Clinical Evaluation of Decellularized Nerve Allograft With Autologous Bone Marrow Aspirate Concentrate (BMAC) to Improve Peripheral Nerve Repair and Functional Outcomes
Phase: NA
Conditions: Peripheral Nerve Injury Upper Limb
Sponsor: Brooke Army Medical Center

 
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1.  PROTOCOL TITLE:  Clinical Evaluation of Decellularized Nerve Allograft with Autologous Bone Marrow Aspirate 
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Concentrate (BMAC) to Improve Peripheral Nerve Repair and Functional Outcomes 
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2.  ABSTRACT:  This study is a prospective, multi-center, proof of principle, phase I human safety study (n=15) 
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evaluating the sequential treatments of the Avance Nerve Graft, a commercially available decellularized processed 
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peripheral nerve allograft, with autologous Bone Marrow Aspirate Concentrate (BMAC), a source of stem cells, for 
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the repair of peripheral nerve injuries of up to 7 cm in length. The purpose of this study is to establish a knowledge 
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product, evaluating the safety profile of the Avance Nerve Graft, followed by the application of BMAC to support 
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further investment into the promising area of using stem cells in conjunction with scaffolds. 
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Each treatment separately is currently approved and used in the standard of care and has an established 
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safety record with no reported serious adverse events. Avance Nerve Graft: (Cho, 2012) (Rinker, 2011) 
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(Isaacs, 2013). BMAC: (Hendrich, 2009) (Jäger, 2009) (Centeno, 2016) (Hernigou, 2013). Subjects who have 
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sustained a nerve conduction block injury in the upper extremity and require reconstruction of a nerve injury 
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will be recruited and enrolled at three institutions. On day of surgery, the Avance Nerve Graft will be used at 
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the site of nerve injury and then after completion of the first surgery, BMAC will be applied before closing the 
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wound. BMAC from each patient will also be sent to Cleveland Clinic in order to confirm that the samples 
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contain autologous bone marrow stem cells. Subjects will be followed post-surgery to evaluate the safety of the 
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sequential treatments. While not powered to achieve statistical significance, due to the size limitation of a small 
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safety study, secondary outcomes to evaluate an indication of efficacy of the two nerve repair treatments will 
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be measured and compared to historic controls. 
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3.  OBJECTIVES/SPECIFIC AIMS/RESEARCH QUESTIONS. The primary objective is to evaluate the safety of the 
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Avance Nerve Graft procedure when followed by application of BMAC containing autologous stem cells as a 
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proof of principle that allows for continued development of the concept of scaffolds and autologous stem cells. 
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This clinical trial is not in support of any specific product or material development. It is intended soley as a 
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knowledge product that supports the future investment in the use of scaffolds and autologous stem cells in 
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regenerative medicine. The secondary objective is to measure the potential efficacy of the sequential 
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treatments over 18 months as compared to historic controls.  
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The sequential use of Avance Nerve Graft and autologous BMAC will have an equivalent safety profile 
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compared to each component individually and may demonstrate an improvement in the quality of nerve 
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regeneration when compared to the current standard of care in a phase I clinical safety evaluation. 
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Specific Aim 1: Assess the safety profile of patients who sequentially receive Avance Nerve Graft followed by 
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application of autologous BMAC for reconstruction of mixed peripheral nerve gaps up to 7 cm. The sequential 
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treatment of the Avance Nerve Graft and BMAC will be compared to historic controls in regards to the number 
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and severity of adverse events. 
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Specific Aim 2: Measure the efficacy of Avance Nerve Graft when followed by application of BMAC and 
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compare levels of functional recovery to historic controls. Additional secondary efficacy endpoints such as: 
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quality of life, extent of reinnervation, and correlation of short and long term outcomes will be measured. 
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Percent recovery to baseline and time to recovery will be calculated based on analysis. 
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Regional Health Command-Central (RHC-C) 
Institutional Review Board 
 
HUMAN SUBJECTS RESEARCH  
 PROTOCOL APPLICATION – Part B 

 
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4.  MILITARY RELEVANCE   Military combat injuries to the extremities from blast, fragmentary, and ballistic injury 
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can result in a spectrum of musculoskeletal trauma to include injuries to the soft tissues, vessels, nerves, and 
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bone. This clinical safety evaluation may result in a knowledge product that provides confidence in the strategy 
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that using a safe scaffold with a safe stem cell source is a safe approach. If successful this would provide 
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validation to the military to continue investment in the area of regenerative medicine towards more complex 
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solutions such as tissue regeneration and re-growing limbs. While not the primary goal of the study, secondary 
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endpoints may indicate that this approach could lead to the treatment of longer nerve gaps, to better functional 
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recovery, and return service members (as well as civilians) to their daily lives with increased functionality, 
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diminished deficit, and ultimately a greater quality of life. 
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 5. BACKGROUND AND SIGNIFICANCE.  Traumatic injury and the associated peripheral nerve damage results 
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in loss of controlled tissue animation, leaving the patient with severe functional disability. The defect in the 
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injured nerve can be substantially more severe than the initial appearance as the zone of injury can 
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necessitate extensive resection to obtain healthy nerve tissue.  Additionally, the damaged distal stump 
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undergoes time-dependent trophic and cellular changes, such as scarring, which degrade the stumps ability to 
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support nerve regeneration (Lundborg, 2000).  Deficits, which cannot be directly approximated, require 
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reconstruction with a bridging material to serve as a conduit for the regenerating axons (Berger, 1978) (Noble, 
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1998) (Dvali, 2003) (IJpma, 2006).  For years, the standard of care for peripheral nerve injuries (PNI) has been 
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autologous nerve grafts, involving excision of a donor nerve from elsewhere on the patient’s limbs and grafting 
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it to the transected nerve site. However, these wounded service members have frequently sustained injuries to 
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multiple limbs, often making autograft sites unavailable. Additionally, it follows that excision of nerve graft from 
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a healthy limb will decrease said limb’s nerve function and expected outcomes using autograft are 
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underwhelming.  A recent meta-analysis showed meaningful recovery rates for mixed nerve reconstructions to 
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be a disappointing 60% (Brushart, 2011).   
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A myriad of synthetic scaffolds have been developed for use in lieu of autograft. However, commercially 
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available nerve tubes have a limited functional length and recent clinical studies have found them to have very 
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limited effectiveness in general clinical utilization (Wangensteen, 2010) (Lohmeyer, 2009).  Undesirable 
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handling characteristics can lead to adverse experiences for the patient, such as pain, soft tissue irritation and 
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tube extrusion (Weber, 2000) (Rinker, 2011). These limitations have relegated their clinical application to non-
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critical sensory nerve defects and coaptation aides. 
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While the utilization of processed allogeneic tissues for the repair of tendon, skin, and bone injuries has been a 
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mainstay for decades, the use of viable cellular nerve allograft was first introduced by Susan Mackinnon, M.D. 
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in the 1990’s. The results of her work were published in 2001 and detailed the outcomes in seven patients 
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(Mackinnon, 2001). The results of this study showed promise, but adoption of cellular nerve allografts as a 
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strategy for nerve reconstruction was hampered by the need for donor matched tissue and prolonged 
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immunosuppression. Because of these limitations, an unprocessed cellular nerve allograft has shown limited 
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clinical utility. The optimal scaffold upon which to place stem cells to improve nerve regeneration has been 
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recognized as a processed decellularized nerve allograft. Only one such commercially available peripheral 
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nerve graft exists, the Avance Nerve Graft.  The Avance Nerve Graft represents an attractive alternative to 
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harvesting autograft by offering numerous benefits to the patient, including decreased operative time and 
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eliminating donor site morbidity. Furthermore, the efficacy and safety of this treatment option has already been 
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established as equivalent to autograft.   
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Avance Nerve Graft: Introduced commercially in 2007, the Avance Nerve Graft is a decellularized, 
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predegenerated, and sterilized extracellular matrix processed from donated human peripheral nerve tissue.  
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The structure of the extracellular matrix is comprised of bundles of small diameter endoneurial tubes. The 
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tissue is processed to remove cellular and non-cellular factors such as Schwann cells, fat, blood, axonal 
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debris, and chondroitin sulfate proteoglycans, while preserving the three dimensional scaffold, vascular 
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structure, and basal lamina structure of the nerve.   
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Regenerating axons can grow through the allograft scaffold, into the patient’s distal nerve tissue toward the 
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target muscle or skin.  Unlike tube conduits, which rely on the host to form a rudimentary and provisional matrix 
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within its hollow structures, the processed nerve allograft provides internal architecture inherent to nerve 
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tissue.  This internal structure is present upon implantation and ready to support regeneration (Graham, 2009) 
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(Whitlock, 2009) (Neubauer, 2010).  Avance Nerve Graft has an established track record for safety and 
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efficacy (Brooks, 2012) (Cho, 2012) (Karabekmez, 2009) (Taras, 2013) (Guo, 2013) (Isaacs, 2013) (Lin, 2013) 
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(Rinker, 2011).  It has been used at a range of institutions; including small rural medical centers, level 1 trauma 
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centers, academic medical centers, Veterans Administration medical centers, and military medical centers.  
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Avance Nerve Graft has been utilized by General Surgeons, Plastic Surgeons, Orthopaedic Surgeons, Hand 
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Surgeons, Neurosurgeons, Trauma Surgeons, Urologic Surgeons, Gynecologic Surgeons, Oral and 
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Maxillofacial Surgeons, Neuro-otologists, Otolaryngologists, Podiatric and Oncologic Surgeons for the 
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reconstruction of traumatic and iatrogenic peripheral nerve discontinuities (See Human Data below).  
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Comprehensive in vitro and in vivo biocompatibility evaluations provide support that Avance Nerve Graft is safe 
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for use in humans. Efficacy studies in rat models have shown that, in terms of axon regeneration, Avance 
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Nerve Graft is superior to a currently available conduit-style nerve guide (Whitlock, 2009) and compares 
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favorably to isograft, which is similar to autograft (Graham, 2009). In a subsequent study examining nerve fiber 
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density, it was found that the processed nerve allograft and isograft had nerve fibers evenly distributed across 
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the cross section of the nerve. The processed nerve allograft density was superior to collagen nerve conduit, 
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whose regeneration was found to be sparse and irregularly clustered throughout the cross section (Johnson, 
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2011).  
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Avance Nerve Graft has also been subjected to well established and accepted test panels for preclinical 
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product safety evaluation and has been found to be non-toxic, non-reactive, non-sensitizing, non-pyrogenic, 
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non-mutagenic, and non-irritant. Overall, studies utilizing well-established and validated animal models have 
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demonstrated efficacy of the Avance Nerve Graft to reconstruct and repair peripheral nerve discontinuities and 
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support axonal regeneration following transection injury.  
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Scaffolds and Stem Cells Including Bone Marrow Aspirate Concentrate (BMAC): Stem cells, when 
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cultured together, do not self-organize into complex tissues due to the limits of transportation of nutrients and 
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diffusion of waste products.  Stem cells require scaffolds and 3-D matrices to grow into larger 3-D structures. 
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The first notable example from the late 90’s, the Vacanti Mouse, demonstrated the need for choosing the 
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optimal scaffold and the optimal stem cell source. Since that demonstration, there has been an explosion in the 
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types of scaffolds and stem cells proposed for use. The optimal scaffold will provide the requisite physical 
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infrastructure upon which stem cells can engaft, transport materials, and rebuild new tissue.   
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This proposed clinical trial has the potential for demonstrating the safety of this proposed approach.  Bone 
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marrow represents the most universally accessible tissue for harvest of stem cells for a broad range of clinical 
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applications.  Bone marrow harvested by aspiration from the iliac crest has been shown to provide a rich, but 
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variable, source of bone marrow stem cells which is then centrifuged in the surgery suite to create what is 
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known as BMAC.  Processing these cells involves “minimal manipulation” (without enzymatic digestion), an 
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important factor in the FDA regulations. The Harvest Technologies system has been shown to achieve the 
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highest number and concentration of progenitor cells after centrifugation (Hedge, 2014) and will be used in this 
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study.   
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Experimental animal data has shown that the addition of stem cells to a nerve allograft scaffold increases the 
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likelihood of successful regeneration and improves functional outcomes.  Reported outcomes for stem cell 
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seeded implants have demonstrated an increase in axonal growth in both conduits and allografts (Hu, 2007) 
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(Dezawa, 2001) (Jackson, 2013) (Wang, 2010); increases in motor function (Hu, 2007) (Jackson, 2013) 
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(Wang, 2010) (Chen, 2007); and superior assessment scores for sensory and mixed neurons (Kragh, 2012) 
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(Chen, 2007) (Mimura, 2004) (Reyes, 2001).  If successful, this clinical evaluation will establish the safety of 
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the proposed approach and justify further development in this materiel approach.  
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The Avance Nerve Graft and BMAC therapy are currently used separately in clinical practice as standard of 
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care. Avance Nerve Graft has an established track record for safety and efficacy (Frykman, 1991) (Meek, 
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2005) (Cho, 2012) (Rinker, 2011) (Isaacs, 2013). BMAC has a clinically significant yield, does not induce 
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immune-rejection, and requires minimal manipulation prior to usage. The use of autologous BMAC is 
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considered a self-transplant and has a long track record of safety (Hendrich, 2009) (Jäger, 2009) (Centeno, 
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2016) (Hernigou, 2013).  The following cited studies demonstrate that the Avance Nerve Graft and BMAC are 
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safe when used separately in humans; large animal data is also provided in support of the two treatment 
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modalities combined.  
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Human Avance Safety Data: 
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The following six studies are provided to reflect the published safety and efficacy profile of the Avance Nerve 
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Graft. These studies showed no report of adverse events related to the use of Avance Nerve Graft and 
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equivalence in efficacy when compared to autograft.  
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Early clinical outcomes with the use of decellularized nerve allograft for repair of sensory defects 
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within the hand. (Karabekmez, 2009)  The Mayo Clinic published their results regarding the performance of 
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Avance Nerve Graft.  Seven patients with ten nerve injuries were treated surgically.  All subjects recovered 
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near normal two point discrimination (2PD).  Relation to current study:  Avance Nerve Graft was 
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demonstrated to be safe and effective with no reported signs of infection, rejection, or graft extrusion. 
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Innovative treatment of peripheral nerve injuries: combined reconstructive concepts.  (Ducic, 2012)  
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Ducic reported on outcomes from 54 discreet nerve repairs that were treated with various repair techniques.  
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The authors found that Avance Nerve Graft returned functional improvements similar to those of other test 
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groups.  Relation to current study:  No safety concerns were discussed and the treatment showed positive 
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outcomes. 
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Allograft reconstruction for digital nerve loss.  (Taras, 2013)  Taras reported on an investigator initiated 
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single center prospective study evaluating the clinical outcomes of digital nerve gaps in the hand measuring 30 
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mm or less repaired with Avance Nerve Graft The study included 14 subjects with 18 nerve repairs.  Relation 
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to current study:  No implant related adverse experiences were reported.   
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Sensory outcomes after reconstruction of lingual and inferior alveolar nerve discontinuities using 
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processed nerve allograft--a case series. (Zuniga, 2015)  Zuniga reported on an investigator initiated case 
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series of Avance Nerve Graft for the reconstruction of lingual and inferior alveolar nerve discontinuities.  The 
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study included 26 subjects and 28 nerve repairs. Improvement in neurosensory function was reported in 87% 
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of repairs.  Relation to current study:  There were no reported adverse experiences in this study. 
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Processed nerve allografts for peripheral nerve reconstruction: a multicenter study of utilization and 
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outcomes in sensory, mixed, and motor nerve reconstructions.  (Brooks, 2012)  Brooks reported on the 
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safety and efficacy of 132 individual nerve injuries treated with nerve allografts.  The mean graft length was 22 
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± 11 (5-50) mm.  Relation to current study:  No implant related adverse experiences were reported. 
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A Multicenter, Retrospective Study of Avance® Nerve Graft Utilization, Evaluations and Outcomes in 
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Peripheral Nerve Injury Repair (RANGER)  The RANGER Study is an AxoGen sponsored ongoing open 
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label registry study designed to collect data about utilization, safety and functional outcomes in patients treated 
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with the Avance Nerve Graft.  There are 18 contributing centers designed to continuously monitor and collect 
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injury, repair, safety and outcomes data for peripheral nerve injuries repaired with the Avance Nerve Graft, 
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nerve autograft and synthetic tubes. As of May 2015, the study included more than 650 nerve repairs enrolled 
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across 18 centers and 40 surgeons (PRWeb, 2015).  From the RANGER database, researchers Cho, Rinker, 
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and Isaacs studied specific subgroups based on specific injuries or treatments.  Cho reported on a subgroup of 
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71 nerves repaired with Avance Nerve Graft (Cho, 2012).  Rinker reported on a subgroup of 24 subjects with 
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37 digital nerve repairs (Rinker, 2011).  Isaacs report on a subgroup of repairs up to 50mm using Avance 
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Nerve Graft in 13 subjects with 15 nerve repairs (Isaacs, 2013).  All outcomes analysis in these studies 
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demonstrated meaningful levels of sensory recovery and no implant related adverse experiences, further 
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suggesting the safety of the Avance Nerve Graft in human subjects.  Relation to current study:  The 
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RANGER clinical study was supported by AxoGen, Inc., the maker of the Avance Nerve Graft to further the 
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understanding and outcomes of peripheral nerve repair.  No safety concerns were discussed in the RANGER 
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study at this time and no safety concerns were observed in the studies conducted by Cho, Rinker, and Isaacs.   
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Human Bone Marrow Safety Data: 
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The following four articles discuss the use of human bone marrow products in human subjects.  None of the 
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studies were associated with negative side effects and all showed positive outcomes with improved recovery 
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associated with bone marrow treatment.  These studies suggest that the use of bone marrow therapies like 
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BMAC are safe and effective for use in human subjects.   
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Safety of autologous bone marrow aspiration concentrate transplantation: initial experiences in 101 
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patients.  (Hendrich, 2009) Summary:  This study evaluated the safety for the use of BMAC for new bone 
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formation in 101 patients who suffer from various bone healing disorders.  Patient recovery was observed 14 
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months after treatment where no complications in the form of infections, excessive new bone formation or 
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renewed increase of complaints were noted.  Subjectively, the bone marrow aspiration was not considered 
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negatively by any of the patients.  Relation to current study: This study demonstrates that the use of BMAC 
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in humans has not shown signs of patient recovery complications and is safe for treatments that include BMAC 
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application in conjunction with a scaffold product.  
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Bone Marrow Concentrate: A Novel Strategy for Bone Defect Treatment. (Jäger, 2009) Summary: This 
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study evaluated the effects of BMAC applied to stimulate bone formation in patients with pseudarthrosis, bone 
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cysts or revision endoprosthetic bone defects.  The observed results for this specific treatment using BMAC 
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had varied outcomes but none of the outcomes were associated with any significant or major complications or 
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side effects.  Relation to current study:  The safety of an extracellular matrix with BMAC was evaluated and 
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did not suggest any increased risk. 
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A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult 
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patients undergoing adult autologous stem cell therapy for orthopaedic conditions. (Centeno, 2016) 
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Summary: This study followed recovery complications in 2372 orthopedic patients treated with stem cell 
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injections for up to nine years.  Within this treatment group with n=1590 (1949 injections) there were 114 
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adverse events, 7 of which were serious.  This represents 7.2% of the group population reporting an AE, a 
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small percentage of the study group.  Bone marrow stem cells and MSC treatments have a lower rate of 
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serious adverse events when compared to more invasive orthopedic procedures.  Relation to current study: 
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The results in Centeno, 2016 suggest that the utilization of bone marrow stem cells, MSC, or BMAC in 
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methods as proposed in this study are safe for human use.  The observed rate of AEs are lower than other 
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treatments that are currently approved as safe for standard of care treatment.  
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Cancer Risk Is Not Increased in Patients Treated for Orthopaedic Diseases with Autologous Bone 
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Marrow Cell Concentrate. (Hernigou, 2013)  Summary: This study addressed the safety of using BMAC for 
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the treatment of orthopedic lesions.  The study specifically assesed the risk of cancer associated with this 
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treatment.  A total of 1873 patients were treated from 1990 to 2006 with BMAC cells and were monitored for 
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cancer incidence from the date of the first operation (1990) until death, or until December 31, 2011.  There was 
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no incidence of cancer formation at the site of treatment, and cancers that formed in other places in the body 
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formed at the expected rate of cancer formation for the general population.  Relation to current study: These 
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results suggest that the use of BMAC for treatment is safe and does not increase the specific disease risk of 
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cancer formation, suggesting that the use of BMAC in this study is safe and does not increase the risk of 
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cancer formation.   
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Large Animal Supporting Data: 
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The following seven large animal trials support the proposed use of peripheral nerve allografts combined with 
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autologous bone marrow stem cells.   Five of the seven animal models discussed below are primate models.  
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These studies showed no increased incidence of AEs and suggest safety for the use in humans.   
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Peripheral nerve defect repair with epineural tubes supported with bone marrow stromal cells: a 
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preliminary report. (Siemionow, 2011) Summary: This study was performed to assess the effects of nerve 
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gap repair with epineural tubes filled with bone marrow stem cells as an alternative to autograft repair.  
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Evidence of successful nerve regeneration was present in all animals at 6 weeks.  All animals had full sensory 
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recovery as at 12 weeks. Assessment did not reveal superiority of any group at 6 weeks post repair. Relation 
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to current study: Bone marrow stem cells enhances nerve regeneration with increased myelinization and 
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neurotrophic factors when used in peripheral nerve repair when combined with a scaffold.  
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Use of Tissue-Engineered Nerve Grafts Scaffold Included with Bone Marrow Mesenchymal Cells for 
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Bridging 50-mm Dog Sciatic Nerve Gaps. (Ding, 2010) Summary: This study evaluated a tissue-engineered 
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nerve grafts consisting of a PLGA-based neural scaffold combined with autologous bone marrow stem cells for 
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bridging 50-mm-long gaps in dog sciatic nerve. Results indicated that introduction of bone marrow stem cells to 
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the scaffold promoted sciatic nerve regeneration and functional recovery. Relation to current study: This 
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study showed that bone marrow stem cells plus nerve graft was better than graft alone and better than 
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autograft, directly supporting the efficacy and safety of scaffolds used in combination with bone marrow stem 
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cell products. 
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Long-term outcome of the repair of 50 mm long median nerve defects in rhesus monkeys with marrow 
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mesenchymal stem cells (MSC)-containing tissue engineered nerve grafts. (Hu, 2013) Summary: This 
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study evaluated the use of autologous bone marrow stem cells with a PLGA-based nerve grafts for bridging a 
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50-mm long median nerve defect in rhesus monkeys. At 12 months after grafting, the recovery of nerve 
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function by graft/bone marrow stem cells was more efficient than that by scaffolds alone. In addition, this study 
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demonstrated that graft/bone marrow stem cells could be safely used in the primate body.  Relation to current 
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study:  The combination of bone marrow stem cells and a scaffold product were safely tolerated and effective 
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in an animal model similar to humans.  
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Bridging small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous 
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bone marrow stromal cells in primates. (Wang, 2008) Summary: This study evaluated the effects of the 
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transplantation of an acellular allogenic nerve graft combined with autologous bone marrow stem cells in a 
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rhesus monkey in the radial nerve.  The group treated with cultured bone marrow stem cells showed a 
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statistically higher number of nerve fibers, conduction velocities and the peak amplitudes of action than those 
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of the controls.  Relation to current study: Direct validation of proposed study using acellular graft with bone 
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marrow stem cells showing improvement over aclleular allograft alone.  
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Repair of extended peripheral nerve lesions in rhesus monkeys using acellular allogenic nerve grafts 
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implanted with autologous mesenchymal stem cells. (Hu, 2007)  Summary: This study utilized acellular 
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allogenic nerve segments implanted with bone marrow stem cells to repair a 40 mm defect in the rhesus 
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monkey ulnar nerve. Results found that severely damaged ulnar nerves were structurally and functionally 
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repaired within 6 months following placement of the MSC seeded allografts in all six animals studied. Findings 
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were the first demonstration of successful acellular allogenic nerve graft usage in primates.  Relation to 
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current study: Further support of safety and efficacy of the proposed approach in primates.  
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Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency 
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of bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. (Wakao, 2010)  
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Summary: This study used a monkey peripheral nervous system injury model.  No abnormalities were 
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observed and suggest that auto-cell transplantation therapy is safe and effective for accelerating the 
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regeneration of transected axons and for functional recovery of injured nerves. Relation to current study: 
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Additional support for safety and use of bone marrow stem cells in peripheral nerve repair. 
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Repairing large radial nerve defects by acellular nerve allografts seeded with autologous bone marrow 
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stromal cells in a monkey model. (Wang, 2010) 
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Summary: This study evaluated the potential of nerve grafts created from acellular allogenic nerve tissues 
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combined with autologous bone marrow stem cells for repairing large peripheral nerve lesions in a rhesus 
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monkey model.  Bone marrow stem cells-laden allografts remarkably facilitated the recovery of the grasping 
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functions of the animals, nerve conduction velocities, peak amplitudes of compound motor action potentials, 
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greater axon growth, and higher target muscle weight. Relation to current study: Bone marrow stem cells 
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plus nerve allografts were shown to be safe and efficacious in rhesus monkeys for large gap repair. 
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6.  RESEARCH DESIGN   This is a prospective, multi-center, phase 1 trial to evaluate the safety of Avance Nerve 
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Graft and BMAC administered in sequential treatments and to measure the efficacy of the sequential treatments 
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for peripheral nerve repair of the ulnar, median, radial, and musculocutaneous nerves of the upper extremities. 
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The size of the nerve injury to be repaired will be limited up to 7 cm in length. To evaluate the safety of the 
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sequential treatments, participants will be monitored on day 0 (day of surgery) and on day 10 (+/- 5 days) post-
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operative to track the number and severity of adverse events, if any, and to compare the adverse events to the 
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results of previous studies that used Avance and BMAC treatments alone. To evaluate efficacy of the sequential 
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treatments, participants will undergo standardized follow up assessments at 1 month, 6 month, 12 month, and 18 
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month post-operative to determine recovery of nerve function post repair as compared to historic controls for 
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Avance Nerve Graft alone. We expect to establish a treatment modality that is both safe and that shows 
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improvement with regard to efficacy without significant drawbacks of harvesting autograft. 
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7.  RESEARCH PLAN 
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7.1 Selection of Subjects 
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7.1.1. Subject Population. Up to 15 male and females at each of three sites between the ages of 18 and 74 
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presenting with peripheral nerve injury in the upper limbs which after resection results in a nerve gap up to 7 cm, 
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inclusive.   
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Target Population: The clinical safety evaluation of the sequential treatments of Avance Nerve Graft and 
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BMAC will be applicable to both civilians and service members (active, retired, and reserves) with nerve 
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injuries to their upper extremities.  
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7.1.2. Source of Research Material.  
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Source of Research Material 
 
Clinical Purposes(Y/N) 
Research Purposes (Y/N) 
 
Demographics 
Y 
Y 
 
Medical History 
Y 
Y 

 
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Mechanism of Injury 
Y 
Y 
 
Nerve Repair 
Y 
Y 
 
Motor Domain  
Y 
Y 
 
Sensory Domain 
Y 
Y 
 
PROMIS assessment 
N 
Y 
 
DASH assessment 
N 
Y 
 
Rosen-Lundborg Study 
Y 
Y 
 
Nerve Conduction Study 
Y 
Y 
Bone Marrow Aspirate Concentrate 
(BMAC) sample 
N 
Y 
 
Adverse Events 
Y 
Y 
 
Concomitant Treatments 
Y 
Y 
 
353 
7.1.3. Inclusion and Exclusion Criteria.  
354 
Inclusion Criteria 
355 
1. Male or non-pregnant female 18 to 74 years of age. 
356 
2. Undergoing peripheral nerve exploration or grafting with allograft in the upper extremity. 
357 
3. Subjects must be inpatients or scheduled for surgery at the time of study enrollment.  
358 
4. Has nerve conduction block injuries to the ulnar, median, radial or musculocutaneous nerve of either 
359 
upper extremities that is less than two years from injury. 
360 
5. Be willing to undergo tension free end-to-end nerve graft coaptation on both the proximal and distal 
361 
portion of the nerve gap with the Avance Nerve Graft.  
362 
6. Be willing to have bone marrow harvested from own body, concentrated, and applied to the site of 
363 
nerve injury following the insertion of the Avance Nerve Graft. 
364 
7. Be willing to participate and able to comply with all aspects of the treatment and evaluation schedule 
365 
over a 18-month duration. 
366 
8. Capable of giving their own consent to participate in the study, and willing to sign and date an IRB-
367 
approved written informed consent prior to initiation of any study procedures. 
368 
9. Nerve conduction injury affecting sensory and motor function or solely motor function in the upper 
369 
extremity. 
370 
10. Nerve gaps following resection, up to 7Cm, inclusive. 
371 
 
372 
Exclusion Criteria 
373 
1. Subjects with Type 1 Diabetes Mellitus or Type 2 Diabetes Mellitus requiring regular insulin therapy. 
374 
2. Subjects who are undergoing or expected to undergo treatment with chemotherapy, radiation therapy, 
375 
or other known treatment which affects the growth of neural and/or vascular system. 
376 
3. History of neurodegenerative disease, neuropathy, or diabetic neuropathy. 
377 
4. History of chronic ischemic condition of the upper extremity. 
378 
5. Cognitive limitation or mental illness preventing informed consent. 
379 
6. Nerve injuries >2 years post initial injury. 
380 
7. Any participant who at the discretion of the Investigator is not suitable for inclusion in the study.  
381 
 
382 
7.1.4. Description of the Recruitment and Prescreening Process.  The treating physician, who may or may not 
383 
be the study surgeon, will identify and refer potential study candidates to the research team by providing the 
384 
patient’s name and SSN or MRN. Under a partial waiver of HIPAA authorization, the research coordinators will 
385 

 
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access and review the health information to assess whether the subject meets inclusion/exclusion criteria, and 
386 
report back to the study surgeon. The study surgeon will then talk to the subject about the study and potential 
387 
enrollment.  
388 
 
389 
 Medical Records used to verify inclusion/exclusion criteria for assessing initial eligibility of the trial will not be 
390 
printed or stored. PHI/PII, including names and MRNs of all consented subjects referred by the treating physicians, 
391 
will be kept on a Master file located in the orthopedic research team’s locked office. The file linking study numbers 
392 
with PII will be password protected. Access to this information will be limited to the orthopedic research team that 
393 
is on the protocol.  
394 
 
395 
7.1.5. Subject Screening Procedures.  All patients between the ages of 18 and 74 admitted to the hospital or 
396 
returning to clinic with an upper extremity injury with motor or sensory loss will be screened for eligibility at each 
397 
site by the local Research Coordinator in close collaboration with treating physician who may refer the patient for 
398 
study consideration and/or the study surgeon.  Participants will be pre-screened according to the 
399 
inclusion/exclusion criteria by the study team in accordance with the approved HIPAA waiver; however, informed 
400 
consent must be obtained and documented prior to initiation of any procedures t(such as physical exams, imaging, 
401 
etc) hat are performed solely for the purpose of determining eligibility for the research.   
402 
 
403 
7.1.6. Consent Process. Informed consent will be obtained before beginning the final in-person screen. The 
404 
conversation will be initiated by the Research Coordinator and investigator together. After reviewing all 
405 
components of the informed consent form, the investigator and the Research Coordinator will answer any 
406 
questions the patient has about participating in the study. The informed consent process will take place in a private 
407 
setting and in the presence of a witness. Following completion of informed consent, the investigator will conduct a 
408 
clinical assessment, medical history, and interview to confirm eligibility. Patients who are ineligible will not continue 
409 
in the study and will be withdrawn. 
410 
 
411 
All patients must be able to provide informed consent. After completion of informed consent, the participant 
412 
information will be entered into the CRF where a subject ID will be assigned and final eligibility criteria confirmed.  
413 
Recognizing the consent is an ongoing process, the research team will encourage the participants to ask 
414 
additional questions that may arise during the course of their participation in the study. To encourage a high level 
415 
of participation from eligible patients, the treating surgeon will be made aware of the research protocol and will be 
416 
available to answer any questions his patient may have about enrollment in the study.  Consent will be obtained in 
417 
accordance with principles of GCP and ICH guidelines. 
418 
 
419 
7.1.7. Compensation for participation.  No compensation will be provided for participation.   
420 
 
421 
7.2 Drugs, Dietary Supplements, Biologics, or Devices.   
422 
 
423 
7.2.1  N/A  
424 
 
425 
7.2.2   
426 
 
427 
Avance Nerve Graft 
428 
 
429 
Avance Nerve Graft is a human tissue for transplantation, processed and distributed in accordance with US FDA 
430 
requirements for Human Cellular and Tissue-based Products (HCT/P) under 21 CFR Part 1271 regulations, US 
431 
State regulations and the guidelines of the American Association of Tissue Banks (AATB). The graft is to be 
432 
dispensed only by, or on the order of, a licensed physician. Indication For Use: The Avance Nerve Graft is 
433 
processed nerve allograft (human) intended for surgical repair of peripheral nerve discontinuities to support 
434 
regeneration across the defect. 
435 
 
436 
Harvest Technologies Smart Prep 2 Centrifuge System 
437 

 
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438 
The Harvest Technologies Smart Prep 2 is cleared by the FDA as a Class II 510K medical device: K052925. 
439 
Indication For Use: This device is intended to be used in the clinical laboratory or intraoperatively at point-of-care 
440 
for the safe and rapid preparation of a cell concentrate from bone marrow. 
441 
 
442 
7.3. Study Procedures/Research Interventions.  The intervention tested is the Avance Nerve Graft and BMAC 
443 
treatments administered sequentially. The sequential treatments are not currently used together routinely at 
444 
SAMMC. However, they are used routinely separately as needed. Surgical standard of care is to explore the 
445 
nerve, identify and evaluate the defect or injury, and graft as indicated. Both treatments will be used 
446 
sequentially at SAMMC for research purposes of the study.  
447 
 
448 
The order of the intervention is as follows:  
449 
1) Pre-Screening: 
450 
 
The following is part of standard of care: 
451 
 
Inclusion Criteria 
452 
 
Exclusion Criteria  
453 
 
Medical History  
454 
2) Informed Consent 
455 
3) Pre-Operative Screening (Within 4 weeks of Operative Day): 
456 
Once informed consent has been obtained, the subject will be assigned a subject ID and the following pre-
457 
operative procedures will be performed at this visit: 
458 
 
Inclusion Criteria 
459 
 
Exclusion Criteria  
460 
 
Medical History (Number of units of blood donated pre-operatively) 
461 
 
Demographics (gender, race, height, weight, history of smoking or tobacco use, alcohol use, co-
462 
morbidities) 
463 
 
Nerve Injury History 
464 
 
Vitals 
465 
4) Operative Day Screening (Day 0): 
466 
 
Inclusion Criteria 
467 
 
Exclusion Criteria  
468 
 
Vitals 
469 
5) Operative Day Treatments (Day 0): 
470 
Procedure 1: 
471 
Prepare Nerve Injury Site: 
472 
Surgeons and other medical staff will prepare the site of nerve injury for surgery in accordance to standard 
473 
surgical fashion.  
474 
 
475 
Complete Avance Nerve Graft Procedure: 
476 
Medical staff specifically surgeons, who are properly trained and licensed will conduct and/or oversee the 
477 
insertion of the Avance Nerve Graft. The Avance Nerve Graft will be inserted in the area of nerve injury 
478 
according to the Instructions For Use in the package insert. See attached.  Below is a picture of the Avance 
479 
Nerve Graft that will be inserted in the nerve injury site (see Figure A). 
480 
 
481 
 
482 
                         
 
483 
Figure A: Avance Nerve Graft 

 
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484 
Steps Of How To Insert Nerve Graft: 
485 
1. Determine the injury nerve diameter in millimeters using a suitable measuring instrument. 
486 
2. Select Avance Nerve Graft(s) of comparable diameter to match the native nerve and of sufficient length to 
487 
ensure a tension free repair. 
488 
3. To prepare the Avance Nerve Graft:  
489 
    a. Remove foil chevron pouch containing nerve graft, instructions for use, patient record labels, and Tissue 
490 
Utilization Report (TUR) from the package. 
491 
    b. Compare the distinct lot number on the foil chevron pouch with the lot number on the package. If the 
492 
numbers do not match, DO NOT USE the product and notify AxoGen Customer Care immediately. 
493 
    c. Using standard aseptic technique, peel open the outer foil chevron pouch and pass the inner chevron 
494 
pouch to the sterile field for further handling.  
495 
    d. Open the chevron pouch and remove the plastic tray.  
496 
    e. Open the plastic tray and fill the pre-modeled thawing reservoir with room temperature sterile saline or 
497 
sterile Lactated Ringer’s solution. Do not heat the graft or add heated saline or Lactated Ringer’s solution 
498 
to the graft. 
499 
    f. Allow Avance Nerve Graft to thaw completely before use which will take about 5 to 10 minutes. Once 
500 
thawed, nerve graft is soft and pliable throughout. The nerve graft must be either implanted or discarded 
501 
within 12 hours.  
502 
5. Handle nerve graft by outer most epineurium and avoid crimping or crushing the graft. 
503 
6. Implant nerve graft using the same tensionless surgical technique used when implanting a nerve autograft. 
504 
Either end of the processed nerve allograft can be coapted to the proximal stump of the host nerve.  
505 
7. Destroy any thawed allograft tissue not used in the surgical procedure in accordance to procedures of 
506 
disposing human tissue. 
507 
8. Complete and send the TUR back to AxoGen.  
508 
 
509 
AxoGen, the company who created the Avance Nerve Graft, will provide training on the surgical implantation of 
510 
the Avance Nerve Graft and how to complete the functional nerve assessments. 
511 
 
512 
Procedure 2: 
513 
Harvest Bone Marrow: 
514 
In the operating room, after induction of anesthesia and prior to initiation of surgery, at a time when the patient 
515 
would not feel pain, the surgeon(s) or other medical staff will use standard operating procedures to harvest 
516 
bone marrow from the bone of the pelvis. General, spinal, local, or a combination will be used to provide 
517 
anesthesia for the bone marrow aspiration from the pelvis. Bone marrow from the pelvis is available by 
518 
aspiration through a single 3 mm incision.  
519 
 
520 
A needle will be used to harvest between 40 to 60 ml of Bone Marrow Aspirate from the anterior or posterior 
521 
iliac crest of the pelvis.  
522 
 
523 
After aspiration, the needle is removed and a sterile bandage is applied similar to when blood is drawn. The 
524 
total volume for all marrow samples will be up to 60 ml. The sterile bandage may be removed two days after 
525 
surgery. The aspiration site is associated with minimal tenderness or pain, and is clinically comparable to 
526 
percutaneous phlebotomy. 
527 
 
528 
Prepare Final BMAC: 
529 
Trained medical staff will use the harvested 40- 60 ml of bone marrow aspirate and the BMAC system (comprised 
530 
of the SmartPrep centrifuge and 60 ml BMAC kit, see figure B and C, respectively) to yield a final BMAC. The 
531 
SmartPrep centrifuge and 60 ml BMAC kit will yield 7 to 10 ml of final BMAC for every 60 ml of aspirate. The 
532 
centrifuge process takes about 15 minutes. For every ml of BMAC, there is a mean count of 88 ± 50 x 106 
533 
nucleated cells (Kevy and Jacobson, 2013) (Kevy and Jacobson, 2012) (Hegde, 2014) (Kevy and Jacobson 2014). 
534 
Of the 7 to 10 ml of final BMAC that is yielded, half (3.5 to 5 ml) of the final concentrate, composed of over 100 
535 

 
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million nucleated cells, will be injected on top of the Avance Nerve Graft following the Avance surgery. The second 
536 
half (3.5 to 5 ml) of the final concentrate will be inserted into a sterile tube containing culture media and then 
537 
properly shipped overnight to Cleveland Clinic for cell processing and colony assay to confirm that the BMAC 
538 
indeed contains autologous bone marrow stem cells.  
539 
 
540 
                   
                                      
        
541 
       
542 
 
543 
Steps On How To Prepare Final BMAC:  
544 
1. Remove processing disposable container from the packaging and place into holder apparatus. 
545 
2. Following asceptic technique, prep the red access site with a clean wipe.  
546 
3. Slowly dispense 60 ml of Bone Marrow Aspirate into marrowed chamber of processing disposable container 
547 
through the red access site. 
548 
4. Place processing disposable container into SmartPrep centrifuge to process Bone Marrow Aspirate into 
549 
BMAC. Make sure white access site on container aligns with white dot on rotor.  
550 
5. Place counterweight balance in rotor across from the disposable container.  
551 
6. Close lid. Press start button. Total process time is about 15 minutes. About 60 ml of aspirate will create 7 to 
552 
10 ml of final concentrate. 
553 
7. After cycle is complete, remove processing disposable container. Place container onto holder apparatus. 
554 
8. Following asceptic technique, prep the white access site with a clean wipe.  
555 
9. For cellur resuspension, use the syringe with blood canula and yellow spacers to withdraw excess plasma 
556 
from the plasma chamber by drawing up plasma until bubble are observed in the syringe.   
557 
10. Remove syringe and re-prep white access site.  
558 
11. To resuspend bone marrow cells into the remaining plasma, withdraw the remaining plasma into the 20 ml 
559 
BMAC syringe with blood canula, but without spacers. Gently inject it back into the plama chamber. Repeat 
560 
step 2 to 3 times until cells are visibly resuspended in the plasma.  
561 
12. Then withdraw the total volume into the syringe. Obeserve the base of the plasma chamber to confirm all 
562 
cells have been withdrawn into the syringe. 
563 
13. Transfer BMAC back into sterile field by connecting the BMAC syringe to the sterile luer-lok connector on a 
564 
20 ml sterile BMAC receiving syringe, which should be held by another medical staff member. Save the BMAC 
565 
receiving syringe filled with final aspirate concentrate for BMAC application, which occurs after the insertion of 
566 
the nerve graft. 
567 
 
568 
Note: The 60 ml BMAC kit is for single-patient use only. Once, the final concentrate is obtained, the BMAC kit 
569 
should be disposed as biohazardous waste. The kit (not including the centrifuge system) will be handled and 
570 
disposed in accordance with standard regulations of the operating room.  
571 
 
572 
Harvest Terumo (formerly Harvest Technologies), the company who supplies the BMAC system, will provide 
573 
training to medical staff on how to use of the BMAC system and how to yield the final BMAC.  
574 
 
575 
Apply BMAC: 
576 
Medical staff, specifically surgeons, who are properly trained and licensed will conduct and/or oversee the 
577 
application of the final BMAC. Following the insertion of the nerve graft, of the 7 to 10 ml of final BMAC that is 
578 
yielded using the BMAC system, half (3.5 to 5 ml) of the final concentrate will be withdrawn using a syringe, 
579 
Figure B: SmartPrep 2 Centrifuge 
Figure C: 60 ml BMAC kit 

 
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which is then injected on top of the nerve graft. The other half of the concentrate (3.5 to 5 ml) of the final 
580 
concentrate will be stored in a tube containing culture media and then properly shipped overnight to Cleveland 
581 
Clinic for cell processing and colony assay. The research team will be responsible for shipping the contents to 
582 
Cleveland Clinic.  
583 
 
584 
6) Analysis of BMAC Samples 
585 
At Cleveland Clinic, the lab staff will only need half of final concentrate (3.5 to 5 ml) for each subject to collect 
586 
data on the following variables:  
587 
 
Cell Concentration,  
588 
 
Connective Tissue Progenitor (CTP) Cells Prevalence 
589 
 
CTP Concentration  
590 
 
591 
Day 6 from when samples are cultured onto slides: Colony Forming Units (CFU) will be counted to calculate the 
592 
mean performance for the following variables:  
593 
 
Mean Cell Number 
594 
 
Mean Cell Density 
595 
 
Mean Cell Area Fraction 
596 
 
Mean Area Fraction of Alkaline Phosphatase Expression  
597 
 
598 
Analyzing the BMAC samples and collecting the data above will confirm that the aspirate contains bone marrow 
599 
stem cells, commonly referred to as CTP cells. 
600 
 
601 
All laboratory evaluations of BMAC slides will be conducted at Cleveland Clinic under the guidance of the 
602 
consultants at that location. At Cleveland Clinic, BMAC samples will first be sterilely suspended in alpha-
603 
Minimal Essential Media complete media. Within 1 to 2 days of receiving the sample, the sample will be 
604 
cultured onto a slide. A hemacytometer will be used to determine a nucleated cell count. Cells will be placed 
605 
into a standardized assay for osteogenic CTPs (CTP-Os) (four chambers on 2 Lab-tek slides). On day 6 from 
606 
when samples were cultured onto slides, the slides will be harvested using fixation and then stained with 
607 
Alkaline phosphatase and DAPI, according to established protocols for colony assay analysis using 
608 
Colonyze™ software. 
609 
 
610 
BMAC samples will be coded and labeled with the subject’s 2-digit ID number upon collection at the performance 
611 
site. Subjects’ names or other identifiers will not be shared with the collaborators at the Cleveland Clinic.  Samples 
612 
will be shipped to, stored, and secured in the Lerner Research Institute at Cleveland Clinic. Access to these 
613 
samples will be limited to the consultants and supporting technicians at Cleveland Clinic. When samples are made 
614 
into slides, the same coding numbers on the samples will be written on the slides. Any left-over aspirate 
615 
concentrate from the sample will be discarded per Cleveland Clinic’s policy. 
616 
 
617 
The automated colony assay system will measure CTP prevalence and the proliferation, migration and 
618 
differentiation of the CTP progeny.  
619 
 
620 
7) Operative and Post-Operative Follow-Up Visits: 
621 
For the primary objective: Adverse events will be captured at Day 0 (day of surgery) and at Day 10 Post-operative 
622 
(+/- 5 days).   
623 
For the secondary objective: Follow-up assessments will occur at Month 1 (+/- 2 weeks), Month 6 (+/- 2 weeks), 
624 
Month 12 (+/- 2 weeks), and Month 18 (+/- 2 weeks) post-surgery. Assessments will be used to evaluate the 
625 
subject’s recovery of the targeted motor functional domain, sensory functional domain, and quality of life. 
626 
Additional assessments will be used in order to compare results to historic controls and to determine the rate and 
627 
level of reinnervation. 
628 
 
629 
Study team personnel will conduct the post-operative follow up visits listed below after Day 0: 
630 

 
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631 
 
Day 0 (Day of Surgery):  
632 
 
633 
Operative Information: 
634 
 Surgery Information: Date of Surgery, Laterality of Site of Nerve Injury Repair 
635 
 Nerve Repair Procedures: Nerve Repair, Nerve Gap, Type of Repair, Suture Type, Suture Size, # of 
636 
Sutures on Proximal End, # of Sutures on Distal End, Sealant Used, and Nerve Graft Wrapped, 
637 
Distance from Proximal Nerve Stump to End Organ, Avance Nerve Graft Product Code, Quantity of 
638 
Nerve Graft Used, Length of Implanted Nerve Graft, Duration of Surgical Procedure, Total Volume of 
639 
Bone Marrow Aspirate Harvested, Total Volume of Final Aspirate Concentrate, Volume of Final 
640 
Aspirate Concentrate Applied on Top of Avance Nerve Graft, Volume of Final Aspirate Concentrate 
641 
Shipped to Cleveland Clinic.  
642 
 
643 
Safety Evaluation:  
644 
 Evaluation of nerve repair site and iliac crest harvest site 
645 
 Assessment for any adverse events (number and level of severity) 
646 
 
647 
    Concomitant Treatments: Concomitant treatments will be captured to determine if the treatments are  
648 
related to nerve injury/repair or related to an adverse event.  
649 
 
650 
 
Day 10 (± 5 days) Post-Operative: 
651 
 
Safety Evaluation: 
652 
 Evaluation of nerve repair site and iliac crest harvest site 
653 
 Assessment for any adverse events (number and level of severity) 
654 
 
655 
Concomitant Treatments (captured to determine if treatments are related to nerve injury/repair or related to an 
656 
adverse event) 
657 
 
658 
 
Month 1 (+/- 2 weeks) Post-Operative: 
659 
 
Motor Domain Study- Effect limb and contralateral side (control) 
660 
 Range of Motion 
661 
 Muscle Strength Testing Grip Strength Testing 
662 
 Pinch Strength Testing  
663 
 
664 
Sensory Domain Study- Effected limb and contralateral side (control): All sensory assessments will be 
665 
conducted using the Neurosensory & Motor Testing System (NSMTS).  
666 
 1 Point Static Discrimination 
667 
 1 Point Moving Discrimination 
668 
 2 Point Static Discrimination 
669 
 2 Point Moving Discrimination 
670 
 
671 
      Rosen-Lundborg Study (compare results to historic controls) 
672 
 Sensory Domain (Innervation, Tactile Gnosis, and Finger Dexterity) 
673 
 Motor Domain (Innervation and Grip Strength) 
674 
 Pain/Discomfort Domain (Cold Intolerance and Hyperesthesia) 
675 
 
676 
Quality of Life (Web-based) 
677 
 PROMIS Adult Self-Reported Physical Health Domain Assessment 
678 
o Physical Function 
679 
o Pain Intensity  
680 

 
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o Pain Interference 
681 
o Fatigue  
682 
o Sleep Disturbance 
683 
o Pain Behavior 
684 
 Quick DASH Assessment 
685 
 
686 
 
Month 6 (± 2 weeks) Post-Operative: 
687 
 
Motor Domain Study- Effect limb and contralateral side (control) 
688 
 Range of Motion 
689 
 Muscle Strength Testing  
690 
 Grip Strength Testing  
691 
 Pinch Strength Testing  
692 
 
693 
Sensory Domain Study- Effected limb and contralateral side (control): All sensory assessments will be 
694 
conducted using NSMTS.  
695 
 1 Point Static Discrimination 
696 
 1 Point Moving Discrimination 
697 
 2 Point Static Discrimination 
698 
 2 Point Moving Discrimination 
699 
 
700 
      Rosen-Lundborg Study (compare results to historic controls) 
701 
 Sensory Domain (Innervation, Tactile Gnosis, and Finger Dexterity) 
702 
 Motor Domain (Innervation and Grip Strength) 
703 
 Pain/Discomfort Domain (Cold Intolerance and Hyperesthesia) 
704 
 
705 
Quality of Life (Web-based) 
706 
 PROMIS Adult Self-Reported Physical Health Domain Assessment 
707 
o Physical Function 
708 
o Pain Intensity  
709 
o Pain Interference 
710 
o Fatigue  
711 
o Sleep Disturbance 
712 
o Pain Behavior 
713 
 Quick DASH Assessment  
714 
 
715 
 
Month 12 (± 2 weeks) Post-Operative: 
716 
 
Motor Domain Study- Effect limb and contralateral side (control) 
717 
 Range of Motion 
718 
 Muscle Strength Testing  
719 
 Grip Strength Testing  
720 
 Pinch Strength Testing  
721 
 
722 
Sensory Domain Study- Effected limb and contralateral side (control): All sensory assessments will be 
723 
conducted using NSMTS.  
724 
 1 Point Static Discrimination 
725 
 1 Point Moving Discrimination 
726 
 2 Point Static Discrimination 
727 
 2 Point Moving Discrimination 
728 
 
729 
      Rosen-Lundborg Study (compare results to historic controls) 
730 

 
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 Sensory Domain (Innervation, Tactile Gnosis, and Finger Dexterity) 
731 
 Motor Domain (Innervation and Grip Strength) 
732 
 Pain/Discomfort Domain (Cold Intolerance and Hyperesthesia) 
733 
 
734 
Quality of Life (Web-based) 
735 
 PROMIS Adult Self-Reported Physical Health Domain Assessment 
736 
o Physical Function 
737 
o Pain Intensity  
738 
o Pain Interference 
739 
o Fatigue  
740 
o Sleep Disturbance 
741 
o Pain Behavior 
742 
 Quick DASH Assessment 
743 
 
744 
Nerve Conduction Study: Nerve conduction velocity (NCV) and Electromyography (EMG) testing will be 
745 
conducted on the target muscle group to assess rate and level of motor and sensory reinnervation.   
746 
 
Rate of Reinnervation (Motor and Sensory Domain) 
747 
 
Level of Reinnervation (Motor and Sensory Domain) 
748 
 
749 
 
Month 18 (± 2 weeks) Post-Operative: 
750 
 
Motor Domain Study- Effect limb and contralateral side (control) 
751 
 Range of Motion 
752 
 Muscle Strength Testing  
753 
 Grip Strength Testing  
754 
 Pinch Strength Testing  
755 
 
756 
Sensory Domain Study- Effected limb and contralateral side (control): All sensory assessments will be 
757 
conducted using NSMTS.  
758 
 1 Point Static Discrimination 
759 
 1 Point Moving Discrimination 
760 
 2 Point Static Discrimination 
761 
 2 Point Moving Discrimination 
762 
 
763 
      Rosen-Lundborg Study (compare results to historic controls) 
764 
 Sensory Domain (Innervation, Tactile Gnosis, and Finger Dexterity) 
765 
 Motor Domain (Innervation and Grip Strength) 
766 
 Pain/Discomfort Domain (Cold Intolerance and Hyperesthesia) 
767 
 
768 
Quality of Life (Web-based) 
769 
 PROMIS Adult Self-Reported Physical Health Domain Assessment 
770 
o Physical Function 
771 
o Pain Intensity 
772 
o Pain Interference 
773 
o Fatigue  
774 
o Sleep Disturbance 
775 
o Pain Behavior 
776 
 Quick DASH Assessment  
777 
 
778 
Nerve Conduction Study: NCV and EMG testing will be conducted on the target muscle group to assess rate 
779 
and level of motor and sensory reinnervation.   
780 

 
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 
Rate of Reinnervation (Motor and Sensory Domain) 
781 
 
Level of Reinnervation (Motor and Sensory Domain) 
782 
 
783 
Timeline of Study 
784 
 
785 
Assessment 
Study Day / 
Visit 
Pre- 
Operative
(-4 wks  
to 0) 
Surgery 
Day 0 
F/U  
Day 10  
(±5 days) 
F/U  
Month 1 
(±2 wks) 
F/U  
Month 6 
(±2 wks) 
F/U  
Month 12 
(± 2 wks) 
F/U  
Month 18 
(±2 wks) 
Informed Consent 
X 
 
 
 
 
 
 
Screening: Inclusion / Exclusion  
Criteria 
X 
X 
 
 
 
 
 
Demographics, Medical History  
& Nerve Injury History 
X 
 
 
 
 
 
 
Operative Information  
 
X 
 
 
 
 
 
Safety Evaluation of Adverse Event
 
X 
X 
 
 
 
 
Concomitant Treatments 
 
X 
X 
 
 
 
 
Motor and Sensory Domain Studies
 
 
 
X 
X 
X 
X 
Rosen-Lundborg Study 
 
 
 
X 
X 
X 
X 
PROMIS Assessment 
 
 
 
X 
X 
X 
X 
Quick DASH Assessment 
 
 
 
X 
X 
X 
X 
Nerve Conduction Study 
 
 
 
 
 
X 
X 
 
786 
 
787 
7.3.1 Collection of Human Biological Specimens.  Human biological (bone marrow aspirate concentrate) samples 
788 
will be collected for this study. 
789 
 
790 
Of the 7 to 10 ml of final BMAC that is yielded using the BMAC system, half (3.5 to 5 ml) of the final concentrate 
791 
will be poured into a tube containing culture media and then properly shipped overnight to Cleveland Clinic for cell 
792 
processing and colony assay. 
793 
 
794 
BMAC samples will be coded and labeled with the subject’s 2-digit ID number upon collection at performance site. 
795 
Samples will be shipped to, stored, and secured in the Lerner Research Institute at Cleveland Clinic. Access to 
796 
these samples will be limited to the consultants and supporting technicians at Cleveland Clinic. When samples are 
797 
cultured into slides, the same coding numbers on the samples will be written on the slides. Any left over aspirate 
798 
concentrate from the sample will be discarded per Cleveland Clinic’s policy. 
799 
 
800 
Shipping Procedure for BMAC Samples: 
801 
1) Place the labeled samples into an insulated shipping container (styrofoam box) with four freezer packs. 
802 
Place Digi-temp temperature strip in box, next to sample, (Cole-Parmer, EW-09035-49). 
803 
2) Seal the shipping container with tape and affix the shipping label. 
804 
3) Record the shipping label information (written documentation of the number and date in the specimen 
805 
tracking log). Also photograph the label to enable sharing with the Muschler Lab. 
806 
4) Promptly transport the shipping container for dispatch, (i.e. UPS or FedEx). 
807 
5) Notify the AI and/or supporting research team at Cleveland Clinic that the sample has been shipped. 
808 
Provide the research team with the sample shipping and tracking information and photograph of the 
809 
shipping label.  
810 
 
811 

 
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7.3.1.1 Laboratory evaluations and special precautions. BMAC samples will be collected and shipped to 
812 
Cleveland Clinic Lerner Research Institute. Samples will be stored in a refrigerator up to 2 days, which then the 
813 
samples are cultured onto slides and then discarded. After samples are made into slides, slides will be stored 
814 
in slide box up to 8 days from when the sample was first received, which then the sample is processed for 
815 
staining and colony analysis.  
816 
 
817 
PI, AIs, and additional research team listed on the delegation logs will have access to the specimens, the 
818 
clinical information, and linkage. After sample analysis, the samples will be discarded, following the 
819 
Cleveland Clinic Lerner Research Institute policy guidelines for sample disposal. No specimens will be 
820 
stored for future research. 
821 
 
822 
The specimens will be analyzed at Cleveland Clinic to collect data on the following variables: cell 
823 
concentration, CTP prevalence, and CTP concentration. CFUs will be counted on day 6 from when samples 
824 
were plated into culture to calculate the mean performance for the following variables: cell number, density, cell 
825 
area fraction, and area fraction of Alkaline Phosphatase expression.  
826 
 
827 
7.3.1.2 Specimen storage. BMAC will be collected and shipped to Cleveland Clinic. After analysis, samples will 
828 
be discarded, following proper Cleveland Clinic Lerner Research Institute policy guidelines for sample disposal.  
829 
 
830 
 
Where and how specimens will be stored (including storage plan, etc.):  
831 
Samples will be stored in a refrigerator until ready for processing and analysis. After samples are made 
832 
into slides, slides will be stored in slide box until they are processed for staining and colony analysis. 
833 
 
How specimens will be labeled: 
834 
All BMAC samples will be coded and labeled with the subject’s 2-digit ID number upon collection at 
835 
performance site. No personal identifiers will be used in the coding of human specimens.  
836 
 
Who will have the access to the specimens, the clinical information, and the linkage: PI, AIs, 
837 
and additional research team listed on the delegation logs will have access to the specimens, the 
838 
clinical information, and linkage. After sample analysis is complete, the samples will be discarded at 
839 
Cleveland Clinic, following their guidelines for sample disposal. 
840 
 
How specimens will be used (general and/or specific use):  
841 
The specimens will be analyzed at Cleveland Clinic to collect data on the following variables: cell 
842 
concentration, CTP prevalence, and CTP concentration. CFUs will be counted on day 6 from when 
843 
samples were plated into culture to calculate the mean performance for the following variables: cell 
844 
number, density, cell area fraction, and area fraction of Alkaline Phosphatase expression. 
845 
 
Specify the length of time that specimens will be stored: The samples will be stored up to 2 days 
846 
until the samples are cultured onto slides and then discarded. The slide for each sample will be stored 
847 
up to 8 days from when the sample was first received. No specimens will be stored for future research.  
848 
  
849 
7.3.2  Data Collection.  The data will be recorded on an approved paper Case Report Form (CRF). All data will 
850 
be coded and then entered electronically via Research Electronic Data Capture (REDCap) which is a secure, 
851 
web-based application designed exclusively to support data capture for research studies. The data collected in 
852 
REDCap will be held as an electronic case report form (eCRF). Data collection from all sites will be overseen 
853 
by the Clinical Manager.  
854 
 
855 
All documentation supporting the CRF data, such as laboratory or hospital records, must be readily available to 
856 
verify entries in the CRF. Documents (including laboratory reports, hospital records subsequent to Serious 
857 
Adverse Events (SAEs), etc.) electronically transmitted will be de-identified and contain no patient identification 
858 
information with the exception of a subject’s assigned subject ID. This will help to ensure subject confidentiality.  
859 
 
860 
Pre-Operative Information: 
861 
Demographics, Nerve Injury History, and Medical History will be collected on the CRF. 
862 

 
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863 
Operative Information:  
864 
Surgery Information: Date of Surgery, Laterality of Site of Nerve Injury Repair 
865 
 
866 
Nerve Repair Procedures: Nerve Repair, Nerve Gap, Type of Repair, Suture Type, Suture Size, # of Sutures 
867 
on Proximal End, # of Sutures on Distal End, Sealant Used, and Nerve Graft Wrapped, Distance from Proximal 
868 
Nerve Stump to End Organ, Avance Nerve Graft Product Code, Quantity of Nerve Graft Used, Length of 
869 
Implanted Nerve Graft, Duration of Surgical Procedure, Total Volume of Bone Marrow Aspirate Harvested, 
870 
Total Volume of Final Aspirate Concentrate, Volume of Final Aspirate Concentrate Applied on Top of Avance 
871 
Nerve Graft, Volume of Final Aspirate Concentrate Shipped to Cleveland Clinic.  
872 
 
873 
Each site will be responsible for site monitoring consistent with ICH/FDA guidelines. Monitoring will include a 
874 
combination of data checks in conjunction with the research monitor every 6 months. This will include 
875 
reviewing the individual subject records, including consent forms, case report forms, supporting data, 
876 
laboratory specimen records, any SAEs, unanticipated problems involving risk to subjects or others, and 
877 
medical records (physicians’ progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of 
878 
study subjects, compliance with the protocol, and accuracy and completeness of records. The site monitor also 
879 
will inspect sites’ regulatory files to ensure those regulatory requirements are being followed. The overall 
880 
Principal Investigator will interact with the research monitor at each site to review SAE reports, data checks 
881 
and resolve safety issues if any should arise. The overall Principal Investigator and the site research monitor 
882 
will determine the course of action necessary to meet safety goals and objectives. The overall Principal 
883 
Investigator will monitor the safety of the data compiled across all sites.  
884 
 
885 
7.3.3. Human Biological Specimens/Tissue/Data Banking. For Protocols Only Establishing a Repository, use Template 
886 
P02R. 
887 
 
888 
N/A  
889 
 
890 
 Statistical Consideration  
891 
 
892 
7.4 7.4.1 Sample Size Estimation.  Approximately 45 subjects total will be recruited total from the performance sites 
893 
combined. Participants will be recruited at the time of peripheral nerve injury diagnosis. Up to 45 subjects will 
894 
be enrolled to account for attrition.   
895 
 
896 
7.4.2 Primary (i.e., primary outcome variables) and secondary endpoints.  
897 
Primary Safety Endpoints: The safety endpoints will be the comparison of the nature and incidence of AEs 
898 
between the group of subjects receiving Avance with BMAC and the historical data of nerve repairs with 
899 
Avance. Specifically, long-term study associated AEs, such as infection, wound dehiscence, neuropathy, 
900 
carpal tunnel syndrome, bleeding, seroma, and lymphocele will be captured and analyzed together with any 
901 
change in incidence of listed AEs which may be precipitated by treatment. AEs will be mapped to a MedDRA 
902 
preferred term and system organ classification. The occurrence of the AEs will be summarized by repair type 
903 
using MedDRA preferred terms, system organ classifications, and severity. All AEs will be listed for individual 
904 
subjects showing both verbatim and preferred terms. Separate summaries of treatment-emergent SAEs and 
905 
AEs related to repair will be generated. 
906 
 
907 
Secondary Efficacy Endpoint Comparing to Autograft: The secondary efficacy endpoint is based on 
908 
the Rosen- Lundborg Scale total score and will be compared using an unpaired t-test. 
909 
 
910 
Secondary Efficacy Endpoint Comparing to Avance Alone: The secondary efficacy endpoint is based 
911 
on the functional recovery rates when using the Rosen- Lundborg Scale total score and will be 
912 
compared using an unpaired t-test. 
913 
 
914 

 
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7.4.3 Data analysis.  
915 
Primary Safety Endpoints: The safety endpoints will be the comparison of the nature and incidence of AEs 
916 
between the group of subjects receiving Avance with BMAC and the historical data of nerve repairs with 
917 
Avance. Specifically, long-term study associated AEs, such as infection, wound dehiscence, neuropathy, 
918 
carpal tunnel syndrome, bleeding, seroma, and lymphocele will be captured and analyzed together with any 
919 
change in incidence of listed AEs which may be precipitated by treatment. AEs will be mapped to a MedDRA 
920 
preferred term and system organ classification. The occurrence of the AEs will be summarized by repair type 
921 
using MedDRA preferred terms, system organ classifications, and severity. All AEs will be listed for individual 
922 
subjects showing both verbatim and preferred terms. Separate summaries of treatment-emergent SAEs and 
923 
AEs related to repair will be generated. 
924 
 
925 
Any event reported on the CRF that occurs on or after the repair is defined as treatment-emergent. 
926 
Additionally, it is assumed that an AE which was reported to have started on Day 0 without an associated 
927 
onset time may have occurred after the repair. Hence, AEs occurring on Day 0 with no associated onset time 
928 
are assumed to be treatment-emergent. Subject disposition will be presented for all subjects. Summaries will 
929 
be broken down by visit as well as being presented over all visits. The number of subjects who completed the 
930 
study and discontinued from the study will be provided. The reasons for early discontinuation also will be 
931 
presented. 
932 
Secondary Efficacy Endpoint Comparing to Autograft: The secondary efficacy endpoint is based on 
933 
the Rosen- Lundborg Scale total score and will be compared using an unpaired t-test. 
934 
Test of non-inferiority and superiority of Avance Nerve Graft to historical nerve autograft scores with respect to 
935 
Rosen-Lundborg will be conducted using closed testing procedures.  The hypotheses being tested are as 
936 
follows: 
937 
H01:  Δ ≤ -Δ0   vs.    H11:  Δ > -Δ0 
938 
H02:  Δ =  0     vs.    H12:  Δ ≠ 0 
939 
where Δ = μC- μA is the difference between the mean Rosen-Lundborg Scores for the Avance Nerve Graft & 
940 
BMAC (μA) and the mean Rosen-Lundborg scores for the historical autograft controls (μC), Δ0 is the non-
941 
inferiority margin 0.51.  The null hypothesis of non-inferiority (H01) will be tested first and, if rejected, then the 
942 
null hypothesis of superiority (H02) will be assessed.  Given that the closed testing procedure is implemented, 
943 
no adjustment for multiple testing will be required.  
944 
 
945 
Secondary Efficacy Endpoint Comparing to Avance Alone: The secondary efficacy endpoint is based 
946 
on the functional recovery rates when using the Rosen- Lundborg Scale total score and will be 
947 
compared using an unpaired t-test. 
948 
Test of non-inferiority of Avance Nerve Graft plus BMAC to Avance Nerve Graft recovery rates with respect to 
949 
Rosen-Lundborg scores will be conducted using closed testing procedures.  The hypothesis being tested is as 
950 
follows: 
951 
H01:  πA - πAB >  Δ   vs.    H11:  πA - πAB < Δ 
952 
where πA is the recovery of Avance Nerve Graft and πAB is the recovery of Avance plus BMAC. Δ is the non-
953 
inferiority margin 25% 
954 
 
955 
Additional secondary endpoints for both comparisons will include: 
956 
 
Percent recovery to baseline (defined as the difference in the measured assessment of the repaired 
957 
nerve as compared with neighboring uninjured and/or contra-lateral side); 
958 
 
Time to recovery; 
959 
 
PROMIS Scores; 
960 
 
DASH scores; 
961 

 
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 
Nerve Conduction Studies 
962 
Baseline Comparability: Baseline characteristics of the sites will be compared using the unpaired t-test or the 
963 
Wilcoxon rank sum test for continuous variables, depending on their distributions. Percentage differences will 
964 
be compared with the Fisher’s exact test (or the 2 test, when appropriate). Additional secondary efficacy 
965 
endpoints (each measure assessed separately) will be compared using non-parametric statistical tests (for 
966 
instance a Kruskal-Wallis followed by corrected Wilcoxon rank sum tests as appropriate).  
967 
 
968 
Sharing study results across all sites: 
969 
The site research coordinator will enter non-personally identifiable information into a central and secured web-
970 
based data management system known as REDCap. REDCap will link all data from each site. This data 
971 
management system has incorporated state-of-the-art features for electronic data collection and is configured 
972 
in accordance with best practices for information technology and research data management.  Data collected 
973 
at the Curtis Hand Center and Cleveland clinic will be communicated back to either SAMMC or WRNMMC by 
974 
specific secure methods for compilation and analysis.  
975 
 
976 
Upon completion of the study, the data management group and biostatisticians will generate the Tables, 
977 
Forms, and Listings for the PI to review. Once verified and approved by the PI, this document will be finalized. 
978 
Based on this study data, the PI will draft a study report. This report along with the Tables, Forms, and Listings 
979 
will be provided to the collaborative investigators for review and edits. A copy will also be provided to the 
980 
research team for review and comments.  
981 
 
982 
Study results, including information that could potentially benefit the subject, will be made available to subject 
983 
participants upon completion of the final study report. Certain results, such as screening results and 
984 
improvement of function as recorded by follow-up assessments, will be shared with the subject during the 
985 
study.  
986 
 
987 
BMAC Culture Analysis Outcomes: Data from all colonies will be used to quantify and compare proliferation, 
988 
migration (i.e., colony density), and differentiation (i.e., % of colonies expressing each marker, area fraction of 
989 
colonies expressing each marker) among tissue types. 
990 
 
991 
Statistical Methods for BMAC Culture Analysis: Descriptive statistics will be used to define the mean, 95% 
992 
confidence interval, range, etc, for each parameter. The mean of each parameter will be compared between 
993 
enrolled subjects and historical controls using Student’s t test or Mann-Whitney nonparametric test. The 
994 
distribution of each (untransformed) parameter will be described in terms of relative fit to a Gaussian 
995 
distribution, skewness, evidence of multimodal distribution, etc. Data that follow a lognormal (skewed) 
996 
distribution will be subjected to a natural-log transformation before each t test is performed, and data that 
997 
cannot be adequately transformed will be analyzed using the Mann-Whitney nonparametric test.   
998 
  
999 
7.7 Confidentiality.  The research team will maintain the list linking the subjects’ name and study number. This link 
000 
will be stored separately from study data. The master list linking study numbers with personally identifiable 
001 
information will be destroyed upon completion of the protocol and all data analysis. Anonymized data will be 
002 
deleted from local site computers no later than five years after completion of the study.  All hardcopy data and 
003 
surveys will be stored in a locked research office cabinet with access only to the research team.  All electronic data 
004 
with be stored on a secure server with access only to research team for a period of no longer than 5 years 
005 
following conclusion of the study.  Research related documents (including electronic data) and medical records will 
006 
be accessible only by key personnel specifically designated and authorized by the Principal Investigator. All such 
007 
personnel will be properly trained and supervised regarding the management and handling of confidential 
008 
materials. The Principal Investigator assumes full responsibility for such training, supervision, and conduct. This 
009 
information will also be available for audit by study monitors and representatives of the local IRB, the MCC, the 
010 
DOD, the FDA and the OHRP 
011 

 
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012 
 
013 
7.7.1 Certificate of Confidentiality.  N/A  
014 
 
015 
8.0  RISKS/BENEFITS ASSESSMENT 
016 
 
017 
8.1  Risks:   
018 
General Operative Risks: 
019 
 
Infection-Rare (Event Rate < 1%) 
020 
 
Blood loss-Rare (Event Rate < 1%) 
021 
 
Anesthesia associated complications-Rare (Event Rate < 1%) 
022 
 
Localized dermatitis-Rare (Event Rate < 1%) 
023 
 
Drop in blood pressure-Rare (Event Rate < 1%) 
024 
 
Syncope (fainting)-Rare (Event Rate < 1%) 
025 
 
Bleeding at surgical site-Rare (Event Rate < 1%) 
026 
 
Pain at surgical site-Likely (5% ≤ Event Rate < 10%) 
027 
Complications Specific to Any Nerve Reconstruction Procedure: 
028 
 
Pain-Likely (5% ≤ Event Rate < 10%) 
029 
 
Neuroma formation-Likely (5% ≤ Event Rate < 10%) 
030 
 
Decreased or increased sensitivity-Likely (5% ≤ Event Rate < 10%) 
031 
 
Impaired motor or sensory function-Likely (5% ≤ Event Rate < 10%) 
032 
 
Risk that nerve may fail to regenerate-Likely (5% ≤ Event Rate < 10%) 
033 
Avance Nerve Graft Risks: 
034 
 
Hypersensitivity, allergic reactions, or other adverse immune responses-Rare (Event Rate < 1%) 
035 
 
Transmission of diseases of unknown etiology-Rare (Event Rate < 1%) 
036 
 
Transmission of known infectious agents including, but not limited to viruses, bacteria, and fungi-Rare 
037 
(Event Rate < 1%) 
038 
Bone Marrow Extraction Risks:  
039 
 
Pain-Rare (Event Rate < 1%) 
040 
 
Infection-Rare (Event Rate < 1%) 
041 
 
Bruises-Rare (Event Rate < 1%) 
042 
Risks of adding BMAC to Avance Nerve Graft 
043 
 
Increased immune response leading to nerve graft failure-Rare (Event Rate < 1%) 
044 
Expected & Anticipated Adverse Events*: 
045 
 
Mild incisional redness- Likely (5% ≤ Event Rate < 10%) 
046 
 
Tenderness of surgical area- Likely (5% ≤ Event Rate < 10%) 
047 
 
Mild edema of surgical area- Likely (5% ≤ Event Rate < 10%) 
048 
 
Numbness- Likely (5% ≤ Event Rate < 10%) 
049 
 
Pain at iliac crest harvest site- Likely (5% ≤ Event Rate < 10%) 
050 
Risks of Nerve Conduction Studies: 
051 
 
Voltage of electrical pulses- very low 
052 
There is often some muscular ache or discomfort to an extremity during physical performance tests. All of your 
053 
performance tests will be done under the supervision of trained study personnel to be sure the performance 
054 
tests are done correctly. 
055 
 
056 
*These adverse events are considered expected and are not required to be recorded on the Adverse Events 
057 
CRF unless they increase in severity. Expected adverse events, which are not serious are reported on the 
058 
Continuing Review (CR) Progress Report. CR is generally performed on a 12-month cycle. 
059 
 
060 

 
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There is also a risk of breach of confidentiality of data belonging to the subjects enrolled in the study. Risk of 
061 
breach of confidentiality will be minimized by keeping master list separate from data collection and consent 
062 
forms. Subjects will be assigned a unique identification number, ID.  
063 
  
064 
8.2 Potential Benefits.  This study does not offer direct benefit from standard treatment to participants but is 
065 
likely to yield important information about the safety of the sequential treatments of Avance Nerve Graft and 
066 
BMAC containing autologous bone marrow stem cells in comparison to the treatment of Avance Nerve Graft 
067 
alone.  
068 
 
069 
The gold standard for nerve gap repair, autografting, carries significant patient risk and permanent morbidity to 
070 
the donor site.  Additionally, sources and quantities of autologous tissue for repairs are limited and, when faced 
071 
with severe trauma, donor sites are often part of the zone of injury and simply not viable for harvest. The latter 
072 
issue can be mitigated with allograft technology, and the use of Avance has shown promise for replacing the 
073 
prevalence of autograft therapy, though improvements in gap repair speed and success rates are required for 
074 
allografts to supplant autografts completely. This multicenter study will provide an evaluation of the safety and 
075 
efficacy of combining Avance and autologous BMAC. Establishing a treatment modality that is non-inferior or 
076 
superior to autograft and allograft alone will reduce procedure time, eliminate donor site morbidity, lower 
077 
amputation rates, reduce long-term disability, promote earlier return to active duty/civilian employment, 
078 
increase quality of life, and lower overall health care costs. The ultimate goal of this project is to provide the 
079 
peripheral nerve injury patient with the safest and most efficacious treatment options. 
080 
 
081 
9.0  ADVERSE EVENTS, UNANTICIPATED PROBLEMS, AND DEVIATIONS 
082 
 
083 
9.1  General Operative Risks: 
084 
 
Infection-Rare (Event Rate < 1%) 
085 
 
Blood loss-Rare (Event Rate < 1%) 
086 
 
Anesthesia associated complications-Rare (Event Rate < 1%) 
087 
 
Localized dermatitis-Rare (Event Rate < 1%) 
088 
 
Drop in blood pressure-Rare (Event Rate < 1%) 
089 
 
Syncope (fainting)-Rare (Event Rate < 1%) 
090 
 
Bleeding at surgical site-Rare (Event Rate < 1%) 
091 
 
Pain at surgical site-Likely (5% ≤ Event Rate < 10%) 
092 
Complications Specific to Any Nerve Reconstruction Procedure: 
093 
 
Pain-Likely (5% ≤ Event Rate < 10%) 
094 
 
Neuroma formation-Likely (5% ≤ Event Rate < 10%) 
095 
 
Decreased or increased sensitivity-Likely (5% ≤ Event Rate < 10%) 
096 
 
Impaired motor or sensory function-Likely (5% ≤ Event Rate < 10%) 
097 
 
Risk that nerve may fail to regenerate-Likely (5% ≤ Event Rate < 10%) 
098 
Avance Nerve Graft Risks: 
099 
 
Hypersensitivity, allergic reactions, or other adverse immune responses-Rare (Event Rate < 1%) 
100 
 
Transmission of diseases of unknown etiology-Rare (Event Rate < 1%) 
101 
 
Transmission of known infectious agents including, but not limited to viruses, bacteria, and fungi-Rare 
102 
(Event Rate < 1%) 
103 
Bone Marrow Extraction Risks:  
104 
 
Pain-Rare (Event Rate < 1%) 
105 
 
Infection-Rare (Event Rate < 1%) 
106 
 
Bruises-Rare (Event Rate < 1%) 
107 
Risks of adding BMAC to Avance Nerve Graft 
108 
 
Increased immune response leading to nerve graft failure-Rare (Event Rate < 1%) 
109 
Expected & Anticipated Adverse Events*: 
110 

 
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 
Mild incisional redness- Likely (5% ≤ Event Rate < 10%) 
111 
 
Tenderness of surgical area- Likely (5% ≤ Event Rate < 10%) 
112 
 
Mild edema of surgical area- Likely (5% ≤ Event Rate < 10%) 
113 
 
Numbness- Likely (5% ≤ Event Rate < 10%) 
114 
 
Pain at iliac crest harvest site- Likely (5% ≤ Event Rate < 10%) 
115 
 
116 
Risks of Nerve Conduction Studies: 
117 
 
Voltage of electrical pulses- very low 
118 
 
119 
There is often some pain and discomfort associated with post-surgical rehabilitation that is no greater than 
120 
standard clinical care. All of your performance tests will be done under the supervision of trained study 
121 
personnel to be sure the performance tests are done correctly. 
122 
 
123 
*These adverse events are considered expected and are not required to be recorded on the Adverse Events 
124 
CRF unless they increase in severity. Expected adverse events, which are not serious are reported on the 
125 
Continuing Review (CR) Progress Report. CR is generally performed on a 12-month cycle. 
126 
 
127 
9.2  Reporting Unanticipated Problems Involving Risks to Subjects or Others, Serious Adverse Events and Deaths to 
128 
the Office of the IRB, RHC-C.  .  
129 
 
130 
All unanticipated problems involving risk to subjects or others, unexpected serious adverse events, 
131 
and all subject deaths related or possibly related to the study will be reported promptly providing initial 
132 
notification of the event as quickly as possible after  the research team’s knowledge of the event, but 
133 
within five (5) business days of identification by phone (210-916-0606/2598), by e-mail 
134 
(usarmy.jbsa.medcom-bamc.mbx.bamc-irb@mail.mil), by facsimile (210-916-1650) or via letter 
135 
addressed to IRB Administrator, Regional Health Command-Central Office of the Institutional Review 
136 
Board, Brooke Army Medical Center, Attn: MCHE-ZQ, Department of Quality and Safety, 3551 Roger 
137 
Brooke Drive, Fort Sam Houston, TX 78234-6315. A complete written report will follow the initial 
138 
notification within 10 working days. 
139 
 
140 
9.3  Research Monitor.   
141 
The research monitor will review all unanticipated problems involving risk to subjects or others, 
142 
serious adverse events and all subject deaths associated with the protocol and provide an unbiased 
143 
written report of the event to the RHC-C IRB. Other responsibilities may be assigned by the IRB. The 
144 
research monitor will comment on the outcomes of the event or problem and in the case of a serious 
145 
adverse event or death comment on the relationship to participation in the study. The research 
146 
monitor will also indicate whether he/she concurs with the details of the report provided by the study 
147 
investigator. Reports for events determined by either the investigator or research monitor to be 
148 
possibly or definitely related to participation and reports of events resulting in death will be promptly 
149 
forwarded to the RHC-C IRB Office. 
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10.0 WITHDRAWAL FROM STUDY PARTICIPATION.  Participants will be informed that they may discontinue the 
152 
study at any time, for any reason. They will be assured that the medical care which they receive at the 
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participating facility will not be affected should they elect to discontinue participation in the study.  
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11.0 USAMRMC Volunteer Registry Database. N/A  
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12.0  REFERENCES.  Berger, A., and Millesi, H. (1978). Nerve grafting. Clin. Orthop. 49–55. 
158 
 
159 
Brooks, D.N., Weber, R.V., Chao, J.D., Rinker, B.D., Zoldos, J., Robichaux, M.R., Ruggeri, S.B., Anderson, K.A., Bonatz, 
160 
E.E., Wisotsky, S.M., et al. (2012). Processed nerve allografts for peripheral nerve reconstruction: a multicenter study of 
161 
utilization and outcomes in sensory, mixed, and motor nerve reconstructions. Microsurgery 32, 1–14. 
162 
 
163 
Brushart, T.M. (2011). Nerve Repair (Oxford University Press). 
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Centeno, Christopher J. et al. “A Multi-Center Analysis of Adverse Events among Two Thousand, Three Hundred and 
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Seventy Two Adult Patients Undergoing Adult Autologous Stem Cell Therapy for Orthopaedic Conditions.” International 
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Orthopaedics 40.8 (2016): 1755–1765.  
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Center for Biologics Evaluation and Research, C. for D. and R.H. Cellular & Gene Therapy Guidances - Minimal 
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Manipulation of Human Cells, Tissues, and Cellular and Tissue-Based Products: Draft Guidance. 
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171 
Chen, C.-J., Ou, Y.-C., Liao, S.-L., Chen, W.-Y., Chen, S.-Y., Wu, C.-W., Wang, C.-C., Wang, W.-Y., Huang, Y.-S., and 
172 
Hsu, S.-H. (2007). Transplantation of bone marrow stromal cells for peripheral nerve repair. Exp. Neurol. 204, 443–453. 
173 
 
174 
Cho, M.S., Rinker, B.D., Weber, R.V., Chao, J.D., Ingari, J.V., Brooks, D., and Buncke, G.M. (2012). Functional outcome 
175 
following nerve repair in the upper extremity using processed nerve allograft. J. Hand Surg. 37, 2340–2349. 
176 
 
177 
Dezawa, M., Takahashi, I., Esaki, M., Takano, M., and Sawada, H. (2001). Sciatic nerve regeneration in rats induced by 
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transplantation of in vitro differentiated bone-marrow stromal cells. Eur. J. Neurosci. 14, 1771–1776. 
179 
 
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Ding, F., Wu, J., Yang, Y., Hu, W., Zhu, Q., Tang, X., Liu, J., and Gu, X. (2010). Use of tissue-engineered nerve grafts 
181 
consisting of a chitosan/poly(lactic-co-glycolic acid)-based scaffold included with bone marrow mesenchymal cells for 
182 
bridging 50-mm dog sciatic nerve gaps. Tissue Eng. Part A 16, 3779–3790. 
183 
 
184 
Ducic, I., Fu, R., & Iorio, M. L. (2012). Innovative treatment of peripheral nerve injuries: combined reconstructive concepts. 
185 
Annals of plastic surgery, 68(2), 180-187. 
186 
Referenced in Section 4 Human Data Ducic et al 2012 
187 
 
188 
Dvali, L., and Mackinnon, S. (2003). Nerve repair, grafting, and nerve transfers. Clin. Plast. Surg. 30, 203–221. 
189 
 
190 
Frykman, G., and Gramyk, K. (1991). Results of Nerve Grafting In: Gelberman R. Operative nerve repair and 
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reconstruction. (JB Lippincott). 
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193 
Galanakos, S.P., Zoubos, A.B., Ignatiadis, I., Papakostas, I., Gerostathopoulos, N.E., and Soucacos, P.N. (2011). Repair 
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of complete nerve lacerations at the forearm: an outcome study using Rosén-Lundborg protocol. Microsurgery 31, 253–
195 
262. 
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Graham, James B., Xue, Qing-Shan, Neubauer, Debbie, and Muir, David (2009). A chondroitinase-treated, decellularized 
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nerve allograft compares favorably to the cellular isograft in rat peripheral nerve repair. 2, 19–29. 
199 
 
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Guo, Y., Chen, G., Tian, G., and Tapia, C. (2013). Sensory recovery following decellularized nerve allograft 
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transplantation for digital nerve repair. J. Plast. Surg. Hand Surg. 47, 451–453. 
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203 
Hegde, V., Shonuga, O., Ellis, S., Fragomen, A., Kennedy, J., Kudryashov, V., & Lane, J. M. (2014). A prospective 
204 
comparison of 3 approved systems for autologous bone marrow concentration demonstrated nonequivalency in progenitor 
205 
cell number and concentration. Journal of orthopaedic trauma, 28(10), 591-598. 
206 
 
207 
Hendrich, Christian et al. “Safety of Autologous Bone Marrow Aspiration Concentration Transplantation: Initial 
208 
Experiences in 101 Patients.” Orthopedic Reviews.  1.2 (2009): e32. PubMed. 
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Hernigou, Philippe et al. “Cancer Risk Is Not Increased in Patients Treated for Orthopaedic Diseases with Autologous 
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Bone Marrow Cell Concentrate.” J Bone Joint Surg Am 95.24 (2013): 2215–2221. jbjs.org. 
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Hu, N., Wu, H., Xue, C., Gong, Y., Wu, J., Xiao, Z., Yang, Y., Ding, F., and Gu, X. (2013). Long-term outcome of the 
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repair of 50 mm long median nerve defects in rhesus monkeys with marrow mesenchymal stem cells-containing, chitosan-
215 
based tissue engineered nerve grafts. Biomaterials 34, 100–111. 
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Hu, J., Zhu, Q.-T., Liu, X.-L., Xu, Y., and Zhu, J.-K. (2007). Repair of extended peripheral nerve lesions in rhesus 
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monkeys using acellular allogenic nerve grafts implanted with autologous mesenchymal stem cells. Exp. Neurol. 204, 
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658–666. 
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IJpma, F.F.A., Nicolai, J.-P.A., and Meek, M.F. (2006). Sural nerve donor-site morbidity: thirty-four years of follow-up. 
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Ann. Plast. Surg. 57, 391–395. 
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223 
Isaacs, J. (2013). Major peripheral nerve injuries. Hand Clin. 29, 371–382. 
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Jackson, W.M., Alexander, P.G., Bulken-Hoover, J.D., Vogler, J.A., Ji, Y., McKay, P., Nesti, L.J., and Tuan, R.S. (2013). 
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Mesenchymal progenitor cells derived from traumatized muscle enhance neurite growth. J. Tissue Eng. Regen. Med. 7, 
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443–451. 
228 
 
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Jäger, M., Jelinek, E., Wess, K., Scharfstädt, A., Jacobson, M., Kevy, S., Krauspe, R. (2009).  Bone Marrow Concentrate: 
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A Novel Strategy for Bone Defect Treatment.  Current Stem Cell Research & Therapy. 4, 34-43.  
231 
 
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Johnson, PJ, Newton, P, Hunter, DA, and Mackinnon, SE (2011). Nerve endoneurial microstructure facilities uniform 
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distribution of regenerative fibers: a post hoc comparison of midgraft nerve fiber densities. J. Reconstr. Microsurg. 27, 83–
234 
90. 
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Karabekmez, F.E., Duymaz, A., and Moran, S.L. (2009). Early clinical outcomes with the use of decellularized nerve 
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allograft for repair of sensory defects within the hand. Hand N. Y. N 4, 245–249. 
238 
 
239 
Kragh, Kirby, J.M., and Ficke, J.R. Combat casualty care : lessons learned from OEF and OIF. Chapter 9: Extremity 
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Injury. (2012) Editor-in-chief, Martha K. Lenhart; medical editor, Eric Savitsky; military editor, Brian Eastridge. Pgs. 393-
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484. 
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Lin, M.Y., Manzano, G., and Gupta, R. (2013). Nerve allografts and conduits in peripheral nerve repair. Hand Clin. 29, 
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331–348. 
245 
 
246 
Lohmeyer, J.A., Siemers, F., Machens, H.-G., and Mailänder, P. (2009). The clinical use of artificial nerve conduits for 
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digital nerve repair: a prospective cohort study and literature review. J. Reconstr. Microsurg. 25, 55–61. 
248 
 
249 
Lundborg, G. (2000). A 25-year perspective of peripheral nerve surgery: evolving neuroscientific concepts and clinical 
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significance. J. Hand Surg. 25, 391–414. 
251 
 
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Lundborg, G., and Rosén, B. (2004). The two-point discrimination test--time for a re-appraisal? J. Hand Surg. Edinb. 
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Scotl. 29, 418–422. 
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Mackinnon, S.E., Doolabh, V.B., Novak, C.B., and Trulock, E.P. (2001). Clinical outcome following nerve allograft 
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transplantation. Plast. Reconstr. Surg. 107, 1419–1429. 
257 
 
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Meek, M.F., Coert, J.H., and Robinson, P.H. (2005). Poor results after nerve grafting in the upper extremity: Quo vadis? 
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Microsurgery 25, 396–402. 
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Mimura, T., Dezawa, M., Kanno, H., Sawada, H., and Yamamoto, I. (2004). Peripheral nerve regeneration by 
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transplantation of bone marrow stromal cell-derived Schwann cells in adult rats. J. Neurosurg. 101, 806–812. 
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Neubauer, D., Graham, J.B., and Muir, D. (2010). Nerve grafts with various sensory and motor fiber compositions are 
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equally effective for the repair of a mixed nerve defect. Exp. Neurol. 223, 203–206. 
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Noble, J., Munro, C.A., Prasad, V.S., and Midha, R. (1998). Analysis of upper and lower extremity peripheral nerve 
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injuries in a population of patients with multiple injuries. J. Trauma 45, 116–122. 
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PRWeb. (2015).  AxoGen Inc.’s Avance Nerve Graft Data Presented During Bese Clinical Papers Session at the 70th 
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Annual Meeting of the American Society for Surgery of the Hand. Vocus, Inc. Sep. 10, 2015.  
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Reyes, M., and Verfaillie, C.M. (2001). Characterization of multipotent adult progenitor cells, a subpopulation of 
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mesenchymal stem cells. Ann. N. Y. Acad. Sci. 938, 231–233; discussion 233–235. 
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Rinker, B., and Liau, J.Y. (2011). A prospective randomized study comparing woven polyglycolic acid and autogenous 
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vein conduits for reconstruction of digital nerve gaps. J. Hand Surg. 36, 775–781. 
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Siemionow, M., Duggan, W., Brzezicki, G., Klimczak, A., Grykien, C., Gatherwright, J., and Nair, D. (2011). Peripheral 
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nerve defect repair with epineural tubes supported with bone marrow stromal cells: a preliminary report. Ann. Plast. Surg. 
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67, 73–84. 
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Taras, J.S., Amin, N., Patel, N., and McCabe, L.A. (2013). Allograft reconstruction for digital nerve loss. J. Hand Surg. 38, 
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1965–1971. 
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Wakao, S., Hayashi, T., Kitada, M., Kohama, M., Matsue, D., Teramoto, N., Ose, T., Itokazu, Y., Koshino, K., Watabe, H., 
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et al. (2010). Long-term observation of auto-cell transplantation in non-human primate reveals safety and efficiency of 
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bone marrow stromal cell-derived Schwann cells in peripheral nerve regeneration. Exp. Neurol. 223, 537–547. 
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Wang, D., Liu, X.-L., Zhu, J.-K., Jiang, L., Hu, J., Zhang, Y., Yang, L.-M., Wang, H.-G., and Yi, J.-H. (2008). Bridging 
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small-gap peripheral nerve defects using acellular nerve allograft implanted with autologous bone marrow stromal cells in 
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primates. Brain Res. 1188, 44–53. 
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Wang, D., Liu, X.-L., Zhu, J.-K., Hu, J., Jiang, L., Zhang, Y., Yang, L.-M., Wang, H.-G., Zhu, Q.-T., Yi, J.-H., et al. (2010). 
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Repairing large radial nerve defects by acellular nerve allografts seeded with autologous bone marrow stromal cells in a 
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monkey model. J. Neurotrauma 27, 1935–1943. 
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Wangensteen, K.J., and Kalliainen, L.K. (2010). Collagen tube conduits in peripheral nerve repair: a retrospective 
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analysis. Hand N. Y. N 5, 273–277. 
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Weber, R.A., Breidenbach, W.C., Brown, R.E., Jabaley, M.E., and Mass, D.P. (2000). A randomized prospective study of 
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polyglycolic acid conduits for digital nerve reconstruction in humans. Plast. Reconstr. Surg. 106, 1036–1045; discussion 
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1046–1048. 
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Whitlock, E.L., Tuffaha, S.H., Luciano, J.P., Yan, Y., Hunter, D.A., Magill, C.K., Moore, A.M., Tong, A.Y., Mackinnon, S.E., 
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and Borschel, G.H. (2009). Processed allografts and type I collagen conduits for repair of peripheral nerve gaps. Muscle 
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Nerve 39, 787–799. 
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Zuniga, JR. (2015). Sensory outcomes after reconstruction of lingual and inferior alveolar nerve discontinuities using 
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processed nerve allograft--a case series. Journal of Oral Maxillofacial Surgery. 73, 734-44. 
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13.0  TIME REQUIRED TO COMPLETE THE RESEARCH (including data analysis). The study is anticipated to require 
311 
60 months from start of enrollment to be completed, including data analysis. Patients will be enrolled at time of PNI 
312 
diagnosis and followed at day 10, 1 month, 6 month, 12 month and 18 month. 
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Data collection from all sites will be overseen and verified for accuracy by the Clinical Manager. De-identified data 
315 
will be shared between performance sites.  
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  14.0  STUDY CLOSURE PROCEDURES  Protocol Closure Report will be submitted at the end of the study. Hard 
318 
copy documents containing subject data and patient identifiers (and contact information) will be stored in secure 
319 
document containers (file cabinets, lockers, drawers, etc.) accessible only to research personnel. The data entered 
320 
in REDCap will downloaded as a compiled data file be kept as electronic records and hard copy signed consent 
321 
forms will be kept in a locked filing cabinet for 6 years following study completion for future audit purposes. The 
322 
research team will maintain the list linking the subjects’ name and study number.  This link will be stored 
323 
separately from study data. The master list linking study numbers with personally identifiable information will be 
324 
destroyed upon completion of the protocol and all data analysis. Anonymized data will be deleted from local site 
325 
computers no later than five years after completion of the study. The signed informed consent documents and 
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HIPPA authorizations will be retained locally for 3 and 6 years respectively.  
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 . 
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