SPINE Volume 31, Number 11, pp 1201–1206 ©2006, Lippincott Williams & Wilkins, Inc. Controlling Bone Morphogenetic Protein Diffusion and Bone Morphogenetic Protein-Stimulated Bone Growth Using Fibrin Glue Vikas V. Patel, MD,*† Li Zhao, MD, PhD,* Pamela Wong, BS,* Linda Kanim, MA,* Hyun W. Bae, MD,* Ben B. Pradhan, MD,* and Rick B. Delamarter, MD* Study Design. An in vitro and in vivo study. Objective. To evaluate the ability of fibrin glue to limit diffusion of recombinant human bone morphogenetic protein (rhBMP)-2 and its ability to protect spinal nerves from rhBMP-2 stimulated bone growth. Summary of Background Data. Studies have shown bone morphogenetic protein (rhBMP-2) stimulated bone growth can encroach on the spinal canal and nerves, caus- ing neural compression. More recently, rhBMP-2 use in the cervical spine has been associated with life-threatening swelling. Fibrin glue has been used as a biologic carrier but has not been evaluated for its ability to limit rhBMP-2. Methods. In phase 1 of the study, rhBMP-2 soaked absorbable collagen sponges (ACS) were encapsulated in fibrin glue and immediately incubated in physiologic lac- tated ringers solution at 38°C. Samples of solution were tested for rhBMP-2 concentration. In phase 2 of the study, rats were surgically treated with laminectomy and place- ment of rhBMP-2/ACS versus laminectomy and place- ment of fibrin glue before placement of rhBMP-2/ACS. After 8 weeks, animals were euthanized and imaged us- ing micro-computerized tomography. Results. The diffusion study showed a significant lim- itation in rhBMP-2 diffusion when encapsulated in fibrin glue. The laminectomy study revealed blockage of bone formation by fibrin glue and protection of the spinal ca- nal. Conclusions. Fibrin glue can limit the diffusion of rh- BMP-2, and, thus, it can be used to help protect the spinal canal and nerve roots from rhBMP-2 stimulated bone growth. Key words: recombinant human bone morphogenetic protein-2, bone morphogenetic protein, fibrin glue, control, diffusion, bone growth stimulation. Spine 2006;31:1201–1206 Recombinant human bone morphogenetic protein-2 (rhBMP)-2 has been commercially available and recently approved for human spine use. It is rapidly becoming popular for augmenting fusion in the lumbar and cervi- cal spine. Use of rhBMP-2 has been reported in anterior and posterior lumbar and cervical fusion surgery, as well as transforaminal lumbar interbody fusion (TLIF) and posterior lumbar interbody fusion (PLIF) type proce- dures. However, rhBMP-2 may stimulate bone growth in areas in which bone is not desired, especially as the ma- terial “leaks” into such spaces. The most detrimental effects of such heterotopic bone are growth into the spi- nal canal and neural foramina. 1–3 In addition, cervical spine soft tissue swelling and airway compromise with rhBMP-2 use prompted a warning letter from Medtronic Sofamor Danek (Minneapolis, MN) of this significant risk. Although this phenomenon has not been thoroughly studied, it implies that the release of rh- BMP-2 into the soft tissues stimulates a rapid, potentially life-threatening, inflammatory reaction. The swelling cer- tainly warrants further study because it may be a carrier or bone morphogenetic protein (rhBMP-2) related, dose de- pendant, or even site specific. Thus, although our ability to stimulate bone growth rapidly increases with additional rhBMP-2s and other osteogenic agents, methods to control the possible adverse events associated with their use have not yet been presented or tested. Fibrin glue has been used as a carrier of many osteoin- ductive materials, including rhBMP-2 and demineralized bone matrix, 4–8 as well as osteogenic cells. 9 –11 It has also been used to improve the material handling of bone graft and bone graft substitutes. 12–14 However, conflict- ing reports show fibrin glue to augment 12 and inhibit 15–18 bone healing and bone formation. Although fibrin glue appears to limit rhBMP-2 diffusion, 5 its efficacy at mod- ulating the clinical effect of rhBMP-2 or controlling its diffusion is not clearly known. The purpose of this 2-phase study was to evaluate the use of fibrin glue to control the diffusion and bone form- ing effects of rhBMP-2. The first phase was an in vitro study of rhBMP-2 diffusion through fibrin glue. The sec- ond phase was to evaluate the ability of fibrin glue to pro- tect the spinal canal and nerve roots from rhBMP-2 stimu- lated bone growth. Although the results may have ramifications relative to soft tissue swelling, this study does not directly eval- uate soft tissue swelling with or without the use of fibrin glue. Materials and Methods For all aspects of this study, commercially available Infuse (Medtronic Sofamor Danek) brand rhBMP-2 was used at a From the *The Spine Institute at St. John’s Hospital, Santa Monica, CA, and †The Spine Center at the University of Colorado Health Sci- ences, Denver, CO. Acknowledgment date: March 28, 2005. First revision date: April 21, 2005. Second revision date: June 2, 2005. Third revision date: June 23, 2005. Acceptance date: June 27, 2005. The device(s)/drug(s) is/are FDA-approved or approved by correspond- ing national agency for this indication. Institutional funds were re- ceived in support of this work. No benefits in any form have been or will be received from a commer- cial party related directly or indirectly to the subject of this manuscript. Address correspondence and reprint requests to Vikas V. Patel, MA, MD, Assistant Professor Orthopaedic and Spine Surgery, University of Colorado Health Sciences, P.O. Box 6508, Mail Stop F476, Aurora, CO 80045; E-mail: vikas.patel@uchsc.edu 1201