Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study

Perri, Brian; Cooper, M. J.; Lauryssen, Carl; Anand, Neel

doi:10.1016/j.spinee.2006.04.010

Cited by 213 publications

(125 citation statements)

References 9 publications

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“…28 While BMPs have successfully induced bone formation in vivo, high dose requirements and paradoxical activities of BMPs on progenitor cells may lead to unexpected side effects such as ectopic bone formation while also rendering high treatment costs to patients. [5][6][7][8] In this study, we employed a small molecule that can effectively complement the pro-osteogenic activity of BMP-2 to maximize biological efficiency, thereby reducing the total dose requirement (cost) and minimizing potential adverse effects associated with BMP-2. Small molecular therapeutics has several advantages over protein-based therapeutics due to their lower cost and ease of manufacturing and storage compared with growth factor proteins.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, along with high cost, application of such high doses has revealed numerous side effects, such as vertebral osteolysis with cyst formation and life-threatening inflammatory cervical swelling, which have been well documented. [5][6][7][8] Thus, there is a need to develop alternative osteoinductive molecular strategies that can effectively complement BMP activity to maximize biological efficiency while reducing BMP dose requirement. One alternative approach is to deliver small molecule compounds targeting osteoblast differentiation that can synergistically promote bone formation with BMPs.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Fan

Cui

et al. 2015

Tissue Engineering Part A

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Bone morphogenetic proteins (BMPs) have been widely used for bone repair in the craniofacial region. However, its high dose requirement in clinical applications revealed adverse effects and inefficient bone formation, along with high cost. Here, we report a novel osteoinductive strategy to effectively complement the osteogenic activity of BMP-2 using phenamil, a small molecule that can induce osteogenic differentiation via stimulation of BMP signaling. Treatment of adipose-derived stem cells (ASCs) with BMP-2 in combination with phenamil significantly promoted the in vitro osteogenic differentiation of ASCs. The efficacy of the combination strategy of phenamil + BMP-2 was further confirmed in a mouse calvarial defect model using scaffolds consisting of poly(lactic-co-glycolic acid) and apatite layer on their surfaces designed to slowly release phenamil and BMP-2. Six weeks after implantation, the scaffolds treated with phenamil + BMP-2 significantly promoted mouse calvarial regeneration as demonstrated by micro-computerized tomography and histology, compared with the groups treated with phenamil or BMP-2 alone. Moreover, the combination treatment reduced the BMP-2 dose without compromising calvarial healing efficacy. These results suggest promising complementary therapeutic strategies for bone repair in more efficient and cost-effective manners.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Fan

Cui

et al. 2015

Tissue Engineering Part A

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“…Recently, attempts have been made to attribute the formation of spinal seromas to the use of rhBMP-2, 1,3,4,[13][14][15] which is a recombinant human protein that has been used off label to promote bone arthrodesis in patients undergoing laminectomy and spinal fusion. It is believed to act through cellular, nuclear, and cytokine signaling to induce osteoblast differentiation and thus facilitate new bone growth.…”

Section: Discussionmentioning

confidence: 99%

“…However, there have been several reports demonstrating an association between sterile postsurgical seroma formation and the use of rhBMP-2. 1,3,4,[12][13][14] Traditionally it is believed that these sterile seromas form as a result of trauma-induced inflammatory mediators that cause increased tissue capillary permeability in excess of local lymphatic drainage capacity. Surgical drainage of the fluid collection is often required, particularly in cases of neurological deterioration, and early detection is critical to prevent sequelae from cord compression.…”

mentioning

confidence: 99%

Surgical seroma formation following posterior cervical laminectomy and fusion without rhBMP-2

Yew¹,

Kimball²,

Lu³

2013

SPI

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Posterior cervical laminectomy and fusion has become a common treatment option for patients with progressive upper-and lower-extremity weakness and MRI evidence of multilevel cervical spondylosis and cord compression. 7,9,11,17 Several agents, including DBM and BMP, have traditionally been used to promote bony fusion in patients at risk for pseudarthrosis. However, there have been several reports demonstrating an association between sterile postsurgical seroma formation and the use of rhBMP-2. 1,3,4,[12][13][14] Traditionally it is believed that these sterile seromas form as a result of trauma-induced inflammatory mediators that cause increased tissue capillary permeability in excess of local lymphatic drainage capacity. Surgical drainage of the fluid collection is often required, particularly in cases of neurological deterioration, and early detection is critical to prevent sequelae from cord compression. Here we describe the first known report of a patient who developed an epidural fluid collection following multilevel laminectomy and fusion with DBM alone. To our knowledge, this is the first case of seroma formation following multilevel laminectomy and fusion that has not been attributed to the use of rhBMP-2. Case ReportHistory. The patient was a 78-year-old female who initially presented with progressive upper-and lowerextremity weakness and severe axial neck pain. Magnetic resonance imaging demonstrated multilevel spondylosis and compression of the cervical spinal cord with associated T2 signal change. Flexion-extension plain radiographs demonstrated instability with anterior subluxation of C-4 on C-5 in flexion, with associated neck pain ( Department of Neurological Surgery, University of California, Los Angeles, CaliforniaSeroma formation following posterior cervical laminectomy and fusion is now recognized as a rare but significant risk. Previous reports have attributed the development of postoperative seromas to the use of recombinant bone morphogenetic protein-2 (rhBMP-2). Here the authors present the case of a 78-year-old female with a history of osteoporosis who developed delayed postoperative neck and shoulder pain following posterior cervical laminectomy and fusion utilizing only autograft bone and demineralized bone matrix (DBM) allograft. Postoperative MRI demonstrated normal hardware placement and a large epidural fluid collection that extended from C-4 to C-6. The patient underwent decompression and drainage of her sterile postoperative seroma. To the authors' knowledge, no case of seroma formation with the use of DBM has been previously reported. This case suggests that although rhBMP-2 is involved in the majority of postoperative seroma developments, other osteoinductive agents such as DBM can contribute to the development of a symptomatic seroma. This report presents an illustrative case study and reviews the current understanding of the development of and treatment for cervical seroma following posterior cervical laminectomy and fusion.

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“…The answer is yes again. Increased numbers of inflammatory cells in sheep [6], increased serum antibody levels against BMPs, generalized edema, bone overgrowth and heterotopic ossification have recently been reported [20]. We must be aware of the side effects of musculoskeletal growth factors to use them safely.…”

mentioning

confidence: 99%

Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors: Editorial Comment

Korkusuz

2009

Clin Orthop Relat Res

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Growth factors are triggering and/or signaling molecules that regulate not only growth but also musculoskeletal repair and regeneration. Bone morphogenetic proteins (BMPs), which regulate cellular proliferation, differentiation and extracellular matrix production, were first described by Dr. Marshall Urist in 1965 [22], and are the most well-known and researched of the musculoskeletal growth factors. They also function in apoptosis [13] and reshaping the extracellular matrix. The membrane receptors and intracellular signaling mechanisms of these growth factors are well-defined [2]. Not only osteoblasts and chondrocytes but also osteoclasts [19] contain these membrane receptors, which indicates growth factors have a key role in the homeostasis of the musculoskeletal system. The externally administered local therapeutic quantity and duration that is required to trigger and/or control the event is, however, substantially higher than that of the endogenous dose. Responsive cells are essential at the administration site to have an optimal healing effect. BMP producing and marketing sources indicate that injecting or implanting these growth factors attracts stem cells. The mechanism of how BMPs work at atrophic nonunions where such cells are lacking needs further investigation. Recent preclinical and clinical studies including those published in this symposium will give insight into these mechanisms.There are several published clinical studies [9,14] with small sample size and a lack of control groups. In most of these studies the growth factor was combined with autografts or allografts. Are we willing to replace autografts and allografts with BMPs? Studies reporting complications of autografts and allografts suggest the answer is yes. BMPs may replace autografts when safety, efficacy and reliability studies are completed. Outcomes of other clinical studies [4,7,12] indicate BMP reduces blood loss between 43 to 336 ml and decreased operation time for 9 to 15 minutes. Although these findings are statistically significant, their clinical importance is open to discussion. The mechanism by which BMPs might reduce infection and improve disability, quality of life and pain scores needs to be explained. Do BMPs have complications? The answer is yes again. Increased numbers of inflammatory cells in sheep [6], increased serum antibody levels against BMPs, generalized edema, bone overgrowth and heterotopic ossification have recently been reported [20]. We must be aware of the side effects of musculoskeletal growth factors to use them safely. Indications of BMPs are expanding [1], however, clinical results on difficult healing fractures such as those of the scaphoid [3] and talus are infrequent. It is obvious that growth factors will find their deserved place in tissue engineering strategies in the near future [2]. Cells, carriers and growth factors are essential elements of this emerging technology. Appropriate carriers [16,21] of BMPs are still a focus of research. Today, nonviral delivery of the gene of the growth factor into...

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Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study

Cited by 213 publications

References 9 publications

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Delivery of Phenamil Enhances BMP-2-Induced Osteogenic Differentiation of Adipose-Derived Stem Cells and Bone Formation in Calvarial Defects

Surgical seroma formation following posterior cervical laminectomy and fusion without rhBMP-2

Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors: Editorial Comment

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