A Prospective, Single Arm Study of Patients Undergoing Posterolateral Lumbar Fusion (Without Interbody) Supplemented With ViviGen Cellular Bone Matrix
Phase: NA
Conditions: Degenerative Disc Disease, Spinal Stenosis, Spondylosis, Spondylolisthesis
Sponsor: Ohio State University

 
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19 July 2021 
 
 
 
 
 
 
 
 
 
 
A Prospective, Single Arm Study of Patients Undergoing 
Posterolateral Lumbar Fusion (without Interbody) 
Supplemented with ViviGen Cellular Bone Matrix 
 
NCT04007094 
 
July 19, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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19 July 2021 
 
 
 
 
 
TABLE OF CONTENTS 
1  
INVESTIGATIONAL PLAN .......................................................................................... 3 
1.1  
Purpose ............................................................................................................................... 3 
2  
INTRODUCTION ............................................................................................................ 3 
2.1  
Background ........................................................................................................................ 3 
2.2  
Device Description ............................................................................................................. 4 
2.2.1  ViviGen .............................................................................................................................. 4 
3  
TRIAL DESIGN ............................................................................................................... 5 
3.1  
Design ................................................................................................................................. 5 
3.2  
Inclusion Criteria ................................................................................................................ 5 
3.3  
Exclusion Criteria ............................................................................................................... 5 
4  
STUDY PROCEDURE .................................................................................................... 6 
4.1  
Screening Assessments ....................................................................................................... 7 
4.1.1  Informed Consent ............................................................................................................. 7 
4.1.2  Medical History and Demographic Data ........................................................................ 7 
4.1.3  Clinical Assessments ......................................................................................................... 7 
4.2 
Surgical Procedure ............................................................................................................. 8 
4.3 
Schedule of Events ............................................................................................................. 9 
4.4 
Follow-Up Assessments ..................................................................................................... 9 
4.5 
Fusion Determination ....................................................................................................... 10 
4.6  
Success Criteria ................................................................................................................ 10 
4.6.1  Primary Objective .......................................................................................................... 10 
4.6.2 
Secondary Objectives ..................................................................................................... 10 
4.7  
Subject Withdrawal .......................................................................................................... 10 
5  
STATISTICAL ANALYSIS PLAN .............................................................................. 11 
6  
REFERENCES ............................................................................................................... 11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1  
INVESTIGATIONAL PLAN 
 
1.1  
Purpose 
 
The purpose of this prospective study is to assess clinical and radiographic outcomes in 
patients who are to undergo Posterolateral Lumbar Fusion (PLF) procedures without 
interbody using ViviGen Cellular Bone Matrix, with pedicle screw instrumentation cleared 
for spinal fusion. 
 
2  
INTRODUCTION 
 
2.1  
Background 
 
In 2012, over 727,000 spinal fusion and non-fusion procedures were performed in the US.1 
This included treatment for various conditions such as DDD, spinal stenosis, spondylosis, 
spinal deformities, tumors, and traumatic spinal injuries. Over time, intervertebral discs 
wear down and lose water and then disc height. The degeneration of these discs can impact 
the spine in several ways, including spinal canal stenosis, spondylolisthesis, and osteophyte 
formation. These changes can impinge on the nerve roots, causing chronic pain. 
Consequently, as the population of elderly in the US expands, demand for treatments that 
address back pain will rise accordingly. The correlation between age and the incidence of 
DDD has been well-documented; for example, one study concluded that there was a direct 
relationship between age and the grade of degeneration caused by DDD.2 Increasing rates 
of obesity in the US will also contribute to growth in spinal fusion and non-fusion volumes 
because obesity represents a risk factor for DDD.3  
 
The premise behind fusion surgery for lower back pain (LBP) is that a degenerated and 
mobile lumbar segment acts as a pain generator. Consequently, if motion is prohibited 
through a fusion, it is expected that the patient will experience improvement in both pain 
and disability which will increase their ability to function. Currently, there is no way to be 
certain which structure or structures actually are causing the pain, but the main interest has 
been focused on the facet joints, the disc, or a combination of both.4 
 
Lumbar spine fusion rates can vary according to the surgical technique.  Although many 
studies on spinal fusion have been conducted and reported, the heterogeneity of the study 
designs and data handling make it difficult to identify which approach yields the highest 
fusion rate. Traditional posterolateral intertransverse fusion (PLF) still remains a good 
procedure with acceptable fusion rates for most degenerative conditions. For solid fusion, 
PLF can be combined with interbody fusion to circumferentially stabilize the relevant 
segment, even though it is unclear whether this improves fusion rates.5  
 
A bone graft or bone graft substitute is required to produce the fusion and can be implanted 
on its own, in the posterolateral gutters, or contained with an interbody device using either 
a posterior or anterior approach. Spinal laminectomy is most often the largest generator of 
bone graft product due to the nature of the procedure. The current gold standard is autograft 
bone, in which tissue is harvested locally or from the iliac crest and is then placed at the 

 
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site. However, local bone graft may be relatively limited and harvesting at the iliac crest 
can easily lead to significant morbidity [6-9].  Complications such as inflammation, 
infection, and chronic pain may outlast the pain of the original surgical procedure.10  
 
Autograft is the gold standard because it possesses all of the characteristics necessary for 
new bone growth—namely, osteoconductivity, osteogenicity, and osteoinductivity. 
Allograft tissues are alternatives to autografts and are taken from donors or cadavers, 
circumventing some of the shortcomings of autografts by eliminating donor-site morbidity 
and issues of limited supply.10 Osteoconductivity refers to the situation in which the graft 
supports the attachment of new osteoblasts and osteoprogenitor cells, providing an 
interconnected structure through which new cells can migrate and new vessels can form.  
Osteogenicity refers to the situation when the osteoblasts that are at the site of new bone 
formation are able to produce minerals to calcify the collagen matrix that forms the 
substrate for new bone. Osteoinductivity refers to the ability of a graft to induce 
nondifferentiated stem cells or osteoprogenitor cells to differentiate into osteoblasts.10 
Using the 2 basic criteria of a successful graft, osteoconduction and osteoinduction, 
investigators have developed several alternatives, some of which are available for clinical 
use and others of which are still in the developmental stage. Many of these alternatives use 
a variety of materials, including natural and synthetic polymers, ceramics, and composites, 
whereas others have incorporated factor- and cell-based strategies that are used either alone 
or in combination with other materials.10  
 
2.2  
Device Description 
All subjects enrolled in this study will be implanted with ViviGen Cellular bone matrix in 
the posterolateral gutters along with a pedicle screw system cleared for lumbar fusion. 
2.2.1  ViviGen  
ViviGen is a Human Cells, Tissues, and Cellular and Tissue-based Product (HCT/P) as 
defined by the U.S. FDA in 21 CFR 1271.3(d). ViviGen meets the criteria set out in 21 
CFR 1271.10 for regulation solely under section 361 of the Public Health Service Act. In 
Canada, ViviGen and the allograft spacers are Human Cells, Tissue and Organs (CTO) 
products per SOR/2007-118. ViviGen is processed by LifeNet Health and is available 
through DePuy Synthes Spine as a formulation of cryopreserved, viable, cortical 
cancellous bone matrix, and demineralized bone. 
 
ViviGen is osteogenic, osteoinductive, and osteoconductive. It contains viable lineage 
committed bone cells that are able to proliferate post thawing. Demineralization of the 
cortical bone component exposes the natural growth factors within the bone matrix. 
ViviGen contains cortico-cancellous chips which provide the natural scaffold for cell 
attachment, migration, and proliferation.11 
ViviGen is processed from donated human tissue and is a generous gift by an individual 
or his/her family. 
 
Every donor for ViviGen must meet LifeNet Health’s strict medical and behavioral risk 
assessment in addition to microbial and serological testing, all of which comply or are 
higher than those required by the AATB and the FDA. LifeNet Health utilizes aseptic 
techniques in ISO Class 4 (certified) clean rooms to eliminate the need to use aggressive 
disinfection and sterilization methods which can have adverse effects on cell viability. 
Each lot of final product is tested for sterility. 
 

 
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Indications for Use: ViviGen Cellular Bone Matrix is intended for repair or 
reconstruction of musculoskeletal defects. It is contraindicated in any patient who has a 
known or suspected allergy to any of the antibiotics and/or reagents listed under the 
Warnings and Precautions section of the Instructions For Use (IFU), in immune 
compromised patients, and as a stand-alone in load- bearing applications. 
 
Packaging and Labeling: ViviGen is supplied in packaging designed to facilitate rapid 
thawing to maximize cell viability. In addition, this allograft arrives in a cryo-
preservative solution containing Dimethyl Sulfoxide (DMSO) and Human Serum 
Albumin (HSA) formulated specifically to protect bone cell viability. 
 
Product Storage and Accountability: After removal from the shipment container, 
ViviGen must be stored immediately in its original packaging at -70°C or colder until 
ready for use. Do not store in liquid phase of the liquid nitrogen (LN2). It is the 
responsibility of the end-user to document and maintain ViviGen storage at these 
conditions. 
 
There is no formal accountability of ViviGen for this type of study. The Investigator, or 
designee, at each site is responsible for recording on the electronic Case Report Form 
(eCRF) (1) the product code(s), (2) lot number(s), and (3) expiration date(s) of ViviGen 
implanted in each study subject. 
 
3  
TRIAL DESIGN 
 
3.1  
Design 
This is a prospective, single-arm post market study of patients to assess fusion in one or 
multiple continuous levels of the lumbosacral spine (L1-S1) using ViviGen Cellular Bone 
Matrix. All subjects will be followed up to 24 months for final assessment.  
 
3.2  
Inclusion Criteria 
 
Subjects will be considered for inclusion in this trial if they satisfy the following 
criteria. 
 
1. Subject is scheduled to undergo a single or multilevel posterolateral spinal 
fusion surgery using ViviGen Cellular Bone matrix. 
2. Subject must be over the age of 18 years old. 
3. Subject has been unresponsive to conservative care for a minimum of 6 
months. 
4. The subject must in the investigator’s opinion, be psychosocially, mentally, 
and physically able to fully comply with this protocol including the required 
follow-up visits, the filling out of required forms, and have the ability to 
understand and give written informed consent. 
 
3.3  
Exclusion Criteria 
 

 
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Subjects will be excluded from this trial if they satisfy any of the following criteria. 
 
1. Subjects requiring additional bone grafting materials other than local autograft 
and ViviGen Cellular Bone Matrix will be excluded from this outcomes study. 
2. Subject has inadequate tissue coverage over the operative site. 
3. Subject has an open wound local to the operative area, or rapid joint disease, 
bone absorption, or osteoporosis. 
4. Subject has a condition requiring medications that may interfere with bone or 
soft tissue healing (i.e., oral or parenteral glucocorticoids, immunosuppressives, 
methotrexate, etc.). 
5. Subject has an active local or systemic infection. 
6. Subject has a metal sensitivity/foreign body sensitivity. 
7. Subject has a body mass index (BMI) greater than 45. 
8. Subject has any medical condition or extenuating circumstance that, in the 
opinion of the investigator, would preclude participation in the study. 
9. Subject is currently involved in another investigational drug or device study 
that could confound study data. 
10. Subject has a history (present or past) of substance abuse (recreational drugs, 
prescription drugs or alcohol) that in the investigator’s opinion may interfere 
with protocol assessments and/or with the subject’s ability to complete the 
protocol required follow-up.  
11. Subjects who are pregnant or plan to become pregnant in the next 24 months or 
who are lactating. 
12. Subject is involved in or planning to engage in litigation or receiving Worker’s 
Compensation related to neck or back pain. 
13. Osteoporosis (per the investigator’s diagnosis or per a T-score > 2.5 SD below 
the mean for a young, healthy adult) that may prevent adequate fixation of 
screws and thus preclude the use of a pedicle screw system.  
14. Subjects who have a known or suspected allergy to any of the following 
antibiotics and/or reagents: Gentamicin Sulfate, Meropenem, Vancomycin, 
Dimethyl Sulfoxide (DMSO), and Human Serum Albumin (HSA); 
15. Immune compromised subjects 
16. Known sensitivity to device materials 
17. Subject is a prisoner. 
 
4  
STUDY PROCEDURE 
 

 
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4.1  
Screening Assessments 
4.1.1  Informed Consent 
Subjects will be provided with an informed consent form and given ample opportunity to 
review the consent and ask questions. The signed informed consent form will be obtained 
before any study specific procedures, that are not part of the investigator’s standard of care, 
begin. A copy of the informed consent will be given to the subject. All subjects who meet 
all of the entry criteria will be considered for inclusion in this trial. Any subject meeting 
any of the exclusion criteria will be excluded from the trial. 
 
All subjects who have agreed to participate in this study, have signed the informed consent 
and who meet the inclusion/exclusion criteria will be considered enrolled and assigned a 
subject ID number. Once a subject ID number has been issued, it cannot be reassigned or 
used for another subject. 
4.1.2  Medical History and Demographic Data  
Within 60 days prior to the surgery date, the following information will be collected: 
• 
Demographic data including year of birth, gender, weight, and height 
• 
Medical history, including a complete history of spinal disorder(s) (non-operative 
or operative treatments performed) 
• 
Physical examination 
• 
X-Rays 
• 
Current pain medications and other drug therapies. 
• 
Neurological status 
4.1.3  Clinical Assessments 
Subject study data will be collected preoperatively, intra-operatively and postoperatively 
at 6 weeks as well as 3, 6, 12 and when available, 24 months.  The following data will be 
recorded on the Case Report Forms (CRFs) and in addition, electronic data entry will be 
employed via an Internet connection when possible using an Electronic Data Capture 
(EDC) system, REDCap. 
 
Oswestry Disability Index v2.1a (ODI):  Pre-operatively the subject will complete the 
Oswestry Disability Index v2.1a for baseline low back pain and functional assessment.  The 
questionnaire is a combined pain and function index which will be used to assess the 
subject’s back pain and how that pain affects the subject’s ability to manage in everyday 
life.  The questionnaire is divided into ten sections designed to assess limitations of various 
activities of daily living. Each section contains six statements and each statement describes 
a greater degree of difficulty in that activity than the preceding statement. The subject 
marks the one statement in each section, which describes his/her limitations most 
accurately. Each section is scored on a 0-5 scale, 5 representing the greatest disability. The 
scores for all sections are added together, giving a possible score of 50.  The total is doubled 
and expressed as a percentage. If a subject marks two statements, the highest scoring 

 
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statement is recorded as a true indication of his disability. If a section is not completed 
because it is inapplicable, the final score is adjusted to obtain a percentage.  
 
Back and Radicular Leg Pain:  Preoperatively all subjects will assess their back and/or 
radicular leg pain in one or both legs using a visual analog scale (VAS) from 0-10 with 10 
being considered most painful.  
 
4.2 
Surgical Procedure 
After receiving antibiotic prophylaxis, the patient is placed under general anesthesia and 
positioned prone. A midline posterior approach is performed, exposing the posterior 
lumbar elements including the facet joints. Polyaxial pedicle screws are placed bilaterally, 
using fluoroscopic guidance, depending on preference of the surgeon.  
 
In cases of neurogenic claudication related to spinal canal stenosis, the central part of the 
spinal canal is decompressed by laminectomy. In cases of radicular leg pain related to 
foraminal stenosis, partial facetectomies will be performed as needed to decompress the 
associated nerve roots.  
 
Titanium rods are then positioned interconnecting the screws on each side. The 
posterolateral cortical bony surfaces are then fully decorticated and supplemented with 
milled local autograft bone on one side and an equal volume of Depuy Synthes ViviGen 
on the other side. 
 
Data will be collected during and immediately after the surgery according to the parameters 
described by the ViviGen Lumbar study CRFs. This includes: diagnosis, duration of 
surgery, blood loss, OR time, length of hospital stay, instrumentation used, type of 
procedure, and surgical level(s). In addition, all intraoperative complications (e.g. 
excessive blood loss, hematoma, vascular injury, etc.) will be reported and recorded as a 
complication in the study CRFs.  
 
Intra-operative (after hardware installation is completed) and immediate post-operative x-
rays will be obtained. Postoperative care will follow the standard of care for subjects who 
undergo fusion procedures.  
 
Postoperative care is extremely important. The subjects will be warned that noncompliance 
with postoperative instructions could lead to breakage of the pedicle screw system 
requiring revision surgery.  
 
 
 
 
 
 
 

 
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4.3 
Schedule of Events 
 
Screening 
/Enrollment 
(-60 days of 
procedure) 
Procedure 
6 weeks 
(± 7 
days) 
3 months 
(± 14 
days) 
6 months 
(± 14 
days) 
12 months  
(± 30 
days) 
24 months  
(± 60 
days)  
Informed consent 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
X** 
Oswestry Disability Index v2.1a 
X 
 
X 
X 
X 
X 
X** 
Visual Analog Scale (VAS) back 
and leg 
X 
 
X 
X 
X 
X 
X** 
Radiographic X-rays (AP/ Lateral 
with Flexion and Extension) 
X 
 
X 
X 
X 
X 
X** 
CT Scan 
 
 
 
 
 
X* 
 
Urine Pregnancy Test 
 
 
 
 
 
X* 
 
AE/ SAE review 
X 
X 
X 
X 
X 
X 
X** 
*CT scan & Urine Pregnancy Test not standard of care. Cost will be covered by study sponsor.  
** Optional time point (when available)_ 
 
 
4.4 
Follow-Up Assessments 
 
Subjects will be asked to return postoperatively at 6 weeks (± 1 week), 3 months (± 2 
weeks), 6 months (± 2 weeks), and 12 months (± 1 month) for a clinical and radiographic 
exam. An additional visit at 24 months (± 2 months) may be scheduled at the request of 
either the physician or the subject. The following data will be recorded on the Case Report 
Forms (CRFs) and in addition, electronic data entry will be employed via an Internet 
connection when using the Electronic Data Capture (EDC) program, REDCap. 
 
Clinical assessment: The investigator will carry out a clinical examination at the 6 week as 
well as the 3, 6, 12 and when available, 24 month visit to assess: 
• 
subject compliance with postoperative care instructions, 
• 
ability to return to work and normal activity, and 
• 
any procedure related or device related adverse events since discharge from 
the hospital  
• 
review of medication usage 
• 
progress towards fusion consolidation 
• 
Neurological status 
Subject self-assessment:   Patient completed forms 

 
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19 July 2021 
• 
Each subject will be asked to complete a follow-up Oswestry Disability Index 
v2.1a (ODI) form and a Back and Leg Pain VAS form at each follow-up visit. 
Radiographic assessment: Each subject will undergo AP and lateral x-rays at the 6 weeks 
as well as 3, 6, 12 and when available, 24 month visits and flexion/extension x-rays at the 
3, 6, 12 and when available, 24 month visits. Additionally each subject will undergo a CT 
scan and urine pregnancy test at the 12 month visit to assess the extent of fusion.  
4.5 
Fusion Determination 
Fusion will be assessed by an independent radiologist using the subjects’ 12 month visit 
CT images. The extent of fusion will be determined using the Lenke classification. The 
scale is as follows:   
• 
Grade A -  Definitely solid with bilateral trabeculated stout fusion masses present 
• 
Grade B - Possibly solid with a unilateral large fusion mass and a contralateral 
small fusion mass 
• 
Grade C - Probably not solid with a small fusion mass bilaterally  
• 
Grade D - Definitely not solid with bone graft resorption or obvious 
pseudoarthrosis bilaterally 
 
Radiographic success: radiographic success is defined as grade A. 
Partial radiographic success: partial radiographic success is defined as grade B. Images 
graded as “B” will be subcategorized by the location of the unilateral large fusion mass 
(autograft side, B-a vs. ViviGen side, B-v).  
Radiographic Failure: radiographic failure is defined as grades C or D. 
 
4.6  
Success Criteria 
4.6.1  Primary Objective  
A subject outcome will be considered a success if fusion is graded as a Grade A. A 
subject outcome will be considered a partial success if fusion is graded as a Grade B. 
Images graded as “B” will be subcategorized by the location of the unilateral large fusion 
mass (autograft side, B-a vs. ViviGen side, B-v). 
4.6.2 
Secondary Objectives 
The secondary measures of effectiveness will be determined by maintenance or 
improvement of pain and disability scores from completed questionnaires (VAS and ODI 
v2.1a) 
 
4.7  
Subject Withdrawal 
 

 
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It is recognized that the subject’s participation in this trial is entirely voluntary, and that 
she/he may refuse to participate and may withdraw from participation at any time without 
jeopardy to any future medical care.  It is also recognized that the investigator, at his/her 
discretion, may withdraw a subject from this study based upon his/her professional 
judgment.  If the subject is withdrawn for any reason at any time a final evaluation form 
will be completed and the Sponsor will be notified. 
 
Other Conditions for Withdrawal: 
 
Any subject who develops a severe concurrent medical illness during the trial should be 
withdrawn.  This type of illness is defined as any illness that would hinder the subject’s 
ability to return for scheduled follow-up appointments.  Such a withdrawal will not be 
counted for the purposes of determining success or failure. 
 
5  
STATISTICAL ANALYSIS PLAN  
 
Statistical analyses will be performed as deemed appropriate to evaluate different healing 
outcomes across the various patient populations. 
 
Primary outcome analysis to assess the final fusion status of all enrolled patients will be 
performed prospectively by the former principal investigator, Dr. H. Francis Farhadi. 
Following his departure from The Ohio State University, the investigator(s) will review 
the 12 month CT scans to evaluate each subject for radiographic success, partial success, 
or failure.  
  
In case early findings reveal a statistical difference in fusion grades comparing the sides of 
autograft and ViviGen Cellular Bone matrix, enrollment will cease as investigators are 
unlikely to maintain clinical equipoise. Similarly, if the analysis suggests it is unlikely the 
study will achieve statistical significance, the investigators may choose to close the trial 
early for futility. Currently enrolled subjects will be followed throughout the remainder of 
the study, up to 12 months post-surgery.   
 
 
6  
REFERENCES 
1. 
Millennium Research Group (MRG) US Markets for Spinal Implants 2013 
2. 
Quint U, Wilke HJ. Grading of degenerative disk disease and functional impairment: 
imaging versus patho-anatomical findings. European Spine Journal. 2008;17(12):1705–
1713. 
3. 
Hangai M, et al. Factors associated with lumbar intervertebral disc degeneration in the 
elderly. Spine.2008;8:732–740. 
4. 
Fritzell P, Hägg O, Wessberg P, Nordwall A; Swedish Lumbar Spine Study Group. 
Chronic low back pain and fusion: a comparison of three surgical techniques: a 
prospective multicenter randomized study from the Swedish lumbar spine study group. 
Spine (Phila Pa 1976). 2002 Jun 1;27(11):1131-41. 
5. 
Lee CS, Hwang CJ, Lee DH, Kim YT, Lee HS. Fusion rates of instrumented lumbar 
spinal arthrodesis according to surgical approach: a systematic review of randomized 

 
Page 12 of 12 
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trials. Clin Orthop Surg. 2011 Mar;3(1):39-47. doi: 10.4055/cios.2011.3.1.39. Epub 2011 
Feb 15. Review. 
6. 
Laurie SW, Kaban LB, Mulliken JB, et al. Donor-site morbidity after harvesting rib and 
iliac bone. Plast Reconstr Surg 1984;73:933–8. 
7. 
Summers BN, Eisenstein SM. Donor site pain from the ilium. A complication of lumbar 
spine fusion. J Bone Joint Surg Br 1989;71:677–80. 
8. 
Younger EM, Chapman MW. Morbidity at bone graft donor sites. J Orthop Trauma 
1989;3:192–5. 
9. 
Fernyhough JC, Schimandle JJ, Weigel MC, et al. Chronic donor site pain complicating 
bone graft harvesting from the posterior iliac crest for spinal fusion. Spine 1992;17:1474–
80. 
10. 
Laurencin C, Khan Y, El-Amin SF. Bone graft substitutes. Expert Rev Med Devices. 
2006 Jan;3(1):49-57. Review. 
11. 
Data on file at LifeNet Health. 2014