either the Masquelet or the 
CTMC defect reconstruction technique as in the study protocol;  
• 
Evidence of infection or neoplasm recurrence post defect reconstruction;  
• 
Evidence of vascular compromise in the affected extremity resulting in secondary intervention 
affecting healing;  
• 
Subject declines continued participation;  
• 
Subject is non-compliant with follow up care and instructions;  
• 
Termination for any reason deemed mandatory by the PIs;  
• 
Defect is completely healed before the end of the follow-up (i.e., 24 months);  Subject becomes 
pregnant before the defect reconstructive surgery;  Subject completes the study.  
Subject Recruitment   
Patients who present to the UTMB hospital with a traumatic segmental defect or a medical condition (nonunion, 
infection, neoplasm) to be treated with segmental bone resection will be recruited either prior to or following 
hospital admission. The PI (Z.G.) will be notified by the admitting physician. The patient and his/her medical 
conditions will be reviewed in accordance with the study inclusion/exclusion criteria. If eligible, patients will be 
approached to discuss their participation in the study.   
The study discussion will include an explanation of the study objectives; the voluntary nature of the research; 
study requirements and/or compliance; randomization into one of the study treatment arms, termination and end 
points; reviewing both the Masquelet and the CTMC surgical defect reconstructive procedures; the alternative 
defect treatment options; the selection of autogenous RIA-harvested bone graft or allogeneic bone in combination 
with DBM, the study risks and benefits, the confidentiality of the subject’s information, medical records and 
study-related documents, the potential costs to the patient and/or the patients insurance (standard of care), the 
costs covered through study funding; the contact persons/agencies for questions.  
Obtaining Signed Informed Consent   
Informed consent will be signed by all eligible patients in the presence of a witness prior to any study activity. 
The independent witness must be a person who is not a member of the research team. The independent witness 
will countersign the informed consent indicating the patient’s verbalized understanding of study and the patient’s 
intent to be enrolled in the study.   
The study PI will be responsible for explaining the study, answering questions, and obtaining informed consent 
from the eligible patients. Eligible patients will be recruited after their presentation/admission to the hospital study 
site. Informed consent will be obtained after procedures determining study eligibility. Eligible patients will be 
offered privacy and time to make the decision regarding their participation in the study; they will be encouraged 
to discuss this decision with their family members or others of their choice.   
The eligible patients’ health status will be reviewed to confirm that his/her cognitive capacity (eg, no mental 
alteration due to administration of any mind-altering substances such as tranquilizers, conscious sedation or 
anesthesia, brain injury, stress/life situations, or volunteer age) permits obtaining full conscious (not under drug 
influence) consent for participation in the study. In cases where such mental alteration exists, the recruitment will 

 
 
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be postponed; these patients will be reassessed, and when appropriate, approached again for recruitment when 
conscious informed consent can be obtained.   
No waiver of the informed consent for study enrollment is sought. Minors are ineligible for participation as per 
the study inclusion/exclusion criteria.  
Subject Reimbursement for Study-Related Expenses  
Reimbursement for time, travel, parking, and meals for each completed study visit is provided.  
In addition and due to time commitment for 2 week, 12 month and the 18 month visits, subjects will receive 
additional reimbursement.  
Total reimbursement is $700. The reimbursement will be only for competed study visits. UTMB Clincard, which 
is a debit card with funds loaded will be issued as follows: $200 at visit 1 (at 2 weeks); $50 at visit 2 (at 6 weeks); 
$50 at visit 3 (at 3 months); $50 at visit 4 (at 6 months); $150 at visit 5 (at 12 months), and $200 at the final visit 
6 (at 18 months). When a study visit is completed, funds will be approved and loaded onto the card. The funds 
will be available within 48 hours. One card will be issued for the duration of the subject participation. All 
information is stored in the Clincard system will be kept and handled in a secure fashion and will be deleted from 
system once the study has been completed and the funds on the card have been all used. 
   
INTERVENTIONS AS THE STUDY RESERCH:  
They study intervention that are performed outside the standard of care and solely for research include:   
1. Randomization to one of the two study arms.  
2. Collection of pre-, intra-, and postoperative data.  
3. Completing outcome questionnaires  
  
INTERVENTIONS AS THE STANDARD OF CARE:  
Procedures Preceding the Defect Reconstruction  
Prior to segmental defect reconstruction with either the Masquelet or the CTMC technique, several preparatory 
non-surgical and surgical procedures must be performed to ensure a clean, de-contaminated wound with viable 
residual bone margins and adjacent soft tissue bed. These procedures constitute the current standard of care for 
all defect reconstruction modalities, and consist of the following:  
• 
Antibiotics: For patients with segmental bone defect without active infection, prophylactic antibiotics will 
be administered; for patients with infected defects therapeutic systemic broad-spectrum antibiotics are 
implemented along with the application of local antibiotics eluted from cement beads or spacer.  
• 
Irrigation & debridement: Foreign bodies, contaminated, devitalized bone and adjacent soft tissue will be 
removed using serial surgical irrigation and debridement. Type of irrigating solution, volume, and mode of 
its application should be adequate to the degree of wound contamination, infection, necrosis.   
• 
Cultures & biopsy: Microbiological evaluation of the defect will be performed to confirm its aseptic status 
and/or infection resolution. Histopathological biopsy assessment is done for neoplasms as a part of routine 
diagnosis.  

 
 
12 
Revised 26-Jan-2016 
• 
Wound closure/coverage: Definitive soft tissue closure/coverage will occur when the wound has been 
adequately de-contaminated of all foreign body, infection and contamination.  
• 
Temporary defect stabilization: Provisional plaster splint (acute defect reconstruction) or spanning external 
fixation (delayed defect reconstruction) will be used to temporary stabilize the defect.  
RIA Autogenous Bone Graft Harvesting (Option A)   
For RIA procedure of autograft harvesting from the femur, a bump will be placed under the ipsilateral hemipelvis 
similar to the position for a free leg femoral nail. The narrowest section of the femur or tibia is templated on 
anterior–posterior (AP) and lateral fluoroscopy to determine the intramedullary canal size. The reamer size then 
selected will be approximately 1-1.5 mm larger in diameter than the measured canal size. The tip of greater 
trochanter is used as an entry postal under the guidance from biplanar fluoroscopy. The standard anterior proximal 
tibia entry portal typically employed for IM tibial nailing will be used for tibia RIA autograft harvesting. A 13-
mm cannulated drill bit is used to create the entry site, after a ball-tip guide wire inserted advanced down into IM 
canal. The RIA system (Synthes US; West Chester, Pennsylvania) is assembled to harvest bone graft. This 
includes attaching a properly sized reamer head, connecting 3-5 liter saline bag to the RIA irrigation port, 
establishing suction to the RIA aspiration port and connecting a suitable graft collecting container with a filter 
with 500 µm pore size (The Screen Trap; Biomet, Warsaw, IN). Gravity flow and vacuum suction are used to 
maintain irrigation flow. The IM canal is subsequently reamed with the properly sized reamer in an alternating 
forward-and-backward pattern. The femur will undergo 2 to 4 RIA reamer IM passes depending on the size of the 
defect to be grafted. For larger defects, autograft harvesting volume can be increased by advancing the guide wire 
sequentially into both the lateral and then the medial femur condyles to enable graft harvesting from both 
locations. After RIA reaming is completed, the trap is disconnected and bone graft collected. The harvested bone 
graft then is immediately packed into the defect with defect biomembrane or into the cylindrical titanium mesh 
cage. Care is taken to apply the RIA autograft into the reconstructed defect in a timely manner in order to 
maximize it biological healing potential.  
  
The Masquelet Technique (Arm I) for Bone Defect Reconstruction   
Overall Concept and Rationale   
In a seminal paper (Masquelet 2000), Masquelet described a two-stage technique for the treatment of large 
segmental bone defects that involves the induction of a biomembrane about a PMMA cement spacer within the 
defect and, following cement removal, autogenous bone grafting of the defect while preserving the biomembrane. 
The typical time interval between the two stages is 6-8 weeks (Masquelet 2010). The biomembrane not only 
assists in retaining the bone graft, but serves as a rich source of vascular supply and growth factors which 
constitute an excellent biological milieu for the graft to consolidate and heal the defect being (Pelissier 2004).  
Description of the Masquelet Technique  
In the first stage of the Masquelet technique, the defect is meticulously irrigated and debrided by removing all 
contaminants, debris, and necrotic or devitalized tissue. At this stage the limb anatomical alignment is also 
restored and provisionally stabilized, the defect is assessed/templated for its size and geometry to determine the 
most suitable type of definitive stabilization. At the second stage procedure the temporary stabilization is removed 
and converted to either a plate-screw construct or an IM nail as the definitive mode of defect fixation. Definitive 
soft tissue coverage is also typically accomplished at this stage after defect sterility has been confirmed by 
microbiology and/or other pathology studies. The PMMA cement is prepared with a volume slightly exceeding 

 
 
13 
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the confines of the defect to eventually accommodate the effective volume of the graft in the second stage. If there 
is an ongoing concern for infection (i.e. a Gustilo Grade II or III open fracture; acute/chronic osteomyelitis), the 
PMMA cement is combined with vancomycin and/or tobramycin at the therapeutic concentrations for local 
antibiotic delivery. Because of exothermic polymerization of the PMMA, adjacent nerve and vessels must be 
retracted/protected until the cement cures and reaches body temperature. PMMA volumetric expansion during 
polymerization should be taken into consideration to adequately adjust the volume of cement at the defect; an 
excessive PMMA spacer might cause problems maintaining an intact biomembrane during its removal.   
The second, bone grafting stage is typically formed at 6-8 weeks post PMMA cement spacer placement. The 
defect is exposed through the same incision used for cement placement. When a plate-screw is used for defect 
stabilization, the biomembrane is typically formed around the plate and the cement spacer. The biomembrane 
surrounding the spacer is incised longitudinally along the plate border leaving a margin sufficient enough to permit 
re-approximation/closure of the biomembrane after bone grafting is performed. Once exposed, the cement spacer 
is removed en bloc or in small fragments using a rongeur and/or drilling. Although it is imperative that all of the 
cement spacer and its fragments are removed, exceptional care is taken to avoid violating the biomembrane 
surrounding the cement apart from the longitudinal incision. After this is accomplished, the biomembrane lodge 
is irrigated copiously to ensure removal of all spacer debris. In case of autogenous bone grafting using RIA, the 
fomoral and/or tibial IM canal(s) are reamed to harvest sufficient bone graft. If the harvested RIA graft is 
insufficient, it can be supplemented with autogenous iliac crest bone. The bone graft is packed into the 
biomembrane void immediately post harvesting and should fill the entire cavity. If allograft is used, a graft 
composite consisting of freeze-dried cancellous croutons mixed with demineralized bone matrix (DBM will be 
prepared using Grafton putty (Osteotech, Eatontown, NJ) at a volume ratio approximately 3-to-1, respectively. 
The allograft composite is fragmented with a rongeur to a consistent fragment size, and then packed to the 
biomembrane lodge filling it tightly. The biomembrane lodge should be filled entirely, but not overpacked to 
cause problems with biomembrane closure. Once the lodge is packed, the biomembrane is carefully closed with 
absorbable suture, followed by wound closure. It is imperative to obtain haemostatic wound closure.  
 
Postoperative Course  
The patient is permitted immediate passive motion using a continuous passive motion (CPM) device when 
appropriate. Pain control is implemented as a routine. Physical therapy will be initiated at 2 days post defect 
reconstruction. Lower extremity weight bearing will be gradually applied as tolerated at about 6 weeks after the 
bone grafting stage of the Masquelet procedure. Full weigh bearing without restrictions is resumed depending 
upon the graft consolidation, defect healing, and the patency of the defect/extremity stabilization.  
The CTMC Technique (Arm II) for Segmental Defect Reconstruction   
Overall Concept and Rationale  
We have demonstrated the biological and biomechanical merits of the CTMC technique in the treatment of large 
segmental bone defects (Cobos 2000; Lindsey 2004). Compared to the Masquelet technique, the CTMC technique 
is a single-stage surgical procedure that immediately restores limb anatomy and alignment, and provides limb 
stability sufficient enough for early, unrestricted mobilization while permitting bone and soft tissue healing. 
Moreover, this reconstruction method pioneers the concept of a “bio-logic implant” (the highly synergistic 
combination of stabilizing implants cage/nail or cage/plate) with a biologically-active graft) (Gugala 2007).   
Description of the CTMC Technique  

 
 
14 
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The indications for the CTMC technique include any clinical setting of a segmental bone defect that warrants 
surgical reconstruction. The CTMC technique can be adapted to long bone segmental lesions in the diaphysis, 
metaphysis-diaphysis segments, or transarticular joint fusion. Prerequisites for the procedure are an aseptic wound 
with a healthy soft tissue envelope, adequate bone quality and anatomy that can accommodate either an IM nail 
or plate/screw fixation, and CTMC augmentation with bone graft or graft substitute. The CTMC technique is not 
only a viable alternative to all standard primary treatment modalities, but it can be used as a salvage procedure 
for any failed standard treatment modalities. The CTMC technique is particularly indicated for patients who 
cannot, for whatever reason, tolerate multiple surgical procedures.  
To ensure the suitability of the defect for reconstruction, the surrounding soft tissues are meticulously debrided 
to de-contaminate the wound. After an aseptic wound has been achieved, the length and diameter of the bone 
defect is determined, and a titanium mesh cage of appropriate size is selected. For diaphyseal defect 
reconstructions, the diameter of the mesh cage should be slightly larger than the adjacent cortex to allow the host 
bone to allow it to axially load the graft material contained within the mesh. Metaphyseal and transarticular 
reconstructions are achieved with the largest diameter cage that can be accommodated at the site. In these cases, 
the span of the cage should be equivalent to the length of the defect, as opposed to the diaphysis where the cage 
length should be 1-2 cm longer than the defect to allow for cage overlap with the host bone. The strength of the 
cage can be reinforced with rings placed along the inner perimeter of the implant and secured with screws.   
After a trial fit of the mesh in the defect confirms its adequate length, the mesh is tightly packed with bone graft. 
Two graft options are offered as per study protocol: autogenous RIA-harvested bone graft (Option A), or 
allogeneic cancellous bone graft from combined with DBM (Option B).  
In cases of IM nail fixation, prior to cage placement into the wound, a guide wire is inserted longitudinally through 
the middle of the packed cage, and the cage/allograft construct is sequentially reamed to a diameter which will 
ultimately permit the passage of an IM nail. The CTMC-graft construct is then positioned in the defect/wound, 
and, under image intensification, a guide wire is passed through the host bone medullary canal, across the cage-
graft, and seated at an appropriate distance within the distal bone fragment. Additional bone graft is placed along 
the periphery of the cage adjacent to muscles, and at the cage-host bone junction. Following wound closure, either 
direct or by soft tissue flap, the host bone/implanted CTMC-graft construct is reamed in situ. A titanium IM nail 
of adequate size and length is inserted in a standard fashion into the medullary canal and across the cage. The 
limb is manually compressed axially over the cage prior to statically interlocking the nail.  
In cases that are not stabilized with an IM nail, the cage is packed with bone graft, placed in the defect, and 
stabilized with a titanium locking plate and screws. The locking plate screws should achieve fixation in at least 
six cortices on each side of the defect. While applying the plate and screws, host bone compression is obtained 
across the graft within the cage. The plate should lie on the host bone cortex in a manner that it allows space for 
the cage that overrides the edges of the defect.  
Postoperative Course  
Immediately post CTMC defect reconstructive surgery, the subject is permitted to mobilize the operated limb as 
tolerated. In lower extremity defects, a CPM device can be applied until the patient can become ambulatory. Pain 
control is implemented as per routine. Standard physical therapy will be initiated at 2 days post defect 
reconstruction. No restrictions will be placed upon the mobilization and/or weight bearing of the operated limb. 
Weight bearing upon the reconstructed extremity is permitted as tolerated. The time needed to achieve full weight 
bearing post-surgery will be documented.  
Study Follow-up  

 
 
15 
Revised 26-Jan-2016 
Surgery and immediate postoperative care will be conducted at the UTMB affiliated hospitals as the study sites, 
while the postoperative care after hospital discharge can be performed in the hospital’s or UTMB outpatient 
clinics.   
Follow up care will be conducted through the PI’s (R.W.L.) practice at the intervals considered as routine. This 
routine follow-up is conducted at 2 weeks, 6 weeks, 3 months, 6 months, 12 months, and 18 months, with a plus 
or minus 5 day window for each visit. Additional unscheduled visits may be needed to evaluate healing and will 
be at the discretion of the PIs. These additional visits will be monitored by the research team to determine interval 
changes impacting protocol events, radiographic evidence of healing or failure and adverse events.  
  
DRUGS / DEVICES / IMPLANTS:   
Medications  
No specific medications related to the Masquelet or the CTMC defect reconstruction procedures will be used. The 
use of prophylactic or therapeutic medications (e.g., antibiotics, anticoagulants, etc.)  in the pre-, intra- or 
postoperative course of defect treatment will follow the standards of care for routine segmental bone defect 
management irrespective of the defect reconstructive technique.   
Metallic Implants as Components of the Defect Stabilization/Reconstruction  
It is imperative that all implants to be used for defect reconstruction/stabilization are made of titanium. Depending 
on the segmental defect location the following orthopaedic implants will be used for the Masquelet or the CTMC 
reconstruction surgery:  
• 
Intramedullary Nail for Defect Stabilization: All eligible IM nails should have the option for static 
interlocking. No preference will be given to any specific nail type or manufacturer providing that the IM 
nail is cleared by the FDA for clinical use. The IM nail application will be in accordance with its approved 
indications and the manufacturer’s recommended technique. These IM nails are part of a standard orthopedic 
surgery implant armamentarium.   
A) Humerus: Antegrade titanium statically-locked IM nail   
B) Tibia:       Antegrade titanium statically-locked IM nail   
C) Femur:     Antegrade titanium femoral statically-locked IM nail                   Cephalomedullary titanium 
statically-locked IM nail  
                 Retrograde titanium femoral statically-locked IM nail  
• 
Plate-Screw Construct for Defect Stabilization: Locking plate and screw should be used as a mode of defect 
stabilization for cases in which an IM nail is not suitable. The plate should be of adequate size (length, 
thickness, width) to span across the defect and permit screw fixation which engages at least six cortices on 
each side of the defects. If applied in combination with the CTMC technique, the plate should be positioned 
at least 5 mm away from the external boundaries of the cortex to permit placement of the cage overlapping 
the defect ends.  
• 
Cylindrical Titanium Mesh Cage for Defect Reconstruction: Presently there are two manufacturers of 
CTMCs available as surgical implants, and both CTMCs are cleared by the FDA for any osseous 

 
 
16 
Revised 26-Jan-2016 
reconstruction and/or reinforcement. The study will not designate the preferred cage; it will be left to the 
PIs’ discretion. There are two cage types amenable for the CTMC technique:  
A) Surgical Titanium MeshTM (Harm’s Cage; DePuy Motech, J&J, Warsaw, IN)   
B) Pyramesh Titanium MeshTM (Sofamor Danek-Medtronic, Memphis, TN)   
Allograft Component (Option B) for the Defect Reconstruction  
The following allograft bone graft from a tissue bank will be used in the study:  
• 
Commercially-available, freeze-dried cancellous bone croutons approved for clinical application will be 
used. The Allograft (tissue) tracking number will be recorded. No preference will be given to the allograft 
provider on condition that it is in compliance with regulations and guidelines established by the FDA and 
the American Association of Tissue Banks. The intraoperative allograft handling and its application will 
strictly follow the provider’s recommendations. The volume of the cancellous croutons should be sufficient 
to pack the cage.  
• 
Demineralized bone matrix (DBM; Grafton PuttyTM; Osteotech®, Eatontown, NJ, USA) is allogeneic bone 
extract without bone mineral component. DBM demonstrates inherent osteoinductive properties, ie it 
induces de novo bone formation. DBM putty will be used in the study consistently. To eliminate inherent 
differences in osteoinductive properties that may occur between DBMs supplied by various vendors, in the 
trial consistently DBM putty supplied by Osteotech will be used Grafton PuttyTM has gained FDA 
clearance/exempt for clinical use and it will be applied in full compliance and following the guidelines of 
the American Association of Tissue Banks. Grafton putty has well documented osteoinductive properties 
and it is the only DBM currently available on the market with clinical efficacy assessed and validated in a 
prospective clinical trial (Lindsey 2006). DBM putty will be uniformly mixed with allograft croutons in a 
ratio of approximately 1-to-3. The cancellous croutons-DBM composite will be used as the graft Option B 
to pack either the space within the biomembrane in the Masquelet technique or the cage in the CTMC 
technique.  
  
  
 
 
 
 
 

 
 
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Study-Specific Procedure Algorithm 

 
 
18 
Revised 26-Jan-2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
19 
Revised 26-Jan-2016 
 
Pre-, Intra-, and Post-operative Data Collection  
 
  
  
DATA MANAGEMENT:  
Methods of Data Collection  
A study specific Case Report Form (CRF) will be designed in accordance to the following principles:  
• 
has unique coded subject study identifier (ID);   
• 
is consistent with the study protocol;  
• 
gathers study data accurately and reliably;  
• 
organizes and labels forms and fields to permit intuitive data entry;  
• 
has error- and/or omission-proof design;  
• 
avoids redundancy;  
• 
facilitates data entry into the study database.  
All data collected in the study will be stored in both printed (hard) and electronic (soft) formats. Customized data 
collection forms (source documents) will be used to ensure the consistency and thoroughness or the data 
acquisition process. The PIs will periodically review the data for its completeness and accuracy. Subject identifiers 
 
 
 
 
 

 
 
20 
Revised 26-Jan-2016 
will be removed from study data collection forms, and the subject will be assigned a specific study ID code with 
a consecutive number. Critical measurements on data collection forms will be bolded.  
Identifiers  
The enrolled subjects will be given a study ID code according to the following coding system:  
code:     TRIAL-XX-MM/YY;  
   where:     
  
    
XX – the consecutive study subject number   
    
MM/YY – date of the enrollment (month/year)  
A list (key) of these codes assigned to the specific subjects’ names will be kept secure by the PIs.    
Confidentiality  
Study records and all information that can identify the subject will be kept confidential as per the federal privacy 
regulations provided under the Health Insurance Portability and Accountability Act (HIPAA) to protect the 
privacy, security, and authorized access of patient records. Following HIPAA regulations subject authorization is 
obtained in the signed informed consent for the use and disclosure of subject’s health information but only for the 
purpose of completing this clinical study. Except when required by law, the subject will not be identified by name, 
social security number, address, telephone number, or any other direct personal identifier in study records 
disclosed outside of study center (UTMB). For all records and information disclosed outside of the UTMB, the 
subject will be assigned a specific study ID code number. The key to the code will be kept in a locked file in PI’s 
(Z.G.) office.    
UTMB institutional policy and guidelines mandate that all study PIs and all members of the research team 
successfully complete HIPAA and CITI Basic Course and Health Information Privacy & Security (HIPS) Training 
for Clinical Investigators.  
All data collected in the study will be stored in a secured location. Data in an electronic format will be stored in a 
PC and backed up daily. The backup tape will be kept in a fireproof safe with a biometric lock. The access to the 
computer with the stored study data will be password controlled (128-bit encryption algorithm). Hard copies of 
the study data will be stored in binders dedicated for each study subject; these will be kept in a locked clinical 
research office with limited access of only approve study personnel.   
The study data will be kept for a minimum of 10 years after the study completion/termination in accordance with 
the International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and in 
accordance with all local laws (UTMB) for retention of study records.  
  
SCREENING PROCEDURES:   
All medical and surgical care will be conducted in accordance with accepted healthcare standards. If the subject 
is female of child-bearing age, and has not undergone a sterilization procedure, a serum pregnancy test will be 
required in order to rule out pregnancy. Female subjects with child-bearing potential will be advised to refrain 
from becoming pregnant while in the study. A urine and serum pregnancy test will be done at time of enrollment 
and again prior to surgery, respectively.   
Patients presenting to the UTMB hospital will undergo standard general medical and orthopedic examinations 
and routine biplanar plain radiography as a screening for presence of segmental bone defect or a medical condition 
(infection, nonunion, tumor) treatable by iatrogenic segmental bone resection. Specific routine laboratory workup 

 
 
21 
Revised 26-Jan-2016 
(blood test, microbiology, biopsy, etc) will be performed to diagnose the patient’s specific medical condition, and 
their eligibility for the iatrogenic segmental bone resection as a suitable treatment. Informed consent will be 
obtained prior to initiation of any screening procedures for the purpose of determining study eligibility.   
All subjects will undergo routine preoperative laboratory testing for surgery screening (standard of care). These 
laboratory studies will include complete blood cell count with differential; basic metabolic profile; 
electrocardiogram for subjects greater than or equal to age 50. Additional standard of care studies may be ordered 
depending on the subject’s underlying medical condition and specific anesthesiologist’s clearance for surgery 
protocol will be required.   
  
RISKS / BENEFITS ASSESSMENT:  
Foreseeable Risks  
Segmental bone defect represents a formidable treatment challenge. The complexity of this condition often results 
in many complications associated with all currently available treatment options. All these treatment modalities 
for segmental bone defects are considered high risk, and therefore, are frequently applied as limb salvage 
operations. Because of the high inherent risks and complications, all currently available segmental bone defect 
treatment procedures carry the ultimate risk of limb amputation.    
The potential specific risks for the subject participating in the study may be related to:  
• 
Cement Spacer: The potential side effects associated with using the cement space include pain excessive 
scarring, and dislodgment.  
• 
Cage:  The potential side effects associated with using the CTMC for bone defect reconstruction include 
local infection, inflammation, cage dislodgment (change of its initial position), and pain.  
• 
Bone Graft:  The potential side effects associated with using bone graft or bone graft substitute are the 
same as in all existing surgical procedures associated with bone grafting and may include:  
A) RIA-harvested autograft (Option A):  harvesting site infection, pain, and fracture;  
B) allograft-DBM (Option B):  local infection and/or inflammation about the defect, delayed or minimal 
healing of the defect;  
• 
Radiation from imaging studies: The amount of radiation to which the subject will be exposed throughout 
the study to monitor the defect healing is relatively small and not different from the standard follow-up 
radiation for all other techniques currently applied for bone defect reconstruction. This amount of radiation 
may be potentially harmful, but these risks are so small that they are difficult to measure.  
• 
Confidentiality:  Participation in the research study is confidential although it may involve some loss of 
privacy. Subject study research records will be handled as confidentially as possible within the law, and 
the researchers will follow all federal and institutional regulations. In order to verify the study data, 
independent research individuals from the sponsoring agency (the Department of Defense) or the FDA may 
access study records. No information that could specifically identify the subject will be used in any reports 
or publications resulting from this study.  
Risk Management and Emergency Response  

 
 
22 
Revised 26-Jan-2016 
Routine measures (standard of care) will be taken to minimize and/or eliminate risks to the study subjects. These 
risks will be monitored and mitigated in accordance to the subject’s medical condition and the pre- and post-
reconstruction medical interventions. Subjects will be routinely followed in the post defect reconstruction and 
beyond the study designated time points, if necessary (in case of ongoing adverse events or pregnancy).   
As per a study inclusion criterion, eligible female patients must have a negative serum pregnancy test to be 
enrolled into the study. Female subjects enrolled in the study will be encouraged not to get pregnant throughout 
the entire study period (ie, 18 months). If subject pregnancy occurs, it will be documented. The subject will be 
advised to notify her obstetrical physician. If the resulting birth is abnormal, the abnormality will be reported as 
an adverse event.  
If the subject sustains physical injury or contracts a disease because of any substance given or procedure 
performed due to participation in this study their injury will be treated.  The subject’s medical insurance will be 
billed and any charges not covered by the subject’s insurance or health care program will be the subject’s 
responsibility. In addition, the subject will be responsible for paying any costs related to illnesses and medical 
events that are not associated with participating in the study.  
ADVERSE EVENTS:   
The PIs and the members of the study research team are responsible for the detection and documentation of events 
defined as an adverse event (AE). The investigators are also responsible for appropriate documenting and 
reporting of all AEs.   
AE monitoring will be conducted at all follow-up intervals (including also those intervals not mandated by the 
protocol).  
AE is defined as any adverse event, whether or not that event is felt to be related, occurring at the time of study. 
AEs will be treated in accordance with accepted medical standards and documented in the subject’s study record 
and monitored by the PIs and research team. AEs will be reported to the UTMB IRB and to the US Army Medical 
Research and Materiel Command’s Office of Research Protections, Human Research Protections Office (HRPO).  
All AEs will be assessed to determine the following:  
A) whether event meets the criteria for an AE;  
B) the relationship to study treatment;  
C) the severity of the event;  
D) the “expectedness” of the event.  
All recorded AEs will include the following information:  
A) specific condition or event;  
B) dates and times of occurrence;  
C) severity;  
D) treatment and outcome.  
AE Rating  
AEs will be rated for severity/intensity according to the following criteria:  
• 
Mild: easily tolerated, causing minimal discomfort and not interfering with normal everyday activities;  

 
 
23 
Revised 26-Jan-2016 
• 
Moderate: sufficiently discomforting to interfere with normal everyday activities (the subject is able to 
continue in the study; treatment for symptoms may be needed);  
• 
Severe: incapacitating and/or preventing normal everyday activities (severity may cause cessation of the 
study, treatment for symptoms is needed).  
• 
Life-Threatening or Disabling  
• 
Lethal  
AE Relation to the Study Treatment  
The following definitions will be considered in assessing the relationship of AEs to the study treatment:  
• 
Not related:  the event is clearly related to other factors such as the subject’s clinical state, other therapeutic 
interventions, or concomitant medications administered to the subject;  
• 
Unlikely:  any event that does not follow a reasonable temporal sequence from administration of study 
treatment  or that is likely produced by other factors such as the subject’s clinical state, other therapeutic 
interventions, or concomitant medications administered to the subject;  
• 
Possible:  the event follows a reasonable temporal sequence from administration of study treatment or that 
follows a known response pattern to the study treatment, but could have been produced by other factors 
such as the subject’s clinical state, other therapeutic interventions, or concomitant medications 
administered to the subject;  
• 
Probable:  the event follows a reasonable temporal sequence from administration of study treatment; and 
cannot be reasonably explained by other factors such as the subject’s clinical state, other therapeutic 
interventions, or concomitant medications administered to the subject;  
• 
Related:  the event follows a reasonable temporal sequence from the time of study treatment; and cannot 
be reasonably explained by other factors such as the subject’s clinical state, other therapeutic interventions, 
or concomitant medications administered to the subject.  
AE and Pre-existing Conditions  
The occurrence of a sign or symptom of a pre-existing condition during the study is not an AE, unless the condition 
worsened in either intensity or frequency. Pre-existing conditions are those illnesses, abnormalities, or problems 
that were part of the patient’s medical history prior to the baseline visit and all of these conditions will be recorded.   
AE Reporting  
All unanticipated problems involving risk to study subjects or others, AEs related to participation in the study, 
and all subject deaths related to participation in the study will be promptly reported by phone, email, or by fax to 
the UTMB IRB and the US Army Medical Research and Materiel Command’s Office of Research  
Protections, Human Research Protections Office. A complete written report will follow the initial notification.   
Potential Study Benefits  
There is no direct benefit to the subject for participation in this study.   
Society Study Benefits  

 
 
24 
Revised 26-Jan-2016 
It is hoped that the information gained from the study will help in the treatment of future patients with segmental 
bone defects.  
  
IRB GUIDELINES - DATA AND SAFETY MONITORING PLAN TEMPLATE  
Federal regulations require the IRB to determine that research plans submitted provide adequate provisions for monitoring 
data collected in order to ensure the safety of subjects.  Monitoring should be commensurate with risks and with the size 
and complexity of the trials.  Phase III clinical trials generally require a data and safety monitoring board.  Investigators 
involved in Phase I and II clinical trials must submit a general description of the data and safety monitoring plan as part of 
the research application and as part of the protocol submission to the IRB.  The following template is provided for 
UMASS investigators as a guide to developing a data and safety monitoring plan.  
I. Protocol Title:  The Comparative Efficacy of the Masquelet versus Titanium Mesh Cage Reconstruction Techniques 
for the Treatment of Large Long Bone Deficiencies  
II. Oversight of this Investigation will be provided by the study PI:  Zbigniew Gugala, MD,PhD; Department of  
Orthopaedic Surgery; University of Texas Medical Branch, Galveston, TX; Phone: 409-747-5760; Fax: 409-747-5747;  
Email: zgugala@utmb.edu; and  the study co-PI: Ronald W. Lindsey, MD; Department of Orthopaedic Surgery; 
University of Texas Medical Branch, Galveston, TX; Phone: 409-747-5700; Fax: 409-747-5747; Email: 
rlindsey@utmb.edu  
III. Purpose of the Study:  
Background: Segmental long bone defects remain a formidable treatment challenge. All the existing standard treatment 
options have major limitations and often culminate in limb amputation or permanent functional deficits. We developed a 
novel, one-stage alternative treatment for segmental bone loss that utilizes the cylindrical titanium mesh cage (CTMC) in 
combination with bone graft, and have established its clinical merits in an initial clinical series. Shortly thereafter, 
Masquelet reported another new defect reconstruction technique that involves two-stage approach: first inducing 
biomembrane formation with a cement spacer, and subsequent spacer removal and bone grafting. Both the Masquelet and 
the CTMC techniques are based on the principle of graft containment to render optimal potential for graft to heal the 
defect; however, they differ in primary biological versus biomechanical functions provided by the containment. The 
Masquelet biomembrane containment, being a rich source of vascular supply and growth factors, creates an excellent 
biological milieu for graft, but requires an additional surgery and is associated with prolonged protected weight bearing 
until graft consolidation occurs. Conversely, the benefit of the CTMC technique is primarily the biomechanical support it 
provides for graft and the reconstructed extremity, thereby permitting immediate functional restoration without mobility or 
weight bearing restrictions during the bone healing process. Although both Masquelet and the CTMC techniques have 
been effective in the treatment of large segmental bone defects, there is no prospective, well-controlled study comparing 
their therapeutic efficacies for specific clinical indications.  
Overall objective: Determining the clinical efficacy and cost-effectiveness of the Masquelet (Arm I) versus the CTMC 
technique (Arm II) in combination with RIA-harvested autograft (Option A) or allograft-demineralized bone matrix 
composite (Option B) in the treatment of segmental long bone deficiencies.  
Specific Aims: 1) Establish the effects of the specific patient and bone defect characteristics on the treatment outcome; 2) 
Determine and compare clinical efficacies of the reconstruction techniques (Arm I vs Arm II); 3) Establish the merits of 
using specific graft type (Option A vs Option B) within and across each study arms; 3) Develop a quantitative predictive 
model to improve clinical decision making, and 4) Assess and compare the cost-effectiveness and resource expenditures 
incurred by the specific treatment selection.  

 
 
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Study Design: Single-center, two-arm, randomized clinical trial. Thirty patients with segmental bone deficiency as a result 
of trauma, gunshot, iatrogenic resection due to infection, nonunion, or neoplasm will be enrolled and randomized to 
receive either the Masquelet (Arm I) or the CTMC as definitive defect treatment (Arm II). Bone graft selection will 
include either RIA-harvested autograft (Option A) or allograft croutons-DBM composite (Option B). Patients will be 
followed up to18 months. The data collected will include routine patient baseline information, systemic and extremity 
injury characteristics, bone defect characteristics, pre- and post-operative clinical examinations and imaging, validated 
functional outcomes measures, and associated cost expenditure. Descriptive statistics will be used to analyze and compare 
the results specifically related to the rate of defect healing and functional recovery. Paired t-test will be used to test the 
effects of the defect reconstruction option on the outcome measures. Analysis of covariance will be used for pair-wise 
comparison between the arms and within/across each bone graft option. Multiple models will be used to produce an 
accurate predictive model which accounts for possible morbidities and interactions. Derived from the joint distribution of 
costs and effects, cost-effectiveness acceptability curves will be established and compared for the study arms.  
Civilian/Military Relevance: Many combat injuries involve extremity trauma with segmental bone loss, and the extent to 
which they can be successfully treated impacts the function and quality of life of the wounded warrior. The Masquelet and 
the CTMC have been developed for civilians in the civilian clinical setting as innovative, biologically-sound defect 
reconstructive techniques to address the complexity of therapeutic concerns associated with these conditions (ie, 
immediate restoration of limb alignment/stability, early motion, weight bearing). The proposed trial aims to compare the 
efficacy of these techniques to identify the one that can be instantly adopted and applied by military surgeons.  
IV. Assessment of Level of Risk  
There is minimal risk associated with the participation in the study. Both treatment options (clinical trial arms), the 
Masquelet and the CTMC technique are approved by the FDA are considered as the standard of care for the treatment of 
segmental bone loss. The research component of the study incudes the randomization to one of the two the study arm, 
collecting the routine medical record and medical chart data, and completing subjective outcome questionnaires. The PI 
and co-PI will monitor for potential adverse events (AEs) that may occur in the study and will notify the UTMB IRB 
immediately if these occur. The questionnaires applicable in the trails will pertain solely to subject’s subjective outcome 
and will not pose harm or discomfort for study subjects.   
Routine measures (standard of care) will be taken to minimize and/or eliminate risks to the study subjects. These risks will 
be monitored and mitigated in accordance to the subject’s medical condition and the pre- and post-reconstruction medical 
interventions. Subjects will be routinely followed in the post defect reconstruction and beyond the study designated time 
points, if necessary (in case of ongoing adverse events or pregnancy).   
As per a study inclusion criterion, eligible female patients must have a negative urine pregnancy test to be enrolled into the 
study, and serum pregnancy test prior to the surgery (standard of care). Female subjects enrolled in the study will be 
encouraged not to get pregnant throughout the entire study period (ie, 18 months). If subject pregnancy occurs, it will be 
documented. The subject will be advised to notify her obstetrical physician. If the resulting birth is abnormal, the 
abnormality will be reported as an adverse event.  
If the subject sustains physical injury or contracts a disease because of any substance given or procedure performed due to 
participation in this study their injury will be treated.  The subject’s medical insurance will be billed and any charges not 
covered by the subject’s insurance or health care program will be the subject’s responsibility. In addition, the subject will 
be responsible for paying any costs related to illnesses and medical events that are not associated with participating in the 
study.  
  
V. Plan for Monitoring Safety/Confidentiality   

 
 
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The PI and co-PI (as listed above) will be responsible for monitoring the safety environment of the participants.  
  
Conditions that would necessitate termination of the subject participation in the study after the subject has been enrolled 
and/or reach study end point include:  
• intraoperative determination of need for surgical procedure outside the study scope or protocol;  
• identifying any valid exclusion criterion after the subject’s enrollment;  
• secondary procedure disrupting or preventing implementation of either the Masquelet or the CTMC defect 
reconstruction technique as in the study protocol;  
• evidence of infection or neoplasm recurrence post defect reconstruction;  
• evidence of vascular compromise in the affected extremity resulting in secondary intervention affecting healing; •  
subject declines continued participation;  
• subject is non-compliant with follow up care and instructions;  
• termination for any reason deemed mandatory by the PIs;  
• defect is completely healed before the end of the follow-up (ie, 24 months); •  subject becomes pregnant before the 
defect reconstructive surgery;  
• subject completes the study.  
  
The PIs will be study medical monitor and they will ensure that:  
• only subjects who meet the study eligibility criteria are enrolled.  
• the informed consent process will be conducted appropriately and that informed consent will be obtained prior to 
proceeding with any study procedures. (any problems with the obtaining the informed consent .  
• data will be collected and analyzed strictly as designated in the protocol.  
• adverse events (AEs) will be reviewed promptly and reported as required (see Section VII below).  
  
Study records and all information that can identify the subject will be kept confidential as per the federal privacy 
regulations provided under the Health Insurance Portability and Accountability Act (HIPAA) to protect the privacy, 
security, and authorized access of patient records. Following HIPAA regulations subject authorization is obtained in the 
signed informed consent for the use and disclosure of subject’s health information but only for the purpose of completing 
this clinical study. Except when required by law, the subject will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier in study records disclosed outside of study center 
(UTMB). For all records and information disclosed outside of the UTMB, the subject will be assigned a specific study ID 
code number. The key to the code will be kept in a locked file in PI’s (Z.G.) office.   
  
VI. Plan for Data Management   
PI (Z.G.) and the study coordinator will responsible for collection and storage of data.  
A study specific Case Report Form (CRF) will be designed in accordance to the following principles:  
• has unique coded subject study identifier (ID);   
• is consistent with the study protocol;  
• gathers study data accurately and reliably;  
• organizes and labels forms and fields to permit intuitive data entry;  
• has error- and/or omission-proof design;  

 
 
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• avoids redundancy;  
• facilitates data entry into the study database.  
All data collected in the study will be stored in both printed (hard) and electronic (soft) formats. Customized data 
collection forms (source documents) will be used to ensure the consistency and thoroughness or the data acquisition 
process. The PIs will periodically review the data for its completeness and accuracy. Subject identifiers will be removed 
from study data collection forms, and the subject will be assigned a specific study ID code with a consecutive number. 
Critical measurements on data collection forms will be bolded.  
  
Identifiers: The enrolled subjects will be given a study ID code according to the following coding system: code:     
TRIAL-XX-MM/YY;     where:     
  
  
  
                 XX – the consecutive study subject number   
    
                                            MM/YY – date of the enrollment (month/year)  
A list (key) of these codes assigned to the specific subjects’ names will be kept secure by the PIs.    
  
All data collected in the study will be stored in a secured location. Data in an electronic format will be stored in a PC and 
backed up daily. The backup tape will be kept in a fireproof safe with a biometric lock. The access to the computer with the 
stored study data will be password controlled (128-bit encryption algorithm). Hard copies of the study data will be stored in 
binders dedicated for each study subject; these will be kept in a locked clinical research office with limited access of only 
approve study personnel.   
The study data will be kept for a minimum of 10 years after the study completion/termination in accordance with the 
International Conference on Harmonisation (ICH) guidelines for Good Clinical Practice (GCP) and in accordance with 
UTMB laws for retention of study records.  
VII. Adverse Event (AE)  
The PIs and the members of the study research team are responsible for the detection and documentation of events defined 
as an adverse event (AE). The investigators are also responsible for appropriate documenting and reporting of all AEs.   
AE monitoring will be conducted at all follow-up intervals (including also those intervals not mandated by the protocol).  
AE is defined as any adverse event, whether or not that event is felt to be study related, occurring at the time of study. AEs 
will be treated in accordance with accepted medical standards and documented in the subject’s study record. AEs will be 
reported to the UTMB IRB and to the US Army Medical Research and Materiel Command’s Office of Research Protections, 
Human Research Protections Office (HRPO).  
All AEs will be assessed to determine the following:  
• whether event meets the criteria for an AE;  
• the relationship to study treatment;  
• the severity of the event;  
• the “expectedness” of the event.  
All recorded AEs will include the following information:  
• specific condition or event;  
• dates and times of occurrence;  
• severity;  
• treatment and outcome.  
AE Rating: AEs will be rated for severity/intensity according to the following criteria:  
• Mild: easily tolerated, causing minimal discomfort and not interfering with normal everyday activities;  

 
 
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• Moderate: sufficiently discomforting to interfere with normal everyday activities (the subject is able to continue in the 
study; treatment for symptoms may be needed);  
• Severe: incapacitating and/or preventing normal everyday activities (severity may cause cessation of the study, 
treatment for symptoms is needed).  
• Life-Threatening or disabling.  
• Lethal  
AE Relation to the Study Treatment: The following definitions will be considered in assessing the relationship of AEs to 
the study treatment:  
• Not related:  the event is clearly related to other factors such as the subject’s clinical state, other therapeutic 
interventions, or concomitant medications administered to the subject;  
• Unlikely:  any event that does not follow a reasonable temporal sequence from administration of study treatment  or 
that is likely produced by other factors such as the subject’s clinical state, other therapeutic interventions, or 
concomitant medications administered to the subject;  
• Possible:  the event follows a reasonable temporal sequence from administration of study treatment or that follows a 
known response pattern to the study treatment, but could have been produced by other factors such as the subject’s 
clinical state, other therapeutic interventions, or concomitant medications administered to the subject;  
• Probable:  the event follows a reasonable temporal sequence from administration of study treatment; and cannot be 
reasonably explained by other factors such as the subject’s clinical state, other therapeutic interventions, or 
concomitant medications administered to the subject;  
• Related:  the event follows a reasonable temporal sequence from the time of study treatment; and cannot be 
reasonably explained by other factors such as the subject’s clinical state, other therapeutic interventions, or 
concomitant medications administered to the subject.  
AE and Pre-existing Conditions: The occurrence of a sign or symptom of a pre-existing condition during the study is not an 
AE, unless the condition worsened in either intensity or frequency. Pre-existing conditions are those illnesses, abnormalities, 
or problems that were part of the patient’s medical history prior to the baseline visit and all of these conditions will be 
recorded.   
AE Reporting: All unanticipated problems involving risk to study subjects or others, SAEs related to participation in the 
study, and all subject deaths related to participation in the study will be promptly reported to the UTMB IRB by phone, 
email, or by fax. A complete written report will follow the initial notification. In addition to the methods above, the complete 
report will be sent to the US Army Medical Research and Materiel Command, ATTN: MCMRZB-P, 504 Scott Street, Fort 
Detrick, Maryland 21702-5012.  
VIII. Protection of Human Research Participants-Computer Based Training  
As per the UTMB institutional policy and guidelines, the study PIs and all members of the research team will successfully 
complete HIPAA and CITI Basic Course and Health Information Privacy & Security (HIPS) Training for Clinical 
Investigators.  
The University of Massachusetts Amherst Institutional Review Board will approve this plan, with the project protocol, 
prior to implementation of the study.  
STUDY TIME FRAME:  
With a proposed study duration of 4 years, the timeline for allocating research efforts and expected objective 
accomplishments is as follows:  

 
 
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1. Preparatory period (0-6 months)  
This period encompasses the time from grant notification to study initiation (approximately 6 months). During 
this period the following task wills be accomplished:  
• Obtain UTMB Institutional Review Board (IRB) approval for the study (timeframe 1-3 months);  
• Finalize all necessary research agreements with the study’s participating hospital sites;  
• Construction of study specific Case Report Form (CRF);  
• Design of study database to capture and  process all collected study variables; Milestone #1: IRB approval  
  
  
2. Study Enrollment Period (32 months)  
This period encompasses the timeframe of the first 32 months from study initiation. This period’s primary 
objective is to successfully enroll 30 eligible patients in the study. In case of slow accrual, specific measures 
(enhanced referral program, study advertisement, etc) will be taken. During this period the following study tasks 
are expected to be accomplished:  
• 
Continuing enrollment of the eligible patients as study subjects;  
• 
Preoperative (baseline) subject data collection;  
• 
Preoperative patient management;  
• 
Perform the Masquelet or the CTMC defect reconstruction surgery;  
• 
Intraoperative data collection;   
• 
Immediate and early postoperative data collection  
Milestone #2: Enrollment of 30 eligible patients  
Milestone #3: The Masquelet or CTMC defect reconstructive surgery  
The recorded preoperative study variables will permit realization of the following study objectives:  
• 
Determine the perioperative safety and efficacy of the Masquelet versus the CTMC defect reconstructive 
technique;  
• 
Identify the specific indications for performing the Masquelet versus the CTMC technique among the 
enrolled subjects;  
• 
Provide a thorough characterization of the patient population that presents with segmental bone defects that 
warrant surgical reconstruction (specific aim 1);  
• 
Establish defect characteristics among the study subjects treated with the Masquelet versus the CTMC 
procedure (part of specific aim 2);  
• 
Collect and analyze the distribution of patients within specific study arms (Option A vs Option B) (part of 
specific aim 3);  
• 
Establish the cost or preoperative and surgical management of the study subjects;  
• 
Provide an analysis of patients with segmental bone deficiency who did not meet study eligibility criteria; 
 Establish the extent of patient compliance with immediate and early postoperative regimen.  
  

 
 
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3. Study Follow-up Period (18 months)  
This period encompasses the timeframe of the last 18 months, i.e. from termination of enrollment to study 
completion. This period’s primary objective is to successfully complete follow-up of all enrolled patients. During 
this period the following study tasks are expected to be accomplished:  
• 
Continuing postoperative data collection;  
• 
Analysis of data collection process (consistency, redundancy, dropout rate);  
• 
Tentative statistical analysis of the collected data;  
• 
Establish costs of subject follow-up incurred;  
• 
Itemize all resource expenditure for total treatment costs assessment.  
Milestone #4: Follow-up completion of 30 study subjects  
  
4. Study Post Completion Period (2-4 months)  
This period encompasses the timeframe after the study has been terminated. The research efforts in this period 
include:  
• 
Thorough analysis of all pre-, intra-, and postoperative variables collected in the study to accomplish the 
specific study aims 2, 3 and 4.   
• 
Assessment of the safety and efficacy of the CTMC defect reconstructive technique   
• 
Establishing the clinical indications and treatment recommendation for CTMC the based upon the treatment 
outcome;  
• 
Assessment of the total resource expenditure related to the CTMC reconstruction technique (in accordance 
with the graft option type) and comparison with the standard defect reconstruction modalities (study 
specific aim 5);   
• 
Data presentation at international/national research meetings.   
• 
Manuscript preparation and submission to a high-impact-factor peer-reviewed journal.   
Milestone #5: Data presentation in research forums  
Milestone #6: Manuscript publication